Regulation von Adipocyte fatty acid binding protein in Abhängigkeit der Nierenfunktion

Adipositas und die damit verbundenen Folgeerkrankungen sind eine der zentralen Gesund-heitsherausforderungen unserer Zeit. Dauerhafte Adipositas führt zu einer Dysregulation fettgewebseigener Peptidhormone. Diese sogenannten Adipokine stellen ein Verbindungsglied zwischen Fettgewebsakkumulation und den vielfältigen Adipositaskomplikationen des gesamten Organismus dar. Adipocyte fatty acid binding protein (AFABP) wurde in den letzten Jahren als zirkulierendes Adipokin mit diabetogenen, proinflammatorischen und proateriosklerotischen Effekten etabliert. Zu Beginn der Dissertation lagen unzureichende Erkenntnisse über die Elimination von AFABP sowie die Regulation des Adipokins bei eingeschränkter Nierenfunktion vor. Aus diesem Grund untersucht die vorliegende Arbeit die AFABP-Regulation in Abhängigkeit von der Nierenfunktion in 532 Patienten mit chronischer Niereninsuffizienz (Studienpopulation 1) und 32 Patienten mit akuter Nierenfunktionsverminderung nach Nephrektomie (Studienpopulation 2). In beiden Kohorten stiegen die medianen AFABP-Serumkonzentrationen mit abfallender Nierenfunktion an. Zudem waren Marker der Nierenfunktion in beiden Studienpopulationen die stärksten unabhängigen Prädiktoren für zirkulierendes AFABP. Untersuchungen aus der Arbeitsgruppe zur AFABP-Regulation in einem Rattenmodell der akuten Niereninsuffizienz unterstützen die klinischen Studienergebnisse. Zusammenfassend zeigen diese Ergebnisse zum ersten Mal signifikant steigende AFABP-Serumspiegel bei chronischer und akuter Nierenfunktionsstörung, sowie bei akutem Abfall der Nierenfunktion. Diese Befunde stützen die Hypothese, dass AFABP renal eliminiert wird. Inwiefern AFABP darüber hinaus in die Pathogenese der chronischen Niereninsuffizienz eingreift, muss in weiterführenden Studien beleuchtet werden

Regulation von Adipocyte fatty acid binding protein in Abhängigkeit der Nierenfunktion

Adipositas und die damit verbundenen Folgeerkrankungen sind eine der zentralen Gesund-heitsherausforderungen unserer Zeit. Dauerhafte Adipositas führt zu einer Dysregulation fettgewebseigener Peptidhormone. Diese sogenannten Adipokine stellen ein Verbindungsglied zwischen Fettgewebsakkumulation und den vielfältigen Adipositaskomplikationen des gesamten Organismus dar. Adipocyte fatty acid binding protein (AFABP) wurde in den letzten Jahren als zirkulierendes Adipokin mit diabetogenen, proinflammatorischen und proateriosklerotischen Effekten etabliert. Zu Beginn der Dissertation lagen unzureichende Erkenntnisse über die Elimination von AFABP sowie die Regulation des Adipokins bei eingeschränkter Nierenfunktion vor. Aus diesem Grund untersucht die vorliegende Arbeit die AFABP-Regulation in Abhängigkeit von der Nierenfunktion in 532 Patienten mit chronischer Niereninsuffizienz (Studienpopulation 1) und 32 Patienten mit akuter Nierenfunktionsverminderung nach Nephrektomie (Studienpopulation 2). In beiden Kohorten stiegen die medianen AFABP-Serumkonzentrationen mit abfallender Nierenfunktion an. Zudem waren Marker der Nierenfunktion in beiden Studienpopulationen die stärksten unabhängigen Prädiktoren für zirkulierendes AFABP. Untersuchungen aus der Arbeitsgruppe zur AFABP-Regulation in einem Rattenmodell der akuten Niereninsuffizienz unterstützen die klinischen Studienergebnisse. Zusammenfassend zeigen diese Ergebnisse zum ersten Mal signifikant steigende AFABP-Serumspiegel bei chronischer und akuter Nierenfunktionsstörung, sowie bei akutem Abfall der Nierenfunktion. Diese Befunde stützen die Hypothese, dass AFABP renal eliminiert wird. Inwiefern AFABP darüber hinaus in die Pathogenese der chronischen Niereninsuffizienz eingreift, muss in weiterführenden Studien beleuchtet werden

