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Aggregation of the Amyloid β (Aβ) peptide to amyloid fibrils is associated with the outbreak of Alzheimer’s disease. Early aggregation intermediates in form of soluble oligomers are of special interest as they are believed to be the major toxic components in the process. These oligomers are of disordered and transient nature. Therefore, their detailed molecular structure is difficult to access experimentally and often remains unknown. In the present work extensive, fully atomistic replica exchange molecular dynamics simulations were performed to study the preaggregated, monomer states and early aggregation intermediates (dimers, trimers) of Aβ(25-35) and Aβ(10-35)-NH2 in aqueous solution. The folding and aggregation of Aβ(25-35) were studied at neutral pH and 293 K. Aβ(25-35) monomers mainly adopt β-hairpin conformations characterized by a β-turn formed by residues G29 and A30, and a β-sheet between residues N27–K28 and I31–I32 in equilibrium with coiled conformations. The β-hairpin conformations served as initial configurations to model spontaneous aggregation of Aβ(25-35). As expected, within the Aβ(25-35) dimer and trimer ensembles many different poorly populated conformations appear. Nevertheless, we were able to distinguish between disordered and fibril-like oligomers. Whereas disordered oligomers are rather compact with few intermolecular hydrogen bonds (HBs), fibril-like oligomers are characterized by the formation of large intermolecular β-sheets. In most of the fibril-like dimers and trimers individual peptides are fully extended forming in- or out-of-register antiparallel β-sheets. A small amount of fibril-like trimers contained V-shaped peptides forming parallel β-sheets. The dimensions of extended and V-shaped oligomers correspond well to the diameters of two distinct morphologies found for Aβ(25-35) fibrils. The transition from disordered to fibril-like Aβ(25-35) dimers is unfavorable but driven by energy. The lower energy of fibril-like dimers arises from favorable intermolecular HBs and other electrostatic interactions which compete with a loss in entropy. Approximately 25 % of the entropic cost correspond to configurational entropy. The rest relates to solvent entropy, presumably caused by hydrophobic and electrostatic effects. In contrast to the transition towards fibril-like dimers the first step of aggregation is driven by entropy. Here, we compared structural and thermodynamic properties of the individual monomer, dimer and trimer ensembles to gain qualitative information about the aggregation process. The β-hairpin conformation observed for monomers is successively dissolved in dimer and trimer ensembles while instead intermolecular β-sheets are formed. As expected upon aggregation the configurational entropy decreases. Additionally, the solvent accessible surface area (SASA), especially the hydrophobic SASA, decreases yielding a favorable solvation free energy which overcompensates the loss in configurational entropy. In summary, the hydrophobic effect, possibly combined with electrostatic effects, yields an increase in solvent entropy which is believed to be one major driving force towards aggregation. Spontaneous folding of the Aβ(10-35)-NH2 monomer was modeled using two force fields, GROMOS96 43a1 and OPLS/AA, and compared to primary NMR data collected at pH 5.6 and 283 K taken from the literature. Unexpectedly, the two force fields yielded significantly different main conformations. Comparison between experimental and calculated nuclear Overhauser effect (NOE) distances is not sufficient to distinguish between the different force fields. Additionally, the comparison with scalar coupling constants suggest that the chosen protonation in both simulations corresponds to a pH lower than in the experiment. Based on this analysis we were unable to determine which force field yields a better description of this system. Dimerization of Aβ(10-35)-NH2 was studied at neutral pH and 300 K. Dimer conformations arrange in many distinct, poorly populated and rather complex alignments or interlocking patterns which are rather stabilized by side chain interactions than by specific intermolecular hydrogen bonds. Similar to Aβ(25-35) dimers, transition towards β-sheet-rich, fibril-like Aβ(10-35) dimers is driven by energy competing with a loss in entropy. Here, transition is mediated by favorable peptide-solvent and solvent-solvent interactions mainly arising from electrostatic interactions.
