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Monoclonal antibodies (mAbs) are engineered immunoglobulins G (IgG) used for more than 20 years as targeted therapy in oncology, infectious diseases and (auto-)immune disorders. Their protein nature greatly influences their pharmacokinetics (PK), presenting typical linear and non-linear behaviors.
While it is common to use empirical modeling to analyze clinical PK data of mAbs, there is neither clear consensus nor guidance to, on one hand, select the structure of classical compartment models and on the other hand, interpret mechanistically PK parameters. The mechanistic knowledge present in physiologically-based PK (PBPK) models is likely to support rational classical model selection and thus, a methodology to link empirical and PBPK models is desirable. However, published PBPK models for mAbs are quite diverse in respect to the physiology of distribution spaces and the parameterization of the non-specific elimination involving the neonatal Fc receptor (FcRn) and endogenous IgG (IgGendo). The remarkable discrepancy between the simplicity of biodistribution data and the complexity of published PBPK models translates in parameter identifiability issues.
In this thesis, we address this problem with a simplified PBPK model—derived from a hierarchy of more detailed PBPK models and based on simplifications of tissue distribution model. With the novel tissue model, we are breaking new grounds in mechanistic modeling of mAbs disposition: We demonstrate that binding to FcRn is indeed linear and that it is not possible to infer which tissues are involved in the unspecific elimination of wild-type mAbs. We also provide a new approach to predict tissue partition coefficients based on mechanistic insights: We directly link tissue partition coefficients (Ktis) to data-driven and species-independent published antibody biodistribution coefficients (ABCtis) and thus, we ensure the extrapolation from pre-clinical species to human with the simplified PBPK model. We further extend the simplified PBPK model to account for a target, relevant to characterize the non-linear clearance due to mAb-target interaction.
With model reduction techniques, we reduce the dimensionality of the simplified PBPK model to design 2-compartment models, thus guiding classical model development with physiological and mechanistic interpretation of the PK parameters. We finally derive a new scaling approach for anatomical and physiological parameters in PBPK models that translates the inter-individual variability into the design of mechanistic covariate models with direct link to classical compartment models, specially useful for PK population analysis during clinical development.
Metabolic systems tend to exhibit steady states that can be measured in terms of their concentrations and fluxes. These measurements can be regarded as a phenotypic representation of all the complex interactions and regulatory mechanisms taking place in the underlying metabolic network. Such interactions determine the system's response to external perturbations and are responsible, for example, for its asymptotic stability or for oscillatory trajectories around the steady state. However, determining these perturbation responses in the absence of fully specified kinetic models remains an important challenge of computational systems biology. Structural kinetic modeling (SKM) is a framework to analyse whether a metabolic steady state remains stable under perturbation, without requiring detailed knowledge about individual rate equations. It provides a parameterised representation of the system's Jacobian matrix in which the model parameters encode information about the enzyme-metabolite interactions. Stability criteria can be derived by generating a large number of structural kinetic models (SK-models) with randomly sampled parameter sets and evaluating the resulting Jacobian matrices. The parameter space can be analysed statistically in order to detect network positions that contribute significantly to the perturbation response. Because the sampled parameters are equivalent to the elasticities used in metabolic control analysis (MCA), the results are easy to interpret biologically. In this project, the SKM framework was extended by several novel methodological improvements. These improvements were evaluated in a simulation study using a set of small example pathways with simple Michaelis Menten rate laws. Afterwards, a detailed analysis of the dynamic properties of the neuronal TCA cycle was performed in order to demonstrate how the new insights obtained in this work could be used for the study of complex metabolic systems. The first improvement was achieved by examining the biological feasibility of the elasticity combinations created during Monte Carlo sampling. Using a set of small example systems, the findings showed that the majority of sampled SK-models would yield negative kinetic parameters if they were translated back into kinetic models. To overcome this problem, a simple criterion was formulated that mitigates such infeasible models and the application of this criterion changed the conclusions of the SKM experiment. The second improvement of this work was the application of supervised machine-learning approaches in order to analyse SKM experiments. So far, SKM experiments have focused on the detection of individual enzymes to identify single reactions important for maintaining the stability or oscillatory trajectories. In this work, this approach was extended by demonstrating how SKM enables the detection of ensembles of enzymes or metabolites that act together in an orchestrated manner to coordinate the pathways response to perturbations. In doing so, stable and unstable states served as class labels, and classifiers were trained to detect elasticity regions associated with stability and instability. Classification was performed using decision trees and relevance vector machines (RVMs). The decision trees produced good classification accuracy in terms of model bias and generalizability. RVMs outperformed decision trees when applied to small models, but encountered severe problems when applied to larger systems because of their high runtime requirements. The decision tree rulesets were analysed statistically and individually in order to explore the role of individual enzymes or metabolites in controlling the system's trajectories around steady states. The third improvement of this work was the establishment of a relationship between the SKM framework and the related field of MCA. In particular, it was shown how the sampled elasticities could be converted to flux control coefficients, which were then investigated for their predictive information content in classifier training. After evaluation on the small example pathways, the methodology was used to study two steady states of the neuronal TCA cycle with respect to their intrinsic mechanisms responsible for stability or instability. The findings showed that several elasticities were jointly coordinated to control stability and that the main source for potential instabilities were mutations in the enzyme alpha-ketoglutarate dehydrogenase.
During this work I built a four wave mixing setup for the time-resolved femtosecond spectroscopy of Raman-active lattice modes. This setup enables to study the selective excitation of phonon polaritons. These quasi-particles arise from the coupling of electro-magnetic waves and transverse optical lattice modes, the so-called phonons. The phonon polaritons were investigated in the optically non-linear, ferroelectric crystals LiNbO₃ and LiTaO₃.
The direct observation of the frequency shift of the scattered narrow bandwidth probe pulses proofs the role of the Raman interaction during the probe and excitation process of phonon polaritons. I compare this experimental method with the measurement where ultra-short laser pulses are used. The frequency shift remains obscured by the relative broad bandwidth of these laser pulses. In an experiment with narrow bandwidth probe pulses, the Stokes and anti-Stokes intensities are spectrally separated. They are assigned to the corresponding counter-propagating wavepackets of phonon polaritons. Thus, the dynamics of these wavepackets was separately studied. Based on these findings, I develop the mathematical description of the so-called homodyne detection of light for the case of light scattering from counter propagating phonon polaritons.
Further, I modified the broad bandwidth of the ultra-short pump pulses using bandpass filters to generate two pump pulses with non-overlapping spectra. This enables the frequency-selective excitation of polariton modes in the sample, which allows me to observe even very weak polariton modes in LiNbO₃ or LiTaO₃ that belong to the higher branches of the dispersion relation of phonon polaritons. The experimentally determined dispersion relation of the phonon polaritons could therefore be extended and compared to theoretical models. In addition, I determined the frequency-dependent damping of phonon polaritons.
Scientific inquiry requires that we formulate not only what we know, but also what we do not know and by how much. In climate data analysis, this involves an accurate specification of measured quantities and a consequent analysis that consciously propagates the measurement errors at each step. The dissertation presents a thorough analytical method to quantify errors of measurement inherent in paleoclimate data. An additional focus are the uncertainties in assessing the coupling between different factors that influence the global mean temperature (GMT).
