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Protamine (PRT) is a positively charged protein, which is widely used in medicine as an adjunct to certain preparations of insulin and as a rapidly-acting antidote for heparin, particularly to neutralize the effects of high heparin concentrations needed for anticoagulation during cardiac surgical procedures using cardiopulmonary bypass. It has been demonstrated that PRT and heparin form multimolecular complexes and that these complexes have high immunogenicity in a mouse model. Studies in this thesis provide new insights into the pathophysiology of anti-PRT/heparin antibodies. The results of study I showed that the administration of PRT combined with heparin is responsible for high immunoglobulin G (IgG) immunization after cardiac surgery. A subset of these antibodies was able to induce platelet activation in a way similar to that observed by heparin-induced thrombocytopenia (HIT). Using an animal model, we demonstrated that anti-PRT/heparin antibodies are capable of platelet destruction in the presence of PRT and heparin. Moreover, our data suggests that platelet-activating anti-PRT/heparin antibodies at surgery are potentially associated with postoperative thrombocytopenia and an increased risk for thromboembolic events. In study II, the immune response against PRT/heparin complexes was investigated. This study showed a relatively fast development of IgG with no general preceding IgM formation. In addition, patients undergoing liver transplantation developed anti-PRT/heparin antibodies without previous exposure to PRT. These results suggest that a previous contact with the antigen(s) itself or other antigens with molecular mimicry induced this immune response. In fact, we were able to identify Neutral Protamine Hagedorn (NPH) insulin and core histones (DNA-binding proteins) as potentially antigenic candidates for a previous immunization. Furthermore, the findings of study III demonstrate the ability of anti-PRT/heparin antibodies to activate platelets in the presence of NPH insulin in a heparin-dependent way suggesting that diabetic patients may have an enhanced risk for thromboembolic complications if treated with NPH insulin and possibly while receiving prophylactic heparin. These observations justify further clinical investigations to assess the impact of the interaction between anti-PRT/heparin antibodies and PRT-mimicking antigens, such as NPH insulin or histones.
This thesis deals with thickness optimization of shells. The overall task is to find an optimal thickness distribution in order to minimize the deformation of a loaded shell with prescribed volume. In addition, lower and upper bounds for the thickness are given. The shell is made of elastic, isotropic, homogeneous material. The deformation is modeled using equations from Linear Elasticity. Here, a basic shell model based on the Reissner-Mindlin assumption is used. Both the stationary and the dynamic case are considered. The continuity and the Gâteaux-differentiability of the control-to-state operator is investigated. These results are applied to the reduced objective with help of adjoint theory. In addition, techniques from shape optimization are compared to the optimal control approach. In the following, the theoretical results are applied to cylindrical shells and an efficient numerical implementation is presented. Finally, numerical results are shown and analyzed for different examples.
This thesis draws a comprehensive picture about the radiation and diversification of truncatelloidean gastropods across the south pacific. It covers three more specifc studies focussing on the Truncelloideans from Fiji, Vanuatu and New Caledonia, respectively. And a conclusive analysis that combines the results of the three more specific studies and enhances them using species from the Austral Islands, Lord Howe Island, the Indonesian island Sulawesi as well as several species from New Zealand and Australia. Molecular phylogenies were calculated using four nuclear gene fragments (ITS2; 18S rRNA; 28S rRNA and Histone 3) besides the mitochondrial COI and 16S rRNA. Further molecuular data was used to calculate dated phylogenies, perform ancestral range reconstructions and develop a modified molecular barcoding approach.
All types of muscles use Ca2+ as their main intracellular messenger. In skeletal muscle fibers abnormal levels of intracellular calcium result in altered contractile properties, altered energy metabolism, and altered gene expression. Moreover, long term failure of normal Ca2+ homeostasis can lead to cell death of muscle fibers by necrosis and apoptosis. Elevations of intracellular Ca2+ levels are more and more regarded as the reason for pathological changes and muscle fiber damage in Duchenne Muscular Dystrophy (DMD). DMD is a severe recessive x-linked muscle disease caused by mutations in the dystrophin gene. The characteristics of DMD are muscle tissue wasting and fibrosis. Both muscle wasting and intracellular Ca2+ are to be reflected in changes of muscle force. Several Ca2+ conducting channels including transient receptor potential (TRP) channels are supposed to account for the abnormal Ca2+ homeostasis in DMD. Gene expressions of TRP channels have been studied in human and mouse skeletal muscle and among others TRPC3, TRPC6 and TRPV4 channels were found to occur in skeletal muscles. The present study followed the hypothesis that TRPC3, TRPC6 and TRPV4 are functional in skeletal muscle fibers and that they contribute to muscular Ca2+ homeostasis. Further, it was assumed that dysfunction of the mentioned TRP channels contributes to abnormal contractile properties and pathology and of dystrophin-deficient muscle. To study Ca2+ changes in mouse skeletal muscle fibers the fluorescent calcium indicator Fura-2 was used. Further, the technique of Mn2+ quench of Fura-2 fluorescence was applied. Muscle force measurements of mouse soleus and diaphragm strips were performed. To elucidate abnormalities of TRP channel function in dystrophin-deficient muscle, muscles and muscle fibers of mdx mice were studied. Hyperforin, an activator of TRPC6 channels elicited increases of calcium levels in wildtype muscle fibers. These increases were partly inhibited by the TRPC6 inhibitor 1-(5-chloronaphthalenesulfonyl) homopiperazine hydrochloride (ML-9). The TRPC3/TPRC6 activator 1-oleoyl-2-acetyl-sn-glycerol (OAG) resulted in increased calcium entry, which was attenuated by ML-9. 2-aminoethoxydiphenylborane (2-APB), an unspecific TRP channel inhibitor, suppressed calcium entry in muscle fibers under basal conditions. In addition, the specific TRPC3 inhibitor Pyr3, strongly inhibited background calcium entry. The TRPV4 activator 4α-phorbol 12,13-didecanoate (4α-PDD) induced significant increased calcium entry and this increase could be inhibited by the TRPV4 inhibitor HC 067047. During muscle force recordings ML-9 significantly inhibited twitches and tetani and accelerated muscle fatigue during sustained repetitive stimulation. The results indicate that TRPC3, TRPC6 and TRPV4 are functionally expressed in mouse muscle fibers. TRPC3 stays active under the basal conditions and contributes to background calcium entry. In contrast, TRPC6 and TRPV4 did not seem to be active at resting conditions, but could be pharmacologically activated. TRPC6 may play a role to counteract the calcium loss under long-term muscle fatigue. Though TRPC3 and C6 play a role for muscular Ca2+ homeostasis, it is unclear whether and how the two channels associate and cross-talk with each other in skeletal muscle cells. In mdx fibers Pyr3 inhibited background calcium influx stronger that in WT fibers, implying a possible over-activation of TRPC3 channels in mdx muscle fibers. At later stages mdx muscle showed marked decrease in force reflecting muscle wasting. Soleus showed moderate decrease and diaphragm showed severe decrease (more than 60%) in force. Resistance to muscle fatigue was shown in mdx soleus muscle when compared with WT soleus muscle. Diaphragm segments of mdx mice showed very strong resistance to muscle fatigue. The results indicate a substantial loss of muscle mass, an increase in oxidative fiber types and a reduction of fast fatigable muscle fibers. It is concluded that the hypothesis of functional expression of TRPC3, TRPC6 and TRPV4 in mouse skeletal muscle has been confirmed. The results give improved knowledge about the relation of Ca2+ homeostasis, mdx pathology and TRP channels. Diaphragms of old mdx mice show severe muscle weakness but the remaining fibers of the diaphragm showed strong fatigue-resistance. The application of a TRPC3 inhibitor may be a promising treatment to prevent high Ca2+ mediated muscle damage in muscular dystrophy.
