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  • image/svg+xml art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos Open Access logo, converted into svg, designed by PLoS. This version with transparent background. http://commons.wikimedia.org/wiki/File:Open_Access_logo_PLoS_white.svg art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos http://www.plos.org/
    Authors: Jurecic, Roland; Li, Linheng; Humphries, R. Keith;

    Better understanding of how hematopoietic stem cells (HSCs) balance self-renewal and differentiation is vital for their application in treatment of various diseases and regenerative medicine. During the last decade tremendous advances have been made in identifying a complex network of cellular and molecular factors that influence self-renewal and differentiation of HSCs and characterizing the cellular and molecular components of niches which harbor HSCs. Improving our understanding of the cellular and molecular mechanisms that regulate self-renewal and differentiation of HSCs will have a profound impact on experimental and clinical HSCs research and clinical application of HSCs. Thus, Stem Cells International set out to publish a special issue devoted to the topic of heterogeneity, self-renewal, and differentiation of hematopoietic stem cells. The ongoing research is continuously increasing our knowledge about HSC niches in the bone marrow and in particular about cell types constituting niches and a plethora of molecules and signals that make up the synapse between HSCs and niche cells. A series of three review articles in this issue discuss the role of hematopoietic niches in regulating behavior and function of hematopoietic stem cells and the role of niches in development of leukemias. K. S. Tieu et al. present a review of quantitative approaches to understanding stem cell niche signaling in the hematopoietic system, as well as in other tissues under conditions of homeostasis and carcinogenesis. They explain the benefits of mathematical models in advancing our understanding of the mechanisms that regulate stem cell fate and how this regulation changes in cancer development. K. S. Tieu and colleagues are also highlighting the synergistic relationship between mathematical predictions and experimental validation and address the potential for mathematical models to predict and optimize therapies targeting the stem cell niche. In their review “Osteoblastic and vascular endothelial niches, their control on normal hematopoietic stem cells, and their consequences on the development of leukemia” B. S. Guerrouahen and colleagues provide some common cellular and molecular principles applying to the osteoblastic and vascular hematopoietic niches and discuss altered microenvironment signaling leading to myeloid lineage disease. They also review the emerging evidence for the role of microenvironment in supporting the leukemia-initiating cells (LICs) and the influence of the microenvironment on chemotherapy resistance. The two predominant niches in the bone marrow, the endosteal and vascular niches, are thought to regulate the self-renewal and differentiation of distinct HSC populations, and also dictate HSC behavior with respect to homeostatic requirements and exogenous stresses. In their review article “The Haematopoietic stem cell niche: new insights into the mechanisms regulating haematopoietic stem cell behaviour” A. J. Lilly and colleagues discuss recent research into the cellular and molecular components of endosteal and vascular niches. Taking into account the crosstalk and overlap between cell types and signaling in these two niches, J. Lilly et al. propose that endosteal and vascular niches should be viewed as subcompartments of a single HSC niche. The review by H. C. O'Neill et al. from Australia focuses on the spleen microenvironment as a site of development of novel dendritic-like cells which are phenotypically and functionally distinct from other described antigen-presenting cells. The discovery that the lineage origin and the progenitors for this new type of tissue-specific antigen-presenting cells differ from that of other known dendritic and myeloid cell types suggests that spleen represents a distinct microenvironment for development of a novel myeloid cell type arising from HSCs or progenitors endogenous to spleen. This paper also highlights the need to explore in more detail the contribution of the spleen and its microenvironment to steady-state hematopoiesis. β-Thalassemia is characterized by reduction or absence of β-globin production, resulting in anemia. Current therapies include blood transfusion combined with iron chelation, BM transplantation which is restricted by the matched donor limitation, and gene therapy with β-globin lentiviral vectors. The review by E. Drakopoulou et al. presents the current status of gene therapy for β-thalassemia, its success and limitations, and the novel promising strategies available involving the therapeutic role of HSCs. This paper reviews achievements in improving vector safety and efficiency to stably transduce HSCs, while minimizing insertional mutagenesis. The authors also discuss strategies that result in higher numbers of genetically modified HSCs, including manipulation of the ex vivo HSC culture conditions, use of mobilized HSC, and generation of HSCs from patient-specific induced pluripotent stem (iPS) cells. These novel strategies could set the ground for more successful β-thalassemia gene therapy clinical trials. The papers in this special issue highlight both the advancements and challenges in understanding the role of niches in HSC biology and fate and in the use of HSCs in disease treatment. Roland Jurecic Linheng Li R. Keith Humphries

