bluuebunny/crossref_metadata_2025 huggingface dataset:
A Pathobiological Role of the Insulin Receptor in Chronic Lymphocytic Leukemia
Authors: Saiya-Cork Kamlai , Collins Roxane , Parkin Brian , Ouillette Peter , Kuizon Erlene , Kujawski Lisa , Erba Harry , Campagnaro Erica , Shedden Kerby , Kaminski Mark , Malek Sami N.
Published: February 2011

Purpose: The chromosomal deletion 11q affects biology and clinical outcome in chronic lymphocytic leukemia (CLL) but del11q-deregulated genes remain incompletely characterized.

Experimental Design: We have employed integrated genomic profiling approaches on CLL cases with and without del11q to identify 11q-relevant genes.

Results: We have identified differential expression of the insulin receptor (INSR) in CLL, including high-level INSR expression in the majority of CLL with del11q. High INSR mRNA expression in 11q CLL (∼10-fold higher mean levels than other genomic categories) was confirmed by quantitative PCR in 247 CLL cases. INSR protein measurements in 257 CLL cases through flow cytometry, compared with measurements in normal CD19+ B cells and monocytes, confirmed that a subset of CLL aberrantly expresses high INSR levels. INSR stimulation by insulin in CLL cells ex vivo resulted in the activation of canonical INSR signaling pathways, including the AKT-mTOR and Ras/Raf/Erk pathways, and INSR activation partially abrogated spontaneous CLL cell apoptosis ex vivo. Higher INSR levels correlated with shorter time to first therapy and shorter overall survival (OS). In bivariate analysis, INSR expression predicted for rapid initial disease progression and shorter OS in ZAP-70–low/negative CLL. Finally, in multivariate analysis (ZAP-70 status, IgVH status, and INSR expression), we detected elevated HRs and trends for short OS for CLL cases with high INSR expression (analyzed inclusive or exclusive of cases with del11q).

Conclusions: Our aggregate biochemical and clinical outcome data suggest biologically meaningful elevated INSR expression in a substantial subset of all CLL cases, including many cases with del11q. Clin Cancer Res; 17(9); 2679–92. ©2011 AACR.
Second-Generation Tyrosine Kinase Inhibitors: The Future of Frontline CML Therapy
Authors: Kantarjian Hagop M. , Baccarani Michele , Jabbour Elias , Saglio Giuseppe , Cortes Jorge E.
Published: February 2011

All available data from ongoing studies of second-generation tyrosine kinase inhibitors (TKIs) for treatment of patients with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP) were reviewed. In two nilotinib phase 2 trials, the speed and depth of molecular and cytogenetic responses were greater than responses to imatinib. Furthermore, only one patient in each study progressed to accelerated or blastic phase. In the phase 3 ENESTnd study, molecular and cytogenetic responses to nilotinib were superior to imatinib, and more patients achieved undetectable levels of disease with nilotinib. Nilotinib also demonstrated significantly lower progression than did imatinib. In the ongoing phase 2 study of dasatinib, the speed and depth of molecular and cytogenetic responses were higher compared with expected responses to imatinib; no patient to date has progressed. In the phase 3 DASISION study, molecular and cytogenetic responses to dasatinib were superior to those of imatinib and fewer patients progressed. The results suggest that second-generation TKIs have the potential to replace imatinib as the standard of care for patients with early CML-CP. Future CML therapy might include earlier use of these agents to help more patients achieve complete molecular response and may be a path to a CML cure. Clin Cancer Res; 17(7); 1674–83. ©2011 AACR.
FOXE1 Polyalanine Tract Length Polymorphism in Patients with Thyroid Hemiagenesis and Subjects with Normal Thyroid
Authors: Szczepanek Ewelina , Ruchala Marek , Szaflarski Witold , Budny Bartlomiej , Kilinska Lidia , Jaroniec Malgorzata , Niedziela Marek , Zabel Maciej , Sowinski Jerzy
Published: February 2011

Background/Aims: Recent studies have pointed to the correlation between FOXE1 polyalanine tract (FOXE1-polyAla) length polymorphism and genetic susceptibility to thyroid dysgenesis causing congenital hypothyroidism. The objective of this study was a first assessment of the role of FOXE1-polyAla expansion in the genetic background of thyroid hemiagenesis (TH). Methods: The group studied consisted of 40 patients with TH, including 6 familial cases and a control group of 89 subjects with a normal thyroid. The polyAla tract and flanking sequence of FOXE1 was amplified using conventional PCR. Subsequently, capillary electrophoresis was performed to estimate the length of products. Results: A short variant of FOXE1-polyAla, containing 12 alanines, was present in 5 control subjects (5.6%), but was not found in TH. The incidence of longer variants (≧16 codons) of FOXE1-polyAla was significantly higher in patients with the familial form of TH in comparison to those with sporadic TH (p = 0.003) and controls (p = 0.005). Conclusions: There is high polymorphic variability of FOXE1-polyAla in both groups. Shorter variants of FOXE1-polyAla are underrepresented in subjects with familial TH. Therefore, FOXE1-polyAla tract expansion may contribute to the molecular background of familial but not sporadic forms of TH. Further studies are still required to confirm such findings.
Selective Pelvic Autonomic Nerve Stimulation with Simultaneous Intraoperative Monitoring of Internal Anal Sphincter and Bladder Innervation
Authors: Kneist W. , Kauff D.W. , Koch K.P. , Schmidtmann I. , Heimann A. , Hoffmann K.P. , Lang H.
Published: February 2011

