bluuebunny/crossref_metadata_2025 huggingface dataset:
Progressive Gray Matter Atrophy in Lacunar Patients with Vascular Mild Cognitive Impairment
Authors: Grau-Olivares Marta , Arboix Adrià , Junqué Carme , Arenaza-Urquijo Eider M. , Rovira Mariana , Bartrés-Faz David
Published: June 2010

Background and Method: We investigated the progression of cognitive and cerebral changes in 30 patients with a first-ever lacunar infarct (LI): 15 with vascular mild cognitive impairment (MCI-V) and 15 without cognitive impairment. All cases were followed up 18 ± 6 months after the stroke and underwent neurological, neuropsychological and MRI assessments at baseline and longitudinally. Results: Differences in the changes in cognitive function over time were observed between the 2 groups, with the MCI-V patients showing slight memory improvements and frontal-lobe-related test impairments from baseline to follow-up evaluations. At baseline, the 2 groups presented similar white matter hyperintensity (WMH) ratings and whole brain gray matter (GM) volumes, and at the follow-up evaluations, both groups had increased WMH lesions and decreased GM volumes; no statistical differences between groups were found. In contrast, a voxel-based morphometry analysis revealed that only MCI-V patients presented clear regional GM volume losses between the first and the second evaluations in cortical (frontal and temporal) and subcortical (pons, cerebellum and caudate) regions. Conclusion: Frontal lobe dysfunction and regional cortical and subcortical GM atrophy best differentiate the clinical course of LI patients with and without cognitive impairment.
Low cut-off values increase diagnostic performance of protein S assays
Authors: Kate Min Ki ten , Kluin-Nelemans Hanneke , Mulder André , Mulder René
Published: June 2010

Conflicting data have been reported on the accuracy of protein S (PS) assays for detection of hereditary PS deficiency. In this study we assessed the diagnostic performance of two total PS antigen assays, four free PS assays and three PS activity assays in a group of 28 heterozygous carriers of mutations in PROS1 and 165 control subjects. Several control groups were formed, one of healthy volunteers and – because PS levels are influenced by oral contraception and pregnancy, and assays measuring PS activity may be influenced by the presence of the factor V Leiden mutation -, we also investigated the influences of these factors. All nine PS assays detected significantly reduced PS levels in subjects with a PROS1 mutation. Eight out of nine PS assays showed a 100% sensitivity and 100% specificity to detect heterozygous carriers of mutations in PROS1 with values far below the lower limit of the reference values obtained from healthy volunteers. Low specificities were found in subjects with a factor V Leiden mutation and in pregnant women. At lower cutoff levels, equal to the highest PS value found in heterozygous carriers of mutations in PROS1, the specificity considerably increased in these subjects. When using low cut-off levels equal to the highest PS value found in heterozygous carriers of mutations in PROS1, ensuring 100% sensitivity, the specificity in all study groups increases considerably, by which misclassification can be maximally avoided.
On the Temporal Characteristics of Radar Coherent Structures in Snow and Rain
Authors: Jameson A. R.
Published: June 2010

Previous work showed that the magnitudes of the radar-backscattered amplitudes have statistically significant periodic components of frequencies ( f ) in excess of those arising from the Doppler velocity fluctuations of incoherent scatter. Analyses in both rain and snow in the earlier work revealed what is interpreted as pervasive coherent scatter. This coherency is thought to come from precipitation structures acting like gratings in resonance with the radar wavelength that, when they move with a velocity component transverse to the beam, induce the observed f. The purpose of this article is to characterize briefly the temporal structure of f and, thereby indirectly, the temporal character of the structures producing the radar coherent backscatter. It is found that these structures last considerably longer than the decorrelation times of a few to 10 milliseconds, characteristic of Doppler velocity fluctuations associated with incoherent scatter. For the data analyzed, though, most last no more than a significant fraction of 1 s. Hence, for the observed transverse velocity of 2 ms−1, the dimensions of the gratings producing the radar coherent backscatter are only on the order of tens of centimeters to a few meters. Therefore, the typically large sampling volumes of most radars will contain many of these grids at any given time. Consequently, during 1 s of observations, one can envision the coherent scatter as coming from many individual grids twinkling on and off, much like the transient spectral reflections off ice crystals falling in sunlight.
On the Accuracy of Deriving Climate Feedback Parameters from Correlations between Surface Temperature and Outgoing Radiation
Authors: Murphy D. M. , Forster P. M.
Published: June 2010

Changes in outgoing radiation are both a consequence and a cause of changes in the earth’s temperature. Spencer and Braswell recently showed that in a simple box model for the earth the regression of outgoing radiation against surface temperature gave a slope that differed from the model’s true feedback parameter. They went on to select input parameters for the box model based on observations, computed the difference for those conditions, and asserted that there is a significant bias for climate studies. This paper shows that Spencer and Braswell overestimated the difference. Differences between the regression slope and the true feedback parameter are significantly reduced when 1) a more realistic value for the ocean mixed layer depth is used, 2) a corrected standard deviation of outgoing radiation is used, and 3) the model temperature variability is computed over the same time interval as the observations. When all three changes are made, the difference between the slope and feedback parameter is less than one-tenth of that estimated by Spencer and Braswell. Absolute values of the difference for realistic cases are less than 0.05 W m−2 K−1, which is not significant for climate studies that employ regressions of outgoing radiation against temperature. Previously published results show that the difference is negligible in the Hadley Centre Slab Climate Model, version 3 (HadSM3).
Who Chooses a Rapid Test for HIV in Los Angeles County, California?
Authors: Marsh Kimberly A. , Reynolds Grace L. , Rogala Bridget E. , Fisher Dennis G. , Napper Lucy E.
Published: June 2010

