Functional role of Nuclear Fators-I in hematopoietic ontogenesis

Nuclear Factor I (NFI) transcriptional factors constitute a family of four members, NFI-A, B, C and X, known for their positive and negative transcriptional regulatory roles in a cell type and promoter specific context. We previously identified NFI-A as a relevant target of the myeloid regulator microRNA-223, then we found that its levels play a key role in directing hematopoietic progenitors to the erythroid or granulocytic lineage. This prompted us to examine whether the expression of NFI-A and/or other NFIs factors could regulate primitive and definitive hematopoiesis in vivo. To this end we initially studied the expression pattern of NFIs factors in different tissues and stages of embryo development of CD1 mice. Our preliminary results indicate that NFI-A presents the most interesting expression pattern among NFIs factors, being express in hematopoietic tissues earlier and at the highest level during embryo development. In addition, performing colony-forming progenitor assays, we found NFI-A expression in primitive erythroid progenitor and during definitive hematopoietic colonies production, implicating it in having a possible role in primitive and definitive hematopoiesis. To elucidate the role of NFI-A in hematopoiesis we used two different strains of NFI-A-/- mice: B6N31 and B6hyb129mice. Histological examinations of hematopoietic tissues of NFI-A-/- mice showed that Nfi-A disruption results in hypocellularity of hematopoietic compartment together with a marked decrease of M/E ratio. Genes expression analysis performed on B6N31 hematopoietic tissues indicates that NFI-A -/- mice have a delay in the repression of embryonic β-globins and a perinatal decrease in adult globins expression, suggesting an involvement for NFI-A in the control of β-globins switching. In addiction NFI-A -/- hematopoietic tissues presents an up-regulation of NFI-B expression, indicating its possible action as compensator of NFI-A. To investigate about the role of NFI-A in adult hematopoiesis, we performed complete blood counts of peripheral blood from adults B6N31 NFI-A +/- and we observed a decreased MCV, an increased RDW and a decreased MCH compared with adult NFI-A +/+ B6N31 mice, demonstrating an haploinsufficiency of NFI-A factor and an altered hemoglobin synthesis. These data indicates that NFI-A could be involved in the pathogenesis of hematological diseases, further underlying its importance in hematopoietic development

Open spaces and environmental design

The urban fabric of any human settlement can be analyzed at two levels: the built fabric and the system of empty spaces. Graphically, the two levels are contrary to each other. The first is the structure generated by the aggregation of the elementary unit that represents its governing and invariable element. It is a component that can be managed and its spatial, functional and structural entity can be controlled due to its “box like” structure. The empty system consists of public and private open spaces that form a network of relational, representative and social spaces but also an interconnecting system. So, the identification of the methods to analyze the environmental characteristics of these empty spaces and, therefore, the criteria to improve the comfort conditions of the users, is the aim of this research. The survey follows the branch of research that studies the methods of intervention in historical centers. The need to carry out project interventions in historic urban fabrics pushes the researchers to find the methods to introduce the comfort levels required by contemporary users and, at the same time, to respect the values to pass down to posterity The choice of a strategy involving a certain degree of invasiveness and reversibility depends on the designer's knowledge of the particular context of intervention For this reason, the project carried out in a context having important values, as it is a minor center, requires a detailed cognitive analysis of the site under study that, inevitably, will limit the designer's freedom. The study area is located in the Abruzzi Region, full of minor historical centers rich in deep cultural values

Economic and environmental assessment of thermal insulation. A case study in the Italian context

Abstract An analysis of the state of the art has shown how current European policy underpins the importance of assessing the impact of different energy efficiency strategies during the life cycle of buildings. In this study a framework is developed for the identification of the optimal material to be used to achieve the highest level of energy efficiency in building retrofits, taking into account environmental and economic elements and comparing different scenarios. For each of these scenarios the Life Cycle Cost Analysis was applied together with related environmental analysis in terms of the production of CO2. The research was applied to an industrial factory in Italy. Results showed that, among ten material with different origin, namely plant, animal, mineral and fossil origin, the optimal thickness varied between 0.023 m of the line fiber, and 0.082 m of the rock wool. From the economic point of view, saving was between 1.58 €/m2 with the linen fiber, and 9.63 €/m2 with the rock wool. Finally, considering the environmental aspect, savings in terms of CO2 was possible only for three of the ten materials, namely cork, sheep wool and fiber glass, respectively equal to 0.14 Kg/m2, 0.65 Kg/m2 and 0.34 Kg/m2. The study has important implications mainly regarding the issue of energy efficiency. Specifically, the opportunity to analyse and compare economic and environmental aspects of a series of alternative materials to improve energy efficiency may provide stakeholders with calculated and objective input for the support of sustainable actions. Sum up, this research has identified a "result oriented" methodology comparing traditional and sustainable materials and measuring the benefits from the correct insulation of a building. These benefits are mainly of an economic and environmental nature and, in this regard, the study helps to strengthen the leadership of the EU for a sustainable use of natural resources within an efficient bioeconomy, essential to achieve Sustainable Development Goals