Background: Pelvic autonomic nerve preservation avoids postoperative functional disturbances. The aim of this feasibility study was to develop a neuromonitoring system with simultaneous intraoperative verification of internal anal sphincter (IAS) activity and intravesical pressure. Methods: 14 pigs underwent low anterior rectal resection. During intermittent bipolar electric stimulation of the inferior hypogastric plexus (IHP) and the pelvic splanchnic nerves (PSN), electromyographic signals of the IAS and manometry of the urinary bladder were observed simultaneously. Results: Stimulation of IHP and PSN as well as simultaneous intraoperative monitoring could be realized with an adapted neuromonitoring device. Neurostimulation resulted in either bladder or IAS activation or concerted activation of both. Intravesical pressure increase as well as amplitude increase of the IAS neuromonitoring signal did not differ significantly between stimulation of IHP and PSN [6.0 cm H2O (interquartile range [IQR] 3.5–9.0) vs. 6.0 cm H2O (IQR 3.0–10.0) and 12.1 µV (IQR 3.0–36.7) vs. 40.1 µV (IQR 9.0–64.3)] (p > 0.05). Conclusions: Pelvic autonomic nerve stimulation with simultaneous intraoperative monitoring of IAS and bladder innervation is feasible. The method may enable neuromonitoring with increasing selectivity for pelvic autonomic nerve preservation.
Hand-Based Disocclusion for the World-in-Miniature Metaphor
Authors: Andujar Carlos
Published: February 2011

The world-in-miniature metaphor (WIM) allows users to select, manipulate, and navigate efficiently in virtual environments. In addition to the first-person perspective offered by typical virtual reality (VR) applications, the WIM offers a second dynamic viewpoint through a hand-held miniature copy of the environment. In this paper we explore different strategies to allow the user to interact with the miniature replica at multiple levels of scale. Unlike competing approaches, we support complex indoor environments by explicitly handling occlusion. We discuss algorithms for selecting the part of the scene to be included in the replica, and for providing a clear view of the region of interest. Key elements of our approach include an algorithm to recompute the active region from a subdivision of the scene into cells, and a view-dependent algorithm to cull occluding geometry. Our cutaway algorithm is based on a small set of slicing planes roughly oriented along the main occluding surfaces, along with depthbased revealing for nonplanar geometry. We present the results of a user study showing that our technique clearly outperforms competing approaches on spatial tasks performed in densely occluded scenes.
Fluid Dynamic Considerations for Realistic Odor Presentation Using Olfactory Display
Authors: Matsukura Haruka
Published: February 2011

This paper describes some fluid dynamic considerations for attaining realistic odor presentation using an olfactory display. Molecular diffusion is an extremely slow process and odor molecules released from their source are spread by being carried off by airflow. Therefore, we propose to use a computational fluid dynamics (CFD) simulation in conjunction with the olfactory display. The CFD solver is employed to calculate the turbulent airflow field in the given environment and the dispersal of odor molecules from their source. The simulation result is used to reproduce at the nose the realistic change in the odor concentration with time and space. However, our initial sensory test for evaluating the proposed method was not completely successful, and we also found some discrepancies between our real-life olfactory sensation and the experience of the CFD-based olfactory display. Here we report some insights to overcome these problems. In the initial sensory test, a nontrivial portion of the subjects did not properly recognize the spatial variation in the odor intensity. The result of our recent sensory test is presented in this paper to show that better contrast in the perceived odor intensity can be provided when the concentration range of the released odor is adjusted for the variation in the olfactory sensitivity of individual subjects. We noted that olfactory adaptation occurred more quickly in the initial sensory test of the CFD-based olfactory display than in real environments. In this paper, we show that olfactory adaptation can be alleviated by modulating the odor concentration randomly to mimic the random fluctuations of the turbulent flow fields in real environments. We also noted in our initial sensory test that there were sometimes discrepancies between our olfactory sensation in real environments and the simulated odor distribution. We show in this paper that the discrepancy can be attributed to the convection caused by the human body temperature that brings an odor vapor that is drifting around our feet up to our noses.
Globalising Touba
Authors: Ross Eric
Published: February 2011

The Muslim holy city of Touba, self-defined ‘capital’ of the Murid Sufi order in Senegal, is increasingly thriving on its global connectedness. This article situates the phenomenon of Touba’s globalisation within current literature on the global city and world city networks. It assesses four of the processes through which the holy city’s values and structures are diffusing across the global North. First, the universality of Touba in Murid historiography is considered. Secondly, the diffusion of the toponym ‘Touba’, through the naming of expatriate associations and institutions, is analysed. Thirdly, the types and distribution of businesses set up in the US by Murids is assessed. Fourthly, the diffusion of typical Murid images is discussed as they too contribute to Touba’s international renown.
Elevated Cardiac Biomarkers With Normal Right Ventricular Size Indicate an Unlikely Diagnosis of Acute Pulmonary Embolism in Stable Patients
Authors: Stein Paul D. , Janjua Muhammad , Matta Fadi , Jaweesh Fadel , Alrifai Ahmed , Yaekoub Abdo Y. , Chughtai Haroon L. , Cotant John F.
Published: February 2011

