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Showing papers by "University of Udine published in 2008"


Journal ArticleDOI
Georges Aad1, M. Ackers2, F. Alberti, M. Aleppo3  +264 moreInstitutions (18)
TL;DR: In this article, the silicon pixel tracking system for the ATLAS experiment at the Large Hadron Collider is described and the performance requirements are summarized and detailed descriptions of the pixel detector electronics and the silicon sensors are given.
Abstract: The silicon pixel tracking system for the ATLAS experiment at the Large Hadron Collider is described and the performance requirements are summarized. Detailed descriptions of the pixel detector electronics and the silicon sensors are given. The design, fabrication, assembly and performance of the pixel detector modules are presented. Data obtained from test beams as well as studies using cosmic rays are also discussed.

709 citations


Journal ArticleDOI
TL;DR: The proposed work addresses anomaly detection by means of trajectory analysis, an approach with several application fields, most notably video surveillance and traffic monitoring, based on single-class support vector machine (SVM) clustering, where the novelty detection SVM capabilities are used for the identification of anomalous trajectories.
Abstract: During the last years, the task of automatic event analysis in video sequences has gained an increasing attention among the research community. The application domains are disparate, ranging from video surveillance to automatic video annotation for sport videos or TV shots. Whatever the application field, most of the works in event analysis are based on two main approaches: the former based on explicit event recognition, focused on finding high-level, semantic interpretations of video sequences, and the latter based on anomaly detection. This paper deals with the second approach, where the final goal is not the explicit labeling of recognized events, but the detection of anomalous events differing from typical patterns. In particular, the proposed work addresses anomaly detection by means of trajectory analysis, an approach with several application fields, most notably video surveillance and traffic monitoring. The proposed approach is based on single-class support vector machine (SVM) clustering, where the novelty detection SVM capabilities are used for the identification of anomalous trajectories. Particular attention is given to trajectory classification in absence of a priori information on the distribution of outliers. Experimental results prove the validity of the proposed approach.

507 citations


Journal ArticleDOI
TL;DR: Primary aldosteronism is associated with a cardiovascular complication rate out of proportion to blood pressure levels that benefits substantially from surgical and medical treatment in the long term.
Abstract: Background Experimental and human studies demonstrate that long-term exposure to elevated aldosterone levels results in cardiac and vascular damage. Methods We investigated long-term cardiovascular outcomes in patients with primary aldosteronism after surgical or medical treatment. Fifty-four patients with or without evidence of adrenal adenomas were prospectively followed up for a mean of 7.4 years after treatment with adrenalectomy or spironolactone. Patients with primary aldosteronism were compared with patients with essential hypertension and were treated to reach a blood pressure of less than 140/90 mm Hg. The main outcome measure was a combined cardiovascular end point comprising myocardial infarction, stroke, any type of revascularization procedure, and sustained arrhythmias. Results At baseline, the prevalence of cardiovascular events was greater in primary aldosteronism (35%) than in essential hypertension (11%) (odds ratio, 4.61; 95% confidence interval, 2.38-8.95; P P = .85). Cox analysis indicated that older age and longer duration of hypertension were factors independently associated with the cardiovascular end point. Cardiovascular outcome was comparable in patients with aldosteronism treated with adrenalectomy vs aldosterone antagonists ( P = .71). Conclusion Primary aldosteronism is associated with a cardiovascular complication rate out of proportion to blood pressure levels that benefits substantially from surgical and medical treatment in the long term.

494 citations


Journal ArticleDOI
TL;DR: New recommendations have been made regarding the following: boundaries between levels I and II and between levels III/IV and VI; terminology of the superior mediastinal nodes; and the method of submitting surgical specimens for pathologic analysis.
Abstract: Objective To update the guidelines for neck dissection terminology, as previously recommended by the American Head and Neck Society. Participants Committee for Neck Dissection Classification, American Head and Neck Society; representation from the Committee for Head and Neck Surgery and Oncology, American Academy of Otolaryngology–Head and Neck Surgery (T.A.D.). Evidence Review of current literature on neck dissection classification. Consensus Process Semiannual face-to-face meetings of the Committee for Neck Dissection Terminology and e-mail correspondence. Conclusions Standardization of terminology for neck dissection is important for communication among clinicians and researchers. New recommendations have been made regarding the following: boundaries between levels I and II and between levels III/IV and VI; terminology of the superior mediastinal nodes; and the method of submitting surgical specimens for pathologic analysis.

