Dynamic features of human mitochondrial DNA maintenance and transcription

Mitochondria are the primary sites for cellular energy production and are required for many essential cellular processes. Mitochondrial DNA (mtDNA) is a 16.6 kb circular DNA molecule that encodes only 13 gene products of the approximately 90 different proteins of the respiratory chain complexes and an estimated 1,200 mitochondrial proteins. MtDNA is, however, crucial for organismal development, normal function, and survival. MtDNA maintenance requires mitochondrially targeted nuclear DNA repair enzymes, a mtDNA replisome that is unique to mitochondria, and systems that control mitochondrial morphology and quality control. Here, we provide an overview of the current literature on mtDNA repair and transcription machineries and discuss how dynamic functional interactions between the components of these systems regulate mtDNA maintenance and transcription. A profound understanding of the molecular mechanisms that control mtDNA maintenance and transcription is important as loss of mtDNA integrity is implicated in normal process of aging, inflammation, and the etiology and pathogenesis of a number of diseases

Barn med utagerende atferdsvansker i barnehagen

I denne kvalitative intervjustudien har jeg utforsket hvordan barnehagelærere beskriver arbeidet med å gi utviklingsstøtte til barn med utagerende atferdsvansker. Studiens problemstilling er: Hvordan beskriver barnehagelærere arbeidet med å gi utviklingsstøtte til barn med utagerende atferdsvansker? Studien belyser tre forskningsspørsmål: 1. Hvordan forstår barnehagelærere barns utagerende atferdsvansker? 2. Hva vektlegger barnehagelærere i arbeidet med å gi utviklingsstøtte til barn med utagerende atferdsvansker? 3. Hvilke tanker eksisterer rundt gjennomføring av tiltak for å gi utviklingsstøtte til barn med utagerende atferdsvansker? Studiens teoretiske grunnlag består av teori om spesialpedagogikkens levende diskurser, hvordan utagerende atferdsvansker kan forstås, beskyttelse- og risikofaktorer sett i lys av Bronfenbrenners teori, samt ulike utviklingsstøttende tiltak i mikro- og mesosystemet. For å besvare problemstillingen er det anvendt kvalitativ forskningsmetode, med en fenomenologisk tilnærming. Datamaterialet er samlet inn gjennom semistrukturerte intervjuer med fire barnehagelærere fra tre ulike kommuner. Studien viser at barn med utagerende atferdsvansker er en mangfoldig gruppe. Det framkommer beskrivelser om at barns utagerende atferdsvansker forståes som en indikasjon på underliggende årsaker, hvor barnet befinner seg i en vanskelig livssituasjon og trenger hjelp. I arbeidet med å gi utviklingsstøtte legges det vekt på systemrettede tiltak som personaltetthet, godt personal- og foreldresamarbeid og gode relasjoner. Barnehagelærernes tanker omkring planlegging og organisering av tiltak viser at det stort sett fungerer godt. Det som imidlertid viser seg å være utfordrende er å få til gjennomføringen i praksis, grunnet mangel på tid og personalet. Konklusjonen viser at slike utfordringer kan være på grunn av politiske føringer og ideologier som styrer. Dette fører igjen til at prioriteringer blir utfordrende i forhold til individrettede tiltak i det systemrettorienterte samfunnet

Evaluating Welfare Technology Implementation in Municipal Care Services Contextual Adaptation of the Measurement Instrument for Determinants of Innovation

The Measurement Instrument for Determinants of Innovations (MIDI) was developed to identify facilitators and barriers during implementation processes in healthcare. Thereby the implementation strategies can be better targeted to obtain successful implementation. MIDI is theory- and evidence based, and provides a generic description of 29 determinants with suggested questions that need to be adapted to the specific innovation and implementation context. This paper aims to describe how MIDI can be contextually adapted; using welfare technology implementation in municipal care services as context. Based on this process we suggest operationalization of specific determinants on item-level in the MIDI adapted to the welfare technology context (MIDI-WT).publishedVersio

Verdienes verdi : verdibasert ledelse hos fylkesmannen i Nordland

Masteroppgave i personalledelse - Universitetet i Nordland, 201

Budsjettbruk i små- og mellomstore nordnorske reiselivsbedrifter. En empirisk studie

Utforming og bruk av styringssystemer er et sentralt tema innenfor fagområdet økonomistyring. Budsjettet, som er ett av flere styringssystemer, er trolig det første formelle styringssystemet bedrifter benytter seg av (King et al., 2010). I denne studien vil vi undersøke om betingelsesfaktorene størrelse, struktur, strategi og oppfattet usikkerhet i omgivelsene er relatert til budsjettpraksisen i små- og mellomstore bedrifter i den nordnorske reiselivsnæringen. Studiens problemstilling er derfor som følger: “Er budsjettbruken i små- og mellomstore nordnorske reiselivsbedrifter relatert til bedriftsstørrelse, struktur, strategi og oppfattet usikkerhet i omgivelsene?” Den norske reiselivsnæringen består av alle typer bedrifter som tilbyr tjenester til mennesker på reise. Næringen er i høy vekst og en viktig kilde til inntekter i norske kommuner. Reiselivet i Nord-Norge sysselsetter mange mennesker, og det anslås ifølge NHO Reiseliv (2019) en global vekst på ca. 50 % fra 2017 til 2030. Studien viser at en betydelig andel av nordnorske reiselivsbedriftene ikke bruker budsjetter. De fleste bedriftene kombinerer produktdifferensiering med en desentralisert struktur. Analysene viser at størrelse målt i ansatte ikke påvirker hvorvidt bedriftene velger å benytte budsjetter eller ikke. En stor del av bedriftene i næringen har en leder/eierstruktur hvor daglig leder og styreleder er samme person. For disse bedriftene vil struktur, fiendtlighet (konkurranseintensitet) og strategi ha ulik betydning for budsjettbruk. Struktur og fiendtlighet reduserer bruk av budsjett, mens strategi øker bruken. I bedrifter med ulik daglig leder og styreleder er dynamikk relatert til negativ budsjettbruk. Et alternativt funn for bedrifter med ulik lederstruktur viser at dersom økonomistyringen i bedriften oppleves som god, vil budsjetter i større grad benyttes. Et annet sentralt funn er at familiebedrifter i den nordnorske reiselivsnæringen er negativt assosiert med budsjetteringspraksis

