Maailmankuva:historia, teoria ja mahdollisuudet maantieteelle

Tiivistelmä. Maailmankuvaa, alun perin ’weltanschauung’ saksan kielestä, käytetään usein tutkimuksissa ja yleisessä kielessä moninaisiin tarkoituksiin. Tästä huolimatta siihen liittyvä tarkempi teoreettinen ja tutkimuksellinen pohdinta sekä määritteleminen jää usein huomattavan vajaaksi. Tämä vajaus asettaa termin omituiseen asemaan, jossa lukijoiden ja tutkijoiden oletetaan ymmärtävään sen merkitys ilman, että sitä koskaan heille suoraan avattaisiin. Maailmankuvaa on kuitenkin ajansaatossa tutkittu ja määritelty monilla eri tutkimusaloilla aina filosofiasta psykologiaan, ja onkin syytä tutkia ja pohtia tätä maantieteen näkökulmasta. Poikkitieteellisenä ajatuksena maailmankuvateoria lupaa käyttökelpoisuutta hyvinkin kimeerisen tutkimuskentän omaavalle maantieteelle, mikä on kuitenkin potentiaalinsa suhteen pitkälti hyödyntämätöntä, tai ainakin epäsäännönmukaista. Tavoitteenani tällä tutkielmalla onkin havainnollistaa maailmankuvaan liittyvää teoriaa ja historiaa sekä sen olemassa olevaa ja mahdollista potentiaalia maantieteen saralla. Nykyään maailmankuvan tutkimus on sovellettavissa erityisen hyvin erilaisten kulttuurien ja käsitysten kohtaamiseen, minkä vuoksi myös ihmismaantiede voi termin omaksumisesta laajempaan käyttöön hyötyä

Continuous Team Semantics

Peer reviewe

Continuous Team Semantics

We study logics with team semantics in computable metric spaces. We show how to define approximate versions of the usual independence/dependence atoms. For restricted classes of formulae, we show that we can assume w.l.o.g.~that teams are closed sets. This then allows us to import techniques from computable analysis to study the complexity of formula satisfaction and model checking

Only IL-1β release is inflammasome-dependent upon ultraviolet B irradiation although IL-18 is also secreted

Abstract DNA damage accumulates in aged postmitotic retinal pigment epithelium (RPE) cells, a phenomenon associated with the development of age-related macular degeneration. In this study, we have experimentally induced DNA damage by ultraviolet B (UVB) irradiation in interleukin-1α (IL-1α)-primed ARPE-19 cells and examined inflammasome-mediated signaling. To reveal the mechanisms of inflammasome activation, cells were additionally exposed to high levels of extracellular potassium chloride, n-acetyl-cysteine, or mitochondria-targeted antioxidant MitoTEMPO, prior to UVB irradiation. Levels of interleukin-18 (IL-18) and IL-1? mRNAs were detected with qRT-PCR and secreted amounts of IL-1?, IL-18, and caspase-1 were measured with ELISA. The role of nucleotide-binding domain and leucine-rich repeat pyrin containing protein 3 (NLRP3) in UVB-induced inflammasome activation was verified by using the NLRP3-specific siRNA. Reactive oxygen species (ROS) levels were measured immediately after UVB exposure using the cell-permeant 2?,7?-dichlorodihydrofluorescein diacetate (H2DCFDA) indicator, the levels of cyclobutane pyrimidine dimers were assayed by cell-based ELISA, and the extracellular levels of adenosine triphosphate (ATP) determined using a commercial bioluminescence assay. We found that pro-IL-18 was constitutively expressed by ARPE-19 cells, whereas the expression of pro-IL-1? was inducible by IL-1α priming. UVB induced the release of mature IL-18 and IL-1? but NLRP3 contributed only to the secretion of IL-1?. At the mechanistic level, the release of IL-1? was regulated by K+ efflux, whereas the secretion of IL-18 was dependent on ROS production. As well as K+ efflux, the cells released ATP following UVB exposure. Collectively, our data suggest that UVB clearly stimulates the secretion of mature IL-18 as a result of ROS induction, and this response is associated with DNA damage. Moreover, in human RPE cells, K+ efflux mediates the UVB-activated NLRP3 inflammasome signaling, leading to the processing of IL-1?.Peer reviewe

Influence of Hsp90 and HDAC Inhibition and Tubulin Acetylation on Perinuclear Protein Aggregation in Human Retinal Pigment Epithelial Cells

