Src Kinase Regulation in Progressively Invasive Cancer

Metastatic progression is a multistep process that involves tumor growth and survival, motility and invasion, and subsequent proliferation in an inappropriate environment. The Src protein tyrosine kinase has been implicated in many of the biochemical pathways that drive these behaviors. Although Src itself is only rarely mutated in human tumors, its aberrant activity has been noted in various cancers and suggested to serve as a barometer of metastatic potential. With these features in mind, we examined Src kinase regulation at the structural, enzymatic, and expression levels as a function of progressively invasive prostate cancer cell lines. Surprisingly, both total Src content and kinase activity decrease with increasing cell line aggressiveness, an observation that appears to be inconsistent with the well-documented role of Src in the signaling pathways that drive growth and invasion. However, we do observe a direct correlation between Src kinase specific activity (total Src kinase activity/total Src content) and metastatic aggressiveness, possibly suggesting that in highly aggressive cell lines, key signaling enzymes are globally recruited to drive the cancerous phenotype. In addition, although the expected enhanced phosphorylation of Src at Tyr-416 (activation site) is present in the most aggressive prostate cancer cell lines, unexpectedly high phosphorylation levels at the Tyr-527 inhibitory site are observed as well. The latter, rather than representative of inhibited enzyme, is more indicative of primed Src responsive to local phosphorylated binding partners.     

High Prevalence of Bovine Tuberculosis in Dairy Cattle in Central Ethiopia: Implications for the Dairy Industry and Public Health

Background

Ethiopia has the largest cattle population in Africa. The vast majority of the national herd is of indigenous zebu cattle maintained in rural areas under extensive husbandry systems. However, in response to the increasing demand for milk products and the Ethiopian government''s efforts to improve productivity in the livestock sector, recent years have seen increased intensive husbandry settings holding exotic and cross breeds. This drive for increased productivity is however threatened by animal diseases that thrive under intensive settings, such as bovine tuberculosis (BTB), a disease that is already endemic in Ethiopia.

Methodology/Principal Findings

An extensive study was conducted to: estimate the prevalence of BTB in intensive dairy farms in central Ethiopia; identify associated risk factors; and characterize circulating strains of the causative agent, Mycobacterium bovis. The comparative intradermal tuberculin test (CIDT), questionnaire survey, post-mortem examination, bacteriology, and molecular typing were used to get a better understanding of the BTB prevalence among dairy farms in the study area. Based on the CIDT, our findings showed that around 30% of 2956 tested dairy cattle from 88 herds were positive for BTB while the herd prevalence was over 50%. Post-mortem examination revealed gross tuberculous lesions in 34/36 CIDT positive cattle and acid-fast bacilli were recovered from 31 animals. Molecular typing identified all isolates as M. bovis and further characterization by spoligotyping and MIRU-VNTR typing indicated low strain diversity within the study area.

Conclusions/Significance

This study showed an overall BTB herd prevalence of 50% in intensive dairy farms in Addis Ababa and surroundings, signalling an urgent need for intervention to control the disease and prevent zoonotic transmission of M. bovis to human populations consuming dairy products coming from these farms. It is suggested that government and policy makers should work together with stakeholders to design methods for the control of BTB in intensive farms in Ethiopia.     

Identifying More Epidemic Clones during a Hospital Outbreak of Multidrug-Resistant Acinetobacter baumannii

Infections caused by multidrug-resistant bacteria are a major concern in hospitals. Current infection-control practices legitimately focus on hygiene and appropriate use of antibiotics. However, little is known about the intrinsic abilities of some bacterial strains to cause outbreaks. They can be measured at a population level by the pathogen’s transmission rate, i.e. the rate at which the pathogen is transmitted from colonized hosts to susceptible hosts, or its reproduction number, counting the number of secondary cases per infected/colonized host. We collected data covering a 20-month surveillance period for carriage of multidrug-resistant Acinetobacter baumannii (MDRAB) in a surgery ward. All isolates were subjected to molecular fingerprinting, and a cluster analysis of profiles was performed to identify clonal groups. We then applied stochastic transmission models to infer transmission rates of MDRAB and each MDRAB clone. Molecular fingerprinting indicated that 3 clonal complexes spread in the ward. A first model, not accounting for different clones, quantified the level of in-ward cross-transmission, with an estimated transmission rate of 0.03/day (95% credible interval [0.012–0.049]) and a single-admission reproduction number of 0.61 [0.30–1.02]. The second model, accounting for different clones, suggested an enhanced transmissibility of clone 3 (transmission rate 0.047/day [0.018–0.091], with a single-admission reproduction number of 0.81 [0.30–1.56]). Clones 1 and 2 had comparable transmission rates (respectively, 0.016 [0.001–0.045], 0.014 [0.001–0.045]). The method used is broadly applicable to other nosocomial pathogens, as long as surveillance data and genotyping information are available. Building on these results, more epidemic clones could be identified, and could lead to follow-up studies dissecting the functional basis for variation in transmissibility of MDRAB lineages.     

