bluuebunny/crossref_metadata_2025_split huggingface dataset:
First, Let's Assume We Have a Can Opener: An Analysis of the Economics of a Single North American Barley Market
Authors: Brooks Harvey G. 
Published: November 2008

SummaryIn summary, it has been shown that the results of the Carter paper are driven, not surprisingly, by the assumptions that were fed into the model used. In addition, it has been shown that many of the assumptions are highly questionable or unrelated to the problem, and therefore limit the applicability of the findings to any “real‐world” prescriptive analysis.The Carter study does not model a change from a single‐desk selling structure to a multiple seller environment. It simply assumes:feed barley yields increase,U.S. demand for feed barley increases by 500,000 t and malting barley demand increases by 400,000 t,all barley shipments to maltsters bypass the primary elevator system, andmalt selection rates are increased by 50%.Any one of these assumptions would lead an economic model to a result of higher net producer income. Carter, however, fails to connect these assumptions to the institution of a CBM. Further, the modeling errors created in trying to “customize” the CRAM model for this use clearly invalidate the results. There are serious flaws in the structural modeling of how a competitive market for malting barley would operate in North America and they invalidate the Carter's results regarding the prices, producer returns and production of malting barley under the CBM scenario.While it is an interesting academic exercise to examine the possible economic impacts of a policy change by “shocking” an economic model, it is quite another matter to represent the results of such an endeavor as being “an exhaustive and definitive analysis of the issues” (Carter 31 March 1993). Besides the questionable assumptions and modeling errors of this paper, the author clearly misrepresents the power and accuracy of mathematical economic modeling.
Predicting needs for nursing home admission – does sense of coherence delay nursing home admission in care dependent older people? A longitudinal study
Authors: Thygesen Elin , Saevareid Hans Inge , Lindstrom Torill Christine , Nygaard Harald A , Engedal Knut 
Published: November 2008

Objectives.  This study examined predisposing, enabling and need variables (Andersen’s Behavioral Model) influencing the need for nursing home admission (NHA) in older people receiving home nursing care. In particular, the potential role of coping ability, measured as ‘sense of coherence’ (SOC), was studied.Design, sample, and measurements.  A survey with baseline‐ and follow‐up data after a 2‐year period was undertaken with 208 patients aged 75+. The measures used were: gender, education, age, social visits, SOC, social provision scale (SPS), self‐rated health (SRH), general health questionnaire (GHQ), clinical dementia rating (CDR), Barthel activities of daily living (ADL) index, and registered illnesses (RI). A Cox proportional model was used to examine factors that could explain risk of NHA.Results.  Measures with predictive properties were Barthel ADL index, SPS, SRH, and gender. SOC, along with subjective health complaints, general health questionnaire, RI and social visits did not predict NHA.Conclusions.  It is concluded that the patients’ subjective evaluations of both their health and perceived social support were important predictors of future NHA needs, and should be seriously taken into consideration, along with the more commonly used objective measures of ADL and CDR.
Conformational Changes in the Solution Structure of the Dengue Virus 5′ End in the Presence and Absence of the 3′ Untranslated Region
Authors: Polacek Charlotta , Foley Jonathan E. , Harris Eva 
Published: November 2008

ABSTRACT
Dengue virus (DENV) is an ∼10.7-kb positive-sense RNA virus that circularizes via RNA-RNA interactions between sequences in the 5′ and 3′ terminal regions. Complementarity between the cyclization sequence (CS) and the upstream AUG region (UAR) has been shown to be necessary for viral replication. Here, we present the solution structure of the 5′ end of DENV type 2 in the presence and absence of the 3′ end. We demonstrate that hybridization between the 5′ and 3′ CSs is independent of the UAR while the 5′ UAR-3′ UAR hybridization is dependent upon the 5′ CS-3′ CS interaction.
Shifts in the Selection-Drift Balance Drive the Evolution and Epidemiology of Foot-and-Mouth Disease Virus
Authors: Tully Damien C. , Fares Mario A. 
Published: November 2008