The exponential expanding of the numbers of web sites and Internet users makes WWW the most important global information resource. From information publishing and electronic commerce to entertainment and social networking, the Web allows an inexpensive and efficient access to the services provided by individuals and institutions. The basic units for distributing these services are the web sites scattered throughout the world. However, the extreme fragility of web services and content, the high competence between similar services supplied by different sites, and the wide geographic distributions of the web users drive the urgent requirement from the web managers to track and understand the usage interest of their web customers. This thesis, "X-tracking the Usage Interest on Web Sites", aims to fulfill this requirement. "X" stands two meanings: one is that the usage interest differs from various web sites, and the other is that usage interest is depicted from multi aspects: internal and external, structural and conceptual, objective and subjective. "Tracking" shows that our concentration is on locating and measuring the differences and changes among usage patterns. This thesis presents the methodologies on discovering usage interest on three kinds of web sites: the public information portal site, e-learning site that provides kinds of streaming lectures and social site that supplies the public discussions on IT issues. On different sites, we concentrate on different issues related with mining usage interest. The educational information portal sites were the first implementation scenarios on discovering usage patterns and optimizing the organization of web services. In such cases, the usage patterns are modeled as frequent page sets, navigation paths, navigation structures or graphs. However, a necessary requirement is to rebuild the individual behaviors from usage history. We give a systematic study on how to rebuild individual behaviors. Besides, this thesis shows a new strategy on building content clusters based on pair browsing retrieved from usage logs. The difference between such clusters and the original web structure displays the distance between the destinations from usage side and the expectations from design side. Moreover, we study the problem on tracking the changes of usage patterns in their life cycles. The changes are described from internal side integrating conceptual and structure features, and from external side for the physical features; and described from local side measuring the difference between two time spans, and global side showing the change tendency along the life cycle. A platform, Web-Cares, is developed to discover the usage interest, to measure the difference between usage interest and site expectation and to track the changes of usage patterns. E-learning site provides the teaching materials such as slides, recorded lecture videos and exercise sheets. We focus on discovering the learning interest on streaming lectures, such as real medias, mp4 and flash clips. Compared to the information portal site, the usage on streaming lectures encapsulates the variables such as viewing time and actions during learning processes. The learning interest is discovered in the form of answering 6 questions, which covers finding the relations between pieces of lectures and the preference among different forms of lectures. We prefer on detecting the changes of learning interest on the same course from different semesters. The differences on the content and structure between two courses leverage the changes on the learning interest. We give an algorithm on measuring the difference on learning interest integrated with similarity comparison between courses. A search engine, TASK-Moniminer, is created to help the teacher query the learning interest on their streaming lectures on tele-TASK site. Social site acts as an online community attracting web users to discuss the common topics and share their interesting information. Compared to the public information portal site and e-learning web site, the rich interactions among users and web content bring the wider range of content quality, on the other hand, provide more possibilities to express and model usage interest. We propose a framework on finding and recommending high reputation articles in a social site. We observed that the reputation is classified into global and local categories; the quality of the articles having high reputation is related with the content features. Based on these observations, our framework is implemented firstly by finding the articles having global or local reputation, and secondly clustering articles based on their content relations, and then the articles are selected and recommended from each cluster based on their reputation ranks.