The purpose of this study was to determine who chooses a rapid test for HIV when given a choice in a community-based or mobile van setting in Long Beach, California. Individuals were given a choice of either rapid or standard HIV testing either alone or in conjunction with testing for sexually transmitted diseases (STD). Of the 2,752 HIV tests performed between March 2005 and March 2009, 917 (33%) were rapid tests. Preference for rapid HIV testing was among men who have sex with men (MSM), who reported using alcohol in the last 48 hr but who did not endorse the use of illicit drugs; individuals reporting sex trading were also more likely to choose the rapid HIV test. African Americans, regardless of sexual identification, were significantly less likely to choose an HIV rapid test. Strategies are needed to encourage HIV rapid testing among both noninjection and injection drug users, and other at-risk groups.
Tracing Trajectories of Practice: Repurposing in One Student’s Developing Disciplinary Writing Processes
Authors: Roozen Kevin
Published: June 2010

An extensive body of scholarship has documented the way disciplinary texts and activities are produced and mediated through their relationship to a wide array of extradisciplinary discourses. This article seeks to complement and extend that line of work by drawing upon Witte’s (1992) notion of intertext to address the way disciplinary activities repurpose, or reuse and transform, extradisciplinary practices. Based on text collection and practice-oriented retrospective accounts of one writer’s processes for a number of textual activities, the article argues that the writer’s developing disciplinary writing process as a graduate student in English literature is mediated by practices she repurposed from previous engagements with keeping a prayer journal as a member of a church youth group and generating visual designs for an undergraduate graphic arts class. Ultimately, the article argues for increased theoretical, methodological, and pedagogical attention to the discursive practices persons recruit and reinvigorate across multiple engagements with reading, writing, making, and doing.
Speaking of speech with the disciplines
Authors: Compton Josh
Published: June 2010

As Lecturer of Speech in the Institute for Writing and Rhetoric at Dartmouth College, I have joined an ongoing conversation about speech that spans disciplines. This article takes a step back from looking at communication across the curriculum as a program and instead looks at one of the earliest stages of the process — conversations about speech with the disciplines. Exploring our meta-communication — our speaking with the disciplines about speech — highlights some of the discoveries we have made about speech through our conversations.
Beyond the schooled form and into the discipline
Authors: Mitchell Sally
Published: June 2010

This article is an introduction to two other articles in this issue, Catherine Maxwell’s ‘Teaching 19th-century aesthetic prose’ and Kirsteen Anderson’s ‘The whole learner: the role of imagination in developing disciplinary learning’. It highlights the significance of the courses described in Maxwell’s and Anderson’s accounts by discussing how the writing tasks that they engage students in contribute to the development of disciplinary understanding, and how, whilst eschewing reliance on the conventional schooled essay, they enable students to develop writing that is essayistic. It points to the potential that reinvisaging disciplinary writing has for curriculum and assessment design.
Human fibroblasts support the expansion of IL-17–producing T cells via up-regulation of IL-23 production by dendritic cells
Authors: Schirmer Christine , Klein Claudia , von Bergen Martin , Simon Jan C. , Saalbach Anja
Published: June 2010

The initiation of immune responses is associated with the maturation of dendritic cells (DCs) and their migration to draining lymph nodes. En route activated DCs encounter cells of the tissue microenvironment, such as fibroblasts. Because we have shown that DCs interact with fibroblasts during immune responses, we studied the impact of skin fibroblasts on human monocyte-derived DC function and subsequent human T-cell (TC) differentiation. We show that fibroblasts support interleukin-23 (IL-23) secretion from DCs preactivated by lipopolysaccharide (DCact) compared with lipopolysaccharide-activated DCs alone. The underlying complex feedback-loop mechanism involves IL-1β/tumor necrosis factor-α (from DCact), which stimulate fibroblasts prostaglandin E2 production. Prostaglandin E2, in turn, acts on DCact and increases their IL-23 release. Furthermore, fibroblast-stimulated DCact are far superior to DCact alone, in promoting the expansion of Th17 cells in a Cox-2-, IL-23-dependent manner. Using CD4+CD45RO+ memory TCs and CD4+CD45RA+ naive TCs, we showed that fibroblasts induce a phenotype of DCact that promotes the expansion of Th17 cells. Moreover, in psoriasis, a prototypic immune response in which the importance of IL-23/Th17 is known, high expression of Cox-2 in fibroblasts was observed. In conclusion, skin fibroblasts are involved in regulation of IL-23 production in DCs and, as a result, of Th17 expansion.
A novel chemogenomics analysis of G protein-coupled receptors (GPCRs) and their ligands: a potential strategy for receptor de-orphanization
Authors: van der Horst Eelke , Peironcely Julio E , IJzerman Adriaan P , Beukers Margot W , Lane Jonathan R , van Vlijmen Herman WT , Emmerich Michael TM , Okuno Yasushi , Bender Andreas
Published: June 2010

Background

G protein-coupled receptors (GPCRs) represent a family of well-characterized drug targets with significant therapeutic value. Phylogenetic classifications may help to understand the characteristics of individual GPCRs and their subtypes. Previous phylogenetic classifications were all based on the sequences of receptors, adding only minor information about the ligand binding properties of the receptors. In this work, we compare a sequence-based classification of receptors to a ligand-based classification of the same group of receptors, and evaluate the potential to use sequence relatedness as a predictor for ligand interactions thus aiding the quest for ligands of orphan receptors.

