bluuebunny/crossref_metadata_2025 huggingface dataset:
Gamma-Ray Flares from the Crab Nebula
Authors: Abdo A. A. , Ackermann M. , Ajello M. , Allafort A. , Baldini L. , Ballet J. , Barbiellini G. , Bastieri D. , Bechtol K. , Bellazzini R. , Berenji B. , Blandford R. D. , Bloom E. D. , Bonamente E. , Borgland A. W. , Bouvier A. , Brandt T. J. , Bregeon J. , Brez A. , Brigida M. , Bruel P. , Buehler R. , Buson S. , Caliandro G. A. , Cameron R. A. , Cannon A. , Caraveo P. A. , Casandjian J. M. , Çelik Ö. , Charles E. , Chekhtman A. , Cheung C. C. , Chiang J. , Ciprini S. , Claus R. , Cohen-Tanugi J. , Costamante L. , Cutini S. , D’Ammando F. , Dermer C. D. , de Angelis A. , de Luca A. , de Palma F. , Digel S. W. , do Couto e Silva E. , Drell P. S. , Drlica-Wagner A. , Dubois R. , Dumora D. , Favuzzi C. , Fegan S. J. , Ferrara E. C. , Focke W. B. , Fortin P. , Frailis M. , Fukazawa Y. , Funk S. , Fusco P. , Gargano F. , Gasparrini D. , Gehrels N. , Germani S. , Giglietto N. , Giordano F. , Giroletti M. , Glanzman T. , Godfrey G. , Grenier I. A. , Grondin M.-H. , Grove J. E. , Guiriec S. , Hadasch D. , Hanabata Y. , Harding A. K. , Hayashi K. , Hayashida M. , Hays E. , Horan D. , Itoh R. , Jóhannesson G. , Johnson A. S. , Johnson T. J. , Khangulyan D. , Kamae T. , Katagiri H. , Kataoka J. , Kerr M. , Knödlseder J. , Kuss M. , Lande J. , Latronico L. , Lee S.-H. , Lemoine-Goumard M. , Longo F. , Loparco F. , Lubrano P. , Madejski G. M. , Makeev A. , Marelli M. , Mazziotta M. N. , McEnery J. E. , Michelson P. F. , Mitthumsiri W. , Mizuno T. , Moiseev A. A. , Monte C. , Monzani M. E. , Morselli A. , Moskalenko I. V. , Murgia S. , Nakamori T. , Naumann-Godo M. , Nolan P. L. , Norris J. P. , Nuss E. , Ohsugi T. , Okumura A. , Omodei N. , Ormes J. F. , Ozaki M. , Paneque D. , Parent D. , Pelassa V. , Pepe M. , Pesce-Rollins M. , Pierbattista M. , Piron F. , Porter T. A. , Rainò S. , Rando R. , Ray P. S. , Razzano M. , Reimer A. , Reimer O. , Reposeur T. , Ritz S. , Romani R. W. , Sadrozinski H. F.-W. , Sanchez D. , Parkinson P. M. Saz , Scargle J. D. , Schalk T. L. , Sgrò C. , Siskind E. J. , Smith P. D. , Spandre G. , Spinelli P. , Strickman M. S. , Suson D. J. , Takahashi H. , Takahashi T. , Tanaka T. , Thayer J. B. , Thompson D. J. , Tibaldo L. , Torres D. F. , Tosti G. , Tramacere A. , Troja E. , Uchiyama Y. , Vandenbroucke J. , Vasileiou V. , Vianello G. , Vitale V. , Wang P. , Wood K. S. , Yang Z. , Ziegler M.
Published: January 2011

Gamma-ray observations of the Crab Nebula by two different space telescopes challenge particle acceleration theory.
Astronomy in the Time Domain
Authors: Bernardini Elisa
Published: January 2011

Coordination between various instruments provides a real-time aspect to observing transient astrophysical events.
Controlled search term vocabularies for finding articles relevant to injury prevention and safety promotion
Authors: Lawrence David W
Published: January 2011

Objectives

To assess the usefulness of the controlled vocabularies of PubMed/MEDLINE and PsycINFO for finding articles on injury prevention and safety promotion (IPSP) topics and to identify specific indexing problems that can contribute to incomplete retrieval.

Methods

Professional reference librarians provided search strategies for finding articles relevant to five topics pertaining to the injury prevention field in the two bibliographic databases. The results of implementing these search strategies were compared with the results of a presumptive gold standard—serial textword searches on the same topics. The index terms assigned to the articles that were missed by the librarian strategies were examined.

Results

The search products of the librarian-constructed search strategies identified 34–91% of the IPSP-relevant articles that were identified through serial textword searches of the two databases. Specific indexing issues were found to contribute to this loss.

Conclusions

Librarians bring expertise to searching, but irregular or incomplete indexing can limit the product of even well-constructed searches for articles on IPSP topics.
Dissecting the genetic basis for the effect of rice chalkiness, amylose content, protein content, and rapid viscosity analyzer profile characteristics on the eating quality of cooked rice using the chromosome segment substitution line population across eight environments
Authors: Liu Xiaolu , Wan Xiangyuan , Ma Xiaodong , Wan Jianmin
Published: January 2011

