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Autismspektrumtillstånd (AST) är en neuropsykiatrisk funktionsnedsättning som medför svårigheter med social interaktion och kommunikation, begränsade och repetitiva beteendemönster samt över- eller underkänslighet för sensoriska stimuli. Syftet med denna studie var att undersöka arbetsterapeutiska interventioner för barn med AST samt effekten av dessa. Studien är en litteraturöversikt med artiklar från databaserna PubMed och CINAHL. Sju artiklar som var publicerad mellan 2014–2023 inkluderades, analyserades och presenterades med två kategorier i resultatet. Resultatet visade att social integration har en positiv effekt på svårigheter med sociala interaktioner, delad uppmärksamhet samt hur föräldrar ska interagera med sina barn. Interventionerna riktad mot sensorisk integrering visade att resultatet kan ha viss positiv effekt, där en intervention visar på klinisk nytta och den andra inte. Lek-baserade interventioner gynnar sociala förmågor hos barn med AST. Föräldrar är en viktig del i barnens utveckling samt har arbetsterapeuten en betydande roll i åtgärdsprocessen vid sociala och sensoriska interventioner.

Autismspektrumtillstånd (AST) är en neuropsykiatrisk funktionsnedsättning som medför svårigheter med social interaktion och kommunikation, begränsade och repetitiva beteendemönster samt över- eller underkänslighet för sensoriska stimuli. Syftet med denna studie var att undersöka arbetsterapeutiska interventioner för barn med AST samt effekten av dessa. Studien är en litteraturöversikt med artiklar från databaserna PubMed och CINAHL. Sju artiklar som var publicerad mellan 2014–2023 inkluderades, analyserades och presenterades med två kategorier i resultatet. Resultatet visade att social integration har en positiv effekt på svårigheter med sociala interaktioner, delad uppmärksamhet samt hur föräldrar ska interagera med sina barn. Interventionerna riktad mot sensorisk integrering visade att resultatet kan ha viss positiv effekt, där en intervention visar på klinisk nytta och den andra inte. Lek-baserade interventioner gynnar sociala förmågor hos barn med AST. Föräldrar är en viktig del i barnens utveckling samt har arbetsterapeuten en betydande roll i åtgärdsprocessen vid sociala och sensoriska interventioner.

Comparing the performance of different continuous glucose monitoring (CGM) systems is challenging due to the lack of comprehensive guidelines for clinical study design. In particular, the absence of concise requirements for the distribution of comparator (reference) blood glucose (BG) concentrations and their rate of change (RoC), that are used to evaluate CGM performance, impairs comparability. For this article, several experts in the field of CGM performance testing have collaborated to propose characteristics of the distribution of comparator measurements that should be collected during CGM performance testing. Specifically, it is proposed that at least 7.5% of comparator BG concentrations are <70 mg/dL (3.9 mmol/L) and >300 mg/dL (16.7 mmol/L), respectively and that at least 7.5% of BG-RoC combinations indicate fast BG changes with impending hypo- or hyperglycemia, respectively. These proposed characteristics of the comparator data can facilitate the harmonization of testing conditions across different studies and CGM systems and ensure that the most relevant scenarios representing real-life situations are established during performance testing. In addition, a study protocol and testing procedure for the manipulation of glucose levels is suggested that enables the collection of comparator data with these characteristics. This work is an important step towards establishing a future standard for the performance evaluation of CGM systems., The authors thank the Diabetes Center Berne and the International Federation of Clinical Chemistry and Laboratory Medicine for supporting this work.

Comparing the performance of different continuous glucose monitoring (CGM) systems is challenging due to the lack of comprehensive guidelines for clinical study design. In particular, the absence of concise requirements for the distribution of comparator (reference) blood glucose (BG) concentrations and their rate of change (RoC) that are used to evaluate CGM performance, impairs comparability. For this article, several experts in the field of CGM performance testing have collaborated to propose characteristics of the distribution of comparator measurements that should be collected during CGM performance testing. Specifically, it is proposed that at least 7.5% of comparator BG concentrations are <70 mg/dL (3.9 mmol/L) and >300 mg/dL (16.7 mmol/L), respectively, and that at least 7.5% of BG-RoC combinations indicate fast BG changes with impending hypo- or hyperglycemia, respectively. These proposed characteristics of the comparator data can facilitate the harmonization of testing conditions across different studies and CGM systems and ensure that the most relevant scenarios representing real-life situations are established during performance testing. In addition, a study protocol and testing procedure for the manipulation of glucose levels are suggested that enable the collection of comparator data with these characteristics. This work is an important step toward establishing a future standard for the performance evaluation of CGM systems.

Comparing the performance of different continuous glucose monitoring (CGM) systems is challenging due to the lack of comprehensive guidelines for clinical study design. In particular, the absence of concise requirements for the distribution of comparator (reference) blood glucose (BG) concentrations and their rate of change (RoC) that are used to evaluate CGM performance, impairs comparability. For this article, several experts in the field of CGM performance testing have collaborated to propose characteristics of the distribution of comparator measurements that should be collected during CGM performance testing. Specifically, it is proposed that at least 7.5% of comparator BG concentrations are <70 mg/dL (3.9 mmol/L) and >300 mg/dL (16.7 mmol/L), respectively, and that at least 7.5% of BG-RoC combinations indicate fast BG changes with impending hypo- or hyperglycemia, respectively. These proposed characteristics of the comparator data can facilitate the harmonization of testing conditions across different studies and CGM systems and ensure that the most relevant scenarios representing real-life situations are established during performance testing. In addition, a study protocol and testing procedure for the manipulation of glucose levels are suggested that enable the collection of comparator data with these characteristics. This work is an important step toward establishing a future standard for the performance evaluation of CGM systems., Comparing the performance of different continuous glucose monitoring (CGM) systems is challenging due to the lack of comprehensive guidelines for clinical study design. In particular, the absence of concise requirements for the distribution of comparator (reference) blood glucose (BG) concentrations and their rate of change (RoC) that are used to evaluate CGM performance, impairs comparability. For this article, several experts in the field of CGM performance testing have collaborated to propose characteristics of the distribution of comparator measurements that should be collected during CGM performance testing. Specifically, it is proposed that at least 7.5% of comparator BG concentrations are <70 mg/dL (3.9 mmol/L) and >300 mg/dL (16.7 mmol/L), respectively, and that at least 7.5% of BG-RoC combinations indicate fast BG changes with impending hypo- or hyperglycemia, respectively. These proposed characteristics of the comparator data can facilitate the harmonization of testing conditions across different studies and CGM systems and ensure that the most relevant scenarios representing real-life situations are established during performance testing. In addition, a study protocol and testing procedure for the manipulation of glucose levels are suggested that enable the collection of comparator data with these characteristics. This work is an important step toward establishing a future standard for the performance evaluation of CGM systems.

Comparing the performance of different continuous glucose monitoring (CGM) systems is challenging due to the lack of comprehensive guidelines for clinical study design. In particular, the absence of concise requirements for the distribution of comparator (reference) blood glucose (BG) concentrations and their rate of change (RoC) that are used to evaluate CGM performance, impairs comparability. For this article, several experts in the field of CGM performance testing have collaborated to propose characteristics of the distribution of comparator measurements that should be collected during CGM performance testing. Specifically, it is proposed that at least 7.5% of comparator BG concentrations are <70 mg/dL (3.9 mmol/L) and >300 mg/dL (16.7 mmol/L), respectively, and that at least 7.5% of BG-RoC combinations indicate fast BG changes with impending hypo- or hyperglycemia, respectively. These proposed characteristics of the comparator data can facilitate the harmonization of testing conditions across different studies and CGM systems and ensure that the most relevant scenarios representing real-life situations are established during performance testing. In addition, a study protocol and testing procedure for the manipulation of glucose levels are suggested that enable the collection of comparator data with these characteristics. This work is an important step toward establishing a future standard for the performance evaluation of CGM systems., Comparing the performance of different continuous glucose monitoring (CGM) systems is challenging due to the lack of comprehensive guidelines for clinical study design. In particular, the absence of concise requirements for the distribution of comparator (reference) blood glucose (BG) concentrations and their rate of change (RoC) that are used to evaluate CGM performance, impairs comparability. For this article, several experts in the field of CGM performance testing have collaborated to propose characteristics of the distribution of comparator measurements that should be collected during CGM performance testing. Specifically, it is proposed that at least 7.5% of comparator BG concentrations are <70 mg/dL (3.9 mmol/L) and >300 mg/dL (16.7 mmol/L), respectively, and that at least 7.5% of BG-RoC combinations indicate fast BG changes with impending hypo- or hyperglycemia, respectively. These proposed characteristics of the comparator data can facilitate the harmonization of testing conditions across different studies and CGM systems and ensure that the most relevant scenarios representing real-life situations are established during performance testing. In addition, a study protocol and testing procedure for the manipulation of glucose levels are suggested that enable the collection of comparator data with these characteristics. This work is an important step toward establishing a future standard for the performance evaluation of CGM systems.