Results

We present a classification of GPCRs that is purely based on their ligands, complementing sequence-based phylogenetic classifications of these receptors. Targets were hierarchically classified into phylogenetic trees, for both sequence space and ligand (substructure) space. The overall organization of the sequence-based tree and substructure-based tree was similar; in particular, the adenosine receptors cluster together as well as most peptide receptor subtypes (e.g. opioid, somatostatin) and adrenoceptor subtypes. In ligand space, the prostanoid and cannabinoid receptors are more distant from the other targets, whereas the tachykinin receptors, the oxytocin receptor, and serotonin receptors are closer to the other targets, which is indicative for ligand promiscuity. In 93% of the receptors studied, de-orphanization of a simulated orphan receptor using the ligands of related receptors performed better than random (AUC > 0.5) and for 35% of receptors de-orphanization performance was good (AUC > 0.7).

Conclusions

We constructed a phylogenetic classification of GPCRs that is solely based on the ligands of these receptors. The similarities and differences with traditional sequence-based classifications were investigated: our ligand-based classification uncovers relationships among GPCRs that are not apparent from the sequence-based classification. This will shed light on potential cross-reactivity of GPCR ligands and will aid the design of new ligands with the desired activity profiles. In addition, we linked the ligand-based classification with a ligand-focused sequence-based classification described in literature and proved the potential of this method for de-orphanization of GPCRs.
Identification of four novel small non-coding RNAs from Xanthomonas campestris pathovar campestris
Authors: Jiang Rui-Ping , Tang Dong-Jie , Chen Xiao-Lin , He Yong-Qiang , Feng Jia-Xun , Jiang Bo-Le , Lu Guang-Tao , Lin Min , Tang Ji-Liang
Published: June 2010

Background

In bacteria, small non-coding RNAs (sRNAs) have been recognized as important regulators of various cellular processes. Approximately 200 bacterial sRNAs in total have been reported. However, very few sRNAs have been identified from phytopathogenic bacteria.

Results

Xanthomons campestris pathovar campestris (Xcc) is the causal agent of black rot disease of cruciferous crops. In this study, a cDNA library was constructed from the low-molecular weight RNA isolated from the Xcc strain 8004 grown to exponential phase in the minimal medium XVM2. Seven sRNA candidates were obtained by sequencing screen of 2,500 clones from the library and four of them were confirmed to be sRNAs by Northern hybridization, which were named sRNA-Xcc 1, sRNA-Xcc 2, sRNA-Xcc 3, and sRNA-Xcc 4. The transcription start and stop sites of these sRNAs were further determined. BLAST analysis revealed that the four sRNAs are novel. Bioinformatics prediction showed that a large number of genes with various known or unknown functions in Xcc 8004 are potential targets of sRNA-Xcc 1, sRNA-Xcc 3 and sRNA-Xcc 4. In contrast, only a few genes were predicted to be potential targets of sRNA-Xcc 2.

Conclusion

We have identified four novel sRNAs from Xcc by a large-scale screen. Bioinformatics analysis suggests that they may perform various functions. This work provides the first step toward understanding the role of sRNAs in the molecular mechanisms of Xanthomonas campestris pathogenesis.
Epigallocatechin-3-gallate suppresses the expression of HSP70 and HSP90 and exhibits anti-tumor activity in vitro and in vivo
Authors: Tran Phan LCHB , Kim Soo-A , Choi Hong Seok , Yoon Jung-Hoon , Ahn Sang-Gun
Published: June 2010

Background

Epigallocatechin-3-gallate (EGCG), one of the major catechins in green tea, is a potential chemopreventive agent for various cancers. The aim of this study was to examine the effect of EGCG on the expression of heat shock proteins (HSPs) and tumor suppression.

Methods

Cell colony formation was evaluated by a soft agar assay. Transcriptional activity of HSP70 and HSP90 was determined by luciferase reporter assay. An EGCG-HSPs complex was prepared using EGCG attached to the cyanogen bromide (CNBr)-activated Sepharose 4B. In vivo effect of EGCG on tumor growth was examined in a xenograft model.

Results

Treatment with EGCG decreased cell proliferation and colony formation of MCF-7 human breast cancer cells. EGCG specifically inhibited the expression of HSP70 and HSP90 by inhibiting the promoter activity of HSP70 and HSP90. Pretreatment with EGCG increased the stress sensitivity of MCF-7 cells upon heat shock (44°C for 1 h) or oxidative stress (H2O2, 500 μM for 24 h). Moreover, treatment with EGCG (10 mg/kg) in a xenograft model resulted in delayed tumor incidence and reduced tumor size, as well as the inhibition of HSP70 and HSP90 expression.

Conclusions

Overall, these findings demonstrate that HSP70 and HSP90 are potent molecular targets of EGCG and suggest EGCG as a drug candidate for the treatment of human cancer.
Associations of ECP (eosinophil cationic protein)-gene polymorphisms to allergy, asthma, smoke habits and lung function in two Estonian and Swedish sub cohorts of the ECRHS II study
Authors: Jönsson Ulla-Britt , Håkansson Lena Douhan , Jõgi Rain , Janson Christer , Venge Per
Published: June 2010

Background

The Eosinophil Cationic Protein (ECP) is a potent multifunctional protein. Three common polymorphisms are present in the ECP gene, which determine the function and production of the protein. The aim was to study the relationship of these ECP gene polymorphisms to signs and symptoms of allergy and asthma in a community based cohort (The European Community Respiratory Health Survey (ECRHS)).

