bluuebunny/crossref_metadata_2025 huggingface dataset:
STAT5 signaling is required for the efficient induction and maintenance of CML in mice
Authors: Ye Dan , Wolff Nicholas , Li Li , Zhang Shumin , Ilaria Robert L.
Published: March 2006

The role of signal transducers and activators of transcription 5 (STAT5) in chronic myelogenous leukemia (CML) is controversial. To clarify the role of STAT5 signaling in P210BCR/ABL leukemogenesis, P210 was introduced into primary murine STAT5A-deficient (STAT5A–/–) bone marrow (BM) cells, which, unlike STAT5A/5B double knockout BM cells, have no major intrinsic hematopoietic defects. Interestingly, only 21% of mice reconstituted with P210-transduced STAT5A–/– BM cells developed classic CML, compared with 80% to 100% of P210/STAT5A+/+ and P210/STAT5A+/–-reconstituted animals. The remainder of P210/STAT5A–/– animals died from an acute B-cell lymphoblastic leukemia (ALL)–like disease (32%) or a CML/ALL mix (47%), reflecting impairment in the induction and maintenance of CML, which normally predominates in this mouse model. Of mice that ultimately developed CML, P210/STAT5A–/– animals had prolonged survival and increased myeloid immaturity. Importantly, reconstitution of wild-type mice with BM cells coexpressing P210 and dominant-negative STAT5 also profoundly reduced the incidence of CML, without impairing the induction of ALL. Altogether, these findings indicate that STAT5 and STAT5A play an important role in the pathogenesis of the CML-like disease in mice. A greater understanding of the STAT5 target genes involved in CML induction may lead to new therapeutic targets that influence CML progenitor cell biology.
Pretreatment cytogenetics add to other prognostic factors predicting complete remission and long-term outcome in patients 60 years of age or older with acute myeloid leukemia: results from Cancer and Leukemia Group B 8461
Authors: Farag Sherif S. , Archer Kellie J. , Mrózek Krzysztof , Ruppert Amy S. , Carroll Andrew J. , Vardiman James W. , Pettenati Mark J. , Baer Maria R. , Qumsiyeh Mazin B. , Koduru Prasad R. , Ning Yi , Mayer Robert J. , Stone Richard M. , Larson Richard A. , Bloomfield Clara D.
Published: March 2006

We investigated the relative prognostic significance of cytogenetics in 635 adult acute myeloid leukemia (AML) patients 60 years of age or older treated on front-line protocols. Classification trees and tree-structured survival analysis (TSSA) were used to identify important cytogenetic groups, and their prognostic significance was then assessed in multivariable analysis (MVA). Overall, 48.5% achieved complete remission (CR); 6.6% survived at 5 years. Complex karyotypes with at least 3 abnormalities (complex ≥ 3) and a group including “rare aberrations” predicted lower CR rates (25% and 30%) versus other patients (56%). Compared with complex ≥ 3, the odds of CR were significantly higher for noncomplex karyotypes without rare aberrations on MVA. Cytogenetically, complex ≥ 5 predicted inferior disease-free survival on TSSA, remaining significant on MVA together with white blood cell count (WBC), sex, and age. For survival, complex ≥ 5, rare aberrations, and core-binding factor (CBF) abnormalities were prognostic (P < .001), with 5-year survivals of 0%, 0%, and 19.4%, respectively, and 7.5% for remaining patients. Together with WBC, marrow blasts, sex, and age, the cytogenetic groups remained significant on MVA. In conclusion, pretreatment cytogenetics adds to other prognostic factors in older AML patients. Patients with complex ≥ 5 appear to benefit minimally from current treatment and are better suited for investigational therapy or supportive care. (Blood. 2006;108:63-73)
Oral chelators deferasirox and deferiprone for transfusional iron overload in thalassemia major: new data, new questions
Authors: Neufeld Ellis J.
Published: March 2006

For nearly 30 years, patients with transfusional iron overload have depended on nightly deferoxamine infusions for iron chelation. Despite dramatic gains in life expectancy in the deferoxamine era for patients with transfusion-dependent anemias, the leading cause of death for young adults with thalassemia major and related disorders has been cardiac disease from myocardial iron deposition. Strategies to reduce cardiac disease by improving chelation regimens have been of the highest priority. These strategies have included development of novel oral iron chelators to improve compliance, improved assessment of cardiac iron status, and careful epidemiologic assessment of European outcomes with deferiprone, an oral alternative chelator available for about a decade. Each of these strategies is now bearing fruit. The novel oral chelator deferasirox was recently approved by the Food and Drug Administration (FDA); a randomized clinical trial demonstrates that deferasirox at 20 to 30 mg/kg/d can maintain or improve hepatic iron in thalassemia as well as deferoxamine. A randomized trial based on cardiac T2* magnetic resonance imaging (MRI) suggests that deferiprone can unload myocardial iron faster than deferoxamine. Retrospective epidemiologic data suggest dramatic reductions in cardiac events and mortality in Italian subjects exposed to deferiprone compared with deferoxamine. These developments herald a new era for iron chelation, but many unanswered questions remain.
Molecular characterization of the murine homologue of the DC-derived protein DC-SCRIPT
Authors: Triantis Vassilis , Moulin Veronique , Looman Maaike W G , Hartgers Franca C , Janssen Richard A J , Adema Gosse J
Published: March 2006

