”Haluaisin olla poliisi mut en mä tyttönä”: puhetta ammatillisesta segregaatiosta

Suomalaiset nuoret valitsevat useimmiten ammattinsa sukupuolensa ohjailemina, sillä kulttuuri, perinteet ja niihin kietoutuvat sosiaaliset normit rajoittavat valinnanmahdollisuuksia. Sukupuolen mukaan eriytyneet koulutusvalinnat ylläpitävät työmarkkinoiden ammatillista segregaatiota, joka on tutkimusaiheeni. Erilaisista tasa-arvohankkeista on jo pitkään haettu apua segregaation purkuun ja sukupuolten välisiin tasa-arvo-ongelmiin. Työ- ja elinkeinoministeriön luotsaaman Valtava-kehittämisohjelman ohessa järjestettiin syksyllä 2014 kampanja, jolla kannustettiin nuoria rikkomaan sukupuolirajoja koulutusvalinnoissaan. Kyseinen Valitse ala päällä -kampanja on yksi tutkielman keskeisistä lähtökohdista. Tutkimusaineistonani toimii kampanjan aikana käydyt verkkokeskustelut tyttöjen ja nuorten naisten suosimalla Demi.fi-sivustolla. Lähestyn tutkimusaineistoani diskurssianalyysin keinoin. Tutkimustuloksina esitän neljä diskurssia, jotka lähestyvät ammatillista segregaatiota joko puolustavista tai haastavista näkökulmista. Vallitsevaa järjestystä ylläpitävät diskurssit tuottavat normalisoitua käsitystä kahtiajakoisesta ja eriarvoisesta sukupuolesta sekä asettavat sukupuolirajojen rikkomisen marginaaliin. Haastavassa diskurssissa kyseenalaistetaan sukupuolisen kurivallan tuottamia stereotypioita ja sukupuolen mukaista työnjakoa. Tuotan diskurssien pohjalta kriittistä tulkintaa sukupuolittuneesta kulttuurista, jossa suomalaiset nuoret tekevät koulutus- ja uravalintojaan. Johtopäätöksenä totean, että sukupuolinormien uusiutuva voima on vahva, vaikka nuoret, erityisesti naiset, tekevätkin enenevissä määrin sukupuolelleen epätyypillisiä valintoja. Toisenlaisen uravalinnan tekeminen vaatii sukupuolitietoisuuden heräämistä ja rohkeutta rikkoa sosiaalisia normeja

Regulation of Osteoblast Differentiation and Gene Expression by Phosphodiesterases and Bioactive Peptides

Bone is a mineralized tissue that enables multiple mechanical and metabolic functions to be carried out in the skeleton. Bone contains distinct cell types: osteoblasts (bone-forming cells), osteocytes (mature osteoblast that embedded in mineralized bone matrix) and the osteoclasts (bone-resorbing cells). Remodelling of bone begins early in foetal life, and once the skeleton is fully formed in young adults, almost all of the metabolic activity is in this form. Bone is constantly destroyed or resorbed by osteoclasts and then replaced by osteoblasts. Many bone diseases, i.e. osteoporosis, also known as bone loss, typically reflect an imbalