Decreased antigen-specific T-cell proliferation by moDC among hepatitis B vaccine non-responders on haemodialysis

Patients with end-stage kidney disease, whether or not on renal replacement therapy, have an impaired immune system. This is clinically manifested by a large percentage of patients unresponsive to the standard vaccination procedure for hepatitis B virus (HBV). In this study, the immune response to HBV vaccination is related to the in vitro function of monocyte-derived dendritic cells (moDC). We demonstrate that mature moDC from nonresponders to HBV vaccination have a less mature phenotype, compared to responders and healthy volunteers, although this did not affect their allostimulatory capacity. However, proliferation of autologous T cells in the presence of tetanus toxoid and candida antigen was decreased in non-responders. Also, HLA-matched CD4+ hsp65-specific human T-cell clones showed markedly decreased proliferation in the group of non-responders. Our results indicate that impairment of moDC to stimulate antigen-specific T cells provides an explanation for the clinical immunodeficiency of patients with end-stage kidney disease

DRhigh+CD45RA−-Tregs Potentially Affect the Suppressive Activity of the Total Treg Pool in Renal Transplant Patients

Recent studies show that regulatory T cells (Tregs) play an essential role in tolerance induction after organ transplantation. In order to examine whether there are differences in the composition of the total CD4+CD127low+/−FoxP3+- Treg cell pool between stable transplant patients and patients with biopsy proven rejection (BPR), we compared the percentages and the functional activity of the different Treg cell subsets (DRhigh+CD45RA−-Tregs, DRlow+CD45RA−-Tregs, DR−CD45RA−-Tregs, DR−CD45RA+-Tregs). All parameters were determined during the three different periods of time after transplantation (0–30 days, 31–1,000 days, >1,000 days). Among 156 transplant patients, 37 patients suffered from BPR. The most prominent differences between rejecting and non-rejecting patients were observed regarding the DRhigh+CD45RA−-Treg cell subset. Our data demonstrate that the suppressive activity of the total Treg pool strongly depends on the presence of these Treg cells. Their percentage within the total Treg pool strongly decreased after transplantation and remained relatively low during the first year after transplantation in all patients. Subsequently, the proportion of this Treg subset increased again in patients who accepted the transplant and reached a value of healthy non-transplanted subjects. By contrast, in patients with acute kidney rejection, the DRhigh+CD45RA−-Treg subset disappeared excessively, causing a reduction in the suppressive activity of the total Treg pool. Therefore, both the monitoring of its percentage within the total Treg pool and the monitoring of the HLA-DR MFI of the DR+CD45RA−-Treg subset may be useful tools for the prediction of graft rejection

Acidithiobacillus ferrooxidans metabolism: from genome sequence to industrial applications

<p>Abstract</p> <p>Background</p> <p><it>Acidithiobacillus ferrooxidans </it>is a major participant in consortia of microorganisms used for the industrial recovery of copper (bioleaching or biomining). It is a chemolithoautrophic, γ-proteobacterium using energy from the oxidation of iron- and sulfur-containing minerals for growth. It thrives at extremely low pH (pH 1–2) and fixes both carbon and nitrogen from the atmosphere. It solubilizes copper and other metals from rocks and plays an important role in nutrient and metal biogeochemical cycling in acid environments. The lack of a well-developed system for genetic manipulation has prevented thorough exploration of its physiology. Also, confusion has been caused by prior metabolic models constructed based upon the examination of multiple, and sometimes distantly related, strains of the microorganism.</p> <p>Results</p> <p>The genome of the type strain <it>A. ferrooxidans </it>ATCC 23270 was sequenced and annotated to identify general features and provide a framework for <it>in silico </it>metabolic reconstruction. Earlier models of iron and sulfur oxidation, biofilm formation, quorum sensing, inorganic ion uptake, and amino acid metabolism are confirmed and extended. Initial models are presented for central carbon metabolism, anaerobic metabolism (including sulfur reduction, hydrogen metabolism and nitrogen fixation), stress responses, DNA repair, and metal and toxic compound fluxes.</p> <p>Conclusion</p> <p>Bioinformatics analysis provides a valuable platform for gene discovery and functional prediction that helps explain the activity of <it>A. ferrooxidans </it>in industrial bioleaching and its role as a primary producer in acidic environments. An analysis of the genome of the type strain provides a coherent view of its gene content and metabolic potential.</p

A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants.

