Chapter II Abstract Human positive cofactor 4 (PC4) is a transcriptional coactivator with a highly conserved single-strand DNA (ssDNA) binding domain of unknown function. We identified PC4 as a suppressor of the oxidative mutator phenotype of the Escherichia coli fpg mutY mutant and demonstrate that this suppression requires its ssDNA binding activity. Saccharomyces cerevisiae mutants lacking their PC4 ortholog Sub1 are sensitive to hydrogen peroxide and exhibit spontaneous and peroxide-induced hypermutability. PC4 expression suppresses the peroxide sensitivity of the yeast sub1Δ mutant, suggesting that the human protein has a similar function. A role for yeast and human proteins in DNA repair is suggested by the demonstration that Sub1 acts in a peroxide resistance pathway involving Rad2 and by the physical interaction of PC4 with the human Rad2 homolog XPG. We show that XPG recruits PC4 to a bubble-containing DNA substrate with a resulting displacement of XPG and formation of a PC4-DNA complex. We discuss the possible requirement for PC4 in either global or transcription-coupled repair of oxidative DNA damage to mediate the release of XPG bound to its substrate. Chapter III Abstract Previously I established that (1) PC4 significantly suppresses oxidative mutagenesis via its single-strand DNA binding activity, (2) a partial suppression of H2O2-induced lethality was observed in a sub1Δ rad2Δ yeast double mutant compared to the sub1Δ mutant, and (3) PC4 interacts with XPG physically and functionally. These results led me to believe that suppression of oxidative mutagenesis and lethality by PC4 is partially due to its function in an XPG/Rad2-dependent pathway and through additional unidentified mechanism(s). In this chapter, I present studies aimed at investigating different DNA repair pathways in which PC4/Sub1 might participate. I address the possible roles of PC4/Sub1 in transcription-coupled repair (TCR) in terms of its binding specificity to oxidative DNA lesions and its ability to allow efficient resumption of transcription after oxidative DNA damaging treatment. To ask if PC4/Sub1 interacts with other DNA repair proteins to protect cells from oxidative DNA damage, I analyzed spontaneous mutation rates among a series of isogenic, haploid yeast mutant strains deficient of SUB1, base excision repair (BER) and/or nucleotide excision repair (NER) functions. I further analyzed genetic interactions between SUB1 and genes critical to various DNA damage avoidance/tolerance mechanisms, such as mismatch repair (MMR), homologous recombination (HR) and translesion synthesis (TLS).

Experiments were conducted to investigate: 1) production of trans-18:1 and cis/trans-18:2 isomers due to input of forage and corn grain in continuous culture fermenters, 2) concentrations of trans-18:1 and cis/trans-18:2 isomers in blood and milk fat of grazing cows fed a grain supplement containing solvent- or mechanically-extracted soybean meal, 3) plasma and milk fatty acid profiles of lactating cows in response to a conjugated linoleic acid (CLA) mixture infused into the rumen, and 4) effects of cis9,trans11-18:2 (9/11CLA) or trans10,cis12-18:2 (10/12CLA) on de novo synthesis and desaturation of milk fatty acids in lactating cows fed unsaturated oils. In the first study, rumen fermenters were fed (50 g DM/d) orchardgrass or red clover with 0, 8, or 16 g/d corn replacing equal portions of forage DM. Outflow of trans11,cis15-18:2 (11/15LA) in effluents was greater when DM input was clover or grass only. With each increment of corn, output of 9/11CLA increased until it was 205% greater compared with forage alone. Trans11-18:1 (TVA), an intermediate in 18:2n6 (LA) and 18:3n3 (LN) hydrogenation, output increased by 28% with corn addition. Outputs of trans10-18:1 and 10/12CLA nearly doubled as corn increment increased. In