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In this thesis we study various aspects of chaos synchronization of time-delayed coupled chaotic maps. A network of identical nonlinear units interacting by time-delayed couplings can synchronize to a common chaotic trajectory. Even for large delay times the system can completely synchronize without any time shift. In the first part we study chaotic systems with multiple time delays that range over several orders of magnitude. We show that these time scales emerge in the Lyapunov spectrum: Different parts of the spectrum scale with the different delays. We define various types of chaos depending on the scaling of the maximum exponent. The type of chaos determines the synchronization ability of coupled networks. This is, in particular, relevant for the synchronization properties of networks of networks where time delays within a subnetwork are shorter than the corresponding time delays between the different subnetworks. If the maximum Lyapunov exponent scales with the short intra-network delay, only the elements within a subnetwork can synchronize. If, however, the maximum Lyapunov exponent scales with the long inter-network connection, complete synchronization of all elements is possible. The results are illustrated analytically for Bernoulli maps and numerically for tent maps. In the second part the attractor dimension at the transition to complete chaos synchronization is investigated. In particular, we determine the Kaplan-Yorke dimension from the spectrum of Lyapunov exponents for iterated maps. We argue that the Kaplan-Yorke dimension must be discontinuous at the transition and compare it to the correlation dimension. For a system of Bernoulli maps we indeed find a jump in the correlation dimension. The magnitude of the discontinuity in the Kaplan-Yorke dimension is calculated for networks of Bernoulli units as a function of the network size. Furthermore the scaling of the Kaplan-Yorke dimension as well as of the Kolmogorov entropy with system size and time delay is investigated. Finally, we study the change in the attractor dimension for systems with parameter mismatch. In the third and last part the linear response of synchronized chaotic systems to small external perturbations is studied. The distribution of the distances from the synchronization manifold, i.e., the deviations between two synchronized chaotic units due to external perturbations on the transmitted signal, is used as a measure of the linear response. It is calculated numerically and, for some special cases, analytically. Depending on the model parameters this distribution has power law tails in the region of synchronization leading to diverging moments. The linear response is also quantified by means of the bit error rate of a transmitted binary message which perturbs the synchronized system. The bit error rate is given by an integral over the distribution of distances and is studied numerically for Bernoulli, tent and logistic maps. It displays a complex nonmonotonic behavior in the region of synchronization. For special cases the distribution of distances has a fractal structure leading to a devil's staircase for the bit error rate as a function of coupling strength. The response to small harmonic perturbations shows resonances related to coupling and feedback delay times. A bi-directionally coupled chain of three units can completely filter out the perturbation. Thus the second moment and the bit error rate become zero.
Medical history of obesity
(2013)
This paper contains the following sections, in approximate chronological order: Early years, Scientific research on energy metabolism, Clinical teaching, Evidence on health risks, Slow recognition of obesity in diabetes, Depression and war, some Obesity research continued in the 1950s and 1960s, New approaches to management, a Universal standard weight for height, Luxuskonsumption, Calories (incompletely) replaced by Joules, Food intakes of obese people, Genetics, unexpected Surge of obesity from 1980, Diabetes, Scarcity of effective, safe drugs for obesity, Leptin and Ghrelin stimulate basic research, Why has the obesity epidemic happened? What is the best weight-reducing diet? Bariatric surgery
Background: Ketogenic diets (KDs) have gained some popularity not only as effective weight-loss diets and treatment options for several diseases, but also among healthy and physically active individuals for various reasons. However, data on the effects of ketosis in the latter group of individuals are scarce. We therefore collected pilot data on the physiological response to a self-prescribed ketogenic diet lasting 5-7 weeks in a small cohort of healthy and physically active individuals. Methods: Twelve subjects (7 males, 5 females, age 24-60 years) who followed moderate to intensive exercise routines underwent blood testing, bioelectrical impedance analysis (BIA) and spiroergometry during an incremental treadmill test. On the next day, they went on a self-prescribed KD for a median of 38 days (range 35-50 days), after which the same tests were performed again. Ketosis was self-monitored by urinary ketone strips. Subjective feeling during the diet was assessed by a questionnaire after the intervention. Due to the small and heterogenous sample, the results are interpreted in the context of the already existing literature. Results: The KDs were tolerated well by the majority of individuals. Impaired recovery from exercise remained the most frequently reported side effect until the end of the study. Most blood parameters remained stable during the intervention. However, there were significant elevations of total and LDL cholesterol concentrations (p<0.01) and a trend towards increased HDL-cholesterol (p=0.05). The drastic reduction of carbohydrates had no statistically significant influence on running performance judged by the time to exhaustion, VO2max and respiratory compensation points. BIA measurements showed significant increases in phase angle (p=0.01) indicating improvements of body composition with an estimated decrease of 3.4 kg of fat mass (p=0.002) and gain of 1.3 kg of fat free mass. We discuss the validity of these estimates taking into account a possibly altered hydration status due to the KD. Conclusions: Active healthy individuals will probably experience no major problems during a short term KD lasting several weeks. The drastically reduced carbohydrate content of the diet seems to be no limiting factor for running performance. In addition, improvements in body composition can be expected. While most biochemical parameters are not influenced by the diet, there seems to be an impact on the blood lipid profile that could be considered problematic with respect to cardiovascular disease risk. However, the predictive role of cholesterol levels alone in individuals undergoing regular physical activity remains to be elucidated.
