Dhafer Laouini | Institut Pasteur de Tunis (original) (raw)

Papers by Dhafer Laouini

We analyzed the transcriptional signatures of mouse bone marrow-derived macrophages at different ... more We analyzed the transcriptional signatures of mouse bone marrow-derived macrophages at different times after infection with promastigotes of the protozoan parasite Leishmania major. Ingenuity Pathway Analysis revealed that the macrophage metabolic pathways including carbohydrate and lipid metabolisms were among the most altered pathways at later time points of infection. Indeed, L. major promastiogtes induced increased mRNA levels of the glucose transporter and almost all of the genes associated with glycolysis and lactate dehydrogenase, suggesting a shift to anaerobic glycolysis. On the other hand, L. major promastigotes enhanced the expression of scavenger receptors involved in the uptake of Low-Density Lipoprotein (LDL), inhibited the expression of genes coding for proteins regulating cholesterol efflux, and induced the synthesis of triacylglycerides. These data suggested that Leishmania infection disturbs cholesterol and triglycerides homeostasis and may lead to cholesterol accumulation and foam cell formation. Using Filipin and Bodipy staining, we showed cholesterol and triglycerides accumulation in infected macrophages. Moreover, Bodipy-positive lipid droplets accumulated in close proximity to parasitophorous vacuoles, suggesting that intracellular L. major may take advantage of these organelles as high-energy substrate sources. While the effect of infection on cholesterol accumulation and lipid droplet formation was independent on parasite development, our data indicate that anaerobic glycolysis is actively induced by L. major during the establishment of infection.

Immunity, 2002

respectively, bind TRAF1 and TRAF5. The intracellular domain of murine CD40, like that of human C... more respectively, bind TRAF1 and TRAF5. The intracellular domain of murine CD40, like that of human CD40, has Children's Hospital and Department of Pediatrics a proline-rich membrane proximal region (aa 222-230), a conserved TRAF6 binding motif, RQDPQE (aa 234-239), Harvard Medical School 2 Immunopathology Unit and a 32 aa stretch (aa 247-278) that is 100% homologous to aa 246-277 of human CD40 and that contains the Massachusetts General Hospital Boston, Massachusetts 02115 TRAF2 and TRAF3 binding motif, PxQxT (aa 251-255). CD40 ligation in B cells causes activation of the MAP kinases JNK and p38 (Li et al., 1996) and of the transcription factor NFB (Berberich et al., 1994; Iciek et al., Summary 1997). Studies in B cell lines suggest that TRAF proteins play an important role in CD40 signaling. TRAF2 lacking To define the role of TRAF proteins in CD40-dependent isotype switching in B cells, we introduced wild-type an amino-terminal RING finger domain is a dominantnegative inhibitor of CD40 activation of NFB (Rothe et (WT) and mutant CD40 transgenes that lacked the binding motifs for TRAF6 (CD40⌬TRAF6), TRAF2 and TRAF3 al., 1995). TRAF2 and TRAF6 synergize in NFB activation (Lee et al., 1999; Tsukamoto et al., 1999). TRAF6, (CD40⌬TRAF2/3), or both (CD40⌬TRAFs) into B cells of CD40 Ϫ/Ϫ mice. The in vivo isotype switch defect in TRAF2, and TRAF3 all have been reported to be involved in JNK and p38 activation by CD40 (Grammer et al., CD40 Ϫ/Ϫ mice was fully corrected by WT and CD40⌬ TRAF6, partially by CD40⌬TRAF2/3, and not at all 1998; Leo et al., 1999a; Reinhard et al., 1997; Song et al., 1997; Sutherland et al., 1999). by CD40⌬TRAFs transgenes. CD40-mediated isotype switching, proliferation, and activation of p38, JNK,

BMC Genomics, 2008

Background: Leishmania (L) are intracellular protozoan parasites that are able to survive and rep... more Background: Leishmania (L) are intracellular protozoan parasites that are able to survive and replicate within the harsh and potentially hostile phagolysosomal environment of mammalian mononuclear phagocytes. A complex interplay then takes place between the macrophage (MΦ) striving to eliminate the pathogen and the parasite struggling for its own survival.