Studien ämnar undersöka hur fyra klädföretag bygger och stärker sina varumärken för att differentiera sig på en konkurrensutsatt marknad. Klädföretag valdes specifikt då branschen är unik med utmaningar och trender som kan påverka varumärkesbyggandet. Detta undersöks genom att fokusera på centrala begrepp inom varumärkeshantering som exempelvis varumärkesidentitet och differentiering. Målet är att få en djupare förståelse för hur klädföretagen använder sina varumärken för att skapa positiva relationer till sina respektive konsumenter. Forskningsdesignen som genomfördes baseras på fallstudier för att utforska ämnet på djupet. En kvalitativ forskningsmetod antas med en abduktiv ansats, där empiri har insamlats genom intervjuer och dokumentstudier. Metoden användes för att kunna ställa specifika frågor och samtidigt ta hänsyn till respondenternas insikter och erfarenheter inom varumärkesbyggande. Studien visar att klädföretag bygger och stärker sina varumärken genom att applicera säregna metodval som innefattar begreppen varumärkesidentitet, varumärkeskapital och syftesdriven marknadsföring. Företag med en tydlig varumärkesidentitet visar att företagen kan differentiera sig från konkurrenterna, där de kommunicerar sin identitet genom specifika målgrupper, unika produkter och värdefulla fördelar. Det framkommer även att ett starkt varumärkeskapital kan ge företaget flera fördelar, men att det finns en variation i hur företagen uppfattar de olika värdena av varumärkeskapitalet. Studien ger vidare stöd till att den syftesdrivna marknadsföringen har en allt mer betydande roll i dagens samhälle. Detta grundar sig på företagens fokus att möta konsumenternas förväntningar, vilket även till stor del handlar om konsumenters unika behov. Slutsatsen är att de studerade klädföretagens varumärkesbyggande grundas på tydliga löften, differentiering genom mervärde och hög kvalitet. Emotionella kopplingar och anpassning till konsumenternas preferenser framkommer som väsentliga aspekter, The study aims to investigate how four clothing companies build and strengthen their brands to differentiate themselves in a competitive market. Clothing companies were specifically chosen as the industry is unique with challenges and trends that can affect branding. This is examined by focusing on central concepts in brand management such as brand identity and differentiation. The goal is to gain a deeper understanding of how clothing companies use their brands to create positive relationships with their respective consumers. The research design conducted is based on case studies to explore the topic in depth. A qualitative research method is adopted with an abductive approach, where empirical evidence has been collected through interviews and document studies. The method was used to be able to ask specific questions and at the same time consider the respondents' insights and experiences in branding. The study shows that clothing companies build and strengthen their brands by applying special method choices that include the concepts of brand identity, brand equity and purpose-driven marketing. Companies with a clear brand identity show that the companies can differentiate themselves from the competition, where they communicate their identity through specific target groups, unique products and valuable benefits. It also appears that a strong brand equity can give the company several advantages, but that there is a variation in how the companies perceive the different values of the brand equity. The study further supports that purpose-driven marketing has an increasingly significant role in today's society. This is based on the companies' focus on meeting consumer expectations, which is also largely about consumers' unique needs. The conclusion is that the branding of the clothing companies studied is based on clear promises, differentiation through added value and high quality. Emotional connections and adaptation to consumer preferences emerge as essential aspects.

I denna uppsats används kriminologisk narrativ metod i syfte att undersöka hur gängkriminella kvinnor framställs i media utifrån ett genusvetenskapligt ramverk. Det empiriska materialet som vi använt för analysen är dokumentärserien Gängkrigen och kvinnorna vilken Karwan Faraj är redaktör samt producent av. Gängkrigen och kvinnorna är en svensk true crime-dokumentärserie i tre delar där vi som åskådare får följa Karwan Faraj som även agerar undersökande journalist i möten med sex kvinnor involverade i gängkriminalitet. Medias framställning av kriminella kvinnor bryter mot den normativa femininiteten vilket lockar till sig många fascinerade åskådare och producerar en säljande samt underhållande historia. Vår analys visar att kvinnornas framställning i dokumentärserien ges utifrån ett manligt perspektiv vilket i sin tur skapar ett ramverk för åskådarnas generella förståelse av gängkriminella kvinnor. De framställs av Karwan Faraj med aktiva roller inom de kriminella gängmiljöerna. För att kvinnorna inte ska bli ett alltför skrämmande samhällshot tonas deras roll som gängkriminell ned genom att dessutom försätta dem i brottsoffer- samt moderskapsrollen. Denna analys ger inte en helhetsbild för hur gängkriminella kvinnor framställs i svensk media utan det är vår tolkning av ett empiriskt material som redogörs för, vilken är en av många som kan göras. Vidare vill vi förtydliga att vi förhåller oss kritiska till den framställning av kvinnorna vi tolkat att Faraj förmedlar. Vi ämnar inte reproducera dessa normativa genusföreställningar trots att denna sort av analys medför just en sådan risk. Studiens bidrag syftar till att öka förståelsen samt medvetenheten kring dokumentärfilmers sanningsanspråk samt tolkningsföreträde. Det genusvetenskapliga ramverket möjliggjorde för oss att kritiskt granska hur kön och genus konstrueras i relation till kvinnors brottslighet utifrån den västerländska normativa föreställningen kring hur kvinnan bör vara. Denna studie utgår från en socia

Bakgrund: Den psykiska ohälsan ökar i Sverige. Det innebär förändringar inom den prehospitala sjukvården. Ambulanssjuksköterskans arbete riktas ofta initialt mot akuta somatiska problem, men att vårda patienter med psykosomatisk bröstsmärta till följd av ångest är också en viktig del av omvårdnadsarbetet. Detta medför stor potentiell patientnytta då obehandlad, svår ångest indirekt kan bli livshotande med hänseende till suicidrisken. För att öka kunskapen om psykosomatisk bröstsmärta finns det ett behov av att beforska området. Syfte: Att beskriva sjuksköterskors upplevelser av mötet med patienter med psykosomatisk bröstsmärta prehospitalt. Metod: Åtta sjuksköterskor varav sex vidareutbildade inom ambulanssjukvård rekryterades från tre olika ambulansstationer i Norrland. Datan insamlades genom individuella semistrukturerade intervjuer och analyserades genom en kvalitativ innehållsanalys med induktiv ansats. Resultat: Vald analysmetod resulterade i tre huvudkategorier: Samtalet har en viktig roll i mötet, Bedömningen av allvarlighetsgrad är utmanande i mötet, och Ett per- soncentrerat förhållningssätt är viktigt i mötet, med sex tillhörande underkategorier som svarar på syftet. Slutsats: Psykisk ohälsa ses vara ett fullvärdigt problem inom den prehospitala sjukvården. Sjuksköterskor inom prehospital sjukvård utesluter i första hand somatisk orsak, men ser samtalet som ett naturligt nästa steg i bemötandet och behandlingen av patienter som söker vård för psykosomatisk bröstsmärta. Samtalet i kombination med ett personcentrerat förhållningssätt anses vara de bästa verktygen i bemötandet.

Bakgrund: Den psykiska ohälsan ökar i Sverige. Det innebär förändringar inom den prehospitala sjukvården. Ambulanssjuksköterskans arbete riktas ofta initialt mot akuta somatiska problem, men att vårda patienter med psykosomatisk bröstsmärta till följd av ångest är också en viktig del av omvårdnadsarbetet. Detta medför stor potentiell patientnytta då obehandlad, svår ångest indirekt kan bli livshotande med hänseende till suicidrisken. För att öka kunskapen om psykosomatisk bröstsmärta finns det ett behov av att beforska området. Syfte: Att beskriva sjuksköterskors upplevelser av mötet med patienter med psykosomatisk bröstsmärta prehospitalt. Metod: Åtta sjuksköterskor varav sex vidareutbildade inom ambulanssjukvård rekryterades från tre olika ambulansstationer i Norrland. Datan insamlades genom individuella semistrukturerade intervjuer och analyserades genom en kvalitativ innehållsanalys med induktiv ansats. Resultat: Vald analysmetod resulterade i tre huvudkategorier: Samtalet har en viktig roll i mötet, Bedömningen av allvarlighetsgrad är utmanande i mötet, och Ett per- soncentrerat förhållningssätt är viktigt i mötet, med sex tillhörande underkategorier som svarar på syftet. Slutsats: Psykisk ohälsa ses vara ett fullvärdigt problem inom den prehospitala sjukvården. Sjuksköterskor inom prehospital sjukvård utesluter i första hand somatisk orsak, men ser samtalet som ett naturligt nästa steg i bemötandet och behandlingen av patienter som söker vård för psykosomatisk bröstsmärta. Samtalet i kombination med ett personcentrerat förhållningssätt anses vara de bästa verktygen i bemötandet.