Dendritic cell-specific transcript (DC-SCRIPT) is a putative DC zinc (Zn) finger-type transcription factor described recently in humans. Here, we illustrate that DC-SCRIPT is highly conserved in evolution and report the initial characterization of the murine ortholog of DC-SCRIPT, which is also preferentially expressed in DC as shown by real-time quantitative polymerase chain reaction, and its distribution resembles that of its human counterpart. Studies undertaken in human embryonic kidney 293 cells depict its nuclear localization and reveal that the Zn finger domain of the protein is mainly responsible for nuclear import. The human and the mouse genes are located in syntenic chromosomal regions and exhibit a similar genomic organization with numerous common transcription factor-binding sites in their promoter region, including sites for many factors implicated in haematopoiesis and DC biology, such as Gfi, GATA-1, Spi-B, and c-Rel. Taken together, these data show that DC-SCRIPT is well-conserved in evolution and that the mouse homologue is more than 80% homologous to the human protein. Therefore, mouse models can be used to elucidate the function of this novel DC marker.
Improved Effective Damping Equation for Equivalent Linear Analysis of Seismic-Isolated Bridges
Authors: Dicleli Murat , Buddaram Srikanth
Published: March 2006

In this study, an improved effective damping (ED) equation is proposed to obtain more reasonable estimates of the actual nonlinear response of seismic-isolated bridges (SIB) using equivalent linear (EL) analysis procedure. For this purpose, first the EL analysis results using AASHTO's ED equation is evaluated using harmonic and seismic ground motions. The effect of several parameters such as substructure stiffness, isolator properties, and the intensity and frequency characteristics of the ground motion are considered in the evaluation. Next, the effect of the superstructure mass on the ED ratio is studied. It is found that the accuracy of the EL analysis results is affected by the frequency characteristics and intensity of the ground motion. It is also demonstrated that AASHTO's ED equation should incorporate the effective period of the SIB and isolator properties for a more accurate estimation of the seismic response quantities. A new ED equation that includes such parameters is formulated and found to improve the accuracy of the EL analysis.
Seismic Risk and Design Loads
Authors: Malhotra Praveen K.
Published: March 2006

The 2003 International Building Code seismic design procedures do not result in uniform risk throughout the country. A comparison is made between the expected lifetime damage to two identical buildings—one in the western United States and other in the central United States. The seismic design accelerations are the same for these buildings, but the expected lifetime damage is very different. The causes of this difference are discussed in the paper.
Seismic Design Method for Reliability-Based Rehabilitation of Buildings
Authors: Montiel Marco A. , Ruiz Sonia E.
Published: March 2006

A reliability-based design method for the rehabilitation of buildings with energy-dissipating devices is proposed. The design method is formulated within the demand and capacity factor design (DCFD) format. The proposed approach is based on verifying that the confidence levels (associated with the serviceability and the ultimate limit states) corresponding to the rehabilitated structure are equal to or larger than the confidence levels associated with a similar conventional structure that is designed in accordance with a reference seismic design code. The method is illustrated with a five-story building rehabilitated with steel TADAS energy-dissipating plates.
Response Spectra for Multicomponent Structural Analysis
Authors: López Oscar A. , Hernández Julio J. , Bonilla Ricardo , Fernández Aura
Published: March 2006

This paper aims to investigate the response spectra characteristics of the principal components of seismic motion, which are required for accurate multicomponent structural analysis. Mean spectra were determined for the three principal uncorrelated acceleration components for an ensemble of 97 earthquake records. The average inclination of the quasi-vertical component from the vertical axis is found to be 11.4°, with a standard deviation of 9.9°. The ratio of the minor and the major quasi-horizontal spectra varies between 0.63 and 0.81, which are lower than the value of 1 commonly used in design codes. Greater differences are found for near-fault motions in the intermediate-period range. The ratio of the quasi-vertical and the major quasi-horizontal spectra varies between 0.34 and 0.69 for far-fault and between 0.3 and 1.33 for near-fault motions, depending on vibration period. Smoothed spectra of the three principal components that can be used in modern multicomponent structural analysis methods are presented.
Updating GIS Building Inventory Data Using High-Resolution Satellite Images for Earthquake Damage Assessment: Application to Metro Manila, Philippines
Authors: Miura Hiroyuki , Midorikawa Saburoh
Published: March 2006

In order to conduct earthquake damage assessment, a methodology for updating GIS building inventory data in Metro Manila, Philippines, using remote sensing data is proposed. The locations of newly constructed mid- and high-rise buildings are detected from high-resolution satellite images using the image analysis technique, while the number of low-rise buildings is estimated from the built-up areas on a land cover classification map. The building inventory data is updated by incorporating the data on the newly constructed buildings into the existing data. The number of buildings in the updated inventory data shows good agreement with the results of the manual interpretation and a recent survey. A building damage assessment for a scenario earthquake is conducted using the updated inventory data.
A Probabilistic Seismic Hazard Analysis of Northeast India
Authors: Das Sandip , Gupta Ishwer D. , Gupta Vinay K.
Published: March 2006

Seismic hazard maps have been prepared for Northeast India based on the uniform hazard response spectra for absolute acceleration at stiff sites. An approach that is free from regionalizing the seismotectonic sources has been proposed for performing the hazard analysis. Also, a new attenuation model for pseudo-spectral velocity scaling has been developed by using 261 recorded accelerograms in Northeast India. In the present study, the entire area of Northeast India has been divided into 0.1° grid size, and the hazard level has been assessed for each node of this grid by considering the seismicity within a 300-km radius around the node. Using the past earthquake data, the seismicity for the area around each node has been evaluated by defining a and b values of the Gutenberg-Richter recurrence relationship, while accounting for the incompleteness of the earthquake catalogue. To consider the spatial distribution of seismicity around each node, a spatially smoothed probability distribution function of the observed epicentral distances has been used. Uniform hazard contours for pseudo-spectral acceleration as the hazard parameter have been obtained for an exposure time of 100 years and for 50% confidence level at different natural periods for both horizontal and vertical components of ground motion. The trends reflected by these contours are broadly consistent with the major seismotectonic features in the region.
Architectural Glass Panels with Rounded Corners to Mitigate Earthquake Damage
Authors: Memari Ali M. , Kremer Paul A. , Behr Richard A.
Published: March 2006