PLoS Neglected Tropical Diseases, 2013

Background: Leishmania (L.) are intracellular protozoan parasites able to survive and replicate i... more Background: Leishmania (L.) are intracellular protozoan parasites able to survive and replicate in the hostile phagolysosomal environment of infected macrophages. They cause leishmaniasis, a heterogeneous group of worldwide-distributed affections, representing a paradigm of neglected diseases that are mainly embedded in impoverished populations. To establish successful infection and ensure their own survival, Leishmania have developed sophisticated strategies to subvert the host macrophage responses. Despite a wealth of gained crucial information, these strategies still remain poorly understood. MicroRNAs (miRNAs), an evolutionarily conserved class of endogenous 22-nucleotide non-coding RNAs, are described to participate in the regulation of almost every cellular process investigated so far. They regulate the expression of target genes both at the levels of mRNA stability and translation; changes in their expression have a profound effect on their target transcripts.

Infection, Genetics and Evolution, 2009

Infection, Genetics and Evolution, 2011

Eukaryotic pathogens (e.g. Plasmodium, Leishmania, Trypanosomes, etc.) are a major source of morb... more Eukaryotic pathogens (e.g. Plasmodium, Leishmania, Trypanosomes, etc.) are a major source of morbidity and mortality worldwide. In Africa, one of the most impacted continents, they cause millions of deaths and constitute an immense economic burden. While the genome sequence of several of these organisms is now available, the biological functions of more than half of their proteins are still unknown. This is a serious issue for bringing to the foreground the expected new therapeutic targets. In this context, the identification of protein domains is a key step to improve the functional annotation of the proteins.

BMC Research Notes, 2012

Background: Leishmaniasis are widespread parasitic-diseases with an urgent need for more active a... more Background: Leishmaniasis are widespread parasitic-diseases with an urgent need for more active and less toxic drugs and for effective vaccines. Understanding the biology of the parasite especially in the context of host parasite interaction is a crucial step towards such improvements in therapy and control. Several experimental approaches including SAGE (Serial analysis of gene expression) have been developed in order to investigate the parasite transcriptome organisation and plasticity. Usual SAGE tag-to-gene mapping techniques are inadequate because almost all tags are normally located in the 3'-UTR outside the CDS, whereas most information available for Leishmania transcripts is restricted to the CDS predictions. The aim of this work is to optimize a SAGE libraries tagto-gene mapping technique and to show how this development improves the understanding of Leishmania transcriptome.

BMC Proceedings, 2011

Based on the knowledge that a cured infection protects the individual from re-infection, the deve... more Based on the knowledge that a cured infection protects the individual from re-infection, the development of a vaccine to prevent leishmaniasis has been a goal for nearly a century. Indeed, it is generally believed that after healing of leishmaniasis, sterile cure is never achieved and that few residual living parasites will remain sequestered within some host cells that offer them a safe shelter and hence maintain anti-parasite immune memory. This statement is mainly supported by data from experimental leishmaniasis in mice of susceptible or resistant phenotype, in which, live parasites could be recovered from lesions even after healing, and in which disease reactivation can be obtained by immune manipulation even after apparent complete cure.

Infection, Genetics and Evolution, 2009

Plos One, 2014

Identification of protein domains is a key step for understanding protein function. Hidden Markov... more Identification of protein domains is a key step for understanding protein function. Hidden Markov Models (HMMs) have proved to be a powerful tool for this task. The Pfam database notably provides a large collection of HMMs which are widely used for the annotation of proteins in sequenced organisms. This is done via sequence/HMM comparisons. However, this approach may lack sensitivity when searching for domains in divergent species. Recently, methods for HMM/HMM comparisons have been proposed and proved to be more sensitive than sequence/HMM approaches in certain cases. However, these approaches are usually not used for protein domain discovery at a genome scale, and the benefit that could be expected from their utilization for this problem has not been investigated. Using proteins of P. falciparum and L. major as examples, we investigate the extent to which HMM/HMM comparisons can identify new domain occurrences not already identified by sequence/HMM approaches. We show that although HMM/HMM comparisons are much more sensitive than sequence/HMM comparisons, they are not sufficiently accurate to be used as a standalone complement of sequence/HMM approaches at the genome scale. Hence, we propose to use domain co-occurrence -the general domain tendency to preferentially appear along with some favorite domains in the proteins -to improve the accuracy of the approach. We show that the combination of HMM/HMM comparisons and co-occurrence domain detection boosts protein annotations. At an estimated False Discovery Rate of 5%, it revealed 901 and 1098 new domains in Plasmodium and Leishmania proteins, respectively. Manual inspection of part of these predictions shows that it contains several domain families that were missing in the two organisms. All new domain occurrences have been integrated in the EuPathDomains database, along with the GO annotations that can be deduced. Citation: Ghouila A, Florent I, Guerfali FZ, Terrapon N, Laouini D, et al. (2014) Identification of Divergent Protein Domains by Combining HMM-HMM Comparisons and Co-Occurrence Detection. PLoS ONE 9(6): e95275.

