100 research outputs found
Phylogenomics of vertebrate serpins
No full textKumar A. Phylogenomics of vertebrate serpins. Bielefeld (Germany): Bielefeld University; 2010.The serpins constitute a superfamily of proteins that fold into a conserved tertiary structure and employ a sophisticated, irreversible suicide-mechanism of inhibition. More than 6000 serpins have been identified, occurring in all three forms of the life - the eukaryotes, the prokaryotes and the archea. Vertebrate serpins can be conveniently classified into six groups (V1 - V6), based on three independent biological features - gene organization, diagnostic amino acid sites and rare indels. In the present work, the phylogenetic relationships of serpins from Nematostella vectensis, Strongylocentrotus purpuratus, Ciona intestinalis, four fish species, frog, chicken and mammals were investigated, using gene architecture analyses and stringent criteria for identification of orthologs. With some deviations, all vertebrate serpin genes fit into one of the six exon/intron gene classes previously identified, dating the existence and maintenance of these gene organizations before or close to the divergence of fishes. Group V1 and V2 gene families underwent rapid adaptive radiation along the lineages leading to mammals as indicated by an up to nine-fold increased number of family members, accompanied by a rapid functional diversification. In contrast, gene groups V3 to V6 display a rather conservative evolution with little changes since the divergence of fishes and the other vertebrates. The orthology assessment indicates that all vertebrates are equipped with a subset of strongly conserved serpins with functions that can be clearly correlated with basic vertebrate-specific physiology.
None of serpin genes from C. intestinalis shares a common exon-intron architecture organisation with any of the vertebrate serpin gene classes, nor was it possible to identify orthologs of vertebrates. The lack of gene architecture similarity and the complete absence of orthology between urochordate and vertebrate serpins indicate that major changes with bursts of character acquisition must have occurred during evolution of serpins in the time interval separating urochordates from chordates, indicating massive intron gains or losses and events providing C and N-terminal sequence extensions characteristic for today's vertebrate serpins. Lancelets and sea urchin genomes, in contrast, share one orthologous serpin with vertebrates. Rare genomic characters are used to show that orthologs of neuroserpin, a prominent representative of vertebrate group V3 serpin genes, exist in early diverging deuterostomes and probably also in cnidarians, indicating that the origin of a mammalian serpin can be traced back far in the history of eumetazoans. A C-terminal address code assigning association with secretory pathway organelles is present in all neuroserpin orthologs, suggesting that supervision of cellular export/import routes by antiproteolytic serpins is an ancient trait.
Phylogenomic comparisons show that, after establishment of canonical exon-intron patterns in the serpin superfamily at the dawn of vertebrate evolution, multiple intron acquisition events have occurred during diversification of a lineage of actinopterygian fishes. The novel introns were acquired within a limited time interval (on an evolutionary timescale), and no such events were observed in other groups of vertebrates. Examination of the sequences flanking the intron insertion points revealed that the genetic requirements for acquisition of novel introns might be less stringent than previously suggested. Finally, we argue that genome compaction, a phenomenon associated with the fish lineage depicting preferential intron gain, might promote intron acquisition
Section 4A Public Order Act 1986: accommodating freedom of expression, Dehal v Crown Prosecution Service [2005] EWHC 2154
No full texthttp://webjcli.ncl.ac.uk/2006/issue5/bettinson5.htm
The aspartic proteinase family of three Phytophthora species