The purpose of this investigation is to assess the prevalence of elevated cardiac biomarkers, with or without estimates of right ventricular (RV) size, in stable patients with acute pulmonary embolism (PE). Our hypothesis is that the combination of high levels of cardiac troponin I (cTnI), high creatine kinase isoenzyme MB (CK-MB), and normal size RV are sufficiently uncommon in stable patients with PE to make the diagnosis of PE unlikely. Retrospective review showed a high cTnI plus high CK-MB in 20 (3.4%) of 585 stable patients with acute PE. A high cTnI plus high CK-MB with normal RV size was shown in 5 (1.9%) of 264 patients. In stable patients with such findings, therefore, PE is unlikely and other diagnoses, particularly acute coronary syndrome, should be considered before pursuing a diagnosis of PE.
Homocysteine and Serum-Lipid Levels in Pulmonary Embolism
Authors: Karalezli Aysegul , Parlak Ebru Sengül , Kanbay Asiye , Senturk Aysegul , Hasanoglu H. Canan
Published: February 2011

Pulmonary embolism (PE) is a fatal disease that arises from genetic and environmental factors. There is little evidence for low high-density lipoprotein cholesterol (HDL-C) with hyperhomocysteinemia to lead to PE. Therefore, we evaluated homocysteine levels and lipid profile in PE patients and to display risk for PE. Forty six patients with proven PE and 46 healthy controls were included in the study. Homocysteine and serum lipid levels were calculated and compared in both groups. There were no significant differences between two groups in terms of total cholesterol, triglyceride, and low-density lipoprotein cholesterol. In PE group, HDL-C levels were found significantly lower in comparison to the control group ( P = .004). Mean homocysteine levels were significantly higher in PE group than in the control group ( P = .001). High-density lipoprotein cholesterol levels were significantly low in which homocysteine levels were high in the PE group. We thought that low HDL-C level with hyperhomocysteinemia is susceptible to PE.
Managers’ practice and managers’ learning as identity formation: Reassessing the MBA contribution
Authors: Warhurst Russell
Published: February 2011

The contribution of MBA study to managers’ work has been increasingly questioned, in particular the relevance of the curriculum and the transfer of MBA knowledge and skills into practice. However, emerging processual understandings of practice emphasize management as a relational activity and manager development as a process of evolving a particular identity in relation to others. While these understandings enable a reassessment of the contributions of MBA study, they have so far offered unconsolidated theoretical tools and empirical evidence of manager-students’ identity-work is limited. This article makes both theoretical and empirical contributions using a case study of MBA manager-students to critically examine the relationality of management, the significance of identity in the respondent managers’ day-to-day practice, and the contribution of MBA study to identity-work. The findings contribute to resolving a key debate in the study of identity formation. The article concludes by developing implications for the redesign of MBA education to better enable manager-students’ identity formation.
Usefulness of Harmonic Focus During Axillary Lymph Node Dissection
Authors: Cavallaro Giuseppe , Polistena Andrea , D’Ermo Giuseppe , Basile Ursula , Orlando Gennaro , Pedullà Giuseppe , Avenia Nicola , De Toma Giorgio
Published: February 2011

Background: Axillary node dissection (ALND) is affected by various complications, (hematoma, seroma, lymphocele, infections). The aim of this study was to evaluate the effectiveness of Harmonic Focus (HF) in reducing these complications. Materials and Methods: 92 patients requiring ALND, were divided into two group: Group A (HF) (33 women, 14 men), and Group B (control) (28 women, 17 men). Results: Operating time was lower in Group A than in Group B. The amount of drain volume was lower in Group A than in Group B, the drain was removed earlier in Group A than in Group B. Seroma incidence was lower in Group A than in Group B. Conclusions: The use of HF during ALND is effective in reducing operating time, drain volume and complications.
Effect of a map width enhancement system on turbocharger centrifugal compressor performance and surge margin
Authors: Mohtar H , Chesse P , Chalet D
Published: February 2011

Engine downsizing is potentially one of the most effective strategies being explored to improve fuel economy. A main problem of downsizing using a turbocharger is the small range of stable functioning of the turbocharger centrifugal compressor at high boost pressures. Several stabilization techniques have been studied to increase the compressor operating range without sacrificing the compressor efficiency. This paper presents an experimental study on a turbocharger compressor equipped with casing treatment (a map width enhancement (MWE) system). A KKK turbocharger was modified and tested at Ecole Centrale de Nantes. The experimental programme mainly dealt with traditional compressor performance measurements for an MWE. Whereas much work has been previously carried out to study the apparatus communicating between the annular flow passage and the impeller wheel, an apparatus with multiple holes has not been previously considered. In this paper experiments have been inducted to study the effect of an MWE structure with plurality of holes on the performance and stable functioning of a turbocharger centrifugal compressor. The effect of extending the length of the inner tubular wall has also been investigated. Two different MWE configurations have been tested and results were analysed while conducting a series of tests. The experimental studies have shown that while the MWE was advantageous in increasing pressure ratio at high compressor speeds, it failed in extending the compressor map. Moreover, extending the inner tube length was efficient in significantly shifting the surge line to low flowrates, by producing a uniform flow at inducer inlet.
Electronic control unit modelling for automotive wire harness simulation using the Capital Harness system
Authors: Kim J H , Lee J C , Park J , Lim H
Published: February 2011

