Could Mycolactone Inspire New Potent Analgesics? Perspectives and Pitfalls.

Pain currently represents the most common symptom for which medical attention is sought by patients. The available treatments have limited effectiveness and significant side-effects. In addition, most often, the duration of analgesia is short.

Effect of well drilling on Buruli ulcer incidence in Benin: a case-control, quantitative survey.

Background: Buruli ulcer is the third most common mycobacterial disease worldwide. The public health burden of this neglected tropical disease is large, particularly in poor areas of west and central Africa. The development of appropriate preventive strategies is hampered by an incomplete understanding of the epidemiology and transmission of the disease.

ArfGAP1 restricts entry by controlling the actin cytoskeleton.

The interaction of (Mtb) with pulmonary epithelial cells is critical for early stages of bacillus colonization and during the progression of tuberculosis. Entry of Mtb into epithelial cells has been shown to depend on F-actin polymerization, though the molecular mechanisms are still unclear. Here, we demonstrate that mycobacterial uptake into epithelial cells requires rearrangements of the actin cytoskeleton, which are regulated by ADP-ribosylation factor 1 (Arf1) and phospholipase D1 (PLD1), and is dependent on the M3 muscarinic receptor (MR).

Mycobacterium tuberculosis Controls Phagosomal Acidification by Targeting CISH-Mediated Signaling.

Pathogens have evolved a range of mechanisms to counteract host defenses, notably to survive harsh acidic conditions in phagosomes. In the case of Mycobacterium tuberculosis, it has been shown that regulation of phagosome acidification could be achieved by interfering with the retention of the V-ATPase complexes at the vacuole. Here, we present evidence that M.

A Bacterial Toxin with Analgesic Properties: Hyperpolarization of DRG Neurons by Mycolactone.

Mycolactone, a polyketide molecule produced by , is the etiological agent of Buruli ulcer. This lipid toxin is endowed with pleiotropic effects, presents cytotoxic effects at high doses, and notably plays a pivotal role in host response upon colonization by the bacillus. Most remarkably, mycolactone displays intriguing analgesic capabilities: the toxin suppresses or alleviates the pain of the skin lesions it inflicts.

Subtelomere organization in the genome of the microsporidian Encephalitozoon cuniculi: patterns of repeated sequences and physicochemical signatures.

Background: The microsporidian Encephalitozoon cuniculi is an obligate intracellular eukaryotic pathogen with a small nuclear genome (2.9 Mbp) consisting of 11 chromosomes. Although each chromosome end is known to contain a single rDNA unit, the incomplete assembly of subtelomeric regions following sequencing of the genome identified only 3 of the 22 expected rDNA units.

Mycobacterial toxin induces analgesia in buruli ulcer by targeting the angiotensin pathways.

Mycobacterium ulcerans, the etiological agent of Buruli ulcer, causes extensive skin lesions, which despite their severity are not accompanied by pain. It was previously thought that this remarkable analgesia is ensured by direct nerve cell destruction. We demonstrate here that M.

A case of guilt by association: Water bug bite incriminated in M. ulcerans infection.

Buruli ulcer is a cutaneous mycobacterial disease caused by Mycobacterium ulcerans, whose incidence is increasing steadily, especially in West Africa. This study reports a first documented case of M. ulcerans infection which can be attributed to a water bug bite at the site of the primary lesion.

Investigation of secreted protein transcripts as early biomarkers for type 1 diabetes in the mouse model.

Type 1 diabetes (T1D) represents a serious health burden in the world, complicated by the fact that disease onset can be preceded by a long time period without evident clinical signs. It would be then of critical importance to detect the disease in its early stages. In this direction, we seek here to identify early preinflammatory markers for autoimmune diabetes, mining our previously reported transcriptome data relevant to distinct early sub-phenotypes in the NOD mouse, associated with early insulin autoantibodies (E-IAA).

SuperPartitions: detection and classification of orthologs.

The proper detection of orthologs is crucial for evolutionary studies of genes and species. Despite large efforts to solve this problem the methodological situation appears unsettled to a large extent and the "quest for orthologs" is still an ongoing task in large-scale genome comparisons. Here, we introduce a simple operational framework for the detection of orthologs and their classification.

Seasonal and regional dynamics of M. ulcerans transmission in environmental context: deciphering the role of water bugs as hosts and vectors.

