Prosjektarbeid som verktøy i endringsprosesser : en kvalitativ casestudie av prosjektarbeid som verktøy i endringsprosesser ved Universitetet i Nordland

Endring i organisasjoner er nødvendig for å skape forbedringer. Prosjektarbeid har vist seg å være en egnet metode for å oppnå vellykkede endringer i virksomheter. Spesielt i taktiske grep for å realisere strategier har prosjekter vist seg som en svært egnet arbeidsmåte. Denne oppgaven vil gjennom en kvalitativ casestudie av prosjekter ved Universitetet i Nordland, finne hvilke områder UiN bør forbedre for lettere å realisere strategiske mål. Problemstillingen i oppgaven er: ”Hvordan fungerer prosjekter som arbeidsform i endringsprosesser ved Universitetet i Nordland, og hvordan kan arbeidsformen videreutvikles for i større grad å oppnå strategiske mål?” For å kunne besvare denne problemstillingen, var det nødvendig å bryte den ned i følgende forskningsspørsmål 1. Hva er de sterke og svake sidene ved hvordan UiN initierer og gjennomfører prosjekter? 2. Hvordan kan UiN forbedre avkastningen fra prosjektvirksomheten? Casebedriften er Universitetet i Nordland, med avgrensning til administrativt initierte prosjekter. Teorivalget er gjort ut fra behovet for å kaste lys over modeller for endringsarbeid og bruk av prosjektarbeid som arbeidsmåte ved endringer i organisasjoner. Metodisk ble det valgt å utføre en kvalitativ casestudie, der det ble utført semistrukturerte intervjuer av fem strategisk kriteriebestemte informanter. Det understrekes at generaliseringen som er gjort i oppgaven kun er basert på fem intervjuer. De identifiserte forbedringsområdene berører kjernen i prosjektvirksomheten, og gir etter min mening valide forslag til hvilke forbedringer som bør gjennomføres for å øke avkastningen fra prosjektvirksomheten. Hovedkonklusjonen er at UiN har forbedringspotenisale i samtlige av de undersøkte faktorene som antas å påvirke prosjektsuksess. Forbedringsforslagene er delt inn prosjekttekniske forbedringsmuligheter og forbedringsforslag for de omliggende prosesser rundt prosjektene. De viktigste prosjekttekniske forbedringsmulighetene innebærer at prosjekteieren i større grad er involvert i fundamentet for prosjektet. Dette anbefales løst ved at det utarbeides et prosjektmandat før prosjektet starter. Prosjektmandatet vil sørge for at det er avklart hvem som er oppdragsgiveren, hvorfor prosjektet opprettes, hvilken endring prosjektarbeidet skal føre til i organisasjonen, hva endringen innebærer for arbeidstakerne som blir berørt av endringen, hva som må endres med systemet (det tekniske) og hva endringen innebærer for organisasjonen. Prosjektmandatet bør også inneholde hva prosjektet konkret skal levere til basisorganisasjonen, hvordan menneskelige ressurser blir fristilt for å jobbe i prosjektet og kostnadsrammen for prosjektet. Analysen viser også at det er avgjørende for en vellykket endring at de som skal bruke prosjektproduktet er involvert i prosessen med å formulere formål og mål for prosjektet. De foreslåtte forbedringene i de omliggende prosessene rundt prosjektene er at UiN først bør etablere et dokument som beskriver fundamentet for prosjektarbeid. Hensikten med dokumentet er å lage et grunnlag som danner basis for alt av prosjektarbeid, og å beskrive hva som er hensikten med å gjennomføre prosjekter. Dokumentet bør også beskrive de ulike rollene som inngår i prosjektarbeidet, hvilket ansvar som ligger til de ulike rollene, hvordan prosjekter på tvers av enheter skal håndteres og føringer for hvordan prosjekter bør prioriteres i forhold til hverandre. Det bør også søkes etablert langtidsplaner for utvikling av hver av enhetene ved UiN. Hensikten med langtidsplaner er å få etablert et forhold til hva som bør endres i de ulike enhetene. Ved å ha en slik plan vil det bli enklere å prioritere prosjekter i forhold til hverandre, fordi det vil bli enklere å se hva som er viktigst å få endret først. Endringsbehov på tvers av enhetene bør også fremkomme i planene. For å få institusjonalisert måten prosjekter initieres og gjennomføres på, bør det etableres et utviklingsprogram