Paleoclimate studies critically rely on `proxy variables' that record climatic signals in natural archives. However, such proxy records inherently involve uncertainties in determining the age of the signal. We present a generic Bayesian approach to analytically determine the proxy record along with its associated uncertainty, resulting in a time-ordered sequence of correlated probability distributions rather than a precise time series. We further develop a recurrence based method to detect dynamical events from the proxy probability distributions. The methods are validated with synthetic examples and
demonstrated with real-world proxy records. The proxy estimation step reveals the interrelations between proxy variability and uncertainty. The recurrence analysis of the East Asian Summer Monsoon during the last 9000 years confirms the well-known `dry' events at 8200 and 4400 BP, plus an additional significantly dry event at 6900 BP.
We also analyze the network of dependencies surrounding GMT. We find an intricate, directed network with multiple links between the different factors at multiple time delays. We further uncover a significant feedback from the GMT to the El Niño Southern Oscillation at quasi-biennial timescales. The analysis highlights the need of a more nuanced formulation of influences between different climatic factors, as well as the limitations in trying to estimate such dependencies.
Automated location of seismic events is a very important task in microseismic monitoring operations as well for local and regional seismic monitoring. Since microseismic records are generally characterised by low signal-to-noise ratio, such methods are requested to be noise robust and sufficiently accurate. Most of the standard automated location routines are based on the automated picking, identification and association of the first arrivals of P and S waves and on the minimization of the residuals between theoretical and observed arrival times of the considered seismic phases. Although current methods can accurately pick P onsets, the automatic picking of the S onset is still problematic, especially when the P coda overlaps the S wave onset. In this thesis I developed a picking free automated method based on the Short-Term-Average/Long-Term-Average (STA/LTA) traces at different stations as observed data. I used the STA/LTA of several characteristic functions in order to increase the sensitiveness to the P wave and the S waves. For the P phases we use the STA/LTA traces of the vertical energy function, while for the S phases, we use the STA/LTA traces of the horizontal energy trace and then a more optimized characteristic function which is obtained using the principal component analysis technique. The orientation of the horizontal components can be retrieved by robust and linear approach of waveform comparison between stations within a network using seismic sources outside the network (chapter 2). To locate the seismic event, we scan the space of possible hypocentral locations and origin times, and stack the STA/LTA traces along the theoretical arrival time surface for both P and S phases. Iterating this procedure on a three-dimensional grid we retrieve a multidimensional matrix whose absolute maximum corresponds to the spatial and temporal coordinates of the seismic event. Location uncertainties are then estimated by perturbing the STA/LTA parameters (i.e the length of both long and short time windows) and relocating each event several times. In order to test the location method I firstly applied it to a set of 200 synthetic events. Then we applied it to two different real datasets. A first one related to mining induced microseismicity in a coal mine in the northern Germany (chapter 3). In this case we successfully located 391 microseismic event with magnitude range between 0.5 and 2.0 Ml. To further validate the location method I compared the retrieved locations with those obtained by manual picking procedure. The second dataset consist in a pilot application performed in the Campania-Lucania region (southern Italy) using a 33 stations seismic network (Irpinia Seismic Network) with an aperture of about 150 km (chapter 4). We located 196 crustal earthquakes (depth < 20 km) with magnitude range 1.1 < Ml < 2.7. A subset of these locations were compared with accurate locations retrieved by a manual location procedure based on the use of a double difference technique. In both cases results indicate good agreement with manual locations. Moreover, the waveform stacking location method results noise robust and performs better than classical location methods based on the automatic picking of the P and S waves first arrivals.
התזות של העבודה
תקופת חז"ל
1. איסור הנישואין מתייחס לשתי נשים – מעוברת ומנקת, ובהתאם לסוגיה הסתמאית בבבלי יבמות, מדובר באיסור שטעמו אחד. למרות תפיסה מקובלת זו, להערכתנו בהלכה הקדומה מדובר היה בשני איסורים שונים: איסור נישואי מעוברת חברו ואיסור נישואי מנקת שמת בעלה.
למסקנה זו הגענו כתוצאה משורה של ראיות:
א. הסוגיה הסתמאית במסכת יבמות מעוררת קשיים רבים (אשר פורטו בעמ' לעבודתנו). קשיים אלה והעובדה כי במחקר המודרני נהוג לשייך סוגיות סתמאיות לסוף תקופת האמוראים ואף לאחר מכן, הביאו אותנו לשער כי סוגיה זו משקפת הצגה מאוחרת של טעם הדין. טעם שונה של הדין מצוי במקורות תנאיים, והוא המשקף כנראה את טעמו הקדום של הדין .
ב. שניים מתוך שלושת המקורות התנאיים, עוסקים האחד רק במנקת והשני רק במעוברת, ולא בשתי הנשים יחד.
ג. ניתוח הלשון של המקורות, מצביע על שורה של שינויים משמעותיים, אשר יש בהם כדי ללמד כי מדובר באיסורים שונים.
2. בהלכה הקדומה נתפס איסור נישואי "מעוברת חברו" כאיסור חמור, והוא הוסמך לפסוקים מהתנ"ך שאסרו הסגת גבול. בשלב מאוחר יותר בתקופת התנאים האיסור פורש ככזה שנועד להבטיח את הנקתו של הילד, צורפה לאיסור הקביעה כי אין לשאת אלמנה מנקת, והיחס לאיסור היה מקל יותר.
למסקנה זו הגענו כתוצאה מהדברים הבאים:
א. בניגוד למקורות תנאיים שנקטו בגישה מקלה במגוון עניינים, ישנם מספר מקורות המציגים גישה מחמירה – לפיה מי שעבר ונשא אלמנה בניגוד לאיסור, "יוציא ולא יחזיר עולמית".
ב. משורה של מקורות שעסקו בדין סוטה, ניכר כי העמדה ההלכתית הקדומה נקטה בגישה לפיה מי שעבר ונשא אלמנה בניגוד לדין והוא חושד כי אשתו סטתה, אינו משקה אותה מי סוטה, שכן היא אסורה עליו עולמית. גישה מקלה יותר, לפיה יכול הוא להפרישה ולהחזירה לאחר זמן ולכן יש טעם בהשקאת הסוטה במקרה כגון זה, התגבשה בספרות התנאית רק בשלב מאוחר יותר. במקביל וללא קשר לדיני סוטה, התפתחה אצל התנאים גישה מקלה, לפיה ישנם חריגים משמעותיים לאיסור נישואי האלמנה (כגון: כאשר הילד נגמל; כאשר הילד נמסר למנקת).
ג. מקור תנאי שעסק רק במעוברת חברו ולא במנקת שמת בעלה, נקט בגישה המחמירה ("יוציא ולא יחזיר עולמית") ולא הזכיר כלל קיומה של גישה מקלה ("יכול הוא להפרישה ולהחזירה לאחר זמן".
ד. מקורות תנאיים בספרות ארץ-ישראלית (מדרש הלכה, התוספתא וברייתא בירושלמי), ראו במי שעבר ונשא כמי שעבר על איסור הנמסך לפסוקים מהתנ"ך (ספר דברים וספר משלי) והאוסרים הסגת גבול. הצענו להבין את הסגת הגבול כמתארת מסגרת שייכות, ולפיה אלמנה שייכת לבעלה המנוח וזאת בכל הקושר לחובתה להבטחת זרעו.
ה. חוקרים (כגון י' גילת) הצביעו על תופעה המאפיינת את המעבר מההלכה הקדומה אל משנתם של התנאים לאחר החורבן: מעבר מגישה מחמירה אשר אינה מכירה בהבחנה בין דין שמעמדו מדאורייתא לדין שמעמדו מדרבנן, אל גישה מקלה יותר המשתלבת עם הנמקה שונה של האיסורים הקדומים והעמדתם במעמד של דרבנן בלבד.
