Buruli ulcer is a neglected emerging disease that has recently been reported in some countries as the second most frequent mycobacterial disease in humans after tuberculosis. Cases have been reported from at least 32 countries in Africa (mainly west), Australia, Southeast Asia, China, Central and South America, and the Western Pacific. Large lesions often result in scarring, contractual deformities, amputations, and disabilities, and in Africa, most cases of the disease occur in children between the ages of 4-15 years. This environmental mycobacterium, Mycobacterium ulcerans, is found in communities associated with rivers, swamps, wetlands, and human-linked changes in the aquatic environment, particularly those created as a result of environmental disturbance such as deforestation, dam construction, and agriculture. Buruli ulcer disease is often referred to as the ''mysterious disease'' because the mode of transmission remains unclear, although several hypotheses have been proposed. The above review reveals that various routes of transmission may occur, varying amongst epidemiological setting and geographic region, and that there may be some role for living agents as reservoirs and as vectors of M. ulcerans, in particular aquatic insects, adult mosquitoes or other biting arthropods. We discuss traditional and non-traditional methods for indicting the roles of living agents as biologically significant reservoirs and/or vectors of pathogens, and suggest an intellectual framework for establishing criteria for transmission. The application of these criteria to the transmission of M. ulcerans presents a significant challenge.

Background Mycobacterium ulcerans is the causative agent of Buruli ulcer (BU), a destructive skin disease found predominantly in sub-Saharan Africa and south-eastern Australia. The precise mode(s) of transmission and environmental reservoir(s) remain unknown, but several studies have explored the role of aquatic invertebrate species. The purpose of this study was to investigate the environmental distribution of M. ulcerans in south-eastern Australia.Methodology/Principal FindingsA range of environmental samples was collected from Point Lonsdale (a small coastal town southwest of Melbourne, Australia, endemic for BU) and from areas with fewer or no reported incident cases of BU. Mycobacterium ulcerans DNA was detected at low levels by real-time PCR in soil, sediment, water residue, aquatic plant biofilm and terrestrial vegetation collected in Point Lonsdale. Higher levels of M. ulcerans DNA were detected in the faeces of common ringtail (Pseudocheirus peregrinus) and common brushtail (Trichosurus vulpecula) possums. Systematic testing of possum faeces revealed that M. ulcerans DNA could be detected in 41% of faecal samples collected in Point Lonsdale compared with less than 1% of faecal samples collected from non-endemic areas (p<0.0001). Capture and clinical examination of live possums in Point Lonsdale validated the accuracy of the predictive value of the faecal surveys by revealing that 38% of ringtail possums and 24% of brushtail possums had laboratory-confirmed M. ulcerans skin lesions and/or M. ulcerans PCR positive faeces. Whole genome sequencing revealed an extremely close genetic relationship between human and possum M. ulcerans isolates.Conclusions/SignificanceThe prevailing wisdom is that M. ulcerans is an aquatic pathogen and that BU is acquired by contact with certain aquatic environments (swamps, slow-flowing water). Now, after 70 years of research, we propose a transmission model for BU in which terrestrial mammals are implicated as reservoirs for M. ulcerans.

Our laboratory has reported that two major noncollagenous dentin proteins, dentin sialoprotein and dentin phosphoprotein, are specific cleavage products of a larger precursor protein termed dentin sialophosphoprotein (MacDougall, M., Simmons, D., Luan, X., Nydegger, J., Feng, J. Q., and Gu, T. T. (1997) J. Biol. Chem. 272:835-842). To confirm our single gene hypothesis and initiate in vitro promoter studies, we have characterized the structural organization of the mouse dentin sialophosphoprotein gene. This gene has a transcription unit of ϳ9.4 kilobase pairs and is organized into 5 exons and 4 introns. Exon 1 contains a noncoding 5 sequence, and exon 2 contains the transcriptional start site, signal peptide, and first two amino acids of the NH 2 terminus. Exons 3 and 4 contain coding information for 29 and 314 amino acids, respectively. The remainder of the coding information and the untranslated 3 region are contained in exon 5. Chromosomal mapping localized the gene to mouse chromosome 5q21 in close proximity to other dentin/bone matrix genes. Computer analysis of the promoter proximal 1.6-kilobase pair sequence revealed a number of potentially important cis-regulatory sequences; these include the recognition elements of AP-1, AP-2, Msx-1, serum response elements, SP-1, and TCF-1. In vitro studies showed that the DSPP promoter is active in an odontoblast cell line, MO6-G3, with basal activity mapped to ؊95 bp. Two potential enhancer and suppresser elements were identified in the regions between ؊1447 and ؊791 bp and ؊791 and ؊95 bp, respectively. The structural organization of the dentin sialophosphoprotein gene confirms our finding that both dentin sialoprotein and dentin phosphoprotein are encoded by a single gene with a continuous open reading frame.The dentin extracellular matrix (DECM) 1 is the result of the cytodifferentiation of cranial neural crest-derived ectomesenchymal cells that line the tooth pulp chamber into highly specialized cells termed odontoblasts. These odontoblasts express specific genes products which form the collagenous DECM. This matrix consists of mostly type I (ϳ86%), type I trimer, type III, type V, and type VI collagens and several noncollagenous proteins also found in bone extracellular matrix, such as osteonectin (OSN, also known as SPARC), osteocalcin, osteopontin (OPN, also known as SSP1), bone sialoprotein, and dentin matrix protein 1 (Dmp-1) (1, 2). However, two DECM proteins, dentin sialoprotein (DSP) and dentin phosphoprotein (DPP, also known as phosphophoryn), have been shown to be tooth specific (for review Ref. 1), being expressed by odontoblasts and transiently by ameloblasts (2-10). These noncollagenous DECM proteins are believed to be essential for initiation and control of mineralization in the transition of predentin to dentin.DSP was first identified as a 95-kDa glycoprotein (11) with a high carbohydrate (30%) and sialic acid (10%) content accounting for 5-8% of the DECM proteins. This protein has an overall resemblance to other sialoproteins like bone sialopro...

A reformulated radiosity algorithm is presented that produces initial images in time linear to the number of patches. The enormous memory costs of the radiosity algorithm are also eliminated by computing form-factors on-the-fly. The technique is based on the approach of rendering by progressive refinement. The algorithm provides a useful solution almost immediately which progresses gracefully and continuously to the complete radiosity solution. In this way the competing demands of realism and interactivity are accommodated. The technique brings the use of radiosity for interactive rendering within reach and has implications for the use and development of current and future graphics workstations.

Genetic variation can affect drug response in multiple ways, though it remains unclear how rare genetic variants affect drug response. The electronic Medical Records and Genomics (eMERGE) Network, collaborating with the Pharmacogenomics Research Network, began eMERGE-PGx, a targeted sequencing study to assess genetic variation in 82 pharmacogenes critical for implementation of “precision medicine.” The February 2015 eMERGE-PGx data release includes sequence-derived data from ~5000 clinical subjects. We present the variant frequency spectrum categorized by variant type, ancestry, and predicted function. We found 95.12% of genes have variants with a scaled CADD score above 20, and 96.19% of all samples had one or more Clinical Pharmacogenetics Implementation Consortium Level A actionable variants. These data highlight the distribution and scope of genetic variation in relevant pharmacogenes, identifying challenges associated with implementing clinical sequencing for drug treatment at a broader level, underscoring the importance for multifaceted research in the execution of precision medicine.