    image/svg+xml art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos Open Access logo, converted into svg, designed by PLoS. This version with transparent background. http://commons.wikimedia.org/wiki/File:Open_Access_logo_PLoS_white.svg art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos http://www.plos.org/ Europe PubMed Centra...arrow_drop_down
    image/svg+xml art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos Open Access logo, converted into svg, designed by PLoS. This version with transparent background. http://commons.wikimedia.org/wiki/File:Open_Access_logo_PLoS_white.svg art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos http://www.plos.org/
    Europe PubMed Central
    Article . 2012
    Data sources: PubMed Central
    image/svg+xml art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos Open Access logo, converted into svg, designed by PLoS. This version with transparent background. http://commons.wikimedia.org/wiki/File:Open_Access_logo_PLoS_white.svg art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos http://www.plos.org/
    Stem Cells International
    Article
    License: CC BY
    Data sources: UnpayWall
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    image/svg+xml art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos Open Access logo, converted into svg, designed by PLoS. This version with transparent background. http://commons.wikimedia.org/wiki/File:Open_Access_logo_PLoS_white.svg art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos http://www.plos.org/
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      image/svg+xml art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos Open Access logo, converted into svg, designed by PLoS. This version with transparent background. http://commons.wikimedia.org/wiki/File:Open_Access_logo_PLoS_white.svg art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos http://www.plos.org/ Europe PubMed Centra...arrow_drop_down
      image/svg+xml art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos Open Access logo, converted into svg, designed by PLoS. This version with transparent background. http://commons.wikimedia.org/wiki/File:Open_Access_logo_PLoS_white.svg art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos http://www.plos.org/
      Europe PubMed Central
      Article . 2012
      Data sources: PubMed Central
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      Stem Cells International
      Article
      License: CC BY
      Data sources: UnpayWall
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      image/svg+xml art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos Open Access logo, converted into svg, designed by PLoS. This version with transparent background. http://commons.wikimedia.org/wiki/File:Open_Access_logo_PLoS_white.svg art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos http://www.plos.org/
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    Authors: David J. Ramnaraign; Charles Godbout; Kalter Hali; Christian Hegner; +5 Authors

    Endothelial progenitor cell (EPC) therapy has been successfully used in orthopaedic preclinical models to heal bone defects. However, no previous studies have investigated the dose-response relationship between EPC therapy and bone healing. This study aimed to assess the effect of different EPC doses on bone healing in a rat model to define an optimal dose. Five-millimeter segmental defects were created in the right femora of Fischer 344 rats, followed by stabilization with a miniplate and screws. Rats were assigned to one of six groups (control, 0.1 M, 0.5 M, 1.0 M, 2.0 M, and 4.0 M; n = 6), receiving 0, 1 × 105, 5 × 105, 1 × 106, 2 × 106, and 4 × 106 EPCs, respectively, delivered into the defect on a gelatin scaffold. Radiographs were taken every two weeks until the animals were euthanized 10 weeks after surgery. The operated femora were then evaluated using micro-computed tomography and biomechanical testing. Overall, the groups that received higher doses of EPCs (0.5 M, 1.0 M, 2.0 M, and 4.0 M) reached better outcomes. At 10 weeks, full radiographic union was observed in 67% of animals in the 0.5 M group, 83% of animals in the 1.0 M group, and 100% of the animals in the 2.0 M and 4.0 M groups, but none in the control and 0.1 M groups. The 2.0 M group also displayed the strongest biomechanical properties, which significantly improved relative to the control and 0.1 M groups. In summary, this study defined a dose-response relationship between EPC therapy and bone healing, with 2 × 106 EPCs being the optimal dose in this model. Our findings emphasize the importance of dosing considerations in the application of cell therapies aimed at tissue regeneration and will help guide future investigations and clinical translation of EPC therapy.

