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Responsible investment is increasingly prevalent, and both financial and moral concerns can drive such investment. In this article, we investigate how responsible investors of different wealth weigh financial and moral arguments. Prior research on different factors that may codetermine responsible investment behavior yield competing predictions about the influence of personal wealth on investment. We conduct a large-scale natural field experiment on responsible investment, wherein we treat investors with financial, moral, and no arguments. We find that there is a statistically and economically significant difference in responsiveness to financial and moral arguments between investors of different wealth. Specifically, financial arguments are more effective than are moral arguments for high wealth investors but not for low wealth investors, and the effect is particularly high for the wealthiest investors. The findings hold for several different measures of wealth. Our findings contribute to the understanding of the moderating effect of wealth on responsible investment choice. Furthermore, these insights may enable more fine-tuned strategies to stimulate responsible investment among different individual investor segments.

Epac1 (exchange protein activated by cAMP) stabilizes the endothelial barrier, but detailed studies are limited by the side effects of pharmacological Epac1 modulators and transient transfections. Here, we compare the key properties of barriers between endothelial cells derived from wild-type (WT) and Epac1-knockout (KO) mice myocardium. We found that KO cell layers, unlike WT layers, had low and cAMP-insensitive trans-endothelial resistance (TER). They also had fragmented VE-cadherin staining despite having augmented cAMP levels and increased protein expression of Rap1, Rac1, RhoA, and VE-cadherin. The simultaneous direct activation of Rac1 and RhoA by CN04 compensated Epac1 loss, since TER was increased. In KO-cells, inhibition of Rac1 activity had no additional effect on TER, suggesting that other mechanisms compensate the inhibition of the Rac1 function to preserve barrier properties. In summary, Epac1 is crucial for baseline and cAMP-mediated barrier stabilization through mechanisms that are at least partially independent of Rac1.

Closet indexers are low-activity mutual funds sold and marketed as active. Their investors are thus only partially receiving the service they pay for. Therefore, regulation is considered by supervisory authorities worldwide. We examine the impact of policy scrutiny by comparing scrutinized closet index funds in Scandinavia with similar unaffected European funds. We find that funds under scrutiny choose to increase activity over reducing fees and updating their investor information to reflect realized strategy. Despite investors getting a more actively managed fund, our findings suggest that value creation decreases. Regulation thus results in the worst of all worlds.

Acute myeloid leukemia (AML) is an aggressive hematological malignancy. Nearly 50% of the patients who receive the most intensive treatment develop chemoresistant leukemia relapse. Although the leukemogenic events leading to relapse seem to differ between patients (i.e., regrowth from a clone detected at first diagnosis, progression from the original leukemic or preleukemic stem cells), a common characteristic of relapsed AML is increased chemoresistance. The aim of the present study was to investigate at the proteomic level whether leukemic cells from relapsed patients present overlapping molecular mechanisms that contribute to this chemoresistance. We used liquid chromatography–tandem mass spectrometry (LC–MS/MS) to compare the proteomic and phosphoproteomic profiles of AML cells derived from seven patients at the time of first diagnosis and at first relapse. At the time of first relapse, AML cells were characterized by increased levels of proteins important for various mitochondrial functions, such as mitochondrial ribosomal subunit proteins (MRPL21, MRPS37) and proteins for RNA processing (DHX37, RNA helicase; RPP40, ribonuclease P component), DNA repair (ERCC3, DNA repair factor IIH helicase; GTF2F1, general transcription factor), and cyclin-dependent kinase (CDK) activity. The levels of several cytoskeletal proteins (MYH14/MYL6/MYL12A, myosin chains; VCL, vinculin) as well as of proteins involved in vesicular trafficking/secretion and cell adhesion (ITGAX, integrin alpha-X; CD36, platelet glycoprotein 4; SLC2A3, solute carrier family 2) were decreased in relapsed cells. Our study introduces new targetable proteins that might direct therapeutic strategies to decrease chemoresistance in relapsed AML.

