Tyhjä taivas : Georges Bataille ja uskonnon kysymys

Empty Heavens. Georges Bataille and the Question of Religion. The dissertation explores the question of religion in the texts of Georges Bataille (1897 1962), the controversial French avant-garde writer and philosopher. Passionate about religion throughout his life, Bataille devoted to it both critical analyses and personal meditations. In this study, Bataille s multifaceted relationship to religion is interpreted as expressing a passion for radical otherness. Bataille is approached as a characteristically modern thinker who, nevertheless, questions some landmarks of modernity insofar as modernity is interpreted as a triumph of secularization. The dissertation is situated at the intersection of comparative religion and philosophy of religion. Methodologically, the study resorts to theoretical contextualization and concept analysis. Acknowledging that Bataille s writings challenge the assumptions about coherent meaning taken for granted in traditional philosophical analysis, the study also pays attention to the literary means and, in general, the performative level of Bataille s texts. The study constructs three theoretical contexts for Bataille s question of religion first of all, the interpretation of Hegel in the mid-20th century French philosophy. In the first section of the study, Bataille s uneasy relationship with Hegel as mediated by Alexandre Kojève is explored. The motivation of his question of radical otherness is argued to arise from his struggle with the Hegelian Kojèvean notion of negativity. The second context is the dialogue with the Christian mystical tradition. Starting from the analysis of two Bataillean notions, dramatization and contestation , it is argued that, firstly, Bataille s approach to radical otherness is analogous to certain procedures of mystical texts while, secondly, the function of otherness providing no firm foundation in Bataille s texts differs from its function in mystical texts. In the third section of the study, Bataille s quest for otherness is concretized by analyzing his views on otherness of other person, on violence, and on death themes that are brought together in Bataille s lasting interest in sacrifice. Bataille s understanding of sacrifice is proportioned to social scientific and philosophical discussions on sacrifice. It is argued that the commitment to the idea of sacrifice accounts for a partial failure in the Bataillean approach to otherness, the otherness of other person remaining its (at least half) blind spot. The study presents an overview of Bataille s thought on religion. It brings out Bataille s view of the paradoxical fundamental yet impossible role of otherness in the construction of human world, as well as his understanding of religious representations as both covering over and indicating this otherness. It describes Bataille s atheological mysticism as a peculiar modern form of religiosity, as an ambivalent mourning for and exaltation of fundamental loss.

Given and News : Media discourse and the construction of community on national days

National anniversaries such as independence days demand precise coordination in order to make citizens change their routines to forego work and spend the day at rest or at festivities that provide social focus and spectacle. The complex social construction of national days is taken for granted and operates as a given in the news media, which are the main agents responsible for coordinating these planned disruptions of normal routines. This study examines the language used in the news to construct the rather unnatural idea of national days and to align people in observing them. The data for the study consist of news stories about the Fourth of July in the New York Times, sampled over 150 years and are supplemented by material from other sources and other countries. The study is multidimensional, applying concepts from pragmatics (speech acts, politeness, information structure), systemic functional linguistics (the interpersonal metafunction and the Appraisal framework) and cognitive linguistics (frames, metaphor) as well as journalism and communications to arrive at an interdisciplinary understanding of how resources for meaning are used by writers and readers of the news stories. The analysis shows that on national anniversaries, nations tend to be metaphorized as persons having birthdays, to whom politeness should be shown. The face of the nation is to be respected in the sense of identifying the nation's interests as one's own (positive face) and speaking of citizen responsibilities rather than rights (negative face). Resources are available for both positive and negative evaluations of events and participants and the newspaper deftly changes footings (Goffman 1981) to demonstrate the required politeness while also heteroglossically allowing for a certain amount of disattention and even protest - within limits, for state holidays are almost never construed as Bakhtinian festivals, as they tend to reaffirm the hierarchy rather than invert it. Celebrations are evaluated mainly for impressiveness, and for the essentially contested quality of appropriateness, which covers norms of predictability, size, audience response, aesthetics, and explicit reference to the past. Events may also be negatively evaluated as dull ("banal") or inauthentic ("hoopla"). Audiences are evaluated chiefly in terms of their enthusiasm, or production of appropriate displays for emotional response, for national days are supposed to be occasions of flooding-out of nationalistic feeling. By making these evaluations, the newspaper reinforces its powerful position as an independent critic, while at the same time playing an active role in the construction and reproduction of emotional order embodied in "the nation's birthday." As an occasion for mobilization and demonstrations of power, national days may be seen to stand to war in the relation of play to fighting (Bateson 1955). Evidence from the newspaper's coverage of recent conflicts is adduced to support this analysis. In the course of the investigation, methods are developed for analyzing large collections of newspaper content, particularly topical soft news and feature materials that have hitherto been considered less influential and worthy of study than so-called hard news. In his work on evaluation in newspaper stories, White (1998) proposed that the classic hard news story is focused on an event that threatens the social order, but news of holidays and celebrations in general does not fit this pattern, in fact its central event is a reproduction of the social order. Thus in the system of news values (Galtung and Ruge 1965), national holiday news draws on "ground" news values such as continuity and predictability rather than "figure" news values such as negativity and surprise. It is argued that this ground helps form a necessary space for hard news to be seen as important, similar to the way in which the information structure of language is seen to rely on the regular alternation of given and new information (Chafe 1994).