Studien ämnar undersöka hur fyra klädföretag bygger och stärker sina varumärken för att differentiera sig på en konkurrensutsatt marknad. Klädföretag valdes specifikt då branschen är unik med utmaningar och trender som kan påverka varumärkesbyggandet. Detta undersöks genom att fokusera på centrala begrepp inom varumärkeshantering som exempelvis varumärkesidentitet och differentiering. Målet är att få en djupare förståelse för hur klädföretagen använder sina varumärken för att skapa positiva relationer till sina respektive konsumenter. Forskningsdesignen som genomfördes baseras på fallstudier för att utforska ämnet på djupet. En kvalitativ forskningsmetod antas med en abduktiv ansats, där empiri har insamlats genom intervjuer och dokumentstudier. Metoden användes för att kunna ställa specifika frågor och samtidigt ta hänsyn till respondenternas insikter och erfarenheter inom varumärkesbyggande. Studien visar att klädföretag bygger och stärker sina varumärken genom att applicera säregna metodval som innefattar begreppen varumärkesidentitet, varumärkeskapital och syftesdriven marknadsföring. Företag med en tydlig varumärkesidentitet visar att företagen kan differentiera sig från konkurrenterna, där de kommunicerar sin identitet genom specifika målgrupper, unika produkter och värdefulla fördelar. Det framkommer även att ett starkt varumärkeskapital kan ge företaget flera fördelar, men att det finns en variation i hur företagen uppfattar de olika värdena av varumärkeskapitalet. Studien ger vidare stöd till att den syftesdrivna marknadsföringen har en allt mer betydande roll i dagens samhälle. Detta grundar sig på företagens fokus att möta konsumenternas förväntningar, vilket även till stor del handlar om konsumenters unika behov. Slutsatsen är att de studerade klädföretagens varumärkesbyggande grundas på tydliga löften, differentiering genom mervärde och hög kvalitet. Emotionella kopplingar och anpassning till konsumenternas preferenser framkommer som väsentliga aspekter, The study aims to investigate how four clothing companies build and strengthen their brands to differentiate themselves in a competitive market. Clothing companies were specifically chosen as the industry is unique with challenges and trends that can affect branding. This is examined by focusing on central concepts in brand management such as brand identity and differentiation. The goal is to gain a deeper understanding of how clothing companies use their brands to create positive relationships with their respective consumers. The research design conducted is based on case studies to explore the topic in depth. A qualitative research method is adopted with an abductive approach, where empirical evidence has been collected through interviews and document studies. The method was used to be able to ask specific questions and at the same time consider the respondents' insights and experiences in branding. The study shows that clothing companies build and strengthen their brands by applying special method choices that include the concepts of brand identity, brand equity and purpose-driven marketing. Companies with a clear brand identity show that the companies can differentiate themselves from the competition, where they communicate their identity through specific target groups, unique products and valuable benefits. It also appears that a strong brand equity can give the company several advantages, but that there is a variation in how the companies perceive the different values of the brand equity. The study further supports that purpose-driven marketing has an increasingly significant role in today's society. This is based on the companies' focus on meeting consumer expectations, which is also largely about consumers' unique needs. The conclusion is that the branding of the clothing companies studied is based on clear promises, differentiation through added value and high quality. Emotional connections and adaptation to consumer preferences emerge as essential aspects.

The use of different approaches for design and results presentation of studies for the clinical performance evaluation of continuous glucose monitoring (CGM) systems has long been recognized as a major challenge in comparing their results. However, a comprehensive characterization of the variability in study designs is currently unavailable. This article presents a scoping review of clinical CGM performance evaluations published between 2002 and 2022. Specifically, this review quantifies the prevalence of numerous options associated with various aspects of study design, including subject population, comparator (reference) method selection, testing procedures, and statistical accuracy evaluation. We found that there is a large variability in nearly all of those aspects and, in particular, in the characteristics of the comparator measurements. Furthermore, these characteristics as well as other crucial aspects of study design are often not reported in sufficient detail to allow an informed interpretation of study results. We therefore provide recommendations for reporting the general study design, CGM system use, comparator measurement approach, testing procedures, and data analysis/statistical performance evaluation. Additionally, this review aims to serve as a foundation for the development of a standardized CGM performance evaluation procedure, thereby supporting the goals and objectives of the Working Group on CGM established by the Scientific Division of the International Federation of Clinical Chemistry and Laboratory Medicine., This literature review and the associated scientific writing activities were funded by the Diabetes Center Berne.

I denna uppsats används kriminologisk narrativ metod i syfte att undersöka hur gängkriminella kvinnor framställs i media utifrån ett genusvetenskapligt ramverk. Det empiriska materialet som vi använt för analysen är dokumentärserien Gängkrigen och kvinnorna vilken Karwan Faraj är redaktör samt producent av. Gängkrigen och kvinnorna är en svensk true crime-dokumentärserie i tre delar där vi som åskådare får följa Karwan Faraj som även agerar undersökande journalist i möten med sex kvinnor involverade i gängkriminalitet. Medias framställning av kriminella kvinnor bryter mot den normativa femininiteten vilket lockar till sig många fascinerade åskådare och producerar en säljande samt underhållande historia. Vår analys visar att kvinnornas framställning i dokumentärserien ges utifrån ett manligt perspektiv vilket i sin tur skapar ett ramverk för åskådarnas generella förståelse av gängkriminella kvinnor. De framställs av Karwan Faraj med aktiva roller inom de kriminella gängmiljöerna. För att kvinnorna inte ska bli ett alltför skrämmande samhällshot tonas deras roll som gängkriminell ned genom att dessutom försätta dem i brottsoffer- samt moderskapsrollen. Denna analys ger inte en helhetsbild för hur gängkriminella kvinnor framställs i svensk media utan det är vår tolkning av ett empiriskt material som redogörs för, vilken är en av många som kan göras. Vidare vill vi förtydliga att vi förhåller oss kritiska till den framställning av kvinnorna vi tolkat att Faraj förmedlar. Vi ämnar inte reproducera dessa normativa genusföreställningar trots att denna sort av analys medför just en sådan risk. Studiens bidrag syftar till att öka förståelsen samt medvetenheten kring dokumentärfilmers sanningsanspråk samt tolkningsföreträde. Det genusvetenskapliga ramverket möjliggjorde för oss att kritiskt granska hur kön och genus konstrueras i relation till kvinnors brottslighet utifrån den västerländska normativa föreställningen kring hur kvinnan bör vara. Denna studie utgår från en socia

Maintenance of appropriate cell states involves epigenetic mechanisms, including Polycomb-group (PcG)-mediated transcriptional repression. While PcG proteins are known to induce chromatin compaction, how PcG proteins gain access to DNA in compact chromatin to achieve long-term silencing is poorly understood. Here, we show that the p300/CREB-binding protein (CBP) co-activator is associated with two-thirds of PcG regions and required for PcG occupancy at many of these in Drosophila and mouse cells. CBP stabilizes RNA polymerase II (Pol II) at PcG-bound repressive sites and promotes Pol II pausing independently of its histone acetyltransferase activity. CBP and Pol II pausing are necessary for RNA-DNA hybrid (R-loop) formation and nucleosome depletion at Polycomb Response Elements (PREs), whereas transcription beyond the pause region is not. These results suggest that non-enzymatic activities of the CBP co-activator have been repurposed to support PcG-mediated silencing, revealing how chromatin regulator interplay maintains transcriptional states.

Dysregulation of the transcription factor MYC is involved in many human cancers. The dimeric transcription factor complexes of MYC/MAX and MAX/MAX activate or inhibit, respectively, gene transcription upon binding to the same enhancer box DNA. Targeting these complexes in cancer is a long-standing challenge. Inspired by the inhibitory activity of the MAX/MAX dimer, we engineered covalently linked, synthetic homo- and heterodimeric protein complexes to attenuate oncogenic MYC-driven transcription. We prepared the covalent protein complexes (∼20 kDa, 167-231 residues) in a single shot via parallel automated flow synthesis in hours. The stabilized covalent dimers display DNA binding activity, are intrinsically cell-penetrant, and inhibit cancer cell proliferation in different cell lines. RNA sequencing and gene set enrichment analysis in A549 cancer cells confirmed that the synthetic dimers interfere with MYC-driven transcription. Our results demonstrate the potential of automated flow technology to rapidly deliver engineered synthetic protein complex mimetics that can serve as a starting point in developing inhibitors of MYC-driven cancer cell growth.

© 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works The nucleus contains diverse phase-separated condensates that compartmentalize and concentrate biomolecules with distinct physicochemical properties. Here, we investigated whether condensates concentrate small-molecule cancer therapeutics such that their pharmacodynamic properties are altered. We found that antineoplastic drugs become concentrated in specific protein condensates in vitro and that this occurs through physicochemical properties independent of the drug target. This behavior was also observed in tumor cells, where drug partitioning influenced drug activity. Altering the properties of the condensate was found to affect the concentration and activity of drugs. These results suggest that selective partitioning and concentration of small molecules within condensates contributes to drug pharmacodynamics and that further understanding of this phenomenon may facilitate advances in disease therapy.