    image/svg+xml art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos Open Access logo, converted into svg, designed by PLoS. This version with transparent background. http://commons.wikimedia.org/wiki/File:Open_Access_logo_PLoS_white.svg art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos http://www.plos.org/ Journal of Tissue En...arrow_drop_down
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      image/svg+xml art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos Open Access logo, converted into svg, designed by PLoS. This version with transparent background. http://commons.wikimedia.org/wiki/File:Open_Access_logo_PLoS_white.svg art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos http://www.plos.org/ Journal of Tissue En...arrow_drop_down
      image/svg+xml art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos Open Access logo, converted into svg, designed by PLoS. This version with transparent background. http://commons.wikimedia.org/wiki/File:Open_Access_logo_PLoS_white.svg art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos http://www.plos.org/
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  • image/svg+xml art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos Open Access logo, converted into svg, designed by PLoS. This version with transparent background. http://commons.wikimedia.org/wiki/File:Open_Access_logo_PLoS_white.svg art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos http://www.plos.org/
    Authors: Weiss, Kurt R.; Biau, David J.; Bhumbra, Rej; Griffin, Anthony M.; +6 Authors

    Introduction. Ewing's sarcomas (EWSs) of bone and soft tissue are neuroectodermal tumors that affect both axial and appendicular locations. We hypothesized that axial location predicted poor outcome in EWS patients.Materials and Methods. Sixty-seven patients (57 with bone EWS and 10 with soft tissue EWS) were identified from our database. Thirty-four (51%) had axial EWS and 33 (49%) had appendicular EWS. Statistical analyses identified predictors of poor outcome.Results and Discussion. Axial location, large size, metastases at presentation, lack of definitive treatment, and positive surgical margins all correlated with poor outcome in univariate analysis. In multivariate analysis, axial location still predicted poor outcome when adjusted for pretreatment variables. Axial location was not statistically predictive of poor outcome when adjusted for treatment variables.Conclusions. Anatomic location has a negative effect on outcome in EWS that cannot be completely explained by pretreatment or treatment factors. Additional studies are required to determine if there is a biologic difference between axial and appendicular EWS.

    image/svg+xml art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos Open Access logo, converted into svg, designed by PLoS. This version with transparent background. http://commons.wikimedia.org/wiki/File:Open_Access_logo_PLoS_white.svg art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos http://www.plos.org/ Europe PubMed Centra...arrow_drop_down
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    Europe PubMed Central
    Article . 2011
    Data sources: PubMed Central
    image/svg+xml art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos Open Access logo, converted into svg, designed by PLoS. This version with transparent background. http://commons.wikimedia.org/wiki/File:Open_Access_logo_PLoS_white.svg art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos http://www.plos.org/
    image/svg+xml art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos Open Access logo, converted into svg, designed by PLoS. This version with transparent background. http://commons.wikimedia.org/wiki/File:Open_Access_logo_PLoS_white.svg art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos http://www.plos.org/
    Sarcoma
    Article
    License: CC BY
    Data sources: UnpayWall
    image/svg+xml art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos Open Access logo, converted into svg, designed by PLoS. This version with transparent background. http://commons.wikimedia.org/wiki/File:Open_Access_logo_PLoS_white.svg art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos http://www.plos.org/
    Sarcoma; DOAJ
    Article . 2011
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      image/svg+xml art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos Open Access logo, converted into svg, designed by PLoS. This version with transparent background. http://commons.wikimedia.org/wiki/File:Open_Access_logo_PLoS_white.svg art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos http://www.plos.org/ Europe PubMed Centra...arrow_drop_down
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      Europe PubMed Central
      Article . 2011
      Data sources: PubMed Central
      image/svg+xml art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos Open Access logo, converted into svg, designed by PLoS. This version with transparent background. http://commons.wikimedia.org/wiki/File:Open_Access_logo_PLoS_white.svg art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos http://www.plos.org/
      image/svg+xml art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos Open Access logo, converted into svg, designed by PLoS. This version with transparent background. http://commons.wikimedia.org/wiki/File:Open_Access_logo_PLoS_white.svg art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos http://www.plos.org/
      Sarcoma
      Article
      License: CC BY
      Data sources: UnpayWall
      image/svg+xml art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos Open Access logo, converted into svg, designed by PLoS. This version with transparent background. http://commons.wikimedia.org/wiki/File:Open_Access_logo_PLoS_white.svg art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos http://www.plos.org/
      Sarcoma; DOAJ
      Article . 2011
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  • image/svg+xml art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos Open Access logo, converted into svg, designed by PLoS. This version with transparent background. http://commons.wikimedia.org/wiki/File:Open_Access_logo_PLoS_white.svg art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos http://www.plos.org/
    Authors: Ghanbari, Kazem;

