Involvement of global genome repair, transcription coupled repair, and chromatin remodeling in UV DNA damage response changes during development

Nucleotide Excision Repair (NER), which removes a variety of helix-distorting lesions from DNA, is initiated by two distinct DNA damage-sensing mechanisms. Transcription Coupled Repair (TCR) removes damage from the active strand of transcribed genes and depends on the SWI/SNF family protein CSB. Global Genome Repair (GGR) removes damage present elsewhere in the genome and depends on damage recognition by the XPC/RAD23/Centrin2 complex. Currently, it is not well understood to what extent both pathways contribute to genome maintenance and cell survival in a developing organism exposed to UV light. Here, we show that eukaryotic NER, initiated by two distinct subpathways, is well conserved in the nematode Caenorhabditis elegans. In C. elegans, involvement of TCR and GGR in the UV-induced DNA damage response changes during development. In germ cells and early embryos, we find that GGR is the major pathway contributing to normal development and survival after UV irradiation, whereas in later developmental stages TCR is predominantly engaged. Furthermore, we identify four ISWI/Cohesin and four SWI/SNF family chromatin remodeling factors that are implicated in the UV damage response in a developmental stage dependent manner. These in vivo studies strongly suggest that involvement of different repair pathways and chromatin remodeling proteins in UV-induced DNA repair depends on developmental stage of cells

Genomic analyses identify hundreds of variants associated with age at menarche and support a role for puberty timing in cancer risk

The timing of puberty is a highly polygenic childhood trait that is epidemiologically associated with various adult diseases. Using 1000 Genomes Project-imputed genotype data in up to similar to 370,000 women, we identify 389 independent signals (P <5 x 10(-8)) for age at menarche, a milestone in female pubertal development. In Icelandic data, these signals explain similar to 7.4% of the population variance in age at menarche, corresponding to similar to 25% of the estimated heritability. We implicate similar to 250 genes via coding variation or associated expression, demonstrating significant enrichment in neural tissues. Rare variants near the imprinted genes MKRN3 and DLK1 were identified, exhibiting large effects when paternally inherited. Mendelian randomization analyses suggest causal inverse associations, independent of body mass index (BMI), between puberty timing and risks for breast and endometrial cancers in women and prostate cancer in men. In aggregate, our findings highlight the complexity of the genetic regulation of puberty timing and support causal links with cancer susceptibility

Genomic analyses identify hundreds of variants associated with age at menarche and support a role for puberty timing in cancer risk

The timing of puberty is a highly polygenic childhood trait that is epidemiologically associated with various adult diseases. Using 1000 Genomes Project–imputed genotype data in up to ~370,000 women, we identify 389 independent signals (P < 5 × 10$^{−8}$) for age at menarche, a milestone in female pubertal development. In Icelandic data, these signals explain ~7.4% of the population variance in age at menarche, corresponding to ~25% of the estimated heritability. We implicate ~250 genes via coding variation or associated expression, demonstrating significant enrichment in neural tissues. Rare variants near the imprinted genes MKRN3 and DLK1 were identified, exhibiting large effects when paternally inherited. Mendelian randomization analyses suggest causal inverse associations, independent of body mass index (BMI), between puberty timing and risks for breast and endometrial cancers in women and prostate cancer in men. In aggregate, our findings highlight the complexity of the genetic regulation of puberty timing and support causal links with cancer susceptibility

Trypsinogen and neutrophil activation in acute Pancreatitis

Background and aims: Acute pancreatitis (AP) is a common condition characterized by premature protease activation, abdominal pain and leakage of pancreatic enzymes to the circulation. Approximately 10% develop systemic inflammation and persistent organ failure. Although persistent organ failure in AP is associated with considerable mortality, no therapies to moderate the disease are at hand. This is in part due to lacking knowledge of the basic pathophysiology. In this thesis, murine models of AP are utilised to investigate pathophysiological mechanisms in vivo. The aim was to explore specific regulatory mechanisms of innate immunity and their potential relationship to protease activation and severity in AP. Results and conclusions: The therapeutic potential of targeting leukocyte rolling adhesive interactions was investigated in paper I. P-selectin mediates leukocyte sequestration and tissue injury, but not protease activation in AP. Paper II addresses the role of Rho-signalling in AP. Rho-kinase inhibition reduced chemokine formation and protease activation in AP. Moreover, Rho-kinase inhibition attenuated pancreatitis-associated systemic inflammation, tissue injury and leukocyte recruitment to the pancreas and lungs. Paper III demonstrates that histone deacetylases (HDACs) regulate severity in pancreatitis. HDAC inhibition reduced pancreatitis-associated gene expression and trypsinogen activation in vitro. These observations were accompanied by reduced leukocyte recruitment and tissue injury of the pancreas and lungs. Formation of neutrophil extracellular traps (NETs) has been observed in septic conditions. In paper IV pancreatitis was demonstrated to provoke NET-formation. Moreover, NETs were found to play an integral part in AP, regulating local tissue destruction and systemic complications. Histones are suggested to be the principal mediators of these processes. In conclusion, this thesis provides new insights in crucial neutrophil functions such as navigation, cell-signalling, acetylation and cytotoxicity. Targeting these mechanisms might be of future value in the management of patients with AP

Projektledare och utvecklaresförhållningssätt tillprojektstyrningsramverk : En kvalitativ studie inom svensk offentlig sektor

Med institutionell teori som teoretiskt ramverk undersöker denna studie projektledare ochutvecklares förhållningssätt till projektstyrningsramverk (PSR) inom den svenska offentligasektorn. Empirisk data samlades in med hjälp av 6 semistrukturerade intervjuer av 7 praktiker.Studien fokuserar på hur praktikernas subjektiva legitimitetsbedömningar påverkar derasförhållningssätt till PSR vilket potentiellt kan bidra till dess isomorfism eller differentiering.Resultaten visar att även om PSR vanligtvis är institutionaliserade och tenderar att vara trögainför förändring så frammanar upplevda missanpassningar av PSR ofta anpassningar.Anpassningar som görs på grund av otillräcklig kunskap kan leda till ytterligaremissanpassningar vilket understryker betydelsen av tillräcklig kunskap för ett effektivimplementation av PSR. Studiens resultat speglar att praktikers förhållningssätt till PSR är ettav responsivitet i anpassningen av PSR. Vidare belyser studiens resultat ett förhållningssättbland praktiker som uttrycks unikt till offentlig sektor samt viss upplevd missanpassning avPSR:s förhållande till offentlig sektor då det uttrycks att väletablerade PSR är konstruerade iåtanke med behov från den privata sektorn som skiljer sig från offentlig sektor.

Användarnytta, hittbarhet och användbarhet i gränssnitt för komplexa informationsmiljöer

Svårigheter att hitta relevant information på internet är ett stort problem som kostar svenskar både tid och pengar. På internet finns komplexa informationsmiljöer med stora mängder data och i dessa miljöer är det särskilt viktigt att användare får stöd i sitt letande. Det finns tidigare forskning inriktad på att kvantitativt undersöka användares informationsletande men en brist på kvalitativ forskning inom området. I denna studie undersöks användarbeteenden kvalitativt genom sex intervjuer och observationer med användare av den komplexa informationsmiljön Uppsala Conflict Data Program (UCDP). För att ta reda på användarnas informationsmål samt hur lätt det är för användare att hitta information i UCDP har gränssnittets upplevda användarnytta, hittbarhet och användbarhet undersökts. Utifrån resultatet av intervjuer och observationer har personas och scenarier skapats vilket har använts för att utveckla en prototyp över ett nytt gränssnitt för UCDP. Prototypen har sedan användartestats och justerats därefter. Utifrån resultatet av studien har nio principer för god användarnytta, hittbarhet och användbarhet i gränssnitt för komplexa informationsmiljöer sammanställts. Dessa principer inkluderar bland annat att utveckla gränssnitt utifrån användarnas mål och behov, presentera mellanliggande information som tydligt visar vad användare kan fördjupa sig i samt ge stöd för flera informationssökningsstrategier. Fortsatt forskning behövs för att utreda principernas validitet samt om det finns ett behov av kompletterande principer.Difficulties in finding relevant information online cause significant problems for users. The internet houses complex information environments with large quantities of data in which users need more assistance in order to find relevant information. There are multiple examples of quantitative studies on user behavior when finding information but a lack of qualitative research in the field. This study investigates user behaviors with qualitative methods including six interviews and observations with users of the complex information environment Uppsala Conflict Data Program (UCDP). UCDP's interface has been evaluated through its perceived usefulness, findability and usability to identify information goals and how easily users find information. Personas and scenarios were created from the information found in the interviews and observations, which were used to develop a prototype of a new interface. The prototype was evaluated through user testing and modified thereafter. Based on the results found in the study nine principles regarding the usefulness, findability and usability for interfaces of complex information environments were summarized. These principles include developing interfaces from user goals and needs, presenting information that allows users to predict what additional information they can find, as well as supporting several information seeking strategies. Further research is necessary to examine if additional principles are needed and to validate the found principles

