What's new for 'Trypanosomatids' in PubMed

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Sent on Saturday, 2010 Oct 23
Search kinetoplastids OR kinetoplastid OR Kinetoplastida OR "trypanosoma brucei" OR leishmania OR brucei OR leishmaniasis OR "African trypanosomiasis"
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PubMed Results

Items 1 - 7 of 7

1.	PLoS Negl Trop Dis. 2010 Oct 12;4(10). pii: e845. CD8 T Cells as a Source of IFN-γ Production in Human Cutaneous Leishmaniasis. Nateghi Rostami M, Keshavarz H, Edalat R, Sarrafnejad A, Shahrestani T, Mahboudi F, Khamesipour A. Medical Parasitology and Mycology Department, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran. Abstract BACKGROUND: In human leishmaniasis Th1/Th2 dichotomy similar to murine model is not clearly defined and surrogate marker(s) of protection is not yet known. In this study, Th1/Th2 cytokines (IL-5, IL-10, IL-13 and IFN-γ) profile induced by purified CD4(+)/CD8(+) T cells in response to Leishmania antigens were assessed at transcript and protein levels in 14 volunteers with a history of self-healing cutaneous leishmaniasis (HCL) and compared with 18 healthy control volunteers. METHODOLOGY/PRINCIPAL FINDINGS: CD4(+)/CD8(+)/CD14(+) cells were purified from peripheral blood using magnetic beads; CD4(+)/CD8(+) T cells were co-cultured with autologous CD14(+) monocytes in the presence of soluble Leishmania antigens (SLA). Stimulation of either CD4(+) T cells or CD8(+) T cells of HCL volunteers with SLA induced a significantly (P<0.05) higher IFN-γ production compared with the cells of controls. Upregulation of IFN-γ gene expression in CD4(+) cells (P<0.001) and CD8(+) cells (P = 0.006) of HCL volunteers was significantly more than that of controls. Significantly (P<0.05) higher fold-expression of IFN-γ gene was seen in CD4(+) cells than in CD8(+) cells. In HCL volunteers a significantly (P = 0.014) higher number of CD4(+) cells were positive for intracellular IFN-γ production than CD8(+) cells. CONCLUSIONS/SIGNIFICANCE: Collectively, the volunteers have shown maintenance of specific long-term immune responses characterized by a strong reaction to leishmanin skin test and IFN-γ production. The dominant IFN-γ response was the result of expansion of both CD4(+) and CD8(+) T cells. The results suggested that immune response in protected individuals with a history of zoonotic cutaneous leishmaniasis (ZCL) due to L. major is mediated not only through the expansion of antigen-specific IFN-γ producing CD4(+) Th1 cells, but also through IFN-γ producing CD8(+) T cells.
	PMID: 20967288 [PubMed - in process]
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2.	PLoS Negl Trop Dis. 2010 Oct 12;4(10). pii: e844. Systemic FasL and TRAIL Neutralisation Reduce Leishmaniasis Induced Skin Ulceration. Tasew G, Nylén S, Lieke T, Lemu B, Meless H, Ruffin N, Wolday D, Asseffa A, Yagita H, Britton S, Akuffo H, Chiodi F, Eidsmo L. Ethiopian Health and Nutrition Research Institute (EHNRI), Parasitology Laboratory, Addis Ababa, Ethiopia. Abstract Cutaneous leishmaniasis (CL) is caused by Leishmania infection of dermal macrophages and is associated with chronic inflammation of the skin. L. aethiopica infection displays two clinical manifestations, firstly ulcerative disease, correlated to a relatively low parasite load in the skin, and secondly non-ulcerative disease in which massive parasite infiltration of the dermis occurs in the absence of ulceration of epidermis. Skin ulceration is linked to a vigorous local inflammatory response within the skin towards infected macrophages. Fas ligand (FasL) and Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) expressing cells are present in dermis in ulcerative CL and both death ligands cause apoptosis of keratinocytes in the context of Leishmania infection. In the present report we show a differential expression of FasL and TRAIL in ulcerative and non-ulcerative disease caused by L. aethiopica. In vitro experiments confirmed direct FasL- and TRAIL-induced killing of human keratinocytes in the context of Leishmania-induced inflammatory microenvironment. Systemic neutralisation of FasL and TRAIL reduced ulceration in a model of murine Leishmania infection with no effect on parasitic loads or dissemination. Interestingly, FasL neutralisation reduced neutrophil infiltration into the skin during established infection, suggesting an additional proinflammatory role of FasL in addition to direct keratinocyte killing in the context of parasite-induced skin inflammation. FasL signalling resulting in recruitment of activated neutrophils into dermis may lead to destruction of the basal membrane and thus allow direct FasL mediated killing of exposed keratinocytes in vivo. Based on our results we suggest that therapeutic inhibition of FasL and TRAIL could limit skin pathology during CL.