This is the author accepted manuscript. The final version is available from Nature Publishing Group via http://dx.doi.org/10.1038/ng.3448Advanced age-related macular degeneration (AMD) is the leading cause of blindness in the elderly, with limited therapeutic options. Here we report on a study of >12 million variants, including 163,714 directly genotyped, mostly rare, protein-altering variants. Analyzing 16,144 patients and 17,832 controls, we identify 52 independently associated common and rare variants (P < 5 × 10(-8)) distributed across 34 loci. Although wet and dry AMD subtypes exhibit predominantly shared genetics, we identify the first genetic association signal specific to wet AMD, near MMP9 (difference P value = 4.1 × 10(-10)). Very rare coding variants (frequency <0.1%) in CFH, CFI and TIMP3 suggest causal roles for these genes, as does a splice variant in SLC16A8. Our results support the hypothesis that rare coding variants can pinpoint causal genes within known genetic loci and illustrate that applying the approach systematically to detect new loci requires extremely large sample sizes.We thank all participants of all the studies included for enabling this research by their participation in these studies. Computer resources for this project have been provided by the high-performance computing centers of the University of Michigan and the University of Regensburg. Group-specific acknowledgments can be found in the Supplementary Note. The Center for Inherited Diseases Research (CIDR) Program contract number is HHSN268201200008I. This and the main consortium work were predominantly funded by 1X01HG006934-01 to G.R.A. and R01 EY022310 to J.L.H

The ongoing pursuit of neuroprotective therapies in Parkinson disease

Many agents developed for neuroprotective treatment of Parkinson disease (PD) have shown great promise in the laboratory, but none have translated to positive results in patients with PD. Potential neuroprotective drugs, such as ubiquinone, creatine and PYM50028, have failed to show any clinical benefits in recent high-profile clinical trials. This 'failure to translate' is likely to be related primarily to our incomplete understanding of the pathogenic mechanisms underlying PD, and excessive reliance on data from toxin-based animal models to judge which agents should be selected for clinical trials. Restricted resources inevitably mean that difficult compromises must be made in terms of trial design, and reliable estimation of efficacy is further hampered by the absence of validated biomarkers of disease progression. Drug development in PD dementia has been mostly unsuccessful; however, emerging biochemical, genetic and pathological evidence suggests a link between tau and amyloid-β deposition and cognitive decline in PD, potentially opening up new possibilities for therapeutic intervention. This Review discusses the most important 'druggable' disease mechanisms in PD, as well as the most-promising drugs that are being evaluated for their potential efficiency in treatment of motor and cognitive impairments in PD

Adaptations to Submarine Hydrothermal Environments Exemplified by the Genome of Nautilia profundicola

Submarine hydrothermal vents are model systems for the Archaean Earth environment, and some sites maintain conditions that may have favored the formation and evolution of cellular life. Vents are typified by rapid fluctuations in temperature and redox potential that impose a strong selective pressure on resident microbial communities. Nautilia profundicola strain Am-H is a moderately thermophilic, deeply-branching Epsilonproteobacterium found free-living at hydrothermal vents and is a member of the microbial mass on the dorsal surface of vent polychaete, Alvinella pompejana. Analysis of the 1.7-Mbp genome of N. profundicola uncovered adaptations to the vent environment—some unique and some shared with other Epsilonproteobacterial genomes. The major findings included: (1) a diverse suite of hydrogenases coupled to a relatively simple electron transport chain, (2) numerous stress response systems, (3) a novel predicted nitrate assimilation pathway with hydroxylamine as a key intermediate, and (4) a gene (rgy) encoding the hallmark protein for hyperthermophilic growth, reverse gyrase. Additional experiments indicated that expression of rgy in strain Am-H was induced over 100-fold with a 20°C increase above the optimal growth temperature of this bacterium and that closely related rgy genes are present and expressed in bacterial communities residing in geographically distinct thermophilic environments. N. profundicola, therefore, is a model Epsilonproteobacterium that contains all the genes necessary for life in the extreme conditions widely believed to reflect those in the Archaean biosphere—anaerobic, sulfur, H2- and CO2-rich, with fluctuating redox potentials and temperatures. In addition, reverse gyrase appears to be an important and common adaptation for mesophiles and moderate thermophiles that inhabit ecological niches characterized by rapid and frequent temperature fluctuations and, as such, can no longer be considered a unique feature of hyperthermophiles