    We study a generalized inverse eigenvalue problem (GIEP),Ax=λBx, in whichAis a semi-infinite Jacobi matrix with positive off-diagonal entriesci>0, andB= diag (b0,b1,…), wherebi≠0fori=0,1,…. We give an explicit solution by establishing an appropriate spectral function with respect to a given set of spectral data.

    image/svg+xml art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos Open Access logo, converted into svg, designed by PLoS. This version with transparent background. http://commons.wikimedia.org/wiki/File:Open_Access_logo_PLoS_white.svg art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos http://www.plos.org/ International Journa...arrow_drop_down
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      image/svg+xml art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos Open Access logo, converted into svg, designed by PLoS. This version with transparent background. http://commons.wikimedia.org/wiki/File:Open_Access_logo_PLoS_white.svg art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos http://www.plos.org/ International Journa...arrow_drop_down
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    Authors: Zhou, Yan; Li, Qingwu; Huo, Guanying;

    We propose a novel automatic side-scan sonar image enhancement algorithm based on curvelet transform. The proposed algorithm uses the curvelet transform to construct a multichannel enhancement structure based on human visual system (HVS) and adopts a new adaptive nonlinear mapping scheme to modify the curvelet transform coefficients in each channel independently and automatically. Firstly, the noisy and low-contrast sonar image is decomposed into a low frequency channel and a series of high frequency channels by using curvelet transform. Secondly, a new nonlinear mapping scheme, which coincides with the logarithmic nonlinear enhancement characteristic of the HVS perception, is designed without any parameter tuning to adjust the curvelet transform coefficients in each channel. Finally, the enhanced image can be reconstructed with the modified coefficients via inverse curvelet transform. The enhancement is achieved by amplifying subtle features, improving contrast, and eliminating noise simultaneously. Experiment results show that the proposed algorithm produces better enhanced results than state-of-the-art algorithms.

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    Mathematical Problems in Engineering
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      Mathematical Problems in Engineering
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    Authors: Victor Rogério Garcia Batista; Rafael Ribeiro Correia; Vítor S. Fernandes; Allice Santos Cruz Veras; +7 Authors

    Arterial hypertension promotes urological complications by modifying the functional capacity of the urinary bladder. On the other hand, physical exercise has been suggested as a nonpharmacological tool to improve blood pressure regulation. High-intensity interval training (HIIT) can effectively increase peak oxygen consumption, body composition, physical fitness, and health-related characteristics of adults; however, its action on the urinary bladder is little discussed. In the present study, we verified the effect of HIIT on the modulation of the redox state, morphology, and inflammatory and apoptotic processes of the urinary bladder of hypertensive rats. Spontaneously hypertensive rats (SHR) were divided into two groups: SHR sedentary and SHR submitted to HIIT. Arterial hypertension promoted an increase in the plasma redox state, modified the volume of the urinary bladder, and increased collagen deposition in detrusor muscle. It was also possible to identify, in the sedentary SHR group, an increase in inflammatory markers such as IL-6 and TNF-α in the urinary bladder, as well as a reduction in BAX expression. However, in the HIIT group, reduced blood pressure levels were observed, together with an improvement in morphology, such as a decrease in collagen deposition. HIIT also regulated the proinflammatory response, promoting increases in IL-10 and BAX expressions and in the number of plasma antioxidant enzymes. The present work highlights the intracellular pathways involved with the oxidative and inflammatory capacity of the urinary bladder and the potential effect of HIIT on the regulation of the urothelium and detrusor muscle of hypertensive rats.