Interactions between bacteria and the human body are manifold and happen constantly. Most parts of the skin and gastrointestinal tract, the saliva, the oral mucosa, the conjunctiva and the vaginal mucosa are colonized with a multitude of bacterial species forming the human microbiota. Strikingly, the estimated amount of bacterial cells outnumbers the human body by 10 to 1. However, most of these bacteria colonize the human body without positive or negative effects and are regarded as commensals. Staphylococcus aureus a Gram positive bacterium is such a commensal bacterium of 25 % to 30 % of the world population. It is also an opportunistic pathogen and is able to cause infections in the lung, skin and heart and to induce sepsis. Its pathogenicity is mainly facilitated by the secretion of a broad spectrum of virulence factors which interact with the host. Some are distracting the immune system, others are targeting the host cell membrane or degrade macromolecular structures of the host in order to provide nutrients. Furthermore S. aureus is able to invade the host cell and to survive and replicate in the host cell cytosol or other compartments. The Gram negative proteobacterium Burkholderia pseudomallei is an environmental bacterium but still has the ability to enter the human body via body orifices or skin wounds. In a very efficient way it penetrates the host cell, replicates intracellular and the uses host structures to spread from cell to cell thereby causing the disease melioidosis often with fatal outcomes. Since the natural habitats of B. pseudomallei are wet soils, the change to the environment in the human body is drastic and requires a high degree of flexibility of the bacterium. Environmental stress conditions such as temperature, pH, nutrient limitation or presence of antibiotics induce a switch of colony morphology which is a special characteristic of this bacterium. Since it is assumed, that changes in colony morphology are connected to adaptive processes to the environmental changes, these morphology switches might also be important during infection. The host organism and the host cell on the other side try to kill and remove the bacterial threat by activating the immune system and cellular defence mechanisms. This includes generation of reactive oxygen and nitrogen species, production of antimicrobial peptides and cellular processes such as phagocytosis, autophagy, apoptosis and activation of the immune response. The actions and reactions on both, the pathogen side and the host side, are summarized as host-pathogen interactions. In the field of functional genomics, methods were developed to understand various levels of host-pathogen interactions. The holistic analysis of the mRNA (the transcriptome) or translated proteins (the proteome) were already very useful tools to describe important cellular processes on the host and the pathogen site. The level of metabolites with regard to host-pathogen interactions however, has been neglected so far. In this dissertation the metabolic composition in the intracellular and extracellular space of the host and the pathogen was analyzed. For this matter biochemical analytical tools were used such as 1H-nuclear magnetic resonance spectroscopy and chromatographic methods (GC and HPLC) coupled to mass spectrometry. The combination of these methods allows a broad coverage of physicochemical diverse metabolites. In accordance to the above mentioned biological levels like mRNA and proteins, the sum of all metabolites is referred as the metabolome. Consequently to transcriptomics and proteomics the analysis of the metabolome is referred as metabolomics. To gain insights into the infection relevant metabolome of the host-pathogen relationship between S. aureus and human lung cells several approaches were developed. First the distribution of the recently identified bacillithiol in different S. aureus strains was investigated with regard to its role during the infection. For that matter a HPLC-methodology was used with fluorescence based detection of labelled low molecular weight thiols (article I: Distribution and infection-related functions of bacillithiol in Staphylococcus aureus). After that the next aim was to reveal the effect of S. aureus on the host cell metabolism. To reduce the complexity of effects on the host cells an artificial model was chosen in a first approach. The lung cells were treated with the staphylococcal virulence factor alpha-hemolysin, a pore forming toxin and a holistic metabolomics approach was performed (article II: Staphylococcus aureus Alpha-Toxin Mediates General and Cell Type-Specific Changes in Metabolite Concentrations of Immortalized Human Airway Epithelial Cells). Using this approach, a protocol for cell culture metabolomics was established and first changes in the host cell metabolome that could be caused by S. aureus were described. However, this only describes specific changes caused by one single virulence factor and does not necessarily describes the reality during a S. aureus infection. Therefore in a next approach, an infection model using a human lung epithelial cell line and the S. aureus strain USA300 was established and used for metabolome analysis. Furthermore a combination of inhibitor treatment and metabolic labelling was used to clarify the metabolic activity in the host cell after exposure to S. aureus (article III: Metabolic features of a human airway epithelial cell line infected with Staphylococcus aureus revealed by a metabolomics approach). Finally this thesis deals with the host-pathogen interaction of B. pseudomallei and its host with a focus on the role of the switch in colony morphology in basic metabolism. Various morphotypes of two strains were generated by nutrient limitation and their uptake of nutrients was monitored. Furthermore the morphotypes were used in in vitro and in vivo infections and subsequently isolated out of the cell line and mice respectively. After isolation, the colony morphology was determined and again the nutrient uptake profile was monitored (article IV: Burkholderia pseudomallei morphotypes show a synchronized metabolic pattern after acute infection). The information provided by this thesis adds a new complexity to the knowledge about the host-pathogen interactions of S. aureus and B. pseudomallei and their hosts. It furthermore lays the groundwork for future studies, which will deal with these and other bacterial host-pathogen interactions in order to understand the interdependencies of infection and metabolism.
Comprehensive study of the discharge mode transition in inductively coupled radio frequency plasmas
(2016)
In this contribution, the mode transition of an inductively coupled radio frequency plasma at low pressure is investigated. Therefore, a comprehensive set of plasma diagnostics were applied to determine plasma and processing parameters. Therewith, the plasma kinetics and especially the important elementary processes were studied. Hence, the reason for the mode transition was identified.
