Association of \u3ci\u3eEscherichia coli\u3c/i\u3e O157:H7 \u3ci\u3etir\u3c/i\u3e polymorphisms with human infection

Background: Emerging molecular, animal model and epidemiologic evidence suggests that Shigatoxigenic Escherichia coli O157:H7 (STEC O157) isolates vary in their capacity to cause human infection and disease. The translocated intimin receptor (tir) and intimin (eae) are virulence factors and bacterial receptor-ligand proteins responsible for tight STEC O157 adherence to intestinal epithelial cells. They represent logical genomic targets to investigate the role of sequence variation in STEC O157 pathogenesis and molecular epidemiology. The purposes of this study were (1) to identify tir and eae polymorphisms in diverse STEC O157 isolates derived from clinically ill humans and healthy cattle (the dominant zoonotic reservoir) and (2) to test any observed tir and eae polymorphisms for association with human (vs bovine) isolate source. Results: Five polymorphisms were identified in a 1,627-bp segment of tir. Alleles of two tir polymorphisms, tir 255 T\u3eA and repeat region 1-repeat unit 3 (RR1-RU3, presence or absence) had dissimilar distributions among human and bovine isolates. More than 99% of 108 human isolates possessed the tir 255 T\u3eA T allele and lacked RR1-RU3. In contrast, the tir 255 T\u3eA T allele and RR1-RU3 absence were found in 55% and 57%, respectively, of 77 bovine isolates. Both polymorphisms associated strongly with isolate source (p \u3c 0.0001), but not by pulsed field gel electrophoresis type or by stx1 and stx2 status (as determined by PCR). Two eae polymorphisms were identified in a 2,755-bp segment of 44 human and bovine isolates; 42 isolates had identical eae sequences. The eae polymorphisms did not associate with isolate source. Conclusion: Polymorphisms in tir but not eae predict the propensity of STEC O157 isolates to cause human clinical disease. The over-representation of the tir 255 T\u3eA T allele in human-derived isolates vs the tir 255 T\u3eA A allele suggests that these isolates have a higher propensity to cause disease. The high frequency of bovine isolates with the A allele suggests a possible bovine ecological niche for this STEC O157 subset

Competition and the origins of novelty: experimental evolution of niche-width expansion in a virus

Competition for resources has long been viewed as a key agent of divergent selection. Theory holds that populations facing severe intraspecific competition will tend to use a wider range of resources, possibly even using entirely novel resources that are less in demand. Yet, there have been few experimental tests of these ideas. Using the bacterial virus (bacteriophage) ϕ6 as a model system, we examined whether competition for host resources promotes the evolution of novel resource use. In the laboratory, ϕ6 exhibits a narrow host range but readily produces mutants capable of infecting novel bacterial hosts. Here, we show that when ϕ6 populations were subjected to intense intraspecific competition for their standard laboratory host, they rapidly evolved new generalist morphs that infect novel hosts. Our results therefore suggest that competition for host resources may drive the evolution of host range expansion in viruses. More generally, our findings demonstrate that intraspecific resource competition can indeed promote the evolution of novel resource-use phenotypes

Sex-specific expression of alternative transcripts in Drosophila

BACKGROUND: Many genes produce multiple transcripts due to alternative splicing or utilization of alternative transcription initiation/termination sites. This 'transcriptome expansion' is thought to increase phenotypic complexity by allowing a single locus to produce several functionally distinct proteins. However, sex, genetic and developmental variation in the representation of alternative transcripts has never been examined systematically. Here, we describe a genome-wide analysis of sex-specific expression of alternative transcripts in Drosophila melanogaster. RESULTS: We compared transcript profiles in males and females from eight Drosophila lines (OregonR and 2b, and 6 RIL) using a newly designed 60-mer oligonucleotide microarray that allows us to distinguish a large proportion of alternative transcripts. The new microarray incorporates 7,207 oligonucleotides, satisfying stringent binding and specificity criteria that target both the common and the unique regions of 2,768 multi-transcript genes, as well as 12,912 oligonucleotides that target genes with a single known transcript. We estimate that up to 22% of genes that produce multiple transcripts show a sex-specific bias in the representation of alternative transcripts. Sexual dimorphism in overall transcript abundance was evident for 53% of genes. The X chromosome contains a significantly higher proportion of genes with female-biased transcription than the autosomes. However, genes on the X chromosome are no more likely to have a sexual bias in alternative transcript representation than autosomal genes. CONCLUSION: Widespread sex-specific expression of alternative transcripts in Drosophila suggests that a new level of sexual dimorphism at the molecular level exists

