Computational immunology : analyses of viral escape, epitope binding and T cell receptor recognition

It has been shown repeatedly that infectious diseases in humans have strong associations with the human leukocyte antigen system, but an understanding of the basis of these associations remains elusive. Adaptive immune responses involving CD4 and CD8 T lymphocytes are dependent on (1) the appropriate and effective processing of a peptide from a protein source, (2) the stable binding of the peptide to the HLA molecule and (3) the recognition of this complex by the T cell receptor. In this thesis, we present work helping to better define such host-virus dynamics, examining aspects relating to each of the described steps. We examined two large patient cohorts, the first infected with HIV-1 and the second with HCV. We identified viral escape mutations and thus potential immune epitopes. Also, we examined the possible effects of HLA genotypes on the development of drug resistance mutations (HIV-1) and the success of antiviral therapy (HCV). To better understand the stable binding of peptides to HLA molecules, we evaluated the performance of diverse HLA class I prediction methods on large datasets, showing that all leading methods are capable of good to excellent performance. Finally, we developed the first algorithms, based on the interactions found in actual experimental structures, which allow for the prediction of interactions between residues in the T cell receptor\u27s CDR loops and residues in the HLA-peptide antigen. The algorithms had good performance under cross-validation.Wiederholt wurden viele Zusammenhänge menschlicher Infektionskrankheiten mit dem Human-Leukozyten-Antigen-System aufgezeigt, doch ein vollständiges Verständnis dieser Zusammenhänge fehlt. Adaptive Immunantworten mit CD4- und CD8-T-Lymphozyten sind abhängig von (1) einer angemessenen und effektiven Bearbeitung eines Peptids, (2) der stabilen Bindung des Peptids an das HLA-Molekül und (3) der Erkennung dieses HLA-Peptid-Komplexes durch den T-Zell-Rezeptor. In dieser Dissertation präsentieren wir Arbeiten, die helfen, diese Wirt-Virus-Dynamik besser zu definieren, indem wir Aspekte jedes dieser beschriebenen Schritte untersuchen. In zwei großen Patientengruppen (die erste mit HIV-1 und die zweite mit HCV infiziert) identifizierten wir virale Escape-Mutationen und damit potentielle Immun-Epitope. Wir untersuchten die möglichen Auswirkungen des HLA-Genotypes auf die Entwicklung von Resistenz-Mutationen (HIV-1) und den Erfolg einer antiviralen Therapie (HCV). Um die stabile Bindung von Peptiden an HLA-Moleküle besser zu verstehen, untersuchten wir die Leistung verschiedener HLA-Klasse I-Prognoseverfahren und zeigten, dass alle führenden Methoden gute bis sehr gute Ergebnisse liefern können. Abschließend haben wir die ersten Algorithmen entwickelt, die die Interaktionen zwischen den Aminosäuren der CDR-Schleifen des T-Zell-Rezeptors und Aminosäuren des HLA-Peptid-Komplexes vorhersagen. Diese Algorithmen zeigten gute Leistung unter Cross-Validierung

Age at onset as stratifier in idiopathic Parkinson’s disease – effect of ageing and polygenic risk score on clinical phenotypes

Several phenotypic differences observed in Parkinson’s disease (PD) patients have been linked to age at onset (AAO). We endeavoured to find out whether these differences are due to the ageing process itself by using a combined dataset of idiopathic PD (n = 430) and healthy controls (HC; n = 556) excluding carriers of known PD-linked genetic mutations in both groups. We found several significant effects of AAO on motor and non-motor symptoms in PD, but when comparing the effects of age on these symptoms with HC (using age at assessment, AAA), only positive associations of AAA with burden of motor symptoms and cognitive impairment were significantly different between PD vs HC. Furthermore, we explored a potential effect of polygenic risk score (PRS) on clinical phenotype and identified a significant inverse correlation of AAO and PRS in PD. No significant association between PRS and severity of clinical symptoms was found. We conclude that the observed non-motor phenotypic differences in PD based on AAO are largely driven by the ageing process itself and not by a specific profile of neurodegeneration linked to AAO in the idiopathic PD patients

Immunoinformatik : Analyse von viraler Flucht, Epitopbindung und T-Zell-Rezeptor-Erkennung

