Showing papers by "Sapienza University of Rome published in 2004"

Hereditary Early-Onset Parkinson's Disease Caused by Mutations in PINK1

Abstract: Parkinson's disease (PD) is a neurodegenerative disorder characterized by degeneration of dopaminergic neurons in the substantia nigra We previously mapped a locus for a rare familial form of PD to chromosome 1p36 (PARK6) Here we show that mutations in PINK1 (PTEN-induced kinase 1) are associated with PARK6 We have identified two homozygous mutations affecting the PINK1 kinase domain in three consanguineous PARK6 families: a truncating nonsense mutation and a missense mutation at a highly conserved amino acid Cell culture studies suggest that PINK1 is mitochondrially located and may exert a protective effect on the cell that is abrogated by the mutations, resulting in increased susceptibility to cellular stress These data provide a direct molecular link between mitochondria and the pathogenesis of PD

Isolation and Expansion of Adult Cardiac Stem Cells From Human and Murine Heart

Abstract: Cardiac myocytes have been traditionally regarded as terminally differentiated cells that adapt to increased work and compensate for disease exclusively through hypertrophy. However, in the past few years, compelling evidence has accumulated suggesting that the heart has regenerative potential. Recent studies have even surmised the existence of resident cardiac stem cells, endothelial cells generating cardiomyocytes by cell contact or extracardiac progenitors for cardiomyocytes, but these findings are still controversial. We describe the isolation of undifferentiated cells that grow as self-adherent clusters (that we have termed "cardiospheres") from subcultures of postnatal atrial or ventricular human biopsy specimens and from murine hearts. These cells are clonogenic, express stem and endothelial progenitor cell antigens/markers, and appear to have the properties of adult cardiac stem cells. They are capable of long-term self-renewal and can differentiate in vitro and after ectopic (dorsal subcutaneous connective tissue) or orthotopic (myocardial infarction) transplantation in SCID beige mouse to yield the major specialized cell types of the heart: myocytes (ie, cells demonstrating contractile activity and/or showing cardiomyocyte markers) and vascular cells (ie, cells with endothelial or smooth muscle markers).

Effectiveness of the global protected area network in representing species diversity

Abstract: The Fifth World Parks Congress in Durban, South Africa, announced in September 2003 that the global network of protected areas now covers 11.5% of the planet's land surface. This surpasses the 10% target proposed a decade earlier, at the Caracas Congress, for 9 out of 14 major terrestrial biomes. Such uniform targets based on percentage of area have become deeply embedded into national and international conservation planning. Although politically expedient, the scientific basis and conservation value of these targets have been questioned. In practice, however, little is known of how to set appropriate targets, or of the extent to which the current global protected area network fulfils its goal of protecting biodiversity. Here, we combine five global data sets on the distribution of species and protected areas to provide the first global gap analysis assessing the effectiveness of protected areas in representing species diversity. We show that the global network is far from complete, and demonstrate the inadequacy of uniform--that is, 'one size fits all'--conservation targets.

Overweight and obesity

Abstract: Being over-weight and obesity are conditions which are becoming ever more common and this trend presents a series of social and psychological problems, apart from the well known health risks such as hypertension, heart disease, type 2 diabetes, orthopaedic problems, cancers of the endometrium and breast etc. The prevention and control of excess weight and obesity is largely based on adopting a healthy lifestyle and above all on diet and exercise. These ideas are also included in the Health Plan for 2002-2004, and are among the ten most important strategic objectives for promoting healthy living, disease prevention and informing the public on health matters.

EFNS guidelines on neuropathic pain assessment.