Retinal pigment epithelial (RPE) cells are continually exposed to oxidative stress that contributes to protein misfolding, aggregation and functional abnormalities during aging. The protein aggregates formed at the cell periphery are delivered along the microtubulus network by dynein-dependent retrograde trafficking to a juxtanuclear location. We demonstrate that Hsp90 inhibition by geldanamycin can effectively suppress proteasome inhibitor, MG-132-induced protein aggregation in a way that is independent of HDAC inhibition or the tubulin acetylation levels in ARPE-19 cells. However, the tubulin acetylation and polymerization state affects the localization of the proteasome-inhibitor-induced aggregation. These findings open new perspectives for understanding the pathogenesis of protein aggregation in retinal cells and can be useful for the development of therapeutic treatments to prevent retinal cell deterioration

Altered contractility in mutation-specific hypertrophic cardiomyopathy : A mechano-energetic in silico study with pharmacological insights

Introduction: Mavacamten (MAVA), Blebbistatin (BLEB), and Omecamtiv mecarbil (OM) are promising drugs directly targeting sarcomere dynamics, with demonstrated efficacy against hypertrophic cardiomyopathy (HCM) in (pre)clinical trials. However, the molecular mechanism affecting cardiac contractility regulation, and the diseased cell mechano-energetics are not fully understood yet.Methods: We present a new metabolite-sensitive computational model of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) electromechanics to investigate the pathology of R403Q HCM mutation and the effect of MAVA, BLEB, and OM on the cell mechano-energetics.Results: We offer a mechano-energetic HCM calibration of the model, capturing the prolonged contractile relaxation due to R403Q mutation (∼33%), without assuming any further modifications such as an additional Ca2+ flux to the thin filaments. The HCM model variant correctly predicts the negligible alteration in ATPase activity in R403Q HCM condition compared to normal hiPSC-CMs. The simulated inotropic effects of MAVA, OM, and BLEB, along with the ATPase activities in the control and HCM model variant agree with in vitro results from different labs. The proposed model recapitulates the tension-Ca2+ relationship and action potential duration change due to 1 µM OM and 5 µM BLEB, consistently with in vitro data. Finally, our model replicates the experimental dose-dependent effect of OM and BLEB on the normalized isometric tension.Conclusion: This work is a step toward deep-phenotyping the mutation-specific HCM pathophysiology, manifesting as altered interfilament kinetics. Accordingly, the modeling efforts lend original insights into the MAVA, BLEB, and OM contributions to a new interfilament balance resulting in a cardioprotective effect.publishedVersionPeer reviewe

UV-B-Induced Inflammasome Activation Can Be Prevented by Cis-Urocanic Acid in Human Corneal Epithelial Cells

PURPOSE. The cornea is continually exposed to highly energetic solar UV-B (280-320 nm). Our aim was to investigate whether UV-B triggers the activation of NLRP3 inflammasomes and the production of IL-1 beta and/or IL-18 in human corneal epithelial (HCE) cells. Additionally, we studied the capability of cis-urocanic acid (cis-UCA) to prevent inflammasome activation or alleviate inflammation through other signaling pathways. METHODS. HCE-2 cell line and primary HCE cells were primed using lipopolysaccharide or TNF-alpha. Thereafter, cells were exposed to UV-B before or after the addition of cis-UCA or caspase-1 inhibitor. Caspase-1 activity was measured from cell lysates by an enzymatic assay. IL-1 beta, IL-18, IL-6, IL-8, and NLRP3 levels were detected using the ELISA method from cell culture media. Additionally, intracellular NLRP3 levels were determined by the Western blot technique, and cytotoxicity was measured by the LDH assay. RESULTS. UV-B exposure significantly increased caspase-1 activity in TNF-alpha-primed HCE cells. This result was consistent with the concurrently induced IL-1 beta secretion. Both caspase-1 activity and release of IL-1 beta were reduced by cis-UCA. Additionally, UV-B stimulated the caspase-1-independent production of IL-18, an effect also reduced by cis-UCA. Cis-UCA decreased the release of IL-6, IL-8, and LDH in a time-dependent manner when administered to HCE-2 cells after UV-B exposure. CONCLUSIONS. Our findings demonstrate that UV-B activates inflammasomes in HCE cells. Cis-UCA can prevent the secretion of IL-1 beta and IL-18 and therapeutically reduces the levels of IL-6, IL-8, and LDH in UV-B-stressed HCE cells.Peer reviewe