Evolution of Mycobacterium ulcerans and other mycolactone-producing mycobacteria from a common Mycobacterium marinum progenitor

It had been assumed that production of the cytotoxic polyketide mycolactone was strictly associated with Mycobacterium ulcerans, the causative agent of Buruli ulcer. However, a recent study has uncovered a broader distribution of mycolactone-producing mycobacteria (MPM) that includes mycobacteria cultured from diseased fish and frogs in the United States and from diseased fish in the Red and Mediterranean Seas. All of these mycobacteria contain versions of the M. ulcerans pMUM plasmid, produce mycolactones, and show a high degree of genetic relatedness to both M. ulcerans and Mycobacterium marinum. Here, we show by multiple genetic methods, including multilocus sequence analysis and DNA-DNA hybridization, that all MPM have evolved from a common M. marinum progenitor to form a genetically cohesive group among a more diverse assemblage of M. marinum strains. Like M. ulcerans, the fish and frog MPM show multiple copies of the insertion sequence IS2404. Comparisons of pMUM and chromosomal gene sequences demonstrate that plasmid acquisition and the subsequent ability to produce mycolactone were probably the key drivers of speciation. Ongoing evolution among MPM has since produced at least two genetically distinct ecotypes that can be broadly divided into those typically causing disease in ectotherms (but also having a high zoonotic potential) and those causing disease in endotherms, such as humans

Validating the Rett Syndrome Gross Motor Scale

© 2016 Downs et al. Rett syndrome is a pervasive neurodevelopmental disorder associated with a pathogenic mutation on the MECP2 gene. Impaired movement is a fundamental component and the Rett Syndrome Gross Motor Scale was developed to measure gross motor abilities in this population. The current study investigated the validity and reliability of the Rett Syndrome Gross Motor Scale. Video data showing gross motor abilities supplemented with parent report data was collected for 255 girls and women registered with the Australian Rett Syndrome Database, and the factor structure and relationships between motor scores, age and genotype were investigated. Clinical assessment scores for 38 girls and women with Rett syndrome who attended the Danish Center for Rett Syndrome were used to assess consistency of measurement. Principal components analysis enabled the calculation of three factor scores: Sitting, Standing and Walking, and Challenge. Motor scores were poorer with increasing age and those with the p.Arg133Cys, p.Arg294* or p.Arg306Cys mutation achieved higher scores than those with a large deletion. The repeatability of clinical assessment was excellent (intraclass correlation coefficient for total score 0.99, 95% CI 0.93–0.98). The standard error of measurement for the total score was 2 points and we would be 95% confident that a change 4 points in the 45-point scale would be greater than within-subject measurement error. The Rett Syndrome Gross Motor Scale could be an appropriate measure of gross motor skills in clinical practice and clinical trials

Sero-Epidemiology as a Tool to Screen Populations for Exposure to Mycobacterium ulcerans

Sero-epidemiological analyses revealed that a higher proportion of sera from individuals living in the Buruli ulcer (BU) endemic Densu River Valley of Ghana contain Mycobacterium ulcerans 18 kDa small heat shock protein (shsp)-specific IgG than sera from inhabitants of the Volta Region, which was regarded so far as BU non-endemic. However, follow-up studies in the Volta Region showed that the individual with the highest anti-18 kDa shsp-specific serum IgG titer of all participants from the Volta Region had a BU lesion. Identification of more BU patients in the Volta Region by subsequent active case search demonstrated that sero-epidemiology can help identify low endemicity areas. Endemic and non-endemic communities along the Densu River Valley differed neither in sero-prevalence nor in positivity of environmental samples in PCR targeting M. ulcerans genomic and plasmid DNA sequences. A lower risk of developing M. ulcerans disease in the non-endemic communities may either be related to host factors or a lower virulence of local M. ulcerans strains

Molecular Dynamics Simulations Suggest Ligand’s Binding to Nicotinamidase/Pyrazinamidase