Other Side of This Life : Death, Value, and Social Being in Thomas Pynchon's Fiction

This dissertation analyzes the interrelationship between death, the conditions of (wo)man s social being, and the notion of value as it emerges in the fiction of the American novelist Thomas Pynchon (1937 ). Pynchon s present work includes six novels V. (1963), The Crying of Lot 49 (1966), Gravity s Rainbow (1973), Vineland (1990), Mason & Dixon (1997), Against the Day (2006) and several short stories. Death constitues a central thematic in Pynchon s work, and it emerges through recurrent questions of mortality, suicide, mass destruction, sacrifice, afterlife, entropy, the relationship between the animate and the inanimate, and the limits of representation. In Pynchon, death is never a mere biological given (or event); it is always determined within a certain historical, cultural, and ideological context. Throughout his work, Pynchon questions the strict ontological separation of life and death by showing the relationship between this separation and social power. Conceptual divisions also reflect the relationship between society and its others, and death becomes that through which lines of social demarcation are articulated. Determined as a conceptual and social "other side", death in Pynchon forms a challenge to modern culture, and makes an unexpected return: the dead return to haunt the living, the inanimate and the animate fuse, and technoscientific attempts at overcoming and controlling death result in its re-emergence in mass destruction and ecological damage. The questioning of the ontological line also affects the structuration of Pynchon's prose, where the recurrent narrated and narrative desire to reach the limits of representation is openly associated with death. Textualized, death appears in Pynchon's writing as a sudden rupture within the textual functioning, when the "other side", that is, the bare materiality of the signifier is foregrounded. In this study, Pynchon s cultural criticism and his poetics come together, and I analyze the subversive role of death in his fiction through Jean Baudrillard s genealogy of the modern notion of death from L échange symbolique et la mort (1976). Baudrillard sees an intrinsic bond between the social repression of death in modernity and the emergence of modern political economy, and in his analysis economy and language appear as parallel systems for generating value (exchange value/ sign-value). For Baudrillard, the modern notion of death as negativity in relation to the positivity of life, and the fact that death cannot be given a proper meaning, betray an antagonistic relation between death and the notion of value. As a mode of negativity (that is, non-value), death becomes a moment of rupture in relation to value-based thinking in short, rationalism. Through this rupture emerges a form of thinking Baudrillard labels the symbolic, characterized by ambivalence and the subversion of conceptual opposites.