Staphylococcus aureus is present in around a third of the human population as a constant commensal in the anterior nares, in a third as an intermittent commensal, and a third are non-carriers. However, S. aureus is also a dangerous pathogen, responsible for many types of infections. Recently, the emerging of methicillin-resistant S. aureus strains has aggravated the health problem. Treating infections caused by the invasive strains has become ineffective with conventional antibiotics. Noticeably, transmission of S. aureus has occurred not only in healthcare settings but also in the community; furthermore, transmission between humans and domestic animals has been reported. Although studies about host-pathogen interactions of S. aureus have advanced our knowledge in the last decades, we still have not fully understood mechanisms of the immune system in responses to S. aureus. The aim of this study is to unravel interactions of the human adaptive immune system to selected S. aureus virulence factors. In particular, the study focuses on two aspects: the reaction of human antibodies to the bacterial extracellular proteins in S. aureus-induced furunculosis with an emphasis on Panton-Valentine Leukocidin and responses of the adaptive immune system to membrane-bound lipoproteins of S. aureus. Furunculosis is a variety of hair follicle infection in which S. aureus is one of the chief causal pathogens involved. The corresponding bacterial strains are generally capable of producing of a pore-forming toxin, known as Panton-Valentine Leukocidin (PVL). Recently, the emerging of pvl-positive methicillin-resistant S. aureus has become a problem for treating the bacterially caused furuncles. Colonization with the bacteria is a risk factor for development of chronic or recurrent boils. It is not yet known why furunculosis patients are largely infants or young adults. In this context, we untangled the responses of antibody IgG antibodies to S. aureus extra-cellular factors, notably the PVL toxin, in families in which the patients were children. Multiplex PCR demonstrated that S. aureus clones, isolated from the patients’ wounds but also from the nares of family members, harbored genes coding for PVL toxin. Spa-typing highlighted that bacterial genotypes were very similar in each family. This suggests that transmission of pvl-positive S. aureus took place between family members. The finding also raises the question why only the young patients but not family members who were colonized by the same S. aureus clones suffered from furunculosis. 2D immune proteomics procedures showed a tendency of higher IgG titers against bacterial virulence factors in family healthy members than in patients. PVL-specific antibodies were measured using ELISA, in which patients’ PVL-specific IgG titers were low. This supports the idea that antibodies, probably in conjunction with T cells, might contribute to clinical protection in furunculosis. This research will serve as a foundation for future studies, in which our results should be validated in a larger cohort. Among S. aureus’ virulence factors are lipoproteins, which are anchored in the bacterial cell membrane. Lipoproteins perform various functions in colonization, immune evasion, and immunomodulation. These proteins are potent activators of the complex of innate immune receptors termed Toll-like receptors (TLR) 2 and 6. This study addressed the specific B-cell and T-cell responses to lipoproteins in human S. aureus carriers and non-carriers. 2D immune proteomics and ELISA approaches revealed that titers of serum antibody (IgG) binding to the S. aureus lipoproteins were very low or even unmeasurable in healthy individuals except for the lipoprotein SaeP. Only patients with cystic fibrosis or epidermolysis bullosa who were heavily exposed to the bacteria, generated an antibody response also to lipoproteins. Proliferation assays and cytokine profiling data showed only subtle responses of T cells in healthy individuals; three out of eight tested lipoproteins did not elicit proliferation. Hence, the robust activation of the innate immune system by S. aureus lipoproteins does not translate into a strong adaptive immune response. Reasons for this may be inaccessibility of lipoproteins for B cells as well as ineffective processing and presentation of the antigens to T cells. The main findings implicate that family members can serve as S. aureus reservoirs causing recurrent furunculosis in young patients and that antibodies may provide partial protection from such infections by S. aureus. We have found that, different from proteins that are secreted by S. aureus, lipoproteins which anchored in the bacterial cell membrane, do not trigger strong responses from the human adaptive immune system. This suggests that these proteins remain mostly hidden in the bacterial cell-wall.
Psychiatric disorders are highly heritable. But the underlying molecular mechanisms are largely unknown or not understood. For many disorders, candidate genes have been proposed which are biologically driven or based on large GWAS studies. In this work different approaches were shown to investigate the impact of genetic risk factors for major psychiatric disorders in the general population. These genetic risk variants include single nucleotide polymorphisms associated with schizophrenia or major depression and were analyzed using the whole-genome information in polygenic scores or candidate marker analysis in GxE studies. Genetic data from SHIP-0 and SHIP-TREND have been used to calculate a polygenic risk score for schizophrenia. Here, the association between this genetic score and brain alterations is shown in three independent samples (SHIP-2, SHIP-TREND and BIG) which revealed no hint of a common genetic basis for schizophrenia and brain structure. These results are in line with other studies that also failed to find a genetic overlap. The same polygenic scores had been used in a PHEWAS analysis in SHIP-0 where an inverse association to migraine was found. This association could be attributed to the NMDA receptor activation via D-serine at the glutamatergic synapse. To assess the impact of environmental factors on the path from genes to phenotype, gene-environment interactions were applied. A significant interaction could be observed between rs7305115 (TPH2) and rs25531 (5-HTTLPR) and childhood abuse on current depression score in SHIP-LEGEND and SHIP-TREND. In summary, genetic variants associated with major psychiatric disorders can exhibit pleiotropic effects on common phenotypes in the general population.
The history of Mathematics has been lead in part by the desire for generalization: once an object was given and had been understood, there was the desire to find a more general version of it, to fit it into a broader framework. Noncommutative Mathematics fits into this description, as its interests are objects analoguous to vector spaces, or probability spaces, etc., but without the commonsense interpretation that those latter objects possess. Indeed, a space can be described by its points, but also and equivalently, by the set of functions on this space. This set is actually a commutative algebra, sometimes equipped with some more structure: *-algebra, C*-algebra, von Neumann algebras, Hopf algebras, etc. The idea that lies at the basis of noncommutative Mathematics is to replace such algebras by algebras that are not necessarily commutative any more and to interpret them as "algebras of functions on noncommutative spaces". Of course, these spaces do not exist independently from their defining algebras, but facts show that a lot of the results holding in (classical) probability or (classical) group theory can be extended to their noncommutative counterparts, or find therein powerful analogues. The extensions of group theory into the realm of noncommutative Mathematics has long been studied and has yielded the various quantum groups. The easiest version of them, the compact quantum groups, consist of C*-algebras equipped with a *-homomorphism &Delta with values in the tensor product of the algebra with itself and verifying some coassociativity condition. It is also required that the compact quantum group verifies what is known as quantum cancellation property. It can be shown that (classical) compact groups are indeed a particular case of compact quantum groups. The area of compact quantum groups, and of quantum groups at large, is a fruitful area of research. Nevertheless, another generalization of group theory could be envisioned, namely by taking a comultiplication &Delta taking values not in the tensor product but rather in the free product (in the category of unital *-algebras). This leads to the theory of dual groups in the sense of Voiculescu, also called H-algebras by Zhang. These objects have not been so thoroughly studied as their quantum counterparts. It is true that they are not so flexible and that we therefore do not know many examples of them and showing that some relations cannot exist in the dual group case because they do not pass the coproduct. Nevertheless, I have been interested during a great part of my PhD work by these objects and I have made some progress towards their understanding, especially regarding quantum Lévy processes defined on them and Haar states.