Food and Chemical Toxicology, 2013

In this study, biological activities of methanolic extracts from Artemisia herba-alba, Ruta chalp... more In this study, biological activities of methanolic extracts from Artemisia herba-alba, Ruta chalpensis L. and Peganum harmala L. plants, collected in Centre of Tunisia, were investigated. Results showed an important phenolic composition of Artemisia herba-alba (123.95 ± 4.3 g GAE/kg of dry mass). The extract of this plant showed, using different antioxidant assays (DPPH, ABTS and AAPH/linoleic acid methods) and an IFN-c/ LPS induced RAW 264.7 murine macrophages' assay, the highest antioxidant (IC50 (DPPH assay) 20.64 ± 0.84 mg/L) and anti-inflammatory (72% inhibition at 150 mg/L) activities, respectively. Excepting Peganum harmala L. extract, the two other extracts showed a high anticancer activity against several cell lines (human bladder carcinoma RT112, human laryngeal carcinoma Hep2 and human myelogenous leukemia K562), for A. herba-laba IC50 = 81.59 ± 4.4, 59.05 ± 3.66 and 90.96 mg/L respectively, but not on normal peripheral blood mononuclear cells. All these biological activities are well correlated with the phenolic contents of these extracts. These findings demonstrate the remarkable potential of these plants as valuable source of antioxidants with exhibit original and interesting anti-inflammatory and anticancer capacities.

Background: Leishmania (L.) are intracellular protozoan parasites able to survive and replicate i... more Background: Leishmania (L.) are intracellular protozoan parasites able to survive and replicate in the hostile phagolysosomal environment of infected macrophages. They cause leishmaniasis, a heterogeneous group of worldwide-distributed affections, representing a paradigm of neglected diseases that are mainly embedded in impoverished populations. To establish successful infection and ensure their own survival, Leishmania have developed sophisticated strategies to subvert the host macrophage responses. Despite a wealth of gained crucial information, these strategies still remain poorly understood. MicroRNAs (miRNAs), an evolutionarily conserved class of endogenous 22-nucleotide non-coding RNAs, are described to participate in the regulation of almost every cellular process investigated so far. They regulate the expression of target genes both at the levels of mRNA stability and translation; changes in their expression have a profound effect on their target transcripts.

BMC Research …, Jan 1, 2012

Background: Leishmaniasis are widespread parasitic-diseases with an urgent need for more active a... more Background: Leishmaniasis are widespread parasitic-diseases with an urgent need for more active and less toxic drugs and for effective vaccines. Understanding the biology of the parasite especially in the context of host parasite interaction is a crucial step towards such improvements in therapy and control. Several experimental approaches including SAGE (Serial analysis of gene expression) have been developed in order to investigate the parasite transcriptome organisation and plasticity. Usual SAGE tag-to-gene mapping techniques are inadequate because almost all tags are normally located in the 3'-UTR outside the CDS, whereas most information available for Leishmania transcripts is restricted to the CDS predictions. The aim of this work is to optimize a SAGE libraries tagto-gene mapping technique and to show how this development improves the understanding of Leishmania transcriptome.

Parasites & …, Jan 1, 2011

Background: Sand fly saliva has been postulated as a potential vaccine or as a vaccine component ... more Background: Sand fly saliva has been postulated as a potential vaccine or as a vaccine component within multi component vaccine against leishmaniasis. It is important to note that these studies were performed using longterm colonized Phlebotomus papatasi. The effect of sand flies colonization on the outcome of Leishmania infection is reported. Results: While pre-immunization of mice with salivary gland homogenate (SGH) of long-term colonized (F5 and beyond) female Phlebotomus papatasi induced protection against Leishmania major co-inoculated with the same type of SGH, pre-immunization of mice with SGH of recently colonized (F2 and F3) female P. papatasi did not confer protection against L. major co-inoculated with the same type of SGH. Our data showed for the first time that a shift from lack of protection to protection occurs at the fourth generation (F4) during the colonization process of P. papatasi. Conclusion: For the development of a sand fly saliva-based vaccine, inferences based on long-term colonized populations of sand flies should be treated with caution as colonization of P. papatasi appears to modulate the outcome of L. major infection from lack of protection to protection.