No full textBackground - Phytophthora species are oomycete plant pathogens with such major social and economic impact that genome sequences have been determined for Phytophthora infestans, P. sojae and P. ramorum. Pepsin-like aspartic proteinases (APs) are produced in a wide variety of species (from bacteria to humans) and contain conserved motifs and landmark residues. APs fulfil critical roles in infectious organisms and their host cells. Annotation of Phytophthora APs would provide invaluable information for studies into their roles in the physiology of Phytophthora species and interactions with their hosts. Results - Genomes of Phytophthora infestans, P. sojae and P. ramorum contain 11-12 genes encoding APs. Nine of the original gene models in the P. infestans database and several in P. sojae and P. ramorum (three and four, respectively) were erroneous. Gene models were corrected on the basis of EST data, consistent positioning of introns between orthologues and conservation of hallmark motifs. Phylogenetic analysis resolved the Phytophthora APs into 5 clades. Of the 12 sub-families, several contained an unconventional architecture, as they either lacked a signal peptide or a propart region. Remarkably, almost all APs are predicted to be membrane-bound. Conclusions - One of the twelve Phytophthora APs is an unprecedented fusion protein with a putative G-protein coupled receptor as the C-terminal partner. The others appear to be related to well-documented enzymes from other species, including a vacuolar enzyme that is encoded in every fungal genome sequenced to date. Unexpectedly, however, the oomycetes were found to have both active and probably-inactive forms of an AP similar to vertebrate BACE, the enzyme responsible for initiating the processing cascade that generates the Aß peptide central to Alzheimer's Disease. The oomycetes also encode enzymes similar to plasmepsin V, a membrane-bound AP that cleaves effector proteins of the malaria parasite Plasmodium falciparum during their translocation into the host red blood cell. Since the translocation of Phytophthora effector proteins is currently a topic of intense research activity, the identification in Phytophthora of potential functional homologues of plasmepsin V would appear worthy of investigation. Indeed, elucidation of the physiological roles of the APs identified here offers areas for future study. The significant revision of gene models and detailed annotation presented here should significantly facilitate experimental design
Recovery of a medieval Brucella melitensis genome using shotgun metagenomics
No full textShotgun metagenomics provides a powerful assumption-free approach to the recovery of pathogen genomes from contemporary and historical material. We sequenced the metagenome of a calcified nodule from the skeleton of a 14th-century middle-aged male excavated from the medieval Sardinian settlement of Geridu. We obtained 6.5-fold coverage of a Brucella melitensis genome. Sequence reads from this genome showed signatures typical of ancient or aged DNA. Despite the relatively low coverage, we were able to use information from single-nucleotide polymorphisms to place the medieval pathogen genome within a clade of B. melitensis strains that included the well-studied Ether strain and two other recent Italian isolates. We confirmed this placement using information from deletions and IS711 insertions. We conclude that metagenomics stands ready to document past and present infections, shedding light on the emergence, evolution, and spread of microbial pathogens
Author Correction: A genomic catalog of Earth’s microbiomes (Nature Biotechnology, (2021), 39, 4, (499-509), 10.1038/s41587-020-0718-6)
No full textIn the version of this article initially published, four people were missing from the alphabetical list of IMG/M Data Consortium members: Lauren V. Alteio of the Centre for Microbiology and Environmental Systems Science, University of Vienna, Vienna, Austria; Jeffrey L. Blanchard of the Biology Department, University of Massachusetts Amherst, Amherst, MA, USA; Kristen M. DeAngelis of the Department of Microbiology, University of Massachusetts Amherst, Amherst, MA, USA; and William Rodriguez-Reillo of the Research Computing Division, Harvard Medical School, Boston, MA, USA. The error has been corrected in the PDF and HTML versions of the article
Impact of Body Mass Index on Survival After Colorectal Cancer Diagnosis: The Cancer Prevention Study-II Nutrition Cohort
No full textPurpose The impact of body mass index (BMI) on survival after colorectal cancer diagnosis is poorly understood. This study assessed the association of pre- and postdiagnosis BMI with all-cause and cause-specific survival among men and women diagnosed with colorectal cancer in a prospective cohort. Patients and Methods Participants in the Cancer Prevention Study-II Nutrition Cohort reported weight and other risk factor information via a self-administered questionnaire at baseline in 1992 to 1993. Updated information on current weight and incident cancer was reported via periodic follow-up questionnaires. This analysis includes 2,303 cohort participants who were diagnosed with nonmetastatic colorectal cancer between baseline and mid 2007 and were observed for mortality from diagnosis through December 2008. Results A total of 851 participants with colorectal cancer died during the 16-year follow-up period, including 380 as a result of colorectal cancer