Morphology of G Cells in Hypergastrinemic Cotton Rats

In a strain of inbred cotton rats, 25-50% of females develop spontaneous gastric hypochlorhydria and  hypergastrinemia. Hypergastrinemic animals develop ECL cell derived gastric carcinomas located in the  oxyntic mucosa, thus being an interesting animal model for studying the role of gastrin in gastric carcinogenesis.  The response to gastric hypoacidity in cotton rats as regards the level of hypergastrinemia is far  more pronounced than in the more commonly used laboratory rat. It is unknown whether the pronounced  hypergastrinemic response in cotton rats is due to a greater population of G cells or a greater capacity of  hormone synthesis in each G cell. The aim of the study was therefore to examine G cell population and  ultrastructure in normogastrinemic and hypergastrinemic cotton rats by the use of immunhistochemical  methods applied on both light- and electron-microscopy. Five hypergastrinemic vs. five normogastrinemic  cotton rats were compared. Cotton rats with gastric hypochlorhydria have a 55-fold increase in serum gastrin levels and a 6-fold  increase in G cell number, but this is not accompanied by significant changes in G cell ultrastructure. The  lack of ultrastructural changes in these activated G cells indicates that previously reported changes in  chronic stimulated G cells are just one of several ways G cells are activated.

Protein phosphatase 1c associated with the cardiac sodium calcium exchanger1 regulates its activity by dephosphorylating serine 68 phosphorylated phospholemman

The sodium (Na+)-calcium (Ca2+) exchanger 1 (NCX1) is an important regulator of intracellular Ca2+ homeostasis. Serine 68-phosphorylated phospholemman (pSer-68-PLM) inhibits NCX1 activity. In the context of Na+/K+-ATPase (NKA) regulation, pSer-68-PLM is dephosphorylated by protein phosphatase 1 (PP1). PP1 also associates with NCX1; however, the molecular basis of this association is unknown. In this study, we aimed to analyze the mechanisms of PP1 targeting to the NCX1-pSer-68-PLM complex and hypothesized that a direct and functional NCX1-PP1 interaction is a prerequisite for pSer-68-PLM dephosphorylation. Using a variety of molecular techniques, we show that PP1 catalytic subunit (PP1c) co-localized, co-fractionated, and co-immunoprecipitated with NCX1 in rat cardiomyocytes, left ventricle lysates, and HEK293 cells. Bioinformatic analysis, immunoprecipitations, mutagenesis, pulldown experiments, and peptide arrays constrained PP1c anchoring to the K(I/V)FF motif in the first Ca2+ binding domain (CBD) 1 in NCX1. This binding site is also partially in agreement with the extended PP1-binding motif K(V/I)FF-X5–8Φ1Φ2-X8–9-R. The cytosolic loop of NCX1, containing the K(I/V)FF motif, had no effect on PP1 activity in an in vitro assay. Dephosphorylation of pSer-68-PLM in HEK293 cells was not observed when NCX1 was absent, when the K(I/V)FF motif was mutated, or when the PLM- and PP1c-binding sites were separated (mimicking calpain cleavage of NCX1). Co-expression of PLM and NCX1 inhibited NCX1 current (both modes). Moreover, co-expression of PLM with NCX1(F407P) (mutated K(I/V)FF motif) resulted in the current being completely abolished. In conclusion, NCX1 is a substrate-specifying PP1c regulator protein, indirectly regulating NCX1 activity through pSer-68-PLM dephosphorylation

Protected sampling is preferable in bronchoscopic studies of the airway microbiome