Formålet med denne masterutredningen er å predikere hvordan boligprisutviklingen mellom Byparken og Åsane ville vært for perioden 2010-2019, i et tenkt scenario hvor Bybanen til Åsane hadde blitt ferdigstilt i 2010. Det finnes mange studier som redegjør for infrastrukturens påvirkning på boligprisnivå. Disse studiene har et økonometrisk perspektiv hvor formålet er å finne en presis fortolkning av hvordan avstand til offentlig transport påvirker boligprisene. Ulikt tidligere studier, søker vår utredning derimot å bygge en prediksjonsmodell som predikerer hvordan boligprisene vil utvikle ved introduksjonen av et offentlig transportmiddel som Bybanen. I mangel på observasjoner mellom Byparken og Åsane som er påvirket av nærhet til Bybanen, overførte vi Bybanens effekt på boligprisene til Åsane-området ved å trene prediksjonesmodellene på et utvalg av boligtransaksjoner mellom Byparken og Flesland, hvor bybanens påvirkning er tilstede. Ettersom det ikke foreligger et testsett som er påvirket av Bybanen mellom Byparken og Åsane, kan vi ikke fastslå hvilken prediksjonsmodell som faktisk vil være den mest presise. Det foreligger imidlertid indikasjoner på at maskinlæringsmodellen Super Learner, uten å transformere noen variabler, vil predikere boligprisene i Åsane mer presist enn den lineære regresjonsmetoden Elastic Net. Videre finner vi at det vil være mest fornuftig å kun benytte observasjoner fra Byparken til Lagunen som treningssett for å best fange opp bybaneeffekten når vi predikerer i Åsane. Resultatene antyder også at prediksjonenes presisjon blir betydelig bedre når en variabel som hensyntar avstand til Bybanen inkluderes som en del av variabelgrunnlaget, alt annet like. Til slutt finner vi indikasjoner på at det er fornuftig å trene- og validere en prediksjonsmodell på observasjoner fra et område hvor Bybanen foreligger til å predikere boligpriser i et annet område hvor vi forestiller oss at Bybanen eksisterer Når vi predikerer utviklingen i boligprisene mellom Byparken og Åsane for perioden 2010-2019, gitt Bybanens inntreden i 2010, finner vi at Bybanen predikeres å påvirke boligprisveksten i nærheten av Bybanen betydelig. Det predikeres videre å foreligge en økt vekst jo nærmere en bolig ligger et bybanestopp. Nøkkelord – Maskinlæring, Prediksjon, Boligpriser nhhmas

We examine the portfolio choices of 70,000 couples following a cancer diagnosis, including choices made in the event the diagnosed partner ends up dying. A matched sample of comparable couples is assembled using an approach that minimizes the likelihood that lifestyle factors differ between the treatment and control group. We find that a cancer diagnosis leads to lower financial risk-taking both in the form of participation in the stock market and a risky share of the financial portfolio. Widowhood decreases stock market participation by a factor of ten relative to non-fatal cancers. The effect depends on the relative importance of the deceased’s human capital. There is no link between prior experience with cancer and current portfolio choice.

Acute myeloid leukemia (AML) is a hematological cancer that mainly affects the elderly. Although complete remission (CR) is achieved for majority of the patients after induction and consolidation therapies, nearly two-thirds relapse within a short interval. Understanding biological factors that determine relapse has therefore become of major clinical interest in AML. We utilized liquid chromatography tandem mass spectrometry (LC-MS/MS) to identify protein changes and protein phosphorylation events associated with AML relapse in primary cells from 41 AML patients at time of diagnosis. Patients were defined as relapse-free if they had not relapsed within a 5-year clinical follow-up after AML diagnosis. Relapse was associated with increased expression of RNA processing proteins and decreased expression of V-ATPase proteins. We also observed an increase in phosphorylation events catalyzed by cyclin-dependent kinases (CDKs) and casein kinase 2 (CSK2). The biological relevance of the proteome findings was supported by cell proliferation assays using inhibitors of V-ATPase (bafilomycin), CSK2 (CX-4945), CDK4/6 (abemaciclib) and CDK2/7/9 (SNS-032). While bafilomycin preferentially inhibited the cells from relapse patients, the kinase inhibitors were less efficient in these cells. This suggests that therapy against the upregulated kinases also could target the factors inducing their upregulation rather than their activity. In conclusion, our study presents markers that could help predict AML relapse and direct therapeutic strategies.

