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Therapeutic Efficacy and Immunological Response of CCL5 Antagonists in Models of Contact Skin Reaction
Miriam Canavese,Fiorella Altruda,Lorenzo Silengo
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0008725
Abstract: Skin-infiltrating T-cells play a predominant role in allergic and inflammatory skin diseases such as atopic dermatitis, psoriasis and allergic contact dermatitis. These T-cells are attracted by several chemotactic factors including the chemokine CCL5/RANTES, a CC chemokine inducing both the migration and activation of specific leukocyte subsets. CCL5 has been found to be associated with various cell-mediated hypersensitive disorders such as psoriasis, atopic dermatitis and irritant contact dermatitis. We have used two antagonists, the first, Met-CCL5, a dual CCR1/CCR5 antagonist and the second, a variant in which GAG binding is abrogated, 44AANA47-CCL5, which acts as a dominant negative inhibitor of CCL5. The antagonists were tested in two models of contact skin reaction. The first, irritant contact dermatitis (ICD) is a pathological non-specific inflammatory skin condition arising from the release of pro-inflammatory cytokines by keratinocytes in response to haptens, usually chemicals. The second, contact hypersensitivity (CHS) is a T-cell dependent model, mimicking in part the T-cell-mediated skin diseases such as psoriasis. In both models, the CCL5 antagonists showed therapeutic efficacy by reducing swelling by 50% as well as the reduction of soluble mediators in homogenates derived from challenged ears. These results demonstrate that blocking the receptor or the ligand are both effective strategies to inhibit skin inflammation.
CLOE: Identification of putative functional relationships among genes by comparison of expression profiles between two species
Maurizio Pellegrino, Paolo Provero, Lorenzo Silengo, Ferdinando Di Cunto
BMC Bioinformatics , 2004, DOI: 10.1186/1471-2105-5-179
Abstract: We demonstrate the capabilities of the approach by testing its predictive power on three proteomically-defined mammalian protein complexes, in comparison with single and multiple species meta-analysis approaches. Our results show that CLOE can find candidate partners for a greater number of genes, if compared to multiple species co-expression analysis, but retains a comparable specificity even when applied to species as close as mouse and human. On the other hand, it is much more specific than single organisms co-expression analysis, strongly reducing the number of potential candidate partners for a given gene of interest.CLOE represents a simple and effective data mining approach that can be easily used for meta-analysis of cDNA microarray experiments characterized by very heterogeneous coverage. Importantly, it produces for genes of interest an average number of high confidence putative partners that is in the range of standard experimental validation techniques.The availability of genome sequences from several model organisms, including humans, and of high-throughput technologies to study gene function is dramatically changing the approach to biological problems. In particular, the consolidated reductionist gene-by-gene strategy is being replaced by a 'modular approach', in which several genes are studied simultaneously to gather a more comprehensive picture of the many different cellular processes [1]: in living organisms, the majority of gene products are part of intricate molecular circuits, composed of physical, functional and regulatory interactions. In higher eukaryotes, the study of gene function is further complicated by the alternative use of transcriptional units, frequently resulting in the production of proteins with different or even antagonistic activities from the same genes [2,3].It is well recognized that one of the most important and widespread mechanisms used by cells to regulate functional modules is the coordinate transcriptional and/or post-
Functional Annotation and Identification of Candidate Disease Genes by Computational Analysis of Normal Tissue Gene Expression Data
Laura Miozzi, Rosario Michael Piro, Fabio Rosa, Ugo Ala, Lorenzo Silengo, Ferdinando Di Cunto, Paolo Provero
PLOS ONE , 2008, DOI: 10.1371/journal.pone.0002439
Abstract: Background High-throughput gene expression data can predict gene function through the “guilt by association” principle: coexpressed genes are likely to be functionally associated. Methodology/Principal Findings We analyzed publicly available expression data on normal human tissues. The analysis is based on the integration of data obtained with two experimental platforms (microarrays and SAGE) and of various measures of dissimilarity between expression profiles. The building blocks of the procedure are the Ranked Coexpression Groups (RCG), small sets of tightly coexpressed genes which are analyzed in terms of functional annotation. Functionally characterized RCGs are selected by means of the majority rule and used to predict new functional annotations. Functionally characterized RCGs are enriched in groups of genes associated to similar phenotypes. We exploit this fact to find new candidate disease genes for many OMIM phenotypes of unknown molecular origin. Conclusions/Significance We predict new functional annotations for many human genes, showing that the integration of different data sets and coexpression measures significantly improves the scope of the results. Combining gene expression data, functional annotation and known phenotype-gene associations we provide candidate genes for several genetic diseases of unknown molecular basis.
