Error-free DNA replication is paramount to maintaining genomic integrity. Despite being highly regulated, the process of DNA replication is often challenged by various intrinsic and extrinsic sources of replication stress. Failure to maintain the DNA replication quality reduces genomic stability, cell survival and results in diseases, such as cancer. Thus, cells rely on the replication stress response that detects perturbations in DNA replication and pauses or arrests cellular replication. Similar to other intrinsic replication obstacles, oncogene expression also induces the replication stress response that acts as a barrier to cancer, thereby mystifying how cancer develops. Here, we demonstrate that oncogene expression, similar to other replication stress inducing agents, induces single-stranded DNA (ssDNA) gaps that reduce cell fitness unless counteracted by translesion synthesis (TLS). Moreover, we find that TLS subverts the replication stress response in a wide range of cancer cell lines indicating that TLS is a previously unappreciated and unique cancer vulnerability. Mechanistically, we reveal that upon replication stress, TLS restricts replication fork slowing, reversal, and fork degradation, while maintaining continuous replication. Furthermore, we demonstrate that a small molecule inhibitor targeting the TLS factor, REV1, not only disrupts DNA replication and cancer cell fitness, but also synergizes with other therapies that induce replication gaps. Thus, our study places TLS at the center of cancer cell fitness as a necessary adaptation to overcome replication stress.

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Calcium, a pivotal ion in various human signaling pathways, holds significant relevance in cancer research and treatment. Investigating the transmission of spontaneous calcium signals between cells and understanding how they are influenced by different treatments is therefore an interesting area of study. This master's thesis presents a newly developed tool designed for analyzing intracellular calcium concentration [Ca2+] fluctuations. The tool encompasses a cell segmentation model, tracking algorithms, nearest neighbor identification, mean intensity measurement, and calculations of dominant frequency of [Ca2+] oscillations and signal correlation among neighboring cells. The tool was applied to fluorescence microscopy images of Madin-Darby Canine Kidney II cells expressing GCaMP6m and either treated with the cardiac glycoside ouabain, a combination of ouabain and the gap junction blocker heptanol, or left untreated for comparison. Additionally, an exploration into the impact of connexin 43 (Cx43) transfection on [Ca2+] fluctuations was undertaken. The transfection rate for Cx43 did not reach a sufficient level, impeding a thorough analysis of its influence on [Ca2+] fluctuations. Furthermore, the investigation into dominant frequencies and signal correlation did not yield conclusive findings regarding the effects of ouabain and heptanol. Nevertheless, a foundational tool for analysis has been developed, with the potential for expansion to analyze more aspects calcium signaling and application to additional cell types and treatments. / Kalcium, en central jon i olika signalvägar hos människan, spelar en viktig roll inom cancerforskning och -behandling. Att undersöka överföringen av spontana kalciumsignaler mellan celler och förstå hur dessa påverkas av olika behandlingar är därav ett intressant studieområde. I denna masteruppsats presenteras ett nyutvecklat verktyg utformat för att analysera variationer i intracellulär kalciumkoncentration [Ca2+] . Verktyget omfattar en cellsegmenteringsmodell, spårningsalgoritmer, identifiering av närmaste grannar, medelintensitetsmätning, beräkningar av dominant frekvens för oscillationer i [Ca2+] samt korrelation i dessa variationer mellan närliggande celler. Verktyget tillämpades på fluorescensmikroskopibilder av Madin-Darby Canine Kidney II-celler som uttryckte GCaMP6m och antingen hade behandlats med hjärtglykosiden ouabain, en kombination av ouabain och gap junction-blockeraren heptanol eller lämnats obehandlade för jämförelse. Dessutom undersöktes hur variationerna i [Ca2+] påverkades om cellerna transfekterades med konnexin 43 (Cx43). Andelen celler per prov som genomgick lyckad transfektion av Cx43 nådde aldrig upp till önskade nivåer, vilket förhindrade närmare analys av påverkan på [Ca2+]. Undersökningen av dominanta frekvenser och korrelation i signaler gav inte heller några entydiga svar på hur ouabain och heptanol påverkar [Ca2+]. Likväl har ett grundläggande verktyg för analys utvecklas, som har potential att utvidgas till analys av fler aspekter av kalciumsignalering och tillämpning på fler celltyper och behandlingar.

