Aurora lucis evangelicae ante saeculum XII in Finlandia fuit exorta

Invocatio: I.N.J.C.

The spindle assembly checkpoint as a drug target - Novel small-molecule inhibitors of Aurora kinases

Cell division (mitosis) is a fundamental process in the life cycle of a cell. Equal distribution of chromosomes between the daughter cells is essential for the viability and well-being of an organism: loss of fidelity of cell division is a contributing factor in human cancer and also gives rise to miscarriages and genetic birth defects. For maintaining the proper chromosome number, a cell must carefully monitor cell division in order to detect and correct mistakes before they are translated into chromosomal imbalance. For this purpose an evolutionarily conserved mechanism termed the spindle assembly checkpoint (SAC) has evolved. The SAC comprises a complex network of proteins that relay and amplify mitosis-regulating signals created by assemblages called kinetochores (KTs). Importantly, minor defects in SAC signaling can cause loss or gain of individual chromosomes (aneuploidy) which promotes tumorigenesis while complete failure of SAC results in cell death. The latter event has raised interest in discovery of low molecular weight (LMW) compounds targeting the SAC that could be developed into new anti-cancer therapeutics. In this study, we performed a cell-based, phenotypic high-throughput screen (HTS) to identify novel LMW compounds that inhibit SAC function and result in loss of cancer cell viability. Altogether, we screened 65 000 compounds and identified eight that forced the cells prematurely out of mitosis. The flavonoids fisetin and eupatorin, as well as the synthetic compounds termed SACi2 and SACi4, were characterized in more detail utilizing versatile cell-based and biochemical assays. To identify the molecular targets of these SAC-suppressing compounds, we investigated the conditions in which SAC activity became abrogated. Eupatorin, SACi2 and SACi4 preferentially abolished the tensionsensitive arm of the SAC, whereas fisetin lowered also the SAC activity evoked by lack of attachments between microtubules (MTs) and KTs. Consistent with the abrogation of SAC in response to low tension, our data indicate that all four compounds inhibited the activity of Aurora B kinase. This essential mitotic protein is required for correction of erratic MT-KT attachments, normal SAC signaling and execution of cytokinesis. Furthermore, eupatorin, SACi2 and SACi4 also inhibited Aurora A kinase that controls the centrosome maturation and separation and formation of the mitotic spindle apparatus. In line with the established profound mitotic roles of Aurora kinases, these small compounds perturbed SAC function, caused spindle abnormalities, such as multi- and monopolarity and fragmentation of centrosomes, and resulted in polyploidy due to defects in cytokinesis. Moreover, the compounds dramatically reduced viability of cancer cells. Taken together, using a cell-based HTS we were able to identify new LMW compounds targeting the SAC. We demonstrated for the first time a novel function for flavonoids as cellular inhibitors of Aurora kinases. Collectively, our data support the concept that loss of mitotic fidelity due to a non-functional SAC can reduce the viability of cancer cells, a phenomenon that may possess therapeutic value and fuel development of new anti-cancer drugs.

Mitotic regulation by Polo-like kinase 1 and the Chromosomal Passenger Complex

During mitosis, the duplicated genome must be accurately divided between two daughter cells. Polo-like kinase 1 (Plk1) and Aurora B kinase, together with its binding partners Incenp, Survivin and Borealin (chromosomal passenger complex, CPC), have key roles in coordinating mitotic events. The accuracy of cell division is safeguarded by a signaling cascade termed the mitotic spindle checkpoint (SC), which ensures that chromosomes are not physically separated before correct bipolar attachments have been formed between kinetochores and spindle microtubules (MT). An inhibitory “wait anaphase” signal, which delays chromosome separation (anaphase onset), is created at individual kinetochores and broadcasted throughout the cell in response to lack of kinetochore-microtubule (kMT) attachment or proper interkinetochore tension. It is believed that the fast turnover of SC molecules at kinetochores contributes to the cell’s ability to produce this signal and enables rapid responses to changing cellular conditions. Kinetochores that lack MT attachment and tension express a certain phosphoepitope called the 3F3/2 phosphoepitope, which has been linked to SC signaling. In the experimental part, we investigated the regulation of the 3F3/2 phosphoepitope, analyzed whether CPC molecules turn over at centromeres, and dissected the mitotic roles of the CPC using a microinjection technique that allowed precise temporal control over its function. We found that the kinetochore 3F3/2 phosphoepitope is created by Plk1, and that CPC proteins exhibit constant exchange at centromeres. Moreover, we found that CPC function is necessary in the regulation of chromatid movements and spindle morphology in anaphase. In summary, we identified new functions of key mitotic regulators Plk1 and CPC, and provided insighs into the coordination of mitotic events.

Index fossilium analysibus chemicis examinatorum

Dedicatio: Zacharias Forsman [ruots. pr.], Eva Aurora Forsman s. Estlander [ruots. pr.].

Läran om den absoluta friheten vid sin öfvergång till ändlighet i viljan

Dedicatio: Zacharias Forsman, Eva Aurora Forsman, f. Estlander.