Comparison between phosphine and NHC-modified Pd catalysts in the telomerization of butadiene with methanol – a kinetic study combined with model-based experimental analysis

The authors thank the European Community within its project SYNFLOW (FP7; grant agreement n8 NMP2-LA-2010-246461) for financial support.The telomerization of butadiene with methanol was investigated in the presence of different palladium catalysts modified either with triphenylphosphine (TPP) or 1,3-dimesityl-imidazol-2-ylidene (IMes) ligand. When pure butadiene was used as substrate, a moderate selectivity for the Pd-TPP catalyst toward the desired product 1-methoxy-2,7-octadiene (1-Mode) of around 87 % was obtained, while the IMes carbene ligand almost exclusively formed 1-Mode with 97.5 % selectivity. The selectivity remained unchanged when the pure butadiene feed was replaced by synthetic crack-C4 (sCC4), a technical feed of 45 mol% butadiene and 55 mol% inerts (butenes and butanes). The TPP-modified catalyst showed a lower reaction rate, which was attributed to the expected dilution effect caused by the inerts. Surprisingly, the IMes-modified catalyst showed a higher rate with sCC4 compared to the pure feed. By means of a model-based experimental analysis, kinetic rate equations could be derived. The kinetic modeling supports the assumption that the two catalyst systems follow different kinetic rate equations. For the Pd-TPP catalyst, the reaction kinetics were related to the Jolly mechanism. In contrast, the Jolly mechanism had to be adapted for the Pd-IMes catalyst as the impact of the base seems to differ strongly from that for the Pd-TPP catalyst. The Pd-IMes system was found to be zero order in butadiene at moderate to high butadiene concentrations and first order in base while the nucleophilicity of the base is influenced by the methanol amount resulting in a negative reaction order for methanol.PostprintPeer reviewe

pH‐dependent protonation of surface carboxylate groups in PsbO enables local buffering and triggers structural changes

Photosystem II (PSII) catalyzes the splitting of water, releasing protons and dioxygen. Its highly conserved subunit PsbO extends from the oxygen‐evolving center (OEC) into the thylakoid lumen and stabilizes the catalytic Mn4CaO5 cluster. The high degree of conservation of accessible negatively charged surface residues in PsbO suggests additional functions, as local pH buffer or by affecting the flow of protons. For this discussion, we provide an experimental basis, through the determination of pKa values of water‐accessible aspartate and glutamate side‐chain carboxylate groups by means of NMR. Their distribution is strikingly uneven, with high pKa values around 4.9 clustered on the luminal PsbO side and values below 3.5 on the side facing PSII. pH‐dependent changes in backbone chemical shifts in the area of the lumen‐exposed loops are observed, indicating conformational changes. In conclusion, we present a site‐specific analysis of carboxylate group proton affinities in PsbO, providing a basis for further understanding of proton transport in photosynthesis

The Atypical Calpains: Evolutionary Analyses and Roles in Caenorhabditis elegans Cellular Degeneration

The calpains are physiologically important Ca2+-activated regulatory proteases, which are divided into typical or atypical sub-families based on constituent domains. Both sub-families are present in mammals, but our understanding of calpain function is based primarily on typical sub-family members. Here, we take advantage of the model organism Caenorhabditis elegans, which expresses only atypical calpains, to extend our knowledge of the phylogenetic evolution and function of calpains. We provide evidence that a typical human calpain protein with a penta EF hand, detected using custom profile hidden Markov models, is conserved in ancient metazoans and a divergent clade. These analyses also provide evidence for the lineage-specific loss of typical calpain genes in C. elegans and Ciona, and they reveal that many calpain-like genes lack an intact catalytic triad. Given the association between the dysregulation of typical calpains and human degenerative pathologies, we explored the phenotypes, expression profiles, and consequences of inappropriate reduction or activation of C. elegans atypical calpains. These studies show that the atypical calpain gene, clp-1, contributes to muscle degeneration and reveal that clp-1 activity is sensitive to genetic manipulation of [Ca2+]i. We show that CLP-1 localizes to sarcomeric sub-structures, but is excluded from dense bodies (Z-disks). We find that the muscle degeneration observed in a C. elegans model of dystrophin-based muscular dystrophy can be suppressed by clp-1 inactivation and that nemadipine-A inhibition of the EGL-19 calcium channel reveals that Ca2+ dysfunction underlies the C. elegans MyoD model of myopathy. Taken together, our analyses highlight the roles of calcium dysregulation and CLP-1 in muscle myopathies and suggest that the atypical calpains could retain conserved roles in myofilament turnover

