bluuebunny/crossref_metadata_2025_split huggingface dataset:
DNA barcoding Central Asian butterflies: increasing geographical dimension does not significantly reduce the success of species identification
Authors: LUKHTANOV VLADIMIR A , SOURAKOV ANDREI , ZAKHAROV EVGENY V. , HEBERT PAUL D. N. 
Published: February 2009

AbstractDNA barcoding employs short, standardized gene regions (5’ segment of mitochondrial cytochrome oxidase subunit I for animals) as an internal tag to enable species identification. Prior studies have indicated that it performs this task well, because interspecific variation at cytochrome oxidase subunit I is typically much greater than intraspecific variation. However, most previous studies have focused on local faunas only, and critics have suggested two reasons why barcoding should be less effective in species identification when the geographical coverage is expanded. They suggested that many recently diverged taxa will be excluded from local analyses because they are allopatric. Second, intraspecific variation may be seriously underestimated by local studies, because geographical variation in the barcode region is not considered. In this paper, we analyse how adding a geographical dimension affects barcode resolution, examining 353 butterfly species from Central Asia. Despite predictions, we found that geographically separated and recently diverged allopatric species did not show, on average, less sequence differentiation than recently diverged sympatric taxa. Although expanded geographical coverage did substantially increase intraspecific variation reducing the barcoding gap between species, this did not decrease species identification using neighbour‐joining clustering. The inclusion of additional populations increased the number of paraphyletic entities, but did not impede species‐level identification, because paraphyletic species were separated from their monophyletic relatives by substantial sequence divergence. Thus, this study demonstrates that DNA barcoding remains an effective identification tool even when taxa are sampled from a large geographical area.
Polymorphic microsatellite loci for primitively eusocial wasp Ropalidia marginata
Authors: JOHNY S. , CHAKRABORTY S. , GADAGKAR R. , NAGARAJU J. 
Published: February 2009

AbstractWe report here development and characterization of 48 novel microsatellite markers for Ropalidia marginata, a tropical, primitively eusocial polistine wasp from peninsular India. Thirty‐two microsatellites showed polymorphism in a wild population of R. marginata (N = 38) collected from Bangalore, India. These markers will facilitate answering some interesting questions in ecology and evolutionary biology of this wasp, such as population structure, serial polygyny, intra‐colony genetic relatedness and the pattern of queen succession.
Is the distribution of nitrogen‐fixing cyanobacteria in the oceans related to temperature?
Authors: Stal Lucas J. 
Published: February 2009

SummaryApproximately 50% of the global natural fixation of nitrogen occurs in the oceans supporting a considerable part of the new primary production. Virtually all nitrogen fixation in the ocean occurs in the tropics and subtropics where the surface water temperature is 25°C or higher. It is attributed almost exclusively to cyanobacteria. This is remarkable firstly because diazotrophic cyanobacteria are found in other environments irrespective of temperature and secondly because primary production in temperate and cold oceans is generally limited by nitrogen. Cyanobacteria are oxygenic phototrophic organisms that evolved a variety of strategies protecting nitrogenase from oxygen inactivation. Free‐living diazotrophic cyanobacteria in the ocean are of the non‐heterocystous type, namely the filamentous Trichodesmium and the unicellular groups A–C. I will argue that warm water is a prerequisite for these diazotrophic organisms because of the low‐oxygen solubility and high rates of respiration allowing the organism to maintain anoxic conditions in the nitrogen‐fixing cell. Heterocystous cyanobacteria are abundant in freshwater and brackish environments in all climatic zones. The heterocyst cell envelope is a tuneable gas diffusion barrier that optimizes the influx of both oxygen and nitrogen, while maintaining anoxic conditions inside the cell. It is not known why heterocystous cyanobacteria are absent from the temperate and cold oceans and seas.
A compositional semantics for CHR
Authors: Gabbrielli Maurizio , Meo Maria Chiara 
Published: February 2009

Constraint Handling Rules (CHR) is a committed-choice declarative language which has been designed for writing constraint solvers. A CHR program consists of multiheaded guarded rules which allow to rewrite constraints into simpler ones until a solved form is reached.
CHR has received considerable attention, both from the practical and from the theoretical side. Nevertheless, due the use of multiheaded clauses, there are several aspects of the CHR semantics which have not been clarified yet. In particular, no compositional semantics for CHR has been defined so far.
In this article we introduce a fix-point semantics which characterizes the input/output behavior of a CHR program and which is and-compositional, that is, which allows to retrieve the semantics of a conjunctive query from the semantics of its components. Such a semantics can be used as a basis to define incremental and modular analysis and verification tools.
Requirements analysis of presence
Authors: Bostan Barbaros 
Published: February 2009

Virtual worlds are computer-based simulations intended to give its users the impression of being in another place.
Presence
, or the sense of “being there,” is a major design requirement for virtual environments where users inhabit an artificial reality in the form of two or three-dimensional graphical representations. Promoting this subjective experience has always been one of the major concerns of designers, but this complex and difficult task requires the awareness of other design requirements and their effects on presence. This article aims to define various psychological and technological aspects of presence based on virtual environment design requirements defined by Stuart [2001].