In this thesis a regression analysis of ten independent data sets is analysed in order toestimate losses and Key Risk Indicators (KRI). Each data set contains a list of objects,impacts that each object contains and revenue stream values (RSV) to each impact.The project investigates the data and simulate yearly losses as response variables in theregression modelling. The three regressors that influence the yearly losses are numberof objects, sum of revenue streams and expected aggregated losses. Given the responsevariable from each data set a percentage scale of KRI’s is determined indicating howlarge losses each set possess., I denna avhandling analyseras en regressionsmodellering av tio oberoende mängderdata för att uppskatta förluster och Key Risk Indicators. Den givna dataupsättningeninnehåller en lista med objekt, påverkan varje objekt erhåller och vad respektiveobjekt omsätter. Projektet undersöker den givma datan och simulerar årliga förlustersom svarsvariabler i regressionsmodelleringen. De tre regressorerna som påverkarde årliga förlusterna är antalet objekt, summan av intäckterna och förvämtadesammanlagda förlusterna. Från den givna svarsvariabeln från varje datamängdbestäms en procentuell skala av KRIer som indikerar hur stora förluster varjeuppsättning har.

Det har blivit allt mer viktigt för företag att ta ansvar inom områdena miljö, ekonomi och samhälle. Företag använder sig av CSR-kommunikation för att visa vilka handlingar de vidtar för att uppfylla dessa förväntningar och erhålla legitimitet. Det förekommer dock att CSR-kommunikationen inte överensstämmer med verkligheten. Det skapas då ett gap mellan företagens symboliska och substantiva handlingar, vilket benämns som CSR-decoupling. Företag i USA kontra Västeuropa befinner sig på olika marknader när det kommer till företagskulturer. Denna studie syftar därför till att undersöka användandet av CSR-decoupling i USA och Västeuropa. Studien undersöker även verkställande direktörens makt och intressenternas krav för att se om dessa faktorer påverkar användandet av CSR-decoupling. Studien är en kvantitativ tvärsnittsstudie som bygger på data bestående av amerikanska börsnoterade företag och västeuropeiska börsnoterade företag. Hypoteserna besvaras utifrån tidigare forskning och resultatet från en regressionsanalys samt t-test. Resultatet från regressionsanalysen visar att användandet av CSR-decoupling är större i USA än i Västeuropa, medan t-testet visar det motsatta. Av studien kunde inget samband fastställas mellan verkställande direktörens makt och CSR-decoupling. Resultatet visade däremot ett positivt samband mellan intressenternas krav och CSR-decoupling, samt att västeuropeiska börsnoterade företag påverkas mer av intressenternas krav när det kommer till användandet av decouplingstrategier., It has become increasingly important for companies to take responsibility in the areas of environment, economy and society. Companies use CSR-communication to show what actions they are taking to meet these expectations and gain legitimacy. However, it happens that CSR-communication does not correspond to reality. This creates a gap between the companies' symbolic and substantive actions, which is referred to as CSR-decoupling. Companies in the U.S versus Western Europe are in different markets when it comes to corporate cultures. This study therefore aims to research the use of CSR-decoupling in the United States and Western Europe. We also examine the CEO's power and stakeholder requirements to see if these factors affect the use of CSR-decoupling. The study is a quantitative cross-sectional study based on data consisting of U.S listed companies and Western European listed companies. The hypotheses are answered based on previous research and the results of a regression analysis and t-test. The results from the regression analysis show that the use of CSR-decoupling is greater in the U.S than in Western Europe, while the t-test show the opposite. From the study, no statistical relationship could be established between the CEO's power and CSR-decoupling. The result, on the other hand, showed a positive statistical relationship between stakeholder requirements and CSR-decoupling, and that Western European listed companies are more affected by stakeholder requirements when it comes to the use of decoupling strategies.

Det har blivit allt mer viktigt för företag att ta ansvar inom områdena miljö, ekonomi och samhälle. Företag använder sig av CSR-kommunikation för att visa vilka handlingar de vidtar för att uppfylla dessa förväntningar och erhålla legitimitet. Det förekommer dock att CSR-kommunikationen inte överensstämmer med verkligheten. Det skapas då ett gap mellan företagens symboliska och substantiva handlingar, vilket benämns som CSR-decoupling. Företag i USA kontra Västeuropa befinner sig på olika marknader när det kommer till företagskulturer. Denna studie syftar därför till att undersöka användandet av CSR-decoupling i USA och Västeuropa. Studien undersöker även verkställande direktörens makt och intressenternas krav för att se om dessa faktorer påverkar användandet av CSR-decoupling. Studien är en kvantitativ tvärsnittsstudie som bygger på data bestående av amerikanska börsnoterade företag och västeuropeiska börsnoterade företag. Hypoteserna besvaras utifrån tidigare forskning och resultatet från en regressionsanalys samt t-test. Resultatet från regressionsanalysen visar att användandet av CSR-decoupling är större i USA än i Västeuropa, medan t-testet visar det motsatta. Av studien kunde inget samband fastställas mellan verkställande direktörens makt och CSR-decoupling. Resultatet visade däremot ett positivt samband mellan intressenternas krav och CSR-decoupling, samt att västeuropeiska börsnoterade företag påverkas mer av intressenternas krav när det kommer till användandet av decouplingstrategier., It has become increasingly important for companies to take responsibility in the areas of environment, economy and society. Companies use CSR-communication to show what actions they are taking to meet these expectations and gain legitimacy. However, it happens that CSR-communication does not correspond to reality. This creates a gap between the companies' symbolic and substantive actions, which is referred to as CSR-decoupling. Companies in the U.S versus Western Europe are in different markets when it comes to corporate cultures. This study therefore aims to research the use of CSR-decoupling in the United States and Western Europe. We also examine the CEO's power and stakeholder requirements to see if these factors affect the use of CSR-decoupling. The study is a quantitative cross-sectional study based on data consisting of U.S listed companies and Western European listed companies. The hypotheses are answered based on previous research and the results of a regression analysis and t-test. The results from the regression analysis show that the use of CSR-decoupling is greater in the U.S than in Western Europe, while the t-test show the opposite. From the study, no statistical relationship could be established between the CEO's power and CSR-decoupling. The result, on the other hand, showed a positive statistical relationship between stakeholder requirements and CSR-decoupling, and that Western European listed companies are more affected by stakeholder requirements when it comes to the use of decoupling strategies.

Malignant transformation is characterized by dysregulation of diverse cellular processes that have been the subject of detailed genetic, biochemical, and structural studies, but only recently has evidence emerged that many of these processes occur in the context of biomolecular condensates. Condensates are membrane-less bodies, often formed by liquid-liquid phase separation, that compartmentalize protein and RNA molecules with related functions. New insights from condensate studies portend a profound transformation in our understanding of cellular dysregulation in cancer. Here we summarize key features of biomolecular condensates, note where they have been implicated—or will likely be implicated—in oncogenesis, describe evidence that the pharmacodynamics of cancer therapeutics can be greatly influenced by condensates, and discuss some of the questions that must be addressed to further advance our understanding and treatment of cancer., NIH (Grants GM123511, CA213333 and CA155258)

© 2019 Elsevier Inc. Enhancers are DNA elements that are bound by transcription factors (TFs), which recruit coactivators and the transcriptional machinery to genes. Phase-separated condensates of TFs and coactivators have been implicated in assembling the transcription machinery at particular enhancers, yet the role of DNA sequence in this process has not been explored. We show that DNA sequences encoding TF binding site number, density, and affinity above sharply defined thresholds drive condensation of TFs and coactivators. A combination of specific structured (TF-DNA) and weak multivalent (TF-coactivator) interactions allows for condensates to form at particular genomic loci determined by the DNA sequence and the complement of expressed TFs. DNA features found to drive condensation promote enhancer activity and transcription in cells. Our study provides a framework to understand how the genome can scaffold transcriptional condensates at specific loci and how the universal phenomenon of phase separation might regulate this process. Shrinivas et al. demonstrate that specific types of motif compositions encoded in DNA drive localized formation of transcriptional condensates. These findings explain how phase separation can occur at specific genomic locations and shed light on why only some genomic loci become highly active enhancers.

In this thesis a regression analysis of ten independent data sets is analysed in order toestimate losses and Key Risk Indicators (KRI). Each data set contains a list of objects,impacts that each object contains and revenue stream values (RSV) to each impact.The project investigates the data and simulate yearly losses as response variables in theregression modelling. The three regressors that influence the yearly losses are numberof objects, sum of revenue streams and expected aggregated losses. Given the responsevariable from each data set a percentage scale of KRI’s is determined indicating howlarge losses each set possess., I denna avhandling analyseras en regressionsmodellering av tio oberoende mängderdata för att uppskatta förluster och Key Risk Indicators. Den givna dataupsättningeninnehåller en lista med objekt, påverkan varje objekt erhåller och vad respektiveobjekt omsätter. Projektet undersöker den givma datan och simulerar årliga förlustersom svarsvariabler i regressionsmodelleringen. De tre regressorerna som påverkarde årliga förlusterna är antalet objekt, summan av intäckterna och förvämtadesammanlagda förlusterna. Från den givna svarsvariabeln från varje datamängdbestäms en procentuell skala av KRIer som indikerar hur stora förluster varjeuppsättning har.