Methods

Swedish and Estonian subjects (n = 757) were selected from the larger cohort of the ECRHS II study cohort. The prevalence of the gene polymorphisms ECP434(G>C) (rs2073342), ECP562(G>C) (rs2233860) and ECP c.-38(A>C) (rs2233859) were analysed by DNA sequencing and/or real-time PCR and related to questionnaire-based information of allergy, asthma, smoking habits and to lung functions.

Results

Genotype prevalence showed both ethnic and gender differences. Close associations were found between the ECP434(G>C) and ECP562(G>C) genotypes and smoking habits, lung function and expression of allergic symptoms. Non-allergic asthma was associated with an increased prevalence of the ECP434GG genotype. The ECP c.-38(A>C) genotypes were independently associated to the subject being atopic.

Conclusion

Our results show associations of symptoms of allergy and asthma to ECP-genotypes, but also to smoking habits. ECP may be involved in impairment of lung functions in disease. Gender, ethnicity and smoking habits are major confounders in the evaluations of genetic associations to allergy and asthma.
The chemopreventive retinoid 4HPR impairs prostate cancer cell migration and invasion by interfering with FAK/AKT/GSK3β pathway and β-catenin stability
Authors: Benelli Roberto , Monteghirfo Stefano , Venè Roberta , Tosetti Francesca , Ferrari Nicoletta
Published: June 2010

Background

Prostate cancer shows an extremely slow progression, appearing in its metastatic, hormone refractory phenotype mostly in elderly men. The chemopreventive targeting of this tumor could accordingly delay its malignancy over life expectancy. The cancer chemopreventive retinoidN-(4 hydroxyphenyl)retinamide (4HPR) has already been shown to restrain prostate cancer growth in vitro and in vivo, though its mechanisms of action are only partially explained.

Results

We found that 4HPR impairs DU145 and PC3 prostate cancer cells migration and invasion by down-regulating FAK and AKT activation and by enhancing β-catenin degradation, causing the downregulation of target genes like cyclin D1, survivin and VEGF. This non-migratory phenotype was similarly produced in both cell lines by stable silencing of β-catenin. 4HPR was able to decrease AKT phosphorylation also when powerfully upregulated by IGF-1 and, consequently, to impair IGF-1-stimulated cell motility. Conversely, the expression of constitutively active AKT (myr-AKT) overcame the effects of 4HPR and β-catenin-silencing on cell migration. In addition, we found that BMP-2, a 4HPR target with antiangiogenic activity, decreased prostate cancer cell proliferation, migration and invasion by down-regulating the pathway described involving AKT phosphorylation, β-catenin stability and cyclin D1 expression.

Conclusion

These data point to 4HPR as a negative regulator of AKT phosphorylation, effectively targeting the β-catenin pathway and inducing a relatively benign phenotype in prostate cancer cells, limiting neoangiogenesis and cell invasion.
Cytokine profile of autologous conditioned serum for treatment of osteoarthritis, in vitroeffects on cartilage metabolism and intra-articular levels after injection
Authors: Rutgers Marijn , Saris Daniël BF , Dhert Wouter JA , Creemers Laura B
Published: June 2010

Introduction

Intraarticular administration of autologous conditioned serum (ACS) recently demonstrated some clinical effectiveness in treatment of osteoarthritis (OA). The current study aims to evaluate the in vitro effects of ACS on cartilage proteoglycan (PG) metabolism, its composition and the effects on synovial fluid (SF) cytokine levels following intraarticular ACS administration.

Methods

The effect of conditioned serum on PG metabolism of cultured OA cartilage explants was compared to unconditioned serum. The effect of serum conditioning on levels of interleukin-1beta (IL-1β), IL-4, IL-6, IL-10, IL-13, interferon gamma (IFN-γ), tumor necrosis factor alpha (TNF-α), osteoprotegerin (OPG), oncostatin M (OSM), interleukin-1 receptor (IL-1ra) and transforming growth factor beta (TGF-β) were measured by multiplex ELISA. As TNF-α levels were found to be increased in conditioned serum, the effect of TNF-α inhibition by etanercept on PG metabolism was studied in cartilage explants cultured in the presence of conditioned serum. Furthermore, cytokine levels in SF were measured three days after intraarticular ACS injection in OA patients to verify their retention time in the joint space.

Results

PG metabolism was not different in the presence of conditioned serum compared to unconditioned serum. Levels of the anti-inflammatory cytokines IL-1ra, TGF-β, IL-10 as well as of pro-inflammatory cytokines IL-1β, IL-6, TNF-α and OSM were increased. IL-4, IL-13 and IFN-γ levels remained similar, while OPG levels decreased. TNF-α inhibition did not influence PG metabolism in cartilage explant culture in the presence of condtioned serum. Although OPG levels were higher and TGF-β levels were clearly lower in ACS than in SF, intraarticular ACS injection in OA patients did not result in significant changes in these cytokine levels.

Conclusions

ACS for treatment of osteoarthritis contains increased levels of anti-inflammatory as well as pro-inflammatory cytokines, in particular TNF-α, but conditioned serum does not seem to have a net direct effect on cartilage metabolism, even upon inhibition of TNF-α. The fast intraarticular clearance of cytokines in the injected ACS may explain the limited effects found previously in vivo.
Technical Advance: Autofluorescence as a tool for myeloid cell analysis
Authors: Mitchell Andrew J , Pradel Lydie C , Chasson Lionel , Van Rooijen Nico , Grau Georges E , Hunt Nicholas H , Chimini Giovanna
Published: June 2010

The autofluorescence of myeloid cell populations is heterogeneous and can be used as a tool for identification and phenotyping of myeloid subsets.