Writing Otherwise than Seeing : Writing and Exteriority in Maurice Blanchot

Maurice Blanchot (1907-2003), the French writer and novelist, is one of the most important figures in post-war French literature and philosophy. The main intention of this study is to figure out his position and originality in the field of phenomenology. Since this thesis concentrates on the notion of vision in Blanchot s work, its primary context is the post-war discussion of the relation between seeing and thinking in France, and particularly the discussion of the conditions of non-violent vision and language. The focus will be on the philosophical conversation between Blanchot and his contemporary philosophers. The central premise is the following: Blanchot relates the criticism of vision to the criticism of the representative model of language. In this thesis, Blanchot s definition of literary language as the refusal to reveal anything is read as a reference pointing in two directions. First, to Hegel s idea of naming as negativity which reveals Being incrementally to man, and second, to Heidegger s idea of poetry as the simultaneity of revealing and withdrawal; the aim is to prove that eventually Blanchot opposes both Hegel s idea of naming as a gradual revelation of the totality of being and Heidegger s conception of poetry as a way of revealing the truth of Being. My other central hypothesis is that for Blanchot, the criticism of the privilege of vision is always related to the problematic of the exteriority. The principal intention is to trace how Blanchot s idea of language as infinity and exteriority challenges both the Hegelian idea of naming as conceptualizing things and Heidegger s concept of language as a way to truth (as aletheia). The intention is to show how Blanchot, with his concepts of fascination, resemblance and image, both affirms and challenges the central points of Heidegger s thinking on language. Blanchot s originality in, and contribution to, the discussion about the violence of vision and language is found in his answer to the question of how to approach the other by avoiding the worst violence . I claim that by criticizing the idea of language as naming both in Hegel and Heidegger, Blanchot generates an account of language which, since it neither negates nor creates Being, is beyond the metaphysical opposition between Being and non-Being.

Concordant molecular and phenotypic data delineate new taxonomy and conservation priorities for the endangered mountain yellow-legged frog

The mountain yellow-legged frog Rana muscosa sensu lato, once abundant in the Sierra Nevada of California and Nevada, and the disjunct Transverse Ranges of southern California, has declined precipitously throughout its range, even though most of its habitat is protected. The species is now extinct in Nevada and reduced to tiny remnants in southern California, where as a distinct population segment, it is classified as Endangered. Introduced predators (trout), air pollution and an infectious disease (chytridiomycosis) threaten remaining populations. A Bayesian analysis of 1901 base pairs of mitochondrial DNA confirms the presence of two deeply divergent clades that come into near contact in the Sierra Nevada. Morphological studies of museum specimens and analysis of acoustic data show that the two major mtDNA clades are readily differentiated phenotypically. Accordingly, we recognize two species, Rana sierrae, in the northern and central Sierra Nevada, and R. muscosa, in the southern Sierra Nevada and southern California. Existing data indicate no range overlap. These results have important implications for the conservation of these two species as they illuminate a profound mismatch between the current delineation of the distinct population segments (southern California vs. Sierra Nevada) and actual species boundaries. For example, our study finds that remnant populations of R. muscosa exist in both the southern Sierra Nevada and the mountains of southern California, which may broaden options for management. In addition, despite the fact that only the southern California populations are listed as Endangered, surveys conducted since 1995 at 225 historic (1899-1994) localities from museum collections show that 93.3% (n=146) of R. sierrae populations and 95.2% (n=79) of R. muscosa populations are extinct. Evidence presented here underscores the need for revision of protected population status to include both species throughout their ranges.

Genetic and Epigenetic Characterization of Colorectal and Endometrial Cancer

Colorectal cancer is one of the three most common cancers today, for both men and women. Approximately 90% of the cases are sporadic while the remaining 10% is hereditary. Among this 10% is hereditary nonpolyposis colorectal cancer (HNPCC), an autosomal dominant disease, accounting for up to 13% of these cases. HNPCC is associated with germline mutations in four mismatch repair (MMR) genes, MLH1, MSH2, MSH6, and PMS2, and is characterized by a familial accumulation of endometrial, gastric, urological, and ovarian tumors, in addition to colorectal cancer. An important etiological characteristic of HNPCC is the presence of microsatellite instability (MSI), caused by mutations of the MMR genes. Approximately 15% of sporadic cases share the MSI+ trait. Colon cancer is believed to be a consequence of an accumulation of mutations in tumor suppressor genes and oncogenes, eventually resulting in tumor development. This phenomena is accelerated in HNPCC due the presence of an inherited mutation in the MMR genes, accounting for one of the two hits proposed to be needed by Knudson (1971) in order for the manifestation of the MSI phenotype. MMR alterations alone, however, do not occur in the majority of sporadic colon cancers, prompting searches for other mechanisms. One such mechanism found to play a role in colon cancer development was DNA methylation, which is known to play a role in MLH1 inactivation. Our objective was clarification of mechanisms associated with tumor development in both HNPCC and sporadic colorectal cancer in relation to tumorigenic mechanisms. Of particular interest were underlying mechanisms of MSI in sporadic colorectal cancers, with attention to DNA methylation changes and their correlation to MSI. Of additional interest were the genetic and epigenetic events leading to the HNPCC tumor spectrum, chiefly colon and endometrial cancers, in regards to what extent the somatic changes in target tissue explained this phenomenon. We made a number of important findings pertaining to these questions. First, MSI tumor development differs epigenetically from stable tumor development, possibly underlying developmental pathway differences. Additionally, while epigenetic modification, principally DNA methylation, is a major mechanism in sporadic MSI colorectal cancer MLH1 inactivation it does not play a significant role in HNPCC tumors with germline MLH1 mutations. This is possibly an explanation for tumorigenic pathways and clinicopathological characteristic differences between sporadic and hereditary MSI colorectal cancers. Finally, despite indistinguishable genetic predisposition for endometrial and colorectal cancers, instability profiles highlighting organ-specific differences, may be important HNPCC tumor spectrum determinants.