The concept of employing architectural glass panels with modified corner geometries and edge finish conditions to improve their resistance to earthquake damage has been developed recently. To accomplish this, material is removed at glass panel corners (e.g., by rounding the glass corners) and glass edges are finished in the modified corner regions to minimize protrusions and edge surface roughness. The concept is applicable to a wide variety of architectural glass types and glazing frame types. Full-scale dynamic racking tests have shown that corner radius and glass edge finish conditions near the reshaped corner regions have significant influences on glass cracking and glass fallout drift resistances of monolithic architectural glass panels used in curtain walls.
Development of Seismic Force Reduction and Displacement Amplification Factors for Autoclaved Aerated Concrete Structures
Authors: Varela Jorge L. , Tanner Jennifer E. , Klingner Richard E.
Published: March 2006

This paper addresses the development and application of a rational procedure to select the seismic force reduction factor ( R) and the displacement amplification factor ( Cd) for the design of autoclaved aerated concrete (AAC) structures. The values of R and Cd are proposed based on a combination of laboratory test results and numerical simulation. The test results are obtained from 14 AAC shear-wall specimens tested under simulated gravity and quasi-static reversed cyclic lateral loads. Analytical responses are predicted using nonlinear analysis models whose hysteretic characteristics are based on the experimentally observed responses. Using an iterative procedure, typical AAC structures are designed using successively larger trial values of the factor, R, until the structure's response (either ductility or drift) exceeds the experimentally determined capacity. A lower fractile of those critical values, modified for probable structural overstrength, is taken as a reasonable value of 3 for R. Using an analogous procedure, a reasonable value of Cd is determined as 3. These values will undoubtedly be refined based on field experience, just as they have been for other structural systems.
Role and Relevance of Neurocognitive Assessment in Clinical Trials of Patients With CNS Tumors
Authors: Meyers Christina A. , Brown Paul D.
Published: March 2006

The inclusion of neurocognitive end points in clinical trials of patients with CNS tumors is increasing. Neurocognitive end points are used to understand what cognitive problems exist before treatment to establish a baseline by which the effect of treatment is judged, and to determine whether different treatment regimens improve neurocognitive function due to better tumor control, slow expected neurocognitive deterioration due to the tumor, or have more or less short- and long-term neurotoxicity. However, the use of neurocognitive end points in clinical trials for patients with CNS tumors is in its infancy, so that long-term outcomes are difficult to predict and the ability to determine the effects of different agents and treatment approaches is scant. Including this aspect of patient evaluation in addition to survival and time to tumor progression will yield better risk-versus-benefit assessments as well as provide a basis for improving interventions.
Whole-Brain Radiotherapy in the Management of Brain Metastasis
Authors: Khuntia Deepak , Brown Paul , Li Jing , Mehta Minesh P.
Published: March 2006

Brain metastases are an important cause of morbidity and mortality, afflicting nearly 170,000 Americans annually. The prognosis for these patients is poor, with median survival times measured in months. In this review article, we present the standard treatment approach of whole-brain radiotherapy and discuss new directions, including the role of chemical modifiers and the management and prevention of neurocognitive deficits.
Resectable Brain Metastases
Authors: Vogelbaum Michael A. , Suh John H.
Published: March 2006

Brain metastases are the most common brain tumors seen in clinical practice, comprising well over half of all brain tumors. For many years, surgical resection of brain metastases was considered a form of palliative therapy only, but more recently it has been shown to have a more important role in extending survival in appropriately selected patients. Newer surgical techniques have helped to reduce the morbidity associated with tumor resection. Although randomized studies have demonstrated the need for postoperative whole-brain radiotherapy, there remains interest in the use of other surgical adjuncts to delay or eliminate the need for fractionated radiotherapy. The use of various treatment modalities, particularly image-guided surgery and stereotactic radiosurgery, allows clinicians who are focused on the treatment of brain metastases to achieve superior levels of tumor control within the brain. As a result, overall survival is much more dependent on the status of the patient's systemic disease.
Advances Toward an Understanding of Brainstem Gliomas
Authors: Donaldson Sarah S. , Laningham Fred , Fisher Paul Graham
Published: March 2006

The diagnosis of brainstem glioma was long considered a single entity. However, since the advent of magnetic resonance imaging in the late 1980s, neoplasms within this anatomic region are now recognized to include several tumors of varying behavior and natural history. More recent reports of brainstem tumors include diverse sites such as the cervicomedullary junction, pons, midbrain, or the tectum. Today, these tumors are broadly categorized as either diffuse intrinsic gliomas, most often in the pons, or the nondiffuse brainstem tumors originating at the tectum, focally in the midbrain, dorsal and exophytic to the brainstem, or within the cervicomedullary junction. Although we briefly discuss the nondiffuse tumors, we focus specifically on those diffuse brainstem tumors that regrettably still carry a bleak prognosis.
Estimated Risk for Developing Autoimmune Addison’s Disease in Patients with Adrenal Cortex Autoantibodies
Authors: Coco Graziella , Dal Pra Chiara , Presotto Fabio , Albergoni Maria Paola , Canova Cristina , Pedini Beniamino , Zanchetta Renato , Chen Shu , Furmaniak Jadwiga , Rees Smith Bernard , Mantero Franco , Betterle Corrado
Published: March 2006

Context: Patients with adrenal cortex autoantibodies (ACA) without overt autoimmune Addison’s disease (AAD) are at risk of adrenal failure.