ABSTRACT
Foot-and-mouth disease virus (FMDV) is the causative agent of an acute vesicular disease affecting wild and domesticated animals. Despite the economic burden of the disease and all efforts to eradicate it, FMD outbreaks continue to emerge unexpectedly in developed and developing countries. Correlation of the mutational dynamics of the virus with its epidemiology remains unexplored. Analysis of 103 complete genomes representing the seven serotypes shows the important role that selection plays in the genomic evolution of viral isolates for serotypes. We identified selection and relaxed constraints due to genetic drift through analyses of synonymous sites. Finally, we investigated interactions between mutations that showed coevolving patterns and analyzed, based on protein structures, slightly deleterious and compensatory mutational dynamics. Specifically, we demonstrate that structurally exposed capsid proteins present a greater number of adaptive mutations and relaxed selection than nonstructural proteins. Such events have been magnified during the evolution of the southern African virus types (SATs). These shifts in selection-drift balance have generated the great antigenic and genetic diversity observed for SAT serotypes and that are responsible for epizootics on the continent of Africa. The high number of slightly deleterious and compensatory mutations in SAT serotypes in structural proteins is testament to such balance plasticity. The significant accumulation of these coevolving mutations in African serotypes supports their contribution in generating adaptive immune-escaping mutants and in establishing persistent infections. The reverse of this pattern in nonstructural proteins reveals the neutral fixation of mutations in the more widely spread and commonly studied Euro-Asiatic serotypes.
Structural and Functional Studies of the Promoter Element for Dengue Virus RNA Replication
Authors: Lodeiro María F. , Filomatori Claudia V. , Gamarnik Andrea V. 
Published: November 2008

ABSTRACTThe 5′ untranslated region (5′UTR) of the dengue virus (DENV) genome contains two defined elements essential for viral replication. At the 5′ end, a large stem-loop (SLA) structure functions as the promoter for viral polymerase activity. Next to the SLA, there is a short stem-loop that contains a cyclization sequence known as the 5′ upstream AUG region (5′UAR). Here, we analyzed the secondary structure of the SLA in solution and the structural requirements of this element for viral replication. Using infectious DENV clones, viral replicons, and in vitro polymerase assays, we defined two helical regions, a side stem-loop, a top loop, and a U bulge within SLA as crucial elements for viral replication. The determinants for SLA-polymerase recognition were found to be common in different DENV serotypes. In addition, structural elements within the SLA required for DENV RNA replication were also conserved among different mosquito- and tick-borne flavivirus genomes, suggesting possible common strategies for polymerase-promoter recognition in flaviviruses. Furthermore, a conserved oligo(U) track present downstream of the SLA was found to modulate RNA synthesis in transfected cells. In vitro polymerase assays indicated that a sequence of at least 10 residues following the SLA, upstream of the 5′UAR, was necessary for efficient RNA synthesis using the viral 3′UTR as template.
Protein Kinase PKR Mediates the Apoptosis Induction and Growth Restriction Phenotypes of C Protein-Deficient Measles Virus
Authors: Toth Ann M. , Devaux Patricia , Cattaneo Roberto , Samuel Charles E. 
Published: November 2008

ABSTRACTThe measles virus (MV) accessory proteins V and C play important roles in MV replication and pathogenesis. Infection with recombinant MV lacking either V or C causes more cell death than infection with the parental vaccine-equivalent virus (MVvac), and C-deficient virus grows poorly relative to the parental virus. Here, we show that a major effector of the C phenotype is the RNA-dependent protein kinase PKR. Using human HeLa cells stably deficient in PKR as a result of RNA interference-mediated knockdown (PKRkdcells), we demonstrated that a reduction in PKR partially rescued the growth defect of C knockout (Cko) virus but had no effect on the growth of either wild-type (WT) or V knockout (Vko) virus. Increased growth of the Ckovirus in PKRkdcells correlated with increased viral protein expression, while defective growth and decreased protein expression in PKR-sufficient cells correlated with increased phosphorylation of PKR and the α subunit of eukaryotic initiation factor 2. Furthermore, infection with WT, Vko, or especially Ckovirus caused significantly less apoptosis in PKRkdcells than in PKR-sufficient cells. Although apoptosis induced by Ckovirus infection in PKR-sufficient cells was blocked by a caspase antagonist, the growth of Ckovirus was not restored to the WT level by treatment with this pharmacologic inhibitor. Taken together, these results indicate that PKR plays an important antiviral role during MV infection but that the virus growth restriction by PKR is not dependent upon the induction of apoptosis. Furthermore, the results establish that a principal function of the MV C protein is to antagonize the proapoptotic and antiviral activities of PKR.
Severe Acute Respiratory Syndrome (SARS) Coronavirus-Induced Lung Epithelial Cytokines Exacerbate SARS Pathogenesis by Modulating Intrinsic Functions of Monocyte-Derived Macrophages and Dendritic Cells
Authors: Yoshikawa Tomoki , Hill Terence , Li Kui , Peters Clarence J. , Tseng Chien-Te K. 
Published: November 2008