With an increase in the number of electrical systems installed in vehicles, the wire harness design has become increasingly complicated and, accordingly, it has become essential that it is validated. Simulation is a good method of validation but it requires models of the installed electrical systems as well as wire harness design tools to support the simulation function. An electronic control unit (ECU) is a particularly important electrical system because it is connected to many other electrical systems through the wire harness and controls their operations. In this study, a method for modelling ECUs is developed, using the Capital Harness system design tool. The model parameters of the ECU are categorized into system parameters, external parameters, network parameters, and power parameters. The electrical structure of an ECU is built on the basis of the types and default states of the parameters. The behaviour of the ECU is defined in terms of simplified combinational logics in a state-machine-based structure since the target of the modelling is to simulate the logical connection conformity of the wire harness. A power-seat ECU model is developed, using the proposed method, and the feasibility of the simulation for wire harness validation is described.
Bcr is a substrate for Transglutaminase 2 cross-linking activity
Authors: Yi Sun-Ju , Groffen John , Heisterkamp Nora
Published: February 2011

Background

Breakpoint cluster region (Bcr) is a multi-domain protein that contains a C-terminal GTPase activating protein (GAP) domain for Rac. Transglutaminase 2 (TG2) regulates Bcr by direct binding to its GAP domain. Since TG2 has transglutaminase activity that has been implicated in the response to extreme stress, we investigated if Bcr can also act as a substrate for TG2.

Results

We here report that activation of TG2 by calcium caused the formation of covalently cross-linked Bcr. Abr, a protein related to Bcr but lacking its N-terminal oligomerization domain, was not cross-linked by TG2 even though it forms a complex with it. A Bcr mutant missing the first 62 amino acid residues remained monomeric in the presence of activated TG2, showing that this specific domain is necessary for the cross-linking reaction. Calcium influx induced by a calcium ionophore in primary human endothelial cells caused cross-linking of endogenous Bcr, which was inhibited by the TG2 inhibitor cystamine. Treatment of cells with cobalt chloride, a hypoxia-mimetic that causes cellular stress, also generated high molecular weight Bcr complexes. Cross-linked Bcr protein appeared in the TritonX-100-insoluble cell fraction and further accumulated in cells treated with a proteasome inhibitor.

Conclusions

Bcr thus represents both an interacting partner under non-stressed conditions and a target of transglutaminase activity for TG2 during extreme stress.
Modification of genetic regulation of a heterologous chitosanase gene in Streptomyces lividans TK24 leads to chitosanase production in the absence of chitosan
Authors: Dubeau Marie-Pierre , Guay Isabelle , Brzezinski Ryszard
Published: February 2011

Background

Chitosanases are enzymes hydrolysing chitosan, a β-1,4 linked D-glucosamine bio-polymer. Chitosan oligosaccharides have numerous emerging applications and chitosanases can be used for industrial enzymatic hydrolysis of chitosan. These extracellular enzymes, produced by many organisms including fungi and bacteria, are well studied at the biochemical and enzymatic level but very few works were dedicated to the regulation of their gene expression. This is the first study on the genetic regulation of a heterologous chitosanase gene (csnN106) in Streptomyces lividans.

Results

Two S. lividans strains were used for induction experiments: the wild type strain and its mutant (ΔcsnR), harbouring an in-frame deletion of the csnR gene, encoding a negative transcriptional regulator. Comparison of chitosanase levels in various media indicated that CsnR regulates negatively the expression of the heterologous chitosanase gene csnN106. Using the ΔcsnR host and a mutated csnN106 gene with a modified transcription operator, substantial levels of chitosanase could be produced in the absence of chitosan, using inexpensive medium components. Furthermore, chitosanase production was of higher quality as lower levels of extracellular protease and protein contaminants were observed.

Conclusions

This new chitosanase production system is of interest for biotechnology as only common media components are used and enzyme of high degree of purity is obtained directly in the culture supernatant.
Dispersion of single-walled carbon nanotubes modified with poly-l-tyrosine in water
Authors: Kojima Mio , Chiba Tomoka , Niishima Junichiro , Higashi Toshiaki , Fukuda Takahiro , Nakajima Yoshikata , Kurosu Shunji , Hanajiri Tatsuro , Ishii Koji , Maekawa Toru , Inoue Akira
Published: February 2011

In this study, complexes composed of poly-l-tyrosine (pLT) and single-walled carbon nanotubes (SWCNTs) were produced and the dispersibility of the pLT/SWCNT complexes in water by measuring the ζ potential of the complexes and the turbidity of the solution were investigated. It is found that the absolute value of the ζ potential of the pLT/SWCNT complexes is as high as that of SWCNTs modified with double-stranded DNA (dsDNA) and that the complexes remain stably dispersed in the water at least for two weeks. Thermogravimetry analysis (TGA) and visualization of the surface structures of pLT/SWCNT complexes using an atomic force microscope (AFM) were also carried out.
Mechanisms Involved in Extraterritorial Facial Pain following Cervical Spinal Nerve Injury in Rats
Authors: Kobayashi Azusa , Shinoda Masamichi , Sessle Barry J , Honda Kuniya , Imamura Yoshiki , Hitomi Suzuro , Tsuboi Yoshiyuki , Okada-Ogawa Akiko , Iwata Koichi
Published: February 2011

Background:

The aim of this study is to clarify the neural mechanisms underlying orofacial pain abnormalities after cervical spinal nerve injury. Nocifensive behavior, phosphorylated extracellular signal-regulated kinase (pERK) expression and astroglial cell activation in the trigeminal spinal subnucleus caudalis (Vc) and upper cervical spinal dorsal horn (C1-C2) neurons were analyzed in rats with upper cervical spinal nerve transection (CNX).