The aim was to evaluate susceptibility of oropharyngeal contamination with various bronchoscopic sampling techniques. 67 patients with obstructive lung disease and 58 control subjects underwent bronchoscopy with small-volume lavage (SVL) through the working channel, protected bronchoalveolar lavage (PBAL) and bilateral protected specimen brush (PSB) sampling. Subjects also provided an oral wash (OW) sample, and negative control samples were gathered for each bronchoscopy procedure. DNA encoding bacterial 16S ribosomal RNA was sequenced and bioinformatically processed to cluster into operational taxonomic units (OTU), assign taxonomy and obtain measures of diversity. The proportion of Proteobacteria increased, whereas Firmicutes diminished in the order OW, SVL, PBAL, PSB (p<0.01). The alpha-diversity decreased in the same order (p<0.01). Also, beta-diversity varied by sampling method (p<0.01), and visualisation of principal coordinates analyses indicated that differences in diversity were smaller between OW and SVL and OW and PBAL samples than for OW and the PSB samples. The order of sampling (left versus right first) did not influence alpha- or beta-diversity for PSB samples. Studies of the airway microbiota need to address the potential for oropharyngeal contamination, and protected sampling might represent an acceptable measure to minimise this problem.publishedVersio

Dissecting the shared genetic basis of migraine and mental disorders using novel statistical tools

Migraine is three times more prevalent in people with bipolar disorder or depression. The relationship between schizophrenia and migraine is less certain although glutamatergic and serotonergic neurotransmission are implicated in both. A shared genetic basis to migraine and mental disorders has been suggested but previous studies have reported weak or non-significant genetic correlations and five shared risk loci. Using the largest samples to date and novel statistical tools, we aimed to determine the extent to which migraine’s polygenic architecture overlaps with bipolar disorder, depression and schizophrenia beyond genetic correlation, and to identify shared genetic loci. Summary statistics from genome-wide association studies were acquired from large-scale consortia for migraine (n cases = 59 674; n controls = 316 078), bipolar disorder (n cases = 20 352; n controls = 31 358), depression (n cases = 170 756; n controls = 328 443) and schizophrenia (n cases = 40 675, n controls = 64 643). We applied the bivariate causal mixture model to estimate the number of disorder-influencing variants shared between migraine and each mental disorder, and the conditional/conjunctional false discovery rate method to identify shared loci. Loci were functionally characterized to provide biological insights. Univariate MiXeR analysis revealed that migraine was substantially less polygenic (2.8 K disorder-influencing variants) compared to mental disorders (8100–12 300 disorder-influencing variants). Bivariate analysis estimated that 800 (SD = 300), 2100 (SD = 100) and 2300 (SD = 300) variants were shared between bipolar disorder, depression and schizophrenia, respectively. There was also extensive overlap with intelligence (1800, SD = 300) and educational attainment (2100, SD = 300) but not height (1000, SD = 100). We next identified 14 loci jointly associated with migraine and depression and 36 loci jointly associated with migraine and schizophrenia, with evidence of consistent genetic effects in independent samples. No loci were associated with migraine and bipolar disorder. Functional annotation mapped 37 and 298 genes to migraine and each of depression and schizophrenia, respectively, including several novel putative migraine genes such as L3MBTL2, CACNB2 and SLC9B1. Gene-set analysis identified several putative gene sets enriched with mapped genes including transmembrane transport in migraine and schizophrenia. Most migraine-influencing variants were predicted to influence depression and schizophrenia, although a minority of mental disorder-influencing variants were shared with migraine due to the difference in polygenicity. Similar overlap with other brain-related phenotypes suggests this represents a pool of ‘pleiotropic’ variants that influence vulnerability to diverse brain-related disorders and traits. We also identified specific loci shared between migraine and each of depression and schizophrenia, implicating shared molecular mechanisms and highlighting candidate migraine genes for experimental validation

Stroke genetics informs drug discovery and risk prediction across ancestries

Previous genome-wide association studies (GWASs) of stroke — the second leading cause of death worldwide — were conducted predominantly in populations of European ancestry1,2. Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis3, and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach4, we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry5. Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries