Arnold Kas

Bio: Arnold Kas is an academic researcher from University of Washington. The author has contributed to research in topics: Gene & Genome. The author has an hindex of 12, co-authored 16 publications receiving 7064 citations. Previous affiliations of Arnold Kas include Howard Hughes Medical Institute & Benaroya Research Institute.

Complete genome sequence of Pseudomonas aeruginosa PAO1, an opportunistic pathogen.

Abstract: Pseudomonas aeruginosa is a ubiquitous environmental bacterium that is one of the top three causes of opportunistic human infections. A major factor in its prominence as a pathogen is its intrinsic resistance to antibiotics and disinfectants. Here we report the complete sequence of P. aeruginosa strain PAO1. At 6.3 million base pairs, this is the largest bacterial genome sequenced, and the sequence provides insights into the basis of the versatility and intrinsic drug resistance of P. aeruginosa. Consistent with its larger genome size and environmental adaptability, P. aeruginosa contains the highest proportion of regulatory genes observed for a bacterial genome and a large number of genes involved in the catabolism, transport and efflux of organic compounds as well as four potential chemotaxis systems. We propose that the size and complexity of the P. aeruginosa genome reflect an evolutionary adaptation permitting it to thrive in diverse environments and resist the effects of a variety of antimicrobial substances.

CD4+ Regulatory T Cells Control TH17 Responses in a Stat3-Dependent Manner

Abstract: Immune responses are kept in check by Foxp3-expressing CD4+-regulatory T cells (Tregs) through a variety of mechanisms. Expression of specific transcription factors directs Treg responses into distinct T helper cell lineages; however, the transcription factors that regulate particular helper lineages have not been completely characterized. Chaudhry et al. (p. [986][1], published online 1 October) show that the transcription factor Stat3, that is required for the initial differentiation of TH17-effector T cells, is also required for Treg cell-mediated suppression of TH17-mediated immune responses. Mice carrying a Treg cellspecific deletion in Stat3 succumb to an intestinal inflammatory disease driven by uncontrolled TH17 responses. Thus, different classes of immune responses can result from the expression of helper lineage–specific transcription factors. [1]: /lookup/doi/10.1126/science.1172702

Regulatory T-cell suppressor program co-opts transcription factor IRF4 to control T H 2 responses

Abstract: In the course of infection or autoimmunity, particular transcription factors orchestrate the differentiation of T(H)1, T(H)2 or T(H)17 effector cells, the responses of which are limited by a distinct lineage of suppressive regulatory T cells (T(reg)). T(reg) cell differentiation and function are guided by the transcription factor Foxp3, and their deficiency due to mutations in Foxp3 results in aggressive fatal autoimmune disease associated with sharply augmented T(H)1 and T(H)2 cytokine production. Recent studies suggested that Foxp3 regulates the bulk of the Foxp3-dependent transcriptional program indirectly through a set of transcriptional regulators serving as direct Foxp3 targets. Here we show that in mouse T(reg) cells, high amounts of interferon regulatory factor-4 (IRF4), a transcription factor essential for T(H)2 effector cell differentiation, is dependent on Foxp3 expression. We proposed that IRF4 expression endows T(reg) cells with the ability to suppress T(H)2 responses. Indeed, ablation of a conditional Irf4 allele in T(reg) cells resulted in selective dysregulation of T(H)2 responses, IL4-dependent immunoglobulin isotype production, and tissue lesions with pronounced plasma cell infiltration, in contrast to the mononuclear-cell-dominated pathology typical of mice lacking T(reg) cells. Our results indicate that T(reg) cells use components of the transcriptional machinery, promoting a particular type of effector CD4(+) T cell differentiation, to efficiently restrain the corresponding type of the immune response.