430 citations


Journal ArticleDOI
TL;DR: Recent developments regarding the basic mechanisms of NASH development are reviewed, including accumulation of triglycerides in the hepatocytes is the result of increased inflow of free fatty acids and de novo lipogenesis.

404 citations


Journal ArticleDOI
14 Nov 2008-Immunity
TL;DR: The demonstrated crosstalk between Treg cells and MCs defines a previously unrecognized mechanism controlling MC degranulation, which may contribute to the severity of allergic responses.

366 citations


Journal ArticleDOI
Justin Albert1, E. Aliu, H. Anderhub2, P. Antoranz3, A. Armada, C. Baixeras4, Juan Abel Barrio3, H. Bartko5, Denis Bastieri6, Julia Becker7, W. Bednarek, K. Berger1, Ciro Bigongiari6, Adrian Biland2, R. K. Bock5, R. K. Bock6, Pol Bordas8, Valentí Bosch-Ramon8, Thomas Bretz1, I. Britvitch2, M. Camara3, E. Carmona5, Ashot Chilingarian9, J. A. Coarasa5, S. Commichau2, Jose Luis Contreras3, Juan Cortina, M. T. Costado10, V. Curtef7, V. Danielyan9, Francesco Dazzi6, A. De Angelis11, C. Delgado10, R. de los Reyes3, B. De Lotto11, E. Domingo-Santamaría, Daniela Dorner1, Michele Doro6, Manel Errando, Michela Fagiolini12, Daniel Ferenc13, E. Fernandez, R. Firpo, Jose Flix, M. V. Fonseca3, Ll. Font4, M. Fuchs5, Nicola Galante5, R. J. García-López10, M. Garczarczyk5, Markus Gaug6, Maria Giller, Florian Goebel5, D. Hakobyan9, Masaaki Hayashida5, T. Hengstebeck14, A. Herrero10, D. Höhne1, J. Hose5, C. C. Hsu5, P. Jacon, T. Jogler5, R. Kosyra5, D. Kranich2, R. Kritzer1, A. Laille13, Elina Lindfors, Saverio Lombardi6, Francesco Longo11, Jorge Andres Lopez Lopez, M. López3, E. Lorenz5, E. Lorenz2, P. Majumdar5, G. Maneva, K. Mannheim1, Oriana Mansutti11, Mosè Mariotti6, M. I. Martínez, Daniel Mazin5, C. Merck5, Mario Meucci12, M. Meyer1, Jose Miguel Miranda3, R. Mirzoyan5, S. Mizobuchi5, Abelardo Moralejo, Daniel Nieto3, K. Nilsson, Jelena Ninkovic5, E. Oña-Wilhelmi, N. Otte14, N. Otte5, I. Oya3, David Paneque5, M. Panniello10, Riccardo Paoletti12, J. M. Paredes8, M. Pasanen, D. Pascoli6, F. Pauss2, R. Pegna12, Massimo Persic11, Massimo Persic15, L. Peruzzo6, A. Piccioli12, M. Poller1, Elisa Prandini6, N. Puchades, A. Raymers9, Wolfgang Rhode7, Marc Ribó8, J. Rico, M. Rissi2, A. Robert4, S. Rügamer1, A. Saggion6, Alvaro Sanchez4, P. Sartori6, V. Scalzotto6, V. Scapin11, R. Schmitt1, T. Schweizer5, M. Shayduk14, M. Shayduk5, K. Shinozaki5, S. N. Shore16, N. Sidro, A. Sillanpää, Dorota Sobczyńska, Antonio Stamerra12, L. S. Stark2, L. O. Takalo, Petar Temnikov, D. Tescaro, Masahiro Teshima5, N. Tonello5, Diego F. Torres17, Nicola Turini12, H. Vankov, V. Vitale11, Robert Wagner5, Tadeusz Wibig, W. Wittek5, F. Zandanel6, Roberta Zanin, J. Zapatero4 
TL;DR: In this article, very high energy (VHE) gamma-ray observations of the Crab Nebula with the MAGIC telescope were reported, where the gamma spectrum can be described by a curved power law dF/dE = f(0)(E/300 GeV).
Abstract: We report about very high energy (VHE) gamma-ray observations of the Crab Nebula with the MAGIC telescope. The gamma-ray flux from the nebula was measured between 60 GeV and 9 TeV. The energy spectrum can be described by a curved power law dF/dE = f(0)(E/300 GeV)([a+b log)((E/300 GeV)])(10) with a flux normalization f(0) of (6.0 +/- 0.2(stat)) x 10(-10) cm(-2) s(-1) TeV-1, a = 2.31 +/- 0.06(stat), and b = 0.26 +/- 0.07(stat). The peak in the spectral energy distribution is estimated at 77 +/- 35 GeV. Within the observation time and the experimental resolution of the telescope, the gamma-ray emission is steady and pointlike. The emission's center of gravity coincides with the position of the pulsar. Pulsed gamma-ray emission from the pulsar could not be detected. We constrain the cutoff energy of the pulsed spectrum to be less than 27 GeV, assuming that the differential energy spectrum has an exponential cutoff. For a superexponential shape, the cutoff energy can be as high as 60 GeV.