Previous research tried to define hypothesized factors of presence by using subjective user responses obtained from questionnaires. This study incorporates a different approach to define potential components of presence, specifying the individual design requirements for virtual worlds based on the conceptual framework designed by Stuart. This framework has not been applied to the analysis of the concept of presence before, and it defines possible factors that contribute to a sense of presence, some of which have not been included in previous work. In order to decompose presence into its components, researchers should also be aware of the design requirements delineated in this framework.
Detailed analysis of design requirements will focus on a computer role-playing game (RPG), giving examples from one of the best titles in the genre. Since role-playing games are social and interactive worlds where players assume the role of a virtual character that can be subjectively defined as a second-self, they are highly relevant to presence research. Thus, selected design requirements will be discussed from a computer-gaming perspective by defining how each relevant requirement is addressed on the selected RPG, and how they should be addressed by game designers.
About Robust Stability of Dynamic Systems with Time Delays through Fixed Point Theory
Authors: De la Sen M. 
Published: February 2009

AbstractThis paper investigates the global asymptotic stability independent of the sizes of the delays of linear time-varying systems with internal point delays which possess a limiting equation via fixed point theory. The error equation between the solutions of the limiting equation and that of the current one is considered as a perturbation equation in the fixed- point and stability analyses. The existence of a unique fixed point which is later proved to be an asymptotically stable equilibrium point is investigated. The stability conditions are basically concerned with the matrix measure of the delay-free matrix of dynamics to be negative and to have a modulus larger than the contribution of the error dynamics with respect to the limiting one. Alternative conditions are obtained concerned with the matrix dynamics for zero delay to be negative and to have a modulus larger than an appropriate contributions of the error dynamics of the current dynamics with respect to the limiting one. Since global stability is guaranteed under some deviation of the current solution related to the limiting one, which is considered as nominal, the stability is robust against such errors for certain tolerance margins.
Alternative Splicing of Cyr61 Is Regulated by Hypoxia and Significantly Changed in Breast Cancer
Authors: Hirschfeld Marc , zur Hausen Axel , Bettendorf Herta , Jäger Markus , Stickeler Elmar 
Published: February 2009

Abstract
Hypoxia is known to induce the transcriptional activation of pathways involved in angiogenesis, growth factor signaling, and tissue invasion and is therefore a potential key regulator of tumor growth. Cyr61 (cysteine rich 61) is a secreted, matricellular protein with proangiogenic capabilities and is transcriptionally induced under hypoxic conditions. High expression levels of Cyr61 were already detected in various cancer types and linked to tumor progression and advanced stages in breast cancer. Besides hypoxia, there is some evidence that posttranscriptional pre-mRNA processing could be involved in the regulation of Cyr61 expression, but was thus far not investigated. We studied the expression pattern of Cyr61 mRNA and protein in breast cancer cell lines as well as in matched pairs of noncancerous breast tissue, preinvasive lesions, and invasive breast cancers, respectively. In addition, we analyzed the potential regulatory capability of hypoxia on Cyr61 expression by functional tissue culture experiments. Our study revealed a stage-dependent induction of Cyr61 mRNA and protein in breast cancer tumorigenesis and for the first time alternative splicing of the Cyr61 gene due to intron retention. Breast carcinogenesis was accompanied by a shift from an intron 3 retaining toward an intron 3 skipping mRNA phenotype consecutively leading to processing of the biological active Cyr61 protein. The functional analyses strongly emphasize that hypoxia serves as a specific inducer of alternative Cyr61 splicing toward the intron skipping mRNA isoform with potential biological consequences in tumor cells. [Cancer Res 2009;69(5):2082–90]
l-Amino Acid Transporter-1 and Boronophenylalanine-Based Boron Neutron Capture Therapy of Human Brain Tumors
Authors: Detta Allah , Cruickshank Garth S. 
Published: February 2009

