1,721,262 research outputs found
Role of Integrase Acetylation in HIV-1 Replication Cycle and Search for Acetylation Inhibitors
Full text linkHIV-1 integrase catalyzes the integration of the viral DNA into the genome
of the host cells. This irreversible event is crucial to the pathogenesis of the
infection and complicates its eradication both by the immune systems and by
pharmacological treatments.
The mode of action of this viral enzyme is still not completely
characterized, although full understanding of some key aspects, as the
mechanism of integration site selection, are relevant both for the development
of new anti-integrase drugs and for potential application of HIV-derived vectors
for gene therapy.
Our group has demonstrated that integrase is post-translationally acetylated
by two cellular histone-acetyl transferases (HATs), chromatin-modifying
enzymes whose major role is that of transcriptional co-activators. Integrase
acetylation is important for the viral infectivity and interaction with HATs
might be one of the determinants of HIV-1 preferential integration in actively
transcribed genomic regions.
Integrase is a poorly exploited target of anti-HIV drugs, while traditional
therapies based on combinations of reverse transcriptase inhibitors and protease
inhibitors are facing the rapid diffusion of multi-drugs resistant viral variants.
This pushes research towards new drugs and new targets, including integrase
and, even better, its interactions with cellular cofactors like, for instance, HATs.
This thesis deals with the selection of novel inhibitors of integrase
acetylation, to be used as lead compound for the development of new
generation anti-integrase drugs.
A selective inhibitor of integrase acetylation was identifyied through in
vitro screening of a library of synthetic compounds, designed based on the
structures of natural HAT inhibitors. Structure-Activity-Relationships (SAR)
studies led to the rational design of a smaller set of compounds, whose activity
was tested with in vitro and in vivo assays. Finally, one molecule was chosen
for further studies with HIV-1 derived lentiviral vectors. This cinnamoil
compound was able to inhibit integrase acetylation in the virus and reduced
viral integration in infected cells. In a reciprocal experiment, viral vectors
containing hyper-acetylated integrase were generated by trans-incorporation of
fusion integrase-HAT proteins, or of isolated HAT domains. The enhanced
infectivity of these virions confirmed the role of acetylation for integrase
function
An ultrasensitive colorimetric test for the detection of somatic rare mutations in DNA
No full textTargeted therapies for cutaneous melanoma, such as those based on specific BRAF inhibitors, have improved the treatment and enhanced the survival rate of patients who harbor the V600E point mutation in the BRAF gene. However, tissue biopsies to characterize BRAF mutation status are prone to sampling bias, due to the intrinsic heterogeneity of a tumor mass. In contrast, blood biopsies, which analyze circulating tumor DNA (ctDNA), offer the most complete and sensitive characterization of the mutation status of a tumor, provide early and more accurate diagnosis, but they require instrumental and costly molecular tests. Therefore, the development of low-cost but highly sensitive tests for the non-invasive identification of BRAFV600E mutation in ctDNA would be of great clinical utility as a routine screening for the early identification of responsive patients and the follow-up of targeted therapy's response. The present work developed a naked-eye, inexpensive, yet very specific colorimetric assay, whose sensitivity is suitable for the detection of BRAFV600E rare mutation in ctDNA. Such test potentially may detect at an early stage the mutation in the tumor mass, when the first mutated cells appear in the blood, by using minimal instrumentation and thus enabling its widespread implementation in the clinics, even in local, minimally equipped laboratories. Indeed, the test detects 0.5% of BRAFV600E in an excess of BRAFWT DNA, which matches the sensitivity of some commercial instrumental assays. Such sensitivity is thus clinically relevant for diagnostic purposes, allowing the early identification of drug-sensitive patients
Combination of pirenzepine (PR) and ranitidine (RN) given by parenteral route vs. ranitidine alone in the treatment of the upper gastrointestinal bleeding
No full text
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
LONG-TERM EFFECTS OF MONOCHLORAMINE DISINFECTION FOR LEGIONELLA AND OTHER WATERBORNE BACTERIA CONTROL IN A HOSPITAL WATER NETWORK.
No full textLONG-TERM EFFICACY OF HOSPITAL WATER NETWORK DISINFECTION BY MONOCHLORAMINE ON LEGIONELLA AND OTHER WATERBORNE BACTERIA
Author/s:
Beatrice CASINI1, Michele TOTARO1, Paola VALENTINI1, Janet STOUT2, Gaetano PRIVITERA1.
Organisation or Affiliation:
1 Department of Translational Research, N.T.M.S., University of Pisa, Italy. 2 Special Pathogens Laboratory, Pittsburgh, PA, USA.
Backgroung: The choice of an appropriate disinfection method represents a determining factor for reducing water-associated infections in healthcare setting.
Objectives: Describe the long-term efficacy of an experimental monochloramine-based (MC) disinfection operated on the hot water loop of the Emergency Department (ED), a 112-bed ward of a teaching hospital.
Methods: Starting from December 2010, on a monthly basis, Legionella and nontuberculous Mycobacteria (NTM) cultures were obtained on 126 water and 121 biofilm samples collected from the faucets of six distal and proximal sites from the MC generator device (Sanipur s.r.l., Italy)
Findings and Conclusions: Before MC disinfection, in all 6 sites water and biofilm resulted positive for Legionella pneumophila ST 269 (mean count 7.2x103 CFU/L), while 3 resulted positive for NTM only in water (mean count 40 CFU/L). An hyper-chlorination shock and super-flushing were performed. Subsequently MC was regulated to 1.5 ppm and Legionella was not found in the next 30 months, except in two instances as a consequence of the device failure (100% positive sites, 8.8x104 CFU/L mean count). Legionella was recovered only in 15% (18/121) of biofilms, always associated with positive waters. An increased log density of viable Mycobacterium gordonae was detected in 5 on 6 sites, with 53% (29/55) of positive biofilms. Following the increase of MC to 2.5 ppm, NTM cultivability was no more regain from 42 water samples and only one biofilm resulted positive (1/42).
Monochloramine resulted very effective although needed to be finely adjusted to get satisfactory results in the control of Legionella as well as other waterborne pathogens
Dispelling the Myths Behind First-author Citation Counts
Full text linkWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
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