Lipids in Health and …, Jan 1, 2012

Background: Preparation of tyrosyl lipophilic derivatives was carried out as a response to the fo... more Background: Preparation of tyrosyl lipophilic derivatives was carried out as a response to the food, cosmetic and pharmaceutical industries' increasing demand for new lipophilic antioxidants.

Journal of Clinical …, Jan 1, 2002

Immunity, Jan 1, 2002

respectively, bind TRAF1 and TRAF5. The intracellular domain of murine CD40, like that of human C... more respectively, bind TRAF1 and TRAF5. The intracellular domain of murine CD40, like that of human CD40, has Children's Hospital and Department of Pediatrics a proline-rich membrane proximal region (aa 222-230), a conserved TRAF6 binding motif, RQDPQE (aa 234-239), Harvard Medical School 2 Immunopathology Unit and a 32 aa stretch (aa 247-278) that is 100% homologous to aa 246-277 of human CD40 and that contains the Massachusetts General Hospital Boston, Massachusetts 02115 TRAF2 and TRAF3 binding motif, PxQxT (aa 251-255). CD40 ligation in B cells causes activation of the MAP kinases JNK and p38 (Li et al., 1996) and of the transcription factor NFB (Berberich et al., 1994; Iciek et al., Summary 1997). Studies in B cell lines suggest that TRAF proteins play an important role in CD40 signaling. TRAF2 lacking To define the role of TRAF proteins in CD40-dependent isotype switching in B cells, we introduced wild-type an amino-terminal RING finger domain is a dominantnegative inhibitor of CD40 activation of NFB (Rothe et (WT) and mutant CD40 transgenes that lacked the binding motifs for TRAF6 (CD40⌬TRAF6), TRAF2 and TRAF3 al., 1995). TRAF2 and TRAF6 synergize in NFB activation (Lee et al., 1999; Tsukamoto et al., 1999). TRAF6, (CD40⌬TRAF2/3), or both (CD40⌬TRAFs) into B cells of CD40 Ϫ/Ϫ mice. The in vivo isotype switch defect in TRAF2, and TRAF3 all have been reported to be involved in JNK and p38 activation by CD40 (Grammer et al., CD40 Ϫ/Ϫ mice was fully corrected by WT and CD40⌬ TRAF6, partially by CD40⌬TRAF2/3, and not at all 1998; Leo et al., 1999a; Reinhard et al., 1997; Song et al., 1997; Sutherland et al., 1999). by CD40⌬TRAFs transgenes. CD40-mediated isotype switching, proliferation, and activation of p38, JNK, The role of TRAF proteins in CD40-mediated isotype switching is not well defined. Both TRAF6 and TRAF2/3 and NFB in B cells were normal in WT and CD40⌬TRAF6 mice, severely impaired in CD40⌬TRAF2/3, and absent binding sites are important for NFB-dependent CD40mediated activation of the C␥1 and C⑀ promoters (Leo in CD40⌬TRAFs mice. These results suggest that binding to TRAF2 and/or TRAF3 but not TRAF6 is essential et al., 1999b). Although isotype switching in B cells of TRAF3 Ϫ/Ϫ and TRAF6 Ϫ/Ϫ mice is defective, these mice for CD40 isotype switching and activation in B cells. die perinatally and have generalized defects in T and B cell activation, making the findings hard to interpret Revy, P., Hivroz, C., Andreu, G., Graber, P., Martinache, C., Fischer, A., and Durandy, A. (1999). Activation of the Janus kinase 3-STAT5a pathway after CD40 triggering of human monocytes but not of resting B cells. J. Immunol. 163, 787-793. Richards, M.L., and Katz, D.H. (1997). Analysis of the promoter elements necessary for IL-4 and anti-CD40 antibody induction of murine Fc epsilon RII (CD23): comparison with the germline epsilon promoter. J. Immunol. 158, 263-272. Rothe, M., Sarma, V., Dixit, V.M., and Goeddel, D.V. (1995). TRAF2mediated activation of NF-kappa B by TNF receptor 2 and CD40.