Background: Creatinine measurement for estimation of glomerular filtration rate (GFR) is a frequently used laboratory test. Differences in analytic creatinine methods have caused large inter-laboratory variation. International and national standardization efforts have been made in the last decade. Methods: This study describes the results of the standardization efforts in Sweden by summarizing data for creatinine concentration in blood plasma in the Equalis quality assessment program during 1996-2014. Results: Non-compensated Jaffe methods dominated in 1996-2001 (91 of 103 laboratories; 90%) and were then gradually replaced by either compensated Jaffe methods or enzymatic creatinine methods. In 2014 a majority of Swedish hospital laboratories (139 of 159; 87%) used enzymatic methods. The reported mean creatinine value by the Swedish laboratories was about 10 mu mol/L higher than the isotope dilution mass spectrometry (IDMS) assured reference value in 2003, but consistent with the reference value from 2009 to 2014. The inter-laboratory CV was 7%-9% for creatinine values until 2007, and thereafter gradually decreased to about 4%-5% in 2014. Conclusions: The introduction of enzymatic methods in Swedish laboratories has contributed to achieving a low inter-laboratory variation. Also, the reported values are lower for enzymatic methods compared to Jaffe methods, and the values obtained with enzymatic methods were consistent with IDMS certified values established at reference laboratories. Thus, many Swedish hospital laboratories reported 10 mu mol/L lower, and more true, creatinine concentrations in 2012 than in 2003, which may cause bias in longitudinal studies.

Denna rapport redogör för ett projekt inom området industriell teknik och hållbarhet. Studien utreder möjligheten att tillämpa en förnyelsebar energikälla där solenergi skall utvinnas genom solceller. Energin som utvinns skall till en viss grad leda till energiförsörjning hos Rosendals Trädgård. Verksamhet har valts som ett hypotetiskt förslag på hur man kan anpassa, beräkna och implementera solceller. För att uppnå ett realistiskt förslag har företaget HP Solartech används som ett “verktyg” och teoretiskt stöd kring solcellstekniker och beräkningsmodeller. Syftet med detta projekt var att ta fram beslutsunderlag för Rosendal, med hjälp av att använda HP Solartechs simuleringsprogram för solcellsanläggningar. Resultatet visade att en solcellsanläggning på Rosendal skulle täcka 24% av den årliga energiförbrukningen och ge en kostnadsbesparing på SEK 160 900., This report describes a project concerning the area within industrial technology and sustainability. The research investigates the possibility to apply a renewable energy source utilizing solar energy through solar cells. The energy that extracts shall, to a certain extent, be applied as an energy source to the establishment Rosendals Trädgård. Rosendals Trädgård was chosen as a hypothetical example of how an implementation of an organization can be successful. The company HP solartech was a leading hand during the study since they attain professional knowledge within this subject. In order to make the study accurate, HP solartech supported the data by sharing the ground theories about solar energy, the difficult calculations and the implementation of solar cells. With their guiding and support, valuable facts and results was attained. The aim to this project is to present a proposition to Rosendals Trädgråd with support from HP solartech. The result for Rosendal turned out to a production of solar energy that covers 24% of their current energy consumption and an economical saving of SEK 160 900 annually.

Denna rapport redogör för ett projekt inom området industriell teknik och hållbarhet. Studien utreder möjligheten att tillämpa en förnyelsebar energikälla där solenergi skall utvinnas genom solceller. Energin som utvinns skall till en viss grad leda till energiförsörjning hos Rosendals Trädgård. Verksamhet har valts som ett hypotetiskt förslag på hur man kan anpassa, beräkna och implementera solceller. För att uppnå ett realistiskt förslag har företaget HP Solartech används som ett “verktyg” och teoretiskt stöd kring solcellstekniker och beräkningsmodeller. Syftet med detta projekt var att ta fram beslutsunderlag för Rosendal, med hjälp av att använda HP Solartechs simuleringsprogram för solcellsanläggningar. Resultatet visade att en solcellsanläggning på Rosendal skulle täcka 24% av den årliga energiförbrukningen och ge en kostnadsbesparing på SEK 160 900., This report describes a project concerning the area within industrial technology and sustainability. The research investigates the possibility to apply a renewable energy source utilizing solar energy through solar cells. The energy that extracts shall, to a certain extent, be applied as an energy source to the establishment Rosendals Trädgård. Rosendals Trädgård was chosen as a hypothetical example of how an implementation of an organization can be successful. The company HP solartech was a leading hand during the study since they attain professional knowledge within this subject. In order to make the study accurate, HP solartech supported the data by sharing the ground theories about solar energy, the difficult calculations and the implementation of solar cells. With their guiding and support, valuable facts and results was attained. The aim to this project is to present a proposition to Rosendals Trädgråd with support from HP solartech. The result for Rosendal turned out to a production of solar energy that covers 24% of their current energy consumption and an economical saving of SEK 160 900 annually.

Super-enhancers (SEs) are clusters of enhancers that cooperatively assemble a high density of the transcriptional apparatus to drive robust expression of genes with prominent roles in cell identity. Here we demonstrate that the SE-enriched transcriptional coactivators BRD4 and MED1 form nuclear puncta at SEs that exhibit properties of liquid-like condensates and are disrupted by chemicals that perturb condensates. The intrinsically disordered regions (IDRs) of BRD4 and MED1 can form phase-separated droplets, and MED1-IDR droplets can compartmentalize and concentrate the transcription apparatus from nuclear extracts. These results support the idea that coactivators form phase-separated condensates at SEs that compartmentalize and concentrate the transcription apparatus, suggest a role for coactivator IDRs in this process, and offer insights into mechanisms involved in the control of key cell-identity genes., National Institutes of Health (U.S.) (Grant GM123511), National Institutes of Health (U.S.) (Grant P01-CA042063), National Science Foundation (U.S.) (Grant PHY-1743900), National Cancer Institute (U.S.) (Grant P30-CA14051)

Studien fokuserar på om könsfördelningen i företagsledningen hos svenska börsnoterade företag påverkar den frivilliga information som redovisas i årsredovisningar. Data har samlats in från databaser och manuellt från årsredovisningar. Studien använder en regressionsanalys och resultatet visar att fler kvinnor i styrelsen eller en kvinnlig ekonomidirektör leder till att företag redovisar mer frivillig information. Vi finner inget samband mellan könet hos den verkställande direktören och frivillig redovisning, något som förmodligen beror på att urvalet endast består av två procent kvinnliga verkställande direktörer. Resultatet bidrar till att öka informationen om frivillig redovisning och hur det påverkas av könsfördelning i svenska företagsledningar. Det är av praktisk relevans för svenska företag och investerare då ökad informationsgivning bidrar till minskad informationsasymmetri vilket ger lägre agent- och kapitalkostnader. Framtida studier kan med fördel använda ett större urval för att undersöka om könsfördelningen i ledningen påverkar mängden frivillig redovisning. Exempelvis genom att även inkludera mindre och onoterade företag.

Studien fokuserar på om könsfördelningen i företagsledningen hos svenska börsnoterade företag påverkar den frivilliga information som redovisas i årsredovisningar. Data har samlats in från databaser och manuellt från årsredovisningar. Studien använder en regressionsanalys och resultatet visar att fler kvinnor i styrelsen eller en kvinnlig ekonomidirektör leder till att företag redovisar mer frivillig information. Vi finner inget samband mellan könet hos den verkställande direktören och frivillig redovisning, något som förmodligen beror på att urvalet endast består av två procent kvinnliga verkställande direktörer. Resultatet bidrar till att öka informationen om frivillig redovisning och hur det påverkas av könsfördelning i svenska företagsledningar. Det är av praktisk relevans för svenska företag och investerare då ökad informationsgivning bidrar till minskad informationsasymmetri vilket ger lägre agent- och kapitalkostnader. Framtida studier kan med fördel använda ett större urval för att undersöka om könsfördelningen i ledningen påverkar mängden frivillig redovisning. Exempelvis genom att även inkludera mindre och onoterade företag.

Transcription activation involves RNA polymerase II (Pol II) recruitment and release from the promoter into productive elongation, but how specific chromatin regulators control these steps is unclear. Here, we identify a novel activity of the histone acetyltransferase p300/CREB-binding protein (CBP) in regulating promoter-proximal paused Pol II. We find that Drosophila CBP inhibition results in "dribbling" of Pol II from the pause site to positions further downstream but impedes transcription through the +1 nucleosome genome-wide. Promoters strongly occupied by CBP and GAGA factor have high levels of paused Pol II, a unique chromatin signature, and are highly expressed regardless of cell type. Interestingly, CBP activity is rate limiting for Pol II recruitment to these highly paused promoters through an interaction with TFIIB but for transit into elongation by histone acetylation at other genes. Thus, CBP directly stimulates both Pol II recruitment and the ability to traverse the first nucleosome, thereby promoting transcription of most genes.