290 citations


Journal ArticleDOI
TL;DR: The proposed technique enables one to take into account kinematic constraints on the robot motion, expressed as upper bounds on the absolute values of velocity, acceleration and jerk, in comparison with those provided by another important trajectory planning technique.
Abstract: A technique for optimal trajectory planning of robot manipulators is presented in this paper. In order to get the optimal trajectory, an objective function composed of two terms is minimized: a first term proportional to the total execution time and another one proportional to the integral of the squared jerk (defined as the derivative of the acceleration) along the trajectory. This latter term ensures that the resulting trajectory is smooth enough. The proposed technique enables one to take into account kinematic constraints on the robot motion, expressed as upper bounds on the absolute values of velocity, acceleration and jerk. Moreover, it does not require the total execution time of the trajectory to be set a priori. The algorithm has been tested in simulation yielding good results, also in comparison with those provided by another important trajectory planning technique.

286 citations


Journal ArticleDOI
TL;DR: This revision of the Utstein Template for Uniform Reporting of Data following Major Trauma will enhance national and international comparisons of trauma systems, and will form the basis for improved prediction models in trauma care.
Abstract: In 1999, an Utstein Template for Uniform Reporting of Data following Major Trauma was published. Few papers have since been published based on that template, reflecting a lack of international consensus on its feasibility and use. The aim of the present revision was to further develop the Utstein Template, particularly with a major reduction in the number of core data variables and the addition of more precise definitions of data variables. In addition, we wanted to define a set of inclusion and exclusion criteria that will facilitate uniform comparison of trauma cases. Over a ten-month period, selected experts from major European trauma registries and organisations carried out an Utstein consensus process based on a modified nominal group technique. The expert panel concluded that a New Injury Severity Score > 15 should be used as a single inclusion criterion, and five exclusion criteria were also selected. Thirty-five precisely defined core data variables were agreed upon, with further division into core data for Predictive models, System Characteristic Descriptors and for Process Mapping. Through a structured consensus process, the Utstein Template for Uniform Reporting of Data following Major Trauma has been revised. This revision will enhance national and international comparisons of trauma systems, and will form the basis for improved prediction models in trauma care.

265 citations


Journal ArticleDOI
Justin Albert1, E. Aliu2, H. Anderhub3, L. A. Antonelli4  +147 moreInstitutions (20)
TL;DR: In this paper, the MAGIC observations were analyzed for a possible correlation with energy, as suggested by some models of quantum gravity (QG), which predict a vacuum refractive index similar or equal to 1 + (E/M-QGn)(n), n = 1, 2.71 +/- 2.57) x 10(-6) s/GeV2, respectively.