The past climate in central Asia, and especially on the Tibetan Plateau (TP), is of great importance for an understanding of global climate processes and for predicting the future climate. As a major influence on the climate in this region, the Asian Summer Monsoon (ASM) and its evolutionary history are of vital importance for accurate predictions. However, neither the evolutionary pattern of the summer monsoon nor the driving mechanisms behind it are yet clearly understood. For this research, I first synthesized previously published Late Glacial to Holocene climatic records from monsoonal central Asia in order to extract the general climate signals and the associated summer monsoon intensities. New climate and vegetation sequences were then established using improved quantitative methods, focusing on fossil pollen records recovered from Tibetan lakes and also incorporating new modern datasets. The pollen-vegetation and vegetation-climate relationships on the TP were also evaluated in order to achieve a better understanding of fossil pollen records. The synthesis of previously published moisture-related palaeoclimate records in monsoonal central Asia revealed generally different temporal patterns for the two monsoonal subsystems, i.e. the Indian Summer Monsoon (ISM) and East Asian Summer Monsoon (EASM). The ISM appears to have experienced maximum wet conditions during the early Holocene, while many records from the area affected by the EASM indicate relatively dry conditions at that time, particularly in north-central China where the maximum moisture levels occurred during the middle Holocene. A detailed consideration of possible driving factors affecting the summer monsoon, including summer solar insolation and sea surface temperatures, revealed that the ISM was primarily driven by variations in northern hemisphere solar insolation, and that the EASM may have been constrained by the ISM resulting in asynchronous patterns of evolution for these two subsystems. This hypothesis is further supported by modern monsoon indices estimated using the NCEP/NCAR Reanalysis data from the last 50 years, which indicate a significant negative correlation between the two summer monsoon subsystems. By analogy with the early Holocene, intensification of the ISM during coming decades could lead to increased aridification elsewhere as a result of the asynchronous nature of the monsoon subsystems, as can already be observed in the meteorological data from the last 15 years. A quantitative climate reconstruction using fossil pollen records was achieved through analysis of sediment core recovered from Lake Donggi Cona (in the north-eastern part of the TP) which has been dated back to the Last Glacial Maximum (LGM). A new data-set of modern pollen collected from large lakes in arid to semi-arid regions of central Asia is also presented herein. The concept of "pollen source area" was introduced to modern climate calibration based on pollen from large lakes, and was applied to the fossil pollen sequence from Lake Donggi Cona. Extremely dry conditions were found to have dominated the LGM, and a subsequent gradually increasing trend in moisture during the Late Glacial period was terminated by an abrupt reversion to a dry phase that lasted for about 1000 years and coincided with the first Heinrich Event of the northern Atlantic region. Subsequent periods corresponding to the warm Bølling-Allerød period and the Younger Dryas cold event were followed by moist conditions during the early Holocene, with annual precipitation of up to about 400 mm. A slightly drier trend after 9 cal ka BP was then followed by a second wet phase during the middle Holocene that lasted until 4.5 cal ka BP. Relatively steady conditions with only slight fluctuations then dominated the late Holocene, resulting in the present climatic conditions. In order to investigate the relationship between vegetation and climate, temporal variations in the possible driving factors for vegetation change on the northern TP were examined using a high resolution late Holocene pollen record from Lake Kusai. Moving-window Redundancy Analyses (RDAs) were used to evaluate the correlations between pollen assemblages and individual sedimentary proxies. These analyses have revealed frequent fluctuations in the relative abundances of alpine steppe and alpine desert components, and in particular a decrease in the total vegetation cover at around 1500 cal a BP. The climate was found to have had an important influence on vegetation changes when conditions were relatively wet and stable. However, after the 1500 cal a BP threshold in vegetation cover was crossed the vegetation appears to have been affected more by extreme events such as dust storms or fluvial erosion than by the general climatic trends. In addition, pollen spectra over the last 600 years have been revealed by Procrustes analysis to be significantly different from those recovered from older samples, which is attributed to an increased human impact that resulted in unprecedented changes to the composition of the vegetation. Theoretical models that have been developed and widely applied to the European area (i.e. the Extended R-Value (ERV) model and the Regional Estimates of Vegetation Abundance from Large Sites (REVEALS) model) have been applied to the high alpine TP ecosystems in order to investigate the pollen-vegetation relationships, as well as for quantitative reconstructions of vegetation abundance. The modern pollen–vegetation relationships for four common pollen species on the TP have been investigated using Poaceae as the reference taxa. The ERV Submodel 2 yielded relatively high PPEs for the steppe and desert taxa (Artemisia Chenopodiaceae), and low PPEs for the Cyperaceae that are characteristic of the alpine Kobresia meadows. The plant abundances on the central and north-eastern TP were quantified by applying these PPEs to four post-Late Glacial fossil pollen sequences. The reconstructed vegetation assemblages for the four pollen sequences always yielded smaller compositional species turnovers than suggested by the pollen spectra, indicating that the strength of the previously-reported vegetation changes may therefore have been overestimated. In summary, the key findings of this thesis are that (a) the two ASM subsystems show asynchronous patterns during both the Holocene and modern time periods, (b) fossil pollen records from large lakes reflect regional signals for which the pollen source areas need to be taken into account, (c) climate is not always the main driver for vegetation change, and (d) previously reported vegetation changes on the TP may have been overestimated because they ignored inter-species variations in pollen productivity.
