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Children’s phonological development has been reported to have both universal and language-specific features. At 3;6, phonological skills are still developing strongly, and children are in the period of systematic phonological development. In Finnish, phonological development is well studied in the early phases, but less is known about children’s phonological skills at 3;6. The phonological skills have been noted to develop in conjunction with lexical skills in early childhood. Auditory word recognition may also be associated with phonological development. Furthermore, some evidence shows connections between phonological and pre-reading skills, at least at the age when reading instruction starts. However, little is known about how these skills are associated with children acquiring Finnish at the age when all the skills are developing concurrently. The current dissertation investigates Finnish-speaking children’s phonological skills at 3;6 (n=67) and the associations with early expressive lexicon size and concurrent lexical skill, auditory word recognition in babble noise, and pre-reading skills. The results show that Finnish-speaking children at 3;6 master the production of all vowels and on average 12/13 consonants. Some challenges were found in the pronunciation of consonant clusters, especially word-initial clusters. Phonological skills correlated significantly with lexical, auditory word recognition, and pre-reading skills. Early expressive lexicon size at 2;0 predicted over 20% of the variation in phonological skills one and a half years later whereas concurrent lexical ability explained only 10%. In the auditory word recognition task, speech sounds were concealed differently based on their acoustic features, as reported in previous studies. Children tended to have difficulties recognizing the phoneme /r/, which was missing from their phoneme inventory, confusing it with /l/, which was /r/’s typical substitution. Good listening conditions in children’s, Tiivistelmä Lapsen fonologisessa kehityksessä on havaittu sekä universaaleja että kielikohtaisia piirteitä. Kolmen ja puolen vuoden iässä lapset ovat fonologisessa kehityksessään systemaattisen kehityksen kaudella, jolloin ympäröivän kielen äänteiden ja niiden yhdistelyn omaksumisprosessi on vielä kesken. Suomea omaksuvien lasten fonologinen kehitys on kartoitettu melko tarkasti varhaisvaiheissa, mutta leikki-ikäisten lasten äänteellinen kehitys tunnetaan heikommin. Lasten fonologiset taidot kasvavat rinnan sanastotaitojen kanssa. Myös kuulonvarainen erottelu ollee yhteydessä fonologisiin taitoihin ja viitteitä fonologian ja lukivalmiustaitojen yhteyksistä on havaittu erityisesti riskilapsilla. Suomea omaksuvien lasten osalta taitojen välisiä yhteyksiä ei kuitenkaan ole juurikaan tutkittu. Tämä väitöskirjatutkimus keskittyy suomea omaksuvien lasten (n=67) fonologisiin taitoihin 3;6 iässä ja kartoittaa niiden mahdollista yhteyttä sanastoon, kuulonvaraiseen erotteluun melussa ja lukivalmiustaitoihin. Havaittiin, että 3;6 iässä lapset hallitsivat jo kaikki suomen vokaalit ja keskimäärin 12 13:sta konsonantista. Lapsilla oli edelleen haasteita erityisesti sananalkuisien konsonanttiyhtymien tuotossa. Fonologiset taidot olivat tilastollisesti merkitsevässä yhteydessä sanastotaitoihin, kuulonvaraiseen erotteluun ja lukivalmiustaitoihin. Varhainen ilmaistu sanasto kaksivuotiaana ennusti yli 20 % fonologisista taidoista puoltatoista vuotta myöhemmin kun taas samanikäisenä arvioitu sanasto selitti 10% variaatiosta. Kuuloerottelutehtävässä äänteiden peittyminen meluun vaihteli äänteiden akustisten ominaisuuksien mukaan, kuten aiemmissa tutkimuksissakin on havaittu. Lapsilla oli haasteita erotella kuulonvaraisesti myöhään kehittyvää /r/-äännettä ja he sekoittivat sen usein /r/:lle tyypilliseen korvausäänteiseen /l/:ään. Hyvien kuunteluolosuhteiden luominen lasten päivittäisiin ääniympäristöihin saattaa tukea myös fonologian kehitystä. Lapset alkavat oppia kirjainten nimiä jo fo

