bluuebunny/crossref_metadata_2025_split huggingface dataset:
Multifaceted Dysregulation of the Epidermal Growth Factor Receptor Pathway in Clear Cell Sarcoma of the Kidney
Authors: Little Suzanne E. , Bax Dorine A. , Rodriguez-Pinilla Maria , Natrajan Rachael , Messahel Boo , Pritchard-Jones Kathy , Vujanic Gordan M. , Reis-Filho Jorge S. , Jones Chris 
Published: July 2007

Abstract
Purpose: Epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase overexpressed in a variety of human malignancies, against which targeted therapies have shown efficacy in lung and brain tumors. Clinical responses to EGFR inhibitors have been found to be highly dependent on the presence of activating mutations, whereas gene amplification, downstream activation of Akt, and abnormalities in PTEN are also reported predictive factors. We sought to evaluate these variables in pediatric renal tumors.
Experimental Design: We screened a series of 307 pediatric renal tumors for EGFR expression by immunohistochemistry and gene amplification by chromogenic in situ hybridization. In identifying a striking predilection for certain tumor types, we further analyzed the clear cell sarcomas of the kidney (CCSK) for mutations in EGFR and PTEN.
Results: Although only 23 of 177 (13.0%) nonanaplastic Wilms' tumors were EGFR positive, 4 of 11 (36.4%) anaplastic tumors showed receptor overexpression. In addition, 5 of 9 (55.6%) mesoblastic nephromas and 12 of 12 (100%) CCSKs were strongly immunoreactive for EGFR. In studying the CCSKs in more detail, we identified gene amplification in 1 of 12 (8.3%) cases and a somatic T790M EGFR mutation in a further case. These two samples additionally harbored mutations in PTEN. Downstream pathway activation, as assayed by phosphorylated Akt expression, was observed in 8 of 12 (66.7%) cases.
Conclusions: Together, these data show dysregulation of the EGFR pathway at multiple levels in CCSKs. Identification of factors predictive of poor response to targeted therapy, including the drug resistance T790M mutation, may provide a rationale for upfront trials with irreversible inhibitors of EGFR in children with these tumors.
Point Mutation in the HCN4 Cardiac Ion Channel Pore Affecting Synthesis, Trafficking, and Functional Expression Is Associated With Familial Asymptomatic Sinus Bradycardia
Authors: Nof Eyal , Luria David , Brass Dovrat , Marek Dina , Lahat Hadas , Reznik-Wolf Haya , Pras Elon , Dascal Nathan , Eldar Michael , Glikson Michael 
Published: July 2007

Background—The hyperpolarization-activated nucleotide-gated channel-HCN4 plays a major role in the diastolic depolarization of sinus atrial node cells. Mutant HCN4 channels have been found to be associated with inherited sinus bradycardia.Methods and Results—Sixteen members of a family with sinus bradycardia were evaluated. Evaluation included a clinical questionnaire, 12-lead ECGs, Holter monitoring, echocardiography, and treadmill exercise testing. Eight family members (5 males) were classified as affected. All affected family members were asymptomatic with normal exercise capacity during long-term follow-up. Electrophysiological testing performed on 2 affected family members confirmed significant isolated sinus node dysfunction. Segregation analysis suggested autosomal-dominant inheritance. Direct sequencing of the exons encoding HCN4 revealed a missense mutation, G480R, in the ion channel pore domain in all affected family members. Function analysis, including expression of HCN4 wild-type and G480R inXenopusoocytes and human embryonic kidney 293 cells, revealed that mutant channels were activated at more negative voltages compared with wild-type channels. Synthesis and expression of the wild-type and mutant HCN4 channel on the plasma membrane tested in human embryonic kidney 293 cells using biotinylation and Western blot analysis demonstrated a reduction in synthesis and a trafficking defect in mutant compared with wild-type channels.Conclusions—We describe an inherited, autosomal-dominant form of sinus node dysfunction caused by a missense mutation in the HCN4 ion channel pore. Despite its critical location, this mutation carries a favorable prognosis without the need for pacemaker implantation during long-term follow-up.
The Law of the Sea Convention and the Northwest Passage
Authors: Kraska James 
Published: July 2007