Mutations in human Atrophin1, a transcriptional corepressor, cause dentatorubral-pallidoluysian atrophy, a neurodegenerative disease. Drosophila Atrophin (Atro) mutants display many phenotypes, including neurodegeneration, segmentation, patterning and planar polarity defects. Despite Atros critical role in development and disease, relatively little is known about Atros binding partners and downstream targets. We present the first genomic analysis of Atro using ChIP-seq against endogenous Atro. ChIP-seq identified 1300 potential direct targets of Atro including engrailed, and components of the Dpp and Notch signaling pathways. We show that Atro regulates Dpp and Notch signaling in larval imaginal discs, at least partially via regulation of thickveins and fringe. In addition, bioinformatics analyses, sequential ChIP and coimmunoprecipitation experiments reveal that Atro interacts with the Drosophila GAGA Factor, Trithorax-like (Trl), and they bind to the same loci simultaneously. Phenotypic analyses of Trl and Atro clones suggest that Atro is required to modulate the transcription activation by Trl in larval imaginal discs. Taken together, these data indicate that Atro is a major Trl cofactor that functions to moderate developmental gene transcription.

Mutations in human Atrophin1, a transcriptional corepressor, cause dentatorubral-pallidoluysian atrophy, a neurodegenerative disease. Drosophila Atrophin (Atro) mutants display many phenotypes, including neurodegeneration, segmentation, patterning and planar polarity defects. Despite Atros critical role in development and disease, relatively little is known about Atros binding partners and downstream targets. We present the first genomic analysis of Atro using ChIP-seq against endogenous Atro. ChIP-seq identified 1300 potential direct targets of Atro including engrailed, and components of the Dpp and Notch signaling pathways. We show that Atro regulates Dpp and Notch signaling in larval imaginal discs, at least partially via regulation of thickveins and fringe. In addition, bioinformatics analyses, sequential ChIP and coimmunoprecipitation experiments reveal that Atro interacts with the Drosophila GAGA Factor, Trithorax-like (Trl), and they bind to the same loci simultaneously. Phenotypic analyses of Trl and Atro clones suggest that Atro is required to modulate the transcription activation by Trl in larval imaginal discs. Taken together, these data indicate that Atro is a major Trl cofactor that functions to moderate developmental gene transcription.

Mutations in human Atrophin1, a transcriptional corepressor, cause dentatorubral-pallidoluysian atrophy, a neurodegenerative disease. Drosophila Atrophin (Atro) mutants display many phenotypes, including neurodegeneration, segmentation, patterning and planar polarity defects. Despite Atros critical role in development and disease, relatively little is known about Atros binding partners and downstream targets. We present the first genomic analysis of Atro using ChIP-seq against endogenous Atro. ChIP-seq identified 1300 potential direct targets of Atro including engrailed, and components of the Dpp and Notch signaling pathways. We show that Atro regulates Dpp and Notch signaling in larval imaginal discs, at least partially via regulation of thickveins and fringe. In addition, bioinformatics analyses, sequential ChIP and coimmunoprecipitation experiments reveal that Atro interacts with the Drosophila GAGA Factor, Trithorax-like (Trl), and they bind to the same loci simultaneously. Phenotypic analyses of Trl and Atro clones suggest that Atro is required to modulate the transcription activation by Trl in larval imaginal discs. Taken together, these data indicate that Atro is a major Trl cofactor that functions to moderate developmental gene transcription.

Transcription activation involves RNA polymerase II (Pol II) recruitment and release from the promoter into productive elongation, but how specific chromatin regulators control these steps is unclear. Here, we identify a novel activity of the histone acetyltransferase p300/CREB-binding protein (CBP) in regulating promoter-proximal paused Pol II. We find that Drosophila CBP inhibition results in dribbling'' of Pol II from the pause site to positions further downstream but impedes transcription through the + 1 nucleosome genome-wide. Promoters strongly occupied by CBP and GAGA factor have high levels of paused Pol II, a unique chromatin signature, and are highly expressed regardless of cell type. Interestingly, CBP activity is rate limiting for Pol II recruitment to these highly paused promoters through an interaction with TFIIB but for transit into elongation by histone acetylation at other genes. Thus, CBP directly stimulates both Pol II recruitment and the ability to traverse the first nucleosome, thereby promoting transcription of most genes.

Mutations in human Atrophin1, a transcriptional corepressor, cause dentatorubral-pallidoluysian atrophy, a neurodegenerative disease. Drosophila Atrophin (Atro) mutants display many phenotypes, including neurodegeneration, segmentation, patterning and planar polarity defects. Despite Atros critical role in development and disease, relatively little is known about Atros binding partners and downstream targets. We present the first genomic analysis of Atro using ChIP-seq against endogenous Atro. ChIP-seq identified 1300 potential direct targets of Atro including engrailed, and components of the Dpp and Notch signaling pathways. We show that Atro regulates Dpp and Notch signaling in larval imaginal discs, at least partially via regulation of thickveins and fringe. In addition, bioinformatics analyses, sequential ChIP and coimmunoprecipitation experiments reveal that Atro interacts with the Drosophila GAGA Factor, Trithorax-like (Trl), and they bind to the same loci simultaneously. Phenotypic analyses of Trl and Atro clones suggest that Atro is required to modulate the transcription activation by Trl in larval imaginal discs. Taken together, these data indicate that Atro is a major Trl cofactor that functions to moderate developmental gene transcription.

Mutations in human Atrophin1, a transcriptional corepressor, cause dentatorubral-pallidoluysian atrophy, a neurodegenerative disease. Drosophila Atrophin (Atro) mutants display many phenotypes, including neurodegeneration, segmentation, patterning and planar polarity defects. Despite Atros critical role in development and disease, relatively little is known about Atros binding partners and downstream targets. We present the first genomic analysis of Atro using ChIP-seq against endogenous Atro. ChIP-seq identified 1300 potential direct targets of Atro including engrailed, and components of the Dpp and Notch signaling pathways. We show that Atro regulates Dpp and Notch signaling in larval imaginal discs, at least partially via regulation of thickveins and fringe. In addition, bioinformatics analyses, sequential ChIP and coimmunoprecipitation experiments reveal that Atro interacts with the Drosophila GAGA Factor, Trithorax-like (Trl), and they bind to the same loci simultaneously. Phenotypic analyses of Trl and Atro clones suggest that Atro is required to modulate the transcription activation by Trl in larval imaginal discs. Taken together, these data indicate that Atro is a major Trl cofactor that functions to moderate developmental gene transcription.

Mutations in human Atrophin1, a transcriptional corepressor, cause dentatorubral-pallidoluysian atrophy, a neurodegenerative disease. Drosophila Atrophin (Atro) mutants display many phenotypes, including neurodegeneration, segmentation, patterning and planar polarity defects. Despite Atros critical role in development and disease, relatively little is known about Atros binding partners and downstream targets. We present the first genomic analysis of Atro using ChIP-seq against endogenous Atro. ChIP-seq identified 1300 potential direct targets of Atro including engrailed, and components of the Dpp and Notch signaling pathways. We show that Atro regulates Dpp and Notch signaling in larval imaginal discs, at least partially via regulation of thickveins and fringe. In addition, bioinformatics analyses, sequential ChIP and coimmunoprecipitation experiments reveal that Atro interacts with the Drosophila GAGA Factor, Trithorax-like (Trl), and they bind to the same loci simultaneously. Phenotypic analyses of Trl and Atro clones suggest that Atro is required to modulate the transcription activation by Trl in larval imaginal discs. Taken together, these data indicate that Atro is a major Trl cofactor that functions to moderate developmental gene transcription.

During cell specification, temporal and spatially restricted gene expression programs are set up, forming different cell types and ultimately a multicellular organism. In this thesis, we have studied the molecular mechanisms by which sequence specific transcription factors and coactivators regulate RNA polymerase II (Pol II) transcription to establish specific gene expression programs and what epigenetic patterns that follows. We found that the transcription factor Dorsal is responsible for establishing discrete epigenetic patterns in the presumptive mesoderm, neuroectoderm and dorsal ectoderm, during early Drosophila embryo development. In addition, these different chromatin states can be linked to distinct modes of Pol II regulation. Our results provide novel insights into how gene regulatory networks form an epigenetic landscape and how their coordinated actions specify cell identity. CBP/p300 is a widely used co-activator and histone acetyltransferase (HAT) involved in transcriptional activation. We discovered that CBP occupies the genome preferentially together with Dorsal, and has a specific role during development in coordinating the dorsal-ventral axis of the Drosophila embryo. While CBP generally correlates with gene activation we also found CBP in H3K27me3 repressed chromatin. Previous studies have shown that CBP has an important role at transcriptional enhancers. We provide evidence that the regulatory role of CBP does not stop at enhancers, but is extended to many genomic regions. CBP binds to insulators and regulates their activity by acetylating histones to prevent spreading of H3K27me3. We further discovered that CBP has a direct regulatory role at promoters. Using a highly potent CBP inhibitor in combination with ChIP and PRO-seq we found that CBP regulates promoter proximal pausing of Pol II. CBP promotes Pol II recruitment to promoters via a direct interaction with TFIIB, and promotes transcriptional elongation by acetylating the first nucleosome., At the time of the doctoral defense, the following paper was unpublished and had a status as follows: Paper 4: Manuscript.

