Cluster K Mycobacteriophages: Insights into the Evolutionary Origins of Mycobacteriophage TM4

Five newly isolated mycobacteriophages –Angelica, CrimD, Adephagia, Anaya, and Pixie – have similar genomic architectures to mycobacteriophage TM4, a previously characterized phage that is widely used in mycobacterial genetics. The nucleotide sequence similarities warrant grouping these into Cluster K, with subdivision into three subclusters: K1, K2, and K3. Although the overall genome architectures of these phages are similar, TM4 appears to have lost at least two segments of its genome, a central region containing the integration apparatus, and a segment at the right end. This suggests that TM4 is a recent derivative of a temperate parent, resolving a long-standing conundrum about its biology, in that it was reportedly recovered from a lysogenic strain of Mycobacterium avium, but it is not capable of forming lysogens in any mycobacterial host. Like TM4, all of the Cluster K phages infect both fast- and slow-growing mycobacteria, and all of them – with the exception of TM4 – form stable lysogens in both Mycobacterium smegmatis and Mycobacterium tuberculosis; immunity assays show that all five of these phages share the same immune specificity. TM4 infects these lysogens suggesting that it was either derived from a heteroimmune temperate parent or that it has acquired a virulent phenotype. We have also characterized a widely-used conditionally replicating derivative of TM4 and identified mutations conferring the temperature-sensitive phenotype. All of the Cluster K phages contain a series of well conserved 13 bp repeats associated with the translation initiation sites of a subset of the genes; approximately one half of these contain an additional sequence feature composed of imperfectly conserved 17 bp inverted repeats separated by a variable spacer. The K1 phages integrate into the host tmRNA and the Cluster K phages represent potential new tools for the genetics of M. tuberculosis and related species

The Virtual Sociality of Rights: The Case of Women\u27s Rights are Human Rights

This essay traces the relationship between activists and academics involved in the campaign for women\u27s rights as human rights as a case study of the relationship between different classes of what I call knowledge professionals self-consciously acting in a transnational domain. The puzzle that animates this essay is the following: how was it that at the very moment at which a critique of rights and a reimagination of rights as rights talk proved to be such fertile ground for academic scholarship did the same rights prove to be an equally fertile ground for activist networking and lobbying activities? The paper answers this question with respect to the work of self-reflexivity in creating a virtual sociality of rights

Genome-wide association identifies nine common variants associated with fasting proinsulin levels and provides new insights into the pathophysiology of type 2 diabetes.

OBJECTIVE: Proinsulin is a precursor of mature insulin and C-peptide. Higher circulating proinsulin levels are associated with impaired β-cell function, raised glucose levels, insulin resistance, and type 2 diabetes (T2D). Studies of the insulin processing pathway could provide new insights about T2D pathophysiology. RESEARCH DESIGN AND METHODS: We have conducted a meta-analysis of genome-wide association tests of ∼2.5 million genotyped or imputed single nucleotide polymorphisms (SNPs) and fasting proinsulin levels in 10,701 nondiabetic adults of European ancestry, with follow-up of 23 loci in up to 16,378 individuals, using additive genetic models adjusted for age, sex, fasting insulin, and study-specific covariates. RESULTS: Nine SNPs at eight loci were associated with proinsulin levels (P < 5 × 10(-8)). Two loci (LARP6 and SGSM2) have not been previously related to metabolic traits, one (MADD) has been associated with fasting glucose, one (PCSK1) has been implicated in obesity, and four (TCF7L2, SLC30A8, VPS13C/C2CD4A/B, and ARAP1, formerly CENTD2) increase T2D risk. The proinsulin-raising allele of ARAP1 was associated with a lower fasting glucose (P = 1.7 × 10(-4)), improved β-cell function (P = 1.1 × 10(-5)), and lower risk of T2D (odds ratio 0.88; P = 7.8 × 10(-6)). Notably, PCSK1 encodes the protein prohormone convertase 1/3, the first enzyme in the insulin processing pathway. A genotype score composed of the nine proinsulin-raising alleles was not associated with coronary disease in two large case-control datasets. CONCLUSIONS: We have identified nine genetic variants associated with fasting proinsulin. Our findings illuminate the biology underlying glucose homeostasis and T2D development in humans and argue against a direct role of proinsulin in coronary artery disease pathogenesis

Cluster k mycobacteriophages: Insights into the evolutionary origins of mycobacteriophage tm4