Abstract
The system l-amino acid transporter-1 (LAT-1) imports p-boronophenylalanine (BPA) into cells and may play a major role in the effectiveness of BPA-based boron neutron capture therapy. The functional status of LAT-1 and its relationship to cell proliferation were simultaneously examined in the same section of human tumor material using a dual-labeling technique. The uptake of BPA (boron inductively coupled plasma mass spectrometry) was profiled in the presence of agonists and antagonists in fresh tumor explants. The number of LAT-1–expressing cells (mean ± SD) was three times higher than that of proliferating cell nuclear antigen (PCNA)–expressing cells (71.5 ± 17.02% versus 23.8 ± 16.5%; P &lt; 0.0001; n = 38 glioblastoma and metastatic tumors). There was no correlation between PCNA cells and the number of LAT-1/PCNA double-stained cells, and not all PCNA-expressing cells coexpressed LAT-1. Boron uptake reached 30 ± 15 μg/g of wet weight of tissue by 4 hours both in tumor and brain around tumor tissue containing tumor cells compared with time 0 (P &lt; 0.005; n = 4 glioblastoma tumors). This uptake was inhibited by both phenylalanine and 2-aminobicyclo-(2,2,1)-heptane-2-carboxylic acid. These LAT-1 data indicate that BPA-based boron neutron capture therapy might affect up to 70% of tumor cells, representing a three times higher proportion of tumor cells than their cell cycle status might suggest. Cells expressing PCNA, but not LAT-1, will require a different therapeutic strategy. [Cancer Res 2009;69(5):2126–32]
Characterization of a Novel Mitogen-Activated Protein Kinase Kinase 1/2 Inhibitor with a Unique Mechanism of Action for Cancer Therapy
Authors: Daouti Sherif , Wang Huisheng , Li Wen-hui , Higgins Brian , Kolinsky Kenneth , Packman Kathryn , Specian Anthony , Kong Norman , Huby Nicholas , Wen Yang , Xiang Qing , Podlaski Frank J. , He Yang , Fotouhi Nader , Heimbrook David , Niu Huifeng 
Published: February 2009

Abstract
The mitogen-activated protein kinase (MAPK) signal transduction pathway plays a central role in regulating tumor cell growth, survival, differentiation, and angiogenesis. The key components of the Ras/Raf/MEK/ERK signal module are frequently altered in human cancers. Targeting this pathway represents a promising anticancer strategy. Small molecule inhibitors targeting MEK1/2 have shown promise in the clinic; however, ultimate clinical proof-of-concept remains elusive. Here, we report a potent and highly selective non–ATP-competitive MEK1/2 inhibitor, RO4927350, with a novel chemical structure and unique mechanism of action. It selectively blocks the MAPK pathway signaling both in vitro and in vivo, which results in significant antitumor efficacy in a broad spectrum of tumor models. Compared with previously reported MEK inhibitors, RO4927350 inhibits not only ERK1/2 but also MEK1/2 phosphorylation. In cancer cells, high basal levels of phospho-MEK1/2 rather than phospho-ERK1/2 seem to correlate with greater sensitivity to RO4927350. Furthermore, RO4927350 prevents a feedback increase in MEK phosphorylation, which has been observed with other MEK inhibitors. We show that B-Raf rather than C-Raf plays a critical role in the feedback regulation. The unique MAPK signaling blockade mediated by RO4927350 in cancer may reduce the risk of developing drug resistance. Thus, RO4927350 represents a novel therapeutic modality in cancers with aberrant MAPK pathway activation. [Cancer Res 2009;69(5):1924–32
Inactivation of the Nijmegen Breakage Syndrome Gene Leads to Excess Centrosome Duplication via the ATR/BRCA1 Pathway
Authors: Shimada Mikio , Sagae Ruri , Kobayashi Junya , Habu Toshiyuki , Komatsu Kenshi 
Published: February 2009