How did the Italian mafia affect honest Italian descendants on the American labor market? This is a study about how an exogenous shock to ethnic discrimination on the labor market affected a whole ethnic group. The goal with this study is to analyze how a massacre by Al Capone’s crew in 1929 affected Italian workers on the American labor market. Using linked census-data of all working-age men 1920-30, this paper studies the ethnic discrimination of second-generation Italian immigrants. The treatment group is Italian men, and the control groups are other immigrants and natives. Three different outcome variables will be used, employment, wage employment, and self-employment. The results suggest that Italians saw lower chances of being employed, lower chances of being wage employed, and higher chances of being self-employed post 1930 compared to other immigrants and natives. This suggest that Italians were forced into self-employment. A conclusion that the ethnic discrimination towards Italians is a result of the tragic massacre cannot be made due to no data on the news distribution. The news distribution system in America could give an indication on how the news were shown in surrounding areas and this could therefore reflect the employers’ attitudes towards Italians. Further studies are therefore required in order to conclude if the massacre gave Italians a harder time on the labor market or not but for now, we have an indication on that Italians were more affected post 1930 compared to other immigrants and natives.

From great African nations like the Ancient Kemites, Akan and Gikuyu, the world witnessed the development of the most powerful social structures, governance systems, ground breaking innovations in science and technology, and systems of thought that still exist today. Hence, in looking at the low performance levels of Black students today, the question becomes, how do the descendants of those who created writing, mathematics, and science; and then in the face of episodic disruptions laid their lives on the line to read, write, and built public schools, Sabbath schools, and Historically Black Colleges and Universities, close the excellence gap between their actual performance and deeply rooted cultural expectations? The present study reviews the essential questions and proposed solutions for closing the excellence gap that have been offered by previous generations of scholars. Africana Studies methodological framing questions were used to examine the long-view experiences of African people as well as a three tier critical ethnographic research methods approach. The study revealed that Black students gained a level of excellence in the face of disruption through: (1) Collective Training, (2) Spiritual and Moral Balance, and (3) Content Mastery. The prerequisite for sustaining educational excellence was found to be in the individual roles female and male representatives play as the primary educators of Black children. Secondly, nurturing a sense of identity through a spiritual understanding of social order and moral responsibility to the collective is also a requirement. Nevertheless, what unites and emerges as the chief element is content mastery. The ability to retain and keep content through listening and reading; and present a level of mastery on that information through speaking, writing and action to solve problems, completes the reciprocal process of educational excellence. / African American Studies

This study investigated how a QMS that is compliant with the Medical Device Regulation (MDR) can be constructed and what the most important aspects are when creating a functional QMS at a Swedish hospital. QMS:s are a fundamental part of a healthcare organization and are used to ensure safe and secure patient care. To establish qualitative healthcare, the Swedish National Board of Health and Welfare has created regulations for hospitals to construct their QMS concerning care processes and handling of medical devices. In addition to these, there are also regulations within the European Union, including the MDR. To facilitate QMS:s work, hospitals can also follow international standards created for quality work. The most common for medical device departments is ISO 13485. Regulations are often perceived as difficult to follow and can be hard to interpret. Swedish regulations mention that a hospital should have a “suitable” QMS based on the organization’s areas of activity. But what is considered appropriate is up to the organization to decide on, which to some extent has been difficult for Swedish hospitals. Furthermore, several studies depict challenges with hospital QMS implementation and getting the QMS to work functionally. A qualitative method has been used to answer the research question where the main source of data gathering has been semi-structured interviews. The interviews have been conducted with quality managers and with experts in regulations and standards for hospitals. The questions were mainly focused on how QMS:s that follow regulations should be constructed and how to effectively implement them in a hospital organization. The study concludes that it basically is impossible to construct a general