Destination Image, Tourist Satisfaction and Destination Loyalty: A Case Study of Hue, Vietnam
(2016)
Several studies have confirmed the interrelationship among destination image, tourist satisfaction and destination loyalty, in which destination image and tourist satisfaction are believed to have great influences on the destination loyalty of tourists. Located in the central region of Vietnam, Hue holds great potential for tourism development and this destination has also obtained numerous significant tourism achievements over recent years.Nevertheless, there are still a lot of issues needed to be addressed by the destination managers in order to make Hue gain a better position and higher level of destination loyalty in the tourism market, in which successfully communicating an attractive destination image to the tourists and improving their satisfaction are the most important tasks. In fact, there exist very few researches concerning destination image, tourist satisfaction or even destination loyalty which have been done in Hue. Moreover, most of these studies are in very small scale and they only examine either the destination image or the tourist satisfaction or the destination loyalty independently. This paper, therefore, aims to deliver the first and comprehensive theoretical and empirical analysis of destination image, tourist satisfaction and destination loyalty as well as the causal relationship among them in the context of Hue. In this study, a destination loyalty research model was proposed and hypotheses were derived. The empirical data base on two tourist surveys with a total number of 2042 questionnaires collected in Hue in 2013 and 2014. In addition, ten experts were interviewed in different periods during the study. The results find that the tourists’ perceptions on the destination image of Hue are quite positive and the positive level is higher for those who completely have no earlier experience in Hue. It is also discovered that the destination is offering tourists with a pretty satisfactory experience, not as high as their initial expectations, but acceptable with positive ratings received from the tourists. However, if the destination is able to better communicate a positive image to tourists and improves the quality of its offers and services, the tourists’ satisfaction will be increased and thus the destination loyalty will also be enhanced. This finding supports the proposed destination loyalty model: (1) destination image directly influences attribute-satisfaction; (2) destination image and attribute-satisfaction are both direct influences of overall-satisfaction; and (3) overall-satisfaction in turn has a direct and positive impact on destination loyalty. The findings also confirm that attribute-satisfaction and destination image are also the direct influences of destination loyalty. Furthermore, the results add to the proposed loyalty model a new relationship: Destination image is influenced strongly by tourist overall-satisfaction and attribute-satisfaction. The outcomes of this research are expected to be used as a valuable reference for the local policy-makers, governmental agencies, tourism companies and other relevant stakeholders. Also, important theoretical and managerial implications are drawn based on the study findings and the recommendations for future researchers are made from the limitations and scopes of the study.
Background: Despite of the remarkable caries reduction in permanent dentition, caries levels of primary teeth has stagnated in Germany. Early Childhood Caries (ECC) or also known as baby bottle tooth decay is the most vulnerable form of caries in young children, but minimal data and information from different German states are available to determine the appropriate preventive programs. Aim: The purpose of the current study is to find the prevalence of ECC among young children in the state of Mecklenburg-Vorpommern (North-East Germany) and to optimize an intervention on ECC prevention in a community setting. In addition to education, fluoride varnish is evaluated on young children with active ECC. Design: In this cross-sectional study, a total of 4283 children living in the state of Mecklenburg-Vorpommern were examined. Four age groups - with an accuracy of one day - were formed as follows: less than one year (n=8), one year (n=293), two years (n=1618) and three years (n=1888). The examination was carried out by community dental service’s examiners whom are calibrated to ECC diagnostic criteria of Robke and Buitkamp (2002), and dmf-t values for caries diagnosis. These data are compared by those of children (n=5355) of same age group for the year 2011-2012. In addition, a structured questionnaire on the starting preventive programme on ECC was filled out by the community dentists and for the city of Greifswald, fluoride varnish (Duraphat®, 5% NaF = 2.26%F, Colgate-Palmolive, Germany) was applied for 32 children previously diagnosed with active ECC (ECC1: n=15, ECC2: n=17). Lesions are identified as active or non active according to texture and luminosity, and oral hygiene index (OHI-S) is measured and re-evaluated at three months follow up. Results: The percentage of children under three years old in 2012-2013 with ECC was comparatively low (4%) which possibly reflects the very young age of the children and a restriction for ECC on the upper incisors. The overall caries prevalence in Mecklenburg-Vorpommern varied from 9% to 15%. Most cavitated lesions are untreated. These results are comparable with the results from other German counties. The interventions of the ECC programme vary considerably among the different counties. There was no significant difference in the oral hygiene index (OHI-S) prior and post fluoride varnish application (p-value = 0.25). The use of fluoride varnish resulted in an 81%, statistically significant decrease of active ECC lesions in Greifswald (p < 0.001). Conclusion: The prevalence of caries among young children was considerable in Mecklenburg-Vorpommern. A preventive intervention in nurseries and fluoride varnish applications for active ECC lesions seems to be a feasible approach in controlling caries in early childhood. However, further quality management and standardization of the program should be reinforced.