Results:

The head withdrawal threshold to mechanical stimulation of the lateral facial skin and head withdrawal latency to heating of the lateral facial skin were significantly lower and shorter respectively in CNX rats compared to Sham rats. These nocifensive effects were apparent within 1 day after CNX and lasted for more than 21 days. The numbers of pERK-like immunoreactive (LI) cells in superficial laminae of Vc and C1-C2 were significantly larger in CNX rats compared to Sham rats following noxious and non-noxious mechanical or thermal stimulation of the lateral facial skin at day 7 after CNX. Two peaks of pERK-LI cells were observed in Vc and C1-C2 following mechanical and heat stimulation of the lateral face. The number of pERK-LI cells in C1-C2 was intensity-dependent and increased when the mechanical and heat stimulations of the face were increased. The decrements of head withdrawal latency to heat and head withdrawal threshold to mechanical stimulation were reversed during intrathecal (i.t.) administration of MAPK/ERK kinase 1/2 inhibitor PD98059. The area of activated astroglial cells was significantly higher in CNX rats (at day 7 after CNX). The heat and mechanical nocifensive behaviors were significantly depressed and the number of pERK-LI cells in Vc and C1-C2 following noxious and non-noxious mechanical stimulation of the face was also significantly decreased following i.t. administration of the astroglial inhibitor fluoroacetate.

Conclusions:

The present findings have demonstrated that mechanical allodynia and thermal hyperalgesia occur in the lateral facial skin after CNX and also suggest that ERK phosphorylation of Vc and C1-C2 neurons and astroglial cell activation are involved in orofacial extraterritorial pain following cervical nerve injury.
The ADP Receptor P2Y1 is Necessary for Normal Thermal Sensitivity in Cutaneous Polymodal Nociceptors
Authors: Molliver Derek C , Rau Kristofer K , McIlwrath Sabrina L , Jankowski Michael P , Koerber H Richard
Published: February 2011

Background:

P2Y1 is a member of the P2Y family of G protein-coupled nucleotide receptors expressed in peripheral sensory neurons. Using ratiometric calcium imaging of isolated dorsal root ganglion neurons, we found that the majority of neurons responding to adenosine diphosphate, the preferred endogenous ligand, bound the lectin IB4 and expressed the ATP-gated ion channel P2X3. These neurons represent the majority of epidermal afferents in hairy skin, and are predominantly C-fiber polymodal nociceptors (CPMs), responding to mechanical stimulation, heat and in some cases cold.

Results:

To characterize the function of P2Y1 in cutaneous afferents, intracellular recordings from sensory neuron somata were made using an ex vivo preparation in which the hindlimb skin, saphenous nerve, DRG and spinal cord were dissected in continuum, and cutaneous receptive fields characterized using digitally-controlled mechanical and thermal stimuli in male wild type mice. In P2Y1−/− mice, CPMs showed a striking increase in mean heat threshold and a decrease in mean peak firing rate during a thermal ramp from 31-52°C. A similar change in mean cold threshold was also observed. Interestingly, mechanical testing of CPMs revealed no significant differences between P2Y1,−/− and WT mice.

Conclusions:

These results strongly suggest that P2Y1 is required for normal thermal signaling in cutaneous sensory afferents. Furthermore, they suggest that nucleotides released from peripheral tissues play a critical role in the transduction of thermal stimuli in some fiber types.
Enhanced immunogenicity of pneumococcal surface adhesin A (PsaA) in mice via fusion to recombinant human B lymphocyte stimulator (BLyS)
Authors: Gor Dennis O , Ding Xuedong , Li Qing , Sultana Dilara , Mambula Salamatu S , Bram Richard J , Greenspan Neil S
Published: February 2011

Background

B lymphocyte stimulator (BLyS) is a member of the tumor necrosis factor superfamily of ligands that mediates its action through three known receptors. BLyS has been shown to enhance the production of antibodies against heterologous antigens when present at elevated concentrations, supporting an immunostimulatory role for BLySin vivo.

Methods

We constructed a fusion protein consisting of human BLyS and Pneumococcal Surface Adhesin A (PsaA) and used this molecule to immunize mice. The immunostimulatory attributes mediated by BLySin vivowere evaluated by characterizing immune responses directed against PsaA.

Results

The PsaA-BLyS fusion protein was able to act as a co-stimulant for murine spleen cell proliferation induced with F(ab')2fragments of anti-IgMin vitroin a fashion similar to recombinant BLyS, and immunization of mice with the PsaA-BLyS fusion protein resulted in dramatically elevated serum antibodies specific for PsaA. Mice immunized with PsaA admixed with recombinant BLyS exhibited only modest elevations in PsaA-specific responses following two immunizations, while mice immunized twice with PsaA alone exhibited undetectable PsaA-specific serum antibody responses. Sera obtained from PsaA-BLyS immunized mice exhibited high titers of IgG1, IgG2a, IgG2b, and IgG3, but no IgA, while mice immunized with PsaA admixed with BLyS exhibited only elevated titers of IgG1 following two immunizations. Splenocytes from PsaA-BLyS immunized mice exhibited elevated levels of secretion of IL-2, IL-4 and IL-5, and a very modest but consistent elevation of IFN-γ followingin vitrostimulation with PsaA. In contrast, mice immunized with either PsaA admixed with BLyS or PsaA alone exhibited modestly elevated to absent PsaA-specific recall responses for the same cytokines. Mice deficient for one of the three receptors for BLyS designated Transmembrane activator, calcium modulator, and cyclophilin ligand [CAML] interactor (TACI) exhibited attenuated PsaA-specific serum antibody responses following immunization with PsaA-BLyS relative to wild-type littermates. TACI-deficient mice also exhibited decreased responsiveness to a standard pneumococcal conjugate vaccine.