Quantitative trait locus (QTL) mapping and stability analysis were carried out for 16 rice ( Oryza sativa L.) quality traits across eight environments, by using a set of chromosome segment substitution lines with ‘Asominori’ as genetic background. The 16 quality traits include percentage of grain with chalkiness (PGWC), area of chalky endosperm (ACE), amylose content (AC), protein content (PC), peak viscosity, hot paste viscosity, cool paste viscosity, breakdown viscosity (BDV), setback viscosity (SBV), consistency viscosity, cooked-rice luster (LT), scent, tenderness (TD), viscosity, elasticity, and the integrated values of organleptic evaluation (IVOE). A total of 132 additive effect QTLs are detected for the 16 quality straits in the eight environments. Among these QTLs, 56 loci were detected repeatedly in at least three environments. Interestingly, several QTL clusters were observed for multiple quality traits. Especially, one QTL cluster near the G1149 marker on chromosome 8 includes nine QTLs: qPGWC-8, qACE-8, qAC-8, qPC-8a, qBDV-8a, qSBV-8b, qLT-8a, qTD-8a, and qIVOE-8a, which control PGWC, ACE, AC, PC, BDV, SBV, LT, TD, and IVOE, respectively. Moreover, this QTL cluster shows high stability and repeatability in all eight environments. In addition, one QTL cluster was located near the C2340 marker on chromosome 1 and another was detected near the XNpb67 marker on chromosome 2; each cluster contained five loci. Near the C563 marker on chromosome 3, one QTL cluster with four loci was found. Also, there were nine QTL clusters that each had two or three loci; however, their repeatability in different environments was relatively lower, and the genetic contribution rate was relatively smaller. Considering the correlations among all of the 16 quality traits with QTL cluster distributions, we can conclude that the stable and major QTL cluster on chromosome 8 is the main genetic basis for the effect of rice chalkiness, AC, PC, and rapid viscosity analyzer profile characteristics on the eating quality of cooked rice. Consequently, this QTL cluster is a novel gene resource for controlling rice high-quality traits and should be of great significance for research on formation mechanism and molecule improvement of rice quality.
Gene expression patterns are correlated with genomic and genic structure in soybean
Authors: Woody Jenna L. , Severin Andrew J. , Bolon Yung-Tsi , Joseph Bindu , Diers Brian W. , Farmer Andrew D. , Weeks Nathan , Muehlbauer Gary J. , Nelson Rex T. , Grant David , Specht James E. , Graham Michelle A. , Cannon Steven B. , May Gregory D. , Vance Carroll P. , Shoemaker Randy C.
Published: January 2011

Studies have indicated that exon and intron size and intergenic distance are correlated with gene expression levels and expression breadth. Previous reports on these correlations in plants and animals have been conflicting. In this study, next-generation sequence data, which has been shown to be more sensitive than previous expression profiling technologies, were generated and analyzed from 14 tissues. Our results revealed a novel dichotomy. At the low expression level, an increase in expression breadth correlated with an increase in transcript size because of an increase in the number of exons and introns. No significant changes in intron or exon sizes were noted. Conversely, genes expressed at the intermediate to high expression levels displayed a decrease in transcript size as their expression breadth increased. This was due to smaller exons, with no significant change in the number of exons. Taking advantage of the known gene space of soybean, we evaluated the positioning of genes and found significant clustering of similarly expressed genes. Identifying the correlations between the physical parameters of individual genes could lead to uncovering the role of regulation owing to nucleotide composition, which might have potential impacts in discerning the role of the noncoding regions.
Comparative analysis of genetic background in eight near-isogenic wheat lines with differentHgenes conferring resistance to Hessian fly
Authors: Xu S. S. , Chu C. G. , Harris M. O. , Williams C. E.
Published: January 2011

Near-isogenic lines (NILs) are useful for plant genetic and genomic studies. However, the strength of conclusions from such studies depends on the similarity of the NILs’ genetic backgrounds. In this study, we investigated the genetic similarity for a set of NILs developed in the 1990s to study gene-for-gene interactions between wheat ( Triticum aestivum L.) and the Hessian fly ( Mayetiola destructor (Say)), an important pest of wheat. Each of the eight NILs carries a single H resistance gene and was created by successive backcrossing for two to six generations to susceptible T. aestivum ‘Newton’. We generated 256 target region amplification polymorphism (TRAP) markers and used them to calculate genetic similarity, expressed by the Nei and Li (NL) coefficient. Six of the NILs (H3, H5, H6, H9, H11, and H13) had the highly uniform genetic background of Newton, with NL coefficients from 0.97 to 0.99. However, genotypes with H10 or H12 were less similar to Newton, with NL coefficients of 0.86 and 0.93, respectively. Cluster analysis based on NL coefficients and pedigree analysis showed that the genetic similarity between each of the NILs and Newton was affected by both the number of backcrosses and the genetic similarity between Newton and the H gene donors. We thus generated an equation to predict the number of required backcrosses, given varying similarity of donor and recurrent parent. We also investigated whether the genetic residues of the donor parents that remained in the NILs were related to linkage drag. By using a complete set of ‘Chinese Spring’ nullisomic-tetrasomic lines, one third of the TRAP markers that showed polymorphism between the NILs and Newton were assigned to a specific chromosome. All of the assigned markers were located on chromosomes other than the chromosome carrying the H gene, suggesting that the genetic residues detected in this study were not due to linkage drag. Results will aid in the development and use of near-isogenic lines for studies of the functional genomics of wheat.
The mosaic of ancestral karyotype blocks in theSinapis albaL. genome
Authors: Nelson Matthew N. , Parkin Isobel A.P. , Lydiate Derek J.
Published: January 2011

The organisation of the Sinapis alba genome, comprising 12 linkage groups (n = 12), was compared with the Brassicaceae ancestral karyotype (AK) genomic blocks previously described in other crucifer species. Most of the S. alba genome falls into conserved triplicated genomic blocks that closely match the AK-defined genomic blocks found in other crucifer species including the A, B, and C genomes of closely related Brassica species. In one instance, an S. alba linkage group (S05) was completely collinear with one AK chromosome (AK1), the first time this has been observed in a member of the Brassiceae tribe. However, as observed for other members of the Brassiceae tribe, ancestral genomic blocks were fragmented in the S. alba genome, supporting previously reported comparative chromosome painting describing rearrangements of the AK karyotype prior to the divergence of the Brassiceae from other crucifers. The presented data also refute previous phylogenetic reports that suggest S. alba was more closely related to Brassica nigra (B genome) than to B. rapa (A genome) and B. oleracea (C genome). A comparison of the S. alba and Arabidopsis thaliana genomes revealed many regions of conserved gene order, which will facilitate access to the rich genomic resources available in the model species A. thaliana for genetic research in the less well-resourced crop species S. alba.
Bacterial genome chimaerism and the origin of mitochondria
Authors: Abhishek Ankur , Bavishi Anish , Bavishi Ashay , Choudhary Madhusudan
Published: January 2011

