The convergence of psychology and neurobiology in flavor-nutrient learning

Flavor evaluation is influenced by learning from experience with foods. One main influence is flavor-nutrient learning (FNL), a Pavlovian process whereby a flavor acts as a conditioned stimulus (CS) that becomes associated with the postingestive effects of ingested nutrients (the US). As a result that flavor becomes preferred and intake typically increases. This learning powerfully influences food choice and meal patterning. This paper summarizes how research elucidating the physiological and neural substrates of FNL has progressed in parallel with work characterizing how FNL affects perception, motivation, and behavior. The picture that emerges from this work is of a robust system of appetition (a term coined by Sclafani in contrast to the better-understood satiation signals) whereby ingested nutrients sensed in the gut evoke positive motivational responses. Appetition signals act within a meal to promote continued intake in immediate response to gut feedback, and act in the longer term to steer preference towards sensory cues that predict nutritional consequences

The convergence of psychology and neurobiology in flavor-nutrient learning

Flavor evaluation is influenced by learning from experience with foods. One main influence is flavor-nutrient learning (FNL), a Pavlovian process whereby a flavor acts as a conditioned stimulus (CS) that becomes associated with the postingestive effects of ingested nutrients (the US). As a result that flavor becomes preferred and intake typically increases. This learning powerfully influences food choice and meal patterning. This paper summarizes how research elucidating the physiological and neural substrates of FNL has progressed in parallel with work characterizing how FNL affects perception, motivation, and behavior. The picture that emerges from this work is of a robust system of appetition (a term coined by Sclafani in contrast to the better-understood satiation signals) whereby ingested nutrients sensed in the gut evoke positive motivational responses. Appetition signals act within a meal to promote continued intake in immediate response to gut feedback, and act in the longer term to steer preference towards sensory cues that predict nutritional consequences

Induction and metastasis of cancer stem cells in pancreatic cancer

Pancreatic cancer is one of the most lethal of all types of cancer with an overall 5-year survival rate of less than 8%. Cancer cells in pancreatic tumor are heterogeneous, and it is poorly understood which population is most responsible for the cancer initiation, progression and metastasis. Recent studies provide evidence for the existence of a highly tumorigenic and metastatic cells within a heterogeneous tumor known as the cancer stem cells (CSCs). Studies also provided ample evidence for the existence of distinct types of CSC populations in a heterogeneous tumor with type specific genotypic, phenotypic and functional characteristics. But, it is not clear how CSCs are induced, and how these cells are involved in the metastasis process. Several external factors such as cigarette smoking and alcohol consumption have been shown to induce CSCs in lung and breast cancers. Cigarette smoking is also associated with 30% of pancreatic cancer cases. The association of smoking with CSC induction is also well appreciated in lung cancer and other cancers. Based on these studies, we aimed to investigate whether and how cigarette smoke induce CSCs in pancreatic cancer in the first part of my dissertation. My second goal primarily explores the metastatic function of CSCs in pancreatic cancer. Previous studies have shown the existence of distinct CSC populations in a heterogeneous tumor. For instance, breast tumors consist of two distinct CSC populations such as ALDH+ and CD44+CD24-. The study also demonstrated that ALDH+ cells rely on oxidative phosphorylation for their energy needs, whereas CD44+CD24- population rely on glycolysis. Recent studies also proposed the propensity of a specific cancer cell with specific metabolic profile metastasizes to specific organ. For instance, liver has a high glycolytic environment, and a metastatic cell required to be highly glycolytic in nature to overcome the glycolytic barrier in the liver. Based on these studies, we have hypothesized that distinct types of CSC populations with type specific stemness and metabolic profiles metastasize to specific organ. Overall, my dissertation is broadly divided into two major chapters. We experimentally demonstrated that cigarette smoke induces pancreatic CSC populations by activating CHRNA7 mediated FOSL1 signaling. We also demonstrated for the first time that pancreatic tumors consist of distinct sub-types of CSC populations with sub-type specific stem cell and metabolic features. I also experimentally proved that distinct sub-types of CSC populations with type-specific metabolic profiles are involved in organ-specific metastasis. Taken together, our findings demonstrate a clear mechanism of CSC induction. In addition, our investigation suggests the existence of distinct sub-types of CSC populations with specific metabolic, stemness and metastatic profiles. In conclusion, our work provides a solid foundation for the understanding of CSCs in pancreatic cancer thereby opening new avenues for further research in developing CSC-targeted therapy for pancreatic cancer and its metastasis

