A number of studies have been conducted on the attrition rates of undergraduate and graduate students. However, the body of knowledge concerning attrition for doctoral students, especially those who have attained the level of “all but dissertation” (ABD), is limited. The purpose of this research was to examine retention and attrition factors of doctoral candidates from a typical Higher Education Doctoral Program (Research II Public Institution) who were admitted to candidacy from 1991 through July 2000. Participation of the subject population was limited to those who had attained the level of ABD--those who had previously fulfilled the residency, coursework, foreign language or tool-subject requirements, and successfully completed the comprehensive/qualifying exams. This population included current ABDs, previously attrited ABDs, and graduates of the degree program. The research study was qualitative and intended to identify the effect of specific, predetermined factors that may have influenced or affected the progress of current, previous, and graduated students towards the doctoral degree in higher education. This study obtained responses to questions from the questionnaire/survey instrument concerning factors that affected program completion or attrition. Students had the opportunity to elaborate on factors from their dissertation, advisement, and personal, financial, and employment experiences that affected their ability to complete the program through open-ended question responses. By examining key factors in the doctoral degree experience from the three sample groups (current ABDs, previous ABDs, and graduated Ed.Ds), this study was able to draw some conclusions about doctoral attrition. Reconstructing and comparing the experiences of ABDs from the point of candidacy to the point of attrition or completion of the program determined trends, commonalities, and issues affecting achievement. Results of this study add to the limited research concerning ABD attrition and provide an insight from the student perspective as to the obstacles and support variables in the quest for the doctoral degree.

HTML clipboard The great advances in DNA technology, e.g. sequencing and recombinant DNA techniques, have given us the genetic information and the tools needed to effectively produce recombinant proteins. Recombinant proteins are valuable means in biotechnological applications and are also emerging as alternatives in therapeutic applications. Traditionally, monoclonal antibodies have been the natural choice for biotechnological and therapeutic applications due to their ability to bind a huge range of different molecules and their natural good affinity. However, the large size of antibodies (150 kDa) limits tissue penetration and the recombinant expression is complicated. Therefore, alternative binders with smaller sizes have been derived from antibodies and alternative scaffolds. In this thesis, two structurally similar domains, Zbasic and ABDz1, have been used as purification tags in different contexts. They are both three-helical bundles and derived from bacterial surface domains, but share no sequence homology. Furthermore, by redesign of the scaffold used for ABDz1, a molecule intended for drug targeting with extended in-vivo half-life has been engineered. In Papers I and II, the poly-cationic tag Zbasic is explored and evaluated. Paper I describes the successful investigation of Zbasic as a purification handle under denaturating conditions. Moreover, Zbasic is evaluated as an interaction domain in matrixassisted refolding. Two different proteins were successfully refolded using the same setup without individual optimization. In Paper II, Zbasic is further explored as a purification handle under non-native conditions in a multi-parallel setup. In total, 22 proteins with varying characteristics are successfully purified using a multi-parallel protein purification protocol and a robotic system. Without modifications, the system can purify up to 60 proteins without manual handling. Paper I and II clearly demonstrate that Zbasic can be used as an interaction domain in matrix-assisted refolding and that it offers a good alternative to the commonly used His6-tag under denaturating conditions. In paper III, the small bifunctional ABDz1 is selected from a phage display library. Endowed with two different binding interfaces, ABDz1 is capable of binding both the HSA-sepharose and the protein A-derived MabSelect SuRe-matrix. The bifunctionality of the domain is exploited in an orthogonal affinity setup. Three target proteins are successfully purified using the HSA-matrix and the MabSelect SuRe-matrix. Furthermore, the purity of the target proteins is effectively improved by combining the two chromatographic steps. Thus, paper III shows that the small ABDz1 can be used as an effective purification handle and dual affinity tag without target specific optimization. Paper IV describes the selection and affinity maturation of small bispecific drug-targeting molecules. First generation binders against tumor necrosis factor-α are selected using phage display. Thereafter on-cell surface display and flow cytometry is used to select second-generation binders. The binding to tumor necrosis factor-α is improved up to 30 times as compared to the best first generation binder, and a 6-fold improvement of the binding strength was possible with retained HSA affinity. Paper III and IV clearly demonstrate that dual interaction surfaces can successfully be grafted on a small proteinaceous domain, and that the strategy in paper IV can be used for dual selection of bifunctional binders. / <p>QC20100610</p>

