Genomic analysis and relatedness of P2-like phages of the Burkholderia cepacia complex

<p>Abstract</p> <p>Background</p> <p>The <it>Burkholderia cepacia </it>complex (BCC) is comprised of at least seventeen Gram-negative species that cause infections in cystic fibrosis patients. Because BCC bacteria are broadly antibiotic resistant, phage therapy is currently being investigated as a possible alternative treatment for these infections. The purpose of our study was to sequence and characterize three novel BCC-specific phages: KS5 (vB_BceM-KS5 or vB_BmuZ-ATCC 17616), KS14 (vB_BceM-KS14) and KL3 (vB_BamM-KL3 or vB_BceZ-CEP511).</p> <p>Results</p> <p>KS5, KS14 and KL3 are myoviruses with the A1 morphotype. The genomes of these phages are between 32317 and 40555 base pairs in length and are predicted to encode between 44 and 52 proteins. These phages have over 50% of their proteins in common with enterobacteria phage P2 and so can be classified as members of the <it>Peduovirinae </it>subfamily and the "P2-like viruses" genus. The BCC phage proteins similar to those encoded by P2 are predominantly structural components involved in virion morphogenesis. As prophages, KS5 and KL3 integrate into an AMP nucleosidase gene and a threonine tRNA gene, respectively. Unlike other P2-like viruses, the KS14 prophage is maintained as a plasmid. The P2 <it>E+E' </it>translational frameshift site is conserved among these three phages and so they are predicted to use frameshifting for expression of two of their tail proteins. The <it>lysBC </it>genes of KS14 and KL3 are similar to those of P2, but in KS5 the organization of these genes suggests that they may have been acquired via horizontal transfer from a phage similar to λ. KS5 contains two sequence elements that are unique among these three phages: an IS<it>Bmu</it>2-like insertion sequence and a reverse transcriptase gene. KL3 encodes an EcoRII-C endonuclease/methylase pair and Vsr endonuclease that are predicted to function during the lytic cycle to cleave non-self DNA, protect the phage genome and repair methylation-induced mutations.</p> <p>Conclusions</p> <p>KS5, KS14 and KL3 are the first BCC-specific phages to be identified as P2-like. As KS14 has previously been shown to be active against <it>Burkholderia cenocepacia in vivo</it>, genomic characterization of these phages is a crucial first step in the development of these and similar phages for clinical use against the BCC.</p

Die Darstellung "afrikanischer" Geschichte des 20. und 21. Jahrhunderts in österreichischen Geschichtsschulbüchern

Die vorliegende Diplomarbeit beschäftigt sich mit der Darstellung der Geschichte „Afrikas“ des 20. und 21. Jahrhunderts in österreichischen Geschichtsschulbüchern. Die These der Arbeit ist, dass es ein gewisses Narrativ im Umgang mit „afrikanischer“ Geschichte in den österreichischen Geschichtsschulbüchern gibt. Dieses Narrativ, so die These, hat eine eurozentristische Prägung und integriert eine tendenziell negative und homogenisierende Darstellung des „afrikanischen“ Kontinents. Nach einer Diskussion der Relevanz der Behandlung „Afrikas“ im Unterricht sowie des Mediums Schulbuch wurden ausgehend von dieser These anhand der bisherigen Schulbuchanalysen aus dem deutschsprachigen Raum Elemente eines Narratives festgemacht. Diese Elemente lassen sich wie folgt zusammenfassen:1.„‚Afrika‘ als homogener Kontinent,2.„‚Afrika‘ als unterentwickelter Kontinent“3.„‚Afrika‘ als geschichtsloser oder passiver Kontinent“4.„‚Afrika als Krisenkontinent“ und5.„‚Afrika‘ als exotischer Kontinent.“ Anhand dieser Elemente wurde eine Analysebogen erstellt, mit dem zwanzig aktuelle Schulbücher der 8., 11. und 12. Schulstufe untersucht wurden. Hierbei konnte festgehalten werden, dass sich zwar ein Narrativ über „Afrika“ in den Schulbüchern des Untersuchungskorpus finden lässt, dieses jedoch keine homogenisierenden Elemente und keine exotisierenden Elemente allerdings passivierende und Elemente von „Afrika“ als „Krisenkontinent“ und als „unterentwickelter Kontinent“ enthält. Dieses Narrativ wird in der Arbeit ausführlich, auch im Hinblick auf dessen Bedeutung für den Unterricht, diskutiert.This thesis deals with the representation of the contemporary history of ‘african countries in austrian history textbooks. My hypothesis is, that there is a certain narrative about ‘african history in these books. This narrative has an eurocentric background and tends to represent Africa` as a homogeneous continent with a negative perspective. After the discussion about the relevance of ‘Africa in school as well as the medium of textbooks I extracted the elements of this narrative from former analysis of textbooks based on my hypothesis. These elements can be summarized as: 1.‘Africa as a homogeneous continent,2.‘Africa as an underdeveloped continent,3.‘Africa as a passive continent without own history,4.‘Africa as an area of conflict and 5.‘Africa as an exotic continent. Based on these elements I created an analysis sheet which I used to analyze twenty current textbooks, which are qualified for the 8th, the 11th and the 12th grade. During my analysis I worked out, that there is a narrative about ‘Afrika in these textbooks, but this narrative doesnt contain homogenizing and exotic elements but elements of ‘Afrika as an ‘underdeveloped, and a ‘passive continent and of ‘africa as an ‘area of conflict. With this conclusion I discussed the narrative also with regard to didactic implications.vorgelegt von Paul Ziermann-ÖsterreicherZusammenfassungen in Deutsch und EnglischAbweichender Titel laut Übersetzung des Verfassers/der VerfasserinKarl-Franzens-Universität Graz, Diplomarbeit, 2019(VLID)357430

LASP1 is a novel BCR-ABL substrate and a phosphorylation-dependent binding partner of CRKL in chronic myeloid leukemia

Chronic myeloid leukemia (CML) is characterized by a genomic translocation generating a permanently active BCR-ABL oncogene with a complex pattern of atypically tyrosine-phosphorylated proteins that drive the malignant phenotype of CML. Recently, the LIM and SH3 domain protein 1 (LASP1) was identified as a component of a six gene signature that is strongly predictive for disease progression and relapse in CML patients. However, the underlying mechanisms why LASP1 expression correlates with dismal outcome remained unresolved. Here, we identified LASP1 as a novel and overexpressed direct substrate of BCR-ABL in CML. We demonstrate that LASP1 is specifically phosphorylated by BCR-ABL at tyrosine-171 in CML patients, which is abolished by tyrosine kinase inhibitor therapy. Further studies revealed that LASP1 phosphorylation results in an association with CRKL - another specific BCR-ABL substrate and bona fide biomarker for BCR-ABL activity. pLASP1-Y171 binds to non-phosphorylated CRKL at its SH2 domain. Accordingly, the BCR-ABL-mediated pathophysiological hyper-phosphorylation of LASP1 in CML disrupts normal regulation of CRKL and LASP1, which likely has implications on downstream BCR-ABL signaling. Collectively, our results suggest that LASP1 phosphorylation might serve as an additional candidate biomarker for assessment of BCR-ABL activity and provide a first step toward a molecular understanding of LASP1 function in CML

Apheresis therapies for NMOSD attacks

$\bf Objective$ To analyze whether 1 of the 2 apheresis techniques, therapeutic plasma exchange (PE) or immunoadsorption (IA), is superior in treating neuromyelitis optica spectrum disorder (NMOSD) attacks and to identify predictive factors for complete remission (CR). $\bf Methods$ This retrospective cohort study was based on the registry of the German Neuromyelitis Optica Study Group, a nationwide network established in 2008. It recruited patients with neuromyelitis optica diagnosed according to the 2006 Wingerchuk criteria or with aquaporin-4 (AQP4-ab)-antibody–seropositive NMOSD treated at 6 regional hospitals and 16 tertiary referral centers until March 2013. Besides descriptive data analysis of patient and attack characteristics, generalized estimation equation (GEE) analyses were applied to compare the effectiveness of the 2 apheresis techniques. A GEE model was generated to assess predictors of outcome. $\bf Results$ Two hundred and seven attacks in 105 patients (87% AQP4-ab-antibody seropositive) were treated with at least 1 apheresis therapy. Neither PE nor IA was proven superior in the therapy of NMOSD attacks. CR was only achieved with early apheresis therapy. Strong predictors for CR were the use of apheresis therapy as first-line therapy (OR 12.27, 95% CI: 1.04–144.91, $\it {p}$ = 0.047), time from onset of attack to start of therapy in days (OR 0.94, 95% CI: 0.89–0.99, $\it {p}$ = 0.014), the presence of AQP4-abantibodies (OR 33.34, 95% CI: 1.76–631.17, $\it {p}$ = 0.019), and monofocal attack manifestation (OR 4.71, 95% CI: 1.03–21.62, $\it {p}$ = 0.046). $\bf Conclusions$ Our findings suggest early use of an apheresis therapy in NMOSD attacks, particularly in AQP4-ab-seropositive patients. No superiority was shown for one of the 2 apheresis techniques. $\textbf {Classification of evidence}$ This study provides Class IV evidence that for patients with NMOSD, neither PE nor IA is superior in the treatment of attacks