Molecular mechanisms of cancer predisposition in HNPCC/Lynch syndrome

Hereditary non-polyposis colorectal carcinoma (HNPCC; Lynch syndrome) is among the most common hereditary cancers in man and a model of cancers arising through deficient DNA mismatch repair (MMR). It is inherited in a dominant manner with predisposing germline mutations in the MMR genes, mainly MLH1, MSH2, MSH6 and PMS2. Both copies of the MMR gene need to be inactivated for cancer development. Since Lynch syndrome family members are born with one defective copy of one of the MMR genes in their germline, they only need to acquire a so called second hit to inactivate the MMR gene. Hence, they usually develop cancer at an early age. MMR gene inactivation leads to accumulation of mutations particularly in short repeat tracts, known as microsatellites, causing microsatellite instability (MSI). MSI is the hallmark of Lynch syndrome tumors, but is present in approximately 15% of sporadic tumors as well. There are several possible mechanisms of somatic inactivation (i.e. the second hit ) of MMR genes, for instance deletion of the wild-type copy, leading to loss of heterozygosity (LOH), methylation of promoter regions necessary for gene transcription, or mitotic recombination or gene conversion. In the Lynch syndrome tumors carrying germline mutations in the MMR gene, LOH was found to be the most frequent mechanism of somatic inactivation in the present study. We also studied MLH1/MSH2 deletion carriers and found that somatic mutations identical to the ones in the germline occurred frequently in colorectal cancers and were also present in extracolonic Lynch syndrome-associated tumors. Chromosome-specific marker analysis implied that gene conversion, rather than mitotic recombination or deletion of the respective gene locus accounted for wild-type inactivation. Lynch syndrome patients are predisposed to certain types of cancers, the most common ones being colorectal, endometrial and gastric cancer. Gastric cancer and uroepithelial tumors of bladder and ureter were observed to be true Lynch syndrome tumors with MMR deficiency as the driving force of tumorigenesis. Brain tumors and kidney carcinoma, on the other hand, were mostly MSS, implying the possibility of alternative routes of tumor development. These results present possible implications in clinical cancer surveillance. In about one-third of families suspected of Lynch syndrome, mutations in MMR genes are not found, and we therefore looked for alternative mechanisms of predisposition. According to our results, large genomic deletions, mainly in MSH2, and germline epimutations in MLH1, together explain a significant fraction of point mutation-negative families suspected of Lynch syndrome and are associated with characteristic clinical and family features. Our findings have important implications in the diagnosis and management of Lynch syndrome families.