AbstractConcern over the loss of sea ice has renewed discussions over the legal status of the Arctic and sub-Arctic transcontinental maritime route connecting the Atlantic and the Pacific, referred to as the "Northwest Passage." Over the last thirty years, Canada has maintained that the waters of the Passage are some combination of internal waters or territorial seas. Applying the rules of international law, as reflected in the 1982 United Nations Law of the Sea Convention, suggests that the Passage is a strait used for international navigation. Expressing concerns over maritime safety and security, recognition of northern sovereignty, and protection of the fragile Arctic environment, Canada has sought to exercise greater authority over the Passage. This article suggests that Canada can best achieve widespread global support for managing its maritime Arctic by acknowledging that the passage constitutes an international strait and then working through the International Maritime Organization to develop a comprehensive package of internationally accepted regulations.
Minding the Gap: The Australia–East Timor Treaty on Certain Maritime Arrangements in the Timor Sea (CMATS)
Authors: Schofield Clive 
Published: July 2007

AbstractThe intertwined issues of the delimitation of maritime boundaries and the division of the resources, particularly petroleum resources, of the Timor Sea have served as a persistent irritant in bilateral relations between Australia and East Timor since the latter's independence in 2002. In 2003 an International Unitization Agreement for the Greater Sunrise complex of fields was signed. This was followed by the conclusion in 2006 of the Treaty on Certain Maritime Arrangements in the Timor Sea. The subsequent entry into force of these agreements, in February 2007, appears to resolve this contentious dispute, at least for the foreseeable future. This article explores the background to the dispute and positions of the parties, traces the progress of negotiations towards its interim resolution and then assesses the agreements themselves. It is concluded that while the agreements are, on balance, somewhat more favourable to Australia than to East Timor, they can still be viewed as beneficial to both parties.
Law of the Sea Aspects of the Negotiations in the WTO to Harmonise Rules of Origin
Authors: Serdy Andrew 
Published: July 2007

AbstractA major source of controversy in the protracted Rules of Origin negotiations at the World Trade Organization is the origin to be ascribed to fish taken from the exclusive economic zone. Participants' positions are polarised between views recalling the old great divide between coastal States and distant-water fishing States, one camp seemingly oblivious to the past 50 years' developments in international fisheries law, the other adhering rigidly to a position elevating origin to the status of one of the coastal State's sovereign rights, even though practical considerations make such a rule unworkable. It is concluded that the rules of origin issue does not lend itself to use as a proxy vehicle for advancing legal and policy interests in international fisheries, and a compromise solution is offered that may enhance international fisheries commissions' authority in managing their species. Some problematic aspects of the much less controversial origin rules on minerals recovered from the deep seabed are also considered.
Key differences in TLR3/poly I:C signaling and cytokine induction by human primary cells: a phenomenon absent from murine cell systems
Authors: Lundberg Anna M. , Drexler Stefan K. , Monaco Claudia , Williams Lynn M. , Sacre Sandra M. , Feldmann Marc , Foxwell Brian M. 
Published: July 2007

AbstractTLR3 recognizes double-stranded RNA, a product associated with viral infections. Many details of TLR3-induced mechanisms have emerged from gene-targeted mice or inhibition studies in transformed cell lines. However, the pathways activated in human immune cells or cells from disease tissue are less well understood. We have investigated TLR3-induced mechanisms of human primary cells of the innate immune system, including dendritic cells (DCs), macrophages (MØs), endothelial cells (ECs), and synovial fibroblasts isolated from rheumatoid arthritis joint tissue (RA-SFs). Here, we report that while these cells all express TLR3, they differ substantially in their response to TLR3 stimulation. The key antiviral response chemokine IP-10 was produced by all cell types, while DCs and MØs failed to produce the proinflammatory cytokines TNFα and IL-6. Unexpectedly, TNFα was found secreted by TLR3-stimulated RA-SF. Furthermore, TLR3 stimulation did not activate NFκB, MAPKs, or IRF-3 in DCs and MØs, but was able to do so in ECs and RA-SF. These findings were specific for human cells, thereby revealing a complexity not previously expected. This is the first report of such cell type– and species-specific response for any TLR stimulation and helps to explain important difficulties in correlating murine models of inflammatory diseases and human inflammation.
Selecting highly affine and well-expressed TCRs for gene therapy of melanoma
Authors: Jorritsma Annelies , Gomez-Eerland Raquel , Dokter Maarten , van de Kasteele Willeke , Zoet Yvonne M. , Doxiadis Ilias I. N. , Rufer Nathalie , Romero Pedro , Morgan Richard A. , Schumacher Ton N. M. , Haanen John B. A. G. 
Published: July 2007