Neisseria meningitidis is a facultative human pathogen that occasionally shows strong resistance against serum complement exposure. Previously described factors that mediate meningococcal serum resistance are for example the capsule, LPS sialylation, and expression of the factor H binding protein. I aimed for identification of novel serum resistance factors, thereby following two approaches, i) the analysis of the impact of global regulators of gene expression on serum resistance; and ii) a comparative analysis of closely related strains differing in serum resistance. (i) Of six meningococcal global regulators of gene expression studied, only mutation of the zinc uptake regulator Zur reduced complement deposition on meningococci. Little was known about meningococcal Zur and regulatory processes in response to zinc. I therefore elucidated the yet unidentified meningococcal Zur regulon comparing the transcriptional response of the N. meningitidis strain MC58 under zinc-rich and zinc-deficient conditions using a common reference design of microarray analysis. The meningococcal Zur regulon comprises 17 genes, of which 15 genes were repressed and two genes were activated at high zinc condition. Amongst the Zur-repressed genes were genes involved in zinc uptake, tRNA modification, and ribosomal assembly. A 23 bp meningococcal consensus Zur binding motif (Zur box) with a conserved central palindrome was established (TGTTATDNHATAACA) and detected in the promoter region of all regulated transcriptional units (genes/operons). In vitro binding of meningococcal Zur to the Zur box of three selected genes was shown for the first time using EMSAs. Binding of meningococcal Zur to DNA depended specifically on zinc, and mutations in the palindromic sequence constrained Zur binding to the DNA motif. ii) Three closely related strains of ST-41/44 cc from invasive disease and carriage which differed in their resistance to serum complement exposure were analysed to identify novel mediators of serum resistance. I compared the strains’ gene content by microarray analysis which revealed six genes being present in both carrier isolates, but absent in the invasive isolate. Four of them are part of two Islands of horizontally transferred DNA, i.e. IHT-B and –C. The working group furthermore applied a comprehensive screening assay, a transcriptome and a proteome analysis leading to identification of three target proteins. I contributed to establish the role of these three proteins in serum resistance: The adhesin Opc mediates serum resistance by binding of vitronectin, a negative regulator of the complement system; the hypothetical protein NMB0865 slightly contributes to serum resistance by a yet unknown mechanism; and NspA, recently identified to bind the negative complement regulator factor H, led to considerable reduced complement-mediated killing.
Bees have had an intimate relationship with humans for millennia, as pollinators of fruit, vegetable and other crops and suppliers of honey, wax and other products. This relationship has led to an extensive understanding of their ecology and behavior. One of the most comprehensively understood species is the Western honeybee, Apis mellifera. Our understanding of sex-specific investment in other bees, however, has remained superficial. Signals and cues employed in bee foraging and mating behavior are reasonably well understood in only a handful of species and functional adaptations are described in some species. I explored the variety of sensory adaptations in three model systems within the bees. Females share a similar ecology and similar functional morphologies are to be expected. Males, engage mainly in mating behavior. A variety of male mating strategies has been described which differ in their spatiotemporal features and in the signals and cues involved, and thus selection pressures. As a consequence, males’ sensory systems are more diverse than those of females. In the first part I studied adaptations of the visual system in honeybees. I compared sex and caste-specific eye morphology among 5 species (Apis andreniformis, A. cerana, A. dorsata, A. florea, A. mellifera). I found a strong correlation between body size and eye size in both female castes. Queens have a relatively reduced visual system which is in line with the reduced role of visual perception in their life history. Workers differed in eye size and functional morphology, which corresponds to known foraging differences among species. In males, the eyes are conspicuously enlarged in all species, but a disproportionate enlargement was found in two species (A. dorsata, A. florea). I further demonstrate a correlation between male visual parameters and mating flight time, and propose that light intensities play an important role in the species-specific timing of mating flights. In the second study I investigated eye morphology differences among two phenotypes of drones in the Western honeybee. Besides normal-sized drones, smaller drones are