Computational identification of transcription factor binding sites by functional analysis of sets of genes sharing overrep-resented upstream motifs
Davide Corà, Ferdinando Di Cunto, Paolo Provero, Lorenzo Silengo, Michele Caselle
BMC Bioinformatics , 2004, DOI: 10.1186/1471-2105-5-57
Abstract: To exploit this fact, we construct sets of genes characterized by the statistical overrepresentation of a certain motif in their upstream regions. Then we study the functional characterization of these sets by analyzing their annotation to Gene Ontology terms. For the sets showing a statistically significant specific functional characterization, we conjecture that the upstream motif characterizing the set is a binding site for a transcription factor involved in the regulation of the genes in the set.The method we propose is able to identify many known binding sites in S. cerevisiae and new candidate targets of regulation by known transcritpion factors. Its application to less well studied organisms is likely to be valuable in the exploration of their regulatory interaction network.The regulation of gene expression in the eukaryotic cell happens at several different levels, the transcriptional one being among the most important. The general mechanism is fairly well understood, and involves the interaction between a trans-acting element, usually a protein, and a cis-acting element, a recognition site located upstream of the coding region of the regulated gene and consisting in a rather short DNA sequence to which the transcription factor is able to bind. When bound to the cis-acting elements, the trans-acting ones interfere with the transcription machinery, and can either enhance or suppress the synthesis of mRNA.While many instances of this mechanism have been known in great detail for some time, it is only recently, thanks to the availability of several fully sequenced genomes and other experimental data on the scale of the entire genome, that a study of transcriptional regulation on a global scale has become possible. Given the sheer size of the data, the computational aspects of this analysis are highly non-trivial, and many algorithms have been proposed to select the most relevant information and exploit it towards a better understanding of the phenomenon.One of
Lack of Plasma Protein Hemopexin Results in Increased Duodenal Iron Uptake
Veronica Fiorito, Simonetta Geninatti Crich, Lorenzo Silengo, Silvio Aime, Fiorella Altruda, Emanuela Tolosano
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0068146
Abstract: Purpose The body concentration of iron is regulated by a fine equilibrium between absorption and losses of iron. Iron can be absorbed from diet as inorganic iron or as heme. Hemopexin is an acute phase protein that limits iron access to microorganisms. Moreover, it is the plasma protein with the highest binding affinity for heme and thus it mediates heme-iron recycling. Considering its involvement in iron homeostasis, it was postulated that hemopexin may play a role in the physiological absorption of inorganic iron. Methods and Results Hemopexin-null mice showed elevated iron deposits in enterocytes, associated with higher duodenal H-Ferritin levels and a significant increase in duodenal expression and activity of heme oxygenase. The expression of heme-iron and inorganic iron transporters was normal. The rate of iron absorption was assessed by measuring the amount of 57Fe retained in tissues from hemopexin-null and wild-type animals after administration of an oral dose of 57FeSO4 or of 57Fe-labelled heme. Higher iron retention in the duodenum of hemopexin-null mice was observed as compared with normal mice. Conversely, iron transfer from enterocytes to liver and bone marrow was unaffected in hemopexin-null mice. Conclusions The increased iron level in hemopexin-null duodenum can be accounted for by an increased iron uptake by enterocytes and storage in ferritins. These data indicate that the lack of hemopexin under physiological conditions leads to an enhanced duodenal iron uptake thus providing new insights to our understanding of body iron homeostasis.