ו. אנו משערים, למרות שהדבר אינו בר הוכחה חותכת, כי תהליך דומה פקד את הדין בו אנו עוסקים: בהלכה הקדומה נאסרה מעוברת חברו, מכוח הפסוק המקראי האוסר על הסגת גבול. איסור זה נחשב כאיסור מהתורה, ולכן היה בו כדי לדחות את מצוות השקאת הסוטה. בשלב מאוחר יותר, כאשר המוסג השגת גבול בכל הנוגע לאלמנה נראה פחות מתאים (בין השאר, הואיל ואלמנה "קונה עצמה" במיתת הבעל – כדברי המשנה בקידושין), הוצע טעם חדש לאיסור – הפגיעה האפשרית בחלב האם. לאור הנמקה זו, חבר אל איסור נישואי מעוברת חברו, גם האיסור לשאת מנקת שמת בעלה, והאיסור בכללותו נתפס בקרב התנאים כאיסור מדרבנן בלבד ושחומרתו קלה יותר. בשלב זה, הפכה הדעה לפיה מי שעבר ונשא "יוציא ולא יחזיר עולמית" לדעת יחיד בלבד(דעת ר' מאיר), ואילו הרבים קבעו כי "יכול הוא להפרישה ולהחזירה לאחר זמן".
3. בתום תקופת האמוראים ואולי אף בתקופה הסבוראית, הוחלט לאמץ את העמדות המחמירות יותר בכל הנוגע לאיסור הנישואין. נקבע כי מלבד מקרה של מות הילד, אין לאיסור חריגים, והאיסור חל גם כאשר הילד כבר אינו יונק. כמו כן נקבע כי משך ההמתנה הנדרש הוא 24 חודשים מהמועד בו נולד הילד. קביעות אלה משקפות הכרעה לאמץ מגמה מחמירה, מתוך מכלול הדעות אשר אפשרו גם אימוץ גישה מקלה יותר.
כפי שהראנו בעבודתנו , ההכרעה לכיוון המחמיר התקבלה ככל הנראה בתקופה הסבוראית. הכרעה זו אינה מובנת מאליה, שכן היו מקורות תנאיים ואמוראיים על בסיסם ניתן היה לקבוע כי יש לאמץ גישה מקלה יותר. לדוגמא, דעת בית הלל ודעת ר' יהודה הייתה כי משך האיסור הוא 18 חודשים בלבד. דעת רשב"ג הייתה כי ניתן לקצר את האיסור בשלושה חודשים נוספים, כך באיסור יהיה למשך 15 חודשים בלבד. לאור זאת, קביעת ההלכתא הסבוראית כי משך ההמתנה הוא 24 חודשים – אינה מובנת מאליה. למרות שאין ביכולתנו להצביע בוודאות על הסבר מדוע אומצה הגישה המחמירה, בעבודתנו הצבענו על ההחמרה במצב היהודים בתקופה הרלבנטית, כרקע אשר עשוי להשתלב עם אימוץ הגישה המחמירה .
תקופת הגאונים
4. בתקופת הגאונים נשמרו חילוקי הדעות בין בני בבל לבני ארץ ישראל, אשר מקורם בהבדלים בין התלמוד הבבלי לתלמוד הירושלמי. הבדלים אלה נוגעים לשאלה מה הדין במקרה בו מת הילד, ולטענתנו גם אודות השאלה האם מי שעבר ונשא יחויב לתת לאשתו גט או שדי בהפרשה בלבד. בסופו של דבר, גאוני בבל הביאו לכך שעמדת הבבלי היא שהתקבלה בעניינים אלה בקרב פוסקי ההלכה.
בעבודתנו עמדנו על היתר שחודש בתקופת הגאונים, ועל שלבים משעורים בהתפתחותו.
תקופת הראשונים
5. בעבודתנו עמדנו על המגמה שאפיינה את פסיקת ההלכה בדין בו אנו עוסקים בתקופת הראשונים. ניסינו להסביר מדוע נעשו ניסיונות לגבש הקלות באיסור הנישואין, ומדוע בסופו של דבר, לדעת רוב הראשונים וכפי שההלכה סוכמה בשלחן ערוך, הגישות המחמירות הן שאומצו. על עניינים אלו.
6. הרחבת היקף פריסתו של האיסור: בניגוד למקורות מתקופת חז"ל מהם נראה כי האיסור חל רק על אלמנה, בתקופת הראשונים נקבע כי האיסור חל גם על גרושה שיש לה ילד מנישואיה הקודמים, וגם על רווקה שילדה ילד מחוץ למסגרת הנישואין. קביעות אלה הביאו להרחבה ניכרת של המקרים בהם חל האיסור.
בעבודתנו עמדנו על הגישות השונות שהיו בסוגיה זו: אודות גרושה אודות מי שילדה בזנות .
עמדנו על כך שישנה קירבה בין שני הנימוקים השונים שהוזכרו בראשית דרכה של ההלכה על טעם האיסור, לבין המחלוקת בין הדעות השונות בשאלת תחולת האיסור על גרושה ועל מי שילדה בזנות. בהתאם לגישה שראתה באיסור משום הסגת גבולו של הבעל הראשון, אין מקום להחלת האיסור כאשר הנישואין הסתיימו בגירושין או כאשר הילד נולד מבלי שהיה קשר נישואין בין הוריו. מנגד, בהתאם לטעם שפורט בבבלי ואשר התמקד בנזק שעלול להיגרם לילד, חשש זה רלבנטי ללא קשר לטיב היחסים בין ההורים ומשכך יש מקום להחיל את איסור הנישואין גם על גרושה וגם על מי שילדה בזנות.
7. פרשיית ר' יעקב מקרקוב והשפעתה על עמדת חכמי ספרד: ר' יעקב מקרקוב סבר כי ניתן לייצר חריגים לאיסור, וזאת על-ידי מסירת הילד למנקת בשכר ועיצוב מנגנון אשר יבטיח שהמנקת לא תפר את התחייבותה להניק את הילד. עמדה זו נדחתה בחריפות על-ידי חכמי אשכנז, אולם נראה כי היא הייתה מקובלת על הרשב"א. כאשר הרא"ש היגר מאשכנז לספרד, הוא הוביל שינוי בתפיסה הספרדית ואימוץ הגישה המחמירה שמקורה באשכנז . העמדות המקלות בסוגיה זו, ככל הנראה צונזרו באופן כה יעיל, עד כי נראה שר' יוסף קארו מחבר השלחן ערוך, לא היה מודע לקיומן.
8. יחסו של הרא"ש להיתר שקבעו הגאונים: עמדנו בפירוט על תהליך העולה ממכלול יצירותיו של הרא"ש: דחיה של היתר שיוחס לגאונים; לאחר מכן אימוץ מהוסס בשעת הדחק של ההיתר; ובסופו של דבר אימוץ היתר רחב יותר העומד בפני עצמו ואינו נשען על משנתם של הגאונים. בהמשך, עמדנו על האופן בו התייחסו חכמי ספרד להיתר הרחב שקבע הרא"ש.
סוגיה זו ממחישה את יחסם השונה של חכמי ספרד וחכמי אשכנז אל תורתם של גאוני בבל, וכן היחס השונה של חכמי ספרד וחכמי אשכנז ללגיטימיות החדשנות ההלכתית. בסוגיה זו, בניגוד לסוגיה שנדונה בסעיף הקודם, הרא"ש גילה גמישות, והסכים להתקרב לעמדת חכמי ספרד (על השערתנו אודות ההסבר לכך).