reared in the colony, and suffer from reduced reproductive success. My results suggest that the smaller phenotype does not differ in spatial resolution of its visual system, but suffers from reduced light and contrast sensitivity which may exacerbate the reduction in reproductive success caused by other factors. In the third study I investigated the morphology of the visual system in bumblebees. I explored the association between male eye size and mating behavior and investigated the diversity of compound eye morphology among workers, queens and males in 11 species. I identified adaptations of workers that correlate with distinct foraging differences among species. Bumblebee queens must, in contrast to honeybees, fulfill similar tasks as workers in the first part of their life, and correspondingly visual parameters are similar among both female castes. Enlarged male eyes are found in several subgenera and have evolved several times independently within the genus, which I demonstrate using phylogenetic informed statistics. Males of these species engage in visually guided mating behavior. I find similarities in the functional eye morphology among large-eyed males in four subgenera, suggesting convergent evolution as adaptation to similar visual tasks. In the remaining species, males do not differ significantly from workers in their eye morphology. In the fourth study I investigated the sexual dimorphism of the visual system in a solitary bee species. Males of Eucera berlandi patrol nesting sites and compete for first access to virgin females. Males have enlarged eyes and better spatial resolution in their frontal eye region. In a behavioral study, I tested the effect of target size and speed on male mate catching success. 3-D reconstructions of the chasing flights revealed that angular target size is an important parameter in male chasing behavior. I discuss similarities to other insects that face similar problems in visual target detection. In the fifth study I examined the olfactory system of E. berlandi. Males have extremely long antennae. To investigate the anatomical grounds of this elongation I studied antennal morphology in detail in the periphery and follow the sexual dimorphism into the brain. Functional adaptations were found in males (e.g. longer antennae, a multiplication of olfactory sensilla and receptor neurons, hypertrophied macroglomeruli, a numerical reduction of glomeruli in males and sexually dimorphic investment in higher order processing regions in the brain), which were similar to those observed in honeybee drones. The similarities and differences are discussed in the context of solitary vs. eusocial lifestyle and the corresponding consequences for selection acting on males.
This paper presents an alternative approach for obtaining a converse Lyapunov theorem for discrete–time systems. The proposed approach is constructive, as it provides an explicit Lyapunov function. The developed converse theorem establishes existence of global Lyapunov functions for globally exponentially stable (GES) systems and semi–global practical Lyapunov functions for globally asymptotically stable systems. Furthermore, for specific classes of sys- tems, the developed converse theorem can be used to establish non–conservatism of a particular type of Lyapunov functions. Most notably, a proof that conewise linear Lyapunov functions are non–conservative for GES conewise linear systems is given and, as a by–product, tractable construction of polyhedral Lyapunov functions for linear systems is attained.
The novel refrigerant 2,3,3,3‐tetrafluoropropene (HFO‐1234yf) as well as the novel foam blowing and precision cleaning agent trans‐1‐chloro‐3,3,3‐trifluoropropene (trans‐HCFO‐1233zd) are both chlorofluorocarbon replacements with low GWPs and a short atmospheric life time. Whereas the hydrofluoroolefin HFO‐1234yf has no negative effect on stratospheric ozone due to the lack of chlorine in its structure, the hydrochlorofluoroolefine trans‐HCFO‐1233zd exhibits a very low potential for ozone depletion (ODP). This is approximately 100 times lower than the ozone depletion potential of precursor compounds such as 1,1,2‐trichloro‐1,2,2‐trifluoroethane (CFC‐113). Principle aims of this thesis were to investigate the unknown metabolism of the new solvent trans‐HCFO‐1233zd and to further investigate a possible biotransformation based toxicity of HFO‐1234yf observed in rabbits. Therefore study specimens of different in vitro and in vivo studies with trans‐HCFO‐1233zd and HFO‐1234yf were analyzed for metabolites using 19FNMR spectroscopy, LC‐MS/MS spectrometry and GC/MS spectrometry. Metabolites were identified by comparison with purchased or synthesized standard substances. Excretion kinetics of the predominant metabolites were determined by LC‐MS/MS quantification,inorganic fluoride was determined by potentiometry. Moreover cytochrome P‐450 2E1 and 3A4 liver enzyme activities were measured in a multi‐exposure study with HFO‐1234yf. ...