Global age-sex-specific fertility, mortality, healthy life expectancy (HALE), and population estimates in 204 countries and territories, 1950-2019 : a comprehensive demographic analysis for the Global Burden of Disease Study 2019

Background: Accurate and up-to-date assessment of demographic metrics is crucial for understanding a wide range of social, economic, and public health issues that affect populations worldwide. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019 produced updated and comprehensive demographic assessments of the key indicators of fertility, mortality, migration, and population for 204 countries and territories and selected subnational locations from 1950 to 2019. Methods: 8078 country-years of vital registration and sample registration data, 938 surveys, 349 censuses, and 238 other sources were identified and used to estimate age-specific fertility. Spatiotemporal Gaussian process regression (ST-GPR) was used to generate age-specific fertility rates for 5-year age groups between ages 15 and 49 years. With extensions to age groups 10–14 and 50–54 years, the total fertility rate (TFR) was then aggregated using the estimated age-specific fertility between ages 10 and 54 years. 7417 sources were used for under-5 mortality estimation and 7355 for adult mortality. ST-GPR was used to synthesise data sources after correction for known biases. Adult mortality was measured as the probability of death between ages 15 and 60 years based on vital registration, sample registration, and sibling histories, and was also estimated using ST-GPR. HIV-free life tables were then estimated using estimates of under-5 and adult mortality rates using a relational model life table system created for GBD, which closely tracks observed age-specific mortality rates from complete vital registration when available. Independent estimates of HIV-specific mortality generated by an epidemiological analysis of HIV prevalence surveys and antenatal clinic serosurveillance and other sources were incorporated into the estimates in countries with large epidemics. Annual and single-year age estimates of net migration and population for each country and territory were generated using a Bayesian hierarchical cohort component model that analysed estimated age-specific fertility and mortality rates along with 1250 censuses and 747 population registry years. We classified location-years into seven categories on the basis of the natural rate of increase in population (calculated by subtracting the crude death rate from the crude birth rate) and the net migration rate. We computed healthy life expectancy (HALE) using years lived with disability (YLDs) per capita, life tables, and standard demographic methods. Uncertainty was propagated throughout the demographic estimation process, including fertility, mortality, and population, with 1000 draw-level estimates produced for each metric. Findings: The global TFR decreased from 2·72 (95% uncertainty interval [UI] 2·66–2·79) in 2000 to 2·31 (2·17–2·46) in 2019. Global annual livebirths increased from 134·5 million (131·5–137·8) in 2000 to a peak of 139·6 million (133·0–146·9) in 2016. Global livebirths then declined to 135·3 million (127·2–144·1) in 2019. Of the 204 countries and territories included in this study, in 2019, 102 had a TFR lower than 2·1, which is considered a good approximation of replacement-level fertility. All countries in sub-Saharan Africa had TFRs above replacement level in 2019 and accounted for 27·1% (95% UI 26·4–27·8) of global livebirths. Global life expectancy at birth increased from 67·2 years (95% UI 66·8–67·6) in 2000 to 73·5 years (72·8–74·3) in 2019. The total number of deaths increased from 50·7 million (49·5–51·9) in 2000 to 56·5 million (53·7–59·2) in 2019. Under-5 deaths declined from 9·6 million (9·1–10·3) in 2000 to 5·0 million (4·3–6·0) in 2019. Global population increased by 25·7%, from 6·2 billion (6·0–6·3) in 2000 to 7·7 billion (7·5–8·0) in 2019. In 2019, 34 countries had negative natural rates of increase; in 17 of these, the population declined because immigration was not sufficient to counteract the negative rate of decline. Globally, HALE increased from 58·6 years (56·1–60·8) in 2000 to 63·5 years (60·8–66·1) in 2019. HALE increased in 202 of 204 countries and territories between 2000 and 2019