Design: To assess the contribution of different clinical, immunological, genetic, and functional factors in the progression to AAD, we followed up 100 ACA-positive and 63 ACA-negative patients without AAD for a maximum of 21 yr (mean 6.0 yr, median 4.8). ACA were measured by immunofluorescence and 21-OH autoantibodies (Abs) by RIA. Adrenal function was assessed by measuring basal levels of cortisol, aldosterone, ACTH, renin activity, and cortisol response to ACTH. The risk of developing AAD was calculated using survival and multivariate analyses.

Results: AAD developed in 31 ACA-positive patients and one ACA-negative patient. The cumulative risk of disease in ACA-positive patients was 48.5% [95% confidence interval (CI) 40.8–56.1]. The cumulative risk was higher in children than adults (100 vs. 31.9%; P < 0.0001), males than females (68.6 vs. 42.7%; P = 0.006), patients with subclinical rather than normal adrenal function at entry (87.4 vs. 30.1%; P < 0.0001), patients with hypoparathyroidism and/or candidiasis than patients with other autoimmune or nonautoimmune diseases (100 vs. 29.7%; P < 0.0001), and patients with high rather than low-medium ACA titers (62.8 vs. 41.2%; P = 0.12). The presence of human leukocyte antigen (HLA)-DRB1 did not appear to contribute to the prediction of AAD. Adjusted hazard ratios by Cox model for the development of AAD were 3.37 for males (CI 1.38–8.24), 5.23 for hypoparathyroidism and/or candidiasis (CI 1.53–17.92), 3.33 for high antibody titers (CI 1.43–7.78), and 6.15 for impaired adrenal function at entry (CI 2.79–13.57).

Conclusions: These results were used to construct a risk algorithm for estimating the probability of developing AAD from the combination of gender, age, adrenal function, antibody titer, and associated autoimmune disorders at entry. The values of estimated risk could be used to decide appropriate follow-up intervals and future immunointervention strategies.
Effects of Obesity, Body Composition, and Adiponectin on Carotid Intima-Media Thickness in Healthy Women
Authors: Lo Janet , Dolan Sara E. , Kanter Jenna R. , Hemphill Linda C. , Connelly Jean M. , Lees Robert S. , Grinspoon Steven K.
Published: March 2006

Context: Increased common carotid intima-media thickness (IMT) is predictive of coronary artery disease and stroke.

Objective: In this study, we investigated common carotid IMT by obesity category in a cohort of healthy women without previously known cardiovascular disease.

Design, Setting, Participants, and Main Outcome Measures: One hundred healthy women (aged 24–59 yr) from the general community enrolled in an observational study conducted at an academic medical center participated in the study. B-mode ultrasound imaging of the common carotid arteries was used to measure common carotid IMT in 99 subjects. Fat distribution was determined by computed tomography. Hormonal and inflammatory parameters related to cardiovascular disease and obesity were measured.

Results: IMT was higher in obese [body mass index (BMI) ≥ 30 kg/m2], compared with overweight women (BMI ≥ 25 and < 30 kg/m2) [0.69 mm, interquartile range (IQR) 0.60–0.75 mm] vs. 0.62 mm [IQR 0.56–0.68 mm), P = 0.044] and in comparison with lean women (BMI < 25 kg/m2) [0.69 mm (IQR 0.60–0.75 mm) vs. 0.59 mm (IQR 0.54–0.67 mm), P = 0.016]. In multivariate modeling, age (beta = 0.0050 mm change in IMT per year of age, P = 0.003), smoking (beta = 0.0044 mm change in IMT per pack-year, P = 0.046), and sc abdominal adiposity (beta = 0.00026 mm change in IMT per square centimeter, P = 0.010) were positively associated with IMT, whereas adiponectin (beta = −0.0042 mm change in IMT per milligram per liter, P = 0.045) was negatively associated with IMT. Visceral adiposity (beta = 0.00048 mm change in IMT per square centimeter, P = 0.092) was not significantly associated with IMT after adjusting for age, race, smoking, sc abdominal adiposity, and adiponectin.

Conclusions: Obesity is associated with increased common carotid IMT in young and middle-aged women. Adiponectin and sc abdominal adiposity are associated with carotid IMT in this population.
Gene silencing reveals a specific function of hVps34 phosphatidylinositol 3-kinase in late versus early endosomes
Authors: Johnson Erin E. , Overmeyer Jean H. , Gunning William T. , Maltese William A.
Published: March 2006