Many studies have sought to determine the origin and evolution of mitochondria. Although the Alphaproteobacteria are thought to be the closest relatives of the mitochondrial progenitor, there is dispute as to what its particular sister group is. Some have argued that mitochondria originated from ancestors of the order Rickettsiales, or more specifically of the Rickettsiaceae family, while others believe that ancestors of the family Rhodospirillaceae are also equally likely the progenitors. To resolve some of these disputes, sequence similarity searches and phylogenetic analyses were performed against mitochondria-related proteins in Saccharomyces cerevisiae . The 86 common matches of 5 Alphaproteobacteria ( Rickettsia prowazekii , Rhodospirillum rubrum , R hodopseudomonas palustris , Rhodobacter sphaeroides , and Ochrobactrum anthropi ) to yeast mitochondrial proteins were distributed fairly evenly among the 5 species when sorted by highest identity or score. Moreover, exploratory phylogenetic analyses revealed that among these common matches, 44.19% (38) had branched most closely with O. anthropi, while only 34.88% (30) corresponded with Rickettsia prowazekii. More detailed phylogenetic analyses with additional Alphaproteobacteria and including genes from the mitochondria of Reclinomonas americana found matches of mitochondrial genes to those of members of the Rickettsiaceae, Anaplasmataceae, and Rhodospirillaceae families. The results support the idea that notable bacterial genome chimaerism has occurred en route to the formation of mitochondria.
Method for simple and rapid enumeration of total epiphytic bacteria in the washing solution of rice plants
Authors: Niwa Rieko , Yoshida Shigenobu , Furuya Naruto , Tsuchiya Kenichi , Tsushima Seiya
Published: January 2011

The phyllosphere is one of the most common habitats for terrestrial bacteria. However, little is known about the populations of bacteria, including unculturable bacteria, that thrive on plant surfaces. Here, we developed a fluorescent nuclear staining technique to easily and rapidly observe and enumerate populations of total and living epiphytic bacteria, with particular emphasis on the concentration by centrifugation and fixation of the epiphytic bacteria. An investigation on the optimal conditions for centrifugation and fixation revealed that centrifugation at 20 400g for 2 min and fixation with 0.5% glutaraldehyde solution were the optimum conditions for observation of the bacteria. Using this technique, we assessed the populations of the total and living bacteria on the surface of rice plants. When epiphytic bacteria were recovered from rice seeds ( Oryza sativa ‘Koshihikari’), the number of total and living bacterial cells was 7.36 and 6.85 log10·g–1(fresh mass) in the seed washing, respectively. In contrast, the numbers of total and living bacterial cells in the leaf sheath washings were 5.5–5.8 and 5.3–5.7 log10·g–1, respectively. Approximately 5%–30% of the total bacteria in the washing solution of rice plant were culturable. The usefulness of the enumeration method and the amount of bacteria on the plant surfaces are discussed.
NON-CANONICAL PERTURBATION THEORY OF NONLINEAR SIGMA MODELS
Authors: ALDAYA V. , CALIXTO M. , LÓPEZ-RUIZ F. F.
Published: January 2011

We explore the O(N)-invariant Non-Linear Sigma Model (NLSM) in a different perturbative regime from the usual relativistic-free-field one, by using non-canonical basic commutation relations adapted to the underlying O(N) symmetry of the system, which also account for the nontrivial (nonflat) geometry and topology of the target manifold.
ON THE EVOLUTION OF AN ENTANGLED LEPTON–NEUTRINO PAIR
Authors: MESZÉNA B. , PATKÓS A.
Published: January 2011

The evolution of the entangled muon–neutrino system emerging from charged pion decay is explored both in vacuum and in matter. The study is based on a Weisskopf–Wigner type wave-packet description. Explicit formulas are derived displaying modulation and attenuation of the oscillations due to additional time scales characterizing the production process. The case of neutrinos disentangled due to the detection of the muon is also considered.
EFFECT OF PARAMETERS RELATED TO CHANNEL AND DESICCANT ON THE SIZE OF DESICCANT ROTOR
Authors: CHUNG JAE DONG , LEE DAE-YOUNG , YOON SEOK MANN
Published: January 2011

The desiccant rotor is the most essential component of desiccant cooling system, but one of its drawbacks to spread out is its rotor size. To reduce the size of rotor the analysis of rotor performance is crucial. Systematic examination on the effect of desiccant and channel geometrics has been conducted based on the numerical program previously developed. Considered parameters related to channel geometrics are channel shape and cross-section area of channel, and parameters related to desiccant are mass fraction, heat capacity, density, maximum water uptake and separation factor of isotherm. Considerable reduction of rotor size is expected by adjusting the parameters.
Lung tissue mechanics as an emergent phenomenon
Authors: Suki Béla , Bates Jason H. T.
Published: January 2011