Abstract
Nijmegen breakage syndrome is characterized by genomic instability and a predisposition for lymphoma and solid tumors. Nijmegen breakage syndrome 1 (NBS1), the protein which is mutated in these patients, functions in association with BRCA1 and ATR as part of the cellular response to DNA double-strand breaks. We show here that NBS1 forms foci at the centrosomes via an interaction with γ-tubulin. Down-regulation of NBS1 by small interfering RNA induces supernumerary centrosomes, and this was confirmed with experiments using Nbs1 knockout mouse cells; the introduction of wild-type NBS1 (wt-NBS1) cDNA into these knockout mouse cells reduced the number of supernumerary centrosomes to normal levels. This phenotype in NBS1-deficient cells is caused by both centrosome duplication and impaired separation of centrioles, which have been observed in BRCA1-inhibited cells. In fact, supernumerary centrosomes were observed in Brca1 knockout mouse cells, and the frequency was not affected by NBS1 down-regulation, suggesting that NBS1 maintains centrosomes via a common pathway with BRCA1. This is consistent with findings that NBS1 physically interacts with BRCA1 at the centrosomes and is required for BRCA1-mediated ubiquitination of γ-tubulin. Moreover, the ubiquitination of γ-tubulin is compromised by either ATR depletion or an NBS1 mutation in the ATR interacting (FHA) domain, which is essential for ATR activation. These results suggest that, although centrosomes lack DNA, the NBS1/ATR/BRCA1 repair machinery affects centrosome behavior, and this might be a crucial role in the prevention of malignances. [Cancer Res 2009;69(5):1768–75]
Acquired Resistance to 17-Allylamino-17-Demethoxygeldanamycin (17-AAG, Tanespimycin) in Glioblastoma Cells
Authors: Gaspar Nathalie , Sharp Swee Y. , Pacey Simon , Jones Chris , Walton Michael , Vassal Gilles , Eccles Suzanne , Pearson Andrew , Workman Paul 
Published: February 2009

AbstractHeat shock protein 90 (HSP90) inhibitors, such as 17-allylamino-17-demethoxygeldanamycin (17-AAG, tanespimycin), which is currently in phase II/phase III clinical trials, are promising new anticancer agents. Here, we explored acquired resistance to HSP90 inhibitors in glioblastoma (GB), a primary brain tumor with poor prognosis. GB cells were exposed continuously to increased 17-AAG concentrations. Four 17-AAG–resistant GB cell lines were generated. High-resistance levels with resistance indices (RI = resistant line IC50/parental line IC50) of 20 to 137 were obtained rapidly (2–8 weeks). After cessation of 17-AAG exposure, RI decreased and then stabilized. Cross-resistance was found with other ansamycin benzoquinones but not with the structurally unrelated HSP90 inhibitors, radicicol, the purine BIIB021, and the resorcinylic pyrazole/isoxazole amide compounds VER-49009, VER-50589, and NVP-AUY922. An inverse correlation between NAD(P)H/quinone oxidoreductase 1 (NQO1) expression/activity and 17-AAG IC50 was observed in the resistant lines. The NQO1 inhibitor ES936 abrogated the differential effects of 17-AAG sensitivity between the parental and resistant lines. NQO1 mRNA levels and NQO1 DNA polymorphism analysis indicated different underlying mechanisms: reduced expression and selection of the inactive NQO1*2 polymorphism. Decreased NQO1 expression was also observed in a melanoma line with acquired resistance to 17-AAG. No resistance was generated with VER-50589 and NVP-AUY922. In conclusion, low NQO1 activity is a likely mechanism of acquired resistance to 17-AAG in GB, melanoma, and, possibly, other tumor types. Such resistance can be overcome with novel HSP90 inhibitors. [Cancer Res 2009;69(5):1966–75]
Functional Significance of UDP-Glucuronosyltransferase Variants in the Metabolism of Active Tamoxifen Metabolites
Authors: Blevins-Primeau Andrea S. , Sun Dongxiao , Chen Gang , Sharma Arun K. , Gallagher Carla J. , Amin Shantu , Lazarus Philip 
Published: February 2009

