Korkorakennemallit ja duraatioanalyysi luottoriskittömien joukkovelkakirjojen korkoriskin arvioinnissa

Only abstract. Paper copies of master’s theses are listed in the Helka database (http://www.helsinki.fi/helka). Electronic copies of master’s theses are either available as open access or only on thesis terminals in the Helsinki University Library.Vain tiivistelmä. Sidottujen gradujen saatavuuden voit tarkistaa Helka-tietokannasta (http://www.helsinki.fi/helka). Digitaaliset gradut voivat olla luettavissa avoimesti verkossa tai rajoitetusti kirjaston opinnäytekioskeilla.Endast sammandrag. Inbundna avhandlingar kan sökas i Helka-databasen (http://www.helsinki.fi/helka). Elektroniska kopior av avhandlingar finns antingen öppet på nätet eller endast tillgängliga i bibliotekets avhandlingsterminaler.Pro gradu -työssäni tehtiin katsaus korkojen aikarakennetta ja luottoriskittömien joukkovelkakirjojen korkoriskin arviointia käsittelevään kirjallisuuteen. Tavoitteena oli tarkastella vaihtoehtoisia lähestymistapoja arvioida luottoriskittömien joukkovelkakirjojen korkoriskiä ja arvioida niiden hyviä ja huonoja puolia sekä teoreettisesti että empiiristen tulosten valossa. Tutkielman lähtökohtana oli, ettei kysymykseen parhaasta korkoriskin arviointimenetelmästä ole yksiselitteistä vastausta. Työssä käsitellään perinteisiä korkojen aikarakennetta selittäviä teorioita, jatkuva-aikaisia korkorakennemalleja sekä niihin liittyviä korkojen dynamiikkaa ohjaavia stokastisia prosesseja. Korkorakennemallien pohjalta johdettuja duraatiomalleja käsitellään sekä diskreetin että jatkuvan ajan kontekstissa. Duraatio on keskeisin joukkovelkakirjojen korkoriskin mittari. Sen avulla voidaan arvioida joukkovelkakirjan hinnan herkkyyttä koron muutoksille. Perinteinen ja käytetyin lähestymistapa korkoriskin arvioinnissa on ollut diskreetin ajan mallien käyttäminen. Niissä korkojen dynamiikkaa koskevat oletukset ovat yksinkertaisia ja rajoittavia, mutta toisaalta ne ovat hyvin helppokäyttöisiä. Jatkuva-aikaiset korkorakennemallit ja niiden pohjalta johdetut duraatiomallit tarjoavat teoreettisesti kehittyneemmän vaihtoehdon arvioida korkoriskiä. Niiden huono puoli on mallien monimutkaisuus ja siitä johtuvat ongelmat. Empiiristen tutkimusten perusteella ei voida tehdä yksiselitteistä johtopäätöstä parhaasta korkoriskin arviointimenetelmästä. Käytetyimmät diskreetin ajan duraatiomallit, Macaulay-duraatio ja modifioitu duraatio ovat teoreettisista puutteistaan huolimatta tuottaneet pääosin yhtä hyviä tuloksia kuin kehittyneemmät yhden faktorin käyttöön perustuvat jatkuva-aikaiset duraatiomallit. Toisaalta osa tutkimuksista antaa viitteitä siitä, että jatkuva-aikaisissa korkorakennemalleissa ja niiden pohjalta johdetuissa duraatiomalleissa käytettävien faktoreiden lukumäärän lisääminen parantaisi mallien kykyä arvioida korkoriskiä. Faktoreiden lukumäärän lisääminen kasvattaa tosin mallien monimutkaisuutta ja heikentää niiden käytettävyyttä käytännön korkoriskin arvioinnissa. Tärkeimmät lähteet: Murto, Risto (1992): Korkorakennemallien käyttö korkoriskin arvioinnissa ja hallinnassa. ETLAn keskusteluaiheita, No. 411. Ilmanen, Antti (1989): Duraatioanalyysin käyttö joukkovelkakirjan korkoriskin arvioinnissa ja hallinnassa. Suomen Pankin keskustelualoitteita 18/89. Bierwag, Gerald O. (1987): Duration Analysis. Managing Interest Rate Risk. Cambridge, Massachussetts. Vasicek, Oldrich (1977): An Equilibrium Characterization of the Term Structure. Journal of Financial Economics, Vol. 5, 177-188. Longstaff, Francis A. – Schwartz, Eduardo S. (1992): Interest Rate Volatility and the Term Structure: A Two-Factor General Equilibrium Model. The Journal of Finance, Vol. 47, No. 4, 1259-1282