Computational identification of transcription factor binding sites by functional analysis of sets of genes sharing overrepresented upstream motifs
Davide Cora',Ferdinando Di Cunto,Paolo Provero,Lorenzo Silengo,Michele Caselle
Quantitative Biology , 2003,
Abstract: BACKGROUND: Transcriptional regulation is a key mechanism in the functioning of the cell, and is mostly effected through transcription factors binding to specific recognition motifs located upstream of the coding region of the regulated gene. The computational identification of such motifs is made easier by the fact that they often appear several times in the upstream region of the regulated genes, so that the number of occurrences of relevant motifs is often significantly larger than expected by pure chance. RESULTS: To exploit this fact, we construct sets of genes characterized by the statistical overrepresentation of a certain motif in their upstream regions. Then we study the functional characterization of these sets by analyzing their annotation to Gene Ontology terms. For the sets showing a statistically significant specific functional characterization, we conjecture that the upstream motif characterizing the set is a binding site for a transcription factor involved in the regulation of the genes in the set. CONCLUSIONS: The method we propose is able to identify many known binding sites in S. cerevisiae and new candidate targets of regulation by known transcription factors. Its application to less well studied organisms is likely to be valuable in the exploration of their regulatory interaction network.
Prediction of Human Disease Genes by Human-Mouse Conserved Coexpression Analysis
Ugo Ala ,Rosario Michael Piro ,Elena Grassi,Christian Damasco,Lorenzo Silengo,Martin Oti,Paolo Provero ,Ferdinando Di Cunto
PLOS Computational Biology , 2008, DOI: 10.1371/journal.pcbi.1000043
Abstract: Background Even in the post-genomic era, the identification of candidate genes within loci associated with human genetic diseases is a very demanding task, because the critical region may typically contain hundreds of positional candidates. Since genes implicated in similar phenotypes tend to share very similar expression profiles, high throughput gene expression data may represent a very important resource to identify the best candidates for sequencing. However, so far, gene coexpression has not been used very successfully to prioritize positional candidates. Methodology/Principal Findings We show that it is possible to reliably identify disease-relevant relationships among genes from massive microarray datasets by concentrating only on genes sharing similar expression profiles in both human and mouse. Moreover, we show systematically that the integration of human-mouse conserved coexpression with a phenotype similarity map allows the efficient identification of disease genes in large genomic regions. Finally, using this approach on 850 OMIM loci characterized by an unknown molecular basis, we propose high-probability candidates for 81 genetic diseases. Conclusion Our results demonstrate that conserved coexpression, even at the human-mouse phylogenetic distance, represents a very strong criterion to predict disease-relevant relationships among human genes.
Selective use patterns of woody plant species by local communities in Mumbwa Game Management Area: A prerequisite for effective management of woodland resources and benefit sharing  [PDF]
Chansa Chomba, Vincent Nyirenda, Mitulo Silengo
Open Journal of Ecology (OJE) , 2013, DOI: 10.4236/oje.2013.38062

Selective patterns of human uses of woody plants in Mumbwa Game Management Area were investigated using quantitative survey methods. Major causes of human encroachment into the wildlife zone were assessed so that appropriate management actions could be taken to ensure continued supply of goods and services to the local community. Woody plant species were found to be diverse with 93 species recorded in the study area. Of these, the community utilized 92 (99%) in different ways. Trees were cut for various reasons, major ones being; building poles, fire wood, fibre, fruit collection, medicine, bee honey collection, house hold tools and utensils and clearing for agriculture. Clearing for agriculture was the most damaging, because it involved removal of below and above ground woody biomass of all sizes and suppression of their regeneration during cultivation in subsequent years. Of the recorded human uses, 2366 kg of woody plant material was consumed per head/yr?1as fire wood. The day to day consumption of firewood varied with season. In the cold season (May-August), a 26 kg (mean weight) bundle of firewood was consumed in three days while in the warm season it lasts five days. Certain species were particularly selected;Julbernardia paniculata,Pericopsis angolensis,Brachystegia speciformis,Brachystegia boehmii,Julbernardia globiflora,Brachystegia longifolia,and Pteleopsis anisoptera. In building and construction, differences were observed in the species and size of poles was used. The mean sizes of roofing poles were 3.5 metres long and 0.18 metres mid-length girth. Wall poles were 2.4 metres long and 0.40 metres mid-length girth. For the main house of about two rooms each, there were an average number of 48 poles in the roof (45,859.2 cm3) and 28 (284,653.6 cm3) in the wall. Clearing for agriculture was the main cause of damage to woody plants in the Game Management Area. The extension of human settlements into the wildlife zone and towards the Itezhi-tezhi road is likely to increase loss of woody vegetation, and will have a negative impact on the habitat for wildlife.