In order to produce predictable and robust systems forprotein purification and detection, well characterized, small,folded domains descending from bacterial receptors have beenused. These bacterial receptors, staphylococcal protein A (SPA)and streptococcal protein G (SPG), possess high affinity to IgGand / or HSA. They are composed of repetitive units in whicheach one binds the ligand independently. The domains foldindependently and are very stable. Since the domains also havewellknown three-dimensional structures and do not containcysteine residues, they are very suitable as frameworks forfurther protein engineering. Streptococcal protein G (SPG) is a multidomain proteinpresent on the cell surface ofStreptococcus. X-ray crystallography has been used todetermine the binding site of the Ig-binding domain. In thisthesis the region responsible for the HSA affinity of ABD3 hasbeen determined by directed mutagenesis followed by functionaland structural analysis. The analysis shows that the HSAbindinginvolves residues mainly in the second α-helix. Most protein-based affinity chromatography media are verysensitive towards alkaline treatment, which is the preferredmethod for regeneration and removal of contaminants from thepurification devices in industrial applications. Here, aprotein engineering strategy has been used to improve thetolerance to alkaline conditions of different domains fromprotein G, ABD3 and C2. Amino acids known to be susceptibletowards high pH were substituted for less alkali susceptibleresidues. The new, engineered variants of C2 and ABD shownhigher stability towards alkaline pH. Also, very important forthe potential use as affinity ligands, these mutated variantsretained the secondary structure and the affinity to HSA andIgG, respectively. Moreover, dimerization was performed toinvestigate whether a higher binding capacity could be obtainedby multivalency. For ABD, binding studies showed that divalentligands coupled using non-directed chemistry demonstrated anincreased molar binding capacity compared to monovalentligands. In contrast, equal molar binding capacities wereobserved for both types of ligands when using a directed ligandcoupling chemistry involving the introduction and recruitmentof a unique C-terminal cysteine residue. The staphylococcal protein A-derived domain Z is also a wellknown and thoroughly characterized fusion partner widely usedin affinity chromatography systems. This domain is consideredto be relatively tolerant towards alkaline conditions.Nevertheless, it is desirable to further improve the stabilityin order to enable an SPA-based affinity medium to withstandeven longer exposure to the harsh conditions associated withcleaning in place (CIP) procedures. For this purpose adifferent protein engineering strategy was employed. Smallchanges in stability due to the mutations would be difficult toassess. Hence, in order to enable detection of improvementsregarding the alkaline resistance of the Z domain, a by-passmutagenesis strategy was utilized, where a mutated structurallydestabilized variant, Z(F30A) was used as a surrogateframework. All eight asparagines in the domain were exchangedone-by-one. The residues were all shown to have differentimpact on the alkaline tolerance of the domain. By exchangingasparagine 23 for a threonine we were able to remarkablyincrease the stability of the Z(F30A)-domain towards alkalineconditions. Also, when grafting the N23T mutation to the Zscaffold we were able to detect an increased tolerance towardsalkaline treatment compared to the native Z molecule. In allcases, the most sensitive asparagines were found to be locatedin the loops region. In summary, the work presented in this thesis shows theusefulness of protein engineering strategies, both to explorethe importance of different amino acids regarding stability andfunctionality and to improve the characteristics of aprotein. <b>Keywords:</b>binding, affinity, human serum albumin (HSA),albumin-binding domain (ABD), affinity chromatography,deamidation, protein A, stabilization, Z-domain, capacity,protein G, cleaning-in-place (CIP), protein engineering, C2receptor.

This thesis analyzes how the Ottomans attempted to survive under the intensified British threat in the Persian Gulf during the period of Abd&uuml / lhamid II (1876-1909). British statesmen at that time and Western sources inspired by these political elites have argued that there was no British menace that aimed to undermine the Ottoman presence in the Persian Gulf but that the Ottomans could not rule and hold the region. This thesis argues the contrary, that there was a formidable British threatening policy toward the Ottoman presence in the Persian Gulf which aimed at keeping the Ottomans out of the region by various effective means, particularly by using local autonomous sheikhs who served as prot&eacute / g&eacute / s in undermining the Ottoman administration in the Gulf region. Furthermore, this thesis argues that the Ottomans generated policy for the region that has formed in response to the British threat. In this regard, the Ottoman government generated several responses, which were also reforms for the local people and administration in the Gulf region, to avert the British threat / however the Ottomans faced the serious challenges of Britain and the autonomous sheikhs in the realization of these responses. In all, this study concludes that the Ottoman Empire did not control the region completely and effectively owing not to its incompetence, yet the British policy did not allow for the Ottoman presence in the region.