Ajankohtaisesti evoluutioteoriasta

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Äitiys : kahle ja voimavara

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Tarkastusten turvallinen ja taloudellinen optimointi kattilalaitoksessa

Vuoden 1999 muutos kansallisessa painelaitelainsäädännössä mahdollistaa perinteisten määräaikaistarkastusten korvaamisen aiempaa joustavimmilla tavoilla. Tarkastusresurssit voidaan uuden mallin mukaisesti kohdentaa laitteisiin olemassa olevan, todellisen riskin perusteella, joka osoitetaan asianmukaisin arviointimenettelyin. Nykyiset riskianalyysit ovat osoittautuneet tähän tarkoitukseen liian raskaiksi ja työläiksi. Tässä työssä on kehitetty nykyisten arviointimenetelmien pohjalta näitä kevyempi, riskiperusteinen analyysimalli, jota on testattu kattilalaitoksen riskikohteiden arvioinnissa. Arviointimenettely on rakennettu ensisijaisesti palvelemaan painelaitteiden kunnonvalvontajärjestelmään sisältyvien tarkastusten määrittelyä, mutta se soveltuu yhtälailla perinteisen tarkastustoiminnan rinnalle. Tällöin vältytään päällekkäisiltä tarkastuksilta ja voidaan hyödyntää lainsäädännön suomaa mahdollisuutta tarkastus-aikavälien pidentämiseen sekä säästetään kustannuksissa. Aiempaan nähden, kohteen potentiaaliset riskit voidaan esittää kehitetyllä riskianalyysimallilla yhteismitallisina, jolloin niiden keskinäinen vertailu ja päätöksenteko ovat helpompia.

Arvoisensa Darwinin juhlakirja

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Functional characterization of proteins required for mitotic progression and the spindle assembly checkpoint

During mitotic cell division, the genetic material packed into chromosomes is divided equally between two daughter cells. Before the separation of the two copies of a chromosome (sister chromatids), each chromosome has to be properly connected with microtubules of the mitotic spindle apparatus and aligned to the centre of the cell. The spindle assembly checkpoint (SAC) monitors connections between microtubules and chromosomes as well as tension applied across the centromere. Microtubules connect to a chromosome via kinetochores, which are proteinaceous organelles assembled onto the centromeric region of the sister chromatids. Improper kinetochore-microtubule attachments activate the SAC and block chromosome segregation until errors are corrected and all chromosomes are connected to the mitotic spindle in a bipolar manner. The purpose of this surveillance mechanism is to prevent loss or gain of chromosomes in daughter cells that according to current understanding contributes to cancer formation. Numerous proteins participate in the regulation of mitotic progression. In this thesis, the mitotic tasks of three kinetochore proteins, Shugoshin 1 (Sgo1), INCENP, and p38 MAP kinase (p38 MAPK), were investigated. Sgo1 is a protector of centromeric cohesion. It is also described in the tension-sensing mechanism of the SAC and in the regulation of kinetochore-microtubule connections. Our results revealed a central role for Sgo1 in a novel branch of kinetochore assembly. INCENP constitutes part of the chromosomal passenger complex (CPC). The other members of the core complex are the Aurora B kinase, Survivin and Borealin. CPC is an important regulatory element of cell division having several roles at various stages of mitosis. Our results indicated that INCENP and Aurora B are highly dynamic proteins at the mitotic centromeres and suggested a new role for CPC in regulation of chromosome movements and spindle structure during late mitosis. The p38 MAPK has been implicated in G1 and G2 checkpoints during the cell cycle. However, its role in mitotic progression and control of SAC signaling has been controversial. In this thesis, we discovered a novel function for p38γ MAPK in chromosome orientation and spindle structure as well as in promotion of viability of mitotic cells.

De harmonia mundi totius cantica tria

Francisco Giorgio tai Franciscus Georgius Venetus (1460–1540) oli fransiskaanijärjestöön kuulunut kabbalisti, juutalaisen salaisen opin tutkija. Hän oli myös mukana Pico della Mirandolan, paavin pannaan julistaman renessanssifilosofin, uskontoa, mystiikkaa ja tiedettä yhdistelevässä filosofipiirissä. Giorgion teokset joutivat pian ilmestymisensä jälkeen kiellettyjen kirjojen luetteloon maininnalla, että ne voitiin antaa käyttöön vasta vaarallisten kohtien peittämisen jälkeen. Erityisen voimakkaasti Francesco Giorgiota, muiden uskonnollisten mystikkojen ohella, kritikoi Marin Mersenne (1588–1648). Kirjan alussa, erillisellä lehdellä on käsinkirjoitettu kuvaus teoksen harvinaisuudesta ja vastaanotosta: "Au sentiment de M:r de la Croze, ce livre de Venetus est rare et fort recherché. Le P. Mersenne l'a refuté dans son Commantaire sur les premiers chapitres de la Genese comme même le titre de son Commentaire le marque...". Berliinin Institut für Judaistik'sta saadun tiedon mukaan Kansalliskirjaston kappale olisi ainoa, tunnettu, sensuroimaton kappale, jossa siis on myös nähtävillä teokseen sisältyvät, kielletyt kabbalistiset kohdat.

Uusi Kristus ja hänen kirkkonsa

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