העת החדשה
9. בעת החדשה, בעקבות קיצור משך ההנקה המקובל, נוצרו שני זרמים מרכזיים ביחס אל איסור הנישואין: הגישה המחמירה מבית מדרשו של החת"ם סופר, והגישה המקלה. הגישה המחמירה מבית מדרשו של החת"ם סופר, הסכימה להתיר את איסור הנישואין, רק כאשר היה חשש שאם איסור הנישואין לא יבוטל, הילד עלול לצאת ממסגרת החיים הדתיים. גישתו המחמירה של החת"ם סופר, הושפעה להערכתנו מהעובדה שאחד מראשוני תנועת הרפורמה, ר' אהרן חורין, טען כי יש לבטל את איסור הנישואין . על-מנת לחזק את תוקפו של האיסור, תלמידו של החת"ם סופר – המהר"ם שיק, טען כי מדובר באיסור מהתורה.
10. הגישה המקלה: גישה זו מורכבת מפסקי הלכה של פוסקים שונים, אשר הסכימו לאמץ הקלות באיסור הנישואין (לפירוט ההקלות העיקריות). הקלות אלה משקפות את גמישותו הרבה של הטקסט המתפרש. אותם טקסטים עצמם שהובנו בעבר באופן מחמיר, פורשו לפתע באופן מקל הרבה יותר. אנו מעריכים כי שינוי הפרשנות נבע משינוי המציאות הסובבת.
11. גם בעלי הגישה המקלה, הושפעו מעמדותיו של החת"ם סופר. השפעה זו באה לידי ביטוי בכך שבעלי הגישה המקלה היו מוכנים לאמץ גישות מקלות שנדחו על-ידי פוסקי ההלכה בעבר, אולם בדרך כלל הם לא היו מוכנים להכיר בצורך בשינוי דרמטי במעמדו של הדין, לאור שינוי המציאות. להערכתנו, עמדה שמרנית זו מובילה לתוצאות בלתי ראויות, והיא אינה משקפת בחינה אמיצה של מידת הרלבנטיות של איסור הנישואין למציאות החיים היהודיים בעשורים האחרונים.
Effect of benzylglucosinolate on signaling pathways associated with type 2 diabetes prevention
(2014)
Type 2 diabetes (T2D) is a health problem throughout the world. In 2010, there were nearly 230 million individuals with diabetes worldwide and it is estimated that in the economically advanced countries the cases will increase about 50% in the next twenty years. Insulin resistance is one of major features in T2D, which is also a risk factor for metabolic and cardiovascular complications. Epidemiological and animal studies have shown that the consumption of vegetables and fruits can delay or prevent the development of the disease, although the underlying mechanisms of these effects are still unclear. Brassica species such as broccoli (Brassica oleracea var. italica) and nasturtium (Tropaeolum majus) possess high content of bioactive phytochemicals, e.g. nitrogen sulfur compounds (glucosinolates and isothiocyanates) and polyphenols largely associated with the prevention of cancer. Isothiocyanates (ITCs) display their anti-carcinogenic potential by inducing detoxicating phase II enzymes and increasing glutathione (GSH) levels in tissues. In T2D diabetes an increase in gluconeogenesis and triglyceride synthesis, and a reduction in fatty acid oxidation accompanied by the presence of reactive oxygen species (ROS) are observed; altogether is the result of an inappropriate response to insulin. Forkhead box O (FOXO) transcription factors play a crucial role in the regulation of insulin effects on gene expression and metabolism, and alterations in FOXO function could contribute to metabolic disorders in diabetes. In this study using stably transfected human osteosarcoma cells (U-2 OS) with constitutive expression of FOXO1 protein labeled with GFP (green fluorescent protein) and human hepatoma cells HepG2 cell cultures, the ability of benzylisothiocyanate (BITC) deriving from benzylglucosinolate, extracted from nasturtium to modulate, i) the insulin-signaling pathway, ii) the intracellular localization of FOXO1 and iii) the expression of proteins involved in glucose metabolism, ROS detoxification, cell cycle arrest and DNA repair was evaluated. BITC promoted oxidative stress and in response to that induced FOXO1 translocation from cytoplasm into the nucleus antagonizing the insulin effect. BITC stimulus was able to down-regulate gluconeogenic enzymes, which can be considered as an anti-diabetic effect; to promote antioxidant resistance expressed by the up-regulation in manganese superoxide dismutase (MnSOD) and detoxification enzymes; to modulate autophagy by induction of BECLIN1 and down-regulation of the mammalian target of rapamycin complex 1 (mTORC1) pathway; and to promote cell cycle arrest and DNA damage repair by up-regulation of the cyclin-dependent kinase inhibitor (p21CIP) and Growth Arrest / DNA Damage Repair (GADD45). Except for the nuclear factor (erythroid derived)-like2 (NRF2) and its influence in the detoxification enzymes gene expression, all the observed effects were independent from FOXO1, protein kinase B (AKT/PKB) and NAD-dependent deacetylase sirtuin-1 (SIRT1). The current study provides evidence that besides of the anticarcinogenic potential, isothiocyanates might have a role in T2D prevention. BITC stimulus mimics the fasting state, in which insulin signaling is not triggered and FOXO proteins remain in the nucleus modulating gene expression of their target genes, with the advantage of a down-regulation of gluconeogenesis instead of its increase. These effects suggest that BITC might be considered as a promising substance in the prevention or treatment of T2D, therefore the factors behind of its modulatory effects need further investigation.
Nowadays, software systems are getting more and more complex. To tackle this challenge most diverse techniques, such as design patterns, service oriented architectures (SOA), software development processes, and model-driven engineering (MDE), are used to improve productivity, while time to market and quality of the products stay stable. Multiple of these techniques are used in parallel to profit from their benefits. While the use of sophisticated software development processes is standard, today, MDE is just adopted in practice. However, research has shown that the application of MDE is not always successful. It is not fully understood when advantages of MDE can be used and to what degree MDE can also be disadvantageous for productivity. Further, when combining different techniques that aim to affect the same factor (e.g. productivity) the question arises whether these techniques really complement each other or, in contrast, compensate their effects. Due to that, there is the concrete question how MDE and other techniques, such as software development process, are interrelated. Both aspects (advantages and disadvantages for productivity as well as the interrelation to other techniques) need to be understood to identify risks relating to the productivity impact of MDE. Before studying MDE's impact on productivity, it is necessary to investigate the range of validity that can be reached for the results. This includes two questions. First, there is the question whether MDE's impact on productivity is similar for all approaches of adopting MDE in practice. Second, there is the question whether MDE's impact on productivity for an approach of using MDE in practice remains stable over time. The answers for both questions are crucial for handling risks of MDE, but also for the design of future studies on MDE success. This thesis addresses these questions with the goal to support adoption of MDE in future. To enable a differentiated discussion about MDE, the term MDE setting'' is introduced. MDE setting refers to the applied technical setting, i.e. the employed manual and automated activities, artifacts, languages, and tools. An MDE setting's possible impact on productivity is studied with a focus on changeability and the interrelation to software development processes. This is done by introducing a taxonomy of changeability concerns that might be affected by an MDE setting. Further, three MDE traits are identified and it is studied for which manifestations of these MDE traits software development processes are impacted. To enable the assessment and evaluation of an MDE setting's impacts, the Software Manufacture Model language is introduced. This is a process modeling language that allows to reason about how relations between (modeling) artifacts (e.g. models or code files) change during application of manual or automated development activities. On that basis, risk analysis techniques are provided. These techniques allow identifying changeability risks and assessing the manifestations of the MDE traits (and with it an MDE setting's impact on software development processes). To address the range of validity, MDE settings from practice and their evolution histories were capture in context of this thesis. First, this data is used to show that MDE settings cover the whole spectrum concerning their impact on changeability or interrelation to software development processes. Neither it is seldom that MDE settings are neutral for processes nor is it seldom that MDE settings have impact on processes. Similarly, the impact on changeability differs relevantly. Second, a taxonomy of evolution of MDE settings is introduced. In that context it is discussed to what extent different types of changes on an MDE setting can influence this MDE setting's impact on changeability and the interrelation to processes. The category of structural evolution, which can change these characteristics of an MDE setting, is identified. The captured MDE settings from practice are used to show that structural evolution exists and is common. In addition, some examples of structural evolution steps are collected that actually led to a change in the characteristics of the respective MDE settings. Two implications are: First, the assessed diversity of MDE settings evaluates the need for the analysis techniques that shall be presented in this thesis. Second, evolution is one explanation for the diversity of MDE settings in practice. To summarize, this thesis studies the nature and evolution of MDE settings in practice. As a result support for the adoption of MDE settings is provided in form of techniques for the identification of risks relating to productivity impacts.