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    Authors: Alireza Mirahmadizadeh; Mehdi Sharafi; Jafar Hassanzadeh; Mozhgan Seif; +1 Authors

    Antiretroviral therapy (ART) has improved survival and clinical course amongst HIV/AIDS patients. CD4 cell count is one of the most critical indicators of the disease progression. With respect to the dynamic nature of CD4 cell count during the clinical history of HIV/AIDS, modeling the CD4 cell count changes, which represents the likelihood of disease progression, is of interest to establish or revise treatment strategies and, specifically, to determine the stage at which giving ART is more clinically effective. In this historical cohort study on 917 HIV/AIDS patients in the Iranian “National Registry of HIV/AIDS Care” database, we used the Markov chain model to predict the effectiveness of the ART based on the transition probability of CD4 cell count, measured before and after initiating ART. We found that when the ART was initiated in the earlier stages of HIV infection, good prognosis might be more accessible; that is, after initiating ART at stateCD4≥500, the probability of staying at this state was statistically increased than before the treatment (P<0.001). Also, it was found that initiating ART significantly decreased the probability of CD4 cell count transition to the lower counts (PCD4≥500‐to‐350≤CD4<500<0.001,P350≤CD4<500‐to‐200≤CD4<350<0.001, andP200≤CD4<350‐to‐CD4<200<0.001). In addition, initiating ART showed a statistically significant increase in the probability of CD4 cell count transition from a lower state (350≤CD4<500) to a higher state (CD4≥500) (P=0.009). Furthermore, When CD4 count reaches under 200, even after the initiation of therapy, the probability of CD4 cell count transition to higher levels was not significant (P>0.05). In summary, these results have a message for primary healthcare organizations to extensively identify HIV patients and initiating ART as early as possible.

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    Authors: Gorczynski, Reginald M.;

    The type 1 membrane glycoprotein CD200, widely expressed on multiple cells/tissues, uses a structurally similar receptor (CD200R1), whose expression is more restricted to cells of the myeloid and lymphoid lineages, to transmit signals affecting responses in multiple physiological systems. Thus CD200 expression is reported to exert effects on cancer growth, autoimmune and allergic disorders, infection, transplantation, bone development and homeostasis, and reproductive biology. It was initially thought, based on the idea that CD200R1 was mostly expressed on cells of myeloid origin, that CD200:CD200R1 interactions were primarily dedicated to controlling myeloid cell function. However additional members of the CD200R family have now also been identified, although their function(s) remain unclear, and CD200R1 itself is now known to be expressed by subsets of T cells and other cells. Together these observations add layers of complexity to our understanding of CD200-related regulation. In common with a number of physiological systems, the mechanism(s) of CD200-induced signaling seem to fit within a similar framework of opposing actions of kinases and phosphatases. This paper highlights the advances in our knowledge of immunoregulation achieved following CD200:CD200R interaction and the potential clinical applicability of that information.

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    Authors: Gordji, M. Eshaghi; Khodaei, H.; Kim, Gwang Hui;

    We establish some stability results overp-adic fields for the generalized quadratic functional equation∑k=2n∑i1=2k∑i2=i1+1k+1⋯∑in-k+1=in-k+1nf(∑i=1,i≠i1,…,in-k+1nxi-∑r=1n-k+1xir)+f(∑i=1nxi)=2n-1∑i=1nf(xi),wheren∈Nandn≥2.

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    Abstract and Applied Analysis
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    Abstract and Applied Analysis
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      Abstract and Applied Analysis
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      Abstract and Applied Analysis
      Other literature type . 2012
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    Authors: Sergio B. Sepulveda-Mora; Sylvain G. Cloutier;

    Homogeneous, highly conductive, and transparent silver nanowire thin films were fabricated using a simple dip-coating technique and a subsequent annealing step. Silver nanowires with two different average lengths (11 μm and 19 μm) were used in the sample preparation to analyze the dependence of the sheet resistance on the length of the one-dimensional nanostructures. The best sample had a sheet resistance of 10.2 Ω/□with optical transmittance of 89.9%. Two figures of merit, the electrical to optical conductivity ratio(σDC/σOP)andϕTC, were obtained for all the samples in order to measure their performance as transparent conductive materials.