Background: Referral to specialized pediatric treatment seems to rise in Germany, especially for children under 5 years of age and mostly due to behaviour management problems, rampant caries and the need for comprehensive dental treatments. There are indications that more dental treatments under general anesthesia were needed in last decade, but there are very few studies on this topic in Germany. Aim: The objectives of this research were to investigate the characteristics and dental features of referred children to Greifswald university dental clinic in 2008 and 2011 as well as to assess dental treatment and characteristics of the children who underwent general anesthesia in 2011 at Greifswald University Clinic in comparison with three specialized pediatric private practices in Germany. Materials and methods: This retrospective analytical comparative study examined the records of all children younger than 18 years of age, whose were referred to the university dental clinic in Greifswald between 2008 and 2011. In addition, all cases that underwent general anesthesia at the university dental clinic and three other private practices in 2011 were analyzed anonymously. All data including age, gender, dental status and caries levels (dmft/DMFT), as well as diagnosis, referral/GA reasons and the dental treatments were collected and then analyzed using the Statistical Package for the Social Sciences program (SPSS, Ver. 16 for Windows). Descriptive analysis was performed, along with univariate analysis of variance (ANOVA) and Chi square tests. Differences between groups were tested through Mann-Whitney U test and Student’s t-test as appropriate. Results: The final study sample for children and adolescents referred to the university consisted of 389 under 18 years old (205 males and 184 females) with a mean age of 8.75 years in 2008 and 7.38 years in 2011. In addition, 297 children (160 males and 137 females) with a mean age of 4.77 years had been treated under general anesthesia in the three specialized private practices (n= 219, age: 4.81±2.06 years) and in the university (n=78, age: 4.65±2.59 years). More patients of age group 1 (5 yrs or younger), as well as, patients residing within a distance of 31-40 km away from the clinic were referred in 2011 (47.2% and 35.9% resp.) in comparison with 2008 (37.1% and 22.7% resp.) Panoramic and intraoral dental x-rays (46.7%, 11.8% resp.) have been widely carried out in 2011 compared to 2008 (29.9%, 6.5% resp. P = 0.002). Statistical analyses have shown that, younger children with higher values of dental caries indices (dmft, DMFT) were referred in 2011 (5.4 and 2.15 resp.) than in 2008 (5.16 and 1.57 resp.) with increasing demand for comprehensive dental treatment under GA. Whereas, more patients were diagnosed to have rampant caries (42.1%) in 2011 followed by orthodontic/oral surgery problems (16.9%) in comparison with 2008 (29.3%, 10.1% resp. P < 0.001). Non-invasive treatment was much more delivered (63%) in first dental visit for referred patients in 2011 followed by dental consultation (23.6%) compared to 2008 (53.6% and 21.3% resp.). While, on the other hand, considerably more fillings were supplied in 2008 (11.5%) compared to 2011 (2.6%). Further dental treatment pattern revealed more treatment under GA (27%) and a slightly more extractions (16.1%) were done in 2011 compared to 2008 (20.9%, 15.5% resp.). On the contrary, less fillings and preventive procedures were performed in 2011 (26.3% and 4.4% resp.) in comparison with 2008. Sixty-one percent of children were referred back to their family dentists in 2011 which was more than it in 2008. Indeed, about a half of children aged 5 years or younger preferred to stay at the University Clinics in 2011, while, the vast majority of children older than 12 years continued their dental care outside the University Clinics. About eighty percent and seventy percent of children underwent GA at both the university clinics and private practices respectively were under five years old. In total 7.1% mental disabilities and 2.4% preterm birth were detected in children treated under GA, as well as, dental caries were mostly diagnosed (37%) among them followed by irreversible pulpitis (21.5%) and Early Childhood Caries (ECC) (18.5%), where only 4.38% of all examined children had no carious lesions. More panoramic radiographs (41%) and less dental films (26.9%) were conducted at the university clinics as in the private practices (15.1% and 52.1% respectively) with a significant reduction in using x-rays at the university (69.2%) compared to private practices (94.1%). Dental extractions were often performed at university clinic (40.2%, 3.14±2.4) followed by fillings (33.9%, 2.65±2.7), while, more restorations and less extractions were supplied at private practices (47.8%, 5.47±3.1 and 16.3%, 1.86±2 resp.). Both of long (106-120 Min) and short (0-15 Min) treatment’s durations were needed in the university clinics to carried out the adequate dental therapy under GA, while, most of the GAs at private practices have lasted between 45 and 90 minutes. Conclusion: There is a growing definite need for specialized pediatric dentistry in Germany, especially for children under 5 years of age being referred with rampant caries and behaviour management problems to specialized pediatric dentistry. This results in a high number of extensive treatment performed under GA. In contrast to other countries, this seems to be a singular event for most children in Germany indicating a solid treatment under GA and possibly also improvements in the caries activity of the affected children afterwards. The range of dental treatment and its outcome at Greifswald University and in the examined three specialized private practices is very similar reflecting in both the profile of the children a valid indication for GA and the subsequent treatment up to date approaches in pediatric dentistry. Thus, the very professional treatment and effective secondary preventive strategies achieve better oral health and reestablished quality of life for these children, but a primary preventive approach would be preferable decreasing the number of children in need of dental treatment under general anaesthesia.
Generally, all works dealt primarily with the biodiversity and phylogeny of leaf-inhabiting fungi of three Ficus species (F. benjamina, F. elastica and F. religiosa) with the exception of the bioprospecting which focused on discovering antimicrobial activities and secondary metabolite production. Investigations took place in natural and urban forests in the Philippines and in tropical greenhouse gardens in Germany.
Ischemic stroke is the second leading cause of death worldwide and a disease with a variety of risk factors including hypotension, nutrition/obesity, and smoking but also increased age. In an ageing society stroke is a great challenge and leaves the survivors with disabilities. The aim of this dissertation was to investigate the immunologic changes post ischemic stroke, in order to use a better understanding for new therapeutic approaches as well as for improvement of translation of results from bench to bedside. Ischemic stroke leads to a local and peripheral immune activation. On the other side an immune dysfunction/suppression occurs, that leads to a higher risk of stroke-associated infections. In this dissertation, a long-lasting elevation of HMGB1 after stroke and a correlation with blood leukocyte numbers could be shown. HMGB1 seems to be an important mediator of an endogenous inflammation and an interesting target for post-stroke immunomodulation. In a further study we showed that the quality of the immune response of infiltrating T cells has an impact on the neurologic outcome and functional recovery after experimental stroke. Importantly, a mechanism of how infections, mimicked by LPS injections, could worsen the outcome of stroke patients was revealed. In the context of stroke-induced immunosuppression regulatory T cells as an immunosuppressive T cells subset seem to not play a role as their suppressive capacity is reduced after stroke. Interestingly, the CD39 expression on Tregs is similarly increasing with age in humans and mice. This shows the importance of an age equivalent in experimental studies. In search of predictors for the outcome after stroke as well as the risk of infections, we performed single nucleotide polymorphism genotyping in the IL-1RN and TLR4 gene of stroke patients. Functional significant variants in the IL-1RN and TLR4 genes may have an impact on outcome and systemic markers of inflammation post stroke but these findings need to be replicated in studies with much larger cohorts.