Journal of Clinical …, Jan 1, 2003

We analyzed the transcriptional signatures of mouse bone marrow-derived macrophages at different ... more We analyzed the transcriptional signatures of mouse bone marrow-derived macrophages at different times after infection with promastigotes of the protozoan parasite Leishmania major. Ingenuity Pathway Analysis revealed that the macrophage metabolic pathways including carbohydrate and lipid metabolisms were among the most altered pathways at later time points of infection. Indeed, L. major promastiogtes induced increased mRNA levels of the glucose transporter and almost all of the genes associated with glycolysis and lactate dehydrogenase, suggesting a shift to anaerobic glycolysis. On the other hand, L. major promastigotes enhanced the expression of scavenger receptors involved in the uptake of Low-Density Lipoprotein (LDL), inhibited the expression of genes coding for proteins regulating cholesterol efflux, and induced the synthesis of triacylglycerides. These data suggested that Leishmania infection disturbs cholesterol and triglycerides homeostasis and may lead to cholesterol accumulation and foam cell formation. Using Filipin and Bodipy staining, we showed cholesterol and triglycerides accumulation in infected macrophages. Moreover, Bodipy-positive lipid droplets accumulated in close proximity to parasitophorous vacuoles, suggesting that intracellular L. major may take advantage of these organelles as high-energy substrate sources. While the effect of infection on cholesterol accumulation and lipid droplet formation was independent on parasite development, our data indicate that anaerobic glycolysis is actively induced by L. major during the establishment of infection.

Immunity, 2002

respectively, bind TRAF1 and TRAF5. The intracellular domain of murine CD40, like that of human C... more respectively, bind TRAF1 and TRAF5. The intracellular domain of murine CD40, like that of human CD40, has Children's Hospital and Department of Pediatrics a proline-rich membrane proximal region (aa 222-230), a conserved TRAF6 binding motif, RQDPQE (aa 234-239), Harvard Medical School 2 Immunopathology Unit and a 32 aa stretch (aa 247-278) that is 100% homologous to aa 246-277 of human CD40 and that contains the Massachusetts General Hospital Boston, Massachusetts 02115 TRAF2 and TRAF3 binding motif, PxQxT (aa 251-255). CD40 ligation in B cells causes activation of the MAP kinases JNK and p38 (Li et al., 1996) and of the transcription factor NFB (Berberich et al., 1994; Iciek et al., Summary 1997). Studies in B cell lines suggest that TRAF proteins play an important role in CD40 signaling. TRAF2 lacking To define the role of TRAF proteins in CD40-dependent isotype switching in B cells, we introduced wild-type an amino-terminal RING finger domain is a dominantnegative inhibitor of CD40 activation of NFB (Rothe et (WT) and mutant CD40 transgenes that lacked the binding motifs for TRAF6 (CD40⌬TRAF6), TRAF2 and TRAF3 al., 1995). TRAF2 and TRAF6 synergize in NFB activation (Lee et al., 1999; Tsukamoto et al., 1999). TRAF6, (CD40⌬TRAF2/3), or both (CD40⌬TRAFs) into B cells of CD40 Ϫ/Ϫ mice. The in vivo isotype switch defect in TRAF2, and TRAF3 all have been reported to be involved in JNK and p38 activation by CD40 (Grammer et al., CD40 Ϫ/Ϫ mice was fully corrected by WT and CD40⌬ TRAF6, partially by CD40⌬TRAF2/3, and not at all 1998; Leo et al., 1999a; Reinhard et al., 1997; Song et al., 1997; Sutherland et al., 1999). by CD40⌬TRAFs transgenes. CD40-mediated isotype switching, proliferation, and activation of p38, JNK,

BMC Genomics, 2008

Background: Leishmania (L) are intracellular protozoan parasites that are able to survive and rep... more Background: Leishmania (L) are intracellular protozoan parasites that are able to survive and replicate within the harsh and potentially hostile phagolysosomal environment of mammalian mononuclear phagocytes. A complex interplay then takes place between the macrophage (MΦ) striving to eliminate the pathogen and the parasite struggling for its own survival.