AbstractA recent phase 1 trial has demonstrated that the generation of tumor-reactive T lymphocytes by transfer of specific T-cell receptor (TCR) genes into autologous lymphocytes is feasible. However, compared with results obtained by infusion of tumor-infiltrating lymphocytes, the response rate observed in this first TCR gene therapy trial is low. One strategy that is likely to enhance the success rate of TCR gene therapy is the use of tumor-reactive TCRs with a higher capacity for tumor cell recognition. We therefore sought to develop standardized procedures for the selection of well-expressed, high-affinity, and safe human TCRs. Here we show that TCR surface expression can be improved by modification of TCR alpha and beta sequences and that such improvement has a marked effect on the in vivo function of TCR gene-modified T cells. From a panel of human, melanoma-reactive TCRs we subsequently selected the TCR with the highest affinity. Furthermore, a generally applicable assay was used to assess the lack of alloreactivity of this TCR against a large series of common human leukocyte antigen alleles. The procedures described in this study should be of general value for the selection of well- and stably expressed, high-affinity, and safe human TCRs for subsequent clinical testing.
Apoptosis in mouse fetal and neonatal oocytes during meiotic prophase one
Authors: Ghafari Fataneh , Gutierrez Carlos G , Hartshorne Geraldine M 
Published: July 2007

AbstractBackgroundThe vast majority of oocytes formed in the fetal ovary do not survive beyond birth. Possible reasons for their loss include the elimination of non-viable genetic constitutions arising through meiosis, however, the precise relationship between meiotic stages and prenatal apoptosis of oocytes remains elusive. We studied oocytes in mouse fetal and neonatal ovaries, 14.5–21 days post coitum, to examine the relationship between oocyte development and programmed cell death during meiotic prophase I.ResultsMicrospreads of fetal and neonatal ovarian cells underwent immunocytochemistry for meiosis- and apoptosis-related markers. COR-1 (meiosis-specific) highlighted axial elements of the synaptonemal complex and allowed definitive identification of the stages of meiotic prophase I. Labelling for cleaved poly-(ADP-ribose) polymerase (PARP-1), an inactivated DNA repair protein, indicated apoptosis. The same oocytes were then labelled for DNA double strand breaks (DSBs) using TUNEL. 1960 oocytes produced analysable results.Oocytes at all stages of meiotic prophase I stained for cleaved PARP-1 and/or TUNEL, or neither. Oocytes with fragmented (19.8%) or compressed (21.2%) axial elements showed slight but significant differences in staining for cleaved PARP-1 and TUNEL to those with intact elements. However, fragmentation of axial elements alone was not a good indicator of cell demise. Cleaved PARP-1 and TUNEL staining were not necessarily coincident, showing that TUNEL is not a reliable marker of apoptosis in oocytes.ConclusionOur data indicate that apoptosis can occur throughout meiotic prophase I in mouse fetal and early postnatal oocytes, with greatest incidence at the diplotene stage. Careful selection of appropriate markers for oocyte apoptosis is essential.
Involvement of the YneS/YgiH and PlsX proteins in phospholipid biosynthesis in both Bacillus subtilis and Escherichia coli
Authors: Yoshimura Mika , Oshima Taku , Ogasawara Naotake 
Published: July 2007

Abstract

Background
Phospholipid biosynthesis commences with the acylation of glycerol-3-phosphate (G3P) to form 1-acyl-G3P. This step is catalyzed by the PlsB protein in Escherichia coli. The gene encoding this protein has not been identified, however, in the majority of bacterial genome sequences, including that of Bacillus subtilis. Recently, a new two-step pathway catalyzed by PlsX and PlsY proteins for the initiation of phospholipid formation in Streptococcus pneumoniae has been reported.