The localization of glucokinase in pancreatic beta-cell nuclei is a controversial issue. Although previous reports suggest such a localization, the mechanism for its import has so far not been identified. Using immunofluorescence, subcellular fractionation and mass spectrometry, we present evidence in support of glucokinase localization in beta-cell nuclei of human and mouse pancreatic sections, as well as in human and mouse isolated islets, and murine MIN6 cells. We have identified a conserved, seven-residue nuclear localization signal (30LKKVMRR36) in the human enzyme. Substituting the residues KK31,32 and RR35,36 with AA led to a loss of its nuclear localization in transfected cells. Furthermore, our data indicates that SUMOylation of glucokinase modulates its nuclear import, while high glucose concentrations do not significantly alter the enzyme nuclear/cytosolic ratio. Thus, for the first time, we provide data in support of a nuclear import of glucokinase mediated by a redundant mechanism, involving a nuclear localization signal, and which is modulated by its SUMOylation. These findings add new knowledge to the functional role of glucokinase in the pancreatic beta-cell.

Epac1 (Exchange protein directly activated by cAMP 1) limits fluid loss from the circulation by tightening the endothelial barrier. We show here that Epac1−/− mice, but not Epac2−/− mice, have prolonged bleeding time, suggesting that Epac1 may limit fluid loss also by restraining bleeding. The Epac1−/− mice had deficient in vitro secondary hemostasis. Quantitative comprehensive proteomics analysis revealed that Epac1−/− mouse platelets (thrombocytes) had unbalanced expression of key components of the glycoprotein Ib-IX-V (GPIb-IX-V) complex, with decrease of GP1bβ and no change of GP1bα. This complex is critical for platelet adhesion under arterial shear conditions. Furthermore, Epac1−/− mice have reduced levels of plasma coagulation factors and fibrinogen, increased size of circulating platelets, increased megakaryocytes (the GP1bβ level was decreased also in Epac1−/− bone marrow) and higher abundance of reticulated platelets. Viscoelastic measurement of clotting function revealed Epac1−/− mice with a dysfunction in the clotting process, which corresponds to reduced plasma levels of coagulation factors like factor XIII and fibrinogen. We propose that the observed platelet phenotype is due to deficient Epac1 activity during megakaryopoiesis and thrombopoiesis, and that the defects in blood clotting for Epac1−/− is connected to secondary hemostasis.

PCB 153 is one of the most abundant PCB congeners detected in biological samples. It is a persistent compound that is still present in the environment despite the ban on production and use of PCBs in the late 1970s. It has strong tendencies to bioaccumulate and biomagnify in biota, and studies have suggested that it is an endocrine and metabolic disruptor. In order to study mechanisms of toxicity, we exposed Atlantic cod (Gadus morhua) to various doses of PCB 153 (0, 0.5, 2 and 8mg/kg body weight) for two weeks and examined the effects on expression of liver proteins using label-free quantitative proteomics. Label-free liquid chromatography-mass spectrometry analysis of the liver proteome resulted in the quantification of 1272 proteins, of which 78 proteins were differentially regulated in the PCB 153-treated dose groups compared to the control group. Functional enrichment analysis showed that pathways significantly affected are related to lipid metabolism, cytoskeletal remodeling, cell cycle and cell adhesion. Importantly, the main effects appear to be on lipid metabolism, with up-regulation of enzymes in the de novo fatty acid synthesis pathway, consistent with previous transcriptomics results. Increased plasma triglyceride levels were also observed in the PCB 153 treated fish, in agreement with the induction of the lipogenic genes and proteins. The results suggest that PCB 153 perturbs lipid metabolism in the Atlantic cod liver. Elevated levels of lipogenic enzymes and plasma triglycerides further suggest increased synthesis of fatty acids and triglycerides.