Global burden of 369 diseases and injuries in 204 countries and territories, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019

Background: In an era of shifting global agendas and expanded emphasis on non-communicable diseases and injuries along with communicable diseases, sound evidence on trends by cause at the national level is essential. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) provides a systematic scientific assessment of published, publicly available, and contributed data on incidence, prevalence, and mortality for a mutually exclusive and collectively exhaustive list of diseases and injuries. Methods: GBD estimates incidence, prevalence, mortality, years of life lost (YLLs), years lived with disability (YLDs), and disability-adjusted life-years (DALYs) due to 369 diseases and injuries, for two sexes, and for 204 countries and territories. Input data were extracted from censuses, household surveys, civil registration and vital statistics, disease registries, health service use, air pollution monitors, satellite imaging, disease notifications, and other sources. Cause-specific death rates and cause fractions were calculated using the Cause of Death Ensemble model and spatiotemporal Gaussian process regression. Cause-specific deaths were adjusted to match the total all-cause deaths calculated as part of the GBD population, fertility, and mortality estimates. Deaths were multiplied by standard life expectancy at each age to calculate YLLs. A Bayesian meta-regression modelling tool, DisMod-MR 2.1, was used to ensure consistency between incidence, prevalence, remission, excess mortality, and cause-specific mortality for most causes. Prevalence estimates were multiplied by disability weights for mutually exclusive sequelae of diseases and injuries to calculate YLDs. We considered results in the context of the Socio-demographic Index (SDI), a composite indicator of income per capita, years of schooling, and fertility rate in females younger than 25 years. Uncertainty intervals (UIs) were generated for every metric using the 25th and 975th ordered 1000 draw values of the posterior distribution. Findings: Global health has steadily improved over the past 30 years as measured by age-standardised DALY rates. After taking into account population growth and ageing, the absolute number of DALYs has remained stable. Since 2010, the pace of decline in global age-standardised DALY rates has accelerated in age groups younger than 50 years compared with the 1990–2010 time period, with the greatest annualised rate of decline occurring in the 0–9-year age group. Six infectious diseases were among the top ten causes of DALYs in children younger than 10 years in 2019: lower respiratory infections (ranked second), diarrhoeal diseases (third), malaria (fifth), meningitis (sixth), whooping cough (ninth), and sexually transmitted infections (which, in this age group, is fully accounted for by congenital syphilis; ranked tenth). In adolescents aged 10–24 years, three injury causes were among the top causes of DALYs: road injuries (ranked first), self-harm (third), and interpersonal violence (fifth). Five of the causes that were in the top ten for ages 10–24 years were also in the top ten in the 25–49-year age group: road injuries (ranked first), HIV/AIDS (second), low back pain (fourth), headache disorders (fifth), and depressive disorders (sixth). In 2019, ischaemic heart disease and stroke were the top-ranked causes of DALYs in both the 50–74-year and 75-years-and-older age groups. Since 1990, there has been a marked shift towards a greater proportion of burden due to YLDs from non-communicable diseases and injuries. In 2019, there were 11 countries where non-communicable disease and injury YLDs constituted more than half of all disease burden. Decreases in age-standardised DALY rates have accelerated over the past decade in countries at the lower end of the SDI range, while improvements have started to stagnate or even reverse in countries with higher SDI. Interpretation: As disability becomes an increasingly large component of disease burden and a larger component of health expenditure, greater research and developm nt investment is needed to identify new, more effective intervention strategies. With a rapidly ageing global population, the demands on health services to deal with disabling outcomes, which increase with age, will require policy makers to anticipate these changes. The mix of universal and more geographically specific influences on health reinforces the need for regular reporting on population health in detail and by underlying cause to help decision makers to identify success stories of disease control to emulate, as well as opportunities to improve. Funding: Bill & Melinda Gates Foundation. © 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 licens

