130,869 research outputs found
Post-transcriptional mechanisms in BCR/ABL leukemogenesis: role of shuttling RNA-binding proteins.
No full textShuttling hnRNPs control the fate of eukaryotic mRNAs throughout their journey from the active site of transcription to that of translation; thus, gain or loss of their function in hematopoietic cells might result in altered hematopoiesis and/or be associated with the process of leukemogenesis. In BCR/ABL-expressing cells, there is a marked increase in the protein levels FUS, hnRNP A1 and hnRNP E2, three RNA-binding proteins involved in the regulation of mRNA processing, nucleocytoplasmic export, and translation. Ectopic expression and/or inhibition of the activity of these RNA-binding proteins affects proliferation, survival, and differentiation of normal and BCR/ABL-expressing cells, suggesting that enhanced expression/activity of certain RNA-binding proteins plays an important, but as yet unrecognized, role in BCR/ABL leukemogenesis. The identification of the mRNA subsets associated with RNA-binding proteins upregulated in BCR/ABL-expressing cells should functionally link the process of leukemogenesis with alteration of mRNA metabolism
Translational regulation by the p210 BCR/ABL oncoprotein
No full textThe ability of oncogenic proteins to regulate the rate of translation of specific mRNA subsets may be a rapid and efficient mechanism to modulate the levels and, in many cases, the activity of the corresponding proteins. In the past few years, we have identified several RNA binding proteins with translation regulatory activity whose expression is markedly activated in the blast crisis of chronic myelogenous leukemia, which represents the most malignant disease stage. Perturbation of the activity of some RNA binding proteins suppresses the leukemogenic potential of BCR/ABL-expressing cells. Most importantly, we have identified some of the targets of these RNA binding proteins. Two of these targets, c/ebp alpha and mdm2 mRNAs, are directly relevant for the altered differentiation and survival of leukemic cells. The identification of mRNA targets translationally regulated by RNA binding proteins overexpressed in tumor cells may lead to the development of therapeutic strategies aimed at modulating the translation rate of specific mRNAs
The biology of CML blast crisis
No full textChronic myelogenous leukemia (CML) evolves from a chronic phase characterized by the Philadelphia chromosome as the sole genetic abnormality into blast crisis, which is often associated with additional chromosomal and molecular secondary changes. Although the pathogenic effects of most CML blast crisis secondary changes are still poorly understood, ample evidence suggests that the phenotype of CML blast crisis cells (enhanced proliferation and survival, differentiation arrest) depends on cooperation of BCR/ABL with genes dysregulated during disease progression. Most genetic abnormalities of CML blast crisis have a direct or indirect effect on p53 or Rb (or both) gene activity, which are primarily required for cell proliferation and survival, but not differentiation. Thus, the differentiation arrest of CML blast crisis cells is a secondary consequence of these abnormalities or is caused by dysregulation of differentiation-regulatory genes (le, C/EBPalpha). Validation of the critical role of certain secondary changes (le, loss of p53 or C/EBPalpha function) in murine models of CMIL blast crisis and in in vitro assays of BCR/ABL transformation of human hematopoietic progenitors might lead to the development of novel therapies based on targeting BCR/ABL and inhibiting or restoring the gene activity gained or lost during disease progression (ie, p53 or C/EBPalpha)
Agro-energy production as a driving force in the socio-ecological transition of rural environments: a significant case study within the Alta Murgia National Park.
No full textPapers on Territorial Intelligence and Sustainable economics within the new culture of development, ENTI, Liège.This paper explores the possibility of considering the productive environment of a South-European rural region, the Alta Murgia National Park in the Italian region of Apulia, as the socio-economic framework for a new culture of territorial development, ingenerated by the local diffusion of dedicated biomass crops. We intend to draw particular attention to the processes involved in the implementation of the green energy and energy efficiency policies, at the territorial and regional levels, and their material and immaterial (social perception) impacts on the local rural landscape.Cette étude se propose d'analyser le contexte socio-économique du territoire rural du Parc National de l'Alta Murgia, au sein de la région italienne de Pouilles, à l'aune des changements induits par la diffusion des cultures dédiées à la production de biomasses et biocarburants et de la conséquente expérimentation d'une nouvelle culture du développement territorial. Cette hypothèse sera explorée à partir d'une réflexion sur l'application des principes de durabilité et d'efficience énergétique au sein des cycles productifs propres aux entreprises agricoles et zootechniques locales, ainsi que sur leur retombées physiques et liées aux représentations sociales du paysage rural
Stability charts based on the finite element method for underground cavities in soft carbonate rocks: validation through case-study applications
No full textThe stability of man-made underground cavities in soft rocks interacting with overlying structures and infrastructures represents a challenging problem to be faced. Based upon the results of a large number of parametric twodimensional (2-D) finite-element analyses of ideal cases of underground cavities, Accounting for the variability both cave geometrical features and rock mechanical properties, specific charts have been recently proposed in the literature to assess at a preliminary stage the stability of the cavities. The purpose of the present paper is to validate the efficacy of the stability charts through the application to several case studies of underground cavities, considering both quarries collapsed in the past and quarries still stable. The stability graphs proposed by Perrotti et al. (2018) can be useful to evaluate, in a preliminary way, a safety margin for cavities that have not reached failure and to detect indications of predisposition to local or general instability phenomena. Alternatively, for sinkholes that already occurred, the graphs may be useful in identifying the conditions that led to the collapse, highlighting the importance of some structural elements (as pillars and internal walls) on the overall stability of the quarry system
Granulocytic differentiation of normal hematopoietic precursor cells induced by transcriptional factor PU.1 correlates with negative regulation of the c-myb promoter.
