Showing papers by "University of Milan published in 2004"

Bioconductor: open software development for computational biology and bioinformatics

Abstract: The Bioconductor project is an initiative for the collaborative creation of extensible software for computational biology and bioinformatics. The goals of the project include: fostering collaborative development and widespread use of innovative software, reducing barriers to entry into interdisciplinary scientific research, and promoting the achievement of remote reproducibility of research results. We describe details of our aims and methods, identify current challenges, compare Bioconductor to other open bioinformatics projects, and provide working examples.

The Swift Gamma-Ray Burst Mission

Abstract: The Swift mission, scheduled for launch in 2004, is a multiwavelength observatory for gamma-ray burst (GRB) astronomy. It is a first-of-its-kind autonomous rapid-slewing satellite for transient astronomy and pioneers the way for future rapid-reaction and multiwavelength missions. It will be far more powerful than any previous GRB mission, observing more than 100 bursts yr � 1 and performing detailed X-ray and UV/optical afterglow observations spanning timescales from 1 minute to several days after the burst. The objectives are to (1) determine the origin of GRBs, (2) classify GRBs and search for new types, (3) study the interaction of the ultrarelativistic outflows of GRBs with their surrounding medium, and (4) use GRBs to study the early universe out to z >10. The mission is being developed by a NASA-led international collaboration. It will carry three instruments: a newgeneration wide-field gamma-ray (15‐150 keV) detector that will detect bursts, calculate 1 0 ‐4 0 positions, and trigger autonomous spacecraft slews; a narrow-field X-ray telescope that will give 5 00 positions and perform spectroscopy in the 0.2‐10 keV band; and a narrow-field UV/optical telescope that will operate in the 170‐ 600 nm band and provide 0B3 positions and optical finding charts. Redshift determinations will be made for most bursts. In addition to the primary GRB science, the mission will perform a hard X-ray survey to a sensitivity of � 1m crab (� 2;10 � 11 ergs cm � 2 s � 1 in the 15‐150 keV band), more than an order of magnitude better than HEAO 1 A-4. A flexible data and operations system will allow rapid follow-up observations of all types of

Anthracyclines: Molecular Advances and Pharmacologic Developments in Antitumor Activity and Cardiotoxicity

Abstract: The clinical use of anthracyclines like doxorubicin and daunorubicin can be viewed as a sort of double-edged sword. On the one hand, anthracyclines play an undisputed key role in the treatment of many neoplastic diseases; on the other hand, chronic administration of anthracyclines induces cardiomyopathy and congestive heart failure usually refractory to common medications. Second-generation analogs like epirubicin or idarubicin exhibit improvements in their therapeutic index, but the risk of inducing cardiomyopathy is not abated. It is because of their janus behavior (activity in tumors vis-a-vis toxicity in cardiomyocytes) that anthracyclines continue to attract the interest of preclinical and clinical investigations despite their longer-than-40-year record of longevity. Here we review recent progresses that may serve as a framework for reappraising the activity and toxicity of anthracyclines on basic and clinical pharmacology grounds. We review 1) new aspects of anthracycline-induced DNA damage in cancer cells; 2) the role of iron and free radicals as causative factors of apoptosis or other forms of cardiac damage; 3) molecular mechanisms of cardiotoxic synergism between anthracyclines and other anticancer agents; 4) the pharmacologic rationale and clinical recommendations for using cardioprotectants while not interfering with tumor response; 5) the development of tumor-targeted anthracycline formulations; and 6) the designing of third-generation analogs and their assessment in preclinical or clinical settings. An overview of these issues confirms that anthracyclines remain "evergreen" drugs with broad clinical indications but have still an improvable therapeutic index.

The webgraph framework I: compression techniques

Abstract: Studying web graphs is often difficult due to their large size. Recently,several proposals have been published about various techniques that allow tostore a web graph in memory in a limited space, exploiting the inner redundancies of the web. The WebGraph framework is a suite of codes, algorithms and tools that aims at making it easy to manipulate large web graphs. This papers presents the compression techniques used in WebGraph, which are centred around referentiation and intervalisation (which in turn are dual to each other). WebGraph can compress the WebBase graph (118 Mnodes, 1 Glinks)in as little as 3.08 bits per link, and its transposed version in as littleas 2.89 bits per link.