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    Journal of Nanomaterials
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    Journal of Nanomaterials
    Article . 2012
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      Journal of Nanomaterials
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      Journal of Nanomaterials
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    Authors: Jurecic, Roland; Li, Linheng; Humphries, R. Keith;

    Better understanding of how hematopoietic stem cells (HSCs) balance self-renewal and differentiation is vital for their application in treatment of various diseases and regenerative medicine. During the last decade tremendous advances have been made in identifying a complex network of cellular and molecular factors that influence self-renewal and differentiation of HSCs and characterizing the cellular and molecular components of niches which harbor HSCs. Improving our understanding of the cellular and molecular mechanisms that regulate self-renewal and differentiation of HSCs will have a profound impact on experimental and clinical HSCs research and clinical application of HSCs. Thus, Stem Cells International set out to publish a special issue devoted to the topic of heterogeneity, self-renewal, and differentiation of hematopoietic stem cells. The ongoing research is continuously increasing our knowledge about HSC niches in the bone marrow and in particular about cell types constituting niches and a plethora of molecules and signals that make up the synapse between HSCs and niche cells. A series of three review articles in this issue discuss the role of hematopoietic niches in regulating behavior and function of hematopoietic stem cells and the role of niches in development of leukemias. K. S. Tieu et al. present a review of quantitative approaches to understanding stem cell niche signaling in the hematopoietic system, as well as in other tissues under conditions of homeostasis and carcinogenesis. They explain the benefits of mathematical models in advancing our understanding of the mechanisms that regulate stem cell fate and how this regulation changes in cancer development. K. S. Tieu and colleagues are also highlighting the synergistic relationship between mathematical predictions and experimental validation and address the potential for mathematical models to predict and optimize therapies targeting the stem cell niche. In their review “Osteoblastic and vascular endothelial niches, their control on normal hematopoietic stem cells, and their consequences on the development of leukemia” B. S. Guerrouahen and colleagues provide some common cellular and molecular principles applying to the osteoblastic and vascular hematopoietic niches and discuss altered microenvironment signaling leading to myeloid lineage disease. They also review the emerging evidence for the role of microenvironment in supporting the leukemia-initiating cells (LICs) and the influence of the microenvironment on chemotherapy resistance. The two predominant niches in the bone marrow, the endosteal and vascular niches, are thought to regulate the self-renewal and differentiation of distinct HSC populations, and also dictate HSC behavior with respect to homeostatic requirements and exogenous stresses. In their review article “The Haematopoietic stem cell niche: new insights into the mechanisms regulating haematopoietic stem cell behaviour” A. J. Lilly and colleagues discuss recent research into the cellular and molecular components of endosteal and vascular niches. Taking into account the crosstalk and overlap between cell types and signaling in these two niches, J. Lilly et al. propose that endosteal and vascular niches should be viewed as subcompartments of a single HSC niche. The review by H. C. O'Neill et al. from Australia focuses on the spleen microenvironment as a site of development of novel dendritic-like cells which are phenotypically and functionally distinct from other described antigen-presenting cells. The discovery that the lineage origin and the progenitors for this new type of tissue-specific antigen-presenting cells differ from that of other known dendritic and myeloid cell types suggests that spleen represents a distinct microenvironment for development of a novel myeloid cell type arising from HSCs or progenitors endogenous to spleen. This paper also highlights the need to explore in more detail the contribution of the spleen and its microenvironment to steady-state hematopoiesis. β-Thalassemia is characterized by reduction or absence of β-globin production, resulting in anemia. Current therapies include blood transfusion combined with iron chelation, BM transplantation which is restricted by the matched donor limitation, and gene therapy with β-globin lentiviral vectors. The review by E. Drakopoulou et al. presents the current status of gene therapy for β-thalassemia, its success and limitations, and the novel promising strategies available involving the therapeutic role of HSCs. This paper reviews achievements in improving vector safety and efficiency to stably transduce HSCs, while minimizing insertional mutagenesis. The authors also discuss strategies that result in higher numbers of genetically modified HSCs, including manipulation of the ex vivo HSC culture conditions, use of mobilized HSC, and generation of HSCs from patient-specific induced pluripotent stem (iPS) cells. These novel strategies could set the ground for more successful β-thalassemia gene therapy clinical trials. The papers in this special issue highlight both the advancements and challenges in understanding the role of niches in HSC biology and fate and in the use of HSCs in disease treatment. Roland Jurecic Linheng Li R. Keith Humphries