ABSTRACTSevere acute respiratory syndrome (SARS), which is caused by a novel coronavirus (CoV), is a highly communicable disease with the lungs as the major pathological target. Although SARS likely stems from overexuberant host inflammatory responses, the exact mechanism leading to the detrimental outcome in patients remains unknown. Pulmonary macrophages (Mφ), airway epithelium, and dendritic cells (DC) are key cellular elements of the host innate defenses against respiratory infections. While pulmonary Mφ are situated at the luminal epithelial surface, DC reside abundantly underneath the epithelium. Such strategic locations of these cells within the airways make it relevant to investigate their likely impact on SARS pathogenesis subsequent to their interaction with infected lung epithelial cells. To study this, we established highly polarized human lung epithelial Calu-3 cells by using the Transwell culture system. Here we report that supernatants harvested from the apical and basolateral domains of infected Calu-3 cells are potent in modulating the intrinsic functions of Mφ and DC, respectively. They prompted the production of cytokines by both Mφ and DC and selectively induced CD40 and CD86 expression only on DC. However, they compromised the abilities of the DC and Mφ in priming naïve T cells and phagocytosis, respectively. We also identified interleukin-6 (IL-6) and IL-8 as key SARS-CoV-induced epithelial cytokines capable of inhibiting the T-cell-priming ability of DC. Taken together, our results provide insights into the molecular and cellular bases of the host antiviral innate immunity within the lungs that eventually lead to an exacerbated inflammatory cascades and severe tissue damage in SARS patients.
A Mechanism To Explain the Selection of the Hepatitis e Antigen-Negative Mutant during Chronic Hepatitis B Virus Infection
Authors: Frelin Lars , Wahlström Therese , Tucker Amy E. , Jones Joyce , Hughes Janice , Lee Byung O. , Billaud Jean-Noel , Peters Cory , Whitacre David , Peterson Darrell , Milich David R. 
Published: November 2008

ABSTRACTHepatitis B virus (HBV) expresses two structural forms of the nucleoprotein, the intracellular nucleocapsid (hepatitis core antigen [HBcAg]) and the secreted nonparticulate form (hepatitis e antigen [HBeAg]). The aim of this study was to evaluate the ability of HBcAg- and HBeAg-specific genetic immunogens to induce HBc/HBeAg-specific CD4+/CD8+T-cell immune responses and the potential to induce liver injury in HBV-transgenic (Tg) mice. Both the HBcAg- and HBeAg-specific plasmids primed comparable immune responses. Both CD4+and CD8+T cells were important for priming/effector functions of HBc/HBeAg-specific cytotoxic T-lymphocyte (CTL) responses. However, a unique two-step immunization protocol was necessary to elicit maximal CTL priming. Genetic vaccination did not prime CTLs in HBe- or HBc/HBeAg-dbl-Tg mice but elicited a weak CTL response in HBcAg-Tg mice. When HBc/HBeAg-specific CTLs were adoptively transferred into HBc-, HBe-, and HBc/HBeAg-dbl-Tg mice, the durations of the liver injury and inflammation were significantly greater in HBeAg-Tg recipient mice than in HBcAg-Tg mice. Importantly, liver injury in HBc/HBeAg-dbl-Tg mice was similar to the injury observed in HBeAg-Tg mice. Loss of HBeAg synthesis commonly occurs during chronic HBV infection; however, the mechanism of selection of HBeAg-negative variants is unknown. The finding that hepatocytes expressing wild-type HBV (containing both HBcAg and HBeAg) are more susceptible to CTL-mediated clearance than hepatocytes expressing only HBcAg suggest that the HBeAg-negative variant may have a selective advantage over wild-type HBV within the livers of patients with chronic infection during an immune response and may represent a CTL escape mutant.
Stress-induced senescence predominates in endothelial cells isolated from atherosclerotic chronic smokers
Authors: Farhat Nada , Thorin-Trescases Nathalie , Voghel Guillaume , Villeneuve Louis , Mamarbachi Maya , Perrault Louis P. , Carrier Michel , Thorin Eric 
Published: November 2008