Wound healing is a complicated biological process that consist of partially overlapping inflammatory, proliferation and tissue remodelling phases. A successful wound healing depends on a proper activation and subsequent termination of the inflammatory phase. The failure to terminate the inflammation halts the completion of wound healing and is a known reason for formation of chronic wounds. Previous studies have shown that wound closure is delayed in plasminogen deficient mice, and a role for plasminogen in dissection of extracellular matrix was suggested. However, our finding that plasminogen is transported to the wound by inflammatory cells early during the healing process, where it potentiates inflammation, indicates that plasminogen may also have other roles in the wound healing process. Here we report that plasminogen-deficient mice have extensive fibrin and neutrophil depositions in the wounded area long after re-epithelialisation, indicating inefficient debridement and chronic inflammation. Delayed formation of granulation tissue suggests that fibroblast function is impaired in the absence of plasminogen. Therefore, in addition to its role in the activation of inflammation, plasminogen is also crucial for subsequent steps, including resolution of inflammation and activation of the proliferation phase. Importantly, supplementation of plasminogen-deficient mice with human plasminogen leads to a restored healing process that is comparable to that in wild-type mice. Besides of being an activator of the inflammatory phase during wound healing, plasminogen is also required for the subsequent termination of inflammation. Based on these results, we propose that plasminogen may be an important future therapeutic agent for wound treatment.

During cell specification, temporal and spatially restricted gene expression programs are set up, forming different cell types and ultimately a multicellular organism. In this thesis, we have studied the molecular mechanisms by which sequence specific transcription factors and coactivators regulate RNA polymerase II (Pol II) transcription to establish specific gene expression programs and what epigenetic patterns that follows. We found that the transcription factor Dorsal is responsible for establishing discrete epigenetic patterns in the presumptive mesoderm, neuroectoderm and dorsal ectoderm, during early Drosophila embryo development. In addition, these different chromatin states can be linked to distinct modes of Pol II regulation. Our results provide novel insights into how gene regulatory networks form an epigenetic landscape and how their coordinated actions specify cell identity. CBP/p300 is a widely used co-activator and histone acetyltransferase (HAT) involved in transcriptional activation. We discovered that CBP occupies the genome preferentially together with Dorsal, and has a specific role during development in coordinating the dorsal-ventral axis of the Drosophila embryo. While CBP generally correlates with gene activation we also found CBP in H3K27me3 repressed chromatin. Previous studies have shown that CBP has an important role at transcriptional enhancers. We provide evidence that the regulatory role of CBP does not stop at enhancers, but is extended to many genomic regions. CBP binds to insulators and regulates their activity by acetylating histones to prevent spreading of H3K27me3. We further discovered that CBP has a direct regulatory role at promoters. Using a highly potent CBP inhibitor in combination with ChIP and PRO-seq we found that CBP regulates promoter proximal pausing of Pol II. CBP promotes Pol II recruitment to promoters via a direct interaction with TFIIB, and promotes transcriptional elongation by acetylating the first nucleosome., At the time of the doctoral defense, the following paper was unpublished and had a status as follows: Paper 4: Manuscript.

Epigenetic patterns of histone modifications contribute to the maintenance of tissue-specific gene expression. Here, we show that such modifications also accompany the specification of cell identities by the NF-kappa B transcription factor Dorsal in the precellular Drosophila embryo. We provide evidence that the maternal pioneer factor, Zelda, is responsible for establishing poised RNA polymerase at Dorsal target genes before Dorsal-mediated zygotic activation. At the onset of cell specification, Dorsal recruits the CBP/p300 coactivator to the regulatory regions of defined target genes in the presumptive neuroectoderm, resulting in their histone acetylation and transcriptional activation. These genes are inactive in the mesoderm due to transcriptional quenching by the Snail repressor, which precludes recruitment of CBP and prevents histone acetylation. By contrast, inactivation of the same enhancers in the dorsal ectoderm is associated with Polycomb-repressed H3K27me3 chromatin. Thus, the Dorsal morphogen gradient produces three distinct histone signatures including two modes of transcriptional repression, active repression (hypoacetylation), and inactivity (H3K27me3). Whereas histone hypoacetylation is associated with a poised polymerase, H3K27me3 displaces polymerase from chromatin. Our results link different modes of RNA polymerase regulation to separate epigenetic patterns and demonstrate that developmental determinants orchestrate differential chromatin states, providing new insights into the link between epigenetics and developmental patterning.

During cell specification, temporal and spatially restricted gene expression programs are set up, forming different cell types and ultimately a multicellular organism. In this thesis, we have studied the molecular mechanisms by which sequence specific transcription factors and coactivators regulate RNA polymerase II (Pol II) transcription to establish specific gene expression programs and what epigenetic patterns that follows. We found that the transcription factor Dorsal is responsible for establishing discrete epigenetic patterns in the presumptive mesoderm, neuroectoderm and dorsal ectoderm, during early Drosophila embryo development. In addition, these different chromatin states can be linked to distinct modes of Pol II regulation. Our results provide novel insights into how gene regulatory networks form an epigenetic landscape and how their coordinated actions specify cell identity. CBP/p300 is a widely used co-activator and histone acetyltransferase (HAT) involved in transcriptional activation. We discovered that CBP occupies the genome preferentially together with Dorsal, and has a specific role during development in coordinating the dorsal-ventral axis of the Drosophila embryo. While CBP generally correlates with gene activation we also found CBP in H3K27me3 repressed chromatin. Previous studies have shown that CBP has an important role at transcriptional enhancers. We provide evidence that the regulatory role of CBP does not stop at enhancers, but is extended to many genomic regions. CBP binds to insulators and regulates their activity by acetylating histones to prevent spreading of H3K27me3. We further discovered that CBP has a direct regulatory role at promoters. Using a highly potent CBP inhibitor in combination with ChIP and PRO-seq we found that CBP regulates promoter proximal pausing of Pol II. CBP promotes Pol II recruitment to promoters via a direct interaction with TFIIB, and promotes transcriptional elongation by acetylating the first nucleosome., At the time of the doctoral defense, the following paper was unpublished and had a status as follows: Paper 4: Manuscript.

During cell specification, temporal and spatially restricted gene expression programs are set up, forming different cell types and ultimately a multicellular organism. In this thesis, we have studied the molecular mechanisms by which sequence specific transcription factors and coactivators regulate RNA polymerase II (Pol II) transcription to establish specific gene expression programs and what epigenetic patterns that follows. We found that the transcription factor Dorsal is responsible for establishing discrete epigenetic patterns in the presumptive mesoderm, neuroectoderm and dorsal ectoderm, during early Drosophila embryo development. In addition, these different chromatin states can be linked to distinct modes of Pol II regulation. Our results provide novel insights into how gene regulatory networks form an epigenetic landscape and how their coordinated actions specify cell identity. CBP/p300 is a widely used co-activator and histone acetyltransferase (HAT) involved in transcriptional activation. We discovered that CBP occupies the genome preferentially together with Dorsal, and has a specific role during development in coordinating the dorsal-ventral axis of the Drosophila embryo. While CBP generally correlates with gene activation we also found CBP in H3K27me3 repressed chromatin. Previous studies have shown that CBP has an important role at transcriptional enhancers. We provide evidence that the regulatory role of CBP does not stop at enhancers, but is extended to many genomic regions. CBP binds to insulators and regulates their activity by acetylating histones to prevent spreading of H3K27me3. We further discovered that CBP has a direct regulatory role at promoters. Using a highly potent CBP inhibitor in combination with ChIP and PRO-seq we found that CBP regulates promoter proximal pausing of Pol II. CBP promotes Pol II recruitment to promoters via a direct interaction with TFIIB, and promotes transcriptional elongation by acetylating the first nucleosome., At the time of the doctoral defense, the following paper was unpublished and had a status as follows: Paper 4: Manuscript.