QMS suitable for every hospital without having to adjust it to the hospital's different and specific work areas, which can look very different from hospital to hospital. Regardless, since ISO 13485 is harmonized with the QMS part of the MDR, it can be helpful for a medical technology department. The authors constructed a gap analysis tool to facilitate the development and implementation process for hospital QMS:s. When it comes to aspects that constitute a successful QMS implementation, the study found the most important aspects being culture, value creation, simplicity, and leadership. / Denna studie har undersökt hur ett kvalitetsledningssystem (KLS) som uppfyller kraven från Medical Device Regulation (MDR) ska konstrueras och implementeras i svenska sjukhus. KLS är en väsentlig del för att säkerhetsställa en säker och trygg patientvård. För att säkerhetsställa en kvalitativ vård har Socialstyrelsen upprättat föreskrifter för sjukhus att basera sina KLS på samt gällande hantering av medicintekniska produkter. Utöver dessa föreskrifter finns också regelverk gemensamma för Europeiska unionen bland vilket bland andra inkluderar MDR. För att underlätta arbetet med kvalitetsledningssystemet utnyttjar sjukhus i hög grad också standarder för sitt kvalitetsledningssystem. Den vanligaste är ISO 13485 för en medicinteknisk avdelning. Föreskrifterna som svenska sjukhus ska efterfölja kan ibland anses svårtolkade. Svenska föreskrifter nämner bland annat att svenska sjukhus ska ha ett “lämpligt” KLS utefter organisationens verksamhetsområden. Vad som anses lämpligt är upp till organisationen att definiera, vilket till viss del varit en svårighet för svenska sjukhus. Speciellt gällande medicintekniska produkter och hur dessa bör och ska hanteras. Hanteringen av medicintekniska produkter är en viktig faktor när KLS ska upprättas, vilket i vissa fall missats i svenska sjukhus. Utöver detta påpekar flera litterära studier på svårigheterna med implementeringen av KLS på sjukhus samt hur man får dessa att fungera optimalt i organisationen. För att besvara frågeställningen har en kvalitativ metod använts där främsta datainsamlingsmetoden varit semi-strukturerade intervjuer. Intervjuerna har genomförts med kvalitetsansvariga, samt med personer kunniga inom föreskrifter och standarder. Frågorna rörde i huvudsak hur ett föreskrifts efterföljande KLS ska konstrueras samt hur detta på ett effektivt sätt ska implementeras i organisationen. Studien kommer fram till att det i princip inte går att konstruera ett generellt KLS utan att detta måste anpassat till sjukhusets specifika arbetsområde vilket också kan skilja sig markant mellan olika avdelningar på sjukhuset. Oavsett så kan ISO 13485, som är harmoniserad mot KLS avsnittet i MDR, vara till hjälp för en medicinteknisk avdelning. Författarna konstruerade ett “gap-analysis tool” för att underlätta en första gapanalys som i studien visat sig vara ett första steg när KLS ska konstrueras. Gällande implementationen finner studien att viktigaste faktorerna är kultur, värdeskapande och enkelhet, samt ledarskap.

This dissertation consists of four chapters on the economics of marriage and divorce in Iran. The first chapter outlines major forces driving the recent transitions in Iran's marriage market. Age structure of the population, the rise of women's education, marriage and divorce laws, and fertility decline are the four main forces influencing marriage transitions, that is, the age of marriage, couple's age and education gaps, quality of marriage (stability, education status of children), and women's power within marriage. Chapter two looks at the change in age structure that influences the sex ratio. I consider the influence of the sex ratio on couples' age and education gaps using data from multiple national surveys from 1984-2007. The findings of this chapter show that a lower sex ratio, i.e. a greater supply of marriage-age women, increases the bargaining power of men at the time of marriage and thereby increases their ability to marry younger and more educated women. In chapter three, I evaluate the effects of demographic change, the sex ratio, and policy change, particularly the provision of family planning programs through health clinics on delayed marriage in rural Iran. I use data from Iran's 2000 Demographic and Health Survey to estimate a hazard model of timing of marriage. The results show that a lower sex ratio decreases the chances of a woman finding a man five years older, and easier access to family planning decreases her probability of marriage. In chapter four, I provide a legal history of Iran's marriage and divorce laws and then discuss how changes in the legal structure of marriage and divorce alter the terms of marital bargaining and force women to circumvent inequitable Iranian laws to improve their position. Then, I present a model of how Mahrieh could improve a woman's position within the household in light of the unequal divorce rights favoring men. As women cannot exit their marriage, they request a conditional and legally enforceable bond known as Mahrieh from their husbands to secure themselves against the risks of divorce or maltreatment within marriage. / Ph. D.