Conclusion

This study identifies covalent attachment of BLyS as a highly effective adjuvant strategy that may yield improved vaccines. In addition, this is the first report demonstrating an unexpected role for TACI in the elicitation of antibodies by the PsaA-BLyS fusion protein.

Reviewers

This article was reviewed by Jonathan Yewdell, Rachel Gerstein, and Michael Cancro (nominated by Andy Caton).
Follicular Phase Endocrine Characteristics during Ovarian Stimulation and GnRH Antagonist Cotreatment for IVF: RCT Comparing recFSH Initiated on Cycle Day 2 or 5
Authors: Blockeel Christophe , Sterrenburg Monique D. , Broekmans Frank J. , Eijkemans Marinus J. C. , Smitz Johan , Devroey Paul , Fauser Bart C. J. M.
Published: February 2011

Context:

Strategies involving mild ovarian stimulation protocols for in vitro fertilization (IVF) might lessen discomfort to the patient and substantially lower complication rates.

Objective:

The objective of the study was to compare the follicular-phase endocrine characteristics and follicular development in patients who started recombinant FSH (recFSH) on cycle day (CD) 2 or CD5 in IVF treatment, using GnRH antagonist as comedication.

Design:

This was a prospective randomized controlled trial in two university centers in Belgium and The Netherlands.

Patients:

Seventy-six IVF/intracytoplasmic sperm injection patients were included in the study.

Interventions:

The control group (CD2) received a standard treatment with 150 IU recFSH from CD2, whereas in the study group (CD5), stimulation was started on d 5 of the cycle. The GnRH antagonist was administered daily from CD6 onward in both treatment arms.

Main Outcome Measure:

Endocrine follicular phase profile during ovarian stimulation was measured.

Results:

Follicular-phase patterns of gonadotropin and steroid concentrations were found to be comparable in both treatment groups, except for serum estradiol being significantly higher in the CD2 group on d 6 of the cycle (295.6 ± 202.5 ng/liter in the CD2 vs. 102.5 ± 47.9 ng/liter in the CD5 group; P < 0.01) and LH being significantly higher in the CD5 group on d 6 of the cycle (1.7 ± 0.7 IU/liter in the CD2 vs. 5.0 ± 2.1 IU/liter in the CD5 group; P < 0.01). With regard to follicular development, there was no difference in the numbers of small follicles (<10 mm), intermediate follicles (10–12 and > 12–14 mm) and large follicles (>14 mm) in both groups.

Conclusions:

This study shows that the administration of recFSH starting on d 2 or d 5 of the cycle in a GnRH antagonist protocol for IVF/intracytoplasmic sperm injection patients yields a comparable endocrine profile and follicular development. Future studies should focus on the design of more patient-tailored ovarian stimulation protocols.
Kinesin-1 tail autoregulation and microtubule-binding regions function in saltatory transport but not ooplasmic streaming
Authors: Moua Pangkong , Fullerton Donna , Serbus Laura R. , Warrior Rahul , Saxton William M.
Published: February 2011

The N-terminal head domain of kinesin heavy chain (Khc) is well known for generating force for transport along microtubules in cytoplasmic organization processes during metazoan development, but the functions of the C-terminal tail are not clear. To address this, we studied the effects of tail mutations on mitochondria transport, determinant mRNA localization and cytoplasmic streaming in Drosophila. Our results show that two biochemically defined elements of the tail – the ATP-independent microtubule-binding sequence and the IAK autoinhibitory motif – are essential for development and viability. Both elements have positive functions in the axonal transport of mitochondria and determinant mRNA localization in oocytes, processes that are accomplished by biased saltatory movement of individual cargoes. Surprisingly, there were no indications that the IAK autoinhibitory motif acts as a general downregulator of Kinesin-1 in those processes. Time-lapse imaging indicated that neither tail region is needed for fast cytoplasmic streaming in oocytes, which is a non-saltatory bulk transport process driven solely by Kinesin-1. Thus, the Khc tail is not constitutively required for Kinesin-1 activation, force transduction or linkage to cargo. It might instead be crucial for more subtle elements of motor control and coordination in the stop-and-go movements of biased saltatory transport.
Regulation of mouse stomach development and Barx1 expression by specific microRNAs
Authors: Kim Byeong-Moo , Woo Janghee , Kanellopoulou Chryssa , Shivdasani Ramesh A.
Published: February 2011

Although microRNAs (miRNAs) are postulated to fine-tune many developmental processes, their relationships with specific targets and tissues remain largely undefined. The mesenchymal transcription factor Barx1 controls spleen and stomach morphogenesis and is required to specify stomach-specific epithelium in adjacent endoderm. Barx1 expression is precisely regulated in space and time, with a sharp drop in stomach levels after epithelial specification. We tested the hypothesis that specific miRNAs mediate this marked decline in Barx1 levels. Depletion of the miRNA-processing enzyme Dicer in cultured stomach mesenchyme and conditional Dicer gene deletion in mice significantly increased Barx1 levels, disrupted stomach and intestine development and caused spleen agenesis. Computational and experimental studies identified miR-7a and miR-203 as candidate miRNAs that regulate Barx1 and are expressed in inverse proportion to it in the fetal mouse stomach. Through specific interactions with cognate sequences in the Barx1 3′ untranslated region, miR-7a and miR-203 repress Barx1 expression in stomach mesenchymal cells and its function in inducing gastric epithelium. These results indicate that miRNAs are required for proper digestive tract organogenesis and that miR-7a and miR-203 control expression of the stomach homeotic regulator Barx1.
A landmark-free morphometric staging system for the mouse limb bud
Authors: Boehm Bernd , Rautschka Michael , Quintana Laura , Raspopovic Jelena , Jan Žiga , Sharpe James
Published: February 2011