	PMID: 20967287 [PubMed - in process]
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3.	Nucleic Acids Res. 2010 Oct 21. [Epub ahead of print] Microhomology-mediated deletion and gene conversion in African trypanosomes. Glover L, Jun J, Horn D. London School of Hygiene and Tropical Medicine, Keppel Street, London, WC1E 7HT, UK. Abstract Antigenic variation in African trypanosomes is induced by DNA double-strand breaks (DSBs). In these protozoan parasites, DSB repair (DSBR) is dominated by homologous recombination (HR) and microhomology-mediated end joining (MMEJ), while non-homologous end joining (NHEJ) has not been reported. To facilitate the analysis of chromosomal end-joining, we established a system whereby inter-allelic repair by HR is lethal due to loss of an essential gene. Analysis of intrachromosomal end joining in individual DSBR survivors exclusively revealed MMEJ-based deletions but no NHEJ. A survey of microhomologies typically revealed sequences of between 5 and 20 bp in length with several mismatches tolerated in longer stretches. Mean deletions were of 54 bp on the side closest to the break and 284 bp in total. Break proximity, microhomology length and GC-content all favored repair and the pattern of MMEJ described above was similar at several different loci across the genome. We also identified interchromosomal gene conversion involving HR and MMEJ at different ends of a duplicated sequence. While MMEJ-based deletions were RAD51-independent, one-sided MMEJ was RAD51 dependent. Thus, we describe the features of MMEJ in Trypanosoma brucei, which is analogous to micro single-strand annealing; and RAD51 dependent, one-sided MMEJ. We discuss the contribution of MMEJ pathways to genome evolution, subtelomere recombination and antigenic variation.
	PMID: 20965968 [PubMed - as supplied by publisher]
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4.	Eur J Med Chem. 2010 Oct 7. [Epub ahead of print] Novel insights for dihydroorotate dehydrogenase class 1A inhibitors discovery. Cheleski J, Rocha JR, Pinheiro MP, Wiggers HJ, da Silva AB, Nonato MC, Montanari CA. Grupo de Estudos em Química Medicinal de Produtos Naturais, NEQUIMED-PN, Instituto de Química de São Carlos, Universidade de São Paulo, Av. Trabalhador Sancarlense 400, 13560-970, São Carlos-SP, Brazil. Abstract The enzyme dihydroorotate dehydrogenase (DHODH) has been suggested as a promising target for the design of trypanocidal agents. We report here the discovery of novel inhibitors of Trypanosoma cruzi DHODH identified by a combination of virtual screening and ITC methods. Monitoring of the enzymatic reaction in the presence of selected ligands together with structural information obtained from X-ray crystallography analysis have allowed the identification and validation of a novel site of interaction (S2 site). This has provided important structural insights for the rational design of T. cruzi and Leishmania major DHODH inhibitors. The most potent compound (1) in the investigated series inhibits TcDHODH enzyme with K(i)(app) value of 19.28 μM and possesses a ligand efficiency of 0.54 kcal mol(-1) per non-H atom. The compounds described in this work are promising hits for further development. Copyright © 2010 Elsevier Masson SAS. All rights reserved.
	PMID: 20965617 [PubMed - as supplied by publisher]
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5.	Cell Microbiol. 2010 Oct 6. doi: 10.1111/j.1462-5822.2010.01534.x. [Epub ahead of print] FISH analysis reveals aneuploidy and continual generation of chromosomal mosaicism in Leishmania major. Sterkers Y, Lachaud L, Crobu L, Bastien P, Pagès M. Université Montpellier 1, UFR Médecine, Laboratoire de Parasitologie-Mycologie, Montpellier, France. CNRS 'Génétique et Evolution des Maladies Infectieuses' UMR2724 (CNRS-IRD-Université Montpellier 1), Montpellier, France. Centre Hospitalier Universitaire de Montpellier, Montpellier, France. Abstract The protozoan parasite Leishmania is generally considered to be diploid, although a few chromosomes have been described as aneuploid. Using fluorescence in situ hybridization (FISH), we determined the number of homologous chromosomes per individual cell in L. major (i) during interphase and (ii) during mitosis. We show that, in Leishmania, aneuploidy appears to be the rule, as it affects all the chromosomes that we studied. Moreover, every chromosome was observed in at least two ploidy states, among monosomic, disomic or trisomic, in the cell population. This variable chromosomal ploidy among individual cells generates intra-strain heterogeneity, here precisely chromosomal mosaicism. We also show that this mosaicism, hence chromosome ploidy distribution, is variable among clones and strains. Finally, when we examined dividing nuclei, we found a surprisingly high rate of asymmetric chromosome allotments, showing that the transmission of genetic material during mitosis is highly unstable in this 'divergent' eukaryote: this leads to continual generation of chromosomal mosaicism. Using these results, we propose a model for the occurrence and persistence of this mosaicism. We discuss the implications of this additional unique feature of Leishmania for its biology and genetics, in particular as a novel genetic mechanism to generate phenotypic variability from genomic plasticity. © 2010 Blackwell Publishing Ltd.