Results
In B. subtilis, 271 genes have been reported to be indispensable, when inactivated singly, for growth in LB medium. Among these, 11 genes encode proteins with unknown functions. As part of a genetic study to identify the functions of these genes, we show here that the B. subtilis ortholog of S. pneumoniae PlsY, YneS, is required for G3P acyltransferase activity, together with PlsX. The B. subtilis genome lacks plsB, and we show in vivo that the PlsX/Y pathway is indeed essential for the growth of bacteria lacking plsB. Interestingly, in addition to plsB, E. coli possesses plsX and the plsY ortholog, ygiH. We therefore explored the functional relationship between PlsB, PlsX and YgiH in E. coli, and found that plsB is essential for E. coli growth, indicating that PlsB plays an important role in 1-acyl-G3P synthesis in E. coli. We also found, however, that the simultaneous inactivation of plsX and ygiH was impossible, revealing important roles for PlsX and YgiH in E. coli growth.

Conclusion
Both plsX and yneS are essential for 1-acyl-G3P synthesis in B. subtilis, in agreement with recent reports on their biochemical functions. In E. coli, PlsB plays a principal role in 1-acyl-G3P synthesis and is also essential for bacterial growth. PlsX and YgiH also, however, play important roles in E. coli growth, possibly by regulating the intracellular concentration of acyl-ACP. These proteins are therefore important targets for development of new antibacterial agents.
Region- or state-related differences in expression and activation of extracellular signal-regulated kinases (ERKs) in naïve and pain-experiencing rats
Authors: Guo She-Wei , Liu Ming-Gang , Long Ya-Li , Ren Li-Ying , Lu Zhuo-Min , Yu Hou-You , Hou Jun-Feng , Li Hua , Gao Cui-Ying , Cui Xiu-Yu , An Yang-Yuan , Li Junfa , Zhao Lan-Feng , Chen Jun 
Published: July 2007

AbstractBackgroundExtracellular signal-regulated kinase (ERK), one member of the mitogen-activated protein kinase (MAPK) family, has been suggested to regulate a diverse array of cellular functions, including cell growth, differentiation, survival, as well as neuronal plasticity. Recent evidence indicates a role for ERKs in nociceptive processing in both dorsal root ganglion and spinal cord. However, little literature has been reported to examine the differential distribution and activation of ERK isoforms, ERK1 and ERK2, at different levels of pain-related pathways under both normal and pain states. In the present study, quantitative blot immunolabeling technique was used to determine the spatial and temporal expression of ERK1 and ERK2, as well as their activated forms, in the spinal cord, primary somatosensory cortex (SI area of cortex), and hippocampus under normal, transient pain and persistent pain states.ResultsIn naïve rats, we detected regional differences in total expression of ERK1 and ERK2 across different areas. In the spinal cord, ERK1 was expressed more abundantly than ERK2, while in the SI area of cortex and hippocampus, there was a larger amount of ERK2 than ERK1. Moreover, phosphorylated ERK2 (pERK2), not phosphorylated ERK1 (pERK1), was normally expressed with a high level in the SI area and hippocampus, but both pERK1 and pERK2 were barely detectable in normal spinal cord. Intraplantar saline or bee venom injection, mimicking transient or persistent pain respectively, can equally initiate an intense and long-lasting activation of ERKs in all three areas examined. However, isoform-dependent differences existed among these areas, that is, pERK2 exhibited stronger response than pERK1 in the spinal cord, whereas ERK1 was more remarkably activated than ERK2 in the S1 area and hippocampus.ConclusionTaken these results together, we conclude that: (1) under normal state, while ERK immunoreactivity is broadly distributed in the rat central nervous system in general, the relative abundance of ERK1 and ERK2 differs greatly among specific regions; (2) under pain state, either ERK1 or ERK2 can be effectively phosphorylated with a long-term duration by both transient and persistent pain, but their response patterns differ from each other across distinct regions; (3) The long-lasting ERKs activation induced by bee venom injection is highly correlated with our previous behavioral, electrophysiological, morphological and pharmacological observations, lending further support to the functional importance of ERKs-mediated signaling pathways in the processing of negative consequences of pain associated with sensory, emotional and cognitive dimensions.
Arabidopsis Gene Family Profiler (aGFP) – user-oriented transcriptomic database with easy-to-use graphic interface
Authors: Dupl'áková Nikoleta , Reňák David , Hovanec Patrik , Honysová Barbora , Twell David , Honys David 
Published: July 2007