Molecular basis of colorectal cancer predisposition

Colorectal cancer (CRC) is one of the most frequent malignancies in Western countries. Inherited factors have been suggested to be involved in 35% of CRCs. The hereditary CRC syndromes explain only ~6% of all CRCs, indicating that a large proportion of the inherited susceptibility is still unexplained. Much of the remaining genetic predisposition for CRC is probably due to undiscovered low-penetrance variations. This study was conducted to identify germline and somatic changes that contribute to CRC predisposition and tumorigenesis. MLH1 and MSH2, that underlie Hereditary non-polyposis colorectal cancer (HNPCC) are considered to be tumor suppressor genes; the first hit is inherited in the germline and somatic inactivation of the wild type allele is required for tumor initiation. In a recent study, frequent loss of the mutant allele in HNPCC tumors was detected and a new model, arguing against the two-hit hypothesis, was proposed for somatic HNPCC tumorigenesis. We tested this hypothesis by conducting LOH analysis on 25 colorectal HNPCC tumors with a known germline mutation in the MLH1 or MSH2 genes. LOH was detected in 56% of the tumors. All the losses targeted the wild type allele supporting the classical two-hit model for HNPCC tumorigenesis. The variants 3020insC, R702W and G908R in NOD2 predispose to Crohn s disease. Contribution of NOD2 to CRC predisposition has been examined in several case-control series, with conflicting results. We have previously shown that 3020insC does not predispose to CRC in Finnish CRC patients. To expand our previous study the variants R702W and G908R were genotyped in a population-based series of 1042 Finnish CRC patients and 508 healthy controls. Association analyses did not show significant evidence for association of the variants with CRC. Single nucleotide polymorphism (SNP) rs6983267 at chromosome 8q24 was the first CRC susceptibility variant identified through genome-wide association studies. To characterize the role of rs6983267 in CRC predisposition in the Finnish population, we genotyped the SNP in the case-control material of 1042 cases and 1012 controls and showed that G allele of rs6983267 is associated with the increased risk of CRC (OR 1.22; P=0.0018). Examination of allelic imbalance in the tumors heterozygous for rs6983267 revealed that copy number increase affected 22% of the tumors and interestingly, it favored the G allele. By utilizing a computer algorithm, Enhancer Element Locator (EEL), an evolutionary conserved regulatory motif containing rs6983267 was identified. The SNP affected the binding site of TCF4, a transcription factor that mediates Wnt signaling in cells, and has proven to be crucial in colorectal neoplasia. The preferential binding of TCF4 to the risk allele G was showed in vitro and in vivo. The element drove lacZ marker gene expression in mouse embryos in a pattern that is consistent with genes regulated by the Wnt signaling pathway. These results suggest that rs6983267 at 8q24 exerts its effect in CRC predisposition by regulating gene expression. The most obvious target gene for the enhancer element is MYC, residing ~335 kb downstream, however further studies are required to establish the transcriptional target(s) of the predicted enhancer element.

Molecular and clinical characteristics of tricarboxylic acid cycle-associated tumors

Hereditary leiomyomatosis and renal cell cancer (HLRCC) is a rare, dominantly inherited tumor predisposition syndrome characterized by benign cutaneous and uterine (ULM) leiomyomas, and sometimes renal cell cancer (RCC). A few cases of uterine leiomyosarcoma (ULMS) have also been reported. Mutations in a nuclear gene encoding fumarate hydratase (FH), an enzyme of the mitochondrial tricarboxylic acid cycle (TCA cycle), underlie HLRCC. As a recessive condition, germline mutations in FH predispose to a neurological defect, FH deficiency (FHD). Hereditary paragangliomatosis (HPGL) is a dominant disorder associated with paragangliomas and pheochromocytomas. Inherited mutations in three genes encoding subunits of succinate dehydrogenase (SDH), also a TCA cycle enzyme, predispose to HPGL. Both FH and SDH seem to act as tumor suppressors. One of the consequences of the TCA cycle defect is abnormal activation of HIF1 pathway ( pseudohypoxia ) in the HLRCC and HPGL tumors. HIF1 drives transcription of genes encoding e.g. angiogenetic factors which can facilitate tumor growth. Recently hypoxia/HIF1 has been suggested to be one of the causes of genetic instability as well. One of the aims of this study was to broaden the clinical definers of HLRCC. To determine the cancer risk and to identify possible novel tumor types associated with FH mutations eight Finnish HLRCC/FHD families were extensively evaluated. The extension of the pedigrees and the Finnish Cancer Registry based tumor search yielded genealogical and cancer data of altogether 868 individuals. The standardized incidence ratio-based comparison of HLRCC/FHD family members with general Finnish population revealed 6.5-fold risk for RCC. Moreover, risk for ULMS was highly increased. However, according to the recent and more stringent diagnosis criteria of ULMS many of the HLRCC uterine tumors previously considered malignant are at present diagnosed as atypical or proliferative ULMs (with a low risk of recurrence). Thus, the formation of ULMS (as presently defined) in HLRCC appears to be uncommon. Though increased incidence was not observed, interestingly the genetic analyses suggested possible association of breast and bladder cancer with loss of FH. Moreover, cancer cases were exceptionally detected in an FHD family. Another clinical finding was the conventional (clear cell) type RCC of a young Spanish HLRCC patient. Conventional RCC is distinct from the types previously observed in this syndrome but according to these results, FH mutation may underlie some of young conventional cancer cases. Secondly, the molecular pathway from defective TCA cycle to tumor formation was intended to clarify. Since HLRCC and HPGL tumors display abnormally activated HIF1, the hypothesis on the link between HIF1/hypoxia and genetic instability was of interest to study in HLRCC and HPGL tumor material. HIF1α (a subunit of HIF1) stabilization was confirmed in the majority of the specimens. However, no repression of MSH2, a protein of DNA mismatch repair system, or microsatellite instability (MSI), an indicator of genetic instability, was observed. Accordingly, increased instability seems not to play a role in the tumorigenesis of pseudohypoxic TCA cycle-deficient tumors. Additionally, to study the putative alternative functions of FH, a recently identified alternative FH transcript (FHv) was characterized. FHv was found to contain instead of exon 1, an alternative exon 1b. Differential subcellular distribution, lack of FH enzyme activity, low mRNA expression compared to FH, and induction by cellular stress suggest FHv to have a role distinct from FH, for example in apoptosis or survival. However, the physiological significance of FHv requires further elucidation.