Five newly isolated mycobacteriophages -Angelica, CrimD, Adephagia, Anaya, and Pixie - have similar genomic architectures to mycobacteriophage TM4, a previously characterized phage that is widely used in mycobacterial genetics. The nucleotide sequence similarities warrant grouping these into Cluster K, with subdivision into three subclusters: K1, K2, and K3. Although the overall genome architectures of these phages are similar, TM4 appears to have lost at least two segments of its genome, a central region containing the integration apparatus, and a segment at the right end. This suggests that TM4 is a recent derivative of a temperate parent, resolving a long-standing conundrum about its biology, in that it was reportedly recovered from a lysogenic strain of Mycobacterium avium, but it is not capable of forming lysogens in any mycobacterial host. Like TM4, all of the Cluster K phages infect both fast- and slow-growing mycobacteria, and all of them - with the exception of TM4 - form stable lysogens in both Mycobacterium smegmatis and Mycobacterium tuberculosis; immunity assays show that all five of these phages share the same immune specificity. TM4 infects these lysogens suggesting that it was either derived from a heteroimmune temperate parent or that it has acquired a virulent phenotype. We have also characterized a widely-used conditionally replicating derivative of TM4 and identified mutations conferring the temperature-sensitive phenotype. All of the Cluster K phages contain a series of well conserved 13 bp repeats associated with the translation initiation sites of a subset of the genes; approximately one half of these contain an additional sequence feature composed of imperfectly conserved 17 bp inverted repeats separated by a variable spacer. The K1 phages integrate into the host tmRNA and the Cluster K phages represent potential new tools for the genetics of M. tuberculosis and related species. © 2011 Pope et al.Fil: Pope, Welkin H.. University of Pittsburgh; Estados UnidosFil: Ferreira, Christina M.. University of Pittsburgh; Estados UnidosFil: Jacobs Sera, Deborah. University of Pittsburgh; Estados UnidosFil: Benjamin, Robert C.. University of North Texas; Estados UnidosFil: Davis, Ariangela J.. Calvin College; Estados UnidosFil: DeJong, Randall J.. Calvin College; Estados UnidosFil: Elgin, Sarah C. R.. Washington University in St. Louis; Estados UnidosFil: Guilfoile, Forrest R.. University of Pittsburgh; Estados UnidosFil: Forsyth, Mark H.. The College Of William And Mary; Estados UnidosFil: Harris, Alexander D.. Calvin College; Estados UnidosFil: Harvey, Samuel E.. The College Of William And Mary; Estados UnidosFil: Hughes, Lee E.. University of North Texas; Estados UnidosFil: Hynes, Peter M.. Washington University in St. Louis; Estados UnidosFil: Jackson, Arrykka S.. The College Of William And Mary; Estados UnidosFil: Jalal, Marilyn D.. University of North Texas; Estados UnidosFil: MacMurray, Elizabeth A.. The College Of William And Mary; Estados UnidosFil: Manley, Coreen M.. University of North Texas; Estados UnidosFil: McDonough, Molly J.. The College Of William And Mary; Estados UnidosFil: Mosier, Jordan L.. University of North Texas; Estados UnidosFil: Osterbann, Larissa J.. Calvin College; Estados UnidosFil: Rabinowitz, Hannah S.. Washington University in St. Louis; Estados UnidosFil: Rhyan, Corwin N.. Washington University in St. Louis; Estados UnidosFil: Russell, Daniel A.. University of Pittsburgh; Estados UnidosFil: Saha, Margaret S.. The College Of William And Mary; Estados UnidosFil: Shaffer, Christopher D.. Washington University in St. Louis; Estados UnidosFil: Simon, Stephanie E.. University of North Texas; Estados UnidosFil: Sims, Erika F.. Washington University in St. Louis; Estados UnidosFil: Tovar, Isabel G.. University of North Texas; Estados UnidosFil: Weisser, Emilie G.. Washington University in St. Louis; Estados UnidosFil: Wertz, John T.. Calvin College; Estados UnidosFil: Weston-Hafer, Kathleen A.. Washington University in St. Louis; Estados UnidosFil: Williamson, Kurt E.. The College Of William And Mary; Estados UnidosFil: Zhang, Bo. Washington University in St. Louis; Estados UnidosFil: Cresawn, Steven G.. James Madison University; Estados UnidosFil: Jain, Paras. Albert Einstein College Of Medicine Of Yeshiva University; Estados UnidosFil: Piuri, Mariana. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. University of Pittsburgh; Estados UnidosFil: Jacobs, William R.. Albert Einstein College Of Medicine Of Yeshiva University; Estados UnidosFil: Hendrix, Roger W.. University of Pittsburgh; Estados UnidosFil: Hatfull, Graham F.. University of Pittsburgh; Estados Unido