Spatial and temporal temperature and moisture patterns across the Tibetan Plateau are very complex. The onset and magnitude of the Holocene climate optimum in the Asian monsoon realm, in particular, is a subject of considerable debate as this time period is often used as an analogue for recent global warming. In the light of contradictory inferences regarding past climate and environmental change on the Tibetan Plateau, I have attempted to explain mismatches in the timing and magnitude of change. Therefore, I analysed the temporal variation of fossil pollen and diatom spectra and the geochemical record from palaeo-ecological records covering different time scales (late Quaternary and the last 200 years) from two core regions in the NE and SE Tibetan Plateau. For interpretation purposes I combined my data with other available palaeo-ecological data to set up corresponding aquatic and terrestrial proxy data sets of two lake pairs and two sets of sites. I focused on the direct comparison of proxies representing lacustrine response to climate signals (e.g., diatoms, ostracods, geochemical record) and proxies representing changes in the terrestrial environment (i.e., terrestrial pollen), in order to asses whether the lake and its catchments respond at similar times and magnitudes to environmental changes. Therefore, I introduced the established numerical technique procrustes rotation as a new approach in palaeoecology to quantitatively compare raw data of any two sedimentary records of interest in order to assess their degree of concordance. Focusing on the late Quaternary, sediment cores from two lakes (Kuhai Lake 35.3°N; 99.2°E; 4150 m asl; and Koucha Lake 34.0°N; 97.2°E; 4540 m asl) on the semi-arid northeastern Tibetan Plateau were analysed to identify post-glacial vegetation and environmental changes, and to investigate the responses of lake ecosystems to such changes. Based on the pollen record, five major vegetation and climate changes could be identified: (1) A shift from alpine desert to alpine steppe indicates a change from cold, dry conditions to warmer and more moist conditions at 14.8 cal. ka BP, (2) alpine steppe with tundra elements points to conditions of higher effective moisture and a stepwise warming climate at 13.6 cal. ka BP, (3) the appearance of high-alpine meadow vegetation indicates a further change towards increased moisture, but with colder temperatures, at 7.0 cal. ka BP, (4) the reoccurrence of alpine steppe with desert elements suggests a return to a significantly colder and drier phase at 6.3 cal. ka BP, and (5) the establishment of alpine steppe-meadow vegetation indicates a change back to relatively moist conditions at 2.2 cal. ka BP. To place the reconstructed climate inferences from the NE Tibetan Plateau into the context of Holocene moisture evolution across the Tibetan Plateau, I applied a five-scale moisture index and average link clustering to all available continuous pollen and non-pollen palaeoclimate records from the Tibetan Plateau, in an attempt to detect coherent regional and temporal patterns of moisture evolution on the Plateau. However, no common temporal or spatial pattern of moisture evolution during the Holocene could be detected, which can be assigned to the complex responses of different proxies to environmental changes in an already very heterogeneous mountain landscape, where minor differences in elevation can result in marked variations in microenvironments. Focusing on the past 200 years, I analysed the sedimentary records (LC6 Lake 29.5°N, 94.3°E, 4132 m asl; and Wuxu Lake 29.9°N, 101.1°E, 3705 m asl) from the southeastern Tibetan Plateau. I found that despite presumed significant temperature increases over that period, pollen and diatom records from the SE Tibetan Plateau reveal only very subtle changes throughout their profiles. The compositional species turnover investigated over the last 200 years appears relatively low in comparison to the species reorganisations during the Holocene. The results indicate that climatically induced ecological thresholds are not yet crossed, but that human activity has an increasing influence, particularly on the terrestrial ecosystem. Forest clearances and reforestation have not caused forest decline in our study area, but a conversion of natural forests to semi-natural secondary forests. The results from the numerical proxy comparison of the two sets of two pairs of Tibetan lakes indicate that the use of different proxies and the work with palaeo-ecological records from different lake types can cause deviant stories of inferred change. Irrespective of the timescale (Holocene or last 200 years) or