Cellular AF is usually considered a hindrance to flow cytometric analysis. Here, we incorporate AF into analysis of complex mixtures of leukocytes. Using a mouse model, we examined cellular AF at multiple excitation and emission wavelengths, and populations with discrete patterns were gated and examined for surface marker expression. In the spleen, all major myeloid populations were identified. In particular, the approach allowed simultaneous characterization of RPM and resident monocytes. When monocytes and RPM were compared, RPM exhibited a phenotype that was consistent with involvement in physiological processes, including expression of genes involved in lipid and iron metabolism. The presence of large amounts of stored ferric iron within RPM enabled purification of these cells using a magnetic-based approach. When adapted for use on leukocytes isolated from a range of other organs, incorporation of AF into analysis allowed identification and isolation of biologically important myeloid populations, including subsets that were not readily identifiable by conventional cytometric analysis.
Impact of Differential P450c17 Phosphorylation by cAMP Stimulation and by Starvation Conditions on Enzyme Activities and Androgen Production in NCI-H295R Cells
Authors: Kempná Petra , Hirsch Andrea , Hofer Gaby , Mullis Primus E. , Flück Christa E.
Published: June 2010

CYP17A1 plays a pivotal role in the biosynthesis of androgens in the adrenals and the gonads. Although this enzyme catalyzes two different reactions on one single active site, its specific activities are regulated independently. Although the 17α-hydroxylase activity is rather constant and regulated by gene expression, the 17,20-lyase activity varies significantly with the amount of cofactors or by protein phosphorylation. cAMP increases CYP17A1 expression, P450c17 phosphorylation, and androgen production. However, the exact mechanism(s) and the specific regulators of CYP17A1 remain unknown. Therefore, we studied the regulation of adrenal androgen biosynthesis in human adrenal H295R cells focusing on CYP17A1. We analyzed androgen production and P450c17 activities in H295R cells grown under normal and serum-free conditions and/or after stimulation with 8-bromoadenosine-cAMP. H295R cells grown in starvation medium produced more androgens and had decreased HSD3B2 expression and activity but increased P450c17-17,20-lyase activity and serine phosphorylation. Although starvation increased serine phosphorylation of P450c17 specifically, cAMP stimulation enhanced threonine phosphorylation exclusively. Time-course experiments revealed that a short cAMP stimulation augmented threonine phosphorylation of P450c17 but did not increase 17,20-lyase activity. By contrast, long cAMP stimulation increased androgen production through increased P450c17 activities by enhancing CYP17A1 gene expression. We conclude that serum withdrawal shifts steroidogenesis of H295R cells towards androgen production, providing a suitable model for detailed studies of androgen regulation. In addition, our study shows that starvation and cAMP stimulation regulate P450c17 phosphorylation differentially and that an increase in P450c17 phosphorylation does not necessarily lead to enhanced enzyme activity and androgen production.
EGR1 Is a Target for Cooperative Interactions between Cholecystokinin and Leptin, and Inhibition by Ghrelin, in Vagal Afferent Neurons
Authors: de Lartigue Guillaume , Lur Gyorgy , Dimaline Rod , Varro Andrea , Raybould Helen , Dockray Graham J.
Published: June 2010

Food intake is regulated by signals from peripheral organs, but the way these are integrated remains uncertain. Cholecystokinin (CCK) from the intestine and leptin from adipocytes interact to inhibit food intake. Our aim was to examine the hypothesis that these interactions occur at the level of vagal afferent neurons via control of the immediate early gene EGR1. We now report that CCK stimulates redistribution to the nucleus of early growth response factor-1 (EGR1) in these neurons in vivo and in culture, and these effects are not dependent on EGR1 synthesis. Leptin stimulates EGR1 expression; leptin alone does not stimulate nuclear translocation, but it strongly potentiates the action of CCK. Ghrelin inhibits CCK-stimulated nuclear translocation of EGR1 and leptin-stimulated EGR1 expression. Expression of the gene encoding the satiety peptide cocaine- and amphetamine-regulated transcript (CARTp) is stimulated by CCK via an EGR1-dependent mechanism, and this is strongly potentiated by leptin. Leptin potentiated inhibition of food intake by endogenous CCK in the rat in conditions reflecting changes in EGR1 activation. The data indicate that by separately regulating EGR1 activation and synthesis, CCK and leptin interact cooperatively to define the capacity for satiety signaling by vagal afferent neurons; manipulation of these interactions may be therapeutically beneficial.
3β-Hydroxysteroid Dehydrogenase Is a Possible Pharmacological Target in the Treatment of Castration-Resistant Prostate Cancer
Authors: Evaul Kristen , Li Rui , Papari-Zareei Mahboubeh , Auchus Richard J. , Sharifi Nima
Published: June 2010