We have created a 2D morphometric analysis of the developing mouse hindlimb bud. This analysis has provided two useful resources for the study of limb development. First, a temporally accurate numerical description of shape changes during normal mouse limb development. Second, a web-based morphometric staging system, which has the advantage of being easy to use, and with a reproducibility of about ±2 hours. It allows users to upload a dorsal-view photo of a limb bud, draw a spline curve and thereby stage the bud within a couple of minutes. We describe how the system is constructed, its robustness to user variation and illustrate one application: the accurate tracking of spatiotemporal dynamics of gene expression patterns.
Commentary—When Is Less More, and How Much More? Thoughts on the Psychological and Economic Implications of Online Targeting and Obtrusiveness
Authors: Lodish Leonard M. , Reed Americus
Published: February 2011

In a very intriguing and groundbreaking study, Goldfarb and Tucker [Goldfarb, A., C. Tucker. 2011. Online display advertising: Targeting and obtrusiveness. Marketing Sci. 30(3) 389–404] show that online advertising targeting and obtrusiveness boost purchase intent independently, but not jointly. The authors rule out recall as an explanatory mechanism and provide preliminary evidence that the effect may be driven by privacy concerns. We comment on the substantive importance of this finding by discussing the psychological and economic implications of the effect.
Commentary—Discussion of “Online Display Advertising: Targeting and Obtrusiveness” by Avi Goldfarb and Catherine Tucker
Authors: Matwyshyn Andrea M.
Published: February 2011

In “Online Display Advertising: Targeting and Obtrusiveness,” Avi Goldfarb and Catherine Tucker present an empirical investigation and discussion of consumers' reactions to obtrusive and targeted Internet advertisements. They find, among other things, that obtrusive advertisements when combined with targeting tend to generate no greater effectiveness in consumer response than either method used alone. Perhaps one of the most interesting findings in their results involves the authors' focus on privacy salience and its connection to advertisement presentation. This brief discussion of their work (1) highlights the importance of further research in line with the well-crafted privacy preference inquiries of Goldfarb and Tucker's study and (2) complements the authors' discussion regarding possible public policy implications with a legal discussion elaborating on existing legal grounds for liability and restrictions on advertising consumers perceive as privacy invasive.
Practice Prize Paper—Applying a Dynamic Model of Consumer Choice to Guide Brand Development at Jetstar Airways
Authors: Danaher Peter J. , Roberts John H. , Roberts Ken , Simpson Alan
Published: February 2011

This paper describes the use of a marketing science model by Jetstar, a subsidiary of Australia's leading airline, Qantas, to effectively and profitably compete in the low-cost carrier marketplace. We trace the evolution of the Jetstar strategy from a baseline calibration of its initial position, to its efforts to attain price competitiveness and service parity, followed by its highly focused, cost-effective service delivery strategy. We develop a hierarchical model with parameters estimated at the individual level. This allows us to study not only how service design and pricing initiatives shift the perceived performance of Jetstar relative to its competitors but also how the airline can move market preferences toward areas in which it has competitive advantage. The contribution of the research is substantial. The Jetstar market share went from 14.0% to 18.1% during the first five quarterly waves of the research, and profits went from $79 million in 2006–2007, before the study was commissioned, to $124 million in 2008–2009.
Protease-Activated Receptor–1 Expression in Rat Microglia after Trimethyltin Treatment
Authors: Pompili Elena , Fabrizi Cinzia , Nori Stefania Lucia , Panetta Barbara , Geloso Maria Concetta , Corvino Valentina , Michetti Fabrizio , Fumagalli Lorenzo
Published: February 2011

In the nervous system, protease-activated receptors (PARs), which are activated by thrombin and other extracellular proteases, are expressed widely at both neuronal and glial levels and have been shown to be involved in several brain pathologies. As far as the glial receptors are concerned, previous experiments performed in rat hippocampus showed that expression of PAR-1, the prototypic member of the PAR family, increased in astrocytes both in vivo and in vitro following treatment with trimethyltin (TMT). TMT is an organotin compound that induces severe hippocampal neurodegeneration associated with astrocyte and microglia activation. In the present experiments, the authors extended their investigation to microglial cells. In particular, by 7 days following TMT intoxication in vivo, confocal immunofluorescence revealed an evident PAR-1-related specific immunoreactivity in OX-42-positive microglial cells of the CA3 and hilus hippocampal regions. In line with the in vivo results, when primary rat microglial cells were treated in vitro with TMT, a strong upregulation of PAR-1 was observed by immunocytochemistry and Western blot analysis. These data provide further evidence that PAR-1 may be involved in microglial response to brain damage.
Cellular Environment Directs Differentiation of Human Umbilical Cord Blood–Derived Neural Stem Cells In Vitro
Authors: Markiewicz Inga , Sypecka Joanna , Domanska-Janik Krystyna , Wyszomirski Tomasz , Lukomska Barbara
Published: February 2011

