Sphingosine 1-phosphate receptor 1 is required for MMP-2 function in bone marrow mesenchymal stromal cells: implications for cytoskeleton assembly and proliferation

Bone marrow-derived mesenchymal stromal cell- (BM-MSC-) based therapy is a promising option for regenerative medicine. An important role in the control of the processes influencing the BM-MSC therapeutic efficacy, namely, extracellular matrix remodelling and proliferation and secretion ability, is played by matrix metalloproteinase- (MMP-) 2. Therefore, the identification of paracrine/autocrine regulators of MMP-2 function may be of great relevance for improving BM-MSC therapeutic potential. We recently reported that BM-MSCs release the bioactive lipid sphingosine 1-phosphate (S1P) and, here, we demonstrated an impairment of MMP-2 expression/release when the S1P receptor subtype S1PR1 is blocked. Notably, active S1PR1/MMP-2 signalling is required for F-actin structure assembly (lamellipodia, microspikes, and stress fibers) and, in turn, cell proliferation. Moreover, in experimental conditions resembling the damaged/regenerating tissue microenvironment (hypoxia), S1P/S1PR1 system is also required for HIF-1α expression and vinculin reduction. Our findings demonstrate for the first time the trophic role of S1P/S1PR1 signalling in maintaining BM-MSCs' ability to modulate MMP-2 function, necessary for cytoskeleton reorganization and cell proliferation in both normoxia and hypoxia. Altogether, these data provide new perspectives for considering S1P/S1PR1 signalling a pharmacological target to preserve BM-MSC properties and to potentiate their beneficial potential in tissue repair

Ribosomal stress activates eEF2K-eEF2 pathway causing translation elongation inhibition and recruitment of Terminal Oligopyrimidine (TOP) mRNAs on polysomes

The synthesis of adequate amounts of ribosomes is an essential task for the cell. It is therefore not surprising that regulatory circuits exist to organize the synthesis of ribosomal components. It has been shown that defect in ribosome biogenesis (ribosomal stress) induces apoptosis or cell cycle arrest through activation of the tumor suppressor p53. This mechanism is thought to be implicated in the pathophysiology of a group of genetic diseases such as Diamond Blackfan Anemia which are called ribosomopathies. We have identified an additional response to ribosomal stress that includes the activation of eukaryotic translation elongation factor 2 kinase with a consequent inhibition of translation elongation. This leads to a translational reprogramming in the cell that involves the structurally defined group of messengers called terminal oligopyrimidine (TOP) mRNAs which encode ribosomal proteins and translation factors. In fact, while general protein synthesis is decreased by the impairment of elongation, TOP mRNAs are recruited on polysomes causing a relative increase in the synthesis of TOP mRNA-encoded proteins compared to other proteins. Therefore, in response to ribosomal stress, there is a change in the translation pattern of the cell which may help restore a sufficient level of ribosomes

Precipitation formation in low-level mixed-phase clouds: determining relevant processes and drivers based on cloud radar observations from a high Arctic site

Low-level mixed-phase clouds (LLMPCs) shroud large portions of Earth’s surface at high latitudes. They have been shown to dramatically affect the surface energy budget, yet, large uncertainties in their model representation remain, both in climate simulations, and in numerical weather prediction. Both computational limitations and poor understanding of a number of processes taking place in LLMPCs are thought to give rise to such uncertainties. In particular, precipitation formation processes have been relatively understudied in LLMPCs, and reaching a refined understanding is expected to lead to an improvement in model performance, as precipitation determines the cloud’s mass sink, and hence lifetime. In this dissertation, precipitation formation processes are investigated in LLMPCs at the high Arctic site of Ny-Ålesund, based on long-term cloud radar observations. Cloud radars are in fact especially suited for ice microphysical studies, due to the wide spectrum of observational fingerprints of ice microphysical processes that they provide. Doppler radar observations provide information on dynamics, multi-frequency radar observations on ice particle size, and polarimetric radar observations on particle shape and concentration. Radar data are combined with thermodynamic information, which further allows to discriminate between ice microphysical processes, due to their high sensitivity to temperature. In the first part of the dissertation, the relevance of the aggregation process for LLMPCs at Ny-Ålesund is assessed. Aggregation occurs when ice particles collide to form larger ice particles. A long-term dataset of dual-frequency radar observations, as well as thermodynamic information, is used to statistically assess the relevance of aggregation and its sensitivity to varying cloud thermodynamic conditions. The study finds that larger aggregate snowflakes are predominantly produced in LLMPCs whose mixed-phase layer is at temperatures compatible with the growth and subsequent mechanical entanglement of dendritic crystals. Surprisingly, the second enhanced aggregation zone close to the 0°C isotherm, typically observed in deeper cloud systems, is absent. In the second part, a novel state-of-the-art long-term dataset developed within this dissertation is presented. It combines dual-frequency and polarimetric Doppler cloud radar observations, together with thermodynamic information, and other auxiliary variables. After detailing the processing and curation approaches, the results on aggregation are confirmed, and expanded upon. Additionally, temperature regimes where columnar ice particles, riming, i.e., the collection of supercooled liquid droplets by ice crystals, and secondary ice production are likely to occur are identified. In the final part of the dissertation, the developed dataset is used to assess the effect of turbulence on aggregation and riming in LLMPCs at Ny-Ålesund. LLMPCs are in fact inherently turbulent, and maintained by turbulent overturning generated at cloud top. The turbulent kinetic energy dissipation rate (EDR) is retrieved, and the sensitivity of aggregation and riming to varying EDR conditions is investigated. It is shown that higher EDR regimes enhance the aggregation of particles, and are associated with signatures of increased ice particle concentration, possibly caused by fragmentation of ice particles. In temperature regimes more favorable to riming, turbulence dramatically enhances the particles’ fall velocities, denoting higher degrees of riming