Age-associated telomere shortening leads to replicative senescence of human endothelial cells (EC). Risk factors for cardiovascular disease (CVD) accelerate ageing, while there is a concomitant rise in oxidative stress known to promote stress-induced senescence (SIS) in vitro. Of all risk factors for CVD, smoking is most associated with the development of inflammation and accelerated atherosclerosis due to a prooxidant–antioxidant imbalance. We tested the hypothesis that SIS predominates in EC isolated from chronic smokers with premature atherosclerosis undergoing coronary artery bypass graft surgery (CABG). We isolated and cultured EC from segments of internal mammary arteries from smoker, former smoker, and nonsmoker coronary patients. Senescence of EC was induced by serial passage and quantified by the measurement of telomere length and senescence-associated β-galactosidase activity. Compared with nonsmokers, smoker patients were 10 years younger at the time of CABG, evidence of premature atherosclerosis. Cellular senescence was independent of telomere length and directly related to oxidative damage. EC exhibited higher expression levels of markers of oxidative stress (lipid peroxydation level and caveolin-1 mRNA), inflammation (angiopoietin-like 2 mRNA), hypoxia (vascular endothelial growth factor (VEGF)-A mRNA), and cell damage (p53 mRNA). In conclusion, a high oxidative stress environment in EC isolated from atherosclerotic chronic smokers predisposes to SIS rather than replicative senescence.
ADAMTS-1 Metalloproteinase Promotes Tumor Development through the Induction of a Stromal Reaction In vivo
Authors: Rocks Natacha , Paulissen Geneviève , Quesada-Calvo Florence , Munaut Carine , Gonzalez Maria-Luz Alvarez , Gueders Maud , Hacha Jonathan , Gilles Christine , Foidart Jean-Michel , Noel Agnès , Cataldo Didier D. 
Published: November 2008

Abstract
ADAMTS-1 (a disintegrin and metalloproteinase with thrombospondin motifs), the first described member of the ADAMTS family, is differentially expressed in various tumors. However, its exact role in tumor development and progression is still unclear. The aim of this study was to investigate the effects of ADAMTS-1 transfection in a bronchial epithelial tumor cell line (BZR) and its potential to modulate tumor development. ADAMTS-1 overexpression did not affect in vitro cell properties such as (a) proliferation in two-dimensional culture, (b) proliferation in three-dimensional culture, (c) anchorage-independent growth in soft agar, (d) cell migration and invasion in modified Boyden chamber assay, (e) angiogenesis in the aortic ring assay, and (f) cell apoptosis. In contrast, ADAMTS-1 stable transfection in BZR cells accelerated the in vivo tumor growth after s.c. injection into severe combined immunodeficient mice. It also promoted a stromal reaction characterized by myofibroblast infiltration and excessive matrix deposition. These features are, however, not observed in tumors derived from cells overexpressing a catalytically inactive mutant of ADAMTS-1. Conditioned media from ADAMTS-1–overexpressing cells display a potent chemotactic activity toward fibroblasts. ADAMTS-1 overexpression in tumors was associated with increased production of matrix metalloproteinase-13, fibronectin, transforming growth factor β (TGF-β), and interleukin-1β (IL-1β). Neutralizing antibodies against TGF-β and IL-1β blocked the chemotactic effect of medium conditioned by ADAMTS-1–expressing cells on fibroblasts, showing the contribution of these factors in ADAMTS-1–induced stromal reaction. In conclusion, we propose a new paradigm for catalytically active ADAMTS-1 contribution to tumor development, which consists of the recruitment of fibroblasts involved in tumor growth and tumor-associated stroma remodeling. [Cancer Res 2008;68(22):9541–50]
Erlotinib Attenuates Homologous Recombinational Repair of Chromosomal Breaks in Human Breast Cancer Cells
Authors: Li Liping , Wang Hong , Yang Eddy S. , Arteaga Carlos L. , Xia Fen 
Published: November 2008