Temporal and spatial analysis of the 2014-2015 Ebola virus outbreak in West Africa

West Africa is currently witnessing the most extensive Ebola virus (EBOV) outbreak so far recorded. Until now, there have been 27,013 reported cases and 11,134 deaths. The origin of the virus is thought to have been a zoonotic transmission from a bat to a two-year-old boy in December 2013 (ref. 2). From this index case the virus was spread by human-to-human contact throughout Guinea, Sierra Leone and Liberia. However, the origin of the particular virus in each country and time of transmission is not known and currently relies on epidemiological analysis, which may be unreliable owing to the difficulties of obtaining patient information. Here we trace the genetic evolution of EBOV in the current outbreak that has resulted in multiple lineages. Deep sequencing of 179 patient samples processed by the European Mobile Laboratory, the first diagnostics unit to be deployed to the epicentre of the outbreak in Guinea, reveals an epidemiological and evolutionary history of the epidemic from March 2014 to January 2015. Analysis of EBOV genome evolution has also benefited from a similar sequencing effort of patient samples from Sierra Leone. Our results confirm that the EBOV from Guinea moved into Sierra Leone, most likely in April or early May. The viruses of the Guinea/Sierra Leone lineage mixed around June/July 2014. Viral sequences covering August, September and October 2014 indicate that this lineage evolved independently within Guinea. These data can be used in conjunction with epidemiological information to test retrospectively the effectiveness of control measures, and provides an unprecedented window into the evolution of an ongoing viral haemorrhagic fever outbreak.status: publishe

Global, regional, and national burden of disorders affecting the nervous system, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021

BackgroundDisorders affecting the nervous system are diverse and include neurodevelopmental disorders, late-life neurodegeneration, and newly emergent conditions, such as cognitive impairment following COVID-19. Previous publications from the Global Burden of Disease, Injuries, and Risk Factor Study estimated the burden of 15 neurological conditions in 2015 and 2016, but these analyses did not include neurodevelopmental disorders, as defined by the International Classification of Diseases (ICD)-11, or a subset of cases of congenital, neonatal, and infectious conditions that cause neurological damage. Here, we estimate nervous system health loss caused by 37 unique conditions and their associated risk factors globally, regionally, and nationally from 1990 to 2021.MethodsWe estimated mortality, prevalence, years lived with disability (YLDs), years of life lost (YLLs), and disability-adjusted life-years (DALYs), with corresponding 95% uncertainty intervals (UIs), by age and sex in 204 countries and territories, from 1990 to 2021. We included morbidity and deaths due to neurological conditions, for which health loss is directly due to damage to the CNS or peripheral nervous system. We also isolated neurological health loss from conditions for which nervous system morbidity is a consequence, but not the primary feature, including a subset of congenital conditions (ie, chromosomal anomalies and congenital birth defects), neonatal conditions (ie, jaundice, preterm birth, and sepsis), infectious diseases (ie, COVID-19, cystic echinococcosis, malaria, syphilis, and Zika virus disease), and diabetic neuropathy. By conducting a sequela-level analysis of the health outcomes for these conditions, only cases where nervous system damage occurred were included, and YLDs were recalculated to isolate the non-fatal burden directly attributable to nervous system health loss. A comorbidity correction was used to calculate total prevalence of all conditions that affect the nervous system combined.FindingsGlobally, the 37 conditions affecting the nervous system were collectively ranked as the leading group cause of DALYs in 2021 (443 million, 95% UI 378–521), affecting 3·40 billion (3·20–3·62) individuals (43·1%, 40·5–45·9 of the global population); global DALY counts attributed to these conditions increased by 18·2% (8·7–26·7) between 1990 and 2021. Age-standardised rates of deaths per 100 000 people attributed to these conditions decreased from 1990 to 2021 by 33·6% (27·6–38·8), and age-standardised rates of DALYs attributed to these conditions decreased by 27·0% (21·5–32·4). Age-standardised prevalence was almost stable, with a change of 1·5% (0·7–2·4). The ten conditions with the highest age-standardised DALYs in 2021 were stroke, neonatal encephalopathy, migraine, Alzheimer's disease and other dementias, diabetic neuropathy, meningitis, epilepsy, neurological complications due to preterm birth, autism spectrum disorder, and nervous system cancer.InterpretationAs the leading cause of overall disease burden in the world, with increasing global DALY counts, effective prevention, treatment, and rehabilitation strategies for disorders affecting the nervous system are needed