Open questions in the social lives of viruses

Social interactions among viruses occur whenever multiple viral genomes infect the same cells, hosts, or populations of hosts. Viral social interactions range from cooperation to conflict, occur throughout the viral world, and affect every stage of the viral lifecycle. The ubiquity of these social interactions means that they can determine the population dynamics, evolutionary trajectory, and clinical progression of viral infections. At the same time, social interactions in viruses raise new questions for evolutionary theory, providing opportunities to test and extend existing frameworks within social evolution. Many opportunities exist at this interface: Insights into the evolution of viral social interactions have immediate implications for our understanding of the fundamental biology and clinical manifestation of viral diseases. However, these opportunities are currently limited because evolutionary biologists only rarely study social evolution in viruses. Here, we bridge this gap by (1) summarizing the ways in which viruses can interact socially, including consequences for social evolution and evolvability; (2) outlining some open questions raised by viruses that could challenge concepts within social evolution theory; and (3) providing some illustrative examples, data sources, and conceptual questions, for studying the natural history of social viruses

Phylogenetic classification of Escherichia coli O157:H7 strains of human and bovine origin using a novel set of nucleotide polymorphisms

Novel SNPs from human and bovine O157:H7 E. coli isolates are mapped, revealing that the majority of human disease is caused by a bovine subset of this strain

Evolutionary rescue and the coexistence of generalist and specialist competitors: an experimental test

Competition for resources is thought to play a critical role in both the origins and maintenance of biodiversity. Although numerous laboratory evolution experiments have confirmed that competition can be a key driver of adaptive diversification, few have demonstrated its role in the maintenance of the resulting diversity. We investigate the conditions that favour the origin and maintenance of alternative generalist and specialist resource-use phenotypes within the same population. Previously, we confirmed that competition for hosts among φ6 bacteriophage in a mixed novel (non-permissive) and ancestral (permissive) host microcosm triggered the evolution of a generalist phenotype capable of infecting both hosts. However, because the newly evolved generalists tended to competitively exclude the ancestral specialists, coexistence between the two phenotypes was rare. Here, we show that reducing the relative abundance of the novel host slowed the increase in frequency of the generalist phenotype, allowing sufficient time for the specialist to further adapt to the ancestral host. This adaptation resulted in ‘evolutionary rescue’ of the specialists, preventing their competitive exclusion by the generalists. Thus, our results suggest that competition promotes both the origin and maintenance of biodiversity when it is strong enough to favour a novel resource-use phenotype, but weak enough to allow adaptation of both the novel and ancestral phenotypes to their respective niches

Light Curves and Period Changes of Type II Cepheids in the Globular Clusters M3 and M5

Light curves in the B, V, and I_c passbands have been obtained for the type II Cepheids V154 in M3 and V42 and V84 in M5. Alternating cycle behavior, similar to that seen among RV Tauri variables, is confirmed for V84. Old and new observations, spanning more than a century, show that V154 has increased in period while V42 has decreased in period. V84, on the other hand, has shown large, erratic changes in period that do not appear to reflect the long term evolution of V84 through the HR diagram.Comment: 28 pages, 12 figure

Interrogating two schedules of the AKT inhibitor MK-2206 in patients with advanced solid tumors incorporating novel pharmacodynamic and functional imaging biomarkers.