Abstract
The epidermal growth factor receptor (EGFR) family has been implicated in several cancers, including breast, and its members have become the target of novel cancer therapies. In this report, we show a novel link between erlotinib, a potent EGFR inhibitor, DNA damage, and homology-directed recombinational repair (HDR) in human breast cancer cells. Erlotinib suppresses HDR. This is not secondary to erlotinib-mediated changes in cell cycle and is associated with increased γ-H2AX foci, which is an in situ marker of chromosomal double-strand breaks. Both Rad51 and BRCA1 are essential components of the HDR machinery. Consistent with decreased HDR in erlotinib-treated cells, erlotinib also attenuates DNA damage-induced Rad51 foci and results in cytoplasmic retention of BRCA1. As BRCA1 is a shuttling protein and its nuclear function of promoting HDR is controlled by its subcellular localization, we further show that targeted translocation of BRCA1 to the cytoplasm enhances erlotinib sensitivity. These findings suggest a novel mechanism of action of erlotinib through its effects on the BRCA1/HDR pathway. Furthermore, BRCA1/HDR status may be an innovative avenue to enhance the sensitivity of cancer cells to erlotinib. [Cancer Res 2008;68(22):9141–6]
Phosphatidylinositol 3-Kinase Hyperactivation Results in Lapatinib Resistance that Is Reversed by the mTOR/Phosphatidylinositol 3-Kinase Inhibitor NVP-BEZ235
Authors: Eichhorn Pieter J.A. , Gili Magüi , Scaltriti Maurizio , Serra Violeta , Guzman Marta , Nijkamp Wouter , Beijersbergen Roderick L. , Valero Vanesa , Seoane Joan , Bernards René , Baselga José 
Published: November 2008

Abstract
Small molecule inhibitors of HER2 are clinically active in women with advanced HER2-positive breast cancer who have progressed on trastuzumab treatment. However, the effectiveness of this class of agents is limited by either primary resistance or acquired resistance. Using an unbiased genetic approach, we performed a genome wide loss-of-function short hairpin RNA screen to identify novel modulators of resistance to lapatinib, a recently approved anti-HER2 tyrosine kinase inhibitor. Here, we have identified the tumor suppressor PTEN as a modulator of lapatinib sensitivity in vitro and in vivo. In addition, we show that two dominant activating mutations in PIK3CA (E545K and H1047R), which are prevalent in breast cancer, also confer resistance to lapatinib. Furthermore, we show that phosphatidylinositol 3-kinase (PI3K)–induced lapatinib resistance can be abrogated through the use of NVP-BEZ235, a dual inhibitor of PI3K/mTOR. Our data show that deregulation of the PI3K pathway, either through loss-of-function mutations in PTEN or dominant activating mutations in PIK3CA, leads to lapatinib resistance, which can be effectively reversed by NVP-BEZ235. [Cancer Res 2008;68(22):9221–30]
p53-Inducible Ribonucleotide Reductase (p53R2/RRM2B) Is a DNA Hypomethylation–Independent Decitabine Gene Target That Correlates with Clinical Response in Myelodysplastic Syndrome/Acute Myelogenous Leukemia
Authors: Link Petra A. , Baer Maria R. , James Smitha R. , Jones David A. , Karpf Adam R. 
Published: November 2008

Abstract
While the therapeutic activity of the deoxycytidine analogue decitabine is thought to reflect its ability to reactivate methylation-silenced genes, this agent is also known to trigger p53-dependent DNA damage responses. Here, we report that p53-inducible ribonucleotide reductase (p53R2/RRM2B) is a robust transcriptional target of decitabine. In cancer cells, decitabine treatment induces p53R2 mRNA expression, protein expression, and promoter activity in a p53-dependent manner. The mechanism of p53R2 gene induction by decitabine does not seem to be promoter DNA hypomethylation, as the p53R2 5′ CpG island is hypomethylated before treatment. Small interfering RNA (siRNA) targeting of DNA methyltransferase 1 (DNMT1) in wild-type p53 cells leads to genomic DNA hypomethylation but does not induce p53R2, suggesting that DNMT/DNA adduct formation is the molecular trigger for p53R2 induction. Consistent with this idea, only nucleoside-based DNMT inhibitors that form covalent DNA adducts induce p53R2 expression. siRNA targeting of p53R2 reduces the extent of cell cycle arrest following decitabine treatment, supporting a functional role for p53R2 in decitabine-mediated cellular responses. To determine the clinical relevance of p53R2 induction, we measured p53R2 expression in bone marrow samples from 15 myelodysplastic syndrome/acute myelogenous leukemia (MDS/AML) patients undergoing decitabine therapy. p53R2 mRNA and protein were induced in 7 of 13 (54%) and 6 of 9 (67%) patients analyzed, respectively, despite a lack of methylation changes in the p53R2 promoter. Most notably, there was a significant association (P = 0.0047) between p53R2 mRNA induction and clinical response in MDS/AML. These data establish p53R2 as a novel hypomethylation-independent decitabine gene target associated with clinical response. [Cancer Res 2008;68(22):9358–66]