Genome-Wide Prediction and Validation of Peptides That Bind Human Prosurvival Bcl-2 Proteins

Programmed cell death is regulated by interactions between pro-apoptotic and prosurvival members of the Bcl-2 family. Pro-apoptotic family members contain a weakly conserved BH3 motif that can adopt an alpha-helical structure and bind to a groove on prosurvival partners Bcl-x[subscript L], Bcl-w, Bcl-2, Mcl-1 and Bfl-1. Peptides corresponding to roughly 13 reported BH3 motifs have been verified to bind in this manner. Due to their short lengths and low sequence conservation, BH3 motifs are not detected using standard sequence-based bioinformatics approaches. Thus, it is possible that many additional proteins harbor BH3-like sequences that can mediate interactions with the Bcl-2 family. In this work, we used structure-based and data-based Bcl-2 interaction models to find new BH3-like peptides in the human proteome. We used peptide SPOT arrays to test candidate peptides for interaction with one or more of the prosurvival proteins Bcl-x[subscript L], Bcl-w, Bcl-2, Mcl-1 and Bfl-1. For the 36 most promising array candidates, we quantified binding to all five human receptors using direct and competition binding assays in solution. All 36 peptides showed evidence of interaction with at least one prosurvival protein, and 22 peptides bound at least one prosurvival protein with a dissociation constant between 1 and 500 nM; many peptides had specificity profiles not previously observed. We also screened the full-length parent proteins of a subset of array-tested peptides for binding to Bcl-x[subscript L] and Mcl-1. Finally, we used the peptide binding data, in conjunction with previously reported interactions, to assess the affinity and specificity prediction performance of different models.National Institutes of Health (U.S.) (Award GM084181)National Science Foundation (U.S.) (Grant 0821391)American Cancer Society (Postdoctoral Fellowship PF-12-155-01-DMC

Transcriptional networks controlling the cell cycle.

In this work, we map the transcriptional targets of 107 previously identified Drosophila genes whose loss caused the strongest cell-cycle phenotypes in a genome-wide RNA interference screen and mine the resulting data computationally. Besides confirming existing knowledge, the analysis revealed several regulatory systems, among which were two highly-specific and interconnected feedback circuits, one between the ribosome and the proteasome that controls overall protein homeostasis, and the other between the ribosome and Myc/Max that regulates the protein synthesis capacity of cells. We also identified a set of genes that alter the timing of mitosis without affecting gene expression, indicating that the cyclic transcriptional program that produces the components required for cell division can be partially uncoupled from the cell division process itself. These genes all have a function in a pathway that regulates the phosphorylation state of Cdk1. We provide evidence showing that this pathway is involved in regulation of cell size, indicating that a Cdk1-regulated cell size checkpoint exists in metazoans

CRISPR/Cas9 screening using unique molecular identifiers

Loss-of-function screening by CRISPR/Cas9 gene knockout with pooled, lentiviral guide libraries is a widely applicable method for systematic identification of genes contributing to diverse cellular phenotypes. Here, Random Sequence Labels (RSLs) are incorporated into the guide library, which act as unique molecular identifiers (UMIs) to allow massively parallel lineage tracing and lineage dropout screening. RSLs greatly improve the reproducibility of results by increasing both the precision and the accuracy of screens. They reduce the number of cells needed to reach a set statistical power, or allow a more robust screen using the same number of cells.Peer reviewe