PURPOSE: Multiple cancers harbor genetic aberrations that impact AKT signaling. MK-2206 is a potent pan-AKT inhibitor with a maximum tolerated dose (MTD) previously established at 60 mg on alternate days (QOD). Due to a long half-life (60-80 hours), a weekly (QW) MK-2206 schedule was pursued to compare intermittent QW and continuous QOD dosing. EXPERIMENTAL DESIGN: Patients with advanced cancers were enrolled in a QW dose-escalation phase I study to investigate the safety and pharmacokinetic-pharmacodynamic profiles of tumor and platelet-rich plasma (PRP). The QOD MTD of MK-2206 was also assessed in patients with ovarian and castration-resistant prostate cancers and patients with advanced cancers undergoing multiparametric functional magnetic resonance imaging (MRI) studies, including dynamic contrast-enhanced MRI, diffusion-weighted imaging, magnetic resonance spectroscopy, and intrinsic susceptibility-weighted MRI. RESULTS: A total of 71 patients were enrolled; 38 patients had 60 mg MK-2206 QOD, whereas 33 received MK-2206 at 90, 135, 150, 200, 250, and 300 mg QW. The QW MK-2206 MTD was established at 200 mg following dose-limiting rash at 250 and 300 mg. QW dosing appeared to be similarly tolerated to QOD, with toxicities including rash, gastrointestinal symptoms, fatigue, and hyperglycemia. Significant AKT pathway blockade was observed with both continuous QOD and intermittent QW dosing of MK-2206 in serially obtained tumor and PRP specimens. The functional imaging studies demonstrated that complex multiparametric MRI protocols may be effectively implemented in a phase I trial. CONCLUSIONS: Treatment with MK-2206 safely results in significant AKT pathway blockade in QOD and QW schedules. The intermittent dose of 200 mg QW is currently used in phase II MK-2206 monotherapy and combination studies (NCT00670488).This study was supported by Merck & Co., Inc. The Drug Development Unit of the Royal Marsden NHS Foundation Trust and The Institute of Cancer Research is supported in part by a program grant from Cancer Research U.K. Support was also provided by the Experimental Cancer Medicine Centre (to The Institute of Cancer Research), the National Institute for Health Research (NIHR) Biomedical Research Centre (jointly to the Royal Marsden NHS Foundation Trust and The Institute of Cancer Research), the NIHR Clinical Research Facility (to the Royal Marsden NHS Foundation Trust) and the Cancer Research UK and EPSRC Cancer Imaging Centre. T.A. Yap is the recipient of the 2011 Rebecca and Nathan Milikowsky – PCF Young Investigator Award and is supported by the NIHR. M.O. Leach is an NIHR Senior Investigator.This is the accepted manuscript. The final version is available from AACR at http://clincancerres.aacrjournals.org/content/early/2014/09/19/1078-0432.CCR-14-0868

Shiga-toxigenic Escherichia coli O157 in Agricultural Fair Livestock, United States

Organisms were common in ruminants, swine, and pest flies

Association of Escherichia coli O157:H7 tir polymorphisms with human infection

<p>Abstract</p> <p>Background</p> <p>Emerging molecular, animal model and epidemiologic evidence suggests that Shiga-toxigenic <it>Escherichia coli </it>O157:H7 (STEC O157) isolates vary in their capacity to cause human infection and disease. The translocated intimin receptor (<it>tir</it>) and intimin (<it>eae</it>) are virulence factors and bacterial receptor-ligand proteins responsible for tight STEC O157 adherence to intestinal epithelial cells. They represent logical genomic targets to investigate the role of sequence variation in STEC O157 pathogenesis and molecular epidemiology. The purposes of this study were (1) to identify <it>tir </it>and <it>eae </it>polymorphisms in diverse STEC O157 isolates derived from clinically ill humans and healthy cattle (the dominant zoonotic reservoir) and (2) to test any observed <it>tir </it>and <it>eae </it>polymorphisms for association with human (vs bovine) isolate source.</p> <p>Results</p> <p>Five polymorphisms were identified in a 1,627-bp segment of <it>tir</it>. Alleles of two <it>tir </it>polymorphisms, <it>tir </it>255 T>A and repeat region 1-repeat unit 3 (RR1-RU3, presence or absence) had dissimilar distributions among human and bovine isolates. More than 99% of 108 human isolates possessed the <it>tir </it>255 T>A T allele and lacked RR1-RU3. In contrast, the <it>tir </it>255 T>A T allele and RR1-RU3 absence were found in 55% and 57%, respectively, of 77 bovine isolates. Both polymorphisms associated strongly with isolate source (p < 0.0001), but not by pulsed field gel electrophoresis type or by <it>stx</it>1 and <it>stx</it>2 status (as determined by PCR). Two <it>eae </it>polymorphisms were identified in a 2,755-bp segment of 44 human and bovine isolates; 42 isolates had identical <it>eae </it>sequences. The <it>eae </it>polymorphisms did not associate with isolate source.</p> <p>Conclusion</p> <p>Polymorphisms in <it>tir </it>but not <it>eae </it>predict the propensity of STEC O157 isolates to cause human clinical disease. The over-representation of the <it>tir </it>255 T>A T allele in human-derived isolates vs the <it>tir </it>255 T>A A allele suggests that these isolates have a higher propensity to cause disease. The high frequency of bovine isolates with the A allele suggests a possible bovine ecological niche for this STEC O157 subset.</p