The EU energy and climate policy revolves around enhancing energy security and affordability, while reducing the environmental impacts of energy use. The European energy transition has been at the centre of debate following the post-pandemic surge in power prices in 2021 and the energy crisis following the 2022 Russia-Ukraine war. Understanding the extent to which electricity prices depend on fossil fuel prices (specifically natural gas) is key to guiding the future of energy policy in Europe. To this end, we quantify the role of fossil-fuelled vs. low-carbon electricity generation in setting wholesale electricity prices in each EU-27 country plus Great Britain (GB) and Norway during 2015-2021. We apply econometric analysis and use sub/hourly power system data to estimate the marginal share of each electricity generation type. The results show that fossil fuel-based power plants set electricity prices in Europe at approximately 58% of the time (natural gas 39%) while generating only 34% of electricity (natural gas 18%) a year. The energy transition has made natural gas the main electricity price setter in Europe, with gas determining electricity prices for more than 80% of the hours in 2021 in several countries such as Belgium, GB, Greece, Italy, and the Netherlands. Hence, Europe’s electricity markets are highly exposed to the geopolitical risk of gas supply and natural gas price volatility, and the economic risk of currency exchange.

Background noise challenges auditory recognition of speech and may reveal the underlying deficits in auditory word recognition skills. Previous studies have reported an association between children’s auditory skills and various linguistic skills, including phonology, although in some languages only. However, language-specific features influence these connections. This study describes the associations between auditory word recognition ability and phonological skills in a representative group of 3;6-year-old children in less studied language, Finnish (N = 65). Auditory recognition was assessed using a closed-set word recognition task presented in multi-talker babble noise (+13 dB) and the phonological skills using Finnish Phonology Test. A significant, moderate correlation was found between Finnish-speaking children’s auditory word recognition and phonological skills. The late-developing phoneme /r/ challenged word recognition. The sibilant /s/ was noted to be the most noise resistant consonant, and the phoneme pair /r/ and /l/ created the most mutual confusion. The accuracy of phonological representations may be a moderating factor for both auditory recognition and phonological skills. Children with strong phonological skills may recognize spoken words more accurately in noisy everyday situations than children with weaker phonological skills. This should be taken into consideration in children’s daily environments, such as daycare centers and preschools.

Previous studies of Finnish children’s phonological development focus mainly on children under 2;0. Earlier findings have suggested that phonological and lexical development are strongly associated at an early age. However, less is known about the longitudinal association. This study describes the phonological skills of Finnish-speaking children at 3;6 and compares them with early lexicon size at 2;0 and lexical ability at 3;6 (N = 67). The children’s phonological development was measured using The Finnish Phonology Test. Lexical development was evaluated using the Finnish, long-form version of the Communicative Development Inventory at 2;0 and the Boston naming test at 3;6 At 3;6, all children mastered the vowels and diphthongs fully, and most of the children also mastered the consonants, with the exception of the phonemes/d/and/r/. Phonotactic skills had also been acquired well at this group level, although the word-medial and, especially, word-initial consonant clusters were still challenging. The percentage of phonemes correct was 95. Both paradigmatic and phonotactic skills at 3;6 were significantly associated with lexicon size at 2;0. In addition phonotactic skills correlated with naming ability at 3;6. Lexical development at 2;0 explained 21% of the variance in the phonological development at 3;6, whereas, the explaining value of simultaneous lexical skill was limited (9%). Present findings propose that associations between lexical and phonological skills weaken as phonological skills become more honed.