Prostate cancer usually responds to androgen deprivation therapy, although the response in metastatic disease is almost always transient and tumors eventually progress as castration-resistant prostate cancer (CRPC). CRPC continues to be driven by testosterone or dihydrotestosterone from intratumoral metabolism of 19-carbon adrenal steroids from circulation, and/or de novo intratumoral steroidogenesis. Both mechanisms require 3β-hydroxysteroid dehydrogenase (3βHSD) metabolism of Δ5-steroids, including dehydroepiandrosterone (DHEA) and Δ5-androstenediol (A5diol), to testosterone. In contrast, reports that DHEA and A5diol directly activate the androgen receptor (AR) suggest that 3βHSD metabolism is not required and that 3βHSD inhibitors would be ineffective in the treatment of CRPC. We hypothesized that activation of AR in prostate cancer by DHEA and A5diol requires their conversion via 3βHSD to androstenedione and testosterone, respectively. Here, we show that DHEA and A5diol induce AR chromatin occupancy and AR-regulated genes. Furthermore, we show that Δ5-androgens undergo 3β-dehydrogenation in prostate cancer and that induction of AR nuclear translocation, AR chromatin occupancy, transcription of PSA, TMPRSS2, and FKBP5, as well as cell proliferation by DHEA and A5diol, are all blocked by inhibitors of 3βHSD. These findings demonstrate that DHEA and A5diol must be metabolized by 3βHSD to activate AR in these models of CRPC. Furthermore, this work suggests that 3βHSD may be exploited as a pharmacologic target in the treatment of CRPC.
Connective Tissue Growth Factor Is Required for Skeletal Development and Postnatal Skeletal Homeostasis in Male Mice
Authors: Canalis Ernesto , Zanotti Stefano , Beamer Wesley G. , Economides Aris N. , Smerdel-Ramoya Anna
Published: June 2010

Connective tissue growth factor (CTGF), a member of the cysteine-rich 61 (Cyr 61), CTGF, nephroblastoma overexpressed (NOV) (CCN) family of proteins, is synthesized by osteoblasts, and its overexpression inhibits osteoblastogenesis and causes osteopenia. The global inactivation of Ctgf leads to defective endochondral bone formation and perinatal lethality; therefore, the consequences of Ctgf inactivation on the postnatal skeleton are not known. To study the function of CTGF, we generated Ctgf+/LacZ heterozygous null mice and tissue-specific null Ctgf mice by mating Ctgf conditional mice, where Ctgf is flanked by lox sequences with mice expressing the Cre recombinase under the control of the paired-related homeobox gene 1 (Prx1) enhancer (Prx1-Cre) or the osteocalcin promoter (Oc-Cre). Ctgf+/LacZ heterozygous mice exhibited transient osteopenia at 1 month of age secondary to decreased trabecular number. A similar osteopenic phenotype was observed in 1-month-old Ctgf conditional null male mice generated with Prx1-Cre, suggesting that the decreased trabecular number was secondary to impaired endochondral bone formation. In contrast, when the conditional deletion of Ctgf was achieved by Oc-Cre, an osteopenic phenotype was observed only in 6-month-old male mice. Osteoblast and osteoclast number, bone formation, and eroded surface were not affected in Ctgf heterozygous or conditional null mice. In conclusion, CTGF is necessary for normal skeletal development but to a lesser extent for postnatal skeletal homeostasis.
Amphiregulin Promotes Intestinal Epithelial Regeneration: Roles of Intestinal Subepithelial Myofibroblasts
Authors: Shao Jinyi , Sheng Hongmiao
Published: June 2010

Epidermal growth factor family plays critical roles in intestinal epithelial proliferation and differentiation. The precise function of amphiregulin (AREG), a member of the epidermal growth factor family, in intestinal biology is largely unknown. The present study attempted to address the functional roles of AREG in intestinal epithelial regeneration. Total body irradiation was performed, and intestinal regeneration was assessed in AREG knockout mice. Genetically disruption of AREG significantly impaired intestinal regeneration after radiation injury. It is known that prostaglandin E2 (PGE2) exerts radio-protective and growth-stimulatory effects on intestinal epithelium. We found that PGE2 radio-protective action did not involve AREG. However, PGE2 growth-stimulatory effects required functional AREG. Localization of AREG expression was determined by immunohistochemistry in regenerative intestine. The immunoreactivity of AREG was predominantly localized in intestinal subepithelial myofibroblasts (ISEMF). Primary ISEMF cultures were established, and growth-stimulatory actions of ISEMF-generated AREG were demonstrated in cell coculture system. In addition, we found that the cAMP/protein kinase A pathway robustly induced AREG in cultured ISEMF. These studies suggest that AREG plays critical roles in intestinal epithelial growth. Modulation of levels of AREG by targeting ISEMF represents a novel strategy for treatment of certain intestinal disorders.
A Large Study of Androgen Receptor Germline Variants and Their Relation to Sex Hormone Levels and Prostate Cancer Risk. Results from the National Cancer Institute Breast and Prostate Cancer Cohort Consortium
Authors: Lindström Sara , Ma Jing , Altshuler David , Giovannucci Edward , Riboli Elio , Albanes Demetrius , Allen Naomi E. , Berndt Sonja I. , Boeing Heiner , Bueno-de-Mesquita H. Bas , Chanock Stephen J. , Dunning Alison M. , Feigelson Heather Spencer , Gaziano J. Michael , Haiman Christopher A. , Hayes Richard B. , Henderson Brian E. , Hunter David J. , Kaaks Rudolf , Kolonel Laurence N. , Le Marchand Loic , Martínez Carmen , Overvad Kim , Siddiq Afshan , Stampfer Meir , Stattin Pär , Stram Daniel O. , Thun Michael J. , Trichopoulos Dimitrios , Tumino Rosario , Virtamo Jarmo , Weinstein Stephanie J. , Yeager Meredith , Kraft Peter , Freedman Matthew L.
Published: June 2010

Background: Androgens are key regulators of prostate gland maintenance and prostate cancer growth, and androgen deprivation therapy has been the mainstay of treatment for advanced prostate cancer for many years. A long-standing hypothesis has been that inherited variation in the androgen receptor (AR) gene plays a role in prostate cancer initiation. However, studies to date have been inconclusive and often suffered from small sample sizes.

