Rapid evolution of virulence and drug resistance in the emerging zoonotic pathogen Streptococcus suis

Background: Streptococcus suis is a zoonotic pathogen that infects pigs and can occasionally cause serious infections in humans. S. suis infections occur sporadically in human Europe and North America, but a recent major outbreak has been described in China with high levels of mortality. The mechanisms of S. suis pathogenesis in humans and pigs are poorly understood. Methodology/Principal Findings: The sequencing of whole genomes of S. suis isolates provides opportunities to investigate the genetic basis of infection. Here we describe whole genome sequences of three S. suis strains from the same lineage: one from European pigs, and two from human cases from China and Vietnam. Comparative genomic analysis was used to investigate the variability of these strains. S. suis is phylogenetically distinct from other Streptococcus species for which genome sequences are currently available. Accordingly, ,40% of the ,2 Mb genome is unique in comparison to other Streptococcus species. Finer genomic comparisons within the species showed a high level of sequence conservation; virtually all of the genome is common to the S. suis strains. The only exceptions are three ,90 kb regions, present in the two isolates from humans, composed of integrative conjugative elements and transposons. Carried in these regions are coding sequences associated with drug resistance. In addition, small-scale sequence variation has generated pseudogenes in putative virulence and colonization factors. Conclusions/Significance: The genomic inventories of genetically related S. suis strains, isolated from distinct hosts and diseases, exhibit high levels of conservation. However, the genomes provide evidence that horizontal gene transfer has contributed to the evolution of drug resistance

Evidence for niche adaptation in the genome of the bovine pathogen Streptococcus uberis.

BACKGROUND: Streptococcus uberis, a Gram positive bacterial pathogen responsible for a significant proportion of bovine mastitis in commercial dairy herds, colonises multiple body sites of the cow including the gut, genital tract and mammary gland. Comparative analysis of the complete genome sequence of S. uberis strain 0140J was undertaken to help elucidate the biology of this effective bovine pathogen. RESULTS: The genome revealed 1,825 predicted coding sequences (CDSs) of which 62 were identified as pseudogenes or gene fragments. Comparisons with related pyogenic streptococci identified a conserved core (40%) of orthologous CDSs. Intriguingly, S. uberis 0140J displayed a lower number of mobile genetic elements when compared with other pyogenic streptococci, however bacteriophage-derived islands and a putative genomic island were identified. Comparative genomics analysis revealed most similarity to the genomes of Streptococcus agalactiae and Streptococcus equi subsp. zooepidemicus. In contrast, streptococcal orthologs were not identified for 11% of the CDSs, indicating either unique retention of ancestral sequence, or acquisition of sequence from alternative sources. Functions including transport, catabolism, regulation and CDSs encoding cell envelope proteins were over-represented in this unique gene set; a limited array of putative virulence CDSs were identified. CONCLUSION: S. uberis utilises nutritional flexibility derived from a diversity of metabolic options to successfully occupy a discrete ecological niche. The features observed in S. uberis are strongly suggestive of an opportunistic pathogen adapted to challenging and changing environmental parameters.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are

Morphogenesis, volume and number of hop (Humulus lupulus L.) glandular trichomes, and their influence on alpha-acid accumulation in fresh bracts of hop cones

The ESEM investigations revealed the morphogenesis of peltate glandular trichomes, which was divided into five phases. In phase one, new peltate glandular trichomes were initiated; in phase two, they were differentiated; in phase three trichomes grew vigorously; in phase four they were determined; in the fifth and final phase they came to maturity. Volume of glandular trichome during the different phases of morphogenesis varied from 0.25 ´ 10–2mm3 in phase 1, to 1.95 ´ 10–2mm3 in phase 5. More glandular trichomes are placed on the base of the adaxial side of bracts (average 7 mm–2) than on the base of abaxial side (average 5.8 mm–2). In this research, positive spearman\u27s rank order correlations were found between the average number of glandular trichomes and content of a-acids as well as between the average volume of glandular trichomes and content of a- acids

Ein effizientes Crossover-Design für klinische Studien zur Untersuchung des QT-Intervalls

Background: Thorough QT studies are typically a requirement of the clinical development program for new investigational drugs. These studies are a major cost factor in early development. The objectives of a typical thorough QT study (TQT) are to demonstrate (a) that therapeutic and supra-therapeutic doses of a new investigational drug do not prolong the ECG QT interval compared to placebo and (b) that an active control does show QT prolongation compared to placebo. In recent years, statistical research has led to substantial improvements in the design and analysis of these studies. We show one example of a recently developed, efficient study design.Methods: TQT studies conventionally follow a crossover design based on a Williams square of order four, as four treatments must be investigated. This design can be improved, since all comparisons in this design are active versus placebo. Hence it is efficient to double the number of placebo periods for each subject in order to reduce the sample size and the overall study costs.Several options for implementing this design are discussed and the preferred option is given. In addition, the corresponding changes in the analysis that are required to account for the multiple placebo periods are shown.Conclusions: Using a five period, four treatment design can lead to a reduction in the study costs of around 10%. Moreover, the number of active treatments administered is reduced which is a potential advantage for the investigation of drugs with a critical safety profile.Hintergrund: Ein wichtiger Bestandteil in der klinischen Entwicklung neuer pharmakologischer Substanzen sind spezielle EKG-QT-Studien (thorough QT - TQT-Studie). Die Durchführung und Auswertung dieser Studien sind für die frühe klinische Entwicklung vergleichsweise teuer. Studienziele einer TQT-Studie sind nachzuweisen, (a) dass therapeutische und supratherapeutische Dosen der Substanz das QT-Intervall im Vergleich zu Placebo nicht verlängern und (b) dass eine aktive Positivkontrolle die erwartete Verlängerung des QT-Intervalls im Vergleich zu Placebo zeigt.In den letzten Jahren führte die statistische Forschung auf diesem Gebiet zu wesentlichen Verbesserungen im Design und in der Analyse dieser Studien. In diesem Artikel wird ein weiterer Vorschlag zur Verbesserung des Designs vorgestellt.Methoden: Ein konventionelles Design für TQT-Studien basiert auf einem Williams Crossover-Design der Ordnung 4, da vier verschiedene Behandlungen untersucht werden sollen. Dieses Design kann verbessert werden, da alle Vergleiche in der Studie den Unterschied von aktiven Substanzen gegen Placebo testen. Es ist deshalb statistisch effizient, die Anzahl der Placebo-Perioden pro Studienteilnehmer zu verdoppeln, da man damit die Fallzahl der Studie und letztlich die gesamten Studienkosten reduzieren kann.In diesem Artikel werden verschiedene Möglichkeiten der Implementierung dieses Designs diskutiert und eine bevorzugte Option vorgeschlagen. Weiterhin werden notwendige Änderungen in der Analyse der Daten - in Bezug auf die mehrfachen Placebo-Behandlungen - vorgestellt.Schlussfolgerung: Mit einem 5-Perioden, 4-Behandlungs-Crossover-Design können die Gesamtkosten einer TQT-Studie um etwa 10% verringert werden. Als weiterer Vorteil für Substanzen mit kritischem Sicherheitsprofil kann die Verringerung der Fallzahl und damit der Einnahme von aktiver Medikation angesehen werden