No full textNumerous transcription factors allow hematopoietic cells to respond to lineage- and stage-specific cytokines and/or to act as their effectors. The transcription factors PU.1 and c-Myb are essential for hematopoiesis, most likely acting at distinct stages of differentiation, but sharing a common set of target genes. To determine whether PU.1 and c-Myb are functionally interrelated, murine bone marrow (BM) cells and 32Dcl3 murine myeloid precursor cells were infected with a retrovirus carrying a PU.1 cDNA and assessed for myeloid colony formation and for granulocytic differentiation, respectively. Compared with noninfected normal BM cells or to cells infected with an empty virus, hematopoietic precursor cells expressing PU.1 formed an increased number of interleukin-3 (IL-3) and granulocyte colony-stimulating factor (G-CSF )–stimulated colonies. Moreover, granulocytic differentiation of 32Dcl3 cells constitutively expressing PU.1 was accelerated, as indicated by morphology and by expression of differentiation markers. Downregulation of c-Myb protein levels by expression of an antisense c-myb construct was also associated with a faster kinetics of 32Dcl3 granulocytic differentiation. Sequence analysis of the 5′ flanking region of the c-myb gene revealed a consensus PU box at position +16 to +21 able to specifically interact in electrophoretic mobility shift assays with either bacterially synthesized PU.1 protein or whole cell extracts from differentiated 32Dcl3 cells. Transient expression of PU.1 in cotransfection assays in different cell lines resulted in inhibition of chloramphenicol acetyl transferase activity driven by different segments of the c-myb promoter. Moreover, such an effect was dependent on an intact PU box. Thus, the ability of PU.1 to potentiate terminal myeloid differentiation appears to involve downregulation of c-myb expression, an essential step during differentiation of hematopoietic precursor cells
Altered mRNA translation: possible mechanism for CML disease progression.
No full textChronic myelogenous leukemia (CML) is a clonal disorder arising from neoplastictransformation of the hematopoietic stem cell.1 The typical clinical course of CMLinvolves progression from a protracted chronic phase (CP) to a rapidly fatal blast crisis(BC) characterized by clonal expansion of an immature population of myeloid blast cellswhich exhibit enhanced proliferative potential, reduced susceptibility to apoptosis, anddifferentiation arrest. The latter feature is typical of CML-BC as apparently normalneutrophils and late myeloid precursors accumulate in the bone marrow and peripheralblood of CML-chronic phase patients.1,2 The introduction of the Abl kinase inhibitorGleevec (imatinib mesylate or STI571) as the drug of choice in the treatment of CML islikely to have a profound effect on the course of chronic phase CML. However, in blastcrisis CML, the therapeutic effect of Gleevec is transient and relapse of the disease is themost frequent outcome.3 Thus, it remains critically important to understand the molecularmechanisms underlying progression of CML from chronic phase to blast crisis, as thisadvanced disease stage does not respond to conventional therapy and is associated with ahigh mortality rate.While there is no doubt that expression of the BCR/ABL oncoprotein in hematopoieticstem cells is the initiating event in CML, it is somewhat controversial whether BCR/ABLplays an equally essential role during disease progression or in the blast crisis disease stage.In growth factor-dependent cell lines, ectopic expression of the BCR/ABL oncoproteinis sufficient to induce factor-independent proliferation, increased survival, and differentiationarrest, a phenotype reminiscent of that of CML blast crisis cells.4,5 However, constitutiveexpression of BCR/ABL in normal primary marrow cells leads to a myeloproliferativedisorder which is, instead, reminiscent of chronic phase CML.6 Thus, it is unclear whetherBCR/ABL oncogenic activity per se accounts for CML disease progression or if secondarygenetic alterations are required. In any case, continuous expression/activity of BCR/ABLis necessary for maintaining the leukemic phenotype in mice.7,8There is evidence that genetic inactivation of p53 occurs in blast crisis CML. Althougha p53-deficient background appears to favor blastic transformation in the appropriatemouse models,9,10 mutations in the p53 gene have been detected only in the 25% of blastcrisis.11 Another recurrent mutation in blast crisis CML is the double Philadelphiachromosome, which is detected in 20% of