region (SE or NE Tibetan Plateau) analysed, the agreement in terms of the direction, timing, and magnitude of change between the corresponding terrestrial data sets is generally better than the match between the corresponding lacustrine data sets, suggesting that lacustrine proxies may partly be influenced by in-lake or local catchment processes whereas the terrestrial proxy reflects a more regional climatic signal. The current disaccord on coherent temporal and spatial climate patterns on the Tibetan Plateau can partly be ascribed to the complexity of proxy response and lake systems on the Tibetan Plateau. Therefore, a multi-proxy, multi-site approach is important in order to gain a reliable climate interpretation for the complex mountain landscape of the Tibetan Plateau.
Resolute readings of later Wittgenstein and the challenge of avoiding hierarchies in philosophy
(2011)
This dissertation addresses the question: How did later Wittgenstein aim to achieve his goal of putting forward a way of dissolving philosophical problems which centered on asking ourselves what we mean by our words – yet which did not entail any claims about the essence of language and meaning? This question is discussed with reference to “resolute” readings of Wittgenstein. I discuss the readings of James Conant, Oskari Kuusela, and Martin Gustafsson. I follow Oskari Kuusela’s claim that in order to fully appreciate how later Wittgenstein meant to achieve his goal, we need to clearly see how he aimed to do away with hierarchies in philosophy: Not only is the dissolution of philosophical problems via the method of clarifying the grammar of expressions to be taken as independent from any theses about what meaning must be – but furthermore, it is to be taken as independent from the dissolution of any particular problem via this method. As Kuusela stresses, this also holds for the problems involving rule-following and meaning: the clarification of the grammar of “rule” and “meaning” has no foundational status – it is nothing on which the method of clarifying the grammar of expressions as such were meant to in any way rely on. The lead question of this dissertation then is: What does it mean to come to see that the method of dissolving philosophical problems by asking “How is this word actually used?” does not in any way rely on the results of our having investigated the grammar of the particular concepts “rule” and “meaning”? What is the relation of such results – results such as “To follow a rule, [...], to obey an order, [...] are customs (uses, institutions)” or “The meaning of a word is its use in the language” – to this method? From this vantage point, I concern myself with two aspects of the readings of Gustafsson and Kuusela. In Gustafsson, I concern myself with his idea that the dissolution of philosophical problems in general “relies on” the very agreement which – during the dissolution of the rule-following problem – comes out as a presupposition for our talk of “meaning” in terms of rules. In Kuusela, I concern myself with his idea that Wittgenstein, in adopting a way of philosophical clarification which investigates the actual use of expressions, is following the model of “meaning as use” – which model he had previously introduced in order to perspicuously present an aspect of the actual use of the word “meaning”. This dissertation aims to show how these two aspects of Gustafsson’s and Kuusela’s readings still fail to live up to the vision of Wittgenstein as a philosopher who aimed to do away with any hierarchies in philosophy. I base this conclusion on a detailed analysis of which of the occasions where Wittgenstein invokes the notions of “use” and “application” (as also “agreement”) have to do with the dissolution of a specific problem only, and which have to do with the dissolution of philosophical problems in general. I discuss Wittgenstein’s remarks on rule-following, showing how in the dissolution of the rule-following paradox, notions such as “use”, “application”, and “practice” figure on two distinct logical levels. I then discuss an example of what happens when this distinction is not duly heeded: Gordon Baker and Peter Hacker’s idea that the rule-following remarks have a special significance for his project of dissolving philosophical problems as such. I furnish an argument to the effect that their idea that the clarification of the rules of grammar of the particular expression “following a rule” could answer a question about rules of grammar in general rests on a conflation of the two logical levels on which “use” occurs in the rule-following remarks, and that it leads into a regress. I