Abstract: In September 2001, a Task Force was set up under the auspices of the European Federation of Neurological Societies with the aim of evaluating the existing evidence about the methods of assessing neuropathic pain and its treatments. This review led to the development of guidelines to be used in the management of patients with neuropathic pain. In the clinical setting a neurological examination that includes an accurate sensory examination is often sufficient to reach a diagnosis. Nerve conduction studies and somatosensory-evoked potentials, which do not assess small fibre function, may demonstrate and localize a peripheral or central nervous lesion. A quantitative assessment of the nociceptive pathways is provided by quantitative sensory testing and laser-evoked potentials. To evaluate treatment efficacy in a patient and in controlled trials, the simplest psychometric scales and quality of life measures are probably the best methods. A laboratory measure of pain that by-passes the subjective report, and thus cognitive influences, is a hopeful aim for the future.

PINK1 mutations are associated with sporadic early-onset parkinsonism.

Abstract: We have recently reported homozygous mutations in the PINK1 gene in three consanguineous families with early-onset parkinsonism (EOP) linked to the PARK6 locus. To further evaluate the pathogenic role of PINK1 in EOP and to draw genotype-phenotype correlates, we performed PINK1 mutation analysis in a cohort of Italian EOP patients, mostly sporadic, with onset younger than 50 years of age. Seven of 100 patients carried missense mutations in PINK1. Two patients had two PINK1 mutations, whereas in five patients only one mutation was identified. Age at onset was in the fourth-fifth decade (range, 37-47 years). The clinical picture was characterized by a typical parkinsonian phenotype with asymmetric onset and rare occurrence of atypical features. Slow progression and excellent response to levodopa were observed in all subject. Two of 200 healthy control individuals also carried one heterozygous missense mutation. The identification of a higher number of patients (5%) than controls (1%) carrying a single heterozygous mutation, along with previous positron emission tomography studies demonstrating a preclinical nigrostriatal dysfunction in PARK6 carriers, supports the hypothesis that haploinsufficiency of PINK1, as well as of other EOP genes, may represent a susceptibility factor toward parkinsonism. However, the pathogenetic significance of heterozygous PINK1 mutations still remains to be clarified.

Extracellular HMGB1, a signal of tissue damage, induces mesoangioblast migration and proliferation.

Abstract: High mobility group box 1 (HMGB1) is an abundant chromatin protein that acts as a cytokine when released in the extracellular milieu by necrotic and inflammatory cells. Here, we show that extracellular HMGB1 and its receptor for advanced glycation end products (RAGE) induce both migration and proliferation of vessel-associated stem cells (mesoangioblasts), and thus may play a role in muscle tissue regeneration. In vitro, HMGB1 induces migration and proliferation of both adult and embryonic mesoangioblasts, and disrupts the barrier function of endothelial monolayers. In living mice, mesoangioblasts injected into the femoral artery migrate close to HMGB1-loaded heparin-Sepharose beads implanted in healthy muscle, but are unresponsive to control beads. Interestingly, α-sarcoglycan null dystrophic muscle contains elevated levels of HMGB1; however, mesoangioblasts migrate into dystrophic muscle even if their RAGE receptor is disabled. This implies that the HMGB1–RAGE interaction is sufficient, but not necessary, for mesoangioblast homing; a different pathway might coexist. Although the role of endogenous HMGB1 in the reconstruction of dystrophic muscle remains to be clarified, injected HMGB1 may be used to promote tissue regeneration.

Development and validation of the Unified Multiple System Atrophy Rating Scale (UMSARS).

Abstract: We aimed to develop and validate a novel rating scale for multiple system atrophy (Unified Multiple System Atrophy Rating Scale-UMSARS). The scale comprises the following components: Part I, historical, 12 items; Part II, motor examination, 14 items; Part III, autonomic examination; and Part IV, global disability scale. For validation purposes, 40 MSA patients were assessed in four centers by 4 raters per center (2 senior and 2 junior raters). The raters applied the UMSARS, as well as a range of other scales, including the Unified Parkinson's Disease Rating Scale (UPDRS) and the International Cooperative Ataxia Rating Scale (ICARS). Internal consistency was high for both UMSARS-I (Crohnbach's alpha = 0.84) and UMSARS-II (Crohnbach's alpha = 0.90) sections. The interrater reliability of most of the UMSARS-I and -II items as well as of total UMSARS-I and -II subscores was substantial (k(w) = 0.6-0.8) to excellent (k(w) > 0.8). UMSARS-II correlated well with UPDRS-III and ICARS (rs > 0.8). Depending on the degree of the patient's disability, completion of the entire UMSARS took 30 to 45 minutes. Based on our findings, the UMSARS appears to be a multidimensional, reliable, and valid scale for semiquantitative clinical assessments of MSA patients.