The data quality of real-world datasets need to be constantly monitored and maintained to allow organizations and individuals to reliably use their data. Especially, data integration projects suffer from poor initial data quality and as a consequence consume more effort and money. Commercial products and research prototypes for data cleansing and integration help users to improve the quality of individual and combined datasets. They can be divided into either standalone systems or database management system (DBMS) extensions. On the one hand, standalone systems do not interact well with DBMS and require time-consuming data imports and exports. On the other hand, DBMS extensions are often limited by the underlying system and do not cover the full set of data cleansing and integration tasks.
We overcome both limitations by implementing a concise set of five data cleansing and integration operators on the parallel data analytics platform Stratosphere. We define the semantics of the operators, present their parallel implementation, and devise optimization techniques for individual operators and combinations thereof. Users specify declarative queries in our query language METEOR with our new operators to improve the data quality of individual datasets or integrate them to larger datasets. By integrating the data cleansing operators into the higher level language layer of Stratosphere, users can easily combine cleansing operators with operators from other domains, such as information extraction, to complex data flows. Through a generic description of the operators, the Stratosphere optimizer reorders operators even from different domains to find better query plans.
As a case study, we reimplemented a part of the large Open Government Data integration project GovWILD with our new operators and show that our queries run significantly faster than the original GovWILD queries, which rely on relational operators. Evaluation reveals that our operators exhibit good scalability on up to 100 cores, so that even larger inputs can be efficiently processed by scaling out to more machines. Finally, our scripts are considerably shorter than the original GovWILD scripts, which results in better maintainability of the scripts.
Today, it is well known that galaxies like the Milky Way consist not only of stars but also of gas and dust. The galactic halo, a sphere of gas that surrounds the stellar disk of a galaxy, is especially interesting. It provides a wealth of information about in and outflowing gaseous material towards and away from galaxies and their hierarchical evolution. For the Milky Way, the so-called high-velocity clouds (HVCs), fast moving neutral gas complexes in the halo that can be traced by absorption-line measurements, are believed to play a crucial role in the overall matter cycle in our Galaxy. Over the last decades, the properties of these halo structures and their connection to the local circumgalactic and intergalactic medium (CGM and IGM, respectively) have been investigated in great detail by many different groups. So far it remains unclear, however, to what extent the results of these studies can be transferred to other galaxies in the local Universe. In this thesis, we study the absorption properties of Galactic HVCs and compare the HVC absorption characteristics with those of intervening QSO absorption-line systems at low redshift. The goal of this project is to improve our understanding of the spatial extent and physical conditions of gaseous galaxy halos in the local Universe. In the first part of the thesis we use HST /STIS ultraviolet spectra of more than 40 extragalactic background sources to statistically analyze the absorption properties of the HVCs in the Galactic halo. We determine fundamental absorption line parameters including covering fractions of different weakly/intermediately/highly ionized metals with a particular focus on SiII and MgII. Due to the similarity in the ionization properties of SiII and MgII, we are able to estimate the contribution of HVC-like halo structures to the cross section of intervening strong MgII absorbers at z = 0. Our study implies that only the most massive HVCs would be regarded as strong MgII absorbers, if the Milky Way halo would be seen as a QSO absorption line system from an exterior vantage point. Combining the observed absorption-cross section of Galactic HVCs with the well-known number density of intervening strong MgII absorbers at z = 0, we conclude that the contribution of infalling gas clouds (i.e., HVC analogs) in the halos of Milky Way-type galaxies to the cross section of strong MgII absorbers is 34%. This result indicates that only about one third of the strong MgII absorption can be associated with HVC analogs around other galaxies, while the majority of the strong MgII systems possibly is related to galaxy outflows and winds. The second part of this thesis focuses on the properties of intervening metal absorbers at low redshift. The analysis of the frequency and physical conditions of intervening metal systems in QSO spectra and their relation to nearby galaxies offers new insights into the typical conditions of gaseous galaxy halos. One major aspect in our study was to regard intervening metal systems as possible HVC analogs. We perform a detailed analysis of absorption line properties and line statistics for 57 metal absorbers along 78 QSO sightlines using newly-obtained ultraviolet spectra obtained with HST /COS. We find clear evidence for bimodal distribution in the HI column density in the absorbers, a trend that we interpret as sign for two different classes of absorption systems (with HVC analogs at the high-column density end). With the help of the strong transitions of SiII λ1260, SiIII λ1206, and CIII λ977 we have set up Cloudy photoionization models to estimate the local ionization conditions, gas densities, and metallicities. We find that the intervening absorption systems studied by us have, on average, similar physical conditions as Galactic HVC absorbers, providing evidence that many of them represent HVC analogs in the vicinity of other galaxies. We therefore determine typical halo sizes for SiII, SiIII, and CIII for L = 0.01L∗ and L = 0.05L∗ galaxies. Based on the covering fractions of the different ions in the Galactic halo, we find that, for example, the typical halo size for SiIII is ∼ 160 kpc for L = 0.05L∗ galaxies. We test the plausibility of this result by searching for known galaxies close to the QSO sightlines and at similar redshifts as the absorbers. We find that more than 34% of the measured SiIII absorbers have galaxies associated with them, with the majority of the absorbers indeed being at impact parameters ρ ≤160 kpc.
The background of civil service reform in Indonesia reveals the emergence of the reformation movement in 1998, following the fall of the authoritarian New Order regime. The reformation movement has seen the introduction of reforms in Indonesia's various governmental institutions, including the civil service. The civil service reforms were marked by the revision of Act 8/ 74 with Act 43 of 1999 on Civil Service Administration. The implementation of the civil service reform program, which was carried out by both central and local governments, required cooperation between the actors (in particular, Ministries, agencies and local governments), known as coordination.
Currently, the coordination that occurs between actors tends to be rigid and hierarchical. As a result, targets are not efficiently and effectively met. Hierarchical coordination, without a strong public sector infrastructure, tends to have a negative impact on achieving the desired outcomes of the civil service reform program. As an intrinsic part of the New Order regime, hierarchical coordination resulted in inefficiency and lack of efficacy. Despite these inefficiencies, the administration and the political environment have changed significantly as a result of the reform process.