In this work the mechanisms leading to the generation of the various reactive oxygen and nitrogen species (RONS) in a cold atmospheric plasma (CAP) jet and means to control their composition were studied. The investigated CAP jet kinpen is typically operated with Ar feed gas (pure or with molecular admixtures), driven at a frequency of approximately 1 MHz and features fast ionization waves or guided streamers, traveling at velocities of several km/s. The complex reaction networks were investigated by numerical and experimental techniques. Detailed experimental, analytical and computational investigations on the mass and heat transport in the plasma plume were performed: A novel analytical approach to diffusion in jet flows, the non-dispersive path mapping approximation (NDPM) was developed. The method for the first time allows for an estimation of the ambient species density in the near-field of jets that feature a non-homogeneous flow-field. The NDPM approximation was employed for the evaluation of laser induced fluorescence measurements on OH. Through combining measurements and NDPM approximation, this approach yielded an estimation for the ambient species density at the position of the guided streamers, not only in the laminar, but also in the (standard) turbulent operating regime. Accurate measurements of the temporally averaged ambient species density and temperature in the plasma plume were obtained by quantitative Schlieren measurements. The method yields temperature values with sub-Kelvin accuracy and, through combination with computational fluid dynamics (CFD) simulations, allowed for an estimation of the calorimetric power of the jet. In order to obtain a defined environment for the jet to operate in, a shielding gas device was designed in this work, which creates a gas curtain of defined composition around the plasma plume. The plasma dynamics on the ns timescale was investigated by phase resolved optical measurements. The effect of different shielding compositions ranging from pure N2 to pure O2 on guided streamer propagation was investigated. An electrostatic focusing mechanisms was discovered, which promotes the propagation of guided streamers along the channels formed by a noble gas in the plume of plasma jets operating in electronegative gases (such as air or O2). Two zero-dimensional (volume averaged) models were developed: First, the local processes in the guided streamer were modeled using an electron impact reaction kinetic model, which is closely correlated to densities of metastable argon (Ar*) obtained by laser atom absorption measurements. This first model shows that Ar* is the species which dominantly drives the plasma chemistry in the plasma plume. This is exploited in the second plug-flow reaction kinetics model, which is employed to investigate the formation of long-living RONS and uses an Ar* source term as sole energy input. The model uses the previous experimental data on mass and heat transport and temporal dynamics as input and is in turn verified by quantitative FTIR absorption measurements on O3, NO2, N2O, HNO3 and N2O5 in the far-field of the jet, where large absorption lengths can be achieved using a multi pass cell. For the evaluation of the zero-dimensional model, the time-of-flight of RONS from their generation to reaching the multi pass cell was determined using CFD simulations. The insight gained through this combined experimental-modeling approach on the reaction networks revealed relevant control parameters and enabled adjusting the plasma chemistry towards a desired RONS output. Through choosing appropriate feed-gas admixtures and shielding gas compositions, it is possible to generate an NOx-dominated plasma chemistry, although the jet usually produces a strongly O/O3-dominated chemistry. Understanding and controlling the plasma chemistry of cold atmospheric plasma sources for medical applications is not only essential for research, but is also the key for designing future plasma sources for specific medical applications that yield an optimum efficacy and avoid potential side effects of plasma treatment.
Heart Failure is currently the most common cardiac disorder and a major public health concern worldwide. The adult mammalian heart harbors a subpopulation of cardiac progenitor cells (CPC) that are capable of improving cardiac function. The scope of this study was to delineate the molecular phenotype of a subpopulation of CPCs characterized by the expression of the stem cells antigen-1 surface marker (Sca-1+) and to further identify molecular alterations occurring under heart failure conditions. In order to understand the underlying cellular mechanisms an integrated approach of proteomics and transcriptomics-based techniques were employed. The first step towards achieving this goal was to unravel the native Sca-1+ cell characteristics of freshly isolated progenitor cells derived from healthy adult murine hearts. The proteome map of Sca-1 cells was established using a gel-based mass-spectrometry (gel LC-MS/MS) approach. For better interpretation, a comparison with the protein profiles of cardiomyocytes and Sca-1- cells obtained under similar experimental conditions was performed. All three cell-types were morphologically different in size and structure, which was also evident from their protein expression profiles. We observed that Sca-1+ cells lack endothelial-like and cardiac contractile phenotypes, unlike Sca-1- cells and cardiomyocytes, respectively. Functional assessment of both protein and gene expression profiles revealed a possible role of Sca-1+ cells in cell adhesion, migration, and proliferation. CPC remain in a dormant state under physiological condition unless challenged by myocardial injury. Previous studies revealed that resident Sca-1+ cells home to the injured myocardium but not to the healthy heart and further differentiate into functional cardiomyocytes. We investigated the molecular background of this behavior of adult Sca-1+ cells under heart failure condition which might provide a better insight into their cardiogenic potential in a pathological milieu. The double transgenic α-myosin heavy chain (MHC)-cyclin T1/Gαq overexpressing mouse was chosen as a model for heart failure. Using the comparative gene expression profiling we could detect the differential regulation of 197 genes with at least a 2-fold difference. Among these BDNF mRNA levels were 5-fold higher in the Sca-1+ cells derived from transgenic mice (Cyc+) in comparison to that of wild-type controls (Wt+). This difference was also observed at protein level. The substantially higher expression of BDNF during heart failure prompted us to investigate its regulatory effect on Sca1+ cells. In this current study we were able to show that small amounts of exogenous BDNF stimulated the migratory potential of Cyc+ cells. This effect was not seen in treated Wt+ cells. Furthermore, pulsed SILAC was employed to monitor BDNF mediated changes following treatment. After BDNF treatment, 58 proteins were differentially regulated of which proteins related to cell proliferation were reduced in level in Cyc+ cells while they displayed increased levels in Wt+ cells. Findings from bromodeoxyuridine (BrdU) assays and immunoblotting indicated that BDNF might initiate a differentiation program by repressing cell proliferation in Cyc+ cells. Taken together, it could be shown that the BDNF effect on protein synthesis of Cyc+ and Wt+ cells varied considerably, suggesting an improvement of the cardiogenic potential of Sca-1+ cells under pathological conditions. Aldosterone levels are known to be elevated during heart failure. In this part of study it was hypothesized that endocrine factors associated with heart failure might influence the migration of CPC, thereby possibly restoring the cardiac function of diseased hearts. It could be shown that high concentrations of aldosterone, similar to those found in the plasma of heart failure patients, induced the migration of Sca-1+ cells by up to 60% when compared to control, while physiological levels had no significant influence. In addition, it could be demonstrated that the aldosterone stimulus led to the activation of the mineralocorticoid receptor (MR) expressed on Sca1+ cells, which in turn facilitated migration. This was supported by application of MR antagonist eplerenone, which significantly reduced the aldosterone-induced increase in cell migration while a glucocorticoid antagonist exhibited no inhibitory effect. Hence, the results support the potential role of aldosterone in the mobilization of CPC. It is currently believed that the beneficial effects of cell-based therapies on cardiac repair are imparted to a large degree via paracrine mechanisms. We therefore focused on understanding the influence of pathophysiological levels of aldosterone on the extracellular environment of Sca-1+ cells. MS-based secretome profiling of cells treated for 24h with aldosterone treatment revealed higher levels of proteins associated with extracellular matrix remodeling and IGF signaling. Additionally, galectin-1 and gelsolin were significantly increased in level under pathological conditions indicating a possible paracrine tissue repair of Sca-1+ cells. To conclude, the global proteome and transcriptome profiles generated here revealed the molecular phenotype of Sca-1+ cells which may be used for future reference. The comparative microarray study provided deeper insight into the endogenous changes in mRNA expression during heart failure and delineated the cardiogenic characteristics of Sca-1+ cells. Moreover, the data presented here shed new light on the potential role of BDNF in regulating the mobilization and proliferation of CPCs. Our study on the influence of aldosterone on the migration and the extracellular proteome of CPCs provided new insights on the beneficial effects of this mineralocorticoid on cardiac cells.