Endothelial cell-cell junctions: happy together.

Abstract: Junctional structures maintain the integrity of the endothelium Recent studies have shown that, as well as promoting cell–cell adhesion, junctions might transfer intracellular signals that regulate contact-induced inhibition of cell growth, apoptosis, gene expression and new vessel formation Moreover, modifications of the molecular organization and intracellular signalling of junctional proteins might have complex effects on vascular homeostasis

Interpenetrating metal–organic and inorganic 3D networks: a computer-aided systematic investigation. Part I. Analysis of the Cambridge structural database

Abstract: The occurrence of interpenetration in metal–organic and inorganic networks has been investigated by a systematic analysis of the CSD and ICSD structural databases. For this purpose, a novel version of TOPOS (a program package for multipurpose crystallochemical analysis) has been employed, where the procedure of recognition of interpenetrating nets is based on the representation of a crystal structure as a finite reduced graph. In this paper we report a comprehensive list (301 Refcodes) of interpenetrating metal–organic 3D structures from CSD, that are analyzed on the basis of their topologies. Interesting trends and novel features have been observed and distinct classes of interpenetrating nets have been envisaged, depending on the relationships of the individual motifs.

State-of-the-art in privacy preserving data mining

Abstract: We provide here an overview of the new and rapidly emerging research area of privacy preserving data mining. We also propose a classification hierarchy that sets the basis for analyzing the work which has been performed in this context. A detailed review of the work accomplished in this area is also given, along with the coordinates of each work to the classification hierarchy. A brief evaluation is performed, and some initial conclusions are made.

Prognostic Value of Troponin I in Cardiac Risk Stratification of Cancer Patients Undergoing High-Dose Chemotherapy

Abstract: Background— In patients with aggressive malignancies who are undergoing high-dose chemotherapy, even minimal elevation of troponin I (TnI) is associated with late left ventricular dysfunction. The time course of the subclinical myocardial damage and its impact on the clinical outcome have never been investigated previously. Methods and Results— In 703 cancer patients, we measured TnI soon after chemotherapy (early TnI) and 1 month later (late TnI). Troponin was considered positive for values ≥0.08 ng/mL. Clinical and left ventricular ejection fraction evaluation (echocardiography) were performed before chemotherapy, 1, 3, 6, and 12 months after the end of the treatment, and again every 6 months afterward. Three different TnI patterns were identified, and patients were grouped accordingly. In 495 patients, both early and late TnI values were <0.08 ng/mL (TnI−/− group); in 145, there was only an early increase (TnI+/− group); and in 63 patients, both values increased (TnI+/+ group). In the TnI−/− group, no ...

DNA end resection, homologous recombination and DNA damage checkpoint activation require CDK1

Abstract: A single double-strand break (DSB) induced by HO endonuclease triggers both repair by homologous recombination and activation of the Mec1-dependent DNA damage checkpoint in budding yeast. Here we report that DNA damage checkpoint activation by a DSB requires the cyclin-dependent kinase CDK1 (Cdc28) in budding yeast. CDK1 is also required for DSB-induced homologous recombination at any cell cycle stage. Inhibition of homologous recombination by using an analogue-sensitive CDK1 protein results in a compensatory increase in non-homologous end joining. CDK1 is required for efficient 5' to 3' resection of DSB ends and for the recruitment of both the single-stranded DNA-binding complex, RPA, and the Rad51 recombination protein. In contrast, Mre11 protein, part of the MRX complex, accumulates at unresected DSB ends. CDK1 is not required when the DNA damage checkpoint is initiated by lesions that are processed by nucleotide excision repair. Maintenance of the DSB-induced checkpoint requires continuing CDK1 activity that ensures continuing end resection. CDK1 is also important for a later step in homologous recombination, after strand invasion and before the initiation of new DNA synthesis.

