Regional value added in Italy over the long run (1891-2001): linking indirect estimates with official figures, and implications

This paper presents value added estimates for the Italian regions, in benchmark years from 1891 until 1951, which are linked to those from official figures available from 1971 in order to offer a long-term picture. Sources and methodology are documented and discussed, whilst regional activity rates and productivity are also presented and compared. Thus some questions are briefly reconsidered: the origins and extent of the north-south divide, the role of migration and regional policy in shaping the pattern of regional inequality, the importance of social capital, and the positioning of Italy in the international debate on regional convergence, where it stands out for the long run persistence of its disparities.

Amplification efficiency: linking baseline and bias in the analysis of quantitative PCR data.

Despite the central role of quantitative PCR (qPCR) in the quantification of mRNA transcripts, most analyses of qPCR data are still delegated to the software that comes with the qPCR apparatus. This is especially true for the handling of the fluorescence baseline. This article shows that baseline estimation errors are directly reflected in the observed PCR efficiency values and are thus propagated exponentially in the estimated starting concentrations as well as 'fold-difference' results. Because of the unknown origin and kinetics of the baseline fluorescence, the fluorescence values monitored in the initial cycles of the PCR reaction cannot be used to estimate a useful baseline value. An algorithm that estimates the baseline by reconstructing the log-linear phase downward from the early plateau phase of the PCR reaction was developed and shown to lead to very reproducible PCR efficiency values. PCR efficiency values were determined per sample by fitting a regression line to a subset of data points in the log-linear phase. The variability, as well as the bias, in qPCR results was significantly reduced when the mean of these PCR efficiencies per amplicon was used in the calculation of an estimate of the starting concentration per sample.

CTL activation is induced by cross-linking of TCR/MHC-peptide-CD8/p56lck adducts in rafts.

To investigate the role of the coreceptor CD8 and lipid rafts in cytotoxic T lymphocyte (CTL) activation, we used soluble mono-and multimeric H-2Kd-peptide complexes and cloned S14 CTL specific for a photoreactive derivative of the Plasmodium berghei circumsporozoite (PbCS) peptide 252-260 [PbCS(ABA)]. We report that activation of CTL in suspension requires multimeric Kd-PbCS(ABA) complexes co-engaging TCR and CD8. Using TCR ligand photo-cross-linking, we find that monomeric Kd-PbCS(ABA) complexes promote association of TCR/CD3 with CD8/p56lck. Dimerization of these adducts results in activation of p56lck in lipid rafts, where phosphatases are excluded. Additional cross-linking further increases p56lck kinase activity, induces translocation of TCR/CD3 and other signaling molecules to lipid rafts and intracellular calcium mobilization. These events are prevented by blocking Src kinases or CD8 binding to TCR-associated Kd molecules, indicating that CTL activation is initiated by cross-linking of CD8-associated p56lck. They are also inhibited by methyl-beta-cyclodextrin, which disrupts rafts and by dipalmitoyl phosphatidylethanolamine, which interferes with TCR signaling. Because efficient association of CD8 and p56lck takes place in rafts, both reagents, though in different ways, impair coupling of p56lck to TCR, thereby inhibiting the initial and essential activation of p56lck induced by cross-linking of engaged TCR.

Linking epigenetics to lipid metabolism: focus on histone deacetylases.

A number of recent studies revealed that epigenetic modifications play a central role in the regulation of lipid and of other metabolic pathways such as cholesterol homeostasis, bile acid synthesis, glucose and energy metabolism. Epigenetics refers to aspects of genome functions regulated in a DNA sequence-independent fashion. Chromatin structure is controlled by epigenetic mechanisms through DNA methylation and histone modifications. The main modifications are histone acetylation and deacetylation on specific lysine residues operated by two different classes of enzymes: Histone acetyltransferases (HATs) and histone deacetylases (HDACs), respectively. The interaction between these enzymes and histones can activate or repress gene transcription: Histone acetylation opens and activates chromatin, while deacetylation of histones and DNA methylation compact chromatin making it transcriptionally silent. The new evidences on the importance of HDACs in the regulation of lipid and other metabolic pathways will open new perspectives in the comprehension of the pathophysiology of metabolic disorders.

The tumor necrosis factor-related apoptosis-inducing ligand receptors TRAIL-R1 and TRAIL-R2 have distinct cross-linking requirements for initiation of apoptosis and are non-redundant in JNK activation.

Overexpression of the tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) receptors, TRAIL-R1 and TRAIL-R2, induces apoptosis and activation of NF-kappaB in cultured cells. In this study, we have demonstrated differential signaling capacities by both receptors using either epitope-tagged soluble TRAIL (sTRAIL) or sTRAIL that was cross-linked with a monoclonal antibody. Interestingly, sTRAIL was sufficient for induction of apoptosis only in cell lines that were killed by agonistic TRAIL-R1- and TRAIL-R2-specific IgG preparations. Moreover, in these cell lines interleukin-6 secretion and NF-kappaB activation were induced by cross-linked or non-cross-linked anti-TRAIL, as well as by both receptor-specific IgGs. However, cross-linking of sTRAIL was required for induction of apoptosis in cell lines that only responded to the agonistic anti-TRAIL-R2-IgG. Interestingly, activation of c-Jun N-terminal kinase (JNK) was only observed in response to either cross-linked sTRAIL or anti-TRAIL-R2-IgG even in cell lines where both receptors were capable of signaling apoptosis and NF-kappaB activation. Taken together, our data suggest that TRAIL-R1 responds to either cross-linked or non-cross-linked sTRAIL which signals NF-kappaB activation and apoptosis, whereas TRAIL-R2 signals NF-kappaB activation, apoptosis, and JNK activation only in response to cross-linked TRAIL.

The effect of standard and high-fluence corneal cross-linking (CXL) on cornea and limbus.

PURPOSE: When treating peripheral ectatic disease-like pellucid marginal degeneration (PMD), corneal cross-linking with UV-A and riboflavin (CXL) must be applied eccentrically to the periphery of the lower cornea, partly irradiating the corneal limbus. Here, we investigated the effect of standard and double-standard fluence corneal cross-linking with riboflavin and UV-A (CXL) on cornea and corneal limbus in the rabbit eye in vivo. METHODS: Epithelium-off CXL was performed in male New Zealand White rabbits with two irradiation diameters (7 mm central cornea, 13 mm cornea and limbus), using standard fluence (5.4 J/cm(2)) and double-standard fluence (10.8 J/cm(2)) settings. Controls were subjected to epithelial removal and riboflavin instillation, but were not irradiated with UV-A. Following CXL, animals were examined daily until complete closure of the epithelium, and at 7, 14, 21, and 28 days. Animals were killed and a corneoscleral button was excised and processed for light microscopy and immunohistochemistry. RESULTS: For both irradiation diameters and fluences tested, no signs of endothelial damage or limbal vessel thrombosis were observed, and time to re-epithelialization was similar to untreated controls. Histological and immunohistochemical analysis revealed no differences in the p63 putative stem cell marker expression pattern. CONCLUSIONS: Even when using fluence twice as high as the one used in current clinical CXL settings, circumferential UV-A irradiation of the corneal limbus does not alter the regenerative capacity of the limbal epithelial cells, and the expression pattern of the putative stem cell marker p63 remains unchanged. This suggests that eccentric CXL may be performed safely in PMD.

Ecology of cutaneous leishmaniasis in Sinai: linking parasites, vectors and hosts

Cutaneous leishmaniasis (CL) is a neglected clinical form of public health importance that is quite prevalent in the northern and eastern parts of Egypt. A comprehensive study over seven years (January 2005-December 2011) was conducted to track CL transmission with respect to both sandfly vectors and animal reservoirs. The study identified six sandfly species collected from different districts in North Sinai: Phlebotomus papatasi, Phlebotomus kazeruni, Phlebotomus sergenti, Phlebotomus alexandri, Sergentomyia antennata and Sergentomyia clydei. Leishmania (-)-like flagellates were identified in 15 P. papatasi individuals (0.5% of 3,008 dissected females). Rodent populations were sampled in the same districts where sandflies were collected and eight species were identified: Rattus norvegicus (n = 39), Rattus rattus frugivorous (n = 13), Rattus rattus alexandrinus (n = 4), Gerbillus pyramidum floweri (n = 38), Gerbillus andersoni (n = 28), Mus musculus (n = 5), Meriones sacramenti (n = 22) and Meriones crassus (n = 10). Thirty-two rodents were found to be positive for Leishmania infection (20.12% of 159 examined rodents). Only Leishmania major was isolated and identified in 100% of the parasite samples. The diversity of both the vector and rodent populations was examined using diversity indices and clustering approaches.