Development of a continuous process for the telomerization of butadiene with methanol

The basic aim of this thesis was the development of a continuous process for the telomerization reaction of butadiene with methanol applying ionic liquids in a biphasic reaction system. Besides this aim, the applicability of NIR spectroscopy for determination of concentrations in reaction mixtures of a homogeneously catalyzed reaction was tested. Furthermore, its applicability in ionic liquid mixtures was studied. The thesis was divided into three parts. The first part comprised the study of NIR spectroscopy in mixtures of the investigated telomerization reaction. In the second part, the telomerization of butadiene with methanol was examined without ionic liquids. The immobilization of the catalyst in the ionic liquid phase and the transfer from batch to conti were studied in the last part. The feasibility and applicability of NIR spectroscopy for the telomerization reaction in monophasic as well as biphasic reaction systems with ionic liquids was shown in this thesis. But also the limitations of NIR spectroscopy were shown. This study could clearly point out that every parameter change has to be considered in the calibration model to receive a robust and flexible calibration. In addition, NIR spectroscopy struggles with components at very low concentrations due to the low intensity of absorption and the broad and overlapping signals. In the second part of this thesis experiments without ionic liquid were carried out in order to compare the two literature known ligands, namely TPP and IMes, in combination with pure butadiene and the technical, diluted butadiene feed (sCC4). In addition, the influence of different reaction parameters was studied in order to optimize the reaction conditions for each ligand. At the same reaction conditions, the two ligands showed a completely different behavior in combination with both feeds. The Pd-TPP catalyst exhibited a higher reaction rate with pure butadiene than with the diluted feed, sCC4. The components of the technical feed, mainly butenes and butanes, were proven to be inert in the telomerization reaction. Thus, the observed behavior for the TPP based catalyst was caused by the expected dilution effect of inert components. In contrast, the Pd-IMes catalyst showed higher conversion values in combination with the diluted feed. The reaction rate was observed to be similar for both feeds resembling an overall reaction of zero order in butadiene. This differing behavior of TPP and IMes was found for all following experiments of this thesis. Based on the experimental observations, a kinetic model was derived on the basis of the Jolly mechanism in cooperation with the SYNFLOW partner RWTH Aachen. For the TPP based catalyst, a reaction order of 2 in butadiene and 1 in methanol was found. For the IMes based catalyst, no kinetic model based on the Jolly mechanism was found which fit the experimental data. Further kinetic experiments showed that the IMes based catalyst is independent of the butadiene concentration but strongly dependent on the base concentration. Methanol has a negative effect on the reaction which might be explained by the influence of this protic solvent on the nucleophilicity of the base. With this knowledge, the Jolly mechanism was adapted and a kinetic model could be derived. The transfer from the batch autoclave to the loop reactor and the commissioning of the latter were successfully carried out for monophasic experiments. The next step for the development of a continuous process was the study of the telomerization reaction in a biphasic reaction system. Here, the choice of the ionic liquid is crucial due to the exhibited extraction efficiency. For a preselection of ionic liquids, a screening of 960 different anion-cation combinations with the computational tool COSMO-RS was carried out. By experimental validation of 9 ionic liquids, the trends of the predicted