The human type III phosphatidylinositol 3-kinase, hVps34, converts phosphatidylinositol (PtdIns) to phosphatidylinositol 3-phosphate [PtdIns(3)P]. Studies using inhibitors of phosphatidylinositide 3-kinases have indicated that production of PtdIns(3)P is important for a variety of vesicle-mediated trafficking events, including endocytosis, sorting of receptors in multivesicular endosomes, and transport of lysosomal enzymes from the trans-Golgi network (TGN) to the endosomes and lysosomes. This study utilizes small interfering (si)RNA-mediated gene silencing to define the specific trafficking pathways in which hVps34 functions in human U-251 glioblastoma cells. Suppression of hVps34 expression reduced the cellular growth rate and caused a striking accumulation of large acidic phase-lucent vacuoles that contain lysosomal membrane proteins LAMP1 and LGP85. Analysis of these structures by electron microscopy suggests that they represent swollen late endosomes that have lost the capacity for inward vesiculation but retain the capacity to fuse with lysosomes. Morphological perturbation of the late endosome compartment was accompanied by a reduced rate of processing of the endosomal intermediate form of cathepsin D to the mature lysosomal form. There was also a reduction in the rate of epidermal growth factor receptor (EGFR) dephosphorylation and degradation following ligand stimulation, consistent with the retention of the EGFR on the limiting membranes of the enlarged late endosomes. By contrast, the suppression of hVps34 expression did not block trafficking of cathepsin D between the TGN and late endosomes, or endocytic uptake of fluid-phase markers, or association of a PtdIns(3)P-binding protein, EEA1, with early endosomes. LAMP1-positive vacuoles were depleted of PtdIns(3)P in the hVps34-knockdown cells, as judged by their inability to bind the PtdIns(3)P probe GFP-2xFYVE. By contrast, LAMP1-negative vesicles continued to bind GFP-2xFYVE in the knockdown cells.

Overall, these findings indicate that hVps34 plays a major role in generating PtdIns(3)P for internal vesicle formation in multivesicular/late endosomes. The findings also unexpectedly suggest that other wortmannin-sensitive kinases and/or polyphosphoinositide phosphatases may be able to compensate for the loss of hVps34 and maintain PtdIns(3)P levels required for vesicular trafficking in the early endocytic pathway or the TGN.
Eph receptors inactivate R-Ras through different mechanisms to achieve cell repulsion
Authors: Dail Monique , Richter Melanie , Godement Pierre , Pasquale Elena B.
Published: March 2006

Eph receptor tyrosine kinases regulate the spatial organization of cells within tissues. Central to this function is their ability to modulate cell shape and movement in response to stimulation by the ephrin ligands. The EphB2 receptor was reported to inhibit cell-matrix adhesion by phosphorylating tyrosine 66 in the effector domain of R-Ras, a Ras family protein known to regulate cell adhesion and motility. Here, we further characterize the role of R-Ras downstream of both EphA and EphB receptors. Our data show that besides inhibiting R-Ras function through phosphorylation, Eph receptors can reduce R-Ras activity through the GTPase-activating protein, p120RasGAP. By using R-Ras mutants that cannot be inactivated by p120RasGAP and/or cannot be phosphorylated at tyrosine 66, we show that the two forms of R-Ras negative regulation - through increased GTP hydrolysis and phosphorylation - differentially contribute to various ephrin-mediated responses. Retraction of the COS cell periphery depends only on R-Ras inactivation through p120RasGAP. By contrast, both reduced R-Ras GTP levels and tyrosine 66 phosphorylation contribute to the ephrin inhibitory effects on COS cell migration and to ephrin-dependent growth cone collapse in primary neurons. Therefore, Eph receptors can regulate R-Ras in two different ways to achieve cell repulsion.
Wnt signalling in osteoblasts regulates expression of the receptor activator of NFκB ligand and inhibits osteoclastogenesis in vitro
Authors: Spencer Gary J. , Utting Jennifer C. , Etheridge Sharon L. , Arnett Timothy R. , Genever Paul G.
Published: March 2006

Reports implicating Wnt signalling in the regulation of bone mass have prompted widespread interest in the use of Wnt mimetics for the treatment of skeletal disorders. To date much of this work has focused on their anabolic effects acting on cells of the osteoblast lineage. In this study we provide evidence that Wnts also regulate osteoclast formation and bone resorption, through a mechanism involving transcriptional repression of the gene encoding the osteoclastogenic cytokine receptor activator of NFκB ligand (RANKL or TNFSF11) expressed by osteoblasts. In co-cultures of mouse mononuclear spleen cells and osteoblasts, inhibition of GSK3β with LiCl or exposure to Wnt3a inhibited the formation of tartrate-resistant acid phosphatase-positive multinucleated cells compared with controls. However, these treatments had no consistent effect on the differentiation, survival or activity of osteoclasts generated in the absence of supporting stromal cells. Activation of Wnt signalling downregulated RANKL mRNA and protein expression, and overexpression of fulllength β-catenin, but not transcriptionally inactive β-catenin ΔC(695-781), inhibited RANKL promoter activity. Since previous studies have demonstrated an absence of resorptive phenotype in mice lacking LRP5, we determined expression of a second Wnt co-receptor LRP6 in human osteoblasts, CD14+ osteoclast progenitors and mature osteoclasts. LRP5 expression was undetectable in CD14-enriched cells and mature human osteoclasts, although LRP6 was expressed at high levels by these cells. Our evidence of Wnt-dependent regulation of osteoclastogenesis adds to the growing complexity of Wnt signalling mechanisms that are now known to influence skeletal function and highlights the requirement to develop novel therapeutics that differentially target anabolic and catabolic Wnt effects in bone.
Excited-State Double-Proton Transfer in the 7-Azaindole Dimer in the Gas Phase. Resolution of the Stepwise versus Concerted Mechanism Controversy and a New Paradigm
Authors: Sekiya Hiroshi , Sakota Kenji
Published: March 2006