It has been shown repeatedly that infectious diseases in humans have strong associations with the human leukocyte antigen system, but an understanding of the basis of these associations remains elusive. Adaptive immune responses involving CD4 and CD8 T lymphocytes are dependent on (1) the appropriate and effective processing of a peptide from a protein source, (2) the stable binding of the peptide to the HLA molecule and (3) the recognition of this complex by the T cell receptor. In this thesis, we present work helping to better define such host-virus dynamics, examining aspects relating to each of the described steps. We examined two large patient cohorts, the first infected with HIV-1 and the second with HCV. We identified viral escape mutations and thus potential immune epitopes. Also, we examined the possible effects of HLA genotypes on the development of drug resistance mutations (HIV-1) and the success of antiviral therapy (HCV). To better understand the stable binding of peptides to HLA molecules, we evaluated the performance of diverse HLA class I prediction methods on large datasets, showing that all leading methods are capable of good to excellent performance. Finally, we developed the first algorithms, based on the interactions found in actual experimental structures, which allow for the prediction of interactions between residues in the T cell receptor's CDR loops and residues in the HLA-peptide antigen. The algorithms had good performance under cross-validation.Wiederholt wurden viele Zusammenhänge menschlicher Infektionskrankheiten mit dem Human-Leukozyten-Antigen-System aufgezeigt, doch ein vollständiges Verständnis dieser Zusammenhänge fehlt. Adaptive Immunantworten mit CD4- und CD8-T-Lymphozyten sind abhängig von (1) einer angemessenen und effektiven Bearbeitung eines Peptids, (2) der stabilen Bindung des Peptids an das HLA-Molekül und (3) der Erkennung dieses HLA-Peptid-Komplexes durch den T-Zell-Rezeptor. In dieser Dissertation präsentieren wir Arbeiten, die helfen, diese Wirt-Virus-Dynamik besser zu definieren, indem wir Aspekte jedes dieser beschriebenen Schritte untersuchen. In zwei großen Patientengruppen (die erste mit HIV-1 und die zweite mit HCV infiziert) identifizierten wir virale Escape-Mutationen und damit potentielle Immun-Epitope. Wir untersuchten die möglichen Auswirkungen des HLA-Genotypes auf die Entwicklung von Resistenz-Mutationen (HIV-1) und den Erfolg einer antiviralen Therapie (HCV). Um die stabile Bindung von Peptiden an HLA-Moleküle besser zu verstehen, untersuchten wir die Leistung verschiedener HLA-Klasse I-Prognoseverfahren und zeigten, dass alle führenden Methoden gute bis sehr gute Ergebnisse liefern können. Abschließend haben wir die ersten Algorithmen entwickelt, die die Interaktionen zwischen den Aminosäuren der CDR-Schleifen des T-Zell-Rezeptors und Aminosäuren des HLA-Peptid-Komplexes vorhersagen. Diese Algorithmen zeigten gute Leistung unter Cross-Validierung

Digitale Transformation logistischer Prozesse in kleinen und mittleren Unternehmen im ländlichen Raum

Auch für kleine und mittelständische Unternehmen spielt die Digitalisierung eine große Rolle. Der Beitrag geht auf die Besonderheiten von KMU - inbesondere im ländlichen Raum ein und schildert die Bedeutung der digitalen Transformation. Es werden technologische Voraussetzungen vorgestellt und digitale Reifegradmodelle auf ihre Eignung für die besonderen Bedingungen in KMU analysiert

Digitalisierung von logistischen Prozessen in KMU im ländlichen Raum

kein Abstract vorhande

Gene regulatory network analysis supports inflammation as a key neurodegeneration process in prion disease.

The activation of immune cells in the brain is believed to be one of the earliest events in prion disease development, where misfolded PrionSc protein deposits are thought to act as irritants leading to a series of events that culminate in neuronal cell dysfunction and death. The role of these events in prion disease though is still a matter of debate. To elucidate the mechanisms leading from abnormal protein deposition to neuronal injury, we have performed a detailed network analysis of genes differentially expressed in several mouse prion model

Drop impact on hot plates: contact times, lift-off and the lamella rupture

When a liquid drop impacts on a heated substrate, it can remain deposited, or violently boil in contact, or lift off with or without ever touching the surface. The latter is known as the Leidenfrost effect. The duration and area of the liquid-substrate contact are highly relevant for the heat transfer, as well as other effects such as corrosion. However, most experimental studies rely on side view imaging to determine contact times, and those are often mixed with the time until the drop lifts off from the substrate. Here, we develop and validate a reliable method of contact time determination using high-speed X-ray imaging and total internal reflection imaging. We exemplarily compare contact and lift-off times on flat silicon and sapphire substrates. We show that drops can rebound even without formation of a complete vapor layer, with a wide range of lift-off times. On sapphire, we find a local minimum of lift-off times that is much shorter than expected from capillary rebound in the comparatively low-temperature regime of transition boiling/thermal atomization. We elucidate the underlying mechanism related to spontaneous rupture of the lamella and receding of the contact area.11Nsciescopu

Downward jetting of a dynamic Leidenfrost drop

Jetting is a universal phenomenon frequently observed in nature and industries, for instance, in rain drop impact, inkjet printing, spray cooling, fuel atomization, etc. In drop impact on a superheated surface, we observe the formation of a vapor cavity beneath the dynamic Leidenfrost drop and a consecutive downward ejection of a jet into the cavity using ultrafast x-ray phase contrast imaging. We reveal that the cavity is induced mostly by the retraction of the drop and the jetting is caused by the convergence of capillary waves along the liquid-cavity interface. We find a jetting criterion based on the viscous damping of capillary waves: [OhWe(2)] <= 66 +/- 10. These results can provide important insight that leads to understanding and modeling of jets in nature.11Nsciescopu

Mutations in ABC1 in Tangier disease and familial high-density lipoprotein deficiency

Genes have a major role in the control of high-density lipoprotein (HDL) cholesterol (HDL-C) levels. Here we have identified two Tangier disease (TD) families, confirmed 9q31 linkage and refined the disease locus to a limited genomic region containing the gene encoding the ATP-binding cassette transporter (ABC1). Familial HDL deficiency (FHA) is a more frequent cause of low HDL levels. On the basis of independent linkage and meiotic recombinants, we localized the FHA locus to the same genomic region as the TD locus. Mutations in ABC1 were detected in both TD and FHA, indicating that TD and FHA are allelic. This indicates that the protein encoded by ABC1 is a key gatekeeper influencing intracellular cholesterol transport, hence we have named it cholesterol efflux regulatory protein (CERP