Objective and Methods: We investigated the association of AR sequence variants with circulating sex hormone levels and prostate cancer risk in 6058 prostate cancer cases and 6725 controls of Caucasian origin within the Breast and Prostate Cancer Cohort Consortium. We genotyped a highly polymorphic CAG microsatellite in exon 1 and six haplotype tagging single nucleotide polymorphisms and tested each genetic variant for association with prostate cancer risk and with sex steroid levels.

Results: We observed no association between AR genetic variants and prostate cancer risk. However, there was a strong association between longer CAG repeats and higher levels of testosterone (P = 4.73 × 10−5) and estradiol (P = 0.0002), although the amount of variance explained was small (0.4 and 0.7%, respectively).

Conclusions: This study is the largest to date investigating AR sequence variants, sex steroid levels, and prostate cancer risk. Although we observed no association between AR sequence variants and prostate cancer risk, our results support earlier findings of a relation between the number of CAG repeats and circulating levels of testosterone and estradiol.
A novel function for the Rab5 effector Rabenosyn-5 in planar cell polarity
Authors: Mottola Giovanna , Classen Anne-Kathrin , González-Gaitán Marcos , Eaton Suzanne , Zerial Marino
Published: June 2010

In addition to apicobasal polarization, some epithelia also display polarity within the plane of the epithelium. To what extent polarized endocytosis plays a role in the establishment and maintenance of planar cell polarity (PCP) is at present unclear. Here, we investigated the role of Rabenosyn-5 (Rbsn-5), an evolutionarily conserved effector of the small GTPase Rab5, in the development of Drosophila wing epithelium. We found that Rbsn-5 regulates endocytosis at the apical side of the wing epithelium and, surprisingly, further uncovered a novel function of this protein in PCP. At early stages of pupal wing development, the PCP protein Fmi redistributes between the cortex and Rab5- and Rbsn-5-positive early endosomes. During planar polarization, Rbsn-5 is recruited at the apical cell boundaries and redistributes along the proximodistal axis in an Fmi-dependent manner. At pre-hair formation, Rbsn-5 accumulates at the bottom of emerging hairs. Loss of Rbsn-5 causes intracellular accumulation of Fmi and typical PCP alterations such as defects in cell packing, in the polarized distribution of PCP proteins, and in hair orientation and formation. Our results suggest that establishment of planar polarity requires the activity of Rbsn-5 in regulating both the endocytic trafficking of Fmi at the apical cell boundaries and hair morphology.
N-cadherin can structurally substitute for E-cadherin during intestinal development but leads to polyp formation
Authors: Libusova Lenka , Stemmler Marc P. , Hierholzer Andreas , Schwarz Heinz , Kemler Rolf
Published: June 2010

We conditionally substituted E-cadherin (E-cad; cadherin 1) with N-cadherin (N-cad; cadherin 2) during intestine development by generating mice in which an Ncad cDNA was knocked into the Ecad locus. Mutant mice were born, demonstrating that N-cad can structurally replace E-cad and establish proper organ architecture. After birth, mutant mice gradually developed a mutant phenotype in both the small and large intestine and died at ~2-3 weeks of age, probably due to malnutrition during the transition to solid food. Molecular analysis revealed an extended domain of cells from the crypt into the villus region, with nuclear localization of β-catenin (β-cat; Ctnnb1) and enhanced expression of several β-cat target genes. In addition, the BMP signaling pathway was suppressed in the intestinal epithelium of the villi, suggesting that N-cad might interfere with BMP signaling in the intestinal epithelial cell layer. Interestingly, mutant mice developed severe dysplasia and clusters of cells with neoplastic features scattered along the crypt-villus axis in the small and large intestine. Our experimental model indicates that, in the absence of E-cad, the sole expression of N-cad in an epithelial environment is sufficient to induce neoplastic transformations.
Will Aging Baby Boomers Bust the Federal Budget?
Authors: Lee Ronald , Skinner Jonathan
Published: June 2010

The authors analyze in three steps the influence of the projected mortality decline on the long-run finances of the Social Security System. First, mortality decline adds person years of life which are distributed across the life cycle. The interaction of this distribution with the age distribution of taxes minus benefits determines the steady state financial consequences of mortality decline. Second, examination of past mortality trends in the United State and of international trends in low mortality populations, suggests that mortality will decline much faster than foreseen by the SSA's forecasts. Third, based on work on stochastic demographic forecasting, stochastic forecasts of the system's actuarial balance are derived, indicating a broader range of demographic uncertainty than in the latest SSA forecasts, and a relatively greater contribution to uncertainty from fertility than mortality.
The Community College: Educating Students at the Margin Between College and Work
Authors: Kane Thomas J , Rouse Cecilia Elena
Published: June 2010

The authors provide background on the history and development of community colleges in the United States in the last half century and survey available evidence on the impacts of community colleges on educational attainment and earnings. They also weigh the evidence on the impact of public subsidies on enrollment at community colleges and explore some weaknesses in the current higher-education financing structure. Finally, the authors reflect on how students who have been responding to the rise in payoff to education are to be absorbed by our postsecondary training institutions.
Going for the Gold: Economists as Expert Witnesses
Authors: Mandel Michael J
Published: June 2010