The 7-azaindole dimer (7AI2) is a prototype of double hydrogen-bonded molecules. 7AI2 has been considered as a model DNA base pair and has attracted much attention to the mechanism of the excited-state double-proton transfer (ESDPT). Two ESDPT mechanisms, stepwise and concerted mechanisms, have been proposed so far. Great efforts have been devoted to clarify the mechanism of ESDPT using experimental and theoretical methods. However, the reaction mechanism had been controversial for more than a decade. We provide the resolution of the two mechanisms on the basis of new data obtained from electronic spectroscopy and picosecond time-resolved spectroscopy in the gas phase. The initial state of the ESDPT reaction has been well characterized by investigating the exciton resonance interaction with UV–UV hole-burning spectroscopy for various 7AI2 isotopomers. The lowest-excited state of 7AI2 has been classified into the weak coupling case of the exciton theory. We have concluded that the ESDPT reaction in 7AI2 occurs via the concerted mechanism on the basis of the results of picosecond time-resolved experiments and the H/D kinetic isotope effect on ESDPT studied by measuring the vibronic-state selective dispersed fluorescence spectra. ESDPT of 7AI2 has a “dynamic cooperative” nature that may arise from the coupling of the two moving protons with the reorganization of electrons. We have provided a new paradigm of ESDPT, where two quantum effects, the exciton resonance interaction and the proton tunneling, are concerned with the ESDPT reaction.
Visible Light-Induced Electron Transfers in Titania Nanosheet and Mesoporous Silica Integrated Films
Authors: Yui Tatsuto , Tsuchino Takako , Akatsuka Kosho , Yamauchi Atsushi , Kobayashi Yuka , Hattori Takeshi , Haga Masa-aki , Takagi Katsuhiko
Published: March 2006

Two spatially different nano-structured inorganic materials, titania nanosheets (TNS) and mesoporous silica (MPS), were integrated onto a glass substrate to form stacked composite thin films. Investigations were then carried out on photoinduced electron transfers between the tetrakis(1-methylpyridinium-4-yl)porphyrinatometal(4+) ion ([M(tmpyp)]4+); M = H2, Zn, and Co) and 1,1′-dimethyl-4,4′-bipyridinium (methyl viologen; MV2+) within the hybrid films. The [M(tmpyp)]4+ molecules were found to be adsorbed only in the MPS nano-cavities, while MV2+ was intercalated only in the TNS layer, i.e., the [M(tmpyp)]4+ and MV2+ molecules could be separately and selectively accommodated into the MPS nano-cavities and TNS layers of the hybrid films, respectively. Upon UV light irradiation (TNS excitation) of the films containing [H2(tmpyp)]4+, the decomposition of [H2(tmpyp)]4+ and the formation of a one-electron reduced MV2+ (MV+•) were observed, clearly indicating photoinduced electron transfers in the MPS/TNS films. Moreover, when the metal-complex [Zn(tmpyp)]4+ or [Co(tmpyp)]4+ was used in place of [H2(tmpyp)]4+, visible light-induced electron transfers could be observed in the present MPS/TNS hybrid films, the first report of such charge separation in consecutively stacked thin films by visible light.
Theoretical Studies on the Li+ Ion Hydration System by the Molecular Dynamics Simulations with Ab Initio IMiC MO Method
Authors: Morita Shoji , Sakai Shogo
Published: March 2006

Molecular dynamics simulations for a lithium cation surrounded with 100 water molecules as a solvent were carried out by using an ab initio integrated multicenter molecular orbitals method (IMiC MO) with HF/6-31G(d,p) level. For the temperature of both 293 and 323 K, the first hydration shell of the lithium cation is preferred to form a tetrahedral structure including four water molecules, and is well separated from the outer hydration shell. The mechanisms for the variation of the coordination number and the exchange of solvent molecules between the first and the second hydration shells were also studied.
Kinetic Study of Radical-Scavenging and Vitamin E-Regenerating Actions of Edaravone (3-Methyl-1-phenyl-2-pyrazolin-5-one)
Authors: Ohara Keishi , Fujii Akiko , Ichimura Yoko , Sato Kazue , Mukai Kazuo
Published: March 2006

A kinetic study was performed for edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one) in order to clarify the mechanism of its free-radical-scavenging and vitamin E-regenerating actions. The second-order rate constants for the radical-scavenging reaction of edaravone were measured in several organic solvents and in a water/methanol mixed solvent at various pH. The keto–enol tautomerism and the acid–base dissociation equilibrium of edaravone produce keto, enol, and anion forms in solutions, and their contributions and activities varied depending on the properties of the solutions. From the results of NMR and kinetic studies, it has been clarified that the keto–enol tautomerism of edaravone actually exists, and the keto form has larger radical-scavenging activity than the enol form. Furthermore, the pH dependence of the rate constants suggests that the anion form produced by the acid–base dissociation equilibrium of edaravone has the highest radical-scavenging activity in the keto, enol, and anion forms.
Spin-Crossover Behaviors of Iron(III) Compounds with Strong Intermolecular Interactions
Authors: Hayami Shinya , Miyazaki Soushi , Yamamoto Masahiko , Hiki Kenji , Motokawa Natsuko , Shuto Aya , Inoue Katsuya , Shinmyozu Teruo , Maeda Yonezo
Published: March 2006

Iron(III) spin-crossover compounds with H3-OMe-salRen ligands [Fe(3-OMe-salRen)2]ClO4 (1–5) were prepared and characterized by single-crystal X-ray diffraction, Mössbauer spectra, magnetic susceptibilities, and electronic spectra, where 3-OMe-salRen is a tridentate ligand derived from 3-methoxysalicylaldehyde and N-R-ethylenediamine (R = H, Me, Et, Pr, and Bu for 1, 2, 3, 4, and 5). The structures of compounds 1, 2, 3, and 5 at 90 and 298 K, and that of compound 4 at 298 K were determined. Compounds 1, 2, 3, and 5 exhibited a spin transition depending on temperature; the transition temperatures for 1, 2, 3, and 5 were >400, 360, 196, and 223 K, respectively. Compound 4 was in the high-spin state in the temperature range of 5 to 400 K. σ–π or π–π interactions exist in compounds 1–5, and the structures of the compounds were made clear in both the high-spin and low-spin states. Compound 3 exhibited a spin transition with thermal hysteresis.
A Spectroscopic Index for Estimating the Age of Amber
Authors: Kimura Hideaki , Tsukada Yoshimi , Mita Hajime , Yamamoto Yasuhiko , Chujo Riichiro , Yukawa Tomohisa
Published: March 2006