The mechanical properties of lung parenchymal tissue are both elastic and dissipative, as well as being highly nonlinear. These properties cannot be fully understood, however, in terms of the individual constituents of the tissue. Rather, the mechanical behavior of lung tissue emerges as a macroscopic phenomenon from the interactions of its microscopic components in a way that is neither intuitive nor easily understood. In this review, we first consider the quasi-static mechanical behavior of lung tissue and discuss computational models that show how smooth nonlinear stress-strain behavior can arise through a percolation-like process in which the sequential recruitment of collagen fibers with increasing strain causes them to progressively take over the load-bearing role from elastin. We also show how the concept of percolation can be used to link the pathologic progression of parenchymal disease at the micro scale to physiological symptoms at the macro scale. We then examine the dynamic mechanical behavior of lung tissue, which invokes the notion of tissue resistance. Although usually modeled phenomenologically in terms of collections of springs and dashpots, lung tissue viscoelasticity again can be seen to reflect various types of complex dynamic interactions at the molecular level. Finally, we discuss the inevitability of why lung tissue mechanics need to be complex.
Role of Rho-kinase signaling and endothelial dysfunction in modulating blood flow distribution in pulmonary hypertension
Authors: Schwenke Daryl O. , Pearson James T. , Sonobe Takashi , Ishibashi-Ueda Hatsue , Shimouchi Akito , Kangawa Kenji , Umetani Keiji , Shirai Mikiyasu
Published: January 2011

Rho-kinase-mediated vasoconstriction and endothelial dysfunction are considered two primary instigators of pulmonary arterial hypertension (PAH). However, their contribution to the adverse changes in pulmonary blood flow distribution associated with PAH has not been addressed. This study utilizes synchrotron radiation microangiography to assess the specific role, and contribution of, Rho-kinase-mediated vasoconstriction and endothelial dysfunction in PAH. Male adult Sprague-Dawley rats were injected with saline (Cont-rats) or monocrotaline (MCT-rats) 3 wk before microangiography was performed on the left lung. We assessed dynamic changes in vessel internal diameter (ID) in response to 1) the Rho-kinase inhibitor fasudil (10 mg/kg iv); or 2) ACh (3 μg · kg−1 · min−1), sodium nitroprusside (SNP, 5 μg · kg−1 · min−1), and Nω-nitro-l-arginine methyl ester (l-NAME, 50 mg/kg iv). We observed that MCT-rats had fewer vessels of the microcirculation compared with Cont-rats. The fundamental result of this study is that fasudil improved pulmonary blood flow distribution and reduced pulmonary pressure in PAH rats, not only by dilating already-perfused vessels (ID > 100 μm), but also by restoring blood flow to vessels that had previously been constricted closed (ID < 100 μm). Endothelium-dependent vasodilation was impaired in MCT-rats primarily in vessels with an ID < 200 μm. Moreover the vasoconstrictor response to l-NAME was accentuated in MCT-rats, but only in the 200- to 300-μm vessels. These results highlight the importance of Rho-kinase-mediated control and endothelial control of pulmonary vascular tone in PAH. Indeed, an effective therapeutic strategy for treating PAH should target both the smooth muscle Rho-kinase and endothelial pathways.
miR-99 Family of MicroRNAs Suppresses the Expression of Prostate-Specific Antigen and Prostate Cancer Cell Proliferation
Authors: Sun Dandan , Lee Yong Sun , Malhotra Ankit , Kim Hak Kyun , Matecic Mirela , Evans Clive , Jensen Roderick V. , Moskaluk Christopher A. , Dutta Anindya
Published: January 2011

MicroRNAs (miRNA) have been globally profiled in cancers but there tends to be poor agreement between studies including in the same cancers. In addition, few putative miRNA targets have been validated. To overcome the lack of reproducibility, we profiled miRNAs by next generation sequencing and locked nucleic acid miRNA microarrays and verified concordant changes by quantitative RT-PCR. Notably, miR-125b and the miR-99 family members miR-99a, -99b, and -100 were downregulated in all assays in advanced prostate cancer cell lines relative to the parental cell lines from which they were derived. All four miRNAs were also downregulated in human prostate tumor tissue compared with normal prostate. Transfection of miR-99a, -99b, or -100 inhibited the growth of prostate cancer cells and decreased the expression of prostate-specific antigen (PSA), suggesting potential roles as tumor suppressors in this setting. To identify targets of these miRNAs, we combined computational prediction of potential targets with experimental validation by microarray and polyribosomal loading analysis. Three direct targets of the miR-99 family that were validated in this manner were the chromatin-remodeling factors SMARCA5 and SMARCD1 and the growth regulatory kinase mTOR. We determined that PSA is posttranscriptionally regulated by the miR-99 family members, at least partially, by repression of SMARCA5. Together, our findings suggest key functions and targets of miR-99 family members in prostate cancer suppression and prognosis. Cancer Res; 71(4); 1313–24. ©2011 AACR.
Targeting Activin Receptor-Like Kinase 1 Inhibits Angiogenesis and Tumorigenesis through a Mechanism of Action Complementary to Anti-VEGF Therapies
Authors: Hu-Lowe Dana D. , Chen Enhong , Zhang Lianglin , Watson Katherine D. , Mancuso Patrizia , Lappin Patrick , Wickman Grant , Chen Jeffrey H. , Wang Jianying , Jiang Xin , Amundson Karin , Simon Ronald , Erbersdobler Andreas , Bergqvist Simon , Feng Zheng , Swanson Terri A. , Simmons Brett H. , Lippincott John , Casperson Gerald F. , Levin Wendy J. , Stampino Corrado Gallo , Shalinsky David R. , Ferrara Katherine W. , Fiedler Walter , Bertolini Francesco
Published: January 2011