251 citations


Journal ArticleDOI
Justin Albert1, E. Aliu, H. Anderhub2, P. Antoranz3, A. Armada, M. Asensio3, C. Baixeras4, Juan Abel Barrio3, H. Bartko5, Denis Bastieri6, Julia Becker7, W. Bednarek, K. Berger1, Ciro Bigongiari6, Adrian Biland2, R. K. Bock6, R. K. Bock5, Pol Bordas8, Valentí Bosch-Ramon8, Thomas Bretz1, I. Britvitch2, M. Camara3, E. Carmona5, Ashot Chilingarian9, Stefano Ciprini, J. A. Coarasa5, S. Commichau2, Jose Luis Contreras3, Juan Cortina, M. T. Costado10, V. Curtef7, V. Danielyan9, Francesco Dazzi6, A. De Angelis11, C. Delgado10, R. de los Reyes3, B. De Lotto11, E. Domingo-Santamaría, Daniela Dorner1, Michele Doro6, Manel Errando, Michela Fagiolini12, Daniel Ferenc13, E. Fernandez, R. Firpo, Jose Flix, M. V. Fonseca3, Ll. Font4, M. Fuchs5, Nicola Galante5, R. J. García-López10, M. Garczarczyk5, Markus Gaug10, Maria Giller, Florian Goebel5, D. Hakobyan9, Masaaki Hayashida5, T. Hengstebeck14, A. Herrero10, D. Höhne1, J. Hose5, S. Huber1, C. C. Hsu5, P. Jacon, T. Jogler5, R. Kosyra5, D. Kranich2, R. Kritzer1, A. Laille13, Elina Lindfors, Saverio Lombardi6, Francesco Longo11, Jorge Andres Lopez Lopez, M. López3, E. Lorenz5, E. Lorenz2, P. Majumdar5, G. Maneva, K. Mannheim1, Mosè Mariotti6, M. I. Martínez, Daniel Mazin, C. Merck5, Mario Meucci12, M. Meyer1, Jose Miguel Miranda3, R. Mirzoyan5, S. Mizobuchi5, Abelardo Moralejo, Daniel Nieto3, K. Nilsson, Jelena Ninkovic5, E. Oña-Wilhelmi, N. Otte5, N. Otte14, I. Oya3, M. Panniello10, Riccardo Paoletti12, J. M. Paredes8, M. Pasanen, D. Pascoli6, F. Pauss2, R. Pegna12, Massimo Persic11, Massimo Persic15, L. Peruzzo6, A. Piccioli12, N. Puchades, Elisa Prandini6, A. Raymers9, Wolfgang Rhode7, Marc Ribó8, J. Rico, M. Rissi2, A. Robert4, S. Rügamer1, A. Saggion6, Takashi Saito5, Alvaro Sanchez4, P. Sartori6, V. Scalzotto6, V. Scapin11, R. Schmitt1, T. Schweizer5, M. Shayduk14, M. Shayduk5, K. Shinozaki5, S. N. Shore16, N. Sidro, A. Sillanpää, Dorota Sobczyńska, Felix Spanier1, Antonio Stamerra12, L. S. Stark2, L. O. Takalo, Petar Temnikov, D. Tescaro, Masahiro Teshima5, Diego F. Torres17, Nicola Turini12, H. Vankov, A. Venturini11, V. Vitale11, Robert Wagner5, Tadeusz Wibig, W. Wittek5, F. Zandanel6, Roberta Zanin, J. Zapatero4 
TL;DR: In this paper, an application of the tree classification method Random Forest (RF), as used in the analysis of data from the ground-based gamma telescope MAGIC, is described, and critical issues of the method and its implementation are discussed.
Abstract: The paper describes an application of the tree classification method Random Forest (RF), as used in the analysis of data from the ground-based gamma telescope MAGIC. In such telescopes, cosmic gamma-rays are observed and have to be discriminated against a dominating background of hadronic cosmic-ray particles. We describe the application of RF for this gamma/hadron separation. The RF method often shows superior performance in comparison with traditional semi-empirical techniques. Critical issues of the method and its implementation are discussed. An application of the RF method for estimation of a continuous parameter from related variables, rather than discrete classes, is also discussed.

Journal ArticleDOI
TL;DR: In this paper the most relevant velocity statistics (for both phases) and particle distribution statistics are discussed and benchmarked by direct comparison between the different numerical predictions.