and 153 as a result of cardiovascular disease (CVD). In analyses of prediagnosis BMI (weight reported at baseline in 1992 to 1993; mean, 7 years before colorectal cancer diagnosis), obese BMI (≥ 30 kg/m2) relative to normal BMI (18.5 to 24.9 kg/m2) was associated with higher risk of mortality resulting from all causes (relative risk [RR], 1.30; 95% CI, 1.06 to 1.58), colorectal cancer (RR, 1.35; 95% CI, 1.01 to 1.80), and CVD (RR, 1.68; 95% CI, 1.07 to 2.65). Postdiagnosis BMI (based on weight reported; mean, 1.5 years after diagnosis) was not associated with all-cause or cause-specific mortality. Conclusion This study suggests that prediagnosis BMI, but not postdiagnosis BMI, is an important predictor of survival among patients with nonmetastatic colorectal cancer. </jats:sec
Crystal Structure of the Escherichia coli Fic Toxin-Like Protein in Complex with Its Cognate Antitoxin
No full textFIC domain proteins mediate post-translational modifications of target proteins, which typically results in their inactivation. Depending on the conservation of crucial active site residues, the FIC fold serves as structural scaffold for various enzymatic activities, mostly target adenylylation. The founding member of the vast Fic protein family, EcFicT, was identified in Escherichia coli some time ago. The G55R point mutant of EcFicT displays the "filamentation induced by cAMP" (Fic) phenotype at high 3',5'-cyclic adenosine monophosphate (cAMP) concentrations and elevated temperature, but the underlying molecular mechanism and any putative biochemical activity of EcFicT have remained unknown. EcFicT belongs to class I Fic toxin proteins that are encoded together with a small inhibitory protein (antitoxin), named EcFicA in E. coli. Here, we report the crystal structures of two mutant EcFicT/EcFicA complexes (EcFicTG55RA and EcFicTAE28G) both showing close resemblance with the structure of the AMP-transferase VbhT from Bartonella schoenbuchensis in complex with its cognate antitoxin VbhA. However, crucial differences in the active site of EcFicT compared to VbhT and other AMP-transferases rationalize the lack of evidence for adenylylation activity. Comprehensive bioinformatic analysis suggests that EcFicT has evolved from canonical AMP-transferases and has acquired a conserved binding site for a yet to be discovered novel substrate. The G55R mutation has no effect on structure or thermal stability of EcFicT, such that the molecular basis for its associated Fic phenotype remains elusive. We anticipate that this structure will inspire further bioinformatic and experimental analyses in order to characterize the enzymatic activity of EcFicT and help revealing its physiological role
Impact of Diabetes Mellitus and Insulin Use on Survival After Colorectal Cancer Diagnosis: The Cancer Prevention Study-II Nutrition Cohort
No full textPurpose To examine the association between type 2 diabetes mellitus (T2DM) and survival among patients with colorectal cancer (CRC) and to evaluate whether this association varies by sex, insulin treatment, and durations of T2DM and insulin use. Patients and Methods This study was conducted among 2,278 men and women diagnosed with nonmetastatic colon or rectal cancer between 1992 and 2007 in the Cancer Prevention Study-II Nutrition Cohort, a prospective study of cancer incidence. In 1992 to 1993, participants completed a detailed, self-administrated questionnaire. Vital status and cause of death were ascertained through the end of 2008. Multivariable-adjusted relative risks (RRs) and 95% CIs were estimated using Cox proportional hazards regression. Results Among the 2,278 men and women with nonmetastatic CRC, there were 842 deaths by the end of follow-up (including 377 deaths from CRC and 152 deaths from cardiovascular disease [CVD]). Among men and women combined, compared with patients without T2DM, patients with CRC and T2DM were at higher risk of all-cause mortality (RR, 1.53; 95% CI, 1.28 to 1.83), CRC-specific mortality (RR, 1.29; 95% CI, 0.98 to 1.70), and CVD-specific mortality (RR, 2.16; 95% CI, 1.44 to 3.24), with no apparent differences by sex or durations of T2DM or insulin use. Insulin use, compared with no T2DM, was associated with increased risk of death from all causes (RR, 1.68; 95% CI, 1.22 to 2.31) and CVD (RR, 3.87; 95% CI, 2.12 to 7.08) but not from CRC (RR, 0.58; 95% CI, 0.28 to 1.19). Conclusion Patients with CRC and T2DM have a higher risk of mortality than patients with CRC who do not have T2DM, especially a higher risk of death from CVD. </jats:sec
Author Correction: A genomic catalog of Earth’s microbiomes
No full textA Correction to this paper has been published: https://doi.org/10.1038/s41587-021-00898-4
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