AbstractTamoxifen (TAM) is a selective estrogen receptor modulator widely used in the prevention and treatment of breast cancer. A major mode of metabolism of the major active metabolites of TAM, 4-OH-TAM and endoxifen, is by glucuronidation via the UDP-glucuronosyltransferase (UGT) family of enzymes. To examine whether polymorphisms in the UGT enzymes responsible for the glucuronidation of active TAM metabolites play an important role in interindividual differences in TAM metabolism, cell lines overexpressing wild-type or variant UGTs were examined for their activities against TAM metabolites in vitro. For variants of active extrahepatic UGTs, the UGT1A8173Ala/277Tyr variant exhibited no detectable glucuronidation activity against the trans isomers of either 4-OH-TAM or endoxifen. Little or no difference in TAM glucuronidating activity was observed for the UGT1A8173Gly/277Cys or UGT1A10139Lys variants compared with their wild-type counterparts. For active hepatic UGTs, the UGT2B7268Tyr variant exhibited significant (P &lt; 0.01) 2- and 5-fold decreases in activity against the trans isomers of 4-OH-TAM and endoxifen, respectively, compared with wild-type UGT2B7268His. In studies of 111 human liver microsomal specimens, the rate of O-glucuronidation against trans-4-OH-TAM and trans-endoxifen was 28% (P &lt; 0.001) and 27% (P = 0.002) lower, respectively, in individuals homozygous for the UGT2B7 Tyr268Tyr genotype compared with subjects with the UGT2B7 His268His genotype, with a significant (P &lt; 0.01) trend of decreasing activity against both substrates with increasing numbers of the UGT2B7268His allele. These results suggest that functional polymorphisms in TAM-metabolizing UGTs, including UGT2B7 and potentially UGT1A8, may be important in interindividual variability in TAM metabolism and response to TAM therapy. [Cancer Res 2009;69(5):1892–900]
A Novel Androgen Receptor Splice Variant Is Up-regulated during Prostate Cancer Progression and Promotes Androgen Depletion–Resistant Growth
Authors: Guo Zhiyong , Yang Xi , Sun Feng , Jiang Richeng , Linn Douglas E. , Chen Hege , Chen Hegang , Kong Xiangtian , Melamed Jonathan , Tepper Clifford G. , Kung Hsing-Jien , Brodie Angela M.H. , Edwards Joanne , Qiu Yun 
Published: February 2009

Abstract
The androgen receptor (AR) plays a key role in progression to incurable androgen ablation–resistant prostate cancer (PCA). We have identified three novel AR splice variants lacking the ligand-binding domain (designated as AR3, AR4, and AR5) in hormone-insensitive PCA cells. AR3, one of the major splice variants expressed in human prostate tissues, is constitutively active, and its transcriptional activity is not regulated by androgens or antiandrogens. Immunohistochemistry analysis on tissue microarrays containing 429 human prostate tissue samples shows that AR3 is significantly up-regulated during PCA progression and AR3 expression level is correlated with the risk of tumor recurrence after radical prostatectomy. Overexpression of AR3 confers ablation-independent growth of PCA cells, whereas specific knockdown of AR3 expression (without altering AR level) in hormone-resistant PCA cells attenuates their growth under androgen-depleted conditions in both cell culture and xenograft models, suggesting an indispensable role of AR3 in ablation-independent growth of PCA cells. Furthermore, AR3 may play a distinct, yet essential, role in ablation-independent growth through the regulation of a unique set of genes, including AKT1, which are not regulated by the prototype AR. Our data suggest that aberrant expression of AR splice variants may be a novel mechanism underlying ablation independence during PCA progression, and AR3 may serve as a prognostic marker to predict patient outcome in response to hormonal therapy. Given that these novel AR splice variants are not inhibited by currently available antiandrogen drugs, development of new drugs targeting these AR isoforms may potentially be effective for treatment of ablation-resistant PCA. [Cancer Res 2009;69(6):2305–13]
Sunitinib Inhibition of Stat3 Induces Renal Cell Carcinoma Tumor Cell Apoptosis and Reduces Immunosuppressive Cells
Authors: Xin Hong , Zhang Chunyan , Herrmann Andreas , Du Yan , Figlin Robert , Yu Hua 
Published: February 2009

Abstract
The novel multitargeted tyrosine kinase inhibitor sunitinib is used as an antiangiogenic agent for the treatment of several types of cancer, including metastatic renal cell carcinoma (RCC). Sunitinib was shown to positively change the immunosuppressive phenotype in RCC patients. To improve its antitumor efficacy, and offer strategies for its combination with other approaches, it is critical to fully elucidate its mechanisms of action. We show that sunitinib induces tumor cell apoptosis and growth arrest in RCC tumor cells, which correlates with signal transducer and activator of transcription 3 (Stat3) activity inhibition. Sunitinib-mediated direct effects on tumor cells occur regardless of von Hippel-Lindau tumor suppressor gene status and hypoxia-inducible transcription factor-2α levels. Reduction of Stat3 activity enhances the antitumor effects of sunitinib, whereas expression of a constitutively activated Stat3 mutant rescues tumor cell death. Intravital multiphoton microscopy data show that sunitinib induces mouse Renca tumor cell apoptosis in vivo before tumor vasculature collapse. Sunitinib also inhibits Stat3 in Renca tumor–associated myeloid-derived suppressor cells (MDSC), down-regulates angiogenic gene expression, and reduces MDSCs and tumor T regulatory cells. These results suggest that Stat3 activity is important for RCC response to sunitinib, and Stat3 inhibition permits the direct proapoptotic activity of sunitinib on tumor cells and positive effects on tumor immunologic microenvironment. [Cancer Res 2009;69(6):2506–13]