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    Europe PubMed Central
    Article . 2012
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    Stem Cells International
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      Europe PubMed Central
      Article . 2012
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      Stem Cells International
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    Authors: David J. Ramnaraign; Charles Godbout; Kalter Hali; Christian Hegner; +5 Authors

    Endothelial progenitor cell (EPC) therapy has been successfully used in orthopaedic preclinical models to heal bone defects. However, no previous studies have investigated the dose-response relationship between EPC therapy and bone healing. This study aimed to assess the effect of different EPC doses on bone healing in a rat model to define an optimal dose. Five-millimeter segmental defects were created in the right femora of Fischer 344 rats, followed by stabilization with a miniplate and screws. Rats were assigned to one of six groups (control, 0.1 M, 0.5 M, 1.0 M, 2.0 M, and 4.0 M; n = 6), receiving 0, 1 × 105, 5 × 105, 1 × 106, 2 × 106, and 4 × 106 EPCs, respectively, delivered into the defect on a gelatin scaffold. Radiographs were taken every two weeks until the animals were euthanized 10 weeks after surgery. The operated femora were then evaluated using micro-computed tomography and biomechanical testing. Overall, the groups that received higher doses of EPCs (0.5 M, 1.0 M, 2.0 M, and 4.0 M) reached better outcomes. At 10 weeks, full radiographic union was observed in 67% of animals in the 0.5 M group, 83% of animals in the 1.0 M group, and 100% of the animals in the 2.0 M and 4.0 M groups, but none in the control and 0.1 M groups. The 2.0 M group also displayed the strongest biomechanical properties, which significantly improved relative to the control and 0.1 M groups. In summary, this study defined a dose-response relationship between EPC therapy and bone healing, with 2 × 106 EPCs being the optimal dose in this model. Our findings emphasize the importance of dosing considerations in the application of cell therapies aimed at tissue regeneration and will help guide future investigations and clinical translation of EPC therapy.

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    Authors: Weiss, Kurt R.; Biau, David J.; Bhumbra, Rej; Griffin, Anthony M.; +6 Authors

    Introduction. Ewing's sarcomas (EWSs) of bone and soft tissue are neuroectodermal tumors that affect both axial and appendicular locations. We hypothesized that axial location predicted poor outcome in EWS patients.Materials and Methods. Sixty-seven patients (57 with bone EWS and 10 with soft tissue EWS) were identified from our database. Thirty-four (51%) had axial EWS and 33 (49%) had appendicular EWS. Statistical analyses identified predictors of poor outcome.Results and Discussion. Axial location, large size, metastases at presentation, lack of definitive treatment, and positive surgical margins all correlated with poor outcome in univariate analysis. In multivariate analysis, axial location still predicted poor outcome when adjusted for pretreatment variables. Axial location was not statistically predictive of poor outcome when adjusted for treatment variables.Conclusions. Anatomic location has a negative effect on outcome in EWS that cannot be completely explained by pretreatment or treatment factors. Additional studies are required to determine if there is a biologic difference between axial and appendicular EWS.

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    Europe PubMed Central
    Article . 2011
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    Sarcoma
    Article
    License: CC BY
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    Sarcoma; DOAJ
    Article . 2011
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      Europe PubMed Central
      Article . 2011
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      Sarcoma
      Article
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      Sarcoma; DOAJ
      Article . 2011
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    Authors: Ghanbari, Kazem;

    We study a generalized inverse eigenvalue problem (GIEP),Ax=λBx, in whichAis a semi-infinite Jacobi matrix with positive off-diagonal entriesci>0, andB= diag (b0,b1,…), wherebi≠0fori=0,1,…. We give an explicit solution by establishing an appropriate spectral function with respect to a given set of spectral data.

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    <