Effects of pet exposure in the first year of life on respiratory and allergic symptoms in 7-yr-old children. The SIDRIA-2 study

The effects of pet exposure on the development of respiratory symptoms have recently been the matter of vivid discussion. Our objective was to determine the effects of exposure to cat or dog in the first year of life on subsequent respiratory/allergic symptoms in children in a large Italian multicentre study. As part of the SIDRIA-2 Study (Studi Italiani sui Disturbi Respiratori dell'Infanzia e l'Ambiente 2002), the parents of 20016 children (median age 7 yr) provided information on indoor exposures at different times in life and respiratory/allergic symptoms through questionnaires. Logistic regression analyses were performed taking into account cat or dog exposure at different times in life and adjusting for the presence of the other pet, mould exposure, gender, age, parental education, maternal smoking during the first year of life, current passive smoking, family history of asthma/rhinitis/eczema and other potential confounders. Neither significant effects of dog exposure in the first year of life nor in other periods were found on respiratory/allergic symptoms after adjusting for the other covariates. Cat exposure in the first year of life was significantly and independently associated with current wheezing [OR (95% CI) 1.88 (1.33-2.68), p < 0.001] and current asthma [1.74 (1.10-2.78), p < 0.05] and border-line associated with current rhinoconjunctivitis [1.43 (0.97-2.11), p = 0.07]. No other effects of cat exposure were found on respiratory/allergic symptoms. Cat, but not dog, exposure in the first year of life is an independent risk factor for current wheezing, current asthma and current rhinoconjunctivitis at the age of 7

Pur-alpha functionally interacts with FUS carrying ALS-associated mutations

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder due to motor neuron loss. Fused in sarcoma (FUS) protein carrying ALS-associated mutations localizes to stress granules and causes their coalescence into larger aggregates. Here we show that Pur-alpha physically interacts with mutated FUS in an RNA-dependent manner. Pur-alpha colocalizes with FUS carrying mutations in stress granules of motoneuronal cells differentiated from induced pluripotent stem cells and that are derived from ALS patients. We observe that both Pur-alpha and mutated FUS upregulate phosphorylation of the translation initiation factor eukaryotic translation initiation factor 2 alpha and consistently inhibit global protein synthesis. In vivo expression of Pur-alpha in different Drosophila tissues significatively exacerbates the neurodegeneration caused by mutated FUS. Conversely, the downregulation of Pur-alpha in neurons expressing mutated FUS significatively improves fly climbing activity. All these findings suggest that Pur-alpha, through the control of mRNA translation, might be involved in the pathogenesis of ALS associated with the mutation of FUS, and that an alteration of protein synthesis may be directly implicated in the disease. Finally, in vivo RNAi-mediated ablation of Pur-alpha produced locomotion defects in Drosophila, indicating a pivotal role for this protein in the motoneuronal function

Big Data Analytics National Educational System Monitoring and Decision Making

This paper reviews the applications of big data in supporting monitoring and decision making in the National Educational System. It describes different types of monitoring methodologies and explores the opportunities, challenges and benefits of incorporating big data applications in order to study the National Educational System. This approach allows to analyze schools as entities, which included in a local context with specific social, economic, and cultural development features. In addition, the paper attempts to identify the prerequisites that support the implementation of data analysis in the national educational system. This review reveals that there are several opportunities for using big data (structured and unstructured information) in the educational system, in order to improve strategic multidimensional knowledge for decision making and developing educational policies; however, there are still many issues and challenges that need to be addressed so as to achieve a better use of this technology

Epidemiological patterns of asbestos exposure and spatial clusters of incident cases of malignant mesothelioma from the Italian national registry.

BACKGROUND: Previous ecological spatial studies of malignant mesothelioma cases, mostly based on mortality data, lack reliable data on individual exposure to asbestos, thus failing to assess the contribution of different occupational and environmental sources in the determination of risk excess in specific areas. This study aims to identify territorial clusters of malignant mesothelioma through a Bayesian spatial analysis and to characterize them by the integrated use of asbestos exposure information retrieved from the Italian national mesothelioma registry (ReNaM). METHODS: In the period 1993 to 2008, 15,322 incident cases of all-site malignant mesothelioma were recorded and 11,852 occupational, residential and familial histories were obtained by individual interviews. Observed cases were assigned to the municipality of residence at the time of diagnosis and compared to those expected based on the age-specific rates of the respective geographical area. A spatial cluster analysis was performed for each area applying a Bayesian hierarchical model. Information about modalities and economic sectors of asbestos exposure was analyzed for each cluster. RESULTS: Thirty-two clusters of malignant mesothelioma were identified and characterized using the exposure data. Asbestos cement manufacturing industries and shipbuilding and repair facilities represented the main sources of asbestos exposure, but a major contribution to asbestos exposure was also provided by sectors with no direct use of asbestos, such as non-asbestos textile industries, metal engineering and construction. A high proportion of cases with environmental exposure was found in clusters where asbestos cement plants were located or a natural source of asbestos (or asbestos-like) fibers was identifiable. Differences in type and sources of exposure can also explain the varying percentage of cases occurring in women among clusters. CONCLUSIONS: Our study demonstrates shared exposure patterns in territorial clusters of malignant mesothelioma due to single or multiple industrial sources, with major implications for public health policies, health surveillance, compensation procedures and site remediation programs