cases.12 In addition, expression of BCR/ABLis higher in mononuclear cells from blast crisis compared to chronic phase CMLpatients,13 and growth factor-independent and differentiation-arrested cell lines expressinghigh doses of BCR/ABL develop from growth factor-dependent cells that express low levelsof the p210 BCR/ABL oncoprotein.14 Thus, high levels of BCR/ABL in the appropriatetarget cells may have a role in blastic transformation. Consistent with this, the increasedexpression of BCR/ABL during disease progression and transformation of growth factor-dependent myeloid precursor cell lines correlates with changes in gene expression, some ofwhich involve regulators of mRNA metabolism like FUS, hnRNP A1, hnRNP E2 andLa.5,14-16In particular, the increased expression of hnRNP E2 and La, two shuttling RNA bindingproteins which function as regulators of mRNA translation,17,18 suggests that BCR/ABLand, perhaps, other oncogenic tyrosine kinases, may modulate gene expression at thetranslational level
Designing Nature as Energy Infrastructure. Envisioning new Aesthetics through Landscape Design
No full textThe main goals of this contribution are twofold. Firstly, it explores the hypothesis of considering landscape as a pervasive energy infrastructure both in action (in esse) and in potentia (in posse). Secondly, this fundamental hypothesis is developed with regard to the emergence of new aesthetics related to the notion of nature as a production and supply system of different forms of energy (endosomatic and exosomatic) and of energy or matter transformation processes (photosynthesis, composting, evapotranspiration, etc.). Our argumentation is developed in three main steps.
In the first part, we assess the potential for landscape as an energy infrastructure, with regard to speculation during the last decade on the notion of “infrastructure” (as a concept and an object) in North-American landscape urbanism, and the consequent development of the landscape infrastructure approach. Our hypothesis of considering landscape as an energy infrastructure is then explored by taking into account the contribution of ecology as the study of nature in terms of matter, energy, and organization.
In the second part, we analyze the role of landscape architecture practice in establishing a new agency and new scales and scopes for the design of landscape infrastructure. If we consider nature in terms of an energy infrastructure, both in esse and in posse, new strategies based on landscape architecture savoir-faire, specific tools, and techniques may emerge with the purpose of capitalizing on the energy potential embedded in the heterogeneous forms of nature.
In the final part, we develop critical considerations of the aesthetic values related to the energetic dimension of landscape as infrastructure. This consideration entails the search for new representations and aesthetic codes of nature, developed at the intersection of the fields of environmental art and natural science, and where nature is intended as a production and supply system of different forms of energy
Mucositis in the treatment of haematological malignancies
No full textP. Niscola, L. Scaramucci, C. Romani, L. Cupelli, A. Tendas, T. Dentamaro, M. Ales, M. Giovannini, D. Piccioni, B. Tolu, M. Giovannini, A. Perrotti, D. Keefe and P. de Fabritii
MeSH term explosion and author rank improve expert recommendations
Get PDFInformation overload is an often-cited phenomenon that reduces the productivity, efficiency and efficacy of scientists. One challenge for scientists is to find appropriate collaborators in their research. The literature describes various solutions to the problem of expertise location, but most current approaches do not appear to be very suitable for expert recommendations in biomedical research. In this study, we present the development and initial evaluation of a vector space model-based algorithm to calculate researcher similarity using four inputs: 1) MeSH terms of publications; 2) MeSH terms and author rank; 3) exploded MeSH terms; and 4) exploded MeSH terms and author rank. We developed and evaluated the algorithm using a data set of 17,525 authors and their 22,542 papers. On average, our algorithms correctly predicted 2.5 of the top 5/10 coauthors of individual scientists. Exploded MeSH and author rank outperformed all other algorithms in accuracy, followed closely by MeSH and author rank. Our results show that the accuracy of MeSH term-based matching can be enhanced with other metadata such as author rank
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