Genome-wide analysis of Foxp3 target genes in developing and mature regulatory T cells

Abstract: Transcription factor Foxp3 (forkhead box P3), restricted in its expression to a specialized regulatory CD4+ T-cell subset (T(R)) with a dedicated suppressor function, controls T(R) lineage development. In humans and mice, Foxp3 deficiency results in a paucity of T(R) cells and a fatal breach in immunological tolerance, causing highly aggressive multi-organ autoimmune pathology. Here, through genome-wide analysis combining chromatin immunoprecipitation with mouse genome tiling array profiling, we identify Foxp3 binding regions for approximately 700 genes and for an intergenically encoded microRNA. We find that a large number of Foxp3-bound genes are up- or downregulated in Foxp3+ T cells, suggesting that Foxp3 acts as both a transcriptional activator and repressor. Foxp3-mediated regulation unique to the thymus affects, among others, genes encoding nuclear factors that control gene expression and chromatin remodelling. In contrast, Foxp3 target genes shared by the thymic and peripheral T(R) cells encode primarily plasma membrane proteins, as well as cell signalling proteins. Together, our studies suggest that distinct transcriptional sub-programmes implemented by Foxp3 establish T(R) lineage during differentiation and its proliferative and functional competence in the periphery.

Whole-Genome Sequence Variation among Multiple Isolates of Pseudomonas aeruginosa

Abstract: Pseudomonas aeruginosa is a ubiquitous environmental bacterium that is of increasing importance as an opportunistic human pathogen. P. aeruginosa infections are common in patients with compromised antibacterial defenses. A particular niche for infections that has been created by advances in pediatric care is the lungs of cystic fibrosis (CF) patients. As effective management of other clinical complications has been introduced and life expectancy has increased, chronic pulmonary infections with P. aeruginosa have emerged as the leading cause of morbidity and mortality in CF (11, 17). Despite steady improvements in treatment, CF pulmonary infections resist eradication with antibiotics and lead, over a period of many years, to irreversible tissue destruction (11). Available data suggest that most CF patients are infected by unique strains of P. aeruginosa acquired from environmental reservoirs (15, 30, 31) and that the infections are frequently clonal (5, 29, 36, 39). During the time that a particular strain is resident in the airways of a CF patient, considerable genetic adaptation occurs. A well-known example of this process is the conversion of strains from nonmucoid to mucoid phenotypes due to mutations in mucA (11, 21, 22), a gene whose product is a negative regulator of the biosynthesis of the secreted polysaccharide alginate. Another example is the frequent loss of O antigen (8, 14, 18, 28, 29), a change that also appears to be due to mutation. Restriction mapping of P. aeruginosa strains from diverse backgrounds indicates that a significant proportion of the variation among isolates is due to insertions and deletions of up to 500 kbp of genomic material (30, 34). In this respect, P. aeruginosa is superficially similar to Escherichia coli. Comparison of the pathogenic O157 and the nonpathogenic K-12 E. coli strains has revealed that much of their difference can be attributed to blocks of DNA that are strain specific (26). These so-called K islands and O islands comprise 12% of the genome of K-12 and 26% of the genome of O157, respectively, and are interspersed in a conserved backbone sequence with relatively little polymorphism (26). In P. aeruginosa, few strain-specific regions have been well characterized. One example is the 50-kbp P. aeruginosa genomic island 1, PAGI-1, found in many clinical isolates of P. aeruginosa in place of the 7-kbp of PAO1 sequence and hypothesized to play a role in evading the host immune response (20). Other examples include a 20-kbp island found in P. aeruginosa strain PAK, containing genes involved in glycosylation of a-type flagellin (2), and the recently described 11 groups of gene clusters at the O-antigen biosynthetic locus (27). However, despite the evidence indicating that genomic islands may play an important role in P. aeruginosa biology, little is known about the sequence and location of other islands. Sequence-based studies of genetic variation in P. aeruginosa appear to support the presence of conserved backbone sequences, similar to the E. coli model. Sequencing of six housekeeping genes in 19 environmental and clinical isolates revealed levels of genetic diversity even lower than in the E. coli comparisons, with average pairwise nucleotide substitution rates on the order of a few tenths of a percentage point (15). These data, along with those from restriction-mapping experiments, suggest that P. aeruginosa genomes have numerous strain-specific regions interspersed in a well-conserved backbone. More detailed studies of DNA sequence variation in P. aeruginosa are needed to define these backbone and strain-specific sequences, which may promote our understanding of the genetic determinants of pathogenicity in CF lung infections. The recent sequencing of the genome of the standard laboratory strain of P. aeruginosa, PAO1 (37), has laid the groundwork for more extensive studies of genomic variation in clinical and environmental isolates of this bacterium. We have carried out whole-genome-sample sequencing of two P. aeruginosa strains isolated from late-stage CF-related infections and a strain from an environmental source. These data provide a detailed view of the pattern of sequence variation among the three new strains relative to the PAO1 reference.

Complete genome sequence of the model actinomycete Streptomyces coelicolor A3(2)

Abstract: Streptomyces coelicolor is a representative of the group of soil-dwelling, filamentous bacteria responsible for producing most natural antibiotics used in human and veterinary medicine. Here we report the 8,667,507 base pair linear chromosome of this organism, containing the largest number of genes so far discovered in a bacterium. The 7,825 predicted genes include more than 20 clusters coding for known or predicted secondary metabolites. The genome contains an unprecedented proportion of regulatory genes, predominantly those likely to be involved in responses to external stimuli and stresses, and many duplicated gene sets that may represent 'tissue-specific' isoforms operating in different phases of colonial development, a unique situation for a bacterium. An ancient synteny was revealed between the central 'core' of the chromosome and the whole chromosome of pathogens Mycobacterium tuberculosis and Corynebacterium diphtheriae. The genome sequence will greatly increase our understanding of microbial life in the soil as well as aiding the generation of new drug candidates by genetic engineering.

Differentiation of Effector CD4 T Cell Populations

Abstract: CD4 T cells play critical roles in mediating adaptive immunity to a variety of pathogens. They are also involved in autoimmunity, asthma, and allergic responses as well as in tumor immunity. During TCR activation in a particular cytokine milieu, naive CD4 T cells may differentiate into one of several lineages of T helper (Th) cells, including Th1, Th2, Th17, and iTreg, as defined by their pattern of cytokine production and function. In this review, we summarize the discovery, functions, and relationships among Th cells; the cytokine and signaling requirements for their development; the networks of transcription factors involved in their differentiation; the epigenetic regulation of their key cytokines and transcription factors; and human diseases involving defective CD4 T cell differentiation.

The MetaCyc database of metabolic pathways and enzymes and the BioCyc collection of pathway/genome databases

Abstract: The MetaCyc database (MetaCyc.org) is a comprehensive and freely accessible resource for metabolic pathways and enzymes from all domains of life. The pathways in MetaCyc are experimentally determined, small-molecule metabolic pathways and are curated from the primary scientific literature. With more than 1400 pathways, MetaCyc is the largest collection of metabolic pathways currently available. Pathways reactions are linked to one or more well-characterized enzymes, and both pathways and enzymes are annotated with reviews, evidence codes, and literature citations. BioCyc (BioCyc.org) is a collection of more than 500 organism-specific Pathway/Genome Databases (PGDBs). Each BioCyc PGDB contains the full genome and predicted metabolic network of one organism. The network, which is predicted by the Pathway Tools software using MetaCyc as a reference, consists of metabolites, enzymes, reactions and metabolic pathways. BioCyc PGDBs also contain additional features, such as predicted operons, transport systems, and pathway hole-fillers. The BioCyc Web site offers several tools for the analysis of the PGDBs, including Omics Viewers that enable visualization of omics datasets on two different genome-scale diagrams and tools for comparative analysis. The BioCyc PGDBs generated by SRI are offered for adoption by any party interested in curation of metabolic, regulatory, and genome-related information about an organism.