Observation of the narrow state X(3872) → J/ψπ+π- in p̄p collisions at √s = 1.96 TeV

Abstract: The observation of a state consistent with X(3872) decaying into J/ψπ+π- was reported. The X(3872) mass was measured to be 3871.3±0.7(stat)±0.4(syst)MeV/c2 from a sample of 730±90 candidates. The observed width was consistent with the detector resolution. The results were found to be converging well with the measurements by the Belle Collaboration using b± decays.

The Molecular Dissection of mtDNA Haplogroup H Confirms That the Franco-Cantabrian Glacial Refuge Was a Major Source for the European Gene Pool

Abstract: Complete sequencing of 62 mitochondrial DNAs (mtDNAs) belonging (or very closely related) to haplogroup H revealed that this mtDNA haplogroup—by far the most common in Europe—is subdivided into numerous subhaplogroups, with at least 15 of them (H1–H15) identifiable by characteristic mutations. All the haplogroup H mtDNAs found in 5,743 subjects from 43 populations were then screened for diagnostic markers of subhaplogroups H1 and H3. This survey showed that both subhaplogroups display frequency peaks, centered in Iberia and surrounding areas, with distributions declining toward the northeast and southeast—a pattern extremely similar to that previously reported for mtDNA haplogroup V. Furthermore, the coalescence ages of H1 and H3 (∼11,000 years) are close to that previously reported for V. These findings have major implications for the origin of Europeans, since they attest that the Franco-Cantabrian refuge area was indeed the source of late-glacial expansions of hunter-gatherers that repopulated much of Central and Northern Europe from ∼15,000 years ago. This has also some implications for disease studies. For instance, the high occurrence of H1 and H3 in Iberia led us to re-evaluate the haplogroup distribution in 50 Spanish families affected by nonsyndromic sensorineural deafness due to the A1555G mutation. The survey revealed that the previously reported excess of H among these families is caused entirely by H3 and is due to a major, probably nonrecent, founder event.

Learning Domain Ontologies from Document Warehouses and Dedicated Web Sites

Abstract: We present a method and a tool, OntoLearn, aimed at the extraction of domain ontologies from Web sites, and more generally from documents shared among the members of virtual organizations. OntoLearn first extracts a domain terminology from available documents. Then, complex domain terms are semantically interpreted and arranged in a hierarchical fashion. Finally, a general-purpose ontology, WordNet, is trimmed and enriched with the detected domain concepts. The major novel aspect of this approach is semantic interpretation, that is, the association of a complex concept with a complex term . This involves finding the appropriate WordNet concept for each word of a terminological string and the appropriate conceptual relations that hold among the concept components. Semantic interpretation is based on a new word sense disambiguation algorithm, called structural semantic interconnections.

Ghrelin, appetite, and gastric motility: the emerging role of the stomach as an endocrine organ

Abstract: Recent progress in the field of energy homeostasis was triggered by the discovery of adipocyte hormone leptin and revealed a complex regulatory neuroendocrine network. A late addition is the novel stomach hormone ghrelin, which is an endogenous agonist at the growth hormone secretagogne receptor and is the motilin-related family of regulatory peptides. In addition to its ability to stimulate GH secretion and gastric motility, ghrelin stimulates appetite and induces a positive energy balance leading to body weight gain. Leptin and ghrelin are complementary, yet antagonistic, signals reflecting acute and chronic changes in energy balance, the effects of which are mediated by hypothalamic neuropeptides such as neuropeptide Y and agouti-related peptide. Endocrine and vagal afferent pathways are involved in these actions of ghrelin and leptin. Ghrelin is a novel neuroendocrine signal possessing a wide spectrum of biological activities that illustrates the importance of the stomach in providing input into the brain. Defective ghrelin signaling from the stomach could contribute to abnormalities in energy balance, growth, and associated gastrointestinal and neuroendocrine functions.