SUMO modification of Huntingtin and Huntington's disease pathology

Abstract: Huntington's disease (HD) is characterized by the accumulation of a pathogenic protein, Huntingtin (Htt), that contains an abnormal polyglutamine expansion. Here, we report that a pathogenic fragment of Htt (Httex1p) can be modified either by small ubiquitin-like modifier (SUMO)-1 or by ubiquitin on identical lysine residues. In cultured cells, SUMOylation stabilizes Httex1p, reduces its ability to form aggregates, and promotes its capacity to repress transcription. In a Drosophila model of HD, SUMOylation of Httex1p exacerbates neurodegeneration, whereas ubiquitination of Httex1p abrogates neurodegeneration. Lysine mutations that prevent both SUMOylation and ubiquitination of Httex1p reduce HD pathology, indicating that the contribution of SUMOylation to HD pathology extends beyond preventing Htt ubiquitination and degradation.

Astrocytes contain a vesicular compartment that is competent for regulated exocytosis of glutamate

Abstract: Astrocytes establish rapid cell-to-cell communication through the release of chemical transmitters. The underlying mechanisms and functional significance of this release are, however, not well understood. Here we identify an astrocytic vesicular compartment that is competent for glutamate exocytosis. Using postembedding immunogold labeling of the rat hippocampus, we show that vesicular glutamate transporters (VGLUT1/2) and the vesicular SNARE protein, cellubrevin, are both expressed in small vesicular organelles that resemble synaptic vesicles of glutamatergic terminals. Astrocytic vesicles, which are not as densely packed as their neuronal counterparts, can be observed in small groups at sites adjacent to neuronal structures bearing glutamate receptors. Fluorescently tagged VGLUT-containing vesicles were studied dynamically in living astrocytes by total internal reflection fluorescence (TIRF) microscopy. After activation of metabotropic glutamate receptors, astrocytic vesicles underwent rapid (milliseconds) Ca2+- and SNARE-dependent exocytic fusion that was accompanied by glutamate release. These data document the existence of a Ca2+-dependent quantal glutamate release activity in glia that was previously considered to be specific to synapses.

IFCC Reference System for Measurement of Hemoglobin A1c in Human Blood and the National Standardization Schemes in the United States, Japan, and Sweden: A Method-Comparison Study

Abstract: Background: The national programs for the harmonization of hemoglobin (Hb)A1c measurements in the US [National Glycohemoglobin Standardization Program (NGSP)], Japan [Japanese Diabetes Society (JDS)/Japanese Society of Clinical Chemistry (JSCC)], and Sweden are based on different designated comparison methods (DCMs). The future basis for international standardization will be the reference system developed by the IFCC Working Group on HbA1c Standardization. The aim of the present study was to determine the relationships between the IFCC Reference Method (RM) and the DCMs. Methods: Four method-comparison studies were performed in 2001–2003. In each study five to eight pooled blood samples were measured by 11 reference laboratories of the IFCC Network of Reference Laboratories, 9 Secondary Reference Laboratories of the NGSP, 3 reference laboratories of the JDS/JSCC program, and a Swedish reference laboratory. Regression equations were determined for the relationship between the IFCC RM and each of the DCMs. Results: Significant differences were observed between the HbA1c results of the IFCC RM and those of the DCMs. Significant differences were also demonstrated between the three DCMs. However, in all cases the relationship of the DCMs with the RM were linear. There were no statistically significant differences between the regression equations calculated for each of the four studies; therefore, the results could be combined. The relationship is described by the following regression equations: NGSP-HbA1c = 0.915(IFCC-HbA1c) + 2.15% ( r 2 = 0.998); JDS/JSCC-HbA1c = 0.927(IFCC-HbA1c) + 1.73% ( r 2 = 0.997); Swedish-HbA1c = 0.989(IFCC-HbA1c) + 0.88% ( r 2 = 0.996). Conclusion: There is a firm and reproducible link between the IFCC RM and DCM HbA1c values.