During cell specification, temporal and spatially restricted gene expression programs are set up, forming different cell types and ultimately a multicellular organism. In this thesis, we have studied the molecular mechanisms by which sequence specific transcription factors and coactivators regulate RNA polymerase II (Pol II) transcription to establish specific gene expression programs and what epigenetic patterns that follows. We found that the transcription factor Dorsal is responsible for establishing discrete epigenetic patterns in the presumptive mesoderm, neuroectoderm and dorsal ectoderm, during early Drosophila embryo development. In addition, these different chromatin states can be linked to distinct modes of Pol II regulation. Our results provide novel insights into how gene regulatory networks form an epigenetic landscape and how their coordinated actions specify cell identity. CBP/p300 is a widely used co-activator and histone acetyltransferase (HAT) involved in transcriptional activation. We discovered that CBP occupies the genome preferentially together with Dorsal, and has a specific role during development in coordinating the dorsal-ventral axis of the Drosophila embryo. While CBP generally correlates with gene activation we also found CBP in H3K27me3 repressed chromatin. Previous studies have shown that CBP has an important role at transcriptional enhancers. We provide evidence that the regulatory role of CBP does not stop at enhancers, but is extended to many genomic regions. CBP binds to insulators and regulates their activity by acetylating histones to prevent spreading of H3K27me3. We further discovered that CBP has a direct regulatory role at promoters. Using a highly potent CBP inhibitor in combination with ChIP and PRO-seq we found that CBP regulates promoter proximal pausing of Pol II. CBP promotes Pol II recruitment to promoters via a direct interaction with TFIIB, and promotes transcriptional elongation by acetylating the first nucleosome., At the time of the doctoral defense, the following paper was unpublished and had a status as follows: Paper 4: Manuscript.

During cell specification, temporal and spatially restricted gene expression programs are set up, forming different cell types and ultimately a multicellular organism. In this thesis, we have studied the molecular mechanisms by which sequence specific transcription factors and coactivators regulate RNA polymerase II (Pol II) transcription to establish specific gene expression programs and what epigenetic patterns that follows. We found that the transcription factor Dorsal is responsible for establishing discrete epigenetic patterns in the presumptive mesoderm, neuroectoderm and dorsal ectoderm, during early Drosophila embryo development. In addition, these different chromatin states can be linked to distinct modes of Pol II regulation. Our results provide novel insights into how gene regulatory networks form an epigenetic landscape and how their coordinated actions specify cell identity. CBP/p300 is a widely used co-activator and histone acetyltransferase (HAT) involved in transcriptional activation. We discovered that CBP occupies the genome preferentially together with Dorsal, and has a specific role during development in coordinating the dorsal-ventral axis of the Drosophila embryo. While CBP generally correlates with gene activation we also found CBP in H3K27me3 repressed chromatin. Previous studies have shown that CBP has an important role at transcriptional enhancers. We provide evidence that the regulatory role of CBP does not stop at enhancers, but is extended to many genomic regions. CBP binds to insulators and regulates their activity by acetylating histones to prevent spreading of H3K27me3. We further discovered that CBP has a direct regulatory role at promoters. Using a highly potent CBP inhibitor in combination with ChIP and PRO-seq we found that CBP regulates promoter proximal pausing of Pol II. CBP promotes Pol II recruitment to promoters via a direct interaction with TFIIB, and promotes transcriptional elongation by acetylating the first nucleosome., At the time of the doctoral defense, the following paper was unpublished and had a status as follows: Paper 4: Manuscript.

BACKGROUND: CREB-binding protein (CBP, also known as nejire) is a transcriptional co-activator that is conserved in metazoans. CBP plays an important role in embryonic development and cell differentiation and mutations in CBP can lead to various diseases in humans. In addition, CBP and the related p300 protein have successfully been used to predict enhancers in both humans and flies when they occur with monomethylation of histone H3 on lysine 4 (H3K4me1). RESULTS: Here, we compare CBP chromatin immunoprecipitation sequencing data from Drosophila S2 cells with modENCODE data and show that CBP is bound at genomic sites with a wide range of functions. As expected, we find that CBP is bound at active promoters and enhancers. In addition, we find that the strongest CBP sites in the genome are found at Polycomb response elements embedded in histone H3 lysine 27 trimethylated (H3K27me3) chromatin, where they correlate with binding of the Pho repressive complex. Interestingly, we find that CBP also binds to most insulators in the genome. At a subset of these, CBP may regulate insulating activity, measured as the ability to prevent repressive H3K27 methylation from spreading into adjacent chromatin. CONCLUSIONS: We conclude that CBP could be involved in a much wider range of functions than has previously been appreciated, including Polycomb repression and insulator activity. In addition, we discuss the possibility that a common role for CBP at all functional elements may be to regulate interactions between distant chromosomal regions and speculate that CBP is controlling higher order chromatin organization., Erratum to: CBP binding outside of promoters and enhancers in Drosophila melanogasterEpigenetics & Chromatin 2016 9:3810.1186/s13072-015-0042-4

BACKGROUND: CREB-binding protein (CBP, also known as nejire) is a transcriptional co-activator that is conserved in metazoans. CBP plays an important role in embryonic development and cell differentiation and mutations in CBP can lead to various diseases in humans. In addition, CBP and the related p300 protein have successfully been used to predict enhancers in both humans and flies when they occur with monomethylation of histone H3 on lysine 4 (H3K4me1). RESULTS: Here, we compare CBP chromatin immunoprecipitation sequencing data from Drosophila S2 cells with modENCODE data and show that CBP is bound at genomic sites with a wide range of functions. As expected, we find that CBP is bound at active promoters and enhancers. In addition, we find that the strongest CBP sites in the genome are found at Polycomb response elements embedded in histone H3 lysine 27 trimethylated (H3K27me3) chromatin, where they correlate with binding of the Pho repressive complex. Interestingly, we find that CBP also binds to most insulators in the genome. At a subset of these, CBP may regulate insulating activity, measured as the ability to prevent repressive H3K27 methylation from spreading into adjacent chromatin. CONCLUSIONS: We conclude that CBP could be involved in a much wider range of functions than has previously been appreciated, including Polycomb repression and insulator activity. In addition, we discuss the possibility that a common role for CBP at all functional elements may be to regulate interactions between distant chromosomal regions and speculate that CBP is controlling higher order chromatin organization., Erratum to: CBP binding outside of promoters and enhancers in Drosophila melanogasterEpigenetics & Chromatin 2016 9:3810.1186/s13072-015-0042-4

BACKGROUND: CREB-binding protein (CBP, also known as nejire) is a transcriptional co-activator that is conserved in metazoans. CBP plays an important role in embryonic development and cell differentiation and mutations in CBP can lead to various diseases in humans. In addition, CBP and the related p300 protein have successfully been used to predict enhancers in both humans and flies when they occur with monomethylation of histone H3 on lysine 4 (H3K4me1). RESULTS: Here, we compare CBP chromatin immunoprecipitation sequencing data from Drosophila S2 cells with modENCODE data and show that CBP is bound at genomic sites with a wide range of functions. As expected, we find that CBP is bound at active promoters and enhancers. In addition, we find that the strongest CBP sites in the genome are found at Polycomb response elements embedded in histone H3 lysine 27 trimethylated (H3K27me3) chromatin, where they correlate with binding of the Pho repressive complex. Interestingly, we find that CBP also binds to most insulators in the genome. At a subset of these, CBP may regulate insulating activity, measured as the ability to prevent repressive H3K27 methylation from spreading into adjacent chromatin. CONCLUSIONS: We conclude that CBP could be involved in a much wider range of functions than has previously been appreciated, including Polycomb repression and insulator activity. In addition, we discuss the possibility that a common role for CBP at all functional elements may be to regulate interactions between distant chromosomal regions and speculate that CBP is controlling higher order chromatin organization., Erratum to: CBP binding outside of promoters and enhancers in Drosophila melanogasterEpigenetics & Chromatin 2016 9:3810.1186/s13072-015-0042-4

Background: CREB-binding protein (CBP, also known as nejire) is a transcriptional co-activator that is conserved in metazoans. CBP plays an important role in embryonic development and cell differentiation and mutations in CBP can lead to various diseases in humans. In addition, CBP and the related p300 protein have successfully been used to predict enhancers in both humans and flies when they occur with monomethylation of histone H3 on lysine 4 (H3K4me1). Results: Here, we compare CBP chromatin immunoprecipitation sequencing data from Drosophila S2 cells with modENCODE data and show that CBP is bound at genomic sites with a wide range of functions. As expected, we find that CBP is bound at active promoters and enhancers. In addition, we find that the strongest CBP sites in the genome are found at Polycomb response elements embedded in histone H3 lysine 27 trimethylated (H3K27me3) chromatin, where they correlate with binding of the Pho repressive complex. Interestingly, we find that CBP also binds to most insulators in the genome. At a subset of these, CBP may regulate insulating activity, measured as the ability to prevent repressive H3K27 methylation from spreading into adjacent chromatin. Conclusions: We conclude that CBP could be involved in a much wider range of functions than has previously been appreciated, including Polycomb repression and insulator activity. In addition, we discuss the possibility that a common role for CBP at all functional elements may be to regulate interactions between distant chromosomal regions and speculate that CBP is controlling higher order chromatin organization.