Die Entwicklung von Interpolationsquadratur- und Differentiationsformeln zu gegebenen Stützstellen mit PL/1-FORMAC

ln der vorliegenden Arbeit wird gezeigt, wie man zu einem Satz vorgegebener Stutzstellen x$_{i}$ die Gewichte A$_{1}$ und das Hauptrestglied einer lnterpolationsquadratur- bzw. Differentiationsformel mit Hilfe von PL/I-FORMAC maschinell ermittelt. Sind die x$_{i}$ rationale Zahlen, so werden die A$_{i}$ exakt mit Hilfe der PL/I-FORMAC-Rationalarithmetik (siehe [2]) bestimmt. Vielfach hat man ja bei der Integration von Messwertfunktionen keine unmittelbar passende Quadraturformnel zur Verfügung (z. B. wenn man nichtdie Messstellen exakt auf die Erfordernisse einer nachträglichen lntegration eingerichtet hat). ln diesem Falle kann das von uns angegebene FORMAC-Unterprogramm die benötigten Quadraturformeln liefern. Wir betrachten die zu verschiedenen Gewichtsfunktionen w(x) gehörigen Formeln der Bauart (1) $\int^{b}_{a} w(x)f(x)dx = \sum^{n}_{i=1} A_{i} f(x_{i}) + R_{Q}(f); \frac{d^{k}}{dx^{k}} (w(x)f(x)) = \sum^{n}_{i=1} B_{i} f(x_{i}) + R_{D}(f)$ Dabei sind die $x_{1}, x_{2}, ..., x_{n}, (x_{1} -1 gelten, um die Existenz sämtlicher Nomenintegrale zu sichern. Für Differentiationsformeln beschränken wir uns hier auf zentrale Differenzenformelnüber dem Intervall [-1;1] mit w(x) = 1. Angeregt wurde diese Arbeit durch ähnliche Untersuchungen von P. Swigert (vgl. [1]). Für einige spezielle Gewichtsfunktionen und Stützstellenverteilungen geben wir im letzen Kapitel die Tabellen der Gewichte an. Dabei verweisen wir im Falle von Quadraturformeln mit den Gewichtsfunktionen 1,$x^{1/2}, x^{-1/2}$, ln x, x ln x auf die Arbeit [1]

Quadraturformeln mit äquidistanten Abszissen zur Berechnungvon Integralen der Form ∫01xA(1−x)Bf(x)dx\int^{1}_{0} x^{A}(1-x)^{B} f(x) dx für spezielle Werte von A und B