Objectif: Cette thèse avait pour objectif principal la mise en oeuvre et la validation de la faisabilité, chez l'humain, du paradigme de modulation du réflexe acoustique de sursaut par un court silence (GPIAS) afin de l'utiliser comme mesure objective de l'acouphène. Pour ce faire, trois expériences ont été réalisées. L'expérience 1 avait pour objectif de valider l'inhibition du réflexe de sursaut par un court silence chez des participants humains normo-entendants (sans acouphène) lors de la présentation d'un bruit de fond centré en hautes et en basses fréquences afin de déterminer les paramètres optimaux du paradigme. L'expérience 2 avait pour objectif de valider la précision et la fidélité d'une méthode de caractérisation psychoacoustique de l'acouphène (appariement en intensité et en fréquence). Finalement, l'expérience 3 avait pour objectif d'appliquer le paradigme d'objectivation de l'acouphène par le réflexe de sursaut à des participants atteints d'acouphènes chroniques en utilisant les techniques développées lors des expériences 1 et 2. Méthodologie : L'expérience 1 incluait 157 participants testés dans l'une des conditions de durée du court silence (5, 25, 50, 100, 200 ms) et dans l'un des deux paradigmes (court silence à l'intérieur du bruit de fond ou suivant celui-ci) à l'aide de bruits de fond en hautes et en basses fréquences. L'expérience 2 incluait deux groupes de participants avec acouphène, l'un musicien (n=16) et l'autre sans expérience musicale (n=16) ainsi qu'un groupe de simulateur sans acouphène (n=18). Ils tous ont été évalués sur leur capacité d'appariement en fréquence et en intensité de leur acouphène. Les mesures ont été reprises chez un sous-groupe de participants plusieurs semaines plus tard. L'expérience 3 incluait 15 participants avec acouphène et 17 contrôles évalués à l'aide du paradigme d'inhibition du réflexe de sursaut à l'aide d'un court silence (GPIAS). Les paramètres psychoacoustiques de l'acouphène ont également été mesurés. Toutes les mesures ont été reprises plusieurs mois plus tard chez un sous-groupe de participants. Résultats : Expérience 1 : le paradigme d'inhibition du réflexe acoustique de sursaut par un court silence est applicable chez l'humain normo-entendant. Expérience 2 : les mesures psychoacoustiques informatisées de l'acouphène incluant l'appariement en fréquence et en intensité sont des mesures précises et fidèles du percept de l'acouphène. Expérience 3 : un déficit d'inhibition au paradigme du GPIAS a été retrouvé chez le groupe de participants avec acouphène pour les bruits de fond en hautes et en basses fréquences au test et au retest. Les mesures d'appariement en fréquence ont révélé un acouphène dont la fréquence prédominante était d'environ 16 000 Hz chez la plupart des participants. Discussion : Il est possible d'appliquer le paradigme d'inhibition du réflexe acoustique de sursaut par un court silence à des participants humains atteints d'acouphène, tel qu'il est utilisé en recherche animale pour « objectiver » la présence d'acouphène. Toutefois, le déficit d'inhibition mesuré n'est pas spécifique à la fréquence de l'acouphène lorsque validé à partir des données d'appariement psychoacoustique. Nos résultats soulèvent des questions quant à l'interprétation originale du paradigme pour détecter la présence d'un acouphène chez les animaux. / Objective: The main objective of this thesis was the implementation and validation of applying the gap prepulse inhibition of the acoustic startle reflex (GPIAS) paradigm in humans, in order to objectively measure tinnitus. To do this, three experiments were carried out. Experiment 1 was designed to validate the inhibition of the acoustic startle reflex by using a short gap within high and low frequency narrowband noise in normal hearing humans (without tinnitus) to determine the optimal paradigm parameters. Experiment 2 was designed to validate the accuracy and the test-retest fidelity of a tinnitus psychoacoustic characterization method (intensity and frequency matching). Finally, Experiment 3 applied the GPIAS paradigm to participants with chronic tinnitus using the techniques developed in experiments 1 and 2. Methods: Experiment 1 included 157 participants tested with only one gap duration (5, 25, 50, 100, 200 ms) and with one of the two paradigms (gap imbedded in the background noise or following it) including high and low frequencies background noise. Experiment 2 included two groups of participants with tinnitus, one group consisting of musicians (n=16) and one group without musical experience (n=16). A third group consisted of adults who were instructed to simulate having tinnitus (n = 18). Tinnitus pitch and intensity matching abilities were assessed for all participants. A subgroup of participants was retested several weeks later. Experiment 3 included 15 participants with tinnitus and 17 controls assessed with the GPIAS. The psychoacoustic parameters of tinnitus were also measured. A subgroup of participants was retested several weeks later. Results: Experiment 1: the GPIAS is applicable in humans with normal hearing. Experiment 2: psychoacoustic measurements of tinnitus frequency and intensity using a