Linking temperature estimates and microstructures in deformed polymineralic mantle rocks

To constrain deformation temperatures of mantle shear zones, we studied a strike-slip shear zone (Hilti massif, Semail ophiolite, Oman) and focused on the interaction between microstructural mechanisms and chemical equilibration processes. Quantitative microfabric analysis on harzburgites with different deformation intensity (porphyroclastic tectonite, mylonite, and ultramylonite) was combined with orthopyroxene geothermometry. The average grain size of all phases decreases with decreasing shear zone thickness. Dynamic recrystallization of porphyroclasts in combination with dissolution-precipitation and nucleation result in small-sized, chemically equilibrated pyroxenes. The composition of orthopyroxene was used to calculate deformation temperatures. In the case of the porphyroclastic tectonites, the chemical composition of orthopyroxene has been reset by diffusion yielding temperature estimates of 880-900 degrees C. The mylonites were deformed by dislocation creep of olivine and show a broad range of calculated temperatures, which result from a combination of grain size reduction and inheritance of equilibrium compositions from earlier high-temperature events and diffusion. In mylonites, diffusion profiles combined with geothermometry and grain size analysis indicate a mylonitic deformation temperature of 800-900 degrees C possibly followed by diffusion. In ultramylonites, the smallest grains (<30 mu m) reveal equilibration at temperatures of similar to 700 degrees C during the last stages of ductile deformation, which was dominated by diffusion creep of olivine. Our results provide a crucial link between temperature and evolution of microstructures from dislocation creep to diffusion creep in mantle shear zones.

Linking life-history traits, ecology, and niche breadth evolution in north american eriogonoids (polygonaceae).

Abstract Macroevolutionary and microevolutionary studies provide complementary explanations of the processes shaping the evolution of niche breadth. Macroevolutionary approaches scrutinize factors such as the temporal and spatial environmental heterogeneities that drive differentiation among species. Microevolutionary studies, in contrast, focus on the processes that affect intraspecific variability. We combine these perspectives by using macroevolutionary models in a comparative study of intraspecific variability. We address potential differences in rates of evolution of niche breadth and position in annual and perennial plants of the Eriogonoideae subfamily of the Polygonaceae. We anticipated higher rates of evolution in annuals than in perennials owing to differences in generation time that are paralleled by rates of molecular evolution. Instead, we found that perennial eriogonoid species present greater environmental tolerance (wider climate niche) than annual species. Niche breadth of perennial species has evolved two to four times faster than in annuals, while niche optimum has diversified more rapidly among annual species than among perennials. Niche breadth and average elevation of species are correlated. Moreover, niche breadth increases more rapidly with mean species elevation in perennials than in annuals. Our results suggest that both environmental gradients and life-history strategy influence rates and patterns of niche breadth evolution.

The effect of university culture and stakeholders' perceptions on university-business linking activities

The present work discusses the effects of university culture and structure on university-business relations, focusing on knowledge transfer activities. It puts forward the thesis that when links between university and business are introduced into the university system as a turn-key proposition rather than as developmental process, the prevailing university culture and structure will exert resistance against change and will oppose the creation of appropriate structures to promote them, with deleterious effects for the university.

An approach for linking score and audio recordings in Makam music of Turkey

The main information sources to study a particular piece of music are symbolic scores and audio recordings. These are complementary representations of the piece and it isvery useful to have a proper linking between the two of the musically meaningful events. For the case of makam music of Turkey, linking the available scores with the correspondingaudio recordings requires taking the specificities of this music into account, such as the particular tunings, the extensive usage of non-notated expressive elements, and the way in which the performer repeats fragmentsof the score. Moreover, for most of the pieces of the classical repertoire, there is no score written by the original composer. In this paper, we propose a methodology to pair sections of a score to the corresponding fragments of audio recording performances. The pitch information obtained from both sources is used as the common representationto be paired. From an audio recording, fundamental frequency estimation and tuning analysis is done to compute a pitch contour. From the corresponding score, symbolic note names and durations are converted to a syntheticpitch contour. Then, a linking operation is performed between these pitch contours in order to find the best correspondences.The method is tested on a dataset of 11 compositions spanning 44 audio recordings, which are mostly monophonic. An F3-score of 82% and 89% are obtained with automatic and semi-automatic karar detection respectively,showing that the methodology may give us a needed tool for further computational tasks such as form analysis, audio-score alignment and makam recognition.

Direct simulation of interface dynamics: linking capillary pressure, interfacial area and surface energy

We perform direct numerical simulations of drainage by solving Navier- Stokes equations in the pore space and employing the Volume Of Fluid (VOF) method to track the evolution of the fluid-fluid interface. After demonstrating that the method is able to deal with large viscosity contrasts and to model the transition from stable flow to viscous fingering, we focus on the definition of macroscopic capillary pressure. When the fluids are at rest, the difference between inlet and outlet pressures and the difference between the intrinsic phase average pressure coincide with the capillary pressure. However, when the fluids are in motion these quantities are dominated by viscous forces. In this case, only a definition based on the variation of the interfacial energy provides an accurate measure of the macroscopic capillary pressure and allows separating the viscous from the capillary pressure components.