extraction efficiencies were proven to be in accordance with the experimental obtained tendencies. The activity of these ionic liquids in the telomerization reaction was studied by a screening of 8 different ionic liquids in combination with a screening of different ligands. The extraction efficiency and the activity in the telomerization reaction were observed to be completely independent. The leaching of the Pd-TPP and Pd-IMes catalyst into the organic phase was too high due to the missing ionic groups. Consequently, sulfonated derivatives of the phosphine ligand were tested as well. The transfer to the loop reactor was carried out using the Pd-TPPMS catalyst and the ionic liquid [BMMIM][NTf2]. In order to further increase the immobilization ability of the Pd-catalyst in the ionic liquid, various optimization steps were carried out. The most efficient optimization step was the change of the ligand from the monosulfonated to the threefold sulfonated phosphine ligand. Although the activity was distinctly lower compared to the continuous runs with the TPPMS modified catalyst, the time on stream and thus the stability of the system increased significantly. The maximum conversion of around 45 % was kept constant for more than 200 hours. With this successful continuous experiment, the challenge of the catalyst immobilization concerning the reactant methanol was met by applying a biphasic reaction system with ionic liquids in combination with ionic ligands. A continuous process which yielded constant activity over 200 h time on stream was successfully established. Thus, the basic aim of this thesis to develop a continuous process for the telomerization of butadiene with methanol was achieved.Ziel dieser Arbeit war die Entwicklung eines kontinuierlichen Prozesses für die Telomerisation von Butadien mit Methanol unter Verwendung eines zweiphasigen Reaktionssystems mit ionischen Flüssigkeiten. Ein weiteres Ziel war es, die Konzentrationsbestimmung online mit Hilfe der NIR-Spektroskopie sowohl in einphasig homogen katalysierten Reaktionen als auch in Reaktionsgemischen mit ionischen Flüssigkeiten zu testen. Aufgrund dieser Aufgabenstellung wurde die vorliegende Arbeit in drei Hauptteile unterteilt. Im ersten Teil wurde die Anwendung der NIR-Spektroskopie untersucht. Der zweite Teil beinhaltete grundlegende Untersuchungen der Telomerisation von Butadien mit Methanol ohne den Einsatz von ionischen Flüssigkeiten. Die Übertragung der Telomerisation in ein zweiphasiges Reaktionssystem mit ionischen Flüssigkeiten und der Transfer vom Batch- zum kontinuierlichen Betrieb wurden im dritten Teil thematisiert Die Anwendung der NIR-Spektroskopie in einphasigen als auch in zweiphasigen Telomerisationssystemen mit ionischen Flüssigkeiten konnte in dieser Arbeit erfolgreich gezeigt werden. Nichtsdestotrotz wurden auch entsprechende Limitierungen herausgearbeitet. Um eine robuste und flexible Kalibrierung zu erhalten, muss jede Parameteränderung bzw. Störung im Kalibriermodell berücksichtigt werden. Des Weiteren ist die Bestimmung für Komponenten mit niedrigen Konzentrationen aufgrund der geringen Absorptionsintensitäten und der überlappenden Signale nur bedingt möglich. Im zweiten Teil der Arbeit wurden Versuche ohne ionische Flüssigkeit durchgeführt, um die beiden literaturbekannten Liganden TPP und IMes mit reinem Butadien und sCC4, einem verdünnten, technischen Feed, zu vergleichen. Des Weiteren wurden verschiedene Reaktionsparameter variiert, um die optimalen Reaktionsbedingungen für jedes einzelne Reaktionssystem zu erarbeiten. Bei gleichen Reaktionsbedingungen zeigten die beiden Liganden ein deutlich unterschiedliches Verhalten. Für den Pd-TPP Katalysator wurde mit reinem Butadien eine deutlich höhere Reaktionsrate erreicht als mit sCC4. Durch weitere Versuche wurde gezeigt, dass alle zusätzlichen Komponenten im sCC4 (Butene und Butane) inerten Charakter in der Telomerisation aufwiesen. Demzufolge lag der Grund