Abstract

Background
Microarray technologies now belong to the standard functional genomics toolbox and have undergone massive development leading to increased genome coverage, accuracy and reliability. The number of experiments exploiting microarray technology has markedly increased in recent years. In parallel with the rapid accumulation of transcriptomic data, on-line analysis tools are being introduced to simplify their use. Global statistical data analysis methods contribute to the development of overall concepts about gene expression patterns and to query and compose working hypotheses. More recently, these applications are being supplemented with more specialized products offering visualization and specific data mining tools. We present a curated gene family-oriented gene expression database, Arabidopsis Gene Family Profiler (aGFP; http://agfp.ueb.cas.cz), which gives the user access to a large collection of normalised Affymetrix ATH1 microarray datasets. The database currently contains NASC Array and AtGenExpress transcriptomic datasets for various tissues at different developmental stages of wild type plants gathered from nearly 350 gene chips.

Results
The Arabidopsis GFP database has been designed as an easy-to-use tool for users needing an easily accessible resource for expression data of single genes, pre-defined gene families or custom gene sets, with the further possibility of keyword search. Arabidopsis Gene Family Profiler presents a user-friendly web interface using both graphic and text output. Data are stored at the MySQL server and individual queries are created in PHP script. The most distinguishable features of Arabidopsis Gene Family Profiler database are: 1) the presentation of normalized datasets (Affymetrix MAS algorithm and calculation of model-based gene-expression values based on the Perfect Match-only model); 2) the choice between two different normalization algorithms (Affymetrix MAS4 or MAS5 algorithms); 3) an intuitive interface; 4) an interactive "virtual plant" visualizing the spatial and developmental expression profiles of both gene families and individual genes.

Conclusion
Arabidopsis GFP gives users the possibility to analyze current Arabidopsis developmental transcriptomic data starting with simple global queries that can be expanded and further refined to visualize comparative and highly selective gene expression profiles.
A comparative map viewer integrating genetic maps for Brassica and Arabidopsis
Authors: Lim Geraldine AC , Jewell Erica G , Li Xi , Erwin Timothy A , Love Christopher , Batley Jacqueline , Spangenberg German , Edwards David 
Published: July 2007

Abstract

Background
Molecular genetic maps provide a means to link heritable traits with underlying genome sequence variation. Several genetic maps have been constructed for Brassica species, yet to date, there has been no simple means to compare this information or to associate mapped traits with the genome sequence of the related model plant, Arabidopsis.

Description
We have developed a comparative genetic map database for the viewing, comparison and analysis of Brassica and Arabidopsis genetic, physical and trait map information. This web-based tool allows users to view and compare genetic and physical maps, search for traits and markers, and compare genetic linkage groups within and between the amphidiploid and diploid Brassica genomes. The inclusion of Arabidopsis data enables comparison between Brassica maps that share no common markers. Analysis of conserved syntenic blocks between Arabidopsis and collated Brassica genetic maps validates the application of this system. This tool is freely available over the internet on http://bioinformatics.pbcbasc.latrobe.edu.au/cmap.

Conclusion
This database enables users to interrogate the relationship between Brassica genetic maps and the sequenced genome of A. thaliana, permitting the comparison of genetic linkage groups and mapped traits and the rapid identification of candidate genes.