Prognostic value of fractional flow reserve: linking physiologic severity to clinical outcomes.

BACKGROUND: Fractional flow reserve (FFR) has become an established tool for guiding treatment, but its graded relationship to clinical outcomes as modulated by medical therapy versus revascularization remains unclear. OBJECTIVES: The study hypothesized that FFR displays a continuous relationship between its numeric value and prognosis, such that lower FFR values confer a higher risk and therefore receive larger absolute benefits from revascularization. METHODS: Meta-analysis of study- and patient-level data investigated prognosis after FFR measurement. An interaction term between FFR and revascularization status allowed for an outcomes-based threshold. RESULTS: A total of 9,173 (study-level) and 6,961 (patient-level) lesions were included with a median follow-up of 16 and 14 months, respectively. Clinical events increased as FFR decreased, and revascularization showed larger net benefit for lower baseline FFR values. Outcomes-derived FFR thresholds generally occurred around the range 0.75 to 0.80, although limited due to confounding by indication. FFR measured immediately after stenting also showed an inverse relationship with prognosis (hazard ratio: 0.86, 95% confidence interval: 0.80 to 0.93; p < 0.001). An FFR-assisted strategy led to revascularization roughly half as often as an anatomy-based strategy, but with 20% fewer adverse events and 10% better angina relief. CONCLUSIONS: FFR demonstrates a continuous and independent relationship with subsequent outcomes, modulated by medical therapy versus revascularization. Lesions with lower FFR values receive larger absolute benefits from revascularization. Measurement of FFR immediately after stenting also shows an inverse gradient of risk, likely from residual diffuse disease. An FFR-guided revascularization strategy significantly reduces events and increases freedom from angina with fewer procedures than an anatomy-based strategy.