Journal ArticleDOI
TL;DR: In this paper, the authors show that the very formation of a trapping horizon can be seriously questioned for a large set of, possibly realistic, scenarios and that the theoretical framework of semiclassical gravity certainly allows the formation of trapping horizons.
Abstract: While the outcome of gravitational collapse in classical general relativity is unquestionably a black hole, up to now no full and complete semiclassical description of black hole formation has been thoroughly investigated. Here we revisit the standard scenario for this process. By analyzing how semiclassical collapse proceeds we show that the very formation of a trapping horizon can be seriously questioned for a large set of, possibly realistic, scenarios. We emphasize that in principle the theoretical framework of semiclassical gravity certainly allows the formation of trapping horizons. What we are questioning here is the more subtle point of whether or not the standard black hole picture is appropriate for describing the end point of realistic collapse. Indeed if semiclassical physics were in some cases to prevent formation of the trapping horizon, then this suggests the possibility of new collapsed objects which can be much less problematic, making it unnecessary to confront the information paradox or the runaway end point problem.

Journal ArticleDOI
TL;DR: The data suggest that NF-κB contributes to thyroid tumor cell survival by controlling iron uptake via NGAL, a protein involved in inflammatory and immune responses, and which is highly expressed in human thyroid carcinomas.
Abstract: NF-κB is constitutively activated in primary human thyroid tumors, particularly in those of anaplastic type. The inhibition of NF-κB activity in the human anaplastic thyroid carcinoma cell line, FRO, leads to an increased susceptibility to chemotherapeutic drug-induced apoptosis and to the blockage of their ability to form tumors in nude mice. To identify NF-κB target genes involved in thyroid cancer, we analyzed the secretome of conditioned media from parental and NF-κB-null FRO cells. Proteomic analysis revealed that the neutrophil gelatinase-associated lipocalin (NGAL), a protein involved in inflammatory and immune responses, is secreted by FRO cells whereas its expression is strongly reduced in the NF-κB-null FRO cells. NGAL is highly expressed in human thyroid carcinomas, and knocking down its expression blocks the ability of FRO cells to grow in soft agar and form tumors in nude mice. These effects are reverted by the addition of either recombinant NGAL or FRO conditioned medium. In addition, we show that the prosurvival activity of NGAL is mediated by its ability to bind and transport iron inside the cells. Our data suggest that NF-κB contributes to thyroid tumor cell survival by controlling iron uptake via NGAL.

Journal ArticleDOI
TL;DR: The finding that amongst the antigravity muscles of the lower limbs, the GM deteriorated to a greater extent than the VL is possibly related to the differences in relative load that this muscle normally experiences during daily loading.
Abstract: The aim of the present study was to investigate the changes in thickness, fascicle length (L f) and pennation angle (θ) of the antigravity gastrocnemius medialis (GM) and vastus lateralis (VL) muscles, and the non-antigravity tibialis anterior (TA) and biceps brachii (BB) muscles measured by ultrasonography in ten healthy males (aged 22.3 ± 2.2 years) in response to 5 weeks of horizontal bed rest (BR). After BR, muscle thickness decreased by 12.2 ± 8.8% (P < 0.05) and 8.0 ± 9.1% (P < 0.005) in the GM and VL, respectively. No changes were observed in the TA and BB muscles. L f and θ decreased by 4.8 ± 5.0% (P < 0.05) and 14.3 ± 6.8% (P < 0.005) in the GM and by 5.9 ± 5.3% (P < 0.05) and 13.5 ± 16.2% (P < 0.005) in the VL, again without any changes in the TA and BB muscles. The finding that amongst the antigravity muscles of the lower limbs, the GM deteriorated to a greater extent than the VL is possibly related to the differences in relative load that this muscle normally experiences during daily loading. The dissimilar response in antigravity and non-antigravity muscles to unloading likely reflects differences in loading under normal conditions. The significant structural alterations of the GM and VL muscles highlight the rapid remodelling of muscle architecture occurring with disuse.