Obvious examples of the reforms are changes in recruitment patterns, placement and remuneration policies. However, in the case of Indonesia, it appears that every state institution has its own policy. Thus, it appears that there has not been policy coherence in the civil service reform program, resulting in the lack of a sustainable program. The important thing to examine is how the coordination mechanisms of the civil service reform program in the central government have developed during the reform era in Indonesia
The purpose of this study is to analyse the linkages between coordination mechanisms and the actual implementation of civil service reform programs. This is undertaken as a basis for intervention based on the structures and patterns of coordination mechanisms in the implementation of civil service reform programs. The next step is to formulate the development coordination mechanisms, particularly to create structures and patterns of civil service reforms which are more sustainable to the specific characteristics of public sector organisations in Indonesia.
The benefits of this research are a stronger understanding of the linkages between the mechanisms of coordination and implementation of civil service reform programs. Through this analysis, the findings can then be applied as a basic consideration in planning a sustainable civil service reform program. In the basis of theoretical issues concerning the linkages between coordination mechanisms and implementation of civil service reform program sustainability, this book explores the type of coordination, which is needed to test the proportional and sustainable concept of the intended civil service reform program in Indonesia.
Research conducted through studies, surveys and donors has shown that poor coordination is the major hindrance to the civil service program reform in Indonesia. This research employs a qualitative approach. In this study, the coordination mechanisms and implementations of civil service reform programs are demonstrated by means of case studies of the State Ministry for Administrative Reform, the National Civil Service Agency and the National Public Administration Institute. The coordination mechanisms in these Ministries and agencies were analysed using indicators of effective and efficient coordination. The analysis of the coordination mechanisms shows a tendency towards rigid hierarchical coordination. This raises concerns about fragmentation among departments and agencies at the central government level and calls for integrated civil service reform both at central and local governmental levels. In the context of implementation programs, a hierarchical mechanism of coordination leverages on various aspects, such as the program formulation, implementation flow of the program, the impact of policies, and achievement targets. In particular, there was a shift process of the mainstream civil service reform in the Ministries and agencies which are marked by the emergence of sectoral interest and inefficiencies in the civil service reform program. The primary result of successful civil service reform is increased professionalism in the civil service.
The findings on hierarchical mechanisms and the prescriptions which will follow show that the professionalism of Indonesia’s civil service is at stake. The implementation of the program through coordination mechanisms in Ministries and agencies is measured in various dimensions: the centre of coordination, integration of coordination, sustainability of coordination and multidimensionality of coordination.
The results of this analysis show that coordination mechanisms and the implementation of civil service reform are more successful when they are integration rather than hierarchical mechanisms. For a successful implementation of the reform program, it is crucial to intervene and change the type of coordination at the central government through the integration approach (hierarchy, market, and network). Furthermore, in order to move towards the integration type mechanism of coordination the separation of the administration and politics in the practice of good governance needs to be carried out immediately and simultaneously. Based on this analysis, it can be concluded that the integration type mechanism of coordination is a suitable for Indonesia for a sustainable civil service reform program. Finally, to achieve coherent civil service reforms, national policies developed according to the central government's priorities are indispensable, establishing a coordination mechanism that can be adhered to throughout all reform sectors.
Zwischen Liberalismus und Christentum : die sozialethischen Aspekte der sozialen Marktwirtschaft
(2014)
In the presented thesis, the most advanced photon reconstruction technique of ground-based γ-ray astronomy is adapted to the H.E.S.S. 28 m telescope. The method is based on a semi-analytical model of electromagnetic particle showers in the atmosphere. The properties of cosmic γ-rays are reconstructed by comparing the camera image of the telescope with the Cherenkov emission that is expected from the shower model. To suppress the dominant background from charged cosmic rays, events are selected based on several criteria. The performance of the analysis is evaluated with simulated events. The method is then applied to two sources that are known to emit γ-rays. The first of these is the Crab Nebula, the standard candle of ground-based γ-ray astronomy. The results of this source confirm the expected performance of the reconstruction method, where the much lower energy threshold compared to H.E.S.S. I is of particular importance. A second analysis is performed on the region around the Galactic Centre. The analysis results emphasise the capabilities of the new telescope to measure γ-rays in an energy range that is interesting for both theoretical and experimental astrophysics. The presented analysis features the lowest energy threshold that has ever been reached in ground-based γ-ray astronomy, opening a new window to the precise measurement of the physical properties of time-variable sources at energies of several tens of GeV.
The Epoch of Reionization marks after recombination the second major change in the ionization state of the universe, going from a neutral to an ionized state. It starts with the appearance of the first stars and galaxies; a fraction of high-energy photons emitted from galaxies permeate into the intergalactic medium (IGM) and gradually ionize the hydrogen, until the IGM is completely ionized at z~6 (Fan et al., 2006). While the progress of reionization is driven by galaxy evolution, it changes the ionization and thermal state of the IGM substantially and affects subsequent structure and galaxy formation by various feedback mechanisms.
Understanding this interaction between reionization and galaxy formation is further impeded by a lack of understanding of the high-redshift galactic properties such as the dust distribution and the escape fraction of ionizing photons. Lyman Alpha Emitters (LAEs) represent a sample of high-redshift galaxies that are sensitive to all these galactic properties and the effects of reionization.
In this thesis we aim to understand the progress of reionization by performing cosmological simulations, which allows us to investigate the limits of constraining reionization by high-redshift galaxies as LAEs, and examine how galactic properties and the ionization state of the IGM affect the visibility and observed quantities of LAEs and Lyman Break galaxies (LBGs).
In the first part of this thesis we focus on performing radiative transfer calculations to simulate reionization. We have developed a mapping-sphere-scheme, which, starting from spherically averaged temperature and density fields, uses our 1D radiative transfer code and computes the effect of each source on the IGM temperature and ionization (HII, HeII, HeIII) profiles, which are subsequently mapped onto a grid. Furthermore we have updated the 3D Monte-Carlo radiative transfer pCRASH, enabling detailed reionization simulations which take individual source characteristics into account.
In the second part of this thesis we perform a reionization simulation by post-processing a smoothed-particle hydrodynamical (SPH) simulation (GADGET-2) with 3D radiative transfer (pCRASH), where the ionizing sources are modelled according to the characteristics of the stellar populations in the hydrodynamical simulation. Following the ionization fractions of hydrogen (HI) and helium (HeII, HeIII), and temperature in our simulation, we find that reionization starts at z~11 and ends at z~6, and high density regions near sources are ionized earlier than low density regions far from sources.
In the third part of this thesis we couple the cosmological SPH simulation and the radiative transfer simulations with a physically motivated, self-consistent model for LAEs, in order to understand the importance of the ionization state of the IGM, the escape fraction of ionizing photons from galaxies and dust in the interstellar medium (ISM) on the visibility of LAEs. Comparison of our models results with the LAE Lyman Alpha (Lya) and UV luminosity functions at z~6.6 reveals a three-dimensional degeneracy between the ionization state of the IGM, the ionizing photons escape fraction and the ISM dust distribution, which implies that LAEs act not only as tracers of reionization but also of the ionizing photon escape fraction and of the ISM dust distribution. This degeneracy does not even break down when we compare simulated with observed clustering of LAEs at z~6.6. However, our results show that reionization has the largest impact on the amplitude of the LAE angular correlation functions, and its imprints are clearly distinguishable from those of properties on galactic scales. These results show that reionization cannot be constrained tightly by exclusively using LAE observations. Further observational constraints, e.g. tomographies of the redshifted hydrogen 21cm line, are required.
