Previous research on paper history has tended to be conducted from an economic perspective and/or as part of the field of book history within a broadly literary framework. This has resulted in understandings of paper history being book-centric and focused on production. We now have a great deal of knowledge about the physical process of hand paper-making, a good knowledge of the actors involved and where in the country paper was manufactured, but there is still very little scholarly discussion of the people, processes and practices associated with paper outside of the mill. Taking inspiration from eighteenth-century ‗it-narratives‘, this thesis takes a holistic approach to the paper trade – loosely based around the framework of social life theory as expounded by Arjun Appadurai and Igor Kopytoff. It encompasses a case study of the rag-collection and paper-wholesale operations of a single Edinburgh firm, a wider examination of paper-retailing in Edinburgh, a look at the ownership of desks in Edinburgh alongside a consideration of advice and instruction relating to desk-use, and closes with an examination of the papers owned by a notable Edinburgh family. The first three chapters consider the scope of the Edinburgh paper trade. Moving through distinct stages in the life of paper, these chapters begin with an account of the Edinburgh rag-trade. Business records relating to the Balerno Company‘s rag-buying operations reveal an active and organised network with connections to a variety of trades. Continuing the focus on the Balerno Company, the second chapter considers the company as paper-wholesalers. It demonstrates that the driving force behind their operations was not the supply of paper for the booktrade but rather the provision of wrapping papers for the purposes of commerce. Using advertisements in local newspapers the third chapter looks at the reach of paper-selling beyond the booktrades. The final two chapters move gradually from the commercial to the personal. Chapter four considers the presentation of desk-use in penmanship manuals and the evidence of desk-ownership in confirmation inventories. Both of which are suggestive of a growing mercantile interest in desk furniture. Finally, this thesis closes by looking at the paper archives of the Innes family of Stow in order to examine the extent to which the findings of previous chapters is reflected in the collection, retention and use of papers across two generations of this family. Overall, this thesis demonstrates the value of adopting an inclusive approach to the study of paper history, as doing so opens up a multifaceted world of paper. Paper history has tended to be understood as the history of writing and printing paper sold by booksellers and stationers. The social life approach allows connections to be made between materials, artefacts and trades; to gain a fuller understanding of the role paper played in people‘s lives.

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RAGs (Recombination Activating Genes) are responsible for generation of antigen receptor diversity in case of B-cells and T-cells, through the process of combinatorial joining of different V (variable), D (diversity) and J (joining) gene segments. Each of these segments are flanked by recombination signal sequences (RSS), which consist of a conserved heptamer and nonamer separated by a less conserved spacer of 12 or 23 bp. RAGs recognize and cleave at the 5’ end of heptamer, leading to the formation of hairpin coding ends and blunt signal ends. The coding ends are joined through the process of no homologous DNA end joining (NHEJ), leading to the rearrangement of variable region of antigen receptors. Apart from its physiological property, RAGs can also act as a structure-specific nuclease. Previously, it has been shown that inadvertent action of RAGs on cryptic RSS and non B-DNA structures can lead to the generation of genomic instability and cancer. A very coordinated expression of RAGs has been observed in pro- and pre-B cells of the lymphoid system, which overlaps with the window of productive rearrangement during V(D)J recombination. Besides, studies by us and others have shown that RAG cleavage at altered DNA structures and cryptic RSS leads to chromosomal translocations resulting into cancer. However, several questions related to regulation of RAG expression and its activity in lymphoid cells remains to be answered. Previous studies have suggested regulation of RAG expression at different levels, such as methylation, ubiquitination, phosphorylation and by coordinate action of various transcription factors. In the present study, we evaluate the potential role of miRNAs in the regulation of RAG expression and its function in lymphoid cells. miRNAs are small, single-stranded non-coding RNAs, which play an important role in the regulation of gene expression. They play a critical role in the regulation of different cellular functions. Although there are miRNAs identified to play critical role during development