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BACKGROUND: Inflammatory events after kidney transplantation (Tx) may lead to activation of the tryptophane-catabolizing enzyme indoleamine 2,3-dioxygenase followed by the formation of kynurenine (KYN). Post-transplant KYN serum levels in kidney allograft recipients were analyzed for their diagnostic value.
MATERIAL AND METHODS: This was a retrospective analysis of KYN levels (normal value: 2.7±0.6 nmol/ml) measured in 4083 blood samples collected from 355 kidney graft recipients in connection with uncomplicated courses, acute rejections (ARs), infections, and type of immunosuppression. We performed descriptive data analysis and analysis of variance.
RESULTS: In 212 recipients with immediately functioning grafts, the KYN levels dropped from pre-Tx 13.3±5.9 nmol/ml to nearly normal values at day 5 (5.8±3.0 nmol/ml). In patients with delayed graft function, the KYN reduction started only after the last hemodialysis treatment. With respect to ARs in recipients with creatinine values <300 µmol/l pre-AR, the increase of KYN levels depended on the severity of ARs (steroid-sensitive ARs: from 4.5±1.4 to 6.0±6.1 nmol/ml; steroid-resistant ARs: from 6.1±3.1 to 12.9±7.1 nmol/ml; vascular rejections: from 5.8±3.0 to 16.9±9.1 nmol/ml). In patients with creatinine values ≥300 µmol/l pre-AR, a further increase of the KYN level (from 10.1 to 13.2 nmol/ml) was only observed in severe, steroid-resistant ARs. With respect to infections evaluated, the KYN levels before diagnosis/start of treatment were 5.7±3.4 nmol/ml in asymptomatic CMV infections, 7.5±4.4 nmol/ml in CMV diseases, 8.3±3.3 nmol/ml in pneumonia, and 10.4±6.5 nmol/ml in bacterial sepsis.
CONCLUSIONS: Serum KYN seems to be a reliable diagnostic tool for the assessment of post-transplant inflammatory complications, already in an early stage, and for monitoring the efficacy of therapeutic interventions. Prospective studies are recommended.
The P300/CBP-associated factor plays a central role in retroviral infection and cancer development, and the C-terminal bromodomain provides an opportunity for selective targeting. Here, we report several new classes of acetyl-lysine mimetic ligands ranging from mM to low micromolar affinity that were identified using fragment screening approaches. The binding modes of the most attractive fragments were determined using high resolution crystal structures providing chemical starting points and structural models for the development of potent and selective PCAF inhibitors.
Ceraceosorus bombacis is an early-diverging lineage of smut fungi and a pathogen of cotton trees (Bombax ceiba). To study the evolutionary genomics of smut fungi in comparison with other fungal and oomycete pathogens, the genome of C. bombacis was sequenced and comparative genomic analyses were performed. The genome of 26.09 Mb encodes for 8,024 proteins, of which 576 are putative-secreted effector proteins (PSEPs). Orthology analysis revealed 30 ortholog PSEPs among six Ustilaginomycotina genomes, the largest groups of which are lytic enzymes, such as aspartic peptidase and glycoside hydrolase. Positive selection analyses revealed the highest percentage of positively selected PSEPs in C. bombacis compared with other Ustilaginomycotina genomes. Metabolic pathway analyses revealed the absence of genes encoding for nitrite and nitrate reductase in the genome of the human skin pathogen Malassezia globosa, but these enzymes are present in the sequenced plant pathogens in smut fungi. Interestingly, these genes are also absent in cultivable oomycete animal pathogens, while nitrate reductase has been lost in cultivable oomycete plant pathogens. Similar patterns were also observed for obligate biotrophic and hemi-biotrophic fungal and oomycete pathogens. Furthermore, it was found that both fungal and oomycete animal pathogen genomes are lacking cutinases and pectinesterases. Overall, these findings highlight the parallel evolution of certain genomic traits, revealing potential common evolutionary trajectories among fungal and oomycete pathogens, shaping the pathogen genomes according to their lifestyle.