PLoS Neglected Tropical Diseases, 2013

Background: Leishmania (L.) are intracellular protozoan parasites able to survive and replicate i... more Background: Leishmania (L.) are intracellular protozoan parasites able to survive and replicate in the hostile phagolysosomal environment of infected macrophages. They cause leishmaniasis, a heterogeneous group of worldwide-distributed affections, representing a paradigm of neglected diseases that are mainly embedded in impoverished populations. To establish successful infection and ensure their own survival, Leishmania have developed sophisticated strategies to subvert the host macrophage responses. Despite a wealth of gained crucial information, these strategies still remain poorly understood. MicroRNAs (miRNAs), an evolutionarily conserved class of endogenous 22-nucleotide non-coding RNAs, are described to participate in the regulation of almost every cellular process investigated so far. They regulate the expression of target genes both at the levels of mRNA stability and translation; changes in their expression have a profound effect on their target transcripts.

Infection, Genetics and Evolution, 2009

Infection, Genetics and Evolution, 2011

Eukaryotic pathogens (e.g. Plasmodium, Leishmania, Trypanosomes, etc.) are a major source of morb... more Eukaryotic pathogens (e.g. Plasmodium, Leishmania, Trypanosomes, etc.) are a major source of morbidity and mortality worldwide. In Africa, one of the most impacted continents, they cause millions of deaths and constitute an immense economic burden. While the genome sequence of several of these organisms is now available, the biological functions of more than half of their proteins are still unknown. This is a serious issue for bringing to the foreground the expected new therapeutic targets. In this context, the identification of protein domains is a key step to improve the functional annotation of the proteins.

BMC Research Notes, 2012

Background: Leishmaniasis are widespread parasitic-diseases with an urgent need for more active a... more Background: Leishmaniasis are widespread parasitic-diseases with an urgent need for more active and less toxic drugs and for effective vaccines. Understanding the biology of the parasite especially in the context of host parasite interaction is a crucial step towards such improvements in therapy and control. Several experimental approaches including SAGE (Serial analysis of gene expression) have been developed in order to investigate the parasite transcriptome organisation and plasticity. Usual SAGE tag-to-gene mapping techniques are inadequate because almost all tags are normally located in the 3'-UTR outside the CDS, whereas most information available for Leishmania transcripts is restricted to the CDS predictions. The aim of this work is to optimize a SAGE libraries tagto-gene mapping technique and to show how this development improves the understanding of Leishmania transcriptome.

BMC Proceedings, 2011

Based on the knowledge that a cured infection protects the individual from re-infection, the deve... more Based on the knowledge that a cured infection protects the individual from re-infection, the development of a vaccine to prevent leishmaniasis has been a goal for nearly a century. Indeed, it is generally believed that after healing of leishmaniasis, sterile cure is never achieved and that few residual living parasites will remain sequestered within some host cells that offer them a safe shelter and hence maintain anti-parasite immune memory. This statement is mainly supported by data from experimental leishmaniasis in mice of susceptible or resistant phenotype, in which, live parasites could be recovered from lesions even after healing, and in which disease reactivation can be obtained by immune manipulation even after apparent complete cure.

Infection, Genetics and Evolution, 2009

Plos One, 2014

Identification of protein domains is a key step for understanding protein function. Hidden Markov... more Identification of protein domains is a key step for understanding protein function. Hidden Markov Models (HMMs) have proved to be a powerful tool for this task. The Pfam database notably provides a large collection of HMMs which are widely used for the annotation of proteins in sequenced organisms. This is done via sequence/HMM comparisons. However, this approach may lack sensitivity when searching for domains in divergent species. Recently, methods for HMM/HMM comparisons have been proposed and proved to be more sensitive than sequence/HMM approaches in certain cases. However, these approaches are usually not used for protein domain discovery at a genome scale, and the benefit that could be expected from their utilization for this problem has not been investigated. Using proteins of P. falciparum and L. major as examples, we investigate the extent to which HMM/HMM comparisons can identify new domain occurrences not already identified by sequence/HMM approaches. We show that although HMM/HMM comparisons are much more sensitive than sequence/HMM comparisons, they are not sufficiently accurate to be used as a standalone complement of sequence/HMM approaches at the genome scale. Hence, we propose to use domain co-occurrence -the general domain tendency to preferentially appear along with some favorite domains in the proteins -to improve the accuracy of the approach. We show that the combination of HMM/HMM comparisons and co-occurrence domain detection boosts protein annotations. At an estimated False Discovery Rate of 5%, it revealed 901 and 1098 new domains in Plasmodium and Leishmania proteins, respectively. Manual inspection of part of these predictions shows that it contains several domain families that were missing in the two organisms. All new domain occurrences have been integrated in the EuPathDomains database, along with the GO annotations that can be deduced. Citation: Ghouila A, Florent I, Guerfali FZ, Terrapon N, Laouini D, et al. (2014) Identification of Divergent Protein Domains by Combining HMM-HMM Comparisons and Co-Occurrence Detection. PLoS ONE 9(6): e95275.