then show that Gustafsson’s view – despite its decisive advance over Baker and Hacker – contains a version of that same idea, and that it likewise leads into a regress. Finally, I show that Kuusela’s idea of a special significance of the model “meaning as use” for the whole of the method of stating rules for the use of words is open to a regress argument of a similar kind as that he himself advances against Baker and Hacker. I conclude that in order to avoid such a regress, we need to reject the idea that the grammatical remark “The meaning of a word is its use in the language” – because of the occurrence of “use” in it – stood in any special relation to the method of dissolving philosophical problems by describing the use of words. Rather, we need to take this method as independent from this outcome of the investigation of the use of the particular word “meaning”.
Cognitive psychology is traditionally interested in the interaction of perception, cognition, and behavioral control. Investigating eye movements in reading constitutes a field of research in which the processes and interactions of these subsystems can be studied in a well-defined environment. Thereby, the following questions are pursued: How much information is visually perceived during a fixation, how is processing achieved and temporally coordinated from visual letter encoding to final sentence comprehension, and how do such processes reflect on behavior such as the control of the eyes’ movements during reading. Various theoretical models have been proposed to account for the specific eye-movement behavior in reading (for a review see Reichle, Rayner, & Pollatsek, 2003). Some models are based on the idea of shifting attention serially from one word to the next within the sentence whereas others propose distributed attention allocating processing resources to more than one word at a time. As attention is assumed to drive word recognition processes one major difference between these models is that word processing must either occur in strict serial order, or that word processing is achieved in parallel. In spite of this crucial difference in the time course of word processing, both model classes perform well on explaining many of the benchmark effects in reading. In fact, there seems to be not much empirical evidence that challenges the models to a point at which their basic assumptions could be falsified. One issue often perceived as being decisive in the debate on serial and parallel word processing is how not-yet-fixated words to the right of fixation affect eye movements. Specifically, evidence is discussed as to what spatial extent such parafoveal words are previewed and how this influences current and subsequent word processing. Four experiments investigated parafoveal processing close to the spatial limits of the perceptual span. The present work aims to go beyond mere existence proofs of previewing words at such spatial distances. Introducing a manipulation that dissociates the sources of long-range preview effects, benefits and costs of parafoveal processing can be investigated in a single analysis and the differing impact is tracked across a three-word target region. In addition, the same manipulation evaluates the role of oculomotor error as the cause of non-local distributed effects. In this respect, the results contribute to a better understanding of the time course of word processing inside the perceptual span and attention allocation during reading.
During reading oculomotor processes guide the eyes over the text. The visual information recorded is accessed, evaluated and processed. Only by retrieving the meaning of a word from the long-term memory, as well as through the connection and storage of the information about each individual word, is it possible to access the semantic meaning of a sentence. Therefore memory, and here in particular working memory, plays a pivotal role in the basic processes of reading. The following dissertation investigates to what extent different demands on memory and memory capacity have an effect on eye movement behavior while reading. The frequently used paradigm of the reading span task, in which test subjects read and evaluate individual sentences, was used for the experimental review of the research questions. The results speak for the fact that working memory processes have a direct effect on various eye movement measurements. Thus a high working memory load, for example, reduced the perceptual span while reading. The lower the individual working memory capacity of the reader was, the stronger was the influence of the working memory load on the processing of the sentence.