Cord blood–derived neural stem cells (NSCs) are proposed as an alternative cell source to repair brain damage upon transplantation. However, there is a lack of data showing how these cells are driven to generate desired phenotypes by recipient nervous tissue. Previous research indicates that local environment provides signals driving the fate of stem cells. To investigate the impact of these local cues interaction, the authors used a model of cord blood–derived NSCs co-cultured with different rat brain–specific primary cultures, creating the neural-like microenvironment conditions in vitro. Neuronal and astro-, oligo-, and microglia cell cultures were obtained by the previously described methods. The CMFDA-labeled neural stem cells originated from, non-transformed human umbilical cord blood cell line (HUCB-NSCs) established in a laboratory. The authors show that the close vicinity of astrocytes and oligodendrocytes promotes neuronal differentiation of HUCB-NSCs, whereas postmitotic neurons induce oligodendrogliogenesis of these cells. In turn, microglia or endothelial cells do not favor any phenotypes of their neural commitment. Studies have confirmed that HUCB-NSCs can read cues from the neurogenic microenvironment, attaining features of neurons, astrocytes, or oligodendrocytes. The specific responses of neurally committed cord blood–derived cells, reported in this work, are very much similar to those described previously for NSCs derived from other “more typical” sources. This further proves their genuine neural nature. Apart from having a better insight into the neurogenesis in the adult brain, these findings might be important when predicting cord blood cell derivative behavior after their transplantation for neurological disorders.
Spatial and Temporal Localization of the Melanocortin 1 Receptor and Its Ligand α–Melanocyte-Stimulating Hormone during Cutaneous Wound Repair
Authors: Muffley Lara A. , Zhu Kathy Q. , Engrav Loren H. , Gibran Nicole S. , Hocking Anne M.
Published: February 2011

Growing evidence indicates that the melanocortin 1 receptor (MC1R) and its ligand α–melanocyte-stimulating hormone (α-MSH) have other functions in the skin in addition to pigment production. Activation of the MC1R/α-MSH signaling pathway has been implicated in the regulation of both inflammation and extracellular matrix homeostasis. However, little is known about the role of MC1R/α-MSH signaling in the regulation of inflammatory and fibroproliferative responses to cutaneous injury. Although MC1R and α-MSH localization has been described in uninjured skin, their spatial and temporal expression during cutaneous wound repair has not been investigated. In this study, the authors report the localization of MC1R and α-MSH in murine cutaneous wounds, human acute burns, and hypertrophic scars. During murine wound repair, MC1R and α-MSH were detected in inflammatory cells and suprabasal keratinocytes at the leading edge of the migrating epithelial tongue. MC1R and α-MSH protein levels were upregulated in human burn wounds and hypertrophic scars compared to uninjured human skin, where receptor and ligand were absent. In burn wounds and hypertrophic scars, MC1R and α-MSH localized to epidermal keratinocytes and dermal fibroblasts. This spatiotemporal localization of MC1R and α-MSH in cutaneous wounds warrants future investigation into the role of MC1R/α-MSH signaling in the inflammatory and fibroproliferative responses to cutaneous injury. This article contains online supplemental material at http://www.jhc.org . Please visit this article online to view these materials.
On finite T-groups and the Wielandt subgroup
Authors: Kaplan Gil
Published: February 2011

The Wielandt subgroup of a group G is the intersection of the normalizers of all the subnormal subgroups of G. A T-group is a group in which all the subnormal subgroups are normal, or, equivalently, a group coinciding with its Wielandt subgroup. We investigate the Wielandt subgroup of finite solvable groups and, in particular, find new properties and characterizations (see Theorems 1, 2 and Corollaries 4, 6) for this subgroup in the case that G is metanilpotent. Furthermore, we provide new characterizations for finite solvable T-groups in Theorem 7.
Imaging escape and avoidance behavior in zebrafish larvae
Authors: Colwill Ruth M. , Creton Robbert
Published: February 2011

This review provides an overview of the assays that are used for measuring escape and avoidance behavior in zebrafish, with a specific focus on zebrafish larvae during the first week of development. Zebrafish larvae display a startle response when exposed to tactile, acoustic, or visual stimuli and will avoid dark areas, moving objects, conspecifics, and open spaces. Emotional states such as fear and anxiety might be induced when larvae are exposed to stimuli that they would normally escape from or avoid. Although these emotional states probably differ between species and change during development, much can be learned about human fear and anxiety using zebrafish as a model system. The molecular mechanisms of fear and anxiety are highly conserved in vertebrates and are present during early zebrafish development. Larvae during the first week of development display elevated cortisol levels in response to stress and are sensitive to the same anxiolytics that are used for the management of anxiety in humans. Zebrafish larvae are well suited for high-throughput analyses of behavior, and automated systems have been developed for imaging and analyzing the behavior of zebrafish larvae in multiwell plates. These high-throughput analyses will not only provide a wealth of information on the genes and environmental factors that influence escape and avoidance behaviors and the emotional states that might accompany them but will also facilitate the discovery of novel pharmaceuticals that could be used in the management of anxiety disorders in humans.
Allelopathic evidence in exotic guava (Psidium guajava L.)
Authors: Chapla Tatiani Elisa , Campos João Batista
Published: February 2011

The allelopathic activity of the leaf aqueous extract of guava (Psidium guajava L.) on seed germination and root growth in lettuce (Lactuca sativa L.) was studied in an experiment consisting of four replicates with 10 seeds each and extract concentrations of 5, 10, and 20%. Guava allelopathic activity occurred during the germination and growth of lettuce roots at 20% extract concentration, as shown by ANOVA. This result suggested the allelopathic potential of the species. Therefore, the success of P. guajava in invading environments could be partially due to allelopathy. Further studies using other plant parts and field experiments should be conducted.