Journal ArticleDOI
TL;DR: It is reported that AID retains its exclusive association with numerous, residual GCs in parotid SS-MALT lymphomas, whereas neoplastic marginal zone-like B cells are consistently AID negative, which strongly support the notion that ectopic lymphoid structures in SS-SGs express the molecular machinery to support local autoantibody production and B cell expansion and may play a crucial role toward lymphomagenesis.
Abstract: Demonstration of ectopic germinal center-like structures (GC-LSs) in chronically inflamed tissues in patients with autoimmune disorders is a relatively common finding. However, to what extent ectopic lymphoid structures behave as true GC and are able to support class switch recombination (CSR) and somatic hypermutation (SHM) of the Ig genes is still debated. In addition, no information is available on whether CSR and SHM can take place in the absence of GCs at extrafollicular sites in an ectopic lymphoid tissue. In this study, we show that in salivary glands (SGs) of Sjogren's syndrome (SS) activation-induced cytidine deaminase (AID), the enzyme responsible for CSR and SHM is invariably expressed within follicular dendritic cell (FDC) networks but is not detectable in SGs in the absence of ectopic GC-LSs, suggesting that FDC networks play an essential role in sustaining the Ag-driven B cell proliferation within SS-SGs. We also show that the recently described population of interfollicular large B cells selectively expresses AID outside ectopic GC in the T cell-rich areas of periductal aggregates. Finally, we report that AID retains its exclusive association with numerous, residual GCs in parotid SS-MALT lymphomas, whereas neoplastic marginal zone-like B cells are consistently AID negative. These results strongly support the notion that ectopic lymphoid structures in SS-SGs express the molecular machinery to support local autoantibody production and B cell expansion and may play a crucial role toward lymphomagenesis.

Journal ArticleDOI
TL;DR: In this article, the authors investigated the development of a chatter detection system for application in industrial conditions, in which the signal characteristics both in time and frequency domain were condensed into a set of chatter indicators, which were further elaborated by means of statistical basic concepts to obtain a chatter identification system.

Journal ArticleDOI
TL;DR: MOPET is a wearable system that supervises a physical fitness activity based on alternating jogging and fitness exercises in outdoor environments and shows how context-aware and user-adaptive techniques can be applied to the fitness domain.

Journal ArticleDOI
01 Jul 2008-Sleep
TL;DR: RLS is significantly associated with MS, especially in patients with severe pyramidal and sensory disability, and these results strengthen the idea that the inflammatory damage correlated with MS may induce a secondary form of RLS.
Abstract: Study objectives: To verify the existence of a symptomatic form of restless legs syndrome (RLS) secondary to multiple sclerosis (MS) and to identify possible associated risk factors. Design: Prospective, multicenter, case-control epidemiologic survey. Settings: Twenty sleep centers certified by the Italian Association of Sleep Medicine. Patients: Eight hundred and sixty-one patients affected by MS and 649 control subjects. Interventions: N/A. Measures and results: Data regarding demographic and clinical factors, presence and severity of RLS, the results of hematologic tests, and visual analysis of cerebrospinal magnetic resonance imaging studies were collected. The prevalence of RLS was 19% in MS and 4.2% in control subjects, with a risk to be affected by RLS of 5.4 (95%confidence interval: 3.56-8.26) times greater for patients with MS than for control subjects. In patients with MS, the following risk factors for RLS were significant: older age; longer MS duration; the primary progressive MS form; higher global, pyramidal, and sensory disability; and the presence of leg jerks before sleep onset. Patients with MS and RLS more often had sleep complaints and a higher intake of hypnotic medications than patients with MS without RLS. RLS associated with MS was more severe than that of control subjects. Conclusions: RLS is significantly associated with MS, especially in patients with severe pyramidal and sensory disability. These results strengthen the idea that the inflammatory damage correlated with MS may induce a secondary form of RLS. As it does in idiopathic cases, RLS has a significant impact on sleep quality in patients with MS; therefore, it should be always searched for, particularly in the presence of insomnia unresponsive to treatment with common hypnotic drugs.