In addition we also use our LAE model to probe the question when a galaxy is visible as a LAE or a LBG. Within our model galaxies above a critical stellar mass can produce enough luminosity to be visible as a LBG and/or a LAE. By finding an increasing duty cycle of LBGs with Lya emission as the UV magnitude or stellar mass of the galaxy rises, our model reveals that the brightest (and most massive) LBGs most often show Lya emission.
Predicting the Lya equivalent width (Lya EW) distribution and the fraction of LBGs showing Lya emission at z~6.6, we reproduce the observational trend of the Lya EWs with UV magnitude. However, the Lya EWs of the UV brightest LBGs exceed observations and can only be reconciled by accounting for an increased Lya attenuation of massive galaxies, which implies that the observed Lya brightest LAEs do not necessarily coincide with the UV brightest galaxies. We have analysed the dependencies of LAE observables on the properties of the galactic and intergalactic medium and the LAE-LBG connection, and this enhances our understanding of the nature of LAEs.
Der Bittergeschmack dient Säugern vermutlich zur Wahrnehmung und Vermeidung toxischer Substanzen. Bitterstoffe können jedoch auch gesund sein oder werden oft bereitwillig mit der Nahrung aufgenommen. Ob sie geschmacklich unterschieden werden können, ist allerdings umstritten. Detektiert werden Bitterstoffe von oralen Bittergeschmacksrezeptoren, den TAS2R (human) bzw. Tas2r (murin). In der Literatur gibt es aber immer mehr Hinweise darauf, dass überdies Tas2r nicht nur in extragustatorischen Organen exprimiert werden, sondern dort auch wichtige Aufgaben erfüllen könnten, was wiederum die Aufklärung ihrer noch nicht vollständig entschlüsselten Funktionsweisen erfordert. So ist noch unbekannt, ob alle bisher als funktionell identifizierten Tas2r wirklich gustatorische Funktionen erfüllen.
Im Rahmen der Charakterisierung neu generierter, im Locus des Bittergeschmacksrezeptors Tas2r131 genetisch modifizierter Mauslinien, wurde in vorliegender Arbeit die gustatorische sowie extragustatorische Expression von Tas2r131 untersucht. Dass Tas2r131 nicht nur in Pilzpapillen, Wall- und Blätterpapillen (VP+FoP), Gaumen, Ductus nasopalatinus, Vomeronasalorgan und Kehldeckel, sondern auch in Thymus, Testes und Nebenhodenkopf, in Gehirnarealen sowie im Ganglion geniculatum nachgewiesen wurde, bildete die Grundlage für weiterführende Studien. Die vorliegende Arbeit zeigt außerdem, dass Tas2r108, Tas2r126, Tas2r135, Tas2r137 und Tas2r143 in Blut exprimiert werden, was auf eine heterogene Funktion der Tas2r hindeutet. Dass zusätzlich erstmals die Expression aller 35 als funktionell beschriebenen Tas2r im gustatorischen VP+FoP-Epithel von C57BL/6-Mäusen nachgewiesen wurde, verweist auf deren Relevanz als funktionelle Geschmacksrezeptoren.
Weiter zeigten Untersuchungen zur Aufklärung eines möglichen Bitter-Unterscheidungsvermögens in Geschmackspapillen von Mäusen mit fluoreszenzmarkierten oder ablatierten Tas2r131-Zellen, dass Tas2r131 exprimierende Zellen eine Tas2r-Zellsubpopulation bilden. Darüber hinaus existieren innerhalb der Bitterzellen geordnete Tas2r-Expressionsmuster, die sich nach der chromosomalen Lage ihrer Gene richten. Isolierte Bitterzellen reagieren heterogen auf bekannte Bitterstoffe. Und Mäuse mit ablatierter Tas2r131-Zellpopulation besitzen noch andere Tas2r-Zellen und schmecken damit einige Bitterstoffe kaum noch, andere aber noch sehr gut. Diese Befunde belegen die Existenz verschiedener gustatorischer Tas2r-Zellpopulationen, welche die Voraussetzung bilden, Bitterstoffe heterogen zu detektieren. Ob dies die Grundlage für ein divergierendes Verhalten gegenüber unverträglichen und harmlosen oder gar nützlichen Bitterstoffen darstellt, kann mit Hilfe der dargelegten Tas2r-Expressionsmuster künftig in Verhaltensexperimenten geprüft werden.
Die Bittergeschmackswahrnehmung in Säugetieren stellt sich als ein hochkomplexer Mechanismus dar, dessen Vielschichtigkeit durch die hier neu aufgezeigten heterogenen Tas2r-Expressions- und Funktionsmuster erneut verdeutlicht wird.
The adaptation of cell growth and proliferation to environmental changes is essential for the surviving of biological systems. The evolutionary conserved Ser/Thr protein kinase “Target of Rapamycin” (TOR) has emerged as a major signaling node that integrates the sensing of numerous growth signals to the coordinated regulation of cellular metabolism and growth. Although the TOR signaling pathway has been widely studied in heterotrophic organisms, the research on TOR in photosynthetic eukaryotes has been hampered by the reported land plant resistance to rapamycin. Thus, the finding that Chlamydomonas reinhardtii is sensitive to rapamycin, establish this unicellular green alga as a useful model system to investigate TOR signaling in photosynthetic eukaryotes.
The observation that rapamycin does not fully arrest Chlamydomonas growth, which is different from observations made in other organisms, prompted us to investigate the regulatory function of TOR in Chlamydomonas in context of the cell cycle. Therefore, a growth system that allowed synchronously growth under widely unperturbed cultivation in a fermenter system was set up and the synchronized cells were characterized in detail. In a highly resolved kinetic study, the synchronized cells were analyzed for their changes in cytological parameters as cell number and size distribution and their starch content. Furthermore, we applied mass spectrometric analysis for profiling of primary and lipid metabolism. This system was then used to analyze the response dynamics of the Chlamydomonas metabolome and lipidome to TOR-inhibition by rapamycin
The results show that TOR inhibition reduces cell growth, delays cell division and daughter cell release and results in a 50% reduced cell number at the end of the cell cycle. Consistent with the growth phenotype we observed strong changes in carbon and nitrogen partitioning in the direction of rapid conversion into carbon and nitrogen storage through an accumulation of starch, triacylglycerol and arginine. Interestingly, it seems that the conversion of carbon into triacylglycerol occurred faster than into starch after TOR inhibition, which may indicate a more dominant role of TOR in the regulation of TAG biosynthesis than in the regulation of starch.
This study clearly shows, for the first time, a complex picture of metabolic and lipidomic dynamically changes during the cell cycle of Chlamydomonas reinhardtii and furthermore reveals a complex regulation and adjustment of metabolite pools and lipid composition in response to TOR inhibition.
Following the principles of green chemistry, a simple and efficient synthesis of functionalised imidazolium zwitterionic compounds from renewable resources was developed based on a modified one-pot Debus-Radziszewski reaction. The combination of different carbohydrate-derived 1,2-dicarbonyl compounds and amino acids is a simple way to modulate the properties and introduce different functionalities. A representative compound was assessed as an acid catalyst, and converted into acidic ionic liquids by reaction with several strong acids. The reactivity of the double carboxylic functionality was explored by esterification with long and short chain alcohols, as well as functionalised amines, which led to the straightforward formation of surfactant-like molecules or bifunctional esters and amides. One of these di-esters is currently being investigated for the synthesis of poly(ionic liquids). The functionalisation of cellulose with one of the bifunctional esters was investigated and preliminary tests employing it for the functionalisation of filter papers were carried out successfully. The imidazolium zwitterions were converted into ionic liquids via hydrothermal decarboxylation in flow, a benign and scalable technique. This method provides access to imidazolium ionic liquids via a simple and sustainable methodology, whilst completely avoiding contamination with halide salts. Different ionic liquids can be generated depending on the functionality contained in the ImZw precursor. Two alanine-derived ionic liquids were assessed for their physicochemical properties and applications as solvents for the dissolution of cellulose and the Heck coupling.