Body image disturbances are core symptoms of eating disorders (EDs). Recent evidence suggests that changes in body image may occur prior to ED onset and are not restricted to in-vivo exposure (e.g. mirror image), but also evident during presentation of abstract cues such as body shape and weight-related words. In the present study startle modulation, heart rate and subjective evaluations were examined during reading of body words and neutral words in 41 student female volunteers screened for risk of EDs. The aim was to determine if responses to body words are attributable to a general negativity bias regardless of ED risk or if activated, ED relevant negative body schemas facilitate priming of defensive responses. Heart rate and word ratings differed between body words and neutral words in the whole female sample, supporting a general processing bias for body weight and shape-related concepts in young women regardless of ED risk. Startle modulation was specifically related to eating disorder symptoms, as was indicated by significant positive correlations with self-reported body dissatisfaction. These results emphasize the relevance of examining body schema representations as a function of ED risk across different levels of responding. Peripheral-physiological measures such as the startle reflex could possibly be used as predictors of females’ risk for developing EDs in the future.
Objective: Brain-computer interfaces (BCIs) provide a non-muscular communication channel for patients with late-stage motoneuron disease (e.g., amyotrophic lateral sclerosis (ALS)) or otherwise motor impaired people and are also used for motor rehabilitation in chronic stroke. Differences in the ability to use a BCI vary from person to person and from session to session. A reliable predictor of aptitude would allow for the selection of suitable BCI paradigms. For this reason, we investigated whether P300 BCI aptitude could be predicted from a short experiment with a standard auditory oddball. Methods: Forty healthy participants performed an electroencephalography (EEG) based visual and auditory P300-BCI spelling task in a single session. In addition, prior to each session an auditory oddball was presented. Features extracted from the auditory oddball were analyzed with respect to predictive power for BCI aptitude. Results: Correlation between auditory oddball response and P300 BCI accuracy revealed a strong relationship between accuracy and N2 amplitude and the amplitude of a late ERP component between 400 and 600 ms. Interestingly, the P3 amplitude of the auditory oddball response was not correlated with accuracy. Conclusions: Event-related potentials recorded during a standard auditory oddball session moderately predict aptitude in an audiory and highly in a visual P300 BCI. The predictor will allow for faster paradigm selection. Significance: Our method will reduce strain on patients because unsuccessful training may be avoided, provided the results can be generalized to the patient population.
Optical in vivo imaging methods have advanced the fields of stem cell transplantation, graft-versus–host disease and graft-versus-tumor responses. Two well known optical methods, based on the transmission of light through the test animal are bioluminescence imaging (BLI) and fluorescence imaging (FLI). Both methods allow whole body in vivo imaging of the same animal over an extended time span where the cell distribution and proliferation can be visualized. BLI has the advantages of producing almost no unspecific background signals and no necessity for external excitation light. Hence, BLI is a highly sensitive and reliable detection method. Yet, the BLI reporter luciferase is not applicable with common microscopy techniques, therefore abolishing this method for cellular resolution imaging. FLI in turn, presents the appealing possibility to use one fluorescent reporter for whole body imaging as well as cellular resolution applying microscopy techniques. The absorption of light occurs mainly due to melanin and hemoglobin in wavelengths up to 650 nm. Therefore, the wavelength range beyond 650 nm may allow sensitive optical imaging even in deep tissues. For this reason, significant efforts are undertaken to isolate or develop genetically enhanced fluorescent proteins (FP) in this spectral range. “Katushka” also called FP635 has an emission close to this favorable spectrum and is reported as one of the brightest far-red FPs. Our experiments also clearly showed the superiority of BLI for whole body imaging over FLI. Based on these results we applied the superior BLI technique for the establishment of a pre-clinical multiple myeloma (MM) mouse model. MM is a B-cell disease, where malignant plasma cells clonally expand in the bone marrow (BM) of older people, causing significant morbidity and mortality. Chromosomal abnormalities, considered a hallmark of MM, are present in nearly all patients and may accumulate or change during disease progression. The diagnosis of MM is based on clinical symptoms, including the CRAB criteria: increased serum calcium levels, renal insufficiency, anemia, and bone lesions (osteolytic lesions or osteoporosis with compression fractures). Other clinical symptoms include hyperviscosity, amyloidosis, and recurrent bacterial infections. Additionally, patients commonly exhibit more than 30% clonal BM plasma cells and the presence of monoclonal protein is detected in serum and/or urine. With current standard therapies, MM remains incurable and patients diagnosed with MM between 2001 and 2007 had a 5-year relative survival rate of only 41%. Therefore, the development of new drugs or immune cell-based therapies is desirable and necessary. To this end we developed the MOPC-315 cell line based syngeneic MM mouse model. MOPC-315 cells were labeled with luciferase for in vivo detection by BLI. We validated the non-invasively obtained BLI data with histopathology, measurement of idiotype IgA serum levels and flow cytometry. All methods affirmed the reliability of the in vivo BLI data for this model. We found that this orthotopic MM model reflects several key features of the human disease. MOPC-315 cells homed efficiently to the BM compartment including subsequent proliferation. Additionally, cells disseminated to distant skeletal parts, leading to the typical multifocal MM growth. Osteolytic lesions and bone remodeling was also detected. We found evidence that the cell line had retained plasticity seen by dynamic receptor expression regulation in different compartments such as the BM and the spleen.