APE1 polymorphic variants cause persistent genomic stress and affect cancer cell proliferation

Apurinic/apyrimidinic endonuclease 1 (APE1) is the main mammalian AP-endonuclease responsible for the repair of endogenous DNA damage through the base excision repair (BER) pathway. Molecular epidemiological studies have identified several genetic variants associated with human diseases, but a well-defined functional connection between mutations in APE1 and disease development is lacking. In order to understand the biological consequences of APE1 genetic mutations, we examined the molecular and cellular consequences of the selective expression of four non-synonymous APE1 variants (L104R, R237C, D148E and D283G) in human cells. We found that D283G, L104R and R237C variants have reduced endonuclease activity and impaired ability to associate with XRCC1 and DNA polymerase \u3b2, which are enzymes acting downstream of APE1 in the BER pathway. Complementation experiments performed in cells, where endogenous APE1 had been silenced by shRNA, showed that the expression of these variants resulted in increased phosphorylation of histone H2Ax and augmented levels of poly(ADP-ribosyl)ated (PAR) proteins. Persistent activation of DNA damage response markers was accompanied by growth defects likely due to combined apoptotic and autophagic processes. These phenotypes were observed in the absence of exogenous stressors, suggesting that chronic replication stress elicited by the BER defect may lead to a chronic activation of the DNA damage response. Hence, our data reinforce the concept that non-synonymous APE1 variants present in the human population may act as cancer susceptibility alleles

A Two-tiered compensatory response to loss of DNA repair modulates aging and stress response pathways

Activation of oxidative stress-responses and downregulation of insulin-like signaling (ILS) is seen in Nucleotide Excision Repair (NER) deficient segmental progeroid mice. Evidence suggests that this is a survival response to persistent transcription-blocking DNA damage, although the relevant lesions have not been identified. Here we show that loss of NTH-1, the only Base Excision Repair (BER) enzyme known to initiate repair of oxidative DNA damage inC. elegans, restores normal lifespan of the short-lived NER deficient xpa-1 mutant. Loss of NTH-1 leads to oxidative stress and global expression profile changes that involve upregulation of genes responding to endogenous stress and downregulation of ILS. A similar, but more extensive, transcriptomic shift is observed in the xpa-1 mutant whereas loss of both NTH-1 and XPA-1 elicits a different profile with downregulation of Aurora-B and Polo-like kinase 1 signaling networks as well as DNA repair and DNA damage response genes. The restoration of normal lifespan and absence oxidative stress responses in nth-1;xpa-1 indicate that BER contributes to generate transcription blocking lesions from oxidative DNA damage. Hence, our data strongly suggests that the DNA lesions relevant for aging are repair intermediates resulting from aberrant or attempted processing by BER of lesions normally repaired by NER

Seasonal and Annual Change in Physiological Ocular Growth of 7- to 11-Year-Old Norwegian Children

Purpose: To investigate seasonal and annual change in physiological eye growth in Norwegian school children. Methods: Measurements of ocular biometry, non-cycloplegic spherical equivalent autorefraction (SER), and choroidal thickness (ChT) were obtained for 92 children (44 females) aged 7 to 11 years at four time points over a year (November 2019–November 2020). Seasons (3- and 5-month intervals) were classified as winter (November–January), winter–spring (January–June), and summer–autumn (June–November). Cycloplegic SER was obtained in January and used to group children. The seasonal and annual changes were tested with a linear mixed-effects model (P values were adjusted for multiple comparisons). Results: All the children experienced annual ocular growth, irrespective of SER, but less so during the summer–autumn. The baseline SER was lower (P < 0.001), axial length (AL) was longer (P < 0.038), and choroids were thicker in 10- to 11-year-old than 7- to 8-year-old mild hyperopes (P = 0.002). Assuming mild hyperopes (n = 65) experience only physiological eye growth, modeling revealed seasonal and annual increases in AL across sex and age (P < 0.018), with less change during the summer–autumn than winter–spring. The 7- to 8-year-olds had a larger decrease annually and over winter–spring in SER (P ≤ 0.036) and in ChT over winter–spring than the 10- to 11-year-olds (P = 0.006). Conclusions: There were significant seasonal and annual changes in AL in children who had physiological eye growth irrespective of age within this cohort. Annual changes in SER and seasonal choroidal thinning were only observed in 7- to 8-year-old children. This indicates continued emmetropization in 7- to 8-year-olds and a transition to maintaining emmetropia in 10- to 11-year-olds.publishedVersio