Journal ArticleDOI
TL;DR: In primary aldosteronism, tissue damage, on several indices, is higher than in age-, sex- and blood pressure-matched controls, reflecting the ability of inappropriately elevated aldosterone for salt status to produce structural and functional changes over and above those produced by high blood pressure.
Abstract: For many years primary aldosteronism was considered a relatively benign form of hypertension. This assumption reflects the primacy accorded to elevated levels of angiotensin in terms of deleterious cardiovascular effects, and the fact that in primary aldosteronism renin and angiotensin levels are low. We now know that primary aldosteronism causes a constellation of cardiovascular, renal and metabolic sequelae which make it far from benign and that these are not merely effects of blood pressure elevation. In primary aldosteronism, tissue damage, on several indices, is higher than in age-, sex- and blood pressure-matched controls, reflecting the ability of inappropriately elevated aldosterone for salt status to produce structural and functional changes over and above those produced by high blood pressure.


Journal ArticleDOI
TL;DR: Reporter transgenic studies in both mouse and zebrafish reveal loss and retention of specific cis-regulatory elements, correlating strongly with the diverged expression of co-orthologues, and providing clear evidence for evolution by subfunctionalization.
Abstract: Gene duplication is a major driver of evolutionary divergence. In most vertebrates a single PAX6 gene encodes a transcription factor required for eye, brain, olfactory system, and pancreas development. In zebrafish, following a postulated whole-genome duplication event in an ancestral teleost, duplicates pax6a and pax6b jointly fulfill these roles. Mapping of the homozygously viable eye mutant sunrise identified a homeodomain missense change in pax6b, leading to loss of target binding. The mild phenotype emphasizes role-sharing between the co-orthologues. Meticulous mapping of isolated BACs identified perturbed synteny relationships around the duplicates. This highlights the functional conservation of pax6 downstream (3′) control sequences, which in most vertebrates reside within the introns of a ubiquitously expressed neighbour gene, ELP4, whose pax6a-linked exons have been lost in zebrafish. Reporter transgenic studies in both mouse and zebrafish, combined with analysis of vertebrate sequence conservation, reveal loss and retention of specific cis-regulatory elements, correlating strongly with the diverged expression of co-orthologues, and providing clear evidence for evolution by subfunctionalization.

Journal ArticleDOI
TL;DR: This review summarizes the involvement of NGF in the regulation of angiogenesis in both normal and pathological conditions and suggests it may contribute to maintenance, survival, and function of endothelial cells by autocrine and/or paracrine mechanisms.

Journal ArticleDOI
TL;DR: It is disclosed that the catalytic site of GPxs has to be redrawn as a tetrad, including Asn136, and a mechanism accounting for the extraordinary catalytic efficiency of GPXs is suggested.
Abstract: In GPxs, the redox-active Se or S, is at hydrogen bonding distance from Gln and Trp residues that contribute to catalysis. From sequence homology of >400 sequences and modeling of the DmGPx as a paradigm, Asn136 emerged as a fourth essential component of the active site. Mutational substitution of Asn136 by His, Ala, or Asp results in a dramatic decline of specific activity. Kinetic analysis indicates that k(+1), the rate constant for the oxidation of the enzyme, decreases by two to three orders of magnitude, whereas the reductive steps characterized by k'(+2) are less affected. Accordingly, MS/MS analysis shows that in Asn136 mutants, the peroxidatic Cys45 stays largely reduced also in the presence of a hydroperoxide, whereas in the wild-type enzyme, it is oxidized, forming a disulfide with the resolving Cys. Computational calculation of pK(a) values indicates that the residues facing the catalytic thiol, Asn136, Gln80, and, to a lesser extent Trp135, contribute to the dissociation of the thiol group, Asn136 being most relevant. These data disclose that the catalytic site of GPxs has to be redrawn as a tetrad, including Asn136, and suggest a mechanism accounting for the extraordinary catalytic efficiency of GPxs.

Journal ArticleDOI
TL;DR: The ECM functions as a scaffold for tissue organization and regulates growth factors and chemokines availability thus contributing to maintain tissue homeostasis and among the different array of ECM molecules a set of proteins can negatively affect cell viability and are thought to play an important role in tumor progression.
Abstract: Extracellular matrix (ECM) is an essential component of the stromal microenvironment both from a structural and a functional point of view. The ECM functions as a scaffold for tissue organization and regulates growth factors and chemokines availability thus contributing to maintain tissue homeostasis. Attachment of cells to ECM is essential to support cell survival, growth, and proliferation, and the lack of these interactions can trigger a type of cell death named anoikis. Several studies point out that alterations of ECM composition are often responsible of many pathological conditions such as cancer, of which it has been demonstrated to be occasionally the main promoter. ECM does not always represent a prosurvival stimulus; among the different array of ECM molecules a set of proteins can negatively affect cell viability and are thought to play an important role in tumor progression. For this reason attention has been focused on these molecules as potential tools or targets for therapy.