Genetic and molecular studies suggest that activin receptor-like kinase 1 (ALK1) plays an important role in vascular development, remodeling, and pathologic angiogenesis. Here we investigated the role of ALK1 in angiogenesis in the context of common proangiogenic factors [PAF; VEGF-A and basic fibroblast growth factor (bFGF)]. We observed that PAFs stimulated ALK1-mediated signaling, including Smad1/5/8 phosphorylation, nuclear translocation and Id-1 expression, cell spreading, and tubulogenesis of endothelial cells (EC). An antibody specifically targeting ALK1 (anti-ALK1) markedly inhibited these events. In mice, anti-ALK1 suppressed Matrigel angiogenesis stimulated by PAFs and inhibited xenograft tumor growth by attenuating both blood and lymphatic vessel angiogenesis. In a human melanoma model with acquired resistance to a VEGF receptor kinase inhibitor, anti-ALK1 also delayed tumor growth and disturbed vascular normalization associated with VEGF receptor inhibition. In a human/mouse chimera tumor model, targeting human ALK1 decreased human vessel density and improved antitumor efficacy when combined with bevacizumab (anti-VEGF). Antiangiogenesis and antitumor efficacy were associated with disrupted co-localization of ECs with desmin+ perivascular cells, and reduction of blood flow primarily in large/mature vessels as assessed by contrast-enhanced ultrasonography. Thus, ALK1 may play a role in stabilizing angiogenic vessels and contribute to resistance to anti-VEGF therapies. Given our observation of its expression in the vasculature of many human tumor types and in circulating ECs from patients with advanced cancers, ALK1 blockade may represent an effective therapeutic opportunity complementary to the current antiangiogenic modalities in the clinic. Cancer Res; 71(4); 1362–73. ©2011 AACR.
The Role of Calcium in the Activation of Estrogen Receptor-Alpha
Authors: Divekar Shailaja D. , Storchan Geoffrey B. , Sperle Katherine , Veselik David J. , Johnson Earl , Dakshanamurthy Sivanesan , Lajiminmuhip Yuse N. , Nakles Rebecca E. , Huang Li , Martin Mary Beth
Published: January 2011

Environmental estrogen mimics, including metalloestrogens that can activate estrogen receptor-alpha (ERα), may contribute to breast cancer risk. However, the underlying mechanisms through which these molecular mimics activate the ERα are generally poorly understood. With concern to this important question, we investigated whether intracellular calcium may mediate the cross-talk between signaling pathways that activate ERα and the ligand-binding domain of ERα. MCF-7 cells treated with EGF, ATP, extracellular calcium, or caffeine to increase intracellular calcium triggered a rapid recruitment of ERα to estrogen-responsive promoters and stimulated expression of estrogen-responsive genes including pS2, complement C3, and progesterone receptor. Induction was blocked by an antiestrogen but also by the chelation of intracellular calcium. Treatment with extracellular calcium also increased the growth of MCF-7 cells through an ER-dependent mechanism. We found that EGF and extracellular calcium activated the C-terminus of ERα and the activation was blocked by the antiestrogen. Mechanistic investigations identified four potential sites on the solvent-accessible surface of the ERα ligand-binding domain as important for calcium activation of the receptor. Taken together, our results suggest that calcium mediates the cross-talk between ERα-activating signaling pathways and the ligand-binding domain of ERα providing a potential explanation for the ability of certain environmental metalloestrogens to activate the receptor. Cancer Res; 71(5); 1658–68. ©2011 AACR.
Increased Efficacy of Breast Cancer Chemotherapy in Thrombocytopenic Mice
Authors: Demers Mélanie , Ho-Tin-Noé Benoit , Schatzberg Daphne , Yang Janie J. , Wagner Denisa D.
Published: January 2011

Platelets contribute to homeostasis of the tumor vasculature by helping prevent hemorrhage. Thus, we hypothesized that inducing thrombocytopenia would increase tumor vascular leakiness and facilitate the effective delivery of chemotherapeutic agents to tumors. In a mammary carcinoma murine model, platelet depletion induced bleeding specifically at the tumor site, favoring the accumulation of fluorescently labeled microspheres only in the tumor. Moreover, induction of thrombocytopenia in tumor-bearing mice before injection of paclitaxel increased its intratumoral accumulation and reduced growth of both slow- and fast-growing tumors, compared with mice with normal platelet counts that were treated only with paclitaxel. Histologic analysis confirmed the expectation of an increase in tumor apoptosis and a reduction in tumor proliferation in thrombocytopenic mice receiving chemotherapy. No increased toxicity was seen in other organs or blood cells. Taken together, our results indicate that low platelet count selectively induces leakiness of tumor vessels and favors the delivery of chemotherapy to tumor sites, enhancing its tumoricidal effects. Cancer Res; 71(5); 1540–9. ©2011 AACR.
Ron Kinase Transphosphorylation SustainsMETOncogene Addiction
Authors: Benvenuti Silvia , Lazzari Luca , Arnesano Addolorata , Li Chiavi Giulia , Gentile Alessandra , Comoglio Paolo M.
Published: January 2011

Receptors for the scatter factors HGF and MSP that are encoded by the MET and RON oncogenes are key players in invasive growth. Receptor cross-talk between Met and Ron occurs. Amplification of the MET oncogene results in kinase activation, deregulated expression of an invasive growth phenotype, and addiction to MET oncogene signaling (i.e., dependency on sustained Met signaling for survival and proliferation). Here we show that cancer cells addicted to MET also display constitutive activation of the Ron kinase. In human cancer cell lines coexpressing the 2 oncogenes, Ron is specifically transphosphorylated by activated Met. In contrast, Ron phosphorylation is not triggered in cells harboring constitutively active kinase receptors other than Met, including Egfr or Her2. Furthermore, Ron phosphorylation is suppressed by Met-specific kinase inhibitors (PHA-665752 or JNJ-38877605). Last, Ron phosphorylation is quenched by reducing cell surface expression of Met proteins by antibody-induced shedding. In MET-addicted cancer cells, short hairpin RNA–mediated silencing of RON expression resulted in decreased proliferation and clonogenic activity in vitro and tumorigenicity in vivo. Our findings establish that oncogene addiction to MET involves Ron transactivation, pointing to Ron kinase as a target for combinatorial cancer therapy. Cancer Res; 71(5); 1945–55. ©2011 AACR.
E-3810 Is a Potent Dual Inhibitor of VEGFR and FGFR that Exerts Antitumor Activity in Multiple Preclinical Models
Authors: Bello Ezia , Colella Gennaro , Scarlato Valentina , Oliva Paolo , Berndt Alexander , Valbusa Giovanni , Serra Sonia Colombo , D'Incalci Maurizio , Cavalletti Ennio , Giavazzi Raffaella , Damia Giovanna , Camboni Gabriella
Published: January 2011