<p>In order to produce predictable and robust systems forprotein purification and detection, well characterized, small,folded domains descending from bacterial receptors have beenused. These bacterial receptors, staphylococcal protein A (SPA)and streptococcal protein G (SPG), possess high affinity to IgGand / or HSA. They are composed of repetitive units in whicheach one binds the ligand independently. The domains foldindependently and are very stable. Since the domains also havewellknown three-dimensional structures and do not containcysteine residues, they are very suitable as frameworks forfurther protein engineering.</p><p>Streptococcal protein G (SPG) is a multidomain proteinpresent on the cell surface of<i>Streptococcus</i>. X-ray crystallography has been used todetermine the binding site of the Ig-binding domain. In thisthesis the region responsible for the HSA affinity of ABD3 hasbeen determined by directed mutagenesis followed by functionaland structural analysis. The analysis shows that the HSAbindinginvolves residues mainly in the second α-helix.</p><p>Most protein-based affinity chromatography media are verysensitive towards alkaline treatment, which is the preferredmethod for regeneration and removal of contaminants from thepurification devices in industrial applications. Here, aprotein engineering strategy has been used to improve thetolerance to alkaline conditions of different domains fromprotein G, ABD3 and C2. Amino acids known to be susceptibletowards high pH were substituted for less alkali susceptibleresidues. The new, engineered variants of C2 and ABD shownhigher stability towards alkaline pH. Also, very important forthe potential use as affinity ligands, these mutated variantsretained the secondary structure and the affinity to HSA andIgG, respectively. Moreover, dimerization was performed toinvestigate whether a higher binding capacity could be obtainedby multivalency. For ABD, binding studies showed that divalentligands coupled using non-directed chemistry demonstrated anincreased molar binding capacity compared to monovalentligands. In contrast, equal molar binding capacities wereobserved for both types of ligands when using a directed ligandcoupling chemistry involving the introduction and recruitmentof a unique C-terminal cysteine residue.</p><p>The staphylococcal protein A-derived domain Z is also a wellknown and thoroughly characterized fusion partner widely usedin affinity chromatography systems. This domain is consideredto be relatively tolerant towards alkaline conditions.Nevertheless, it is desirable to further improve the stabilityin order to enable an SPA-based affinity medium to withstandeven longer exposure to the harsh conditions associated withcleaning in place (CIP) procedures. For this purpose adifferent protein engineering strategy was employed. Smallchanges in stability due to the mutations would be difficult toassess. Hence, in order to enable detection of improvementsregarding the alkaline resistance of the Z domain, a by-passmutagenesis strategy was utilized, where a mutated structurallydestabilized variant, Z(F30A) was used as a surrogateframework. All eight asparagines in the domain were exchangedone-by-one. The residues were all shown to have differentimpact on the alkaline tolerance of the domain. By exchangingasparagine 23 for a threonine we were able to remarkablyincrease the stability of the Z(F30A)-domain towards alkalineconditions. Also, when grafting the N23T mutation to the Zscaffold we were able to detect an increased tolerance towardsalkaline treatment compared to the native Z molecule. In allcases, the most sensitive asparagines were found to be locatedin the loops region.</p><p>In summary, the work presented in this thesis shows theusefulness of protein engineering strategies, both to explorethe importance of different amino acids regarding stability andfunctionality and to improve the characteristics of aprotein.</p><p><b>Keywords:</b>binding, affinity, human serum albumin (HSA),albumin-binding domain (ABD), affinity chromatography,deamidation, protein A, stabilization, Z-domain, capacity,protein G, cleaning-in-place (CIP), protein engineering, C2receptor.</p>

This thesis traces the development of the concept of freedom through three generations of the Modern Arab Renaissance (Nahda). The first chapter challenges the claim that the concept of freedom, in the sense of a political right, was absent from Arab thought prior to the French occupation of Egypt (1798-1801). ‘Abd al-Rahman al-Jabarti’s (1754-1825/6) chronicle of the occupation reveals that he possessed the concept of freedom despite the lack of an Arabic word to identify it. Therefore, when Rifa’a Rafi’ al-Tahtawi (1801-73) translated the French term liberté into Arabic, through a semantic expansion of the word hurriyah, he was naming rather than introducing the concept. The second chapter turns to Syria and examines how Butrus al-Bustani’s (1819-83) advocacy of the freedom of conscience (hurriyat al-damir) as an individual right reflects the influence of his American missionary mentors. However, while the missionaries used this concept to defend their narrow sectarian interests, Bustani believed that the freedom of all citizens must be protected equally by a secular government. The third chapter follows two Syrian friends, Muhammad Rashid Rida (1865-1935) and Farah Antun (1874-1922), who migrated to Egypt where their differing visions of reform brought them into conflict on the pages of their respective literary journals. While Antun argued that secularism provides the best guarantee of freedom, Rida contended that true freedom is only found in Islam. Despite this divide, they shared the same fundamental understanding of the value and meaning of freedom. This chapter shows that the concept of freedom is compatible with differing political ideologies while maintaining its core semantic field. Although there were some changes in how Arab intellectuals conceived of freedom during the nineteenth century, this study demonstrates that there was considerable continuity. / text