The use of economists as expert witnesses and consultants has grown dramatically in recent years, driven by such factors as the explosion of mergers and acquisitions. On the plus side, the expert witness boom will likely lead to better regulatory and legal decisions, while infusing real-world examples into classroom teaching. Yet the growing importance of consulting income could divert time and energy away from academic research and teaching, while impeding intellectual debate. A new standard of behavior for academic economists who serve as expert witnesses and consultants may be needed, including full disclosure of clients.
Healthy Bodies and Thick Wallets: The Dual Relation Between Health and Economic Status
Authors: Smith James P
Published: June 2010

This paper sketches theoretical reasons why health may alter household savings and provides evidence on the empirical impact of health shocks on household wealth. The impacts on saving are quantitatively large and only partly explained by increased out-of-pocket medical expenses. Other contributing factors include reduced earnings and a revision in life expectancy. The author also delves into reasons why economic status, access to medical care, and deleterious personal behaviors have been rejected as insufficient explanations. New theories emphasize long-term impacts of early childhood or even intrauterine factors, cumulative effects of prolonged exposures to stress, or reactions of macrosocietal factors like rising levels of income inequality.
From the Editors…
Authors: Keller L. Robin , Kophazi Kelly M.
Published: June 2010

We review the past year in this issue's “From the Editors” column, which is coauthored with Managing Editor Kelly M. Kophazi. In our first article, Jason R. W. Merrick and Laura A. McLay ask “Is Screening Cargo Containers for Smuggled Nuclear Threats Worthwhile?” Next, Robert A. Dees, Matthew F. Dabkowski, and Gregory S. Parnell present a “Decision-Focused Transformation of Additive Value Models to Improve Communication.” Our third article, “Valuing Multifactor Real Options Using an Implied Binomial Tree,” is by Tianyang Wang and James S. Dyer. The next article, by the late Samuel Kotz (deceased March 2010) and Johan René van Dorp, is on “Generalized Diagonal Band Copulas with Two-Sided Generating Densities.” In our final article, Ali E. Abbas and János Aczél discuss “The Role of Some Functional Equations in Decision Analysis.”
Who Wants To Be A Millionaire®: The Classroom Edition
Authors: Cochran James J.
Published: June 2010

This paper introduces a version of the internationally popular television game show Who Wants To Be A Millionaire® that has been created for use in the classroom using Microsoft PowerPoint®. A suggested framework for its classroom use is presented, instructions on operating and editing the classroom version of Who Wants To Be A Millionaire® are provided, and sample feedback from students who have played the classroom version of Who Wants To Be A Millionaire® is offered.
Teaching Computational Discrete Optimization at the Undergraduate Level
Authors: Alpers Andreas , Trotter Leslie E.
Published: June 2010

We describe a new course on computational discrete optimization that the authors designed and taught at Cornell University. Conceptually new, this course is targeted toward senior-level undergraduate students and not, as is usually the case, toward advanced graduate students. We discuss how recent availability of high quality free software facilitated this undertaking. We hope the ideas and supporting teaching materials in this paper will find further application. Computational implementation and experimentation is an intriguing and challenging approach that can be used extensively in teaching students important skills for solving real-world discrete optimization problems.
Building a Better Game through Dynamic Programming: A Flip Analysis
Authors: Trick Michael A.
Published: June 2010

Flip is a solitaire board game produced by craft woodworkers. We analyze Flip and suggest modifications to the rules to make the game more marketable. In addition to being an interesting application of dynamic programming, this case shows the use of operations research in managerial decision making.
Social Contagion and Information Technology Diffusion: The Adoption of Electronic Medical Records in U.S. Hospitals
Authors: Angst Corey M. , Agarwal Ritu , Sambamurthy V. , Kelley Ken
Published: June 2010

We use a social contagion lens to study the dynamic, temporal process of the diffusion of electronic medical records in the population of U.S. hospitals. Social contagion acknowledges the mutual influence among organizations within an institutional field and implicates information transmission through direct contact and observation as the mechanisms underlying influence transfer. We propose hypotheses predicting a hospital's likelihood of adopting electronic medical records as a function of its susceptibility to the influence of prior adopters, the infectiousness or potency of influence exerted by adopting hospitals, and its social and spatial proximity to prior adopters. Results obtained by fitting a heterogeneous diffusion model to data from a sample drawn from an annual survey, spanning 1975 to 2005, of almost 4,000 U.S. hospitals suggest that diffusion can be accelerated if specific attention is given to increasing social contagion effects. In particular, with respect to susceptibility to influence, greater hospital size and age are positively related to the likelihood of adoption for nonadopters, whereas younger hospitals are associated with greater infectiousness for adopters. A hospital's “celebrity” status also contributes to its infectiousness. We further find strong effects for social proximity and significant regional effects for spatial proximity and hospital size, suggesting that geographical covariates should be included in diffusion studies. Results also reinforce the importance of theorizing about and including interactions in examinations of social contagion.
Nancy K. Stalker, Prophet Motive: Deguchi Onisaburo, Oomoto, and the Rise of New Religions in Imperial Japan.
Authors: Cusack Carole M.
Published: June 2010

Nancy K. Stalker, Prophet Motive: Deguchi Onisaburo, Oomoto, and the Rise of New Religions in Imperial Japan. University of Hawai’i Press, Honolulu, 2008, pp. x + 265, ISBN 978-0-8248-3172-1 (hardback).