A corpus of full-text journal articles is a robust evaluation tool for revealing differences in performance of biomedical natural language processing tools

ABSTRACT: BACKGROUND: We introduce the linguistic annotation of a corpus of 97 full-text biomedical publications, known as the Colorado Richly Annotated Full Text (CRAFT) corpus. We further assess the performance of existing tools for performing sentence splitting, tokenization, syntactic parsing, and named entity recognition on this corpus. RESULTS: Many biomedical natural language processing systems demonstrated large differences between their previously published results and their performance on the CRAFT corpus when tested with the publicly available models or rule sets. Trainable systems differed widely with respect to their ability to build high-performing models based on this data. CONCLUSIONS: The finding that some systems were able to train high-performing models based on this corpus is additional evidence, beyond high inter-annotator agreement, that the quality of the CRAFT corpus is high. The overall poor performance of various systems indicates that considerable work needs to be done to enable natural language processing systems to work well when the input is full-text journal articles. The CRAFT corpus provides avaluable resource to the biomedical natural language processing community for evaluation and training of new models for biomedical full text publications.     

Diverse Lifestyles and Strategies of Plant Pathogenesis Encoded in the Genomes of Eighteen Dothideomycetes Fungi

The class Dothideomycetes is one of the largest groups of fungi with a high level of ecological diversity including many plant pathogens infecting a broad range of hosts. Here, we compare genome features of 18 members of this class, including 6 necrotrophs, 9 (hemi)biotrophs and 3 saprotrophs, to analyze genome structure, evolution, and the diverse strategies of pathogenesis. The Dothideomycetes most likely evolved from a common ancestor more than 280 million years ago. The 18 genome sequences differ dramatically in size due to variation in repetitive content, but show much less variation in number of (core) genes. Gene order appears to have been rearranged mostly within chromosomal boundaries by multiple inversions, in extant genomes frequently demarcated by adjacent simple repeats. Several Dothideomycetes contain one or more gene-poor, transposable element (TE)-rich putatively dispensable chromosomes of unknown function. The 18 Dothideomycetes offer an extensive catalogue of genes involved in cellulose degradation, proteolysis, secondary metabolism, and cysteine-rich small secreted proteins. Ancestors of the two major orders of plant pathogens in the Dothideomycetes, the Capnodiales and Pleosporales, may have had different modes of pathogenesis, with the former having fewer of these genes than the latter. Many of these genes are enriched in proximity to transposable elements, suggesting faster evolution because of the effects of repeat induced point (RIP) mutations. A syntenic block of genes, including oxidoreductases, is conserved in most Dothideomycetes and upregulated during infection in L. maculans, suggesting a possible function in response to oxidative stress.     

Ortho-carbaborane derivatives of indomethacin as cyclooxygenase (COX)-2 selective inhibitors

A series of novel indomethacin analogues with carbaboranes as three-dimensional substitutes for the chlorophenyl ring have been prepared. Their cyclooxygenase (COX) inhibition and enzyme selectivity has been tested and compared to the corresponding adamantyl analogues. Surprisingly, only the ortho-carbaborane derivatives were active compounds. Preliminary biological studies gave an interesting insight into the validity of employing carbaboranes as pharmacophores.     

An endosymbiotic conidial fungus, Scopulariopsis brevicaulis, protects the American dog tick, Dermacentor variabilis, from desiccation imposed by an entomopathogenic fungus

The functional role of an endosymbiotic conidial fungus (Scopulariopsis brevicaulis) prevalent within the integumental glands and hemocoel of the American dog tick (Dermacentor variabilis) was investigated to explore the nature of this tick/fungus association. D. variabilis is normally highly resistant to Metarhizium anisopliae, a widely-distributed entomopathogenic fungus, but when mature female ticks harboring S. brevicaulis were fed a solution containing a mycotoxin (Amphotericin B) to purge this mycobiont internally, the ticks inoculated with M. anisopliae displayed classic signs of pathogenicity, as evidenced by recovery of M. anisopliae from ticks by internal fungus culture, greatly accelerated net transpiration water loss rates (nearly 3x faster than ticks containing S. brevicaulis naturally) and elevation of critical equilibrium humidity (CEH) closer to saturation, implying a reduced capacity to absorb water vapor and disruption of water balance (water gain not equal water loss) that resulted in tick death. The presence of S. brevicaulis within the tick was previously puzzling: the fungus is transmitted maternally and there is no apparent harm inflicted to either generation. This study suggests that S. brevicaulis provides protection to D. variabilis ticks against M. anisopliae. Thus, the S. brevicaulis/tick association appears to be mutualistic symbiosis. Given that both organisms are of medical-veterinary importance, disruption of this symbiosis has potential for generating novel tools for disease control.