Measurements of the transverse momentum (pt) spectra of K0 s and Λ(Λ̄) in Pb–Pb and pp collisions at √sNN = 2.76TeV with the ALICE detector at the LHC at CERN up to pt = 20GeV/c and pt = 16GeV/c, respectively, are presented in this thesis. In addition, the particle rapidity densities at mid-rapidity and nuclear modification factors of K0 s and Λ(Λ̄) are shown and discussed. The analysis was performed using the Pb–Pb data set from 2010 and the pp data set from 2011. For the identification of K0 s and Λ(Λ̄), the on-the-fly V0 finder was employed on tracking information from the TPC and ITS detectors. The Λ and Λ̄ spectra were feed-down corrected using the measured published Ξ− spectra as input.
Regarding the rapidity density at mid-rapidity, a suppression of the strange particle production in pp as compared to Pb–Pb collisions is observed at all centralities, whereas the production per pion rapidity density stays constant as a function of dNch/dη including both systems. Furthermore, the relative increase of the individual particle species in pp and AA collisions is compatible for non- and single-strange particles when going from RHIC (√sNN = 0.2TeV) to LHC energies. On the other hand, in case of multi-strange baryons, a stronger increase in the particle production in pp is seen. The Λ̄ and Λ production in Pb–Pb and pp collisions was found to be equal. Concerning the nuclear modification factors, at lower pt (pt <5GeV/c), an enhancement of the RAA of Λ with respect to that of K0 s and charged hadrons is observed. This baryon-to-meson enhancement appearing in central Pb–Pb collisions at RHIC and LHC is currently explained by the interplay of the radial flow and recombination as the dominant particle production mechanism in this pt sector. The effect of radial flow is thus also seen in the low and intermediate pt region of RAA, where a mass hierarchy is discovered among the baryons and mesons, respectively, with the heaviest particle being least suppressed. When comparing the results from RHIC and LHC, the RCP is found to be similar at low-to-intermediate pt, while a significantly smaller RAA of K0 s and Λ in central and peripheral events at the LHC is observed in this pt region as compared to the RHIC results. This can be attributed to the larger radial flow in AA collisions and to the harder spectra at the LHC. At high pt (pt > 8GeV/c), a strong suppression in central Pb–Pb collisions with respect to pp collisions is found for K0 s and Λ(Λ̄). A significant high-pt suppression of these hadrons is also observed in the ratio of central-to-peripheral collisions. The nuclear modification of K0 s and Λ(Λ̄) is compatible with the modification of charged hadrons at
high pt. The calculations with the transport model BAMPS agree with these results suggesting a similar energy loss for all light quarks, i.e. u, d and s. Moreover, a compatible suppression for c-quarks appears in the ALICE measurements via the D meson RAA as well as in the BAMPS calculations, which hints to a flavour-independent suppression if light- and c-quarks are regarded. Within this consideration, no indication for a medium-modified fragmentation is found yet.
To summarize, for the particle production in Pb–Pb collisions at the LHC relative to pp neither at lower pt (rapidity density) nor at higher pt (nuclear modification factor) a significant difference of K0 s and Λ(Λ̄) carrying strangeness to hadrons made of u- and d-quarks was found.
Mit der hier vorliegenden Arbeit ist das Entladungsverhalten einer Dielektrischen Barriere Entladung anhand der elektrischen Parameter untersucht worden. Dazu wurde ein planparallele Elektrodenkonfiguration entwickelt und aufgebaut, die mit einer Sinus-Spannungs von maximal 5000 Vss und einer Frequenz von 5 kHz-20 kHz angesteuert wurde. Als Arbeitsgas wurde Argon im Druckbereich von 100 mbar - 1000 mbar verwendet. Auf diese Weise konnte ein Plasma erzeugt werden, in das bei einer maximalen Transfereffiienz von 96%, eine mittlere Leistung von bis zu 845 mW eingekoppelt werden konnte.
Da die Dielektrische Barriere Entladung auf Grund der Abschirmung der Elektroden vom Gasraum einige Besonderheiten gegenüber eines klassischen kapazitiv eingekoppelten Plasmas aufweist, können keine Rückschlüsse mittels einer einfachen Strom-Spannungsmessung auf die Vorgänge im Plasma gemacht werden.