Food and Chemical Toxicology, 2013

In this study, biological activities of methanolic extracts from Artemisia herba-alba, Ruta chalp... more In this study, biological activities of methanolic extracts from Artemisia herba-alba, Ruta chalpensis L. and Peganum harmala L. plants, collected in Centre of Tunisia, were investigated. Results showed an important phenolic composition of Artemisia herba-alba (123.95 ± 4.3 g GAE/kg of dry mass). The extract of this plant showed, using different antioxidant assays (DPPH, ABTS and AAPH/linoleic acid methods) and an IFN-c/ LPS induced RAW 264.7 murine macrophages' assay, the highest antioxidant (IC50 (DPPH assay) 20.64 ± 0.84 mg/L) and anti-inflammatory (72% inhibition at 150 mg/L) activities, respectively. Excepting Peganum harmala L. extract, the two other extracts showed a high anticancer activity against several cell lines (human bladder carcinoma RT112, human laryngeal carcinoma Hep2 and human myelogenous leukemia K562), for A. herba-laba IC50 = 81.59 ± 4.4, 59.05 ± 3.66 and 90.96 mg/L respectively, but not on normal peripheral blood mononuclear cells. All these biological activities are well correlated with the phenolic contents of these extracts. These findings demonstrate the remarkable potential of these plants as valuable source of antioxidants with exhibit original and interesting anti-inflammatory and anticancer capacities.

Background: Leishmania (L.) are intracellular protozoan parasites able to survive and replicate i... more Background: Leishmania (L.) are intracellular protozoan parasites able to survive and replicate in the hostile phagolysosomal environment of infected macrophages. They cause leishmaniasis, a heterogeneous group of worldwide-distributed affections, representing a paradigm of neglected diseases that are mainly embedded in impoverished populations. To establish successful infection and ensure their own survival, Leishmania have developed sophisticated strategies to subvert the host macrophage responses. Despite a wealth of gained crucial information, these strategies still remain poorly understood. MicroRNAs (miRNAs), an evolutionarily conserved class of endogenous 22-nucleotide non-coding RNAs, are described to participate in the regulation of almost every cellular process investigated so far. They regulate the expression of target genes both at the levels of mRNA stability and translation; changes in their expression have a profound effect on their target transcripts.

BMC Research …, Jan 1, 2012

Background: Leishmaniasis are widespread parasitic-diseases with an urgent need for more active a... more Background: Leishmaniasis are widespread parasitic-diseases with an urgent need for more active and less toxic drugs and for effective vaccines. Understanding the biology of the parasite especially in the context of host parasite interaction is a crucial step towards such improvements in therapy and control. Several experimental approaches including SAGE (Serial analysis of gene expression) have been developed in order to investigate the parasite transcriptome organisation and plasticity. Usual SAGE tag-to-gene mapping techniques are inadequate because almost all tags are normally located in the 3'-UTR outside the CDS, whereas most information available for Leishmania transcripts is restricted to the CDS predictions. The aim of this work is to optimize a SAGE libraries tagto-gene mapping technique and to show how this development improves the understanding of Leishmania transcriptome.

Parasites & …, Jan 1, 2011

Background: Sand fly saliva has been postulated as a potential vaccine or as a vaccine component ... more Background: Sand fly saliva has been postulated as a potential vaccine or as a vaccine component within multi component vaccine against leishmaniasis. It is important to note that these studies were performed using longterm colonized Phlebotomus papatasi. The effect of sand flies colonization on the outcome of Leishmania infection is reported. Results: While pre-immunization of mice with salivary gland homogenate (SGH) of long-term colonized (F5 and beyond) female Phlebotomus papatasi induced protection against Leishmania major co-inoculated with the same type of SGH, pre-immunization of mice with SGH of recently colonized (F2 and F3) female P. papatasi did not confer protection against L. major co-inoculated with the same type of SGH. Our data showed for the first time that a shift from lack of protection to protection occurs at the fourth generation (F4) during the colonization process of P. papatasi. Conclusion: For the development of a sand fly saliva-based vaccine, inferences based on long-term colonized populations of sand flies should be treated with caution as colonization of P. papatasi appears to modulate the outcome of L. major infection from lack of protection to protection.