für die erwähnte geringere Reaktionsrate mit dem Butadiengemisch in einem Verdünnungseffekt durch die inerten Komponenten. Im Gegensatz zum Pd-TPP System zeigte der Pd-IMes Katalysator ein umgekehrtes Verhalten. Mit reinem Butadien lag der Umsatzverlauf unter dem mit sCC4. Ein Vergleich der Reaktionsraten zeigte, dass diese bis zum jeweiligen Vollumsatz nahezu gleich waren. Der lineare Verlauf der Reaktionsraten deutete darauf hin, dass die Telomerisation für den Pd-IMes Katalysator eine Gesamtreaktionsordnung von 0 aufweist. Dieses beschriebene, unterschiedliche Verhalten der beiden Katalysatorsysteme wurde in allen folgenden Versuchen zur Reaktionsoptimierung beobachtet. Basierend auf diesen Ergebnissen wurden in Zusammenarbeit mit dem SYNFLOW Partner RWTH Aachen kinetische Modelle für die beiden Katalysatorsysteme erstellt. Die Modellierung wurde auf Basis des Jolly Mechanismus durchgeführt. Hierbei wurden für das Pd-TPP System Reaktionsordnungen von 2 in Butadien und 1 in Methanol ermittelt. Die Herleitung eines kinetischen Modells für den Pd-IMes Katalysator war auf Basis des Jolly Mechanismus nicht möglich. Weitere kinetische Untersuchungen zeigten, dass der Pd-IMes Katalysator unabhängig von der Butadienkonzentration ist, allerdings eine starke Abhängigkeit von der Base sowie ein negativer Einfluss durch Methanol vorliegt. Dieser negative Einfluss des Methanols ist wahrscheinlich begründet im Einfluss des protischen Lösungsmittels auf die Nukleophilität der Base. Mit diesem Wissen konnte der Jolly Mechanismus angepasst und ein kinetisches Modell hergeleitet werden, welches die experimentellen Daten sehr gut wiedergibt. Der Transfer vom Batch-Autoklaven zum Schlaufenreaktor und die Inbetriebnahme des Schlaufenreaktors wurden für einphasige Versuche erfolgreich durchgeführt. Der nächste Schritt zur Entwicklung eines kontinuierlichen Prozesses waren Experimente im zweiphasigen Reaktionssystem mit ionischen Flüssigkeiten. Für die Anwendung eines zweiphasigen Reaktionssystems als Immobilisierungskonzept ist die Wahl der Katalysatorphase wichtig. Diese sollte eine gute Extraktionseigenschaft für die entstehenden Produkte aufweisen. Um eine Vorauswahl der ionischen Flüssigkeit zu treffen, wurde ein Screening von 960 verschiedenen Anion-Kation Kombinationen mit Hilfe der computerbasierten Methode COSMO-RS durchgeführt. Die vorhergesagten Trends der Extraktionseigenschaften wurden im Anschluss mit 9 ionischen Flüssigkeiten erfolgreich validiert. Neben der Extraktionseffizienz einer ionischen Flüssigkeit sollte diese keinen negativen Einfluss auf die katalysierte Reaktion aufweisen. Um den Einfluss auf die Aktivität zu testen, wurden 8 ionische Flüssigkeiten mit verschiedenen Liganden untersucht. Hierbei wurde beobachtet, dass die Extraktionseffizienz und der Einfluss auf die Aktivität unabhängig waren. Da die mit den Liganden TPP und IMes modifizierten Katalysatorkomplexe keine ionischen Gruppen aufweisen, war der Immobilisierungseffekt der ionischen Flüssigkeit nicht ausreichend. Deshalb wurden auch sulfonierte Phosphinliganden, TPPMS, TPPTS und [BMMIM]-TPPMS, getestet. Für den Transfer zum kontinuierlichen Betrieb wurde der TPPMS modifizierte Katalysator und die ionische Flüssigkeit [BMMIM][NTf2] verwendet. Um die Immobilisierungsfähigkeit des Pd-Katalysators in der ionischen Flüssigkeit weiter zu verbessern, wurden verschiedene Optimierungsschritte durchgeführt. Der effizienteste Optimierungsschritt war die Variation des Liganden von TPPMS auf TPPTS. Obwohl die Aktivität deutlich geringer war als mit TPPMS, konnte mit dem TPPTS modifizierten Katalysatorsystem ein langzeitstabiles System entwickelt werden. Der maximale Umsatz von 45 % war mehr als 200 Stunden Prozessdauer konstant. Mit diesem erfolgreichen kontinuierlichen Experiment konnte das Ziel dieser Arbeit auf Basis eines zweiphasigen Reaktionssystems mit ionischen Flüssigkeiten in Kombination mit ionischen Liganden erfolgreich erreicht werden