Background: Measles virus (MV) causes T cell suppression by interference with phosphatidylinositol-3-kinase (PI3K) activation. We previously found that this interference affected the activity of splice regulatory proteins and a T cell inhibitory protein isoform was produced from an alternatively spliced pre-mRNA. Hypothesis: Differentially regulated and alternatively splice variant transcripts accumulating in response to PI3K abrogation in T cells potentially encode proteins involved in T cell silencing. Methods: To test this hypothesis at the cellular level, we performed a Human Exon 1.0 ST Array on RNAs isolated from T cells stimulated only or stimulated after PI3K inhibition. We developed a simple algorithm based on a splicing index to detect genes that undergo alternative splicing (AS) or are differentially regulated (RG) upon T cell suppression. Results: Applying our algorithm to the data, 9% of the genes were assigned as AS, while only 3% were attributed to RG. Though there are overlaps, AS and RG genes differed with regard to functional regulation, and were found to be enriched in different functional groups. AS genes targeted extracellular matrix (ECM)-receptor interaction and focal adhesion pathways, while RG genes were mainly enriched in cytokine-receptor interaction and Jak-STAT. When combined, AS/RG dependent alterations targeted pathways essential for T cell receptor signaling, cytoskeletal dynamics and cell cycle entry. Conclusions: PI3K abrogation interferes with key T cell activation processes through both differential expression and alternative splicing, which together actively contribute to T cell suppression.
Atomare Ketten, sogenannte Nano-Drähte, entstehen durch Selbstorganisation adsorbierter Metallatome auf einer Halbleiteroberfläche. Aufgrund der starken räumlichen Einschränkung der Ladungsträger innerhalb dieser Ketten entsteht dabei oftmals eine metallische Bandstruktur mit starker Anisotropie. Im Falle phononischer Ankopplung an das Substrat kann so ein eindimensionales (1D) Metall instabil gegen eine periodische Gitterverzerrung werden, bei der es zu einer Ausbildung einer Energielücke kommt. Dieser Metall-Isolator-Übergang wird dabei als Peierls Übergang bezeichnet. Für verschwindend geringe Kopplung der Ketten untereinander bzw. an das Substrat, d.h. im strikt eindimensionalen Fall, bricht das Fermi Flüssigkeitsmodell für dreidimensionale (3D) Metalle zusammen. Dessen Quasiteilchen werden durch kollektive Anregungen von Spin und Ladung ersetzt. Diesen Zustand bezeichnet man als Tomonaga-Luttinger Flüssigkeit. Beide Phänomene, Peierlsübergang und Tomonaga-Luttinger Flüssigkeit lassen sich anhand der elektronischen Bandstruktur experimentell nachweisen. Bei dem hier untersuchten Probensystem handelt es sich um Gold-induzierte Nandrähte auf der Germanium (001)-Oberfläche, kurz Au/Ge(001). Deren Wachstum erfolgt epitaktisch entlang der durch das Substrat vorgegebenen Dimer-Reihen, welche die freie Germaniumoberfläche in Form einer (2×1)-Symmetrie einnimmt. Die abwechselnde Stapelfolge ABAB des Substrates führt dabei zu zwei unterschiedlichen Drahtrichtungen, die jeweils um 90° zueinander gedreht sind, wenn man eine Einfachstufe von 1.4 A von einer A-Terrasse auf eine B-Terrasse oder umgekehrt geht. Die vorherrschende Kinetik während der Gold-Deposition bzw. das Benetzungsverhalten ermöglicht dabei eine vollständige Bedeckung der vormals freien Oberfläche mit Nanodrähten, deren Abmessungen einzig und allein durch Defekte bzw. die Größe der darunterliegenden Ge-Terrasse begrenzt sind. Um die Längenskala der Subtrat-Terrassen zu optimieren, wurde eine Reinigungsprozedur für Ge (001) entwickelt, bei der nass-chemisches Ätzen mit anschliessender Trocken-Oxidation zum Einsatz kommt. Die darauf aufbauenden Nanodrähte wurden im Anschluss mittels winkelaufgelöster Photoelektronenspektroskopie auf ihre elektronische Bandstruktur untersucht. Dabei wurden zwei neuartige Zustände beobachtet: ein metallischer, zweidimensionaler Loch-Zustand, der seinen Ursprung höchstwahrscheinlich in tieferen Schichten des Germaniums hat; und ein eindimensionaler Oberflächenzustand mit elektronenartiger