Solid-state 13C NMR characterization of cross-linkage formation between the exocyclic methylene groups of labdane polymers in amber demonstrated that the process is an apparent first-order reaction with a half-life of ≈13 million years.
Efficient Synthesis, Structure, and Redox Reactions of 1,4,6,9-Tetraisopropylchalcogenanthrenes
Authors: Yamamoto Tatsuya , Ogawa Satoshi , Sugawara Mutsumi , Kawai Yasushi , Sato Ryu
Published: March 2006

1,4,7,10-Tetraisopropyldibenzo[c,g][1,2,5,6]tetrachalcogenocins that were readily synthesized from 4,7-diisopropyl-2,2-dimethyl-1,3,2-benzodichalcogenastannoles underwent selective ring contraction under irradiation with a high-pressure mercury lamp to give the corresponding 1,4,6,9-tetraisopropylchalcogenanthrenes having bulky substituents on the benzene ring at adjacent positions of the 6-membered dichalcogenin unit in moderate yields. X-ray crystal structure determination of 1,4,6,9-tetraisopropylthianthrene revealed that the substituents of bulky substituents such as isopropyl groups scarcely affected the structure of the parent dithiin framework. Measurements of the cyclic voltammetry of thianthrene showed a well-defined reversible redox property, whereas the voltammograms of selenium-containing analogues showed irreversible oxidation waves. In contrast to electrical observations, facile reversible one-electron redox reaction systems were observed between the chalcogenanthrenes and the corresponding chalcogenanthrenium radical cations by chemical oxidation or reduction reactions.
Asymmetric Synthesis of the Polyol Subunit of the Macrolide Antibiotic, Ossamycin: A Unique Approach Utilizing Stereochemical Specificity
Authors: Kutsumura Noriki , Nishiyama Shigeru
Published: March 2006

An asymmetric synthesis of the C1–C16 polyol subunit 2 of the macrolide antibiotic ossamycin (1) has been achieved through stepwise carbon-chain elongation reaction from d-glucose, based on a chiral pool approach. An outstanding point of this strategy is asymmetric induction by utilizing steric hindrance of neighboring groups. The stereogenic centers at the C4 and C5 positions of 2 were constructed by mCPBA epoxidation, and the C6 and C7 positions of 2 were produced by catalytic OsO4 dihydroxylation under highly stereoselective conditions.
6-Nitro-2-benzothiazolyl α-Mannoside: A Highly Efficient Mannosyl Donor in Constructing β-Man(1→4)GlcN Linkage and Its Application to the Synthesis of the Pentasaccharide Core of N-Glycans
Authors: Mandai Hiroki , Mukaiyama Teruaki
Published: March 2006

An efficient and concise synthesis of the β-Man(1→4)GlcN linkage that exists in N-linked glycans has been established. Direct β-mannosylations of the 4-OH group of glucosamine derivatives by using 6-nitro-2-benzothiazolyl 3,6-di-O-allyl-2,4-di-O-benzyl-α-d-mannopyranoside (3α) proceed smoothly in the presence of a catalytic amount of HB(C6F5)4 in CH2Cl2 at −78 °C to afford the desired β-mannosides in high yields. The β-trisaccharide 14β, a key building block for the synthesis of the pentasaccharide core 20, is directly prepared from the mannosyl donor 3α and chitobiose acceptor 10 in high yield. In addition, this mannosylation method has successfully been applied to a wide range of glycosyl acceptors derived from glucosamine in a highly efficient manner. Further, the pentasaccharide core 20 that is commonly present in N-linked glycans can also be synthesized readily according to this direct mannosylation strategy.
A Simple Synthesis of 4H-1,3-Benzodioxin-2-one Derivatives by Iodocyclization of t-Butyl o-Vinylphenyl Carbonate Derivatives
Authors: Kobayashi Kazuhiro , Nakamura Daizo , Miyamoto Kazuna , Morikawa Osamu , Konishi Hisatoshi
Published: March 2006

The first general method for the synthesis of 4H-1,3-benzodioxin-2-one derivatives has been developed. Treatment of t-butyl 2-vinylphenyl carbonates with iodine in the presence of sodium hydrogencarbonate gave 4-iodomethyl-4H-1,3-benzodioxin-2-one derivatives in moderate to good yields. These iodides were reduced with tributyltin hydride to give the corresponding 4-methyl-4H-1,3-benzodioxin-2-one derivatives.
Functional Group Compatible Palladium-Catalyzed Cross-Coupling Reactions between Aryllithium and Aryl Halide Mediated by a Five-Membered Cyclic Silyl Ether
Authors: Son Eun-Cheol , Tsuji Hayato , Saeki Tomoyuki , Tamao Kohei
Published: March 2006