the second experiment, Holstein cows grazing mixed clover-grass pastures were fed a grain supplement (6.7 kg/d) containing 1.7 kg solvent-extracted soybean meal (SES, 15 mg LA/g of DM), 1.9 kg mechanically-extracted soybean meal (MES, 24 mg LA/g of DM), or 1.9 kg MES plus 30 g of liquid methionine hydroxy analog (MESM). Cows fed MES or MESM had greater concentrations of LA, TVA, 9/11CLA, and 11/15LA in blood compared with cows fed SES. Daily yields of 18:0 (SA), LA, LN, TVA, and 9/11CLA in milk fat also were greater for cows fed MES or MESM compared with SES. In experiment 3, four Holstein cows were used in a 4 x 4 Latin square to determine plasma and milk fatty acid profiles during infusion of a CLA mixture at 0, 45, 90, or 180 g/d for 48 h into the rumen. Relative to the control, infusion of 180 g CLA/d decreased milk fat percentage and yield. Lower milk fat yield resulted from depressed concentrations of saturated 6:0 to 16:0 medium-chain fatty acids (MCFA). Concentrations of TVA, trans10-18:1, and 10/12CLA in blood plasma, and yields in milk fat increased in response to each dose of CLA. Stearic acid yield also increased as dose of CLA increased. Yield of cis9-18:1 (OA) in milk fat, however, was lower at 180 g CLA/d. In experiment 4, four cows were fed high-oleic (HO) or high-linoleic (HL) (2.5% of DM) oil for 11 d prior to abomasal infusion (15 g/d) of 9/11CLA or 10/12CLA for 48 h (2 x 2 factorial). Milk fat percentage and yield decreased 25% due to infusion of 10/12CLA compared with 9/11CLA, regardless of diet. Lower fat yields resulted from lower MCFA concentrations and yields. Regardless of diet, concentration (but not yield) of SA increased 40% when 10/12CLA was infused compared with 9/11CLA. Concentrations and yields of OA, 9/11CLA, and 20:4n6 also were reduced by infusing 10/12CLA compared with 9/11CLA regardless of diet. Thus, in addition to inhibiting de novo fatty acid synthesis, 10/12CLA appeared to inhibit desaturation via delta-6 and delta-9 desaturases. Significant implications from the above studies include: 1) 11/15LA and TVA are the primary intermediates flowing out of the rumen during hydrogenation of pasture lipids, 2) replacing forage DM with starch, OA, and LA increases synthesis of trans10-18:1 and 10/12CLA in the rumen, 3) desaturation of TVA produced in the rumen provides an alternate source for 9/11CLA in milk fat, and 4) 10/12CLA decreases de novo synthesis and desaturation of milk fatty acids. / Ph. D.

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1 ABSTRACT The aim of the thesis was to explore the approach of schools towards trans and nonbinary students in Czech Republic. The theoretical part presents an analysis and comparison of various approaches to this issue and places it in the context of the Czech educational system. The practical part of the thesis brings quantitative research devoted to the assessment of the whole situation in a comprehensive form from the perspective of trans and nonbinary students themselves, with an extension of qualitative insight. The survey conducted through electronic questionnaires focused on experiences in the field of: school procedure after coming out; solving specific situations; the school's approach to queer and gender themes; safety in the school environment. The research involved 105 people who provided 122 experiences from schools in primary, secondary and tertiary education. The results provided a detailed description of the current situation and its significant diversity, while also pointing to specific problematic aspects and differences in the degree of respect for the identities of students growing along with the level of education. The variability of research results and frequently mentioned disregarding attitudes and approaches correlate with the theoretical finding that there are no officially...