Colorectal cancer (CRC) is the fourth cause of death from cancer worldwide mainly due to the high incidence of drug-resistance. During a screen for new actionable targets in drug-resistant tumours we recently identified p65BTK – a novel oncogenic isoform of Bruton's tyrosine kinase. Studying three different cohorts of patients here we show that p65BTK expression correlates with histotype and cancer progression. Using drug-resistant TP53-null colon cancer cells as a model we demonstrated that p65BTK silencing or chemical inhibition overcame the 5-fluorouracil resistance of CRC cell lines and patient-derived organoids and significantly reduced the growth of xenografted tumours. Mechanistically, we show that blocking p65BTK in drug-resistant cells abolished a 5-FU-elicited TGFB1 protective response and triggered E2F-dependent apoptosis. Taken together, our data demonstrated that targeting p65BTK restores the apoptotic response to chemotherapy of drug-resistant CRCs and gives a proof-of-concept for suggesting the use of BTK inhibitors in combination with 5-FU as a novel therapeutic approach in CRC patients. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

The PLZF transcription factor is essential for osteogenic differentiation of hMSCs; however, its regulation and molecular function during this process is not fully understood. Here, we revealed that the ZBTB16 locus encoding PLZF, is repressed by Polycomb (PcG) and H3K27me3 in naive hMSCs. At the pre-osteoblast stage of differentiation, the locus lost PcG binding and H3K27me3, gained JMJD3 recruitment, and H3K27ac resulting in high expression of PLZF. Subsequently, PLZF was recruited to osteogenic enhancers, influencing H3K27 acetylation and expression of nearby genes important for osteogenic function. Furthermore, we identified a latent enhancer within the ZBTB16/PLZF locus itself that became active, gained PLZF, p300 and Mediator binding and looped to the promoter of the nicotinamide N-methyltransferase (NNMT) gene. The increased expression of NNMT correlated with a decline in SAM levels, which is dependent on PLZF and is required for osteogenic differentiation

The use of compounds is described which are capable of functionally blocking at least one of the genes chosen from the group composed of EphA1, EphA2, EphA8, EphB2, CSF1R, VEGFR2, RAMP2, RAMP3, CLRN1, MAPK4, PIK3C2A, PIK3CG, GSK3alpha, GSK3beta, IRAK3, DAPK1, JAK1, PIM1, TRB3, BTG1, LATS1, LIMK2, MYLK, PAK1, PAK2, CDC2, BTK, PNRC2, NCOA4, NR2C1, TPR, RBBP8, TRPC7, FXYD1, ERN1, PRSS16, RPS3, CCL23 and SERPINE1, for the manufacture of a medicament destined to diminish the resistance to chemotherapeutic drugs in the therapeutic treatment of epithelial tumor pathologies. Also described is a method for the determination of the drug resistance in tumor cells, as well as a method for the identification of tumor stem cells

The use of compounds is described which are capable of functionally blocking at least one of the genes chosen from the group composed of EphA1, EphA2, EphA8, EphB2, CSF1R, VEGFR2, RAMP2, RAMP3, CLRN1, MAPK4, PIK3C2A, PIK3CG, GSK3alpha, GSK3beta, IRAK3, DAPK1, JAK1, PIM1, TRB3, BTG1, LATS1, LIMK2, MYLK, PAK1, PAK2, CDC2, BTK, PNRC2, NCOA4, NR2C1, TPR, RBBP8, TRPC7, FXYD1, ERN1, PRSS16, RPS3, CCL23 and SERPINE1, for the manufacture of a medicament destined to diminish the resistance to chemotherapeutic drugs in the therapeutic treatment of epithelial tumour pathologies. Also described is a method for the determination of the drug resistance in tumour cells, as well as a method for the identification of tumour stem cells

L’invenzione riguarda l’uso di composti per la produzione di un medicamento in grado di modulare, ed in particolare di diminuire la resistenza farmacologia in cellule tumorali epiteliali umane. Essa è altresì diretta ad un metodo per la determinazione della resistenza farmacologia in cellule tumorali nonché ad un metodo per la identificazione di cellule tumorali staminali.