Linking microtubules to the activation of CDC42 in fission yeast

Cell polarity is an essential property of most cell types and relies on a dynamic cytoskeleton of actin filaments and microtubules. In rod-shaped S. pombe cells microtubules are organized along the length of the cell and transport polarity factors to cell tips to regulate cell polarity. An important cell polarity factor is the protein Tea4, which is responsible for correct cell morphogenesis and bipolar growth. During my research I confirmed the known transport mechanism of Tea4 and I also showed alternative localization and anchoring mechanisms at the cell ends. Tea4 contains a conserved SH3 domain, the function of which was unknown and my results show that the SH3 domain of Tea4 is essential for Tea4 function in vivo. First, cells with tea4SH3 mutations show aberrant cell shapes and monopolar growth patterns similar to tea4A and in addition SH3 domain is important for proper localization of multiple cell polarity proteins. Second, I showed that Tea4 associates with Type 1 Phosphatase Dis2 through both its SH3 domain and an RVxF motif. Tea4 also binds the DYRK kinase Pomi through its SH3 domain. In addition Tea4 is proposed to promote the local dephosphorylation of Pomi by Dis2 to induce the formation of a cortical gradient from cell ends essential for cell size homeostasis. Polarized growth is also controlled by cell tip-localized Cdc42. This Rho- family GTPase is activated by the Guanine Exchange Factors Gef1 and Scd1 and inactivated by the Rho GTPase Activating Protein Rga4. In this study, I investigated the mechanisms of how Tea4 promotes Cdc42 activation. My work suggests that Tea4 promotes the local exclusion of Rga4, which in turn allows the accumulation of active Cdc42, which may result in growth. Exclusion of Rga4 by Tea4 is likely to be mediated by Dis2-dependent dephosphorylation. These results suggest a molecular pathway that links the microtubule- associated factor Tea4 with Cdc42 to promote cell polarization and morphogenesis. - La polarité cellulaire est une propriété essentielle de la plupart des types cellulaires et s'appuie sur une dynamique des cytosquelettes d'actine et de microtubules. Dans les cellules en forme de bâtonnet de S. pombe les microtubules sont alignés selon l'axe longitudinal de la cellule et les facteurs de polarité transportés aux extrémité cellulaires afin de réguler la polarité cellulaire. Un facteur important de polarité cellulaire est la protéine Tea4, qui est responsable de la morphogenèse des cellules et leur croissance bipolaire. Au cours de mes recherches, j'ai confirmé les mécanismes connus de transport de Tea4 et j'ai aussi mis en évidence d'autres mechanismes de localisation et d'ancrage de Tea4 aux extrémités cellulaires. Tea4 contient un domaine SH3 conservé, dont la fonction était inconnue et mes résultats montrent que le domaine SH3 est essentiel pour la fonction de Tea4 in vivo. Tout d'abord, les cellules avec des mutations tea4sm ont des formes aberrantes et leur croissance est monopolaire de manière similaire au mutant tea4A. De plus ce domaine SH3 est important pour la localisation correcte de plusieurs protéines de polarité cellulaire. Deuxièmement, j'ai montré que Tea4 s'associe avec la Phosphatase de Type-1 Dis2 par son domaine SH3 et un motif RVxF. Tea4 se lie également la kinase DYRK Pomi par son domaine SH3. De plus, Tea4 pourrait favoriser la déphosphorylation locale de Pomi par Dis2 afin d'induire la formation d'un gradient cortical de Pomi essentiel pour l'homéostasie de la longueur des cellules. La croissance polarisée est également contrôlée par la protéine Cdc42 localisée aux extrémités cellulaires. Cette GTPase de la famille de Rho GTPase est activée par les facteurs échange de guanine Gef1 et Scd1 et inactivée par la protéine "Rho GTPase activating" Rga4. Dans cette étude, j'ai étudié les mécanismes d' activation de Cdc42 par Tea4. Mes résultats suggèrent que Tea4 favorise l'exclusion locale de Rga4, ce qui permet l'accumulation de Cdc42 active, nécessaire à la croissance. L' exclusion de Rga4 par Tea4 est vraisemblablement médiée par une déphosphorylation Dis2- dépendente. Ces résultats suggèrent une voie moléculaire qui lie le facteur associé aux microtubules Tea4 à Cdc42 pour promouvoir la polarisation cellulaire et la morphogenèse. - Cell polarity is important for several essential biological functions such as generation of distinct cell fates during development and function of differentiated cells. Defective cell polarity has been related to uncontrolled cell division and subsequently to cancer initiation. Cell polarity depends on a functional cytoskeleton that consists of actin filaments and microtubules, which maintains cell shape, helps cellular motion, enables intracellular protein transport and plays a vital role in cell division. A component of cytoskeleton is microtubules that regulate cell polarization in diverse cell types. During my research, I worked with Schizosaccharomyces pombe, also named fission yeast, a powerful unicellular model organism that allows combination of genetic, biochemical and microscopic analysis for the proper study of cell polarity. Microtubule-associated protein Tea4 is transported to cell tips where it is thought to organize polarized growth. I showed that Tea4 and its evolutionarily conserved SH3 domain play an important role for maintenance of fission yeast cells shape and growth. Furthermore, Tea4 is responsible for the proper localization of multiple polarity proteins and acts as a mediator to control the local activity of an essential polarity regulator called Cdc42. Thus, my results provide a better understanding of the molecular mechanisms that regulate cell polarity. - La polarité cellulaire est importante pour plusieurs fonctions biologiques essentielles telles que la différenciation cellulaires au cours du développement et de la fonction de cellules différenciées. Les défauts de la polarité cellulaire ont été liés à des divisions cellulaires incontrôlées et à l'initiation de tumeur. La polarité cellulaire dépend d'un cytosquelette fonctionnel, qui maintient la forme des cellules, aide à la migration cellulaire, permet le transport intracellulaire des protéines et joue un rôle essentiel dans la division cellulaire. Un composant du cytosquelette est constitué de microtubules qui régissent la polarisation cellulaire dans divers types cellulaires. Au cours de mes recherches, j'ai travaillé avec Schizosaccharomyces pombe, appelé également levure fissipare, un modèle unicellulare puissant qui permet la combinaison de différentes d'approches expérimentales: génétiques, biochimiques et microscopiques pour l'étude de la polarité cellulaire. La protéine Tea4 associée aux microtubules est transportée aux extrémités cellulaires où elle organise la croissance polarisée. J'ai montré que Tea4 et son domaine conservé SH3 jouent un rôle important pour le maintien de la forme des cellules de levure et leur croissance. De plus, Tea4 est responsable de la localisation correcte de multiples facteurs de polarité et agit comme un médiateur pour contrôler l'activité locale d'un régulateur de polarité essentiel appelé Cdc42. Ainsi, mes résultats permettent de mieux comprendre les mécanismes moléculaires qui régulent la polarité cellulaire.