	PMID: 20964798 [PubMed - as supplied by publisher]
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6.	J Dermatolog Treat. 2010 Oct 22. [Epub ahead of print] Is topical nitric oxide and cryotherapy more effective than cryotherapy in the treatment of old world cutaneous leishmaniasis? Jowkar F, Dehghani F, Jamshidzadeh A. Dermatology Department. Abstract Abstract Background: Current systemic treatments for cutaneous leishmaniasis are limited by their toxicity, high cost, side effects and the emergence of drug resistance. New approaches, including topical therapies, are urgently needed. Nitric oxide (NO) produced by human and canine macrophages has long been demonstrated to be involved in the intracellular killing of Leishmania. Objective: This study was designed to determine the clinical responses (healing, or non-healing) and effectiveness of NO plus cryotherapy for the treatment of old world cutaneous leishmaniasis (CL). Methods: A double-blind, randomized, placebo-controlled clinical trial was performed for the evaluation of therapy with topical nitric oxide 3% and cryotherapy in 63 Iranian patients with CL in the south of Iran. Results: Thirty of 36 participants (83.3%) had complete improvement in the treatment group as did 20 of 27 (74.1%) from the control group (p = 0.627). Erythema, a burning sensation and irritation occurred in seven participants from the treatment group and one patient from the placebo group (p = 0.063). Conclusion: This study could not show any more effectiveness from combining a 12-week course of treatment with 3% nitric oxide cream and a once-weekly treatment with cryotherapy in comparison with cryotherapy and placebo in patients with CL.
	PMID: 20964568 [PubMed - as supplied by publisher]
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7.	Biochemistry. 2010 Sep 28;49(38):8434-41. Comparative kinetics of cofactor association and dissociation for the human and trypanosomal S-adenosylhomocysteine hydrolases. 3. Role of lysyl and tyrosyl residues of the C-terminal extension. Cai S, Fang J, Li QS, Borchardt RT, Kuczera K, Middaugh CR, Schowen RL. Department of Molecular Biosciences, The University of Kansas, Lawrence, Kansas 66047, USA. Abstract On the basis of the available X-ray structures of S-adenosylhomocysteine hydrolases (SAHHs), free energy simulations employing the MM-GBSA approach were applied to predict residues important to the differential cofactor binding properties of human and trypanosomal SAHHs (Hs-SAHH and Tc-SAHH), within 5 Å of the cofactor NAD(+)/NADH binding site. Among the 38 residues in this region, only four are different between the two enzymes. Surprisingly, the four nonidentical residues make no major contribution to differential cofactor binding between Hs-SAHH and Tc-SAHH. On the other hand, four pairs of identical residues are shown by free energy simulations to differentiate cofactor binding between Hs-SAHH and Tc-SAHH. Experimental mutagenesis was performed to test these predictions for a lysine residue and a tyrosine residue of the C-terminal extension that penetrates a partner subunit to form part of the cofactor binding site. The K431A mutant of Tc-SAHH (TcK431A) loses its cofactor binding affinity but retains the wild type's tetrameric structure, while the corresponding mutant of Hs-SAHH (HsK426A) loses both cofactor affinity and tetrameric structure [Ault-Riche, D. B., et al. (1994) J. Biol. Chem. 269, 31472-31478]. The tyrosine mutants HsY430A and TcY435A alter the NAD(+) association and dissociation kinetics, with HsY430A increasing the cofactor equilibrium dissociation constant from approximately 10 nM (Hs-SAHH) to ∼800 nM and TcY435A increasing the cofactor equilibrium dissociation constant from approximately 100 nM (Tc-SAHH) to ∼1 mM. Both changes result from larger increases in the off rate combined with smaller decreases in the on rate. These investigations demonstrate that computational free energy decomposition may be used to guide experimental studies by suggesting sensitive sites for mutagenesis. Our finding that identical residues in two orthologous proteins may give significantly different binding free energy contributions strongly suggests that comparative studies of homologous proteins should investigate not only different residues but also identical residues in these proteins.
	PMID: 20687591 [PubMed - indexed for MEDLINE]
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