The ROSAT-ESO Flux Limited X-ray (REFLEX) Galaxy cluster survey. V. The cluster catalogue

Abstract: We present the catalogue of the REFLEX Cluster Survey providing information on the X-ray properties, redshifts, and some identification details of the clusters in the REFLEX sample. The catalogue describes a statistically complete X-ray flux-limited sample of 447 galaxy clusters above an X-ray flux of 3 x 10 -12 erg s -1 cm -2 (0.1 to 2.4 keV) in an area of 4.24 ster in the southern sky. The cluster candidates were first selected by their X-ray emission in the ROSAT-A11 Sky Survey and subsequently spectroscopically identified in the frame of an ESO key programme. Previously described tests have shown that the sample is more than 90% complete and there is a conservative upper limit of 9% on the fraction of clusters with a dominant X-ray contamination from AGN. In addition to the cluster catalogue we also describe the complete selection criteria as a function of the sky position and the conversion functions used to analyse the X-ray data. These are essential for the precise statistical analysis of the large-scale cluster distribution. This data set is at present the largest, statistically complete X-ray galaxy cluster sample. Together with these data set we also provide for the first time the full three-dimensional selection function. The sample forms the basis of several cosmological studies, one of the most important applications being the assessment of the statistics of the large-scale structure of the universe and the test of cosmological models. Part of these cosmological results have already been published.

Sox2 deficiency causes neurodegeneration and impaired neurogenesis in the adult mouse brain.

Abstract: In many species, the Sox2 transcription factor is a marker of the nervous system from the beginning of its development, and we have previously shown that Sox2 is expressed in embryonic neural stem cells. It is also expressed in, and is essential for, totipotent inner cell mass stem cells and other multipotent cell lineages, and its ablation causes early embryonic lethality. To investigate the role of Sox2 in the nervous system, we generated different mouse mutant alleles: a null allele ( Sox2 β-geo `knock-in'), and a regulatory mutant allele ( Sox2 ΔENH), in which a neural cell-specific enhancer is deleted. Sox2 is expressed in embryonic early neural precursors of the ventricular zone and, in the adult, in ependyma (a descendant of the ventricular zone). It is also expressed in the vast majority of dividing precursors in the neurogenic regions, and in a small proportion of differentiated neurones, particularly in the thalamus, striatum and septum. Compound Sox2 β-geo/ΔENH heterozygotes show important cerebral malformations, with parenchymal loss and ventricle enlargement, and L-dopa-rescuable circling behaviour and epilepsy. We observed striking abnormalities in neurones; degeneration and cytoplasmic protein aggregates, a feature common to diverse human neurodegenerative diseases, are observed in thalamus, striatum and septum. Furthermore, ependymal cells show ciliary loss and pathological lipid inclusions. Finally, precursor cell proliferation and the generation of new neurones in adult neurogenic regions are greatly decreased, and GFAP/nestin-positive hippocampal cells, which include the earliest neurogenic precursors, are strikingly diminished. These findings highlight a crucial and unexpected role for Sox2 in the maintenance of neurones in selected brain areas, and suggest a contribution of neural cell proliferative defects to the pathological phenotype.

VEGA--an open platform to develop chemo-bio-informatics applications, using plug-in architecture and script programming.

Abstract: In this paper we present the expandability and flexibility features of the VEGA program (downloadable free of charge at http://www.ddl.unimi.it), for the development of custom applications, using it as a multipurpose graphical environment. VEGA can be customized using both plug-in architecture and script programming. The first is useful to add new features and functions, using homemade routines, written with the VEGA Plug-in Development Kit (SDK). With the second approach it is possible to design scripts in VEGA, using the REBOL language, in order to (1) add new functions or customize existing ones; (2) automate common procedures; and (3) allow network communications, by creating a bridge between VEGA and other applications (or other PCs) through the TCP/IP protocol.