Equilibrium cluster phases and low-density arrested disordered states: the role of short-range attraction and long-range repulsion.

Abstract: We study a model in which particles interact with short-ranged attractive and long-ranged repulsive interactions, in an attempt to model the equilibrium cluster phase recently discovered in sterically stabilized colloidal systems in the presence of depletion interactions. At low packing fractions, particles form stable equilibrium clusters which act as building blocks of a cluster fluid. We study the possibility that cluster fluids generate a low-density disordered arrested phase, a gel, via a glass transition driven by the repulsive interaction. In this model the gel formation is formally described with the same physics of the glass formation.

Multiple Distinct Sets of Stereotyped Antigen Receptors Indicate a Role for Antigen in Promoting Chronic Lymphocytic Leukemia

Abstract: Previous studies suggest that the diversity of the expressed variable (V) region repertoire of the immunoglobulin (Ig)H chain of B-CLL cells is restricted. Although limited examples of marked constraint in the primary structure of the H and L chain V regions exist, the possibility that this level of restriction is a general principle in this disease has not been accepted. This report describes five sets of patients, mostly with unmutated or minimally mutated IgV genes, with strikingly similar B cell antigen receptors (BCRs) arising from the use of common H and L chain V region gene segments that share CDR3 structural features such as length, amino acid composition, and unique amino acid residues at recombination junctions. Thus, a much more striking degree of structural restriction of the entire BCR and a much higher frequency of receptor sharing exists among patients than appreciated previously. The data imply that either a significant fraction of B-CLL cells was selected by a limited set of antigenic epitopes at some point in their development and/or that they derive from a distinct B cell subpopulation with limited Ig V region diversity. These shared, stereotyped Ig molecules may be valuable probes for antigen identification and important targets for cross-reactive idiotypic therapy.

Advanced freight transportation systems for congested urban areas

Abstract: Urban freight transportation constitutes both an extremely important and a rather disturbing activity. Increasingly, one observes efforts to measure and control freight movements within city centers. We introduce a possible organizational and technological framework for the integrated management of urban freight transportation and identify important associated planning and operation issues and models. We then describe a formulation for one of these problems, the design of the proposed logistical structure, and discuss algorithmic and implementation issues. Our model city and challenge is Rome.

Direct numerical simulation and analysis of a spatially evolving supersonic turbulent boundary layer at M=2.25

Abstract: A spatially developing supersonic adiabatic flat plate boundary layer flow (at M∞=2.25 and Reθ≈4000) is analyzed by means of direct numerical simulation. The numerical algorithm is based on a mixed weighted essentially nonoscillatory compact-difference method for the three-dimensional Navier–Stokes equations. The main objectives are to assess the validity of Morkovin’s hypothesis and Reynolds analogies, and to analyze the controlling mechanisms for turbulence production, dissipation, and transport. The results show that the essential dynamics of the investigated turbulent supersonic boundary layer flow closely resembles the incompressible pattern. The Van Driest transformed mean velocity obeys the incompressible law-of-the-wall, and the mean static temperature field exhibits a quadratic dependency upon the mean velocity, as predicted by the Crocco–Busemann relation. The total temperature has been found not to be precisely uniform, and total temperature fluctuations are found to be non-negligible. Consiste...