Um trotzdem Einblick in die Entladung zu erhalten, wurde das von [Tra08] vorgeschlagene Ladungstransportmodel für die Analyse herangezogen und an den hier vorliegenden experimentellen Aufbau angepasst. So konnte unter anderem der Ein
uss der auf den Dielektrika befindlichen Restladungsträger auf die Ausbildung der Entladung untersucht werden. Des Weiteren ist aus den gewonnen Größen die Elektronendichte des Plasmas bestimmt worden. Diese liegt bei der hier untersuchten dielektrischen Glimmentladung, je nach Gasdruck und Frequenz, im Bereich zwischen 5 X 10exp9 - 2 X 10exp10 1/cm3 . Auch konnten in diesem Zusammenhang qualitative Aussagen über die Entwicklung der Elektronentemperatur gemacht werden.
Zusammen mit Kurzzeitaufnahmen, die den Verlauf der Entladung dokumentieren und den in [Sch11] gemachten Untersuchungen zur Excimerstrahlung konnte so ein umfassendes Bild der Vorgänge im Plasma erstellt und Kriterien erarbeitet werden, die den für eine Dielektrische Barriere Entladung typischen Ubergang zwischen einer Glimmentladung zu einer filamentierten Entladung erklären können.
Crystallization and X-ray diffraction studies of a complete bacterial fatty-acid synthase type I
(2015)
While a deep understanding of the fungal and mammalian multi-enzyme type I fatty-acid synthases (FAS I) has been achieved in recent years, the bacterial FAS I family, which is narrowly distributed within the Actinomycetales genera Mycobacterium, Corynebacterium and Nocardia, is still poorly understood. This is of particular relevance for two reasons: (i) although homologous to fungal FAS I, cryo-electron microscopic studies have shown that bacterial FAS I has unique structural and functional properties, and (ii) M. tuberculosis FAS I is a drug target for the therapeutic treatment of tuberculosis (TB) and therefore is of extraordinary importance as a drug target. Crystals of FAS I from C. efficiens, a homologue of M. tuberculosis FAS I, were produced and diffracted X-rays to about 4.5 Å resolution.
Little evidence exists on the financing decisions of newly founded firms or on the financing dynamics of these firms over their life cycle. We aim to help filling this gap by investigating the financing dynamics of 2,456 French manufacturing firms founded between 2004 and 2006 through their legally required and reported financial statements. Because we observe significant heterogeneity in the financing decision in the firms' founding year, we focus on analyzing whether these differences widen, persist, or converge by using different convergence concepts. We identify a persistence-cum-convergence pattern. We find the existence of ß-convergence (implying that e.g. firms with lower initial levels of debt accumulate more debt over time) but not of σ-convergence (i.e. we observe an increase in the cross-sectional dispersion of the financing structure). We also show that the dynamics of financing matter for the growth path of the firms.
We compared outcomes from a single-arm study of blinatumomab in adult patients with B-precursor Ph-negative relapsed/refractory acute lymphoblastic leukemia (R/R ALL) with a historical data set from Europe and the United States. Estimates of complete remission (CR) and overall survival (OS) were weighted by the frequency distribution of prognostic factors in the blinatumomab trial. Outcomes were also compared between the trial and historical data using propensity score methods. The historical cohort included 694 patients with CR data and 1112 patients with OS data compared with 189 patients with CR and survival data in the blinatumomab trial. The weighted analysis revealed a CR rate of 24% (95% CI: 20–27%) and a median OS of 3.3 months (95% CI: 2.8–3.6) in the historical cohort compared with a CR/CRh rate of 43% (95% CI: 36–50%) and a median OS of 6.1 months (95% CI: 4.2–7.5) in the blinatumomab trial. Propensity score analysis estimated increased odds of CR/CRh (OR=2.68, 95% CI: 1.67–4.31) and improved OS (HR=0.536, 95% CI: 0.394–0.730) with blinatumomab. The analysis demonstrates the application of different study designs and statistical methods to compare novel therapies for R/R ALL with historical data.
This article reviews the most recent results concerning second harmonic generation (SHG) experiments of non-phase matchable and phase matchable powder samples at high pressures and explains the pressure dependence of the intensity of the SHG signal by correlating it to the ratio between the average coherence length and the average particle size. The examples discussed here include pressure-induced structural changes in quartz, ZnO, ice VII and KIO3. It is shown that the second harmonic generation technique is a unique tool for the detection of pressure-induced structural phase transitions. It is laboratory based and allows fast measurements. It is complementary to X-ray diffraction and provides additional information about the presence of an inversion center for unknown or controversially discussed structures at high pressure.