of immune system, several key questions such as its role in the regulation of RAGs is yet to be addressed. In the current study, we have used bioinformatics approach to extract potential miRNAs that bind to 3’UTR of RAG1 and RAG2. miRNA expression datasets were downloaded from NCBI SRA database and extensive evaluation was done using various bioinformatics tools such as Bowtie, Sam tools, Bam tools, Bed tools and R package. We screened the miRNA expression profile across different stages of B-cell development (pro, pre, immature and mature B-cells), which overlap with the narrow window of RAG expression. The shortlisted miRNAs were further analyzed using miRNA databases such as miRBase, Targetscan and EMBL. Results showed that 33 miRNAs were specific to RAG1, among that one (miRNA1) followed RAG expression profile in B-cells. Besides miRNA2, which is a novel miRNA, was selected only on the basis of RAGs expression profile in a stage specific manner and the complementarity of the seed sequence of miRNA2 to the 3’UTR of RAG1 was checked manually. Interestingly, we observed that RAG1 expression was significantly down regulated in the presence of these miRNAs. However, there was no significant difference in the levels of other genes analysed. Further, semi-quantitative RT-PCR analysis confirmed the endogenous processing of pre-miRNA into mature miRNA using the cellular machinery. Besides, enrichment of 3’UTR of seed region of these miRNAs, enhanced the expression level of RAG1. Importantly, the enhancement in RAG1 expression level was limited in case of mature B-cells, where RAG expression is normally not observed. Further, transfection of lymphoid cells with miRNA inhibitors, specific to the miRNAs under study, showed the enhancement in RAG1 expression in lymphoid cells. In addition to this, specificity of selected miRNAs was confirmed by performing 3’UTR reporter assays, where enhanced luciferase expression was observed in case of mutant 3’UTR, while it was minimal in case of wild type constructs. Endogenous expression levels of selected miRNAs were evaluated in both lymphoid and nonlymphoid normal tissues and cancer cells using RT-PCR. Interestingly, we observed inverse correlation of expression levels of miRNA and RAG expression in all the cells tested. Besides, miRNA expression levels were less in pre-B cells and T-cells, owing to the increased expression of RAGs. Apart from this, recombinogenic potential of candidate miRNAs was assessed using episomal based V(D)J recombination assays. Interestingly we observed significant decrease (2-4 fold) in the V(D)J recombination efficiency when miRNA1 or 2 constructs were transfected in Nalm6 cells, as compared to that of controls, where no miRNAs were used. However, in case of Reh cells upon transfection with miRNA1construct, the decrease in recombination potential was upto 9 fold. Hence, we identify two miRNAs that can play an important role in the regulation of RAG1 expression and its physiological activity. Further, studies are being carried out to confirm their role in the regulation of RAG1 during different developmental stages of lymphoid cells in mice. As stated above, in addition to the sequence-specific activity, RAG possesses structure-specific nuclease activity as well. It has been shown that RAGs can cleave different types of altered DNA structures. Studies from our laboratory showed that even when RAGs act as a structure-specific nuclease there is a sequence bias. Presence of cytosine and thymine at the single-stranded region of heteroduplex DNA is important for RAG nicking and double-strand break (DSB) formation. In addition, proximity of a nonamer to bubble structures can enhance RAG cleavage. However, the role of immediate flanking sequences in the RAG mediated cleavage at heteroduplex regions is not understood. We investigated the role of flanking double-stranded DNA sequences in the regulation of RAG cleavage on non-B DNA structures. We found that RAG binding and cleavage on heteroduplex DNA is dependent on the length of double-stranded flanking region. Besides, immediate flanking regions of the heteroduplex DNA affected the RAG binding and cleavage in a sequence dependent manner. Interestingly, we also observed that the cleavage efficiency of RAGs at heteroduplex region was influenced by the phasing of DNA. Thus, our results suggest that sequence, length and phase positions of the DNA can affect the efficiency of RAG cleavage when it acts as a structure-specific nuclease. These findings provide novel insights into regulation of the pathological action of RAGs. Previous studies have shown that in addition to formation of coding and signal joints during V(D)J recombination, nonstandard V(D)J recombination products known as hybrid joints and open-shut joints may be formed, particularly in certain aberrant conditions such as defective NHEJ machinery. Interestingly, the hybrid and open-shut joints closely resemble the transposition mechanisms associated with transposons oretroviruses. Studies