Tumor angiogenesis is a degenerate process regulated by a complex network of proangiogenic factors. Existing antiangiogenic drugs used in clinic are characterized by selectivity for specific factors. Antiangiogenic properties might be improved in drugs that target multiple factors and thereby address the inherent mechanistic degeneracy in angiogenesis. Vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF) family members and their cognate receptors are key players in promoting tumor angiogenesis. Here we report the pharmacologic profile of E-3810, a novel dual inhibitor of the VEGF and FGF receptors. E-3810 potently and selectively inhibited VEGF receptor (VEGFR)-1, -2, and -3 and FGF receptor (FGFR)-1 and -2 kinases in the nanomolar range. Ligand-dependent phosphorylation of VEGFR-2 and FGFR-1 was suppressed along with human vascular endothelial cell growth at nanomolar concentrations. In contrast, E-3810 lacked cytotoxic effects on cancer cell lines under millimolar concentrations. In a variety of tumor xenograft models, including early- or late-stage subcutaneous and orthotopic models, E-3810 exhibited striking antitumor properties at well-tolerated oral doses administered daily. We found that E-3810 remained active in tumors rendered nonresponsive to the general kinase inhibitor sunitinib resulting from a previous cycle of sunitinib treatment. In Matrigel plug assays performed in nude mice, E-3810 inhibited basic FGF–induced angiogenesis and reduced blood vessel density as assessed by histologic analysis. Dynamic contrast-enhanced magnetic resonance imaging analysis confirmed that E-3810 reduced the distribution of angiogenesis-sensitive contrast agents after only 5 days of treatment. Taken together, our findings identify E-3810 as a potent antiangiogenic small molecule with a favorable pharmacokinetic profile and broad spectrum antitumor activity, providing a strong rationale for its clinical evaluation. Cancer Res; 71(4); 1396–405. ©2011 AACR.
Significance and Mechanism of Lymph Node Metastasis in Cancer Progression
Authors: Kawada Kenji , Taketo Makoto M.
Published: January 2011

The effect of local therapy, such as surgical lymph node (LN) dissection and radiotherapy, on the survival of cancer patients has been debated for decades. Several lines of recent clinical evidence support that LN metastasis plays significant roles in systemic dissemination of cancer cells, although the effects of surgical LN dissection on survival was downplayed historically because of controversial data. Molecular studies of LN metastasis suggest that the microenvironment within LNs, including chemokines and lymphangiogenesis, can mediate the metastatic spread to the sentinel LNs, and beyond. It has been shown that chemokine receptor CXCR3 is involved in LN metastasis, and its inhibition may improve patient prognosis. Although it remains to be determined whether local therapy is best pursued through LN dissection or through a combination of resection with radiation, prevention of regional metastases is an important goal in the treatment of cancer patients to achieve a better survival. Cancer Res; 71(4); 1214–8. ©2011 AACR.
Carotid Intima-Media Thickness in Psoriatic Arthritis
Authors: Di Minno Matteo Nicola Dario , Iervolino Salvatore , Peluso Rosario , Scarpa Raffaele , Di Minno Giovanni
Published: January 2011

Objective—

Subjects with psoriatic arthritis (PsA) have an abnormally high prevalence of vascular risk factors (VRFs) and are predisposed to vascular mortality. Tumor necrosis factor (TNF)-α, a major determinant of inflammation, is involved in atherosclerosis. Ultrasonographic carotid intima-media thickness (C-IMT) evaluation allows for subclinical atherosclerosis detection.

Methods and Results—

Two hundred twenty-four PsA patients (120 on TNF-α blockers and 104 on traditional disease-modifying antirheumatic drugs [DMARDs]) underwent a C-IMT ultrasound assessment. As many as 305 matched subjects without any inflammatory/rheumatologic disease served as controls. The C-IMT of PsA subjects without VRFs was higher (
P
<0.0001) than that of controls, the C-IMT of PsA subjects with ≥1 VRF(s) was lower (
P
<0.0001) than that of controls, and the C-IMT was lower (
P
<0.0001) in those on TNF-α blockers than in those on DMARDs. Carotid plaques were detected in 15.8% of those on TNF-α blockers and in 40.4% of those on DMARDs (
P
<0.0001). Treatment duration inversely (β=−0.317,
P
<0.0001) predicted C-IMT in PsA subjects on TNF-α blockers but not in those on DMARDs (
P
=0.313).

Conclusion—

Among PsA individuals, the C-IMT is higher in subjects on DMARDs than in those on TNF-α blockers. The reduction of inflammation may hamper the cascade that causes the raised vascular risk in PsA patients.
Dimethylarginine Dimethylaminohydrolase 1 Modulates Endothelial Cell Growth Through Nitric Oxide and Akt
Authors: Zhang Ping , Hu Xinli , Xu Xin , Chen Yingjie , Bache Robert J.
Published: January 2011

Objective—

Dimethylarginine dimethylaminohydrolase 1 (DDAH1) modulates NO production by degrading the endogenous nitric oxide (NO) synthase (NOS) inhibitors asymmetrical dimethylarginine (ADMA) and L-NG-monomethyl arginine (L-NMMA). This study examined whether, in addition to degrading ADMA, DDAH1 exerts ADMA-independent effects that influence endothelial function.