Electronic spectra of simple main group inorganic and organometallic systems

The purpose underlying the researches described in this thesis is an attempt to understand the bonding and electronic structure of some simple inorganic and organometallic systems. The particular molecules chosen for study were the Selenium containing linear triatomic species OCSe, SCSe, CSe₂ and the main group metallocenes M(C₅H₅)n n = 1, M = Tl & In ; n= 2, M =Pb, Sn &Hg.In all cases the technique of ultraviolet photoelectron spectroscopy was employed and the (vacuum) ultraviolet absorption spectra of OCSe, SCSe & CSe₂ were also recorded. The major features of the photoelectron spectra were interpreted as arising from ionization from the filled valence levels obtained from simple schemes derived from Mulliken-Hund molecular orbital theory3. The absorption spectra were analysed in terms of transitions from these filled valence shell orbitals to the various empty valence and atomic like Rydberg4 orbitals of the molecule. In addition, weaker features in the photoelectron spectra of CSe₂ and SCSe were attributed to formally forbidden one photon transitions involving simultaneous ionization and electronic excitation

Theoretical Analysis of Biomolecular Systems: Computational Simulations, Core-set Markov State Models, Clustering, Molecular Docking

The analysis of the structural and the dynamical behavior of biomolecules is very important to under- stand their biological function, stability or physico-chemical properties. In this thesis, it is highlighted how different theoretical methods to characterize the aforementioned structural and dynamical properties can be used and combined, to obtain kinetic information or to detect biomolecule-ligand interactions. The basis for most of the analyses, performed in the course of this work, are molecular dynamics sim- ulations sampling the conformational space of the biomolecule of interest. Using molecular dynamics simulations, the remarkable stable water-soluble-binding-protein is examined first. On a theoretical ba- sis, structural modifications that can influence the stability of the protein are discussed. Additionally, by combining the simulations with a QM/MM optimization scheme and quantum chemical calculations, spectroscopical properties can be investigated. Markov State Models are applied frequently to capture the slow dynamics within simulation trajectories. They are based on a discretization of the conformational space. This discretization, however, introduces an error in the outcome of the analysis. The application of a core-set discretization can reduce this error. In this thesis, it is discussed how density-based cluster algorithms can be used to determine these core sets, and the application on linear and cyclic peptides is highlighted. The performance of a promising cluster algorithm is investigated and error sources in the construction of the Markov models are discussed. Finally, it is shown how molecular docking combined with molecular dynamics simulations can be used to determine the binding behavior of ligands towards biomolecules. In this context, the important in- teractions within the active site of an enzyme, and different binding modes of DNA intercalators are identified

Ultraviolet Absorption Properties of Diatomic Sulfur

Diatomic Sulfur, S2, is present in the atmospheres of Jupiter and its moon, Io. It is very difficult to obtain an S2 spectrum in the laboratory; when heated, elemental sulfur forms many different gaseous species including S2, S3, and S4. We use a two-temperature furnace and absorption cell to create conditions of high temperature and low pressure, which favor pure S2 formation. Using high resolution measurements from the National Institute of Standards and Technology in Gaithersburg, Maryland, we quantified oscillator strengths for atmospheric modeling purposes. This work is generously supported by the Jerome A. Schiff Fellowship

Exchange representations in Kohn-Sham theory

Kohn-Sham density functional theory (DFT) is the most widely used method in quantum chemistry. It has the potential to provide accurate results at low computational cost. The quality of a DFT calculation is determined by the exchange-correlation energy functional. Hybrid functionals, which contain a fraction of exact orbital exchange, are extensively used due to their accuracy in a variety of applications. However, as commonly implemented, these functionals are outside the Kohn-Sham scheme, since the exchange operator is not a local multiplicative potential. In order to handle orbital dependent functionals correctly, schemes which determine a local multiplicative potential must be employed. The implementation and application of several such methods is the focus of this thesis. In Chapter 1 we outline the Hartree-Fock scheme, which defines the exchange energy, and overview wavefunction based procedures that recover correlation energy. Alternative theories based on the electron density are then considered and the foundations of modern DFT are reviewed. The formalism of the optimized effective potential (OEP) method is introduced, which is the rigorous way to handle orbital dependent functionals. A number of approximations to the exchange only OEP method are outlined in Chapter 2 and their implementation is described. The methods are applied to the calculation of NMR shielding constants, highlighting differences between the approximations; their use in the construction of multiplicative hybrid functionals is also considered. In Chapter 3 these approximations are further investigated in the calculation of excited states and structural perturbations. In Chapter 4, the theory and implementation of a direct optimization procedure to determine OEPs is outlined, along with an implementation of the constrained search procedure, which allows the determination of the Kohn-Sham exchange-correlation potential from any input density. Chapter 5 compares the performance of the approximate exchange potentials with those of OEP, highlighting the presence of correlated character in some of the approximate methods. The OEP implementation is extended to include hybrid exchange-correlation functionals in Chapter 6. The performance of these methods for the calculation of NMR shielding constants, rotational g tensors and transition metal NMR chemical shifts is investigated. In all cases, substantial improvements over conventional results are obtained. In Chapter 7 DFT is used to investigate an interaction of relevance in organic chemistry. Concluding remarks are given in Chapter 8