have also shown that RAGs possess structural similarity with integrases in domain organization. Both the proteins have Zinc Finger Binding domain (ZFB) which helps in multimerization of the protein, a central catalytic core domain comprising three acidic amino acids D, D and E essential for enzymatic activity and C-terminal domain (CTD) responsible for nonspecific binding to the DNA. Previous studies from our laboratory showed that, Elvitegravir, an inhibitor of integrase could interfere with the biochemical functions of the RAGs in vitro. Specifically, it inhibited the RAG binding and cleavage at RSS, hairpin formation, post-cleavage complex formation involving 12RSS and 23RSS. Using the episomal assay system that mimics signal joints (pGG49) and coding joints (pGG51), we show that Elvitegravir can inhibit V(D)J recombination inside cells. Interestingly we observed 3-6 fold decrease in the recombination frequency in signal ends joining, when treated with increasing concentrations (100, 500 and 1000 nM) of Elvitegravir. A 5-8 fold decrease in coding joints formation was also observed upon treatment with the inhibitor. The presence of recombination was confirmed by restriction digestion followed by sequencing analysis. Further analysis of recombination junctions revealed extensive deletion before joining in the case of Elvitegravir treated samples. Insertions or substitutions near to the recombination junctions were also prominent in treated samples. In depth analysis of sequenced junctions showed the presence of sequence having the features to form hairpins both upstream and downstream to the RSS sequences and was the site of cleavage in cases were higher deletion was observed. The analyzed recombinants did not show any signal joints or coding joints formation in treated samples. This suggests that Elvitegravir affects the physiological function, the V(D)J recombination of RAGs inside the cells. Thus, in the present study, we show that RAGs can be regulated by specific miRNAs. We have identified two potential miRNAs, which can regulate the RAG expression as well as its function in different stages of B- and T-cell development. Further, we also identify a novel regulatory mechanism for the structure-specific activity of the RAG complex. In addition to this, we find that integrase inhibitor, Elvitegravir, affects V(D)J recombination within B-cells, indicating its potential deleterious impact in HIV patients, which needs to be further evaluated.

Recombination Activating Genes (RAGs) orchestrate the process called V (D) J recombination, which enables the vertebrate adaptive immune system to specifically recognize millions of antigens. During this recombination process, V (variable), D (diversity) and J (joining) gene segments of antibody (B cell receptor) and TCR (T cell receptor) join by different possible combinations to generate antigen receptor diversity. This unique site specific recombination process is actuated by lymphoid specific proteins called RAG1 and RAG2 (RAGs or RAG complex). RAGs recognize a conserved sequence motif flanking the above subexons called Recombination Signal Sequence (RSS). There are two types of RSS known as 12-RSS and 23-RSS, where a conserved heptamer sequence and nonameric sequence is separated by 12 or 23 bp, respectively. RAGs specifically bind to RSS by RAG1 Nonamer Binding Domain (NBD) and generate nicks which are converted to DSBs via a hairpin intermediate and finally repaired by Non-Homologous DNA End Joining (NHEJ), a major DSB repair pathway in eukaryotes. Thus, RAGs act as a sequence specific endonuclease, and is unique to higher eukaryotes. Therefore, reduced or loss of RAG activity could result in immune deficiency syndromes like Omenn Syndrome (OS) and Severe Combined Immunodeficiency (SCID). Apart from acting as a sequence specific nuclease, RAGs have been shown to cleave on altered DNA structures like mismatches (bubbles), hairpins, flaps, gaps, triplexes and 3’ overhangs. This structure specific nuclease activity is implicated in causing genomic instability in B and T cells, particularly leading to generation of chromosomal translocations in certain lymphoid cancers. However, unlike the sequence- specific cleavage activity, this novel property of RAGs is poorly understood. Structure-specific nuclease activity of RAGs was characterized by using heteroduplex DNA substrate containing bubble region. RAG proteins were overexpressed and purified from human cell line and used for the assay. Results showed that RAGs cleave different bubble substrates with different efficiency. The role of DNA sequence at single-stranded region of heteroduplex DNA on RAG cleavage was investigated by synthesizing the substrate DNA having either adenineguanine/ thymine/ cytosine in the bubble sequence. Interestingly, efficient RAG cleavage was observed only when cytosines were present at single-stranded region, while thymine bubbles were cleaved with much lower efficiency. Adenine and guanine containing bubbles were