Lipids in Health and …, Jan 1, 2012

Background: Preparation of tyrosyl lipophilic derivatives was carried out as a response to the fo... more Background: Preparation of tyrosyl lipophilic derivatives was carried out as a response to the food, cosmetic and pharmaceutical industries' increasing demand for new lipophilic antioxidants.

Journal of Clinical …, Jan 1, 2002

Immunity, Jan 1, 2002

respectively, bind TRAF1 and TRAF5. The intracellular domain of murine CD40, like that of human C... more respectively, bind TRAF1 and TRAF5. The intracellular domain of murine CD40, like that of human CD40, has Children's Hospital and Department of Pediatrics a proline-rich membrane proximal region (aa 222-230), a conserved TRAF6 binding motif, RQDPQE (aa 234-239), Harvard Medical School 2 Immunopathology Unit and a 32 aa stretch (aa 247-278) that is 100% homologous to aa 246-277 of human CD40 and that contains the Massachusetts General Hospital Boston, Massachusetts 02115 TRAF2 and TRAF3 binding motif, PxQxT (aa 251-255). CD40 ligation in B cells causes activation of the MAP kinases JNK and p38 (Li et al., 1996) and of the transcription factor NFB (Berberich et al., 1994; Iciek et al., Summary 1997). Studies in B cell lines suggest that TRAF proteins play an important role in CD40 signaling. TRAF2 lacking To define the role of TRAF proteins in CD40-dependent isotype switching in B cells, we introduced wild-type an amino-terminal RING finger domain is a dominantnegative inhibitor of CD40 activation of NFB (Rothe et (WT) and mutant CD40 transgenes that lacked the binding motifs for TRAF6 (CD40⌬TRAF6), TRAF2 and TRAF3 al., 1995). TRAF2 and TRAF6 synergize in NFB activation (Lee et al., 1999; Tsukamoto et al., 1999). TRAF6, (CD40⌬TRAF2/3), or both (CD40⌬TRAFs) into B cells of CD40 Ϫ/Ϫ mice. The in vivo isotype switch defect in TRAF2, and TRAF3 all have been reported to be involved in JNK and p38 activation by CD40 (Grammer et al., CD40 Ϫ/Ϫ mice was fully corrected by WT and CD40⌬ TRAF6, partially by CD40⌬TRAF2/3, and not at all 1998; Leo et al., 1999a; Reinhard et al., 1997; Song et al., 1997; Sutherland et al., 1999). by CD40⌬TRAFs transgenes. CD40-mediated isotype switching, proliferation, and activation of p38, JNK, The role of TRAF proteins in CD40-mediated isotype switching is not well defined. Both TRAF6 and TRAF2/3 and NFB in B cells were normal in WT and CD40⌬TRAF6 mice, severely impaired in CD40⌬TRAF2/3, and absent binding sites are important for NFB-dependent CD40mediated activation of the C␥1 and C⑀ promoters (Leo in CD40⌬TRAFs mice. These results suggest that binding to TRAF2 and/or TRAF3 but not TRAF6 is essential et al., 1999b). Although isotype switching in B cells of TRAF3 Ϫ/Ϫ and TRAF6 Ϫ/Ϫ mice is defective, these mice for CD40 isotype switching and activation in B cells. die perinatally and have generalized defects in T and B cell activation, making the findings hard to interpret Revy, P., Hivroz, C., Andreu, G., Graber, P., Martinache, C., Fischer, A., and Durandy, A. (1999). Activation of the Janus kinase 3-STAT5a pathway after CD40 triggering of human monocytes but not of resting B cells. J. Immunol. 163, 787-793. Richards, M.L., and Katz, D.H. (1997). Analysis of the promoter elements necessary for IL-4 and anti-CD40 antibody induction of murine Fc epsilon RII (CD23): comparison with the germline epsilon promoter. J. Immunol. 158, 263-272. Rothe, M., Sarma, V., Dixit, V.M., and Goeddel, D.V. (1995). TRAF2mediated activation of NF-kappa B by TNF receptor 2 and CD40.

Journal of Clinical …, Jan 1, 2003