The role of uptake and efflux transporters in the pharmacokinetics of ß1-receptor blocker talinolol
(2016)
Introduction: The β1-adrenergic receptor antagonist talinolol is a probe drug for P-glycoprotein (P-gp). It is absorbed erratically and incompletely from the gastrointestinal tract. However, its pharmacokinetics might also be influenced by further uptake and efflux transporters as concluded from interaction studies with naringin and verapamil in human. Additionally, the transcellular transport through the different tissues, including enterocytes, hepatocytes and kidney tubular cells, is not completely understood so far. Therefore, we aimed to measure the affinity of talinolol to drug transporting proteins (OCT1-3, PEPT1, OCTN2, ASBT, NTCP, MRP 1-3 and P-gp as well as OATP 1B1, 1B3, 2B1 and 1A2) and some of their genetic variants known to be of pharmacokinetic relevance (OATP1A2 *2 and*3 as well as OATP2B1 V201M, R312Q and S486F). In a further step, we retrospectively evaluated the impact of clinically relevant genetic polymorphisms of transporters on the pharmacokinetics of talinolol in healthy subjects. Materials and Methods: Time and concentration-dependent uptake assays with [3H]-talinolol were performed either in stable transfected HEK293 or MDCKII cells expressing OATP1A2 *1, *2 and *3, OATP1B1, OATP1B3, OATP2B1 (and its genetic variants p.V201M, p.R312Q and p.S486F), NTCP, ASBT, PEPT1, OCTN2, OCT 1-3 and the respective vector control or in inside-out lipovesicles expressing the efflux transporters MRP1-3 and P-gp. Talinolol was quantified by liquid scintillation counting. The transport rates were then corrected by the transporter proteomics measured in the cellular membrane. Regarding the pharmacogenomic evaluation, it was carried out retrospectively in 39 healthy subjects who had participated in former pharmacokinetic studies with talinolol. This evaluation included a variety of transporter related genetic variants, known to be of a clinical meaning for their substrates. Results: Among the uptake transporters, talinolol was shown to be a substrate of OATP1B3 (Km= 153 ± 137 μmol/l; Vmax= 168 ± 30.3 μmol/mgxmin), OATP1B1 (Km= 301 ± 133 μmol/l; Vmax= 1135 ± 348 μmol/mgxmin), OATP2B1 (Km= 459 ± 260 μmol/l; Vmax= 4.32 ± 1.33 μmol/mgxmin), OATP1A2 (Km= 477 ± 158 μmol/l; Vmax= 0.61 ± 0.1 μmol/mgxmin) and NTCP (Km= 2560 ± 781 μmol/l; Vmax= 15944 ± 3741 μmol/mgxmin) but not a substrate of OCT1-3, OCTN2, PEPT1 or ASBT. When it comes to the efflux transporters, talinolol was transported by both P-gp (Km = 175 ± 206 mol/l; Vmax = 14 ± 10.8 nmol/mgxmin) and MRP3 (Km= 86.8 ± 62.8 μmol/l; Vmax= 133 ± 51.5 μmol/mgxmin) but not by MRP2. The pharmacogenomic analysis supported the in-vitro results, as it showed a significant decrease in talinolol absorption (AUC and Cmax) in subjects with the loss of function variant MRP3 211C>T and in those with a decreased P-gp function due to having less than 5 T-allels in the haplotype P-gp 1236-2677-3435-TTT. No significant changes were found associated with other transporters’ genetic variants. Conclusion: Our in-vitro results suggested the vectorial transport of talinolol through the enterocytes to consist mainly of apical OATP2B1 and P-gp and basolateral MRP3. Additionally in the hepatocytes, apical OATP1B1, OATP1B3 and NTCP seem to be involved as well. This vectorial transport was demonstrated in-vivo for the first time by our pharmacogenomic analysis, where talinolol absorption was significantly influenced by both P-gp and MRP3 genetic variants.