The exchange proteins directly activated by cAMP 1 and 2 (Epac1 and Epac2) are expressed in a cell specific manner in the liver, but their biological functions in this tissue are poorly understood. The current study was undertaken to begin to determine the potential roles of Epac1 and Epac2 in liver physiology and disease. Male C57BL/6J mice in which expression of Epac1 and/or Epac2 are deleted, were subjected to partial hepatectomy and the regenerating liver was analyzed with regard to lipid accumulation, cell replication and protein expression. In response to partial hepatectomy, deletion of Epac1 and/or Epac2 led to increased hepatocyte proliferation 36 h post surgery, and the transient steatosis observed in wild type mice was virtually absent in mice lacking both Epac1 and Epac2. The expression of the protein cytochrome P4504a14, which is implicated in hepatic steatosis and fibrosis, was substantially reduced upon deletion of Epac1/2, while a number of factors involved in lipid metabolism were significantly decreased. Moreover, the number of Küpffer cells was affected, and Epac2 expression was increased in the liver of wild type mice in response to partial hepatectomy, further supporting a role for these proteins in liver function. This study establishes hepatic phenotypic abnormalities in mice deleted for Epac1/2 for the first time, and introduces Epac1/2 as regulators of hepatocyte proliferation and lipid accumulation in the regenerative process.

Poly(L-lactide-co-ε-caprolactone) scaffolds were functionalised by 10 or 20 µg/mL of human demineralised dentine matrix. Release kinetics up to 21 days and their osteogenic potential on human bone marrow stromal cells after 7 and 21 days were studied. A total of 390 proteins were identified by mass spectrometry. Bone regeneration proteins showed initial burst of release. Human bone marrow stromal cells were cultured on scaffolds physisorbed with 20 µg/mL and cultured in basal medium (DDM group) or physisorbed and cultured in osteogenic medium or cultured on non-functionalised scaffolds in osteogenic medium. The human bone marrow stromal cells proliferated less in demineralised dentine matrix group and activated ERK/1/2 after both time points. Cells on DDM group showed highest expression of IL-6 and IL-8 at 7 days and expressed higher collagen type 1 alpha 2, SPP1 and bone morphogenetic protein-2 until 21 days. Extracellular protein revealed higher collagen type 1 and bone morphogenetic protein-2 at 21 days in demineralised dentine matrix group. Cells on DDM group showed signs of mineralisation. The functionalised scaffolds were able to stimulate osteogenic differentiation of human bone marrow stromal cells.

AimEpac1-/- mice, but not Epac2-/- mice have elevated baseline permeability to albumin. This study extends the investigations of how Epac-dependent pathways modulate transvascular exchange in response to the classical inflammatory agent histamine. It also evaluates the limitations of models of blood-to-tissue exchange in transgenic mice in DCE-MRI measurements.MethodsWe measured DCE-MRI signal intensity in masseter muscle of wt and Epac1-/- mice with established approaches from capillary physiology to determine how changes in blood flow and vascular permeability contribute to overall changes of microvascular flux. We used two tracers, the high molecular weight tracer (Gadomer-17, MW 17 kDa, apparent MW 30-35 kDa) is expected to be primarily limited by diffusion and therefore less dependent on changes in blood flow and the low molecular weight tracer (Dotarem (MW 0.56 kDa) whose transvascular exchange is determined by both blood flow and permeability. Paired experiments in each animal combined with analytical methods provided an internally consistent description of microvascular transport.ResultsEpac1-/- mice had elevated baseline permeability relative to wt control mice for Dotarem and Gadomer-17. In contrast to wt mice, Epac1-/- mice failed to increase transvascular permeability in response to histamine. Dotarem underestimated blood flow and vascular volume and Gadomer-17 has limited sensitivity in extravascular accumulation.ConclusionThe study suggests that the normal barrier loosening effect of histamine in venular microvessels do not function when the normal barrier tightening effect of Epac1 is already compromised. The study also demonstrated that the numerical analysis of DCE-MRI data with tracers of different molecular weight has significant limitations.