Molecular classification of familial colorectal and endometrial carcinoma

Hereditary nonpolyposis colorectal cancer (HNPCC) is the most common known clearly hereditary cause of colorectal and endometrial cancer (CRC and EC). Dominantly inherited mutations in one of the known mismatch repair (MMR) genes predispose to HNPCC. Defective MMR leads to an accumulation of mutations especially in repeat tracts, presenting microsatellite instability. HNPCC is clinically a very heterogeneous disease. The age at onset varies and the target tissue may vary. In addition, families that fulfill the diagnostic criteria for HNPCC but fail to show any predisposing mutation in MMR genes exist. Our aim was to evaluate the genetic background of familial CRC and EC. We performed comprehensive molecular and DNA copy number analyses of CRCs fulfilling the diagnostic criteria for HNPCC. We studied the role of five pathways (MMR, Wnt, p53, CIN, PI3K/AKT) and divided the tumors into two groups, one with MMR gene germline mutations and the other without. We observed that MMR proficient familial CRC consist of two molecularly distinct groups that differ from MMR deficient tumors. Group A shows paucity of common molecular and chromosomal alterations characteristic of colorectal carcinogenesis. Group B shows molecular features similar to classical microsatellite stable tumors with gross chromosomal alterations. Our finding of a unique tumor profile in group A suggests the involvement of novel predisposing genes and pathways in colorectal cancer cohorts not linked to MMR gene defects. We investigated the genetic background of familial ECs. Among 22 families with clustering of EC, two (9%) were due to MMR gene germline mutations. The remaining familial site-specific ECs are largely comparable with HNPCC associated ECs, the main difference between these groups being MMR proficiency vs. deficiency. We studied the role of PI3K/AKT pathway in familial ECs as well and observed that PIK3CA amplifications are characteristic of familial site-specific EC without MMR gene germline mutations. Most of the high-level amplifications occurred in tumors with stable microsatellites, suggesting that these tumors are more likely associated with chromosomal rather than microsatellite instability and MMR defect. The existence of site-specific endometrial carcinoma as a separate entity remains equivocal until predisposing genes are identified. It is possible that no single highly penetrant gene for this proposed syndrome exists, it may, for example be due to a combination of multiple low penetrance genes. Despite advances in deciphering the molecular genetic background of HNPCC, it is poorly understood why certain organs are more susceptible than others to cancer development. We found that important determinants of the HNPCC tumor spectrum are, in addition to different predisposing germline mutations, organ specific target genes and different instability profiles, loss of heterozygosity at MLH1 locus, and MLH1 promoter methylation. This study provided more precise molecular classification of families with CRC and EC. Our observations on familial CRC and EC are likely to have broader significance that extends to sporadic CRC and EC as well.