Dispersion, dessen bandintegrierte Spektralfunktion von der einer Fermiflüssigkeit abweicht. Stattdessen wird ein exponentieller Abfall des spektralen Gewichtes als Funktion der Energie zum Ferminiveau hin beobachtet. Dieses Verhalten kann über einen weiten Temperaturbereich beobachtet werden und lässt sich mit der Tomonaga-Luttinger Flüssigkeit für strikt eindimensionale Systeme erklären. Zum weiteren theoretischen Verständnis dieses Phänomes, beispielsweise durch Bandstrukuturrechnungen mittels Dichte-Funktional-Theorie, bedarf es der genauen Kenntnis der atomaren Struktur dieser Ketten. Selbige wurde mittels Oberflächenröntgenbeugung (engl. surface x-ray diffraction, SXRD) untersucht. Auf Basis der gewonnenen Patterson-Karte lassen sich Rückschlüsse auf die interatomaren Abstände der Goldatome untereinander in der Einheitszelle ziehen. Dies stellt einen ersten wichtigen Schritt auf dem Weg zu einem vollständigen Strukturmodell dar. Darüber hinaus wurden erste vielversprechende Schritte unternommen, das Nanodrahtsystem kontrolliert zu manipulieren. Durch geringfügige, zusätzliche Deposition von Kalium konnte dabei eine schrittweise Erhöhung der Bandfüllung erzielt werden. Für weitergehende Kaliumanlagerungen im (Sub-)Monolagenbereich konnte sogar eine neue Rekonstruktion erzielt werden.
Introduction: Colon cancer is one of the major human malignancies worldwide, and much effort has been applied to understand the process of colon carcinogenesis, as well as the role of potential treatments and co-therapeutical agents against it. A growing body of evidence suggests that the use of fluoxetine (FLX), an antidepressant belonging to the selective serotonin reuptake inhibitors (SSRIs), may be associated with a reduced colon cancer risk. However, controversial opinions have been published and an identification of the mechanisms of the activity of FLX on colon cells would help in the clarification of this controversy. Objectives: Using several in vitro and in vivo-based methods and analyses, we aimed to verify whether FLX has antioxidant, pro-oxidant or DNA-damaging potential in standard toxicological assays; to check whether and how FLX could prevent and reduce colon preneoplastic lesions; to ascertain whether FLX has any oncostatic potential against colon tumors; and, to investigate whether FLX activity could be comparable with a known and current applied chemotherapeutic agent against colon cancer. Results: FLX did not have any antioxidant potential in our experiments. Although it did not induce reactive oxygen species (ROS) generation or DNA-damage in fibroblast and colon tumor cell lines, FLX reduced dysplasia and proliferation in two different carcinogen models. Further, a significant decrease in colon stromal reactivity and angiogenesis was found in both carcinogen-induced preneoplasia models. In a xenograft model of colon cancer, FLX shrank tumors, reduced tumor proliferation, arrested cancer cells at the G0/G1 cell-cycle phase, and took ROS generation under control. Such effects were detected together with an intracellular acidification and loss of mitochondrial membrane potential in FLX-treated cells. Modulating mitochondrial respiratory chain, HIF-1 expression and Akt/mTOR signaling pathway, FLX was found to reduce colon tumors similar to the widely used chemotherapeutic agent 5-Fluoracil activity. Conclusion: Our collective data suggest that FLX is a remarkable chemopreventive and oncostatic agent against colon preneoplastic lesions and tumors, acting without DNA-damage or ROS generation.
Neurotrophic factor signaling modulates differentiation, axon growth and maintenance, synaptic plasticity and regeneration of neurons after injury. Ciliary neurotrophic factor (CNTF), a Schwann cell derived neurotrophic factor, has an exclusive role in axon maintenance, sprouting and synaptic preservation. CNTF, but not GDNF, has been shown to alleviate motoneuron degeneration in pmn mutant mice carrying a missense mutation in Tbce gene, a model for Amyotrophic Lateral Sclerosis (ALS). This current study elucidates the distinct signaling mechanism by which CNTF rescues the axonal degeneration in pmn mutant mice. ...