More than 40 years ago, the present standard induction therapy for acute myeloid leukemia (AML) was developed. This consists of the metabolic inhibitor cytarabine (AraC) and the cytostatic topoisomerase 2 inhibitor daunorubucin (DNR). In light of the high chance for relapse, as well as the large heterogeneity, novel therapies are needed to improve patient outcome. We have tested the anti-AML activity of 15 novel compounds based on the scaffolds pyrrolo[2,3-a]carbazole-3-carbaldehyde, pyrazolo[3,4-c]carbazole, pyrazolo[4,3-a]phenanthridine, or pyrrolo[2,3-g]indazole. The compounds were inhibitors of Pim kinases, but could also have inhibitory activity against other protein kinases. Ser/Thr kinases like the Pim kinases have been identified as potential drug targets for AML therapy. The compound VS-II-173 induced AML cell death with EC50 below 5 μmol/L, and was 10 times less potent against nonmalignant cells. It perturbed Pim-kinase–mediated AML cell signaling, such as attenuation of Stat5 or MDM2 phosphorylation, and synergized with DNR to induce AML cell death. VS-II-173 induced cell death also in patients with AML blasts, including blast carrying high-risk FLT3-ITD mutations. Mutation of nucleophosmin-1 was associated with good response to VS-II-173. In conclusion new scaffolds for potential AML drugs have been explored. The selective activity toward patient AML blasts and AML cell lines of the pyrazolo-analogue VS-II-173 make it a promising drug candidate to be further tested in preclinical animal models for AML.

Background: Multiple sclerosis (MS) is an autoimmune, neuroinflammatory disease, with an unclear etiology. How‑ ever, T cells play a central role in the pathogenesis by crossing the blood–brain‑barrier, leading to inflammation of the central nervous system and demyelination of the protective sheath surrounding the nerve fibers. MS has a complex inheritance pattern, and several studies indicate that gene interactions with environmental factors contribute to disease onset. Methods: In the current study, we evaluated T cell dysregulation at the protein level using electrospray liquid chro‑ matography–tandem mass spectrometry to get novel insights into immune‑cell processes in MS. We have analyzed the proteomic profiles of CD4+ and CD8+ T cells purified from whole blood from 13 newly diagnosed, treatment‑ naive female patients with relapsing–remitting MS and 14 age‑ and sex‑matched healthy controls. Results: An overall higher protein abundance was observed in both CD4+ and CD8+ T cells from MS patients when compared to healthy controls. The differentially expressed proteins were enriched for T‑cell specific activation path‑ ways, especially CTLA4 and CD28 signaling in CD4+ T cells. When selectively analyzing proteins expressed from the genes most proximal to > 200 non‑HLA MS susceptibility polymorphisms, we observed differential expression of eight proteins in T cells between MS patients and healthy controls, and there was a correlation between the genotype at three MS genetic risk loci and protein expressed from proximal genes. Conclusion: Our study provides evidence for proteomic differences in T cells from relapsing–remitting MS patients compared to healthy controls and also identifies dysregulation of proteins encoded from MS susceptibility genes. The study was funded by the South Eastern Norway Regional Health Authority (Grant No. 2017114), the Norwegian Research Council (Grant No. 240102), OsloMet – Oslo Metropolitan University, Biogen, Sanofi Genzyme and the Odd Fellow Society.