Genetic alterations in microsatellite-unstable colorectal cancer

Colorectal cancer (CRC) is the third most common cancer in Finland. Of all CRC tumors, 15% display microsatellite-instability (MSI) caused by defective cellular mismatch repair. Cells displaying MSI accumulate a high number of mutations genome-wide, especially in short repeat areas, microsatellites. When targeting genes essential for cell growth or death, MSI can promote tumorigenesis. In non-coding areas, microsatellite mutations are generally considered as passenger events. Since the discovery of MSI and its linkage to cancer, more that 200 genes have been investigated for a role in MSI tumorigenesis. Although various criteria have been suggested for MSI target gene identification, the challenge has been to distinguish driver mutations from passenger mutations. This study aimed to clarify these key issues in the research field of MSI cancer. Prior to this, background mutation rate in MSI cancer has not been studied in a large-scale. We investigated the background mutation rate in MSI CRC by analyzing the spectrum of microsatellite mutations in non-coding areas. First, semenogelin I was studied for a possible role in MSI carcinogenesis. The intronic T9 repeat of semenogelin I was frequently mutated but no evidence for selection during tumorigenesis was obtained. Second, a sequencing approach was utilized to evaluate the general background mutation rate in MSI CRC. Both intronic and intergenic repeats harbored extremely high mutation rates of ≤ 87% and intergenic repeats were more unstable than the intronic repeats. As mutation rates of presumably neutral microsatellites can be high in MSI CRC in the absence of apparent selection pressure, high mutation frequency alone is not sufficient evidence for identification of driver MSI target genes. Next, an unbiased approach was designed to identify the mutatome of MSI CRC. By combining expression array data and a database search we identified novel genes possibly related to MSI CRC carcinogenesis. One of the genes was studied further. In the functional analysis this gene was observed to cause an abnormal cancer-prone cellular phenotype, possibly through altered responses to DNA damage. In our recent study, smooth muscle myosin heavy chain 11 (MYH11) was identified as a novel MSI CRC gene. Additionally, MYH11 has a well established role in acute myeloid leukemia (AML) through an oncogenic fusion protein CBFB-MYH11. We investigated further the role of MYH11 in AML by sequencing. Three novel missense variants of MYH11 were identified. None of the variants were present in the population-based control material. One of the identified variants, V71A, lies in the N-terminal SH3-like domain of MYH11 of unknown function. The other two variants, K1059E and R1792Q are located in the coil-coiled myosin rod essential for the regulation and filament formation of MYH11. The variant K1059E lies in the close proximity of the K1044N that has been functionally assessed in our earlier work of CRC and has been reported to cause total loss of MYH11 protein regulation. As the functional significance of the three novel variants examined in this work remains unknown, future studies should clarify the further role of MYH11 in AML leukaemogenesis and in other malignancies.

Study of synchronously mode-locked and internally frequency-doubledcw dye laser

The analysis of the characteristics of a synchronously mode-locked and internally frequency-doubled dye laser is presented. Dependence of dye laser pulse characteristics on the cavity length mismatch of the pump laser and dye laser is studied. Variation of the minimum pulsewidth with intracavity bandwidth and the harmonic conversion efficiency is presented in the form of graphs.

Essays on Labor Market Frictions, Technological Change and Macroeconomic Fluctuations

The dissertation consists of an introductory chapter and three essays that apply search-matching theory to study the interaction of labor market frictions, technological change and macroeconomic fluctuations. The first essay studies the impact of capital-embodied growth on equilibrium unemployment by extending a vintage capital/search model to incorporate vintage human capital. In addition to the capital obsolescence (or creative destruction) effect that tends to raise unemployment, vintage human capital introduces a skill obsolescence effect of faster growth that has the opposite sign. Faster skill obsolescence reduces the value of unemployment, hence wages and leads to more job creation and less job destruction, unambiguously reducing unemployment. The second essay studies the effect of skill biased technological change on skill mismatch and the allocation of workers and firms in the labor market. By allowing workers to invest in education, we extend a matching model with two-sided heterogeneity to incorporate an endogenous distribution of high and low skill workers. We consider various possibilities for the cost of acquiring skills and show that while unemployment increases in most scenarios, the effect on the distribution of vacancy and worker types varies according to the structure of skill costs. When the model is extended to incorporate endogenous labor market participation, we show that the unemployment rate becomes less informative of the state of the labor market as the participation margin absorbs employment effects. The third essay studies the effects of labor taxes on equilibrium labor market outcomes and macroeconomic dynamics in a New Keynesian model with matching frictions. Three policy instruments are considered: a marginal tax and a tax subsidy to produce tax progression schemes, and a replacement ratio to account for variability in outside options. In equilibrium, the marginal tax rate and replacement ratio dampen economic activity whereas tax subsidies boost the economy. The marginal tax rate and replacement ratio amplify shock responses whereas employment subsidies weaken them. The tax instruments affect the degree to which the wage absorbs shocks. We show that increasing tax progression when taxation is initially progressive is harmful for steady state employment and output, and amplifies the sensitivity of macroeconomic variables to shocks. When taxation is initially proportional, increasing progression is beneficial for output and employment and dampens shock responses.