A Role for Hemopexin in Oligodendrocyte Differentiation and Myelin Formation
Noemi Morello,Federico Tommaso Bianchi,Paola Marmiroli,Elisabetta Tonoli,Virginia Rodriguez Menendez,Lorenzo Silengo,Guido Cavaletti,Alessandro Vercelli,Fiorella Altruda,Emanuela Tolosano
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0020173
Abstract: Myelin formation and maintenance are crucial for the proper function of the CNS and are orchestrated by a plethora of factors including growth factors, extracellular matrix components, metalloproteases and protease inhibitors. Hemopexin (Hx) is a plasma protein with high heme binding affinity, which is also locally produced in the CNS by ependymal cells, neurons and glial cells. We have recently reported that oligodendrocytes (OLs) are the type of cells in the brain that are most susceptible to lack of Hx, as the number of iron-overloaded OLs increases in Hx-null brain, leading to oxidative tissue damage. In the current study, we found that the expression of the Myelin Basic Protein along with the density of myelinated fibers in the basal ganglia and in the motor and somatosensory cortex of Hx-null mice were strongly reduced starting at 2 months and progressively decreased with age. Myelin abnormalities were confirmed by electron microscopy and, at the functional level, resulted in the inability of Hx-null mice to perform efficiently on the Rotarod. It is likely that the poor myelination in the brain of Hx-null mice was a consequence of defective maturation of OLs as we demonstrated that the number of mature OLs was significantly reduced in mutant mice whereas that of precursor cells was normal. Finally, in vitro experiments showed that Hx promotes OL differentiation. Thus, Hx may be considered a novel OL differentiation factor and the modulation of its expression in CNS may be an important factor in the pathogenesis of human neurodegenerative disorders.
The RNA Binding Protein ESRP1 Fine-Tunes the Expression of Pluripotency-Related Factors in Mouse Embryonic Stem Cells
Sharmila Fagoonee, Claudia Bearzi, Ferdinando Di Cunto, John G. Clohessy, Roberto Rizzi, Markus Reschke, Emanuela Tolosano, Paolo Provero, Pier Paolo Pandolfi, Lorenzo Silengo, Fiorella Altruda
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0072300
Abstract: In pluripotent stem cells, there is increasing evidence for crosstalk between post-transcriptional and transcriptional networks, offering multifold steps at which pluripotency can be controlled. In addition to well-studied transcription factors, chromatin modifiers and miRNAs, RNA-binding proteins are emerging as fundamental players in pluripotency regulation. Here, we report a new role for the RNA-binding protein ESRP1 in the control of pluripotency. Knockdown of Esrp1 in mouse embryonic stem cells induces, other than the well-documented epithelial to mesenchymal-like state, also an increase in expression of the core transcription factors Oct4, Nanog and Sox2, thereby enhancing self-renewal of these cells. Esrp1-depleted embryonic stem cells displayed impaired early differentiation in vitro and formed larger teratomas in vivo when compared to control embryonic stem cells. We also show that ESRP1 binds to Oct4 and Sox2 mRNAs and decreases their polysomal loading. ESRP1 thus acts as a physiological regulator of the finely-tuned balance between self-renewal and commitment to a restricted developmental fate. Importantly, both mouse and human epithelial stem cells highly express ESRP1, pinpointing the importance of this RNA-binding protein in stem cell biology.
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