not cleaved by RAGs. This was the first observation showing sequence specificity during structure-specific nuclease activity of RAGs. Besides, it was observed that RAG cleavage on bubbles with cytosines resulted in DSB formation, which is essential for generation of chromosomal translocations. Further, such specificity and cytosine preference was observed, even when RAGs acted on other altered DNA substrates like hairpin loops, 3’ overhangs and gaps. When the role of flanking duplex region on RAG cleavage was tested, only the 5’ duplex nucleotide was critical for RAG cleavage reaction and cytosine was the most preferred nucleotide. By systematic mutation of bubble region, it was observed that the two cytosines present at the double strand-single strand junction are critical for RAG cleavage. A single nucleotide bubble (mismatch) with cytosines was cleaved by RAGs with low but detectable efficiency. A bubble with at least 2 nt length possessing cytosine was cleaved with higher efficiency resulting in both single-stranded nicks and DSBs. Based on these studies, “C(d)C(s)C(s)” was proposed as a novel recognition motif for RAG cleavage, on altered DNA structures, where“d” and “s” represent double- and single-strand region, respectively. To be targeted by RAGs in vivo, the altered DNA substrates have to compete with RSS, the physiological substrate. It is not known whether such structures will be cleaved by RAGs, when present along with RSS. Besides, the regulation of the both structure and sequence specific nuclease activities are not studied. To address the above questions, RAG cleavage on bubble substrates was performed in presence of RSS either in cis or trans configuration. Results showed that both bubble substrates and RSS were cleaved with similar efficiency by RAGs. In fact, they can compete out each other in a concentration dependent manner. When kinetics of RSS and bubble cleavage were performed, RSS cleavage reaction was faster and saturated within 10-15 min, while bubbles cleavage started slow and went on increasing with time. This difference in kinetics persisted when both substrates were present together. This could be a regulatory mechanism for targeting RAGs to RSS sites and limiting bubble cleavage which can be deleterious to cells. HMGB1, a DNA binding protein which is shown to enhance RSS binding and synapsis, does not affect RAG action on bubble substrates. RAG postcleavage complex is formed during V(D)J recombination process where RAGs remain bound to cleaved RSS after cleavage, which limits further RAG action on other sites. Such cleavage complex was not detected on bubble substrates, which suggests that after cleavage RAGs were not associated to DSBs of bubble cleavage. Finally, the nonamer binding domain of RAG1 involved in RSS binding in V(D)J recombination, was found to be dispensable for the structure-specific nuclease activity and it appears that RAGs bind to bubble substrates using a different domain. In summary, in this study, the structure-specific nuclease activity of RAGs was characterized. A novel sequence motif that can regulate this activity of RAGs was identified. Though altered structures can be equally favored substrates as RSS, differences in reaction kinetics, cleavage complex formation and separate DNA binding domains regulate RAG cleavage, when it acts as a structure-specific nuclease. Thus, this study may help in the better understanding of RAG induced genomic instabilities in lymphoid tissues.

There is a link between the tactile and optical modes of perception. Woven textiles’ materiality and ability to take three dimensional form, make them a good medium for creating shapes containing several pattern scales and textures. By conciously working with tactile-visual qualities and aesthetics one can achieve the most powerful effects, and in turn, the textile can take the role of a sensation director. By interpreting Kasuri with large scaled threads on a computerized hand loom and in space, an exploration of details and spatial installation can be conducted simultaneously. The five examples developed in this project demonstrate different approaches to dimensional hand weaving, intending to build a better understanding of micro and macro spatial features in woven textiles. Significantly, the project challenges the scale of hand weaving as well as the design process: stretching from thread to dimensional weave empowers the designer. By highlighting crafted details on a large scale, a sequence of events can be discerned that makes the spectator aware of quality and of the production process. Parallels between the body of work and our perception of lines and interspaces are drawn as an attempt to refine our relation to the objects around us.

Die Kathedrale von Santiago de Compostela im Nordwesten der Iberischen Halbinsel gehört zu den am dichtesten beforschten Bauwerken der Kunstgeschichte. Hier sind auch die zahlreichen Beiträge hervorzuheben, welche der Jubilar selbst im Laufe der vergangenen Jahre verfasste.