Critical illness like sepsis, shock, and intestinal bowel disease are one of the leading causes of morbidity and mortality in the US and around the world. At present, studies to define new therapeutic interventions that can protect tissues and cells against injury and attenuate inflammation are fields of intense investigation. While research over the past decade has clearly identified GLN as a vital stress substrate facilitating cellular survival following injury, the initiation steps in GLN’s cytoprotective molecular mechanism still remain elusive. Previously published work suggested that stabilization of ECM proteins and activation of ECM receptor osmosignaling may play a central role in the orchestration of many cellular pathways following stress. Thus, I hypothesized that preservation of ECM protein and EGFR levels as well as ECM receptor signaling play key roles in the molecular mechanisms underlying GLN’s protection against thermal injury in the intestine. I was able to confirm via Western blotting and by using silencing RNA against FN, Ntn-1, EGFR, and their negative controls, that GLN-mediated preservation of FN, Ntn-1, and EGFR levels is critical in GLN’s protection against hyperthermia in IEC-6 cells. By using a selective FN-Integrin interaction inhibitor GRGDSP, its negative control peptide GRGESP, and Src-kinase inhibitor PP2, I showed that FN-Integrin signaling and Src-kinase activation are essential in GLN-mediated protection in the intestine. This applied to EGFR signaling as demonstrated using the EGFR tyrosine kinase inhibitor AG1478. In addition to GRGDSP and AG1478, ERK1/2 inhibitors PD98059 and UO126 as well as the p38MAPK inhibitor SB203580 revealed that GLN is protective by activating ERK1/2 and dephosphorylating p38MAPK via FN-Integrin and EGFR signaling. However, GLN-mediated PI3-K/Akt/Hsp70 activation seems to occur independently of FN-Integrin and EGFR signaling as indicated by Western blots as well as experiments using the PI3-K inhibitor LY294002, GRGDSP, and AG1478. The results showed that GLN activates cell survival signaling pathways via integrins as well as EGFRs after hyperthermia. Moreover, I found that GLN-mediated preservation of FN expression after HS is regulated via PI3-K signaling. Whether GLN-mediated PI3-K signaling happens simultaneously to FN-Integrin and EGFR signaling or whether PI3-K signaling coordinates FN-Integrin and EGFR signaling needs to be investigated in future studies. Further, experiments with PD98059 and GRGDSP revealed that ERK1/2 assists in mediating transactivation of HSF-1 following HS. This leads to increases in Hsp70 expression via FN-Integrin signaling, which is known to attenuate apoptosis after thermal injury. Fluorescence microscopy results indicated that HS and GLN regulate cell are size changes and the morphology of F-actin via FN-Integrin signaling. Experiments using GRGDSP and GRGESP showed that GLN enhances cellular survival via FN-Integrin signaling in a manner that does not require increased intracellular GLN concentrations (as quantified using LC-MS/MS). In summary, my thesis work gives new and potentially clinically relevant mechanistic insights into GLN-mediated molecular cell survival pathways. These results warrant clinical translation to assess if clinical outcome of critically ill patients suffering from gastrointestinal diseases can be improved by GLN treatment and/or by targeting the molecular pathways found in my studies.
The functional role of human gut microbiota has attracted substantial interest and recent research has uncovered various aspects of the interplay between the complex communities of microorganisms colonizing the intestine and their hosts’ health. The present review focuses on nutrition-derived bioactive metabolites produced by gut microbiota with potential beneficial effects upon human health. Thereby, the emphasis is on newly generated bacterial metabolites that are not concomitantly present at higher amounts in dietary sources and that have been previously detected in human blood samples. Since a multitude of different substances is generated by gut microbes primarily those metabolites which exert a more pronounced activity than their immediate precursor compound are discussed here. Specifically, the in vitro and in vivo nutridynamics as well as the nutrikinetics of equol, enterolactone / enterodiol, urolithins, 8-prenylnaringenin, 3,4-dihydroxyphenylacetic acid and 5-(3’,4’-dihydroxyphenyl)-g-valerolactone, the short-chain fatty acids butyrate, propionate and acetate, and indole-3-propionic acid are reviewed. Though the metabolites’ mechanism of action and the influence of health conditions on metabolite production are not always fully understood yet, there are many reasons to direct the attention to “gut health”. It could offer new options for preventing or treating a variety of disease states and nutrition-derived microbial products might inspire future drug development.
The aim of this study was both to investigate the influence of cognitive control on unconscious processing, and to investigate the influence of unconscious processing on cognitive control. At first, different mechanisms and accounts to explain unconscious priming are presented. Here, perceptual and motor processes, as well as stimulus-response learning, semantic categorization, and the action trigger account as theories to explain motor priming are discussed. Then, the issue of the potential limits of unconscious processing is presented. Findings that indicate that active current intentions and expertise modulate unconscious processing are illustrated. Subsequently, results that imply an influence of unconsciously presented stimuli that goes beyond motor processes are discussed, with a special focus on inhibition processes, orienting of attention, task set activation, and conflict adaptation. Then I present the results of my own empirical work. Experiment 1 shows that the effective processing of unconsciously presented stimuli depends on expertise, even when potentially confounding difference between the expert and novice groups are controlled. The results of Experiments 2 and 3 indicate that the intention to use particular stimuli is a crucial factor for the effectiveness of these stimuli when they are presented unconsciously. Additionally, these findings show that shifts of attention can be triggered by centrally presented masked arrow cues. Experiments 4 and 5 broaden these results to cue stimuli that are not inherently associated with a spatial meaning. The finding corroborate that typically endogenously controlled shifts of attention can also be induced by unconscious stimuli. Experiments 6 and 7 demonstrate that even a central cognitive control process like task set activation is not contingent on conscious awareness, but can in contrast be triggered through unconscious stimulation. Finally, these results are integrated and I discuss how the concept of cognitive control and the limits of unconscious processing may have to be reconsidered. Furthermore, potential future research possibilities in this field are presented.