Journal ArticleDOI
TL;DR: The larger volumes in posterior brain areas may reflect atypical neurodevelopmental processes that underlie early-onset persistent antisocial and aggressive behavior.
Abstract: Most violent crimes in Western societies are committed by a small group of men who display antisocial behavior from an early age that remains stable across the life-span. It is not known if these men display abnormal brain structure. We compared regional brain volumes of 26 persistently violent offenders with antisocial personality disorder and substance dependence and 25 healthy men using magnetic resonance imaging volumetry and voxel-based morphometry (VBM). The violent offenders, as compared with the healthy men, had markedly larger white matter volumes, bilaterally, in the occipital and parietal lobes, and in the left cerebellum, and larger grey matter volume in right cerebellum (effect sizes up to 1.24, P<0.001). Among the offenders, volumes of these areas were not associated with psychopathy scores, substance abuse, psychotropic medication, or global IQ scores. By contrast, VBM analyses of grey matter revealed focal, symmetrical, bilateral areas of atrophy in the postcentral gyri, frontopolar cortex, and orbitofrontal cortex among the offenders as compared with the healthy men (z-scores as high as 5.06). Offenders with psychopathy showed the smallest volumes in these areas. The larger volumes in posterior brain areas may reflect atypical neurodevelopmental processes that underlie early-onset persistent antisocial and aggressive behavior.

Journal ArticleDOI
TL;DR: The observed reduction in subregions of the hippocampus in unmedicated bipolar patients suggests a possible neural correlate for memory deficits frequently reported in this illness, and increased hippocampal volume in lithium-treated bipolar patients may reflect postulated neurotrophic effects of this agent.

Journal ArticleDOI
TL;DR: Chronopharmacokinetics can explain individual differences in drug levels revealed by therapeutic drug monitoring and can be used to optimise the management of patients receiving drug therapy.
Abstract: In clinical practice, it is important to consider circadian rhythms in pharmacokinetics and cell responses to therapy in order to design proper protocols for drug administration. Scientists have arrived at this conclusion after several experiments in animals and in humans have clearly demonstrated that all organisms are highly organised according to circadian rhythms. These temporal cycles influence different physiological functions and, consequently, can influence the pharmacokinetic phases of drugs. A drug's pharmacokinetics can be modified according to the time of drug administration. In fact, the circadian changes of > 100 different compounds have been documented. The results obtained have led several scientific societies to provide guidelines concerning the timing of drug dosing for anticancer, cardiovascular, respiratory, anti-ulcer, anti-inflammatory, immunosuppressive and antiepileptic drugs. Absorption may be influenced by circadian rhythms and most lipophilic drugs seem to be absorbed faster when the drug is taken in the morning compared with the evening; for water-soluble compounds, no circadian variation in the absorption of drugs has been found. Concerning drug distribution, the higher the blood flow fraction an organ receives, the higher the rate constant for transferring drugs out of the capillaries. This drug pharmacokinetic phase may be influenced by circadian variations in the protein binding of acidic and basic drugs. Drug metabolism may be influenced by daily modifications of blood flow. For drugs with a high extraction ratio, metabolism depends on hepatic blood flow, while that of drugs with a low extraction ratio depends on liver enzyme activity. Hepatic blood flow has been shown to be greatest at 8 am and metabolism seems to be reduced during the night. Finally, concerning drug elimination, the clearance of 'flow-limited' drugs that present a high extraction rate is affected by the blood flow delivered to the organ, independent of the cardiac output fraction supplied. Chronopharmacokinetics can explain individual differences in drug levels revealed by therapeutic drug monitoring and can be used to optimise the management of patients receiving drug therapy.


Journal ArticleDOI
TL;DR: The results indicate that P2X7 is involved in the proliferative cell response toLL-37 and that the structural/aggregational properties of LL-37 determine its capacity to modulate the activation state of P2 X7.