Methods and Results—

Using selective gene silencing of DDAH1 with small interfering RNA and overexpression of DDAH1 in human umbilical vein endothelial cells, we found that DDAH1 acts to promote endothelial cell proliferation, migration, and tube formation by Akt phosphorylation, as well as through the traditional role of degrading ADMA. Incubation of human umbilical vein endothelial cells with the NOS inhibitors
l
-NG-nitro-arginine methyl ester (L-NAME) or ADMA, the soluble guanylyl cyclase inhibitor 1H-(1,2,4)oxadiazolo-(4,3–2)quinoxalin-1-one, or the cGMP analog 8-(4-Chlorophenylthio)-cGMP had no effect on phosphorylated (p)-Akt
Ser473
, indicating that the increase in p-Akt
Ser473
produced by DDAH1 was independent of the NO-cGMP signaling pathway. DDAH1 formed a protein complex with Ras, and DDAH1 overexpression increased Ras activity. The Ras inhibitor manumycin-A or dominant-negative Ras significantly attenuated the DDAH1-induced increase in p-Akt
Ser473
. Furthermore, DDAH1 knockout impaired endothelial sprouting from cultured aortic rings, and overexpression of constitutively active Akt or DDAH1 rescued endothelial sprouting in the aortic rings from these mice.

Conclusion—

DDAH1 exerts a unique role in activating Akt that affects endothelial function independently of degrading endogenous NOS inhibitors.
Oxidative Stress–Induced Degradation of Thioredoxin-1 and Apoptosis Is Inhibited by Thioredoxin-1–Actin Interaction in Endothelial Cells
Authors: Zschauer Tim-Christian , Kunze Kerstin , Jakob Sascha , Haendeler Judith , Altschmied Joachim
Published: January 2011

Objective—

Thioredoxin-1 (Trx-1), one important antioxidative enzyme in endothelial cells, is required for apoptosis inhibition. Apoptosis induction is dependent on cytoskeletal changes, which depend on actin rearrangements. Therefore, we wanted to elucidate whether a physical interaction exists between Trx-1 and actin and what the functional consequences are.

Methods and Results—

Combined immunoprecipitation/mass spectrometry identified actin as a new binding partner for Trx-1. A separate pool of Trx-1 forms a complex with apoptosis signaling kinase 1. Actin is required for stress fiber formation; thus, the interaction of actin with Trx-1 might interfere with this process. Stress fiber formation, which is directly linked to the phosphorylation of focal adhesion kinase (FAK), occurs as early as 1 hour after H
2
O
2
treatment. It is inhibited by Trx-1 overexpression, treatment with exogenous Trx-1, or inhibition of FAK. Prolonged incubation with H
2
O
2
induced stress fiber formation, reduced Trx-1 protein levels, and increased apoptosis. All these processes were inhibited by preincubation with the FAK inhibitor PF573228. On the contrary, incubation with PF573228 1 hour after H
2
O
2
treatment did not block stress fiber formation, degradation of Trx-1, or apoptosis.

Conclusion—

These data demonstrate that the actin–Trx-1 complex protects Trx-1 from degradation and, thus, endothelial cells from apoptosis. Reciprocally, Trx-1 prevents stress fiber formation.
Genetic Variation in NCAM1 Contributes to Left Ventricular Wall Thickness in Hypertensive Families
Authors: Arnett Donna K. , Meyers Kristin J. , Devereux Richard B. , Tiwari Hemant K. , Gu Charles C. , Vaughan Laura K. , Perry Rodney T. , Patki Amit , Claas Steven A. , Sun Yan V. , Broeckel Ulrich , Kardia Sharon L.
Published: January 2011

Rationale:

Left ventricular (LV) mass and related phenotypes are heritable, important predictors of cardiovascular disease, particularly in hypertensive individuals.

Objective:

Identify genetic predictors of echocardiographic phenotypes in hypertensive families.

Methods and Results:

A multistage genome-wide association study (GWAS) was conducted in hypertensive-ascertained black families (HyperGEN, stage I; GENOA, stage II); findings were replicated in HyperGEN white families (stage III). Echocardiograms were collected using a common protocol, and participants were genotyped with the Affymetrix Genome-Wide Human SNP 6.0 Array. The following were analyzed using mixed models adjusted for ancestry: in stages I and II, 1258 and 989 blacks, respectively; and in stage III, 1316 whites. Phenotypes included LV mass, LV internal dimension (LVID), wall thicknesses (posterior [PWT] and intraventricular septum [IVST]), and relative wall thickness (RWT). In stage I, 5 single nucleotide polymorphisms (SNPs) had
P
≤10
−6
. In stage II, 1 SNP (rs1436109;
NCAM1
intron 1) replicated with the same phenotype (PWT,
P
=0.025) in addition to RWT (
P
=0.032). In stage III, rs1436109 was associated with RWT (
P
=5.47×10
−4
) and LVID (
P
=1.86×10
−4
). Fisher combined probability value for all stages was RWT=3.80×10
−9
, PWT=3.12×10
−7
, IVST=8.69×10
−7
, LV mass=2.52×10
−3
, and LVID=4.80×10
−4
.

Conclusions:

This GWAS conducted in hypertensive families identified a variant in
NCAM1
associated with LV wall thickness and RWT. NCAM is upregulated during the remodeling period of hypertrophy to heart failure in Dahl salt–sensitive rats. Our initial screening in hypertensive blacks may have provided the context for this novel locus.
Microinfarct Pathology, Dementia, and Cognitive Systems
Authors: Arvanitakis Zoe , Leurgans Sue E. , Barnes Lisa L. , Bennett David A. , Schneider Julie A.
Published: January 2011

Background and Purpose—

Little is known about the role of microinfarcts in dementia and cognition. We examined microinfarcts and dementia, global cognition, and 5 cognitive systems in community-dwelling older persons.