Användarnytta, hittbarhet och användbarhet i gränssnitt för komplexa informationsmiljöer

Svårigheter att hitta relevant information på internet är ett stort problem som kostar svenskar både tid och pengar. På internet finns komplexa informationsmiljöer med stora mängder data och i dessa miljöer är det särskilt viktigt att användare får stöd i sitt letande. Det finns tidigare forskning inriktad på att kvantitativt undersöka användares informationsletande men en brist på kvalitativ forskning inom området. I denna studie undersöks användarbeteenden kvalitativt genom sex intervjuer och observationer med användare av den komplexa informationsmiljön Uppsala Conflict Data Program (UCDP). För att ta reda på användarnas informationsmål samt hur lätt det är för användare att hitta information i UCDP har gränssnittets upplevda användarnytta, hittbarhet och användbarhet undersökts. Utifrån resultatet av intervjuer och observationer har personas och scenarier skapats vilket har använts för att utveckla en prototyp över ett nytt gränssnitt för UCDP. Prototypen har sedan användartestats och justerats därefter. Utifrån resultatet av studien har nio principer för god användarnytta, hittbarhet och användbarhet i gränssnitt för komplexa informationsmiljöer sammanställts. Dessa principer inkluderar bland annat att utveckla gränssnitt utifrån användarnas mål och behov, presentera mellanliggande information som tydligt visar vad användare kan fördjupa sig i samt ge stöd för flera informationssökningsstrategier. Fortsatt forskning behövs för att utreda principernas validitet samt om det finns ett behov av kompletterande principer.Difficulties in finding relevant information online cause significant problems for users. The internet houses complex information environments with large quantities of data in which users need more assistance in order to find relevant information. There are multiple examples of quantitative studies on user behavior when finding information but a lack of qualitative research in the field. This study investigates user behaviors with qualitative methods including six interviews and observations with users of the complex information environment Uppsala Conflict Data Program (UCDP). UCDP's interface has been evaluated through its perceived usefulness, findability and usability to identify information goals and how easily users find information. Personas and scenarios were created from the information found in the interviews and observations, which were used to develop a prototype of a new interface. The prototype was evaluated through user testing and modified thereafter. Based on the results found in the study nine principles regarding the usefulness, findability and usability for interfaces of complex information environments were summarized. These principles include developing interfaces from user goals and needs, presenting information that allows users to predict what additional information they can find, as well as supporting several information seeking strategies. Further research is necessary to examine if additional principles are needed and to validate the found principles

Projektledare och utvecklaresförhållningssätt tillprojektstyrningsramverk : En kvalitativ studie inom svensk offentlig sektor