Widespread Regulation of Translation by Elongation Pausing in Heat Shock

Global repression of protein synthesis is a hallmark of the cellular stress response and has been attributed primarily to inhibition of translation initiation, although this mechanism may not always explain the full extent of repression. Here, using ribosome footprinting, we show that 2 hr of severe heat stress triggers global pausing of translation elongation at around codon 65 on most mRNAs in both mouse and human cells. The genome-wide nature of the phenomenon, its location, and features of protein N termini suggested the involvement of ribosome-associated chaperones. After severe heat shock, Hsp70’s interactions with the translational machinery were markedly altered and its association with ribosomes was reduced. Pretreatment with mild heat stress or overexpression of Hsp70 protected cells from heat shock-induced elongation pausing, while inhibition of Hsp70 activity triggered elongation pausing without heat stress. Our findings suggest that regulation of translation elongation in general, and by chaperones in particular, represents a major component of cellular stress responses.National Institute of General Medical Sciences (U.S.) (NIGMS fellowship number F32GM095060)Machiah FoundationEuropean Molecular Biology Organization (EMBO long-term fellowship)Weitzmann Institute of Science (National Postdoctoral Award Program for Advancing Women in Science

Stress of conscience in healthcare in turbulent times : A longitudinal study

Background: Healthcare workers frequently face ethically demanding situations in their work, potentially leading to stress of conscience. Long-term work intensification (more and more effort demanded year after year), organizational change and COVID-19 may be risk factors concerning stress of conscience. Aims: The main aim was to investigate the relationship between long-term work intensification and stress of conscience among the personnel in a healthcare organization. Organizational change management was considered a mediator and COVID-19-related work stress a moderator in the association between work intensification and stress of conscience. Research design, participants and context: A total of 211 healthcare district employees participated in a longitudinal survey using questionnaires collected in 2019 (major organizational change in the planning stage) and 2021 (organizational change completed). Ethical considerations: The study was implemented according to the guidelines of the Finnish National Board on Research Integrity. The Finnish instructions were that no review by an ethics committee was necessary because participation was voluntary, informed consent was requested, participants were assured that they were free to withdraw from the longitudinal study at any time and no health data were collected. Findings: Long-term work intensification was associated with more severe stress of conscience. Long-term work intensification was partially mediated through change management to stress of conscience. High COVID-19 stress strengthened the association between long-term work intensification and stress of conscience. Conclusions: Long-term work intensification must be addressed to reduce stress of conscience in healthcare, otherwise the healthcare system will be vulnerable to changes and crisis. Extra resources for personnel and management should be allocated because of work intensification during organizational change and health crises like the COVID-19 pandemic to alleviate stress of conscience.Peer reviewe

Genome-wide analysis of ETS-family DNA-binding in vitro and in vivo

Peer reviewe

Genome-wide screen of cell-cycle regulators in normal and tumor cells identifies a differential response to nucleosome depletion

PMID: 27929715Peer reviewe

Development of actionable targets of multi-kinase inhibitors (AToMI) screening platform to dissect kinase targets of staurosporines in glioblastoma cells

Therapeutic resistance to kinase inhibitors constitutes a major unresolved clinical challenge in cancer and especially in glioblastoma. Multi-kinase inhibitors may be used for simultaneous targeting of multiple target kinases and thereby potentially overcome kinase inhibitor resistance. However, in most cases the identification of the target kinases mediating therapeutic effects of multi-kinase inhibitors has been challenging. To tackle this important problem, we developed an actionable targets of multi-kinase inhibitors (AToMI) strategy and used it for characterization of glioblastoma target kinases of staurosporine derivatives displaying synergy with protein phosphatase 2A (PP2A) reactivation. AToMI consists of interchangeable modules combining drug-kinase interaction assay, siRNA high-throughput screening, bioinformatics analysis, and validation screening with more selective target kinase inhibitors. As a result, AToMI analysis revealed AKT and mitochondrial pyruvate dehydrogenase kinase PDK1 and PDK4 as kinase targets of staurosporine derivatives UCN-01, CEP-701, and K252a that synergized with PP2A activation across heterogeneous glioblastoma cells. Based on these proof-of-principle results, we propose that the application and further development of AToMI for clinically applicable multi-kinase inhibitors could provide significant benefits in overcoming the challenge of lack of knowledge of the target specificity of multi-kinase inhibitors.Peer reviewe