Die vorliegende Studie untersucht die gesellschaftliche Rolle des gegenwärtigen Mathematikunterrichts an deutschen allgemeinbildenden Schulen aus einer soziologisch-kritischen Perspektive. In Zentrum des Interesses steht die durch den Mathematikunterricht erfahrene Sozialisation. Die Studie umfasst unter anderem eine Literaturdiskussion, die Ausarbeitung eines soziologischen Rahmens auf der Grundlage des Werks von Michel Foucault und zwei Teilstudien zur Soziologie der Logik und des Rechnens. Abschließend werden Dispositive des Mathematischen beschrieben, die darlegen, in welcher Art und mit welcher persönlichen und gesellschaftlichen Folgen der gegenwärtige Mathematikunterricht eine spezielle Geisteshaltung etabliert.
Reading is a complex cognitive task based on the analyses of visual stimuli. Due to the physiology of the eye, only a small number of letters around the fixation position can be extracted with high visual acuity, while the visibility of words and letters outside this so-called foveal region quickly drops with increasing eccentricity. As a consequence, saccadic eye movements are needed to repeatedly shift the fovea to new words for visual word identification during reading. Moreover, even within a foveated word fixation positions near the word center are superior to other fixation positions for efficient word recognition (O’Regan, 1981; Brysbaert, Vitu, and Schroyens, 1996). Thus, most reading theories assume that readers aim specifically at word centers during reading (for a review see Reichle, Rayner, & Pollatsek, 2003). However, saccades’ landing positions within words during reading are in fact systematically modulated by the distance of the launch site from the word center (McConkie, Kerr, Reddix, & Zola, 1988). In general, it is largely unknown how readers identify the center of upcoming target words and there is no computational model of the sensorimotor translation of the decision for a target word into spatial word center coordinates. Here we present a series of three studies which aim at advancing the current knowledge about the computation of saccade target coordinates during saccade planning in reading. Based on a large corpus analyses, we firstly identified word skipping as a further factor beyond the launch-site distance with a likewise systematic and surprisingly large effect on within-word landing positions. Most importantly, we found that the end points of saccades after skipped word are shifted two and more letters to the left as compared to one-step saccades (i.e., from word N to word N+1) with equal launch-site distances. Then we present evidence from a single saccade experiment suggesting that the word-skipping effect results from highly automatic low-level perceptual processes, which are essentially based on the localization of blank spaces between words. Finally, in the third part, we present a Bayesian model of the computation of the word center from primary sensory measurements of inter-word spaces. We demonstrate that the model simultaneously accounts for launch-site and saccade-type contingent modulations of within-word landing positions in reading. Our results show that the spatial saccade target during reading is the result of complex estimations of the word center based on incomplete sensory information, which also leads to specific systematic deviations of saccades’ landing positions from the word center. Our results have important implications for current reading models and experimental reading research.
Enterprise-specific in-memory data managment : HYRISEc - an in-memory column store engine for OLXP
(2014)
Ziel der Arbeit war die Entwicklung von farbstoffmarkierten Polymeren, die einen temperaturgetriebenen Knäuel-Kollaps-Phasenübergang in wässriger Lösung ("thermo-responsive Polymere") zeigen und diesen in ein optisches Signal übersetzen können. Solche Polymere unterliegen innerhalb eines kleinen Temperaturintervalls einer massiven Änderung ihres Verhaltens, z B. ihrer Konformation und ihres Quellungsgrads. Diese Änderungen sind mit einem Wechsel der Löseeigenschaften von hydrophil zu hydrophob verbunden. Als Matrixpolymere wurden Poly-N-isopropylacrylamid (polyNIPAm), Poly(oligoethylen-glykolacrylat) (polyOEGA) und Poly(oligoethylenglykolmethacrylat) (polyOEGMA) ein-gesetzt, in die geeignete Farbstoffen durch Copolymerisation eingebaut wurden. Als besonders geeignet, um den Phasenübergang in ein optisches Signal zu übersetzen, erwiesen sich hierfür kompakte, solvatochrome Cumarin- und Naphthalimidderivate. Diese beeinträchtigten weder das Polymerisationsverhalten noch den Phasenübergang, reagierten aber sowohl bezüglich Farbe als auch Fluoreszenz stark auf die Polarität des Lösemittels. Weiterhin wurden Systeme entwickelt, die mittels Energietransfer (FRET) ein an den Phasenübergang gekoppeltes optisches Signal erzeugen. Hierbei wurde ein Cumarin als Donor- und ein Polythiophen als Akzeptorfarbstoff eingesetzt. Es zeigte sich, dass trotz scheinbarer Ähnlichkeit bestimmte Polymere ausgeprägt auf einen Temperaturstimulus mit Änderung ihrer spektralen Eigenschaften reagieren, andere aber nicht. Hierfür wurden die molekularen Ursachen untersucht. Als wahrscheinliche Gründe für das Ausbleiben einer spektralen Änderung in Oligo(ethylenglykol)-basierten Polymeren sind zum einen die fehlende Dehydratationseffektivität infolge des Fehlens eines selbstgenügenden Wasserstoffbrückenbindungsmotivs zu nennen und zum anderen die sterische Abschirmung der Farbstoffe durch die Oligo(ethylenglykol)-Seitenketten. Als Prinzipbeweis für die Nützlichkeit solcher Systeme für die Bioanalytik wurde ein System entwickelt, dass die Löslichkeitseigenschaft eines thermoresponsiven Polymers durch Antikörper-Antigen-Reaktion änderte. Die Bindung selbst kleiner Mengen eines Antikörpers ließ sich so direkt optisch auslesen und war bereits mit dem bloßen Auge zu erkennen.
Unterschiedliche Verfahren zur Ermittlung von Georadar-Wellengeschwindigkeiten wurden entwickelt und erfolgreich angewendet. Für die Verfahren wurden statistische Methoden und Schwarmintelligenz-Algorithmen benutzt. Es wurde gezeigt, dass die neuen Verfahren schneller, präziser und besser reproduzierbare Ergebnisse für Georadar-Wellengeschwindigkeit erzielen als herkömmliche Verfahren.
Mit verbesserten Werten der Georadar-Wellengeschwindigkeit lassen sich die verzerrten dreidimensionalen Abbilder der obersten zehn Meter des Untergrundes, welche sich mit Georadar-Daten erzeugen lassen, korrigieren. In diesen korrigierten Abbildern sind dann realistische Tiefen von Schichten oder Objekten im Untergrund besser messbar. Außerdem verbessern präzisere Wellengeschwindigkeiten die Bestimmung von Bodenparametern, wie Wassergehalt oder Tonanteil. Die präsentierten Verfahren erlauben eine quantitative Angabe von Fehlern der bestimmten Wellengeschwindigkeit und der daraus folgenden Tiefen und Bodenparametern im Untergrund. Die Vorteile dieser neu entwickelten Verfahren zur Charakterisierung des Untergrundes der oberen Meter wurde an Feldbeispielen demonstriert.