This study examines the impact of academic and personal life on graduate student persistence and transformation. Of particular interest are the relationships, emotions, and life management skills required throughout the graduate experience and how socialization, emotional intelligence, and advising aid students through their academic program. With an average of seven to eight years required to complete a doctoral program, life happens. Students enter and leave relationships, children are born, family members have emergencies, health issues arise, and emotional growth takes place. Therefore, students transform not only academically, but in many ways. These are intertwined as evidenced by the data-derived system representation. The importance of understanding the interconnected links in graduate experience spans academic, social, economic, and societal spheres. Each year hundreds of thousands of students enter graduate school. However, for doctoral students, there is an enormous gap between acceptance and completion. After seven years, approximately 50 percent complete their program and after ten years the rate climbs to only 57 percent (Council of Graduate Schools, 2010). This study offers a systemic representation and a four-stage model of graduate student development, incorporating student-identified factors: Faculty Impact, Life Management, Relationships, Playing the Game, Growth/Transformation, Emotions, and Reward/Purpose. Stage I: Orientation and Socialization Stage II: Adjustment and Transition Stage III: Navigation and Transformation Stage IV: Completion and Advancement The results, presented as a systems-based model, along with analysis, may be used to support faculty, advisors, and administrators in creating better advising, orientation, evaluation, and support systems. Departmental policies may be improved to identify at-risk students, provide mentorship opportunities, or obtain continual feedback to understand the underlying factors that may stop students from progressing. This research might also help identify students during the application/admission process. The methodological framework used to create the system produced in this study is Interactive Qualitative Analysis (Northcutt & McCoy, 2004), a methodology that provides the quantitative rigor of algorithmically generated data analysis, combined with the qualitative descriptiveness of interviews, in order to provide insights into the drivers of graduate school persistence. This methodology uses a systematic, protocol-driven research procedure to construct a unified, descriptive diagram to illustrate the phenomenon. / text

Recently HER3, member of the epidermal growth factor receptor family (EGFR), has been found to play a crucial role in the development of resistance towards inhibitors that are given to patients with HER1- and HER2-driven cancers. As HER3 is up-regulated or over-activated in several types of human cancers, it is of outmost importance that new innovative drugs target its oncologic activity. The Affibody® Molecule Z08698 inhibits the heregulin induced signalling of HER3 with high affinity (KD~50 pM). As the Affibody® Molecule is small, has high solubility and outstanding folding kinetics, an effective penetration of tumour tissue is suggested together with a rationalized manufacturing process. Further coupling to an albumin binding domain (ABD) expands the plasma half-life of the molecule, hence increasing the molecule's potential of serving as a therapeutic. A process development for production of Z08698-VDGS-ABD094 has been established, where the molecule is efficiently produced in the E. coli host strain BL21(DE3), through a T7 based expression system. Cultivations were performed with a fed-batch fermentation process and the conditions were further optimized in order to obtain highest expression, while avoiding undesirable modifications like gluconoylations. By employing Design of experiments in combination with multivariate data analysis, a production process resulting in ~3.5 g product/ l culture could be verified. Moreover, thermolysis was evaluated as a suitable method for cell disruption, enabling an easy and cost-effective manufacturing process of the ABD fused Affibody® Molecule.

This dissertation is a study of the Futūḥ Miṣr (Conquest of Egypt) of Ibn 'Abd al-Ḥakam (d. 257/871), the earliest extant Arabic history of Egypt. Its primary aim is not to assess whether its information is 'authentic' - i.e. corresponding to an objective historical reality - though my findings are of relevance for those engaged in debates over authenticity. My goal instead is to explore the ideas about the past which are conveyed by this particular conglomeration of historical information and to propose methods through which we can expose and analyse different layers and types of authorial activity within a multi-vocal text like Futūḥ Miṣr. Ultimately, I use this analysis as the basis of a case study suggesting how we might more effectively historicise the generation and transmission of historical ideas in the early Islamic period. Part I of the thesis consists of three chapters which explore Futūḥ Miṣr as a whole, literary text which can be understood as an instantiation of the historical worldview of its composer. Part II of the thesis contains three chapters which each illuminate features of Ibn 'Abd al-Ḥakam's historical practice which are important prerequisites for the stratigraphic reading of Futūḥ Miṣr performed in Part III. Part III of the thesis uses the understanding of Ibn 'Abd al-Ḥakam's authorial techniques developed in Part II to expose the earlier packages of historical information which underpin Futūḥ Miṣr. These final three chapters demonstrate how Ibn 'Abd al-Ḥakam reinvested these pre-existing narratives with meaning at a micro-level - by interjecting commentary and accounts from other sources - and at a macro-level - by integrating them into the larger narrative structure of Futūḥ Miṣr. In sum, this thesis is the first systematic study of the sources, structure, and authorship of an early Arabic history, which both tests and expands our current understanding of the dynamics of early Islamic historical writing, and sheds light on numerous aspects of the changing uses of the past among the Muslim scholars of Umayyad and 'Abbāsid Egypt.

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