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Bakgrund: Psykisk ohälsa kopplat till personer som identifierar sig som trans-och ickebinära och vilken del skolan kan ha i det hälsofrämjande och förebyggande arbetet är en högaktuell diskussion. Utifrån svensk kontext vet vi att skolornas ansvar enligt lag är att arbeta inkluderande och med frågor som handlar om normkritik och diskrimineringsgrunder. Men forskning och myndighetsrapporter visar att det finns stora brister i skolors arbete med dessa frågor.Syfte: Studiens syfte är att utifrån en queerfenomenologiskt teoretisk ansats undersöka trans-och ickebinära personers upplevelser av sin skolgång, med fokus på upplevelser av bemötande, inkludering och miljö.Metod: Studien har en fenomenologisk ansats och baseras på kvalitativa intervjuer med 7 unga vuxna i åldrarna 18-30 som identifierar sig som trans- eller ickebinära, med varierade begreppsdefinitioner. Empirin analyserade med hjälp av en reflexiv tematisk analys.Resultat: Resultatet presenteras i fyra huvudteman som är genomgående för mina intervjuer och resulterade i följande teman är: Att navigera i tvåkönsnormen, trygghet, otrygghet och andrafiering, det queera estetiska rummet och avslutningsvis den queera queerheten.Diskussion: Mitt resultat överensstämde till stor del med tidigare forskning sett till informanternas upplevelse av skolan som en normativ arena att befinna sig på samt den samstämmiga slutsatsen att det finns ett kunskapsglapp mellan vad personal bör ha kunskap kring och vad de faktiskt förmedlar. Vidare framkom hur olika former av identiteter också interagerade med varandra i form av exempelvis funktionsvariation, etnicitet, sexualitet och könsidentitet. Denna intersektionella interaktion kunde vara en betydelsefull del i den egna processen i att hitta sin identitet och att detta perspektiv var viktigt att lyfta i skolan. Kopplingen mellan estetiska uttrycksformer och queera identiteter på andra arenor var också ett gemensamt tema som framkom från mina informanter som jag inte funnit i den forskning jag läst. Detta fynd skulle kunna vara en implikation på ett nytt sätt för skolor att arbeta på, utifrån att främja psykisk hälsa och välmående på ett inkluderande sätt. / Background: Mental illness among people who identify as trans and non-binary and the role schools play to prevent this has been a hotly debated issue in recent years. Based on the Swedish context, we know that the schools' responsibility according to law is to work inclusively and normcritically, with a focus on preventing discrimination. Reports regarding how schools work with these issues varies, yet studies indicate that there are significant shortcomings in schools’ work with inclusion and anti-discrimination regarding trans and non-binary pupils.Aim: By adopting a queerphenomenological theoretical approach this study investigates trans and non-binary people’s experiences of their time in school, with a focus on experiences of treatment, inclusion and school environment.Method: This phenomenological study is based on qualitative interviews with 7 young adults aged 18-30, all of whom identified under the umbrellaterms trans and non-binary. When the data was collected, it was analysed using a reflexive thematic analysis.Results: The result was presented in four main themes that were consistent with my interviews. The themes were, navigating in the binary norm, safety, unsafety and othering, the queer artistic room and the queer queerness.Discussion: My results were largely consistent with previous research regarding the informants experience of the school as a normative arena. The results point to a lack of knowledge among teachers and schoolstaff on LGBTQ issues and how which influenced lessons and the non inclusive language used by the staff.The results further indicate that identity navigation in school among informants included the interaction between various identity categories such as gender identity, ethnicity, sexuality and disability and the importance of an intersectional perspective, when working in a school enviroment. Lastly, an important result was the importance of engaging in various aesthetic forms of expression and queer identity among the informants. The artistic theme could inform future approaches to preventive work in schools regar

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Type 2 diabetes mellitus (T2DM) is classified as a metabolic disorder characterized by hyperglycemia that results from defects in insulin action and/or secretion, and currently affects 8.3% of the US population according to the CDC’s 2011 National Diabetes Fact Sheet. Several contributing factors have been identified to development of this disease. Published evidence indicates type 2 diabetes mellitus (T2DM) patients display lower overall paraoxonase activity and that this may be partially due to genetic variations in the paraoxonase-1 (PON-1) gene. Some bioaccumulative organochlorine (OC) pesticides have been shown to contribute to increased T2DM prevalence. In addition, these OC compound levels have been associated with alterations in adipocyte cytokine levels as well as increased inflammatory markers. Three hundred blood samples with clinical and demographic information were obtained from two US Air Force hospitals. A total of 151 non-diabetics and 149 T2DM subjects were evaluated for PON-1 activity, PON-1 Q192R and L55M genetic polymorphisms, OC compound concentrations, inflammatory marker levels and adipokine concentrations. PON-1 activity, using diazoxon as the substrate, was decreased in the T2DM subjects. Some of the PON-1 genetic polymorphisms tested were also associated with decreased PON-1 activity. OC compound levels were increased in the T2DM subjects. The non-diabetic subjects possessing elevated DDE and trans-nonachlor were associated with increased inflammation, a common hallmark of early T2DM development. Additionally, elevated OC levels were seen in association with altered adipokine concentrations. Overall, a decrease in the antioxidant properties of PON-1 as well as factors contributing to chronic low level inflammation such as elevated OC plasma concentration appear to be significant contributors to T2DM prevalence in the population studied.