computerized matching procedure produced precise and accurate measurements of the tinnitus percept. Experiment 3: an inhibition deficit was found using the GPIAS paradigm in the tinnitus group for background noise of high and low frequency compared to the control group, at test and retest. The frequency matching measurements revealed a 16,000 Hz tinnitus predominant frequency for most tinnitus participants. Discussion: It is possible to apply the gap prepulse inhibition of the startle reflex paradigm on human participants with tinnitus, as used in animal research to "objectify" the presence of tinnitus. However, the inhibition deficit found in the tinnitus group was not specific to their tinnitus frequency. This was validated by psychoacoustic tinnitus pitch matching. Our results question the original interpretation of the GPIAS paradigm for objectifying the presence of tinnitus.

<p>Many design agencies and designers like to see design as a longtime strategic investment for any company. However, knowledge of design as a strategic resource depends on ones professional background and ones knowledge of design as such. It is common today that clients meet design agencies and therefore design with a certain skepticism concerning its role in the company. Within the prodctdevelopment-process the company’s different functions meet. Those are people differing in education, background and knowledge. This fact and the differing visions concerning design lead to gaps within the cooperation between design agency and their client.</p><p>This study’s aim was to explain these gaps from the industrial design agency’s perspective.Especially when the cooperation intends to strengthen the client’s brand through product design. We tried to gain insight in the design agencies’ working-process and their attitude towards cooperation and their clients through case studies. Three design agencies in the greater Stockholm area were chosen and interviews were made in November 2007. The collected data was then mainly analyzed through gap analysis. The study shows that the contact between design agency and the client’s management level</p><p>plays a vital role in preventing the management gap. This gap is a result of differing visions of the design service and can lead to different levels of ambition between the partners. By taking this gap into consideration early on, the design-agency can access important</p><p>information about the client’s company and design can be used efficiently as a strategic resource. In addition to that the project’s brief influences the quality of the cooperation strongly.</p><p>The interpretation of brand values to design features is reason for communication-problems between agency and client. Visualizing of ideas, early prototyping and regular meetings can help minimizing this gap. However, a basic condition for successful brand communication is the client’s internal organization. It is vital that Marketing and Research and Development find a common language in order for the design project to become a success.</p>

Many design agencies and designers like to see design as a longtime strategic investment for any company. However, knowledge of design as a strategic resource depends on ones professional background and ones knowledge of design as such. It is common today that clients meet design agencies and therefore design with a certain skepticism concerning its role in the company. Within the prodctdevelopment-process the company’s different functions meet. Those are people differing in education, background and knowledge. This fact and the differing visions concerning design lead to gaps within the cooperation between design agency and their client. This study’s aim was to explain these gaps from the industrial design agency’s perspective.Especially when the cooperation intends to strengthen the client’s brand through product design. We tried to gain insight in the design agencies’ working-process and their attitude towards cooperation and their clients through case studies. Three design agencies in the greater Stockholm area were chosen and interviews were made in November 2007. The collected data was then mainly analyzed through gap analysis. The study shows that the contact between design agency and the client’s management level plays a vital role in preventing the management gap. This gap is a result of differing visions of the design service and can lead to different levels of ambition between the partners. By taking this gap into consideration early on, the design-agency can access important information about the client’s company and design can be used efficiently as a strategic resource. In addition to that the project’s brief influences the quality of the cooperation strongly. The interpretation of brand values to design features is reason for communication-problems between agency and client. Visualizing of ideas, early prototyping and regular meetings can help minimizing this gap. However, a basic condition for successful brand communication is the client’s internal organization. It is vital that Marketing and Research and Development find a common language in order for the design project to become a success.