Redox bases underlying the anti-tumor activity of garlic-contained organo-sulfur compounds: Implication in chemoprevention and chemotherapy

The beneficial effects of phytochemicals on human health have been extensively addressed. The majority of this outcome derives from their capability to function as antioxidants, thus the consumption of foods rich in these compounds is considered an advisable preventive therapy in slowing oxidative stress-mediated degenerative processes, such as those occurring during aging. Nevertheless, high concentrations of redox-active compounds could switch the antioxidant property to a pro-oxidant action leading to cell cycle arrest and death. This aspect place phytochemicals as promising therapeutics particularly for cancer prevention or treatment. Although their beneficial properties are known from ancient times, only during the recent years the molecular mechanisms underlying the anti-proliferative effects mediated by garlic-derived organo-sulfur compounds (OSC) are going to be clarified, with particular regard to what their pro-apoptotic features concerns. This chapter discusses the main findings that have contributed to the comprehension of OSC-mediated redox-dependent events governing growth arrest and apoptosis. Particularly, we report the mechanisms through which OSC have been suggested to generate reactive oxygen species and to modulate the redox state of specific reactive cysteines. Both processes will be argued as necessary events in inducing either irreversible damage to cellular macromolecules (e.g. DNA and cytoskeleton proteins), or waves of signaling finally resulting in the activation of the apoptotic program. In this perspective, the classes of proteins which have been indicated to represent the targets of OSC-mediated oxidative modifications, and to have a role in cellular redox response will be discussed

p38(MAPK)/p53 signalling axis mediates neuronal apoptosis in response to tetrahydrobiopterin-induced oxidative stress and glucose uptake inhibition: implication for neurodegeneration.

BH4 (tetrahydrobiopterin) induces neuronal demise via production of ROS (reactive oxygen species). In the present study we investigated the mechanisms of its toxicity and the redox signalling events responsible for the apoptotic commitment in SH-SY5Y neuroblastoma cells and in mouse primary cortical neurons. We identified in p38(MAPK)/p53 a BH4-responsive pro-apoptotic signalling axis, as demonstrated by the recovery of neuronal viability achieved by gene silencing or pharmacological inhibition of both p38(MAPK) and p53. BH4-induced oxidative stress was characterized by a decrease in the GSH/GSSG ratio, an increase in protein carbonylation and DNA damage. BH4 toxicity and the redox-activated apoptotic pathway were counteracted by the H2O2-scavengers catalase and N-acetylcysteine and enhanced by the GSH neo-synthesis inhibitor BSO (buthionine sulfoximine). We also demonstrated that BH4 impairs glucose uptake and utilization, which was prevented by catalase administration. This effect contributes to the neuronal demise, exacerbating BH4-induced nuclear damage and the activation of the pro-apoptotic p38(MAPK)/p53 axis. Inhibition of glucose uptake was also observed upon treatment with 6-hydroxydopamine, another redox-cycling molecule, suggesting a common mechanism of action for auto-oxidizable neurotoxins

Redox bases underlying the anti-tumor activity of garlic-contained organo-sulfur compounds: Implication in chemoprevention and chemotherapy

The beneficial effects of phytochemicals on human health have been extensively addressed. The majority of this outcome derives from their capability to function as antioxidants, thus the consumption of foods rich in these compounds is considered an advisable preventive therapy in slowing oxidative stress-mediated degenerative processes, such as those occurring during aging. Nevertheless, high concentrations of redox-active compounds could switch the antioxidant property to a pro-oxidant action leading to cell cycle arrest and death. This aspect place phytochemicals as promising therapeutics particularly for cancer prevention or treatment. Although their beneficial properties are known from ancient times, only during the recent years the molecular mechanisms underlying the anti-proliferative effects mediated by garlic-derived organo-sulfur compounds (OSC) are going to be clarified, with particular regard to what their pro-apoptotic features concerns. This chapter discusses the main findings that have contributed to the comprehension of OSC-mediated redox-dependent events governing growth arrest and apoptosis. Particularly, we report the mechanisms through which OSC have been suggested to generate reactive oxygen species and to modulate the redox state of specific reactive cysteines. Both processes will be argued as necessary events in inducing either irreversible damage to cellular macromolecules (e.g. DNA and cytoskeleton proteins), or waves of signaling finally resulting in the activation of the apoptotic program. In this perspective, the classes of proteins which have been indicated to represent the targets of OSC-mediated oxidative modifications, and to have a role in cellular redox response will be discussed