Where West Meets East: The Complex mtDNA Landscape of the Southwest and Central Asian Corridor

Abstract: The southwestern and Central Asian corridor has played a pivotal role in the history of humankind, witnessing numerous waves of migration of different peoples at different times. To evaluate the effects of these population movements on the current genetic landscape of the Iranian plateau, the Indus Valley, and Central Asia, we have analyzed 910 mitochondrial DNAs (mtDNAs) from 23 populations of the region. This study has allowed a refinement of the phylogenetic relationships of some lineages and the identification of new haplogroups in the southwestern and Central Asian mtDNA tree. Both lineage geographical distribution and spatial analysis of molecular variance showed that populations located west of the Indus Valley mainly harbor mtDNAs of western Eurasian origin, whereas those inhabiting the Indo-Gangetic region and Central Asia present substantial proportions of lineages that can be allocated to three different genetic components of western Eurasian, eastern Eurasian, and south Asian origin. In addition to the overall composite picture of lineage clusters of different origin, we observed a number of deep-rooting lineages, whose relative clustering and coalescent ages suggest an autochthonous origin in the southwestern Asian corridor during the Pleistocene. The comparison with Y-chromosome data revealed a highly complex genetic and demographic history of the region, which includes sexually asymmetrical mating patterns, founder effects, and female-specific traces of the East African slave trade.

Phospholipases C and A2 control lysosome-mediated IL-1β secretion: Implications for inflammatory processes

Abstract: Blocking the activity of IL-1β has entered the clinical arena of treating autoimmune diseases. However, a successful outcome of this approach requires a clear definition of the mechanisms controlling IL-1β release. These are still unclear as IL-1β, lacking a secretory signal peptide, follows a nonclassical pathway of secretion. Here, we analyze the molecular mechanism(s) undergoing IL-1β processing and release in human monocytes and provide a unifying model for the regulated secretion of the cytokine. Our data show that in a first step, pro-caspase-1 and endotoxin-induced pro-IL-1β are targeted in part to specialized secretory lysosomes, where they colocalize with other lysosomal proteins. Externalization of mature IL-1β and caspase-1 together with lysosomal proteins is then facilitated by extracellular ATP. ATP triggers the efflux of K+ from the cell, followed by Ca2+ influx and activation of three phospholipases: phosphatidylcholine-specific phospholipase C and calcium-independent and -dependent phospholipase A2. Whereas calcium-independent phospholipase A2 is involved in processing, phosphatidylcholine-specific phospholipase C and calcium-dependent phospholipase A2 are required for secretion. Dissection of the events that follow ATP triggering allowed to demonstrate that K+ efflux is responsible for phosphatidylcholine-specific phospholipase C induction, which in turn allows the rise in intracellular free calcium concentration required for activation of phospholipase A2. This activation is ultimately responsible for lysosome exocytosis and IL-1β secretion.

The effective mutation rate at Y chromosome short tandem repeats, with application to human population-divergence time.

Abstract: We estimate an effective mutation rate at an average Y chromosome short-tandem repeat locus as 6.9×10 −4 per 25 years, with a standard deviation across loci of 5.7×10 −4 , using data on microsatellite variation within Y chromosome haplogroups defined by unique-event polymorphisms in populations with documented short-term histories, as well as comparative data on worldwide populations at both the Y chromosome and various autosomal loci. This value is used to estimate the times of the African Bantu expansion, the divergence of Polynesian populations (the Maoris, Cook Islanders, and Samoans), and the origin of Gypsy populations from Bulgaria.

Regulation of the p300 HAT domain via a novel activation loop

Abstract: The transcriptional coactivator p300 is a histone acetyltransferase (HAT) whose function is critical for regulating gene expression in mammalian cells. However, the molecular events that regulate p300 HAT activity are poorly understood. We evaluated autoacetylation of the p300 HAT protein domain to determine its function. Using expressed protein ligation, the p300 HAT protein domain was generated in hypoacetylated form and found to have reduced catalytic activity. This basal catalytic rate was stimulated by autoacetylation of several key lysine sites within an apparent activation loop motif. This post-translational modification and catalytic regulation of p300 HAT activity is conceptually analogous to the activation of most protein kinases by autophosphorylation. We therefore propose that this autoregulatory loop could influence the impact of p300 on a wide variety of signaling and transcriptional events.