Hereditary and acquired angioedema: problems and progress: proceedings of the third C1 esterase inhibitor deficiency workshop and beyond.

Abstract: Hereditary angioedema (HAE), a rare but life-threatening condition, manifests as acute attacks of facial, laryngeal, genital, or peripheral swelling or abdominal pain secondary to intra-abdominal edema. Resulting from mutations affecting C1 esterase inhibitor (C1-INH), inhibitor of the first complement system component, attacks are not histamine-mediated and do not respond to antihistamines or corticosteroids. Low awareness and resemblance to other disorders often delay diagnosis; despite availability of C1-INH replacement in some countries, no approved, safe acute attack therapy exists in the United States. The biennial C1 Esterase Inhibitor Deficiency Workshops resulted from a European initiative for better knowledge and treatment of HAE and related diseases. This supplement contains work presented at the third workshop and expanded content toward a definitive picture of angioedema in the absence of allergy. Most notably, it includes cumulative genetic investigations; multinational laboratory diagnosis recommendations; current pathogenesis hypotheses; suggested prophylaxis and acute attack treatment, including home treatment; future treatment options; and analysis of patient subpopulations, including pediatric patients and patients whose angioedema worsened during pregnancy or hormone administration. Causes and management of acquired angioedema and a new type of angioedema with normal C1-INH are also discussed. Collaborative patient and physician efforts, crucial in rare diseases, are emphasized. This supplement seeks to raise awareness and aid diagnosis of HAE, optimize treatment for all patients, and provide a platform for further research in this rare, partially understood disorder.

Endometriosis: epidemiology and aetiological factors

Abstract: Estimates of the frequency of endometriosis vary widely. Based on the few reliable data, the prevalence of the condition can reasonably be assumed to be around 10%. Although no consistent information is available on the incidence of the disease, temporal trends suggest an increase among women of reproductive age. This could be explained-at least in part-by changing reproductive habits. Numerous epidemiological studies have indicated that nulliparous women and women reporting short and heavy menstrual cycles are at increased risk of developing endometriosis; data on other risk factors are less consistent. These epidemiological findings strongly support the menstrual reflux hypothesis. Additional evidence in favour of this theory includes the demonstration of viable endometrial cells in the menstrual effluent and peritoneal fluid, experimental implantation and growth of endometrium within the peritoneal cavity, observation of some degree of retrograde menstruation in most women undergoing laparoscopy during menses, and an association between obstructed menstrual outflow and endometriosis.

Safety of statins : Focus on clinical pharmacokinetics and drug interactions

Abstract: Statin monotherapy is generally well tolerated, with a low frequency of adverse events. The most important adverse effects associated with statins are myopathy and an asymptomatic increase in hepatic transaminases, both of which occur infrequently. Because statins are prescribed on a long-term basis, however, possible interactions with other drugs deserve particular attention, as many patients will typically receive pharmacological therapy for concomitant conditions during the course of statin treatment. This review summarizes the pharmacokinetic properties of statins and emphasizes their clinically relevant drug interactions.

On the generalization ability of on-line learning algorithms

Abstract: In this paper, it is shown how to extract a hypothesis with small risk from the ensemble of hypotheses generated by an arbitrary on-line learning algorithm run on an independent and identically distributed (i.i.d.) sample of data. Using a simple large deviation argument, we prove tight data-dependent bounds for the risk of this hypothesis in terms of an easily computable statistic M/sub n/ associated with the on-line performance of the ensemble. Via sharp pointwise bounds on M/sub n/, we then obtain risk tail bounds for kernel perceptron algorithms in terms of the spectrum of the empirical kernel matrix. These bounds reveal that the linear hypotheses found via our approach achieve optimal tradeoffs between hinge loss and margin size over the class of all linear functions, an issue that was left open by previous results. A distinctive feature of our approach is that the key tools for our analysis come from the model of prediction of individual sequences; i.e., a model making no probabilistic assumptions on the source generating the data. In fact, these tools turn out to be so powerful that we only need very elementary statistical facts to obtain our final risk bounds.