Zur Berechnung von Integralen der Form $\int^{1}_{0} x^{A}(1-x)^{B} f(x) dx$ mit Hilfe von Mittelwertformeln der Gestalt $\int^{1}_{0}x^{A}(1-x)^{B} \cdot f(x) dx = \sum^{n}_{i=1} A_{i} \cdot f(x_{i}) + R$ stellten KRYLOV, LUGIN und JANOVI$\check{C}$ Tafeln GAUSS'scher Quadraturformeln auf (vgl. [1]). Für Anwendungen ist es jedoch oft besser, Quadraturformeln mit äquidistanten Stützstellen zur Verfügung zu haben. Wir wählen daher die Stützstellen $X_{i} = \frac{i-1}{n-1}, i = 1(1)n$ und geben Tabellen der Gewichte A$_{i}$ für Formeln der Bauart $\frac{1}{BETAFKT(A+1, B+1)} \int^{1}_{0} x^{A}(1-x)^{B} \cdot f(x) dx = \sum^{n}_{i=1} A_{i} \cdot f(x_{i}) + R.$ Dabei sind die Gewichte A$_{i}$ als rationale Zahlen mittels eines PL/I - FORMAC - Programms $\underline{exakt}$ berechnet. Die erforderlichen Normierungsfaktoren BETAFKT (A+1, B+1) sind in einer zweiten Tabelle angehängt. Für programmtechnische Fragen und theoretische Herleitung des Rechenverfahrens verweisen wir auf [2]. Zu jeder Formel geben wir das zugehörige Restglied R an, wobei das Argument als geeignet gewählter Zwischenpunkt des Stützintervalles anzusehen ist. Die Rechnungen wurden auf der IBM 360-75 des Zentralinstituts für Angewandte Mathematik der Kernforschungsanlage Jülich ausgeführt. Die Tabellen sind druckfehlerfrei, da der Original-Output auf photomechanischem Wege direkt übertragen wurde. Wir wählen n = 10 und A = - 0.9 (0.1) 1.0; B=A (0.1) 1.0 Ein Beispiel: Für A = B = - 1/2 ergibt sich die Formel (s.S. 75, N = 05) $\frac{1}{\pi} \int^{1}_{0} \frac{f(t)dt}{\sqrt{t(t-1)}} = \frac{1}{6} [f(o] + 2 f(\frac{1}{4}) + 2 f(\frac{3}{4}) + f(1) ] + R$ Diese Formel soll zur Berechnung der confluenten hypergeometrischen Funktion $M (a_{j};b_{j};x) = \frac{\Gamma(b)}{\Gamma(b-a) \Gamma(a)} \int^{1}_{0} e^{xt}t^{a-1} (1-t)^{b-a-1} dt$ angewendet werden. Für $a = \frac{1}{2}$ und b = 1 erhält man $M (\frac{1}{2} ; 1 ; x) = \frac{1}{\pi} \int^{1}_{0} t^{-1/2} (1 - t)^{-1/2} e^{xt} dt$ und als Näherungslösung (die unterstrichenen Dezimalen sind fehlerhaft) : [...] Für x $\epsilon$ [0;1] ist der Fehlerbetrag < 2 $\cdot 10^{-6}$. Die Gewichte A$_{i}$ sind, der Numerierung der Stützstellen entsprechend, fortlaufend nebeneinander angeordnet. Bei Überschreitung der Zeilenlänge wird in der nächsten Zeile fortgefahren

Die numerische Behandlung der energieabhängigen, eindimensionalen Transportgleichung mit Quellterm

Das in diesem Bericht behandelte Problem entstammt einem Auftrag des Instituts für Neutronenphysik der Kernforschungsanlage Jülich. Die Transportgleichung, eine Integro-Differentialgleichung, wurde auf Anregung von Herrn Prof. Dr. V. G. Avakumovic, Marburg, unter Berücksichtigung der Randbedingungen auf eine Fredholm'sche Integralgleichung 2. Art zurückgeführt. Die numerische Lösung dieser Integralgleichung erfolgte nach geeigneter Behandlung der auftretenden Singularitäten mittels Approximation durch ein inhomogenes System linearer Gleichungen. Die zweidimensionale Struktur der Aufgabenstellung führte zwangsläufig zu sehr großen Gleichungssystemen, die nur auf Rechenanlagen großer Speicherkapazität und hoher interner Verarbeitungsgeschwindigkeit gelöst werden können. Die in diesem Bericht erwähnten Programme wurden für die Rechenanlage IBM 7090 geschrieben und fast ausschließlich im Deutschen Rechenzentrum in Darmstadtausgeführt. Zur Durchrechnung eines abschließenden Beispiels wurde die Rechenanlage CD 6400 des Rechenzentrums der T. H. Aachen benutzt. Das hier verwendete Verfahren wurde am Beispiel des winkelunabhängigen freien Gaskerns geprüft, um Erfahrungen zur Behandlung des in diesem Bericht diskutierten, physikalisch sinnvolleren Nelkinkerns zu sammeln