Background: Buruli ulcer, the third mycobacterial disease after tuberculosis and leprosy, is caused by the environmental mycobacterium M. ulcerans. Various modes of transmission have been suspected for this disease, with no general consensus acceptance for any of them up to now.

GC content and recombination: reassessing the causal effects for the Saccharomyces cerevisiae genome.

Recombination plays a crucial role in the evolution of genomes. Among many chromosomal features, GC content is one of the most prominent variables that appear to be highly correlated with recombination. However, it is not yet clear (1) whether recombination drives GC content (as proposed, for example, in the biased gene conversion model) or the converse and (2) what are the length scales for mutual influences between GC content and recombination.

Probabilistic sequence alignments: realistic models with efficient algorithms.

Alignment algorithms usually rely on simplified models of gaps for computational efficiency. Based on correspondences between alignments and structural models for nucleic acids, and using methods from statistical mechanics, we show that alignments with realistic laws for gaps can be computed with fast algorithms. Improved performances of probabilistic alignments with realistic models of gaps are illustrated.

Protection against Mycobacterium ulcerans lesion development by exposure to aquatic insect saliva.

Background: Buruli ulcer is a severe human skin disease caused by Mycobacterium ulcerans. This disease is primarily diagnosed in West Africa with increasing incidence. Antimycobacterial drug therapy is relatively effective during the preulcerative stage of the disease, but surgical excision of lesions with skin grafting is often the ultimate treatment.

Evolution of proteomes: fundamental signatures and global trends in amino acid compositions.

Background: The evolutionary characterization of species and lifestyles at global levels is nowadays a subject of considerable interest, particularly with the availability of many complete genomes. Are there specific properties associated with lifestyles and phylogenies? What are the underlying evolutionary trends? One of the simplest analyses to address such questions concerns characterization of proteomes at the amino acids composition level.

Results: In this work, amino acid compositions of a large set of 208 proteomes, with significant number of representatives from the three phylogenetic domains and different lifestyles are analyzed, resorting to an appropriate multidimensional method: Correspondence analysis.

Genome trees from conservation profiles.

The concept of the genome tree depends on the potential evolutionary significance in the clustering of species according to similarities in the gene content of their genomes. In this respect, genome trees have often been identified with species trees. With the rapid expansion of genome sequence data it becomes of increasing importance to develop accurate methods for grasping global trends for the phylogenetic signals that mutually link the various genomes.

GadE (YhiE): a novel activator involved in the response to acid environment in Escherichia coli.

In several Gram-positive and Gram-negative bacteria glutamate decarboxylases play an important role in the maintenance of cellular homeostasis in acid environments. Here, new insight is brought to the regulation of the acid response in Escherichia coli. Overexpression of yhiE, similarly to overexpression of gadX, a known regulator of glutamate decarboxylase expression, leads to increased resistance of E.

GeneFizz: A web tool to compare genetic (coding/non-coding) and physical (helix/coil) segmentations of DNA sequences. Gene discovery and evolutionary perspectives.

The GeneFizz (http://pbga.pasteur.fr/GeneFizz) web tool permits the direct comparison between two types of segmentations for DNA sequences (possibly annotated): the coding/non-coding segmentation associated with genomic annotations (simple genes or exons in split genes) and the physics-based structural segmentation between helix and coil domains (as provided by the classical helix-coil model).

The Plasmodium falciparum family of Rab GTPases.

Rab GTPases are key regulators of vesicular traffic in eukaryotic cells. Here we sought a global characterization and description of the Plasmodium falciparum family of Rab GTPases. We used a combination of bioinformatic analyses, experimental testing of predictions, structure modelling and phylogenetics.

Amino acid composition of genomes, lifestyles of organisms, and evolutionary trends: a global picture with correspondence analysis.

Can we infer the lifestyle of an organism from the characteristic properties of its genome? More precisely, what are the relations between easily quantifiable properties from genomic sequences, such as amino-acid compositions, and more subtle characteristics concerning for example lifestyles or evolutionary trends? Here, we seek a global picture for such properties, based on a large number (56) of complete genomes, including significant numbers of representatives from the three domains of life. We consider the amino acid compositions of the predicted proteomes, and we use correspondence analysis, as a multivariate method to extract the relevant information from the large-scale data. From these analyses we derive a series of conclusions, concerning lifestyles, as well as physico-chemical and evolutionary trends: (1) correspondence analysis of the amino acid compositions permits discrimination between the three known lifestyles (mesophily/thermophily/hyperthermophily).