Methods—

Four hundred twenty-five subjects enrolled in the Religious Orders Study underwent annual clinical evaluations, including 19 neuropsychological tests and assessment for dementia, and brain autopsy (39% men; mean age at death, 87; Mini-Mental State Examination score, 21). Neuropathologic examination documented the presence, number, and location of chronic microinfarcts on 6-μm hematoxylin–eosin-stained sections from cortical and subcortical regions. Multiple regression analyses adjusted for age at death, sex, education, macroscopic infarcts, Alzheimer disease pathology, and Lewy bodies.

Results—

Microinfarcts were present in 129 of 425 (30%) persons (54 cortical, 80 subcortical, 49 multiple); 58 of 129 (45%) of persons with microinfarcts did not exhibit macroscopic infarcts. Persons with microinfarcts had increased odds of dementia (OR, 1.77; 95% CI, 1.07–2.92), especially those persons with multiple cortical microinfarcts. Microinfarcts were also associated with lower average global cognition (estimate, −0.287; SE, 0.113;
P
=0.012), particularly for persons with multiple cortical microinfarcts. Microinfarcts were specifically associated with lower episodic memory (estimate, −0.279; SE, 0.138;
P
=0.044), semantic memory (estimate, −0.391; SE, 0.130;
P
=0.003), and perceptual speed (estimate, −0.400; SE, 0.117;
P
<0.001). In addition, single, multiple, and cortical microinfarcts were associated with worse semantic memory and perceptual speed (all
P
<0.028). Neither macroscopic infarcts nor AD pathology modified these associations (all
P
>0.154).

Conclusions—

Microinfarcts are common, and persons with multiple cortical microinfarcts have higher odds of dementia. Microinfarcts are also associated with lower cognition, specifically perceptual speed and semantic and episodic memory.
Impacts of Urban Processes and Urbanization on Summer Precipitation: A Case Study of Heavy Rainfall in Beijing on 1 August 2006
Authors: Miao Shiguang , Chen Fei , Li Qingchun , Fan Shuiyong
Published: January 2011

Finescale simulations (with 500-m grid spacing) using the Weather Research and Forecasting Model (WRF) were used to investigate impacts of urban processes and urbanization on a localized, summer, heavy rainfall in Beijing. Evaluation using radar and gauge data shows that this configuration of WRF with three-dimensional variational data assimilation of local weather and GPS precipitable water data can simulate this event generally well. Additional WRF simulations were conducted to test the sensitivity of simulation of this storm to different urban processes and urban land-use scenarios. The results confirm that the city does play an important role in determining storm movement and rainfall amount. Comparison of cases with and without the presence of the city of Beijing with respect to the approaching storm shows that the urban effect seems to lead to the breaking of the squall line into convective cells over the urban area. The change of precipitation amount depends on the degree of urbanization (i.e., the change over time in the extent of Beijing city). Model results show that an early urbanization prior to 1980 decreases the maximum rainfall, whereas further urbanization in Beijing is conducive to bifurcating the path of rainfall. According to sensitivity results with a single-layer urban canopy model, the thermal transport (sensible and latent heating) induced by the presence of an urban area apparently is more important than associated momentum transport, with latent and sensible heating apparently having equally important roles in the modification of simulated precipitation. Urban surfaces tend to cause the rainfall to be more locally concentrated. High-rise urban cores may bifurcate the path of rainfall as well as increase the area percentage of heavy rainfall.
Ocean–Atmosphere Influences on Low-Frequency Warm-Season Drought Variability in the Gulf Coast and Southeastern United States
Authors: Ortegren Jason T. , Knapp Paul A. , Maxwell Justin T. , Tyminski William P. , Soulé Peter T.
Published: January 2011

From the 344 state climate divisions in the conterminous United States, nine distinct regions of warm-season drought variability are identified using principal component analysis. The drought metric used is the Palmer hydrological drought index for the period 1895–2008. The focus of this paper is multidecadal drought variability in the Southeast (SEUS) and eastern Gulf South (EGS) regions of the United States, areas in which the low-frequency forcing mechanisms of warm-season drought are still poorly understood. Low-frequency drought variability in the SEUS and EGS is associated with smoothed indexed time series of major ocean–atmosphere circulation features, including two indices of spatiotemporal variability in the North Atlantic subtropical anticyclone (Bermuda high). Long-term warm-season drought conditions are significantly out of phase between the two regions. Multidecadal regimes of above- and below-average moisture in the SEUS and EGS are closely associated with slow variability in sea surface temperatures in the North Atlantic Ocean and with the summer mean position and mean strength of the Bermuda high. Multivariate linear regression indicates that 82%–92% of the low-frequency variability in warm-season moisture is explained by two of the three leading principal components of low-frequency variability in the climate indices. The findings are important for water resource managers and water-intensive industries in the SEUS and EGS. The associations identified in the paper are valuable for enhanced drought preparedness and forecasting in the study area and potentially for global models of coupled ocean–atmosphere variability.
Using an Integrated Response-Function Method to Explore Agro-Climatic Suitability for Spring Soybean Growth in North China
Authors: He Yingbin , Yao Yanmin , Tang Huajun , Chen Youqi , Li Jianping , Yang Peng , Chen Zhongxin , Xin Xiaoping , Wang Limin , Li Dandan , Deng Hui
Published: January 2011

To understand agro-climatic suitability for spring soybean growth in north China, an integrated crop-response-function method was developed. This method includes crop-response functions for temperature, precipitation, and sunshine and is assessed by a weighting method based on the coefficient of determination. The results show that the most suitable area (S1) for spring soybean growth occupied approximately 21.35% of the total area of north China. Among three types of spring soybeans of early maturity, middle maturity, and late maturity, middle maturity was the most suitable variety to grow in the study area, covering nearly 1.133 × 106 km2 or about 99.75% of the total area of S1. As a result of this study, the authors suggest that breeders pay more attention to middle-maturity cultivars in north China. The findings from this study may provide useful information for policy makers issuing guidelines for agricultural production.