Magnetic Circular Dichroism of Cobalt-Copper and Zinc-Copper Bovine Superoxide Dismutase

Abstract The magnetic circular dichroism of the d-d transitions of Co(II) when substituted for Zn(II) in the Zn(II)-Cu(II) enzyme bovine superoxide dismutase enzyme is reported. Magnetic circular dichroism of the Co(II) chromophore in the Co(II)-Cu(II) enzyme is typical of tetrahedral Co(II) compounds. The magnetic circular dichroism band pattern is almost identical with the magnetic circular dichroism of the anion complexes of Co(II) carbonic anhydrase, implying similar coordination geometries in the two enzyme Co(II) complexes. The Cu(II) chromophore is only weakly induced by the magnetic field, with induced ellipticity an order of magnitude less than that of the Co(II) chromophore. Reduction of the Co(II)-Cu(II) protein causes minor, but significant, changes in the Co(II) site as measured by magnetic circular dichroism

Reactive oxygen species-dependent c-Jun NH2-terminal kinase/c-Jun signaling cascade mediates neuroblastoma cell death induced by diallyl disulfide

The pharmacological properties of garlic and its derivatives are long known, and their underling mechanisms are being extensively investigated. In this study we have addressed the effects of diallyl disulfide (DADS), an oil-soluble garlic molecule, on cell growth of neuroblastoma cell SH-SY5Y, focusing on the redox events associated with this compound. Treatment of SH-SY5Y cells with DADS resulted in arrest of cell cycle in G(2)/M phase and commitment to apoptosis through the activation of the mitochondrial pathway (Bcl-2 down-regulation, cytochrome c release into the cytosol, and activation of caspase-9 and caspase-3). The earliest oxidative event observed after DADS treatment was the increase of production of reactive oxygen species, which reached the maximum yield on 30 min of DADS treatment. The oxidative burst resulted in protein and lipid damage as demonstrated by protein carbonyl accumulation and lipid peroxidation. We demonstrated that apoptosis induction was highly dependent on the activation of the redox-sensitive c-Jun NH2-terminal kinase (JNK)/c-jun pathway. In particular, we established that DADS treatment induces JNK dissociation from glutathione S-transferase and its activation by phosphorylation. Moreover, treatment with JNK inhibitor I significantly reduced DADS-induced apoptosis and treatment with the spin trap 5,5'-dimethyl-1-pyrroline N-oxide or overexpression of the antioxidant enzyme copper, zinc superoxide dismutase, resulted in the inhibition of DADS-mediated toxicity through attenuation of JNK/c-jun pathway activation. Overall, the results suggest a pivotal role for oxidative stress in DADS-induced apoptosis and, taking into account that tumor cells are deficient in antioxidants, suggest a plausible utilization of this compound as an antiproliferative agent in cancer therapy

Solar Photovoltaic Optimal Tilt Angles in Public Building

Abstract The reduction of the consumption of fossil fuels that cause climate change and the encouragement of the use of cleaner renewable sources, appears to be a fundamental objective for achieving the climate aims agreed in Paris. Moreover, the sustainability of the implementation of solutions for energy efficiency in public administration buildings has played a fundamental role in recent years, strengthened also by the regulatory context of energy and environmental policies of European countries. The research fits into this context and it intends to promote a methodology that is able to evaluate the economic and environmental performance of a photovoltaic system applied in a school located in Italy when only the roof inclination angle changes. The economic and environmental performances are evaluated respectively through Life Cycle Cost Analysis and the avoided CO2 emissions. The results show that although the case study does not present the optimal roof inclination angle, there are economic and environmental advantages. Furthermore, the research notes that, considering the characteristics of the photovoltaic system concerned, the optimal roof inclination angle is equal to 40 degrees from an economic and environmental point of view. This methodology could easily support the decision-making process of designers and administrators to make the energy upgrading choices for the promotion of renewable sources. It was applied to a case study, that is a school located in Italy, in the Abruzzo region, in the province of L'Aquila, but it could be easily replicated in other existing public buildings in different locations