A functional group compatible palladium-catalyzed cross-coupling reaction between aryllithiums and aryl halides mediated by a five-membered cyclic silyl ether as a precursor for an activated arylsilane has been developed. The reaction proceeds under mild conditions without the addition of a fluoride salt or a base to activate the silyl reagent.
Utilization of Industrially Available 2,3-Dichloro-1,3-butadiene for Direct Synthesis of 2,3-Diaryl-1,3-butadienes
Authors: Yamamoto Takakazu , Yasuda Takuma , Kobayashi Kazuaki , Yamaguchi Isao , Koizumi Take-aki , Ishii Daisuke , Nakagawa Masaru , Mashiko Yoshihiro , Shimizu Norihiro
Published: March 2006

It is shown that industrially available 2,3-dichloro-1,3-butadiene is a useful starting material for the synthesis of 2,3-diaryl-1,3-butadienes. Ni(II)-catalyzed cross-coupling reaction of 2,3-dichloro-1,3-butadiene with ArMgBr (Ar = 2-thienyl, phenyl, 4-dodecyloxyphenyl, and 4-fluorophenyl) gives the corresponding 2,3-diaryl-1,3-butadienes in good yields.
2005 Franz Edelman Award for Achievement in Operations Research and the Management Sciences
Authors: Milne R. John , Graves Stephen C.
Published: March 2006

This special issue of Interfaces is devoted to the finalists of the 34th annual competition for the Franz Edelman Award for Achievement in Operations Research and the Management Sciences, the profession’s prestigious award for the practice of operations research. R. John Milne, chair of the competition, and Stephen C. Graves, editor of this special issue, provide an overview of the competition and introduce the finalists and winner.
PLATO Helps Athens Win Gold: Olympic Games Knowledge Modeling for Organizational Change and Resource Management
Authors: Beis D. A. , Loucopoulos P. , Pyrgiotis Y. , Zografos K. G.
Published: March 2006

Planning, designing, and implementing systems to support venue operations at the Olympic Games is complicated. The organizing committees must create designs that result in reliable, high-quality venue operations at reasonable cost. The organizational backdrop is unique. The organizing committee has a limited lifetime, it has no organizational memory, any learning disappears with its dissolution, and during its lifetime it must change rapidly from a function-oriented entity to a process-oriented one. The Athens 2004 Olympic Games Organizing Committee (ATHOC) used innovative techniques from management science, systems engineering, and information technology to change the planning, design, and operation of venues. We developed the Process Logistics Advanced Technical Optimization (PLATO) approach for the games. In the PLATO project, we developed a systematic process for planning and designing venue operations by using knowledge modeling and resource-management techniques and tools. We developed a rich library of models that is directly transferable to future Olympic organizing committees and other sports-oriented events. The direct financial benefit to ATHOC was the reduction of the costs of managing venue operations by over $69.7 million. The success of the games raised Greece’s international profile in terms of capabilities in managing large and complex projects which, in the medium to long term, will yield financial, political, and social benefits. Internationally, the PLATO legacy of its Olympics knowledge base will enable future organizers of large-scale events to reuse and customize the knowledge to gain benefits and reduce the financial burdens on governments and society.
Improving Preference Assessment: Limiting the Effect of Context Through Pre-exposure to Attribute Levels
Authors: Carlson Kurt A. , Bond Samuel D.
Published: March 2006

This paper introduces a technique for improving preference assessment by reducing the influence of context on preferential choices. We propose that a decision maker who is exposed to relevant attribute levels will form spontaneous valuations, which will then insulate the decision maker from the effects of context during subsequent preference assessment. Results from three studies supported this hypothesis. Pre-exposure to product attribute levels undermined the impact of attribute priming, decision framing, and asymmetric dominance on preferential choices. A fourth study demonstrated that similar results can be obtained by allowing decision makers to pregenerate lists of attribute levels on their own.
Behavioral Causes of the Bullwhip Effect and the Observed Value of Inventory Information
Authors: Croson Rachel , Donohue Karen
Published: March 2006

The tendency of orders to increase in variability as one moves up a supply chain is commonly known as the bullwhip effect. We study this phenomenon from a behavioral perspective in the context of a simple, serial, supply chain subject to information lags and stochastic demand. We conduct two experiments on two different sets of participants. In the first, we find the bullwhip effect still exists when normal operational causes (e.g., batching, price fluctuations, demand estimation, etc.) are removed. The persistence of the bullwhip effect is explained to some extent by evidence that decision makers consistently underweight the supply line when making order decisions. In the second experiment, we find that the bullwhip, and the underlying tendency of underweighting, remains when information on inventory levels is shared. However, we observe that inventory information helps somewhat to alleviate the bullwhip effect by helping upstream chain members better anticipate and prepare for fluctuations in inventory needs downstream. These experimental results support the theoretically suggested notion that upstream chain members stand to gain the most from information-sharing initiatives.
How Does Residual Income Affect Investment? The Role of Prior Performance Measures
Authors: Balachandran Sudhakar V.
Published: March 2006

This paper examines whether “you get what you pay for” in firms that implement residual income (RI)–based compensation. Specifically, this paper explores differences in investment patterns of firms that implement RI-based compensation plans conditional on whether the firms switched from earnings or return on investment (ROI)–based compensation. I find that the pattern of investment for firms switching to RI from earnings-based compensation is opposite to that of firms switching from ROI-based compensation. Changes in investment within each individual subgroup yield weaker, mixed results. In addition, this paper documents that delivered RI increases in firms that implement RI. My paper contributes to the literature on the investment effects of RI by examining the relevance of a set of arguments that have been made in management accounting textbooks since 1965. These arguments are still found in current textbooks and are commonly taught to students in graduate level managerial accounting classes. The arguments help us to examine a natural experiment in which we can better specify the conditions under which RI use is expected to be associated with changes in investment.