. This thesis consists of an introduction and four previously published articles. The joint empirical focus is papermaking based on textile rags as fibre raw material. Furthermore the physical environment is central in the studies. The relationship between continuity and change is a prevailing theme. The thesis also pays attention to the use of different sorts of rags and to the connection between this kind of papermaking and the textile industry. The overall purpose is to throw new light upon the paper industry based on rags – a part of early industry seldom mentioned in historical surveys of the industrialization process in Sweden. The aim is also to question the prevalent Swedish historical writing commissioned by the branch, characterized by set divisions between different phases of technical and industrial development, from simple craft to modern industry. One of these borderlines has been drawn between papermaking by hand and papermaking by machine, with the 1830s as the selected transition period. By studying and analysing changes in the traditional and seemingly static papermaking as well as the opposite: the traditional that has lingered in the new, this thesis shows that the course of events was much more complicated than that. An outcome of the studies is that the industrialization of the rag based paper industry has been a complex, uneven and prolonged process. The first main part of the thesis consists of two Swedish regional studies centred on the province of Östergötland in a long-time perspective. The focus is mainly on the long continuity of papermaking by hand, which was carried out between 1628 and 1968. The study shows that a variety of types and sizes of mills regarding ownership, forms of production, location, paper qualities and techniques can be identified. Continuity was the dominating feature but within this framework technological and industrial change also took place. The second main part of the thesis has a Nordic perspective and deals with a shorter period, mainly 1830-1870. One study examines the introduction of the paper-machine and the establishment of the first machine-made paper mills in Denmark, Sweden, Norway and Finland with special attention given to the Swedish mill Holmen in Norrköping and the Finnish Tammerfors mill, both situated in textile mill towns. A second Nordic study surveys hand-made paper mills founded during and after the time when the paper-machine technology had been established. As the studies show, two parallel development tracks were prevalent in the paper industry in the Nordic countries during the period 1830-1870 – papermaking by machine and papermaking by hand. The first paper machines were imported from Britain to some of the oldest and largest paper mills. The introduction of the new technology led to changes in for instance the paper mill buildings and the organization of work regarding the papermaking process. In the preparatory and finishing work manual methods remained, and as before it employed mostly women. At the same time, papermaking by hand continued to change and new hand-made paper mills were founded until as late as the 1890s. The study discusses possible explanations, among them growing markets for special qualities and combinations with other branches of industry. All the studies show a connection between hand-made paper mills and wool mills on one hand, and machine-made paper mills and cotton and linen mills on the other hand. The paper industry based on rags could in fact be characterized as a kind of textile industry / <p>QC 20101129</p>

<p>. This thesis consists of an introduction and four previously published articles. The joint empirical focus is papermaking based on textile rags as fibre raw material. Furthermore the physical environment is central in the studies. The relationship between continuity and change is a prevailing theme. The thesis also pays attention to the use of different sorts of rags and to the connection between this kind of papermaking and the textile industry.</p><p>The overall purpose is to throw new light upon the paper industry based on rags – a part of early industry seldom mentioned in historical surveys of the industrialization process in Sweden. The aim is also to question the prevalent Swedish historical writing commissioned by the branch, characterized by set divisions between different phases of technical and industrial development, from simple craft to modern industry. One of these borderlines has been drawn between papermaking by hand and papermaking by machine, with the 1830s as the selected transition period. By studying and analysing changes in the traditional and seemingly static papermaking as well as the opposite: the traditional that has lingered in the new, this thesis shows that the course of events was much more complicated than that. An outcome of the studies is that the industrialization of the rag based paper industry has been a complex, uneven and prolonged process.</p><p>The first main part of the thesis consists of two Swedish regional studies centred on the province of Östergötland in a long-time perspective. The focus is mainly on the long continuity of papermaking by hand, which was carried out between 1628 and 1968. The study shows that a variety of types and sizes of mills regarding ownership, forms of production, location, paper qualities and techniques can be identified. Continuity was the dominating feature but within this framework technological and industrial change also took place.</p><p>The second main part of the thesis has a Nordic perspective and deals with a shorter period, mainly 1830-1870. One study examines the introduction of the paper-machine and the establishment of the first machine-made paper mills in Denmark, Sweden, Norway and Finland with special attention given to the Swedish mill Holmen in Norrköping and the Finnish Tammerfors mill, both situated in textile mill towns. A second Nordic study surveys hand-made paper mills founded during and after the time when the paper-machine technology had been established. As the studies show, two parallel development tracks were prevalent in the paper industry in the Nordic countries during the period 1830-1870 – papermaking by machine and papermaking by hand.</p><p>The first paper machines were imported from Britain to some of the oldest and largest paper mills. The introduction of the new technology led to changes in for instance the paper mill buildings and the organization of work regarding the papermaking process. In the preparatory and finishing work manual methods remained, and as before it employed mostly women.</p><p>At the same time, papermaking by hand continued to change and new hand-made paper mills were founded until as late as the 1890s. The study discusses possible explanations, among them growing markets for special qualities and combinations with other branches of industry.</p><p>All the studies show a connection between hand-made paper mills and wool mills on one hand, and machine-made paper mills and cotton and linen mills on the other hand. The paper industry based on rags could in fact be characterized as a kind of textile industry</p>