Med institutionell teori som teoretiskt ramverk undersöker denna studie projektledare ochutvecklares förhållningssätt till projektstyrningsramverk (PSR) inom den svenska offentligasektorn. Empirisk data samlades in med hjälp av 6 semistrukturerade intervjuer av 7 praktiker.Studien fokuserar på hur praktikernas subjektiva legitimitetsbedömningar påverkar derasförhållningssätt till PSR vilket potentiellt kan bidra till dess isomorfism eller differentiering.Resultaten visar att även om PSR vanligtvis är institutionaliserade och tenderar att vara trögainför förändring så frammanar upplevda missanpassningar av PSR ofta anpassningar.Anpassningar som görs på grund av otillräcklig kunskap kan leda till ytterligaremissanpassningar vilket understryker betydelsen av tillräcklig kunskap för ett effektivimplementation av PSR. Studiens resultat speglar att praktikers förhållningssätt till PSR är ettav responsivitet i anpassningen av PSR. Vidare belyser studiens resultat ett förhållningssättbland praktiker som uttrycks unikt till offentlig sektor samt viss upplevd missanpassning avPSR:s förhållande till offentlig sektor då det uttrycks att väletablerade PSR är konstruerade iåtanke med behov från den privata sektorn som skiljer sig från offentlig sektor.

Non-invasive fibrosis scoring systems can predict future metabolic complications and overall mortality in non-alcoholic fatty liver disease (NAFLD)

BACKGROUND AND AIM: Progression to fibrosis in non-alcoholic fatty liver disease (NAFLD) is associated with an increased risk of liver-related events, overall mortality and possibly metabolic comorbidities. Our aim was to determine if non-invasive fibrosis scoring systems can predict the future risk of diabetes mellitus, cardiovascular disease (CVD), chronic kidney disease (CKD), liver-related events and overall mortality.METHODS: Patients with biopsy-proven NAFLD 1978 to 2006 were identified from a computerised register in Malmö, Sweden. Medical records were scrutinised in detail to collect data from inclusion to endpoint (death or end of 2016). Non-invasive fibrosis scoring systems (FIB-4-index, NAFLD fibrosis score (NFS), APRI and BARD score) were calculated and the scores classified into three risk categories (low, intermediate and high risk for advanced fibrosis). Chronic kidney disease was evaluated using the CKD-EPI equation.RESULTS: One hundred and forty-four patients with biopsy-proven NAFLD were included, with a mean age of 53.2 years and a mean follow-up time of 18.8 years. At inclusion, 18% had advanced fibrosis. NFS was the only score that could predict the future risk of all included outcomes with fairly good accuracy (Area-under-ROC curve). Multivariate-adjusted hazard ratios revealed that both the intermediate and high-risk category of FIB-4-index and NFS could significantly predict metabolic outcomes. All four scoring systems significantly predicted overall mortality in the high-risk category.CONCLUSIONS: Non-invasive fibrosis scoring systems, especially NFS and FIB-4-index, can be used to identify patients at risk of future liver-related events, overall mortality, metabolic comorbidities and CKD

The initial course of il1β, il-6, il-8, il-10, il-12, ifn-γ and tnf-α with regard to severity grade in acute pancreatitis

Clinical reports on early immune dysregulation in acute pancreatitis (AP) are scarce. Herein we investigate the initial temporal development of selected biomarkers. Blood samples were taken at 0–24 and 25–48 h after onsets of AP were acquired. Mean values and temporal intermediate difference (delta-values) of IL-1β, IL-6, IL-8, IL-10, IL-12, IFN-γ and TNF-α were calculated. Differences between severity groups, predictive capacity of the biomarkers and association with severe disease were analyzed. Paired comparison of samples (n = 115) taken at 0–24 and 25–48 h after onsets of AP showed a change over time for IL-1β, IL-6, IL-8 and IL-10 (p < 0.05) and a significant difference between severity groups after 24 h. In ROC-analysis an IL-6 cut-off level of 196.6 pg/mL could differentiate severe AP (sensitivity 81.9, specificity 91.3). The delta-values of IL-1β and IL-6 were significantly associated with severe outcomes (odds ratios 1.085 and 1.002, respectively). Data of this work demonstrate a distinct change in IL-1β, IL-8, IL-10 and IL-6 over the first 48 h after onset of AP. The temporal development of biomarkers can assist in the early stratification of the disease. Herein IL-1β and IL-6 were associated with severe disease, however the prognostic capacity of investigated biomarkers is low