The Restless Love of Thinking : The Concept Liebe in Hegel's Philosophy

The German philosopher G.W.F.Hegel (1770–1831) is best known for his idealistic system philosophy, his concept of spirit [Geist] and for his dictum that the existing and the rational overlap. This thesis offers a new perspective: it examines the working of the concept ‘love’ in Hegel’s philosophy by looking at the contexts and function he puts it to, from his earliest writings to the very last lectures he gave. The starting point of the inquiry is that he applied the concept Liebe to different contexts for different purposes, but each time to provide an answer to a specific philosophical problem. His formulation, reformulation and use of ‘love’ give possible solutions to problems the solving of which was crucial to the development of his thought as a whole. The study is divided into three parts, each analysing the different problems and solutions to which Hegel applied the concept of love. The first part, "Love, morality and ethical life", examines these interconnected themes in Hegel’s early work. The main questions he addressed during this period concerned how to unite Kant’s philosophy and the Greek ideal of the good life. In this context, the concept ‘love’ did three things. First, it served to formulate his grounding idea of the relation between unity and difference, or the manifold. Secondly, it was the key to his attempt to base an ideal folk religion on Christianity interpreted as a religion of love. Finally, it provided the means to criticise Kant’s moral philosophy. The question of the moral value of love helped Hegel to break away from Kant’s thought and develop his own theory about love and ethical life. The second part of the study, "Love and the political realm", considers the way 'Liebe' functions in connection with questions concerning the community and political life in Hegel’s work. In addition to questioning the universal applicability of the concept of recognition as a key to his theory of social relations, the chapters focus on gender politics and the way he conceptualised the gender category ‘woman’ through the concept ‘love’. Another line of inquiry is the way the figure of Antigone was used to conceptualise the differentiated spheres of action for men and women, and the part ‘love’ played in Hegel’s description of Antigone’s motives. Thirdly, Hegel’s analogy of the family and the state and the way ‘love’ functions in an attempt to promote understanding of the relation between citizens and the state are examined. The third and final part of the study, "Love as absolute spirit", focuses on ‘love’ within Hegel’s systemic thought and the way he continued to characterise Geist through the language of Liebe up until and including his very last works. It is shown how Liebe functions in his hierarchical organisation of the domains of art, religion and philosophy, and how both art and religion end up in similar structural positions with regard to philosophy. One recurrent theme in the third part is Hegel’s complex relation to Romantic thought. Another line of investigation is how he reconstructed Christianity as a religion of love in his mature work. In striking contrast to his early thought, in his last works Hegel introduced a new concept of love that incorporated negativity, and that could also function as the root of political action.

Entanglement production due to quench dynamics of an anisotropic XY chain in a transverse field

We compute concurrence and negativity as measures of two-spin entanglement generated by a power-law quench (characterized by a rate tau(-1) and an exponent alpha) which takes an anisotropic XY chain in a transverse field through a quantum critical point (QCP). We show that only spins separated by an even number of lattice spacings get entangled in such a process. Moreover, there is a critical rate of quench, tau(-1)(c), above which no two-spin entanglement is generated; the entire entanglement is multipartite. The ratio of the entanglements between consecutive even neighbors can be tuned by changing the quench rate. We also show that for large tau, the concurrence (negativity) scales as root alpha/tau(alpha/tau), and we relate this scaling behavior to defect production by the quench through a QCP.