Die Auswirkung von Zigarettenrauch auf das Atemwegsepithelium von Drosophila melanogaster zur Modellierung von COPD-ähnlichen Phänotypen

Cigarette smoking is the major risk factor for Chronic obstructive pulmonary disease (COPD) and lung cancer. Although COPD is one of the most important chronic lung diseases, our knowledge about the underlying molecular framework is only fragmentary. Hence, this study introduces D. melanogaster as a novel model for basic COPD research. Various cigarette smoke exposure (CSE) models using different exposure regimes were implemented in the course of this study and the in vivo impact of CSE was analyzed using 3rd instar larvae. The airways showed a strong structural modification and an activation of JAK-STAT signaling in the epithelial cells of CS treated animals. Both, upd2 and upd3 and the receptor dome of the JAK-STAT pathway, were strongly expressed at the posterior end of the dorsal branches, indicative for an autocrine signaling. The exact function and role of these ligands, especially in the tracheal system of D. melanogaster is still poorly understood. In silico analysis of the structures of upd3 with IL-6 of mouse, implied an ancestral relationship between both cytokines. Moreover, an ectopic expression of the JAK-STAT pathway components in the trachea resulted into epithelial barrier disruption in form of meta- and hyperplasia. To unravel potential upstream regulators of these upd ligands, flies deficient in expression of either dFoxO or relish were used and exposed to CS. Especially, in dFoxO deficient flies, induction of upd2 and upd3 transcripts were significantly reduced. Electrophoretic mobility shift assays underlining the potential role of dFoxO in directly regulating upd2 and upd3 expression. Furthermore, CS results in structural remodeling including thickening of the epithelial layer, in parallel with JAK/STAT signaling activation that may be triggered by dFoxO. Beside this CSE based model for COPD research, destruction of the terminal airway structure via strong activation of cAMP signaling was induced.Tabakrauchen ist der größte Risikofaktor für COPD und Lungenkrebs. Unser Wissen über die zugrunde liegenden molekularen Signalwege und Gene ist derzeit nur bruchstückhaft. Die vorliegende Arbeit hatte daher zum Ziel, D. melanogaster als ein neues Modell für die Grundlagenforschung der COPD einzuführen. Die Relevanz von Zigarettenrauch im Atemwegsepithelium wurde untersucht und eine epitheliale Immunreaktion gezeigt. Die Applikation von Zigarettenrauch hatte eine Beeinträchtigung der epithelialen Barriere und eine Aktivierung des JAK-STAT-Signalwegs zur Folge. Es erfolgte eine induzierte Expression von Upd2 und Upd3 sowie des Rezeptors Domeless an den dorsalen Verzweigungen der primären Tracheen, was für ein autokrines Signalisierungssystem spricht. Die Funktion dieser Liganden sind vor allem in den Tracheen noch weitgehend unverstanden. Daher wurden sowohl strukturelle Vergleiche von upd3 mit der bekannten Kristallstruktur von IL-6 als auch eine funktionelle Überexpression dieser Liganden in den Tracheen vorgenommen, um diese näher charakterisieren zu können. Eine ektopische Expression im Atemwegsepithel führte zu einer Störung der Epithelbarriere in Form einer Meta- und Hyperplasie. Um mögliche Regulatorgene für die Expression der Upd-Liganden zu entschlüsseln, wurden Mutanten, defizient in den Transkriptionsfaktoren dFoxO und Relish verwendet und beraucht. Insbesondere in dFoxO defizienten Fliegen war die Induktion der Upd2 und Upd3- Transkripte deutlich reduziert. Bandshiftassays unterstreichen die potentielle Rolle von dFoxo in seiner direkten Regulation von Upd2 und Upd3. Weiterhin führt Zigarettenrauch zur Atemwegsmodelierung in Form einer verdickten Epithelschicht, das mit einer parallelen Aktivierung des JAK-STAT-Signalweges einhergeht, welcher vermutlich dFoxO abhängig ist. Neben dem Zigarettenrauch-Modell für die COPD-Forschung, wurde ein alternatives Modell entwickelt, das sich der Bedeutung des cAMP-Signalings im Atemwegsepithel widmet