Renewal of fear is one form of relapse that occurs after successful therapy, resulting from an encounter with a feared object in a context different from the context of the exposure therapy. According to Bouton (1994), the return of fear, provoked by context change, indicates that the fear was not erased in the first place. More importantly, the return of fear indicates that during the exposure session a new association was learned that connected the feared object with “no fear”; yet, as Bouton further argues, this association is context dependent. Such dependence could explain effects like renewal. In a new context, the therapeutic association will not be expressed and thus will no longer inhibit the fear. The assumption that an association is context dependent has been tested and showed robust results (Balooch & Neumann, 2011; Siavash Bandarian Balooch, Neumann, & Boschen, 2012; Culver, Stoyanova, & Craske, 2011; Kim & Richardson, 2009; Neumann & Kitlertsirivatana, 2010). Research for the treatment of anxiety disorders, aiming to reduce fear and, more importantly, prevent relapse, is flourishing. There are several exposure protocols currently under investigation: multiple contexts exposure (MCE), which aims at reducing the return of fear due to renewal (e.g., Balooch & Neumann, 2011); prolonged exposure (PE), which aims at strengthening the inhibitory association during the extinction learning (e.g., Thomas, Vurbic, & Novak, 2009); and reconsolidation update (RU), which aims at “updating” the reconsolidation process by briefly exposing the CS+ before the actual extinction takes place (Schiller et al., 2010). So far, however, few clinical studies conducted on humans have investigated these novel treatment protocols, and as far as I know none has investigated the mechanisms of action behind these protocols with a human clinical sample. The present thesis has three main goals. The first is to demonstrate that exposure therapy in multiple contexts reduces the likelihood of renewal. The second is to examine the mechanisms contributing to the effect of MCE and the third is to shed light on the concept of context in the framework of the conditioning and extinction paradigm. To this end, three studies were conducted. The first study investigated the effect of MCE on renewal, the second and third studies examined working mechanisms of MCE. In the first study thirty spider-phobic participants were exposed four times to a virtual spider. The exposure trials were conducted either in one single context or in four different contexts. Finally, all participants completed both a virtual renewal test, with the virtual spider presented in a novel virtual context, and an in vivo behavioral avoidance test with a real spider. This study successfully demonstrated the efficacy of MCE on reducing renewal. Study 2 investigated the working mechanisms behind MCE by utilizing a differential conditioning paradigm and conducting the extinction in multiple contexts, targeting similar renewal attenuation as achieved in study 1. This was followed by two tests that attempted to reveal extinction-relevant associations like ones causing context inhibitory effects. This study had three main hypotheses: (1) The extinction context is associated with the exposure, and thus operates as a safety signal at some point during the extinction; it will therefore compete with the safety learning of the CS, leading to a decreased extinction effect on the CS if the extinction is conducted in only one context. (2) The elements (e.g., room color, furniture) of the extinction context are connected to the therapeutic association and therefore should serve as reminders of the extinction, causing a stronger fear inhibition when presented during a test. (3) Therapy process factors, according to emotional processing theory, determine the renewal effect (e.g., initial fear activation, and within-session and between-session activation are correlated with the strength of renewal). In this study, however, no differences between the groups at the renewal phase were observed, presumably because the extinction was too strong to enable a renewal of fear at the test phase conducted immediately following the extinction. This hence rendered the two inhibitory tests useless. Study 3 aimed at defining the concept of context in the conditioning and exposure framework. Study 3 utilized the phenomenon known as generalization decrement, whereby a conditioned response is reduced due to change in the environment. This allowed context similarity to be quantified. After an acquisition phase in one context, participants were tested in one of three contexts, two of which differed in only one dimension (configuration of objects vs. features). The third group was tested in the same context and served as control group. The goal was to show that both configuration and features play an important role in the definition of context. There was, however, no significant statistical difference between the groups at the test phases, likely because of context novelty effects (participants exposed to a new context following extinction in another context expected a second extinction phase, and thus demonstrated greater fear than expected in all three groups).