The research on the binding process of ligand to pyrazinamidase (PncA) is crucial for elucidating the inherent relationship between resistance of Mycobacterium tuberculosis and PncA’s activity. In the present study, molecular dynamics (MD) simulation methods were performed to investigate the unbinding process of nicotinamide (NAM) from two PncA enzymes, which is the reverse of the corresponding binding process. The calculated potential of mean force (PMF) based on the steered molecular dynamics (SMD) simulations sheds light on an optimal binding/unbinding pathway of the ligand. The comparative analyses between two PncAs clearly exhibit the consistency of the binding/unbinding pathway in the two enzymes, implying the universality of the pathway in all kinds of PncAs. Several important residues dominating the pathway were also determined by the calculation of interaction energies. The structural change of the proteins induced by NAM’s unbinding or binding shows the great extent interior motion in some homologous region adjacent to the active sites of the two PncAs. The structure comparison substantiates that this region should be very important for the ligand’s binding in all PncAs. Additionally, MD simulations also show that the coordination position of the ligand is displaced by one water molecule in the unliganded enzymes. These results could provide the more penetrating understanding of drug resistance of M. tuberculosis and be helpful for the development of new antituberculosis drugs

The phenotype associated with a large deletion on MECP2

Multiplex ligation-dependent Probe Amplification (MLPA) has become available for the detection of a large deletion on the MECP2 gene allowing genetic confirmation of previously unconfirmed cases of clinical Rett syndrome. This study describes the phenotype of those with a large deletion and compares with those with other pathogenic MECP2 mutations. Individuals were ascertained from the Australian Rett Syndrome and InterRett databases with data sourced from family and clinician questionnaires, and two case studies were constructed from the longitudinal Australian data. Regression and survival analysis were used to compare severity and age of onset of symptoms in those with and without a large deletion. Data were available for 974 individuals including 51 with a large deletion and ages ranged from 1 year 4 months to 49 years (median 9 years). Those with a large deletion were more severely affected than those with other mutation types. Specifically, individuals with large deletions were less likely to have learned to walk (OR 0.42, 95% CI: 0.22–0.79, P=0.007) and to be currently walking (OR 0.53, 95% CI: 0.26–1.10, P=0.089), and were at higher odds of being in the most severe category of gross motor function (OR 1.84, 95% CI: 0.98–3.48, P=0.057) and epilepsy (OR 2.72, 95% CI: 1.38–5.37, P=0.004). They also developed epilepsy, scoliosis, hand stereotypies and abnormal breathing patterns at an earlier age. We have described the disorder profile associated with a large deletion from the largest sample to date and have found that the phenotype is severe with motor skills particularly affected

Quantifying Microstructural Evolution in Moving Magma

Many of the grand challenges in volcanic and magmatic research are focused on understanding the dynamics of highly heterogeneous systems and the critical conditions that enable magmas to move or eruptions to initiate. From the formation and development of magma reservoirs, through propagation and arrest of magma, to the conditions in the conduit, gas escape, eruption dynamics, and beyond into the environmental impacts of that eruption, we are trying to define how processes occur, their rates and timings, and their causes and consequences. However, we are usually unable to observe the processes directly. Here we give a short synopsis of the new capabilities and highlight the potential insights that in situ observation can provide. We present the XRheo and Pele furnace experimental apparatus and analytical toolkit for the in situ X-ray tomography-based quantification of magmatic microstructural evolution during rheological testing. We present the first 3D data showing the evolving textural heterogeneity within a shearing magma, highlighting the dynamic changes to microstructure that occur from the initiation of shear, and the variability of the microstructural response to that shear as deformation progresses. The particular shear experiments highlighted here focus on the effect of shear on bubble coalescence with a view to shedding light on both magma transport and fragmentation processes. The XRheo system is intended to help us understand the microstructural controls on the complex and non-Newtonian evolution of magma rheology, and is therefore used to elucidate the many mobilization, transport, and eruption phenomena controlled by the rheological evolution of a multi-phase magmatic flows. The detailed, in situ characterization of sample textures presented here therefore represents the opening of a new field for the accurate parameterization of dynamic microstructural control on rheological behavior