Bacterial infections represent an increasing threat in human health and hospital- acquired infections meanwhile account for 99,000 deaths every year in the United States (Ventola, 2015). Live-threating bacterial infections will certainly emerge to an even more serious concern in future, essentially by accelerated development of antibiotic resistance. Only recently, the discovery of plasmid-encoded mcr-1, that confers resistance against colistin, marks the point where this highly transmissible resistance mechanism is now reported for every so far developed antibiotic (Liu et al., 2016). Staphylococcus aureus is a Gram-positive bacterium and well-known for its ability to quickly acquire resistance toward antibiotics either by chromosomal mutations and/or horizontal gene transfer (Pantosti et al., 2007). Although approximately 30% of the population is colonized with S. aureus (Kluytmans et al., 1997), it can transform to an invasive pathogen that causes a wide range of severe infections including pneumonia. The success of S. aureus as opportunistic pathogen can be attributed to combinations of several beneficial properties and capabilities including the expression of an arsenal of virulence factors (Archer, 1998), intracellular persistence (Garzoni & Kelley, 2009) and subversion of host cell defense mechanisms (Schnaith et al., 2007). The airway epithelium is the first line of defense against bacterial pathogens by forming a relative impermeable physical barrier composed of epithelial cells that are linked by tight junctions, desmosomes and adherence junctions (Davies & Garrod, 1997). Additionally, the airway epithelium mediates the detection of bacterial pathogens via toll-like receptors (TLRs) that recognize a variety of bacterial molecular patterns such as lipopolysaccharide (LPS), peptidoglycan and flaggelin (Sha et al., 2012). This interaction is transduced via protein phosphorylations into the cell in order to promote adaptation to the infection by initiation of the adaptive and innate immune defense. Although few insights where obtained of the signaling host responses towards staphylococcal infections (Agerer et al., 2003; 2005; Ellington et al., 2001), a comprehensive description of the host signaling network is largely missing. Thus, this dissertation thesis focuses on the decipherment of phosphorylation-mediated signaling responses towards S. aureus infections in non- professional and professional phagocytes by mass spectrometry-based phosphoproteomic techniques. The results of this thesis are summarized in the four chapters. Chapter I introduces to recent advances in the development of methodologies applied in the field of phosphoproteomics, including quantification strategies, peptide fractionation techniques and phosphopeptide enrichment methods applied for the system-wide characterization of protein phosphorylations by mass spectrometry. Additionally, publications reporting phosphorylation-based host signaling responses towards bacterial pathogens or their molecular patterns that applied mass spectrometry-based phosphoproteomics are discussed. In chapter II, the responses of the human bronchial epithelial cell lines 16HBE14o- and S9 following challenge with staphylococcal alpha- toxin at the level of proteome and phosphoproteome are summarized. General and cell type-specific signaling events are highlighted and evidences linking the activity of the epidermal growth factor receptor (EGFR) with differences in tolerance toward alpha-toxin are provided. Chapter III describes the modulation of the host signaling network of 16HBE14o- airway epithelial cells triggered by infection with S. aureus including temporal dissection of signaling events. Several protein kinases were identified as important signaling hubs mediating the host response. Targeted pharmaceutical inhibition of these kinases was probed and resulted in reduction of intracellular bacterial load. Chapter IV describes the rearrangement of the kinome by the differentiation of THP-1 monocytes to macrophage-like cells by application of quantitative kinomics. This approach identified the kinase MAP3K7 (TAK1) as key mediator of bacterial clearance, chemokine secretion and the differentiation process itself.
In this Ph.D. project a method is developed to measure the magnetic field and to derive variations in the total plasma pressure due to (dia-) magnetic effects. For this purpose a plasma diagnostic has been set up at the fusion experiment ASDEX Upgrade to measure spectroscopically polarized light. The light is emitted from fast beam-particles excited by the plasma. Since the fast atoms travel through a magnetic field at high velocity, a strong Lorentz field is seen in the moving frame. This electric field gives rise to the so-called motional Stark-effect (MSE) and it is possible to conclude from the Stark-spectrum on the magnetic field.
The focus of this study is on the geochronological and paleo-climatic characterization of late Pleistocene glaciations in Turgen and the Khangai Mountains located in central and western Mongolia. These two mountain ranges form a 700 km long NW-SE transect through Mongolia and allow assumptions of the temporal and causal dynamics of the regional late Quaternary glaciations and their correlation to other mountain glacier records from Central and High Asia. In order to evaluate extent and timing of the Pleistocene glaciations in Mongolia, geomorphological mapping and cosmogenic radionuclide (CRN) surface exposure dating (10Be) were carried out in four valley systems located in the Khangai and Turgen Mountains. Additionally, a coupled 2-D surface energy balance and ice flow model was used to determine steady-state conditions for glaciers under various climatic scenarios. With this model it is possible to test combinations of temperature and precipitation settings, which would produce glacier configurations that fit the field-mapped ice extent. In total, 47 glacial boulders and roche moutonnées were sampled, prepared and AMS measured to determine the absolute timing of moraine formation and ice retreat based on 10Be surface exposure dating. Of these, 27 samples were obtained from the Khangai Mountains (three separate moraine sequences) and 20 samples were taken from the Turgen Mountains (two moraine sequences). The dating results (presented as minimum ages) give evidence for a late Pleistocene maximum ice expansion during late MIS 5 (81−78 ka) and major ice advances during MIS 2 (26−20 ka) in both mountain ranges. Only in the Khangai Mountains (central Mongolia) very significant glacier advances also occurred during mid-MIS 3 (49−35 ka), which exceeded the ice limits set during the MIS 2 glaciation. A final ice position, constructed shortly before the onset of full ice retreat was formed between 19-16 ka, and is likely to represent a recessional ice stillstand, or alternatively a final ice readvance during the early part of the last-glacial-interglacial-transition (LGIT) in both mountain ranges. Energy/mass balance and ice flow modeling results suggest that climatic conditions during the MIS 5 and MIS 3 maximum advances in the Khangai Mountains were depressed between a ∆T of -6.0 to -5.2 °C with a precipitation factor of 1.25-1.75 (P = 125-175 %, compared to modern conditions), and a ∆T of -5.3 to -4.4 °C (P = 75-125 %), respectively. For the MIS 2 ice advances modeling results from the Turgen and Khangai Mountains suggest a temperature depression ∆T of -5.7 to -4.6 °C (at 22 ka; P = 25-50 %) in the East-Turgen, and a ∆T of -7.5 to -6.6 °C (at 20 ka; P = 25-50 %) in the Chulut area (Khangai Mountains). These results document a 1.8 - 2 °C difference of the modeled temperatures required to expand the studied paleo-glaciers in the Turgen and Khangai mountains to their field-mapped MIS 2 ice limits, highlighting a spatially differentiated pattern of paleo-temperature lowering across the studied 700 km NW-SE transect. Taken together, the presented record indicates that the largest ice advance in both investigated mountain ranges occurred during the MIS 5 / MIS 4 transition, despite earlier suggestions by previous studies that the local glacial maximum would be associated with the coldest periods of the last glacial cycle (i.e. MIS 4 or MIS 2). Glacier systems in the Khangai Mountains also increased substantially during MIS 3 (local LGM) in response to cool but comparable wet conditions, probably with a greater-than-today input from winter precipitation and an additional input of recycled moisture from expanded paleo-lakes in the Valley of the Great Lakes. The lack of a severe cooling during the MIS 3 ice advances, and probably also during the late MIS 5 ice expansion, suggests that variations in atmospheric circulation patterns, with its significance for controlling the regional precipitation/moisture supply, was a key driver for these late Pleistocene ice advances in Mongolia. This notwithstanding, there is also clear evidence for the development of an extensive glaciation during MIS 2, coinciding with a period of severe cooling and hyperarid conditions. This highlights that glacier systems in Mongolia responded sensitively, both, to variations in moisture supply and its seasonal distribution, and to the marked insolation minima during the last glacial cycle.