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Syftet med studien var att undersöka socialarbetares transkompetens och deras trygghet i att arbeta med transpersoner, samt hur dessa varierar med yrkesroller och arbetsplatsens rutiner och riktlinjer. Studien genomfördes med en kvantitativ enkätundersökning och vände sig till yrkesverksamma socialarbetare som möter klienter/patienter i sitt arbete. Enkäten skickades ut till socialarbetare anställda inom kommun och region i ett län i Mellansverige och besvarades av 89 socialarbetare. Empirin analyserades med hjälp av korstabeller, sambandstest och tvåvägs ANOVA, samt tolkades med ett kritiskt perspektiv, queerteori samt begreppen kompetens och bemötande. Resultatet visade att socialarbetare upplever att de har en ganska hög kunskap samt ganska hög trygghet i arbete med transpersoner, och att en hög upplevd kunskap ökade deras upplevelse av hög trygghet. Kuratorer upplevde en högre kunskap och trygghet jämfört med socialsekreterare. En transinkluderande arbetsplats med tydliga rutiner och riktlinjer hade positiv inverkan på både upplevd kunskap och trygghet, men hög kunskap var den främsta och betydande faktorn för att uppnå en hög trygghet. Socialarbetare anser att arbetsplatser främst kan utveckla sitt arbete med att möta transpersoner genom utbildning, samt att respekt, lyhördhet och öppenhet är de mest betydelsefulla egenskaperna att ha som yrkesverksam i mötet med transpersoner. Sammantaget tolkas resultatet som att socialarbetarna har en måttlig transkompetens. Vidare forskning behövs för att undersöka ytterligare hur HBTQI-certifiering samt implementering av konkreta insatser för att vara mer transinkluderande inom organisationer, främst inom socialtjänsten, kan ha en positiv inverkan på vård och stöd för transpersoner. / The purpose of this study was to examine social workers transgender competence and perceived comfort in working with transgender people, and to investigate if perceived knowledge and comfort was connected to work title and different organizational factors. A quantitative study was conducted towards social workers who meet clients/patients in their work. An online-survey was constructed and sent to social workers employed within a county in mid-Sweden, with a total of 89 respondents. The data was analyzed with crosstabs, correlation tests and a two-way ANOVA, and interpreted using a critical perspective, queertheory and the theoretical concepts of competence and service experience. The results discovered that social workers experience a quite high level of perceived knowledge and comfort in working with transgender clients/patients. The perceived level of comfort increased when the level of perceived knowledge increased. Counselors perceived a higher level of knowledge and comfort than social workers in the social services. A transgender-inclusive workplace with clear routines had a positive impact on perceived knowledge and comfort, but high level of knowledge was the most significant factor in achieving high level of comfort. Social workers found that workplaces could develop their work with transgender people through education, and that respect, responsiveness and openness were the most valuable qualities for a professional working with transgender people. The conclusion was that social workers had a moderate level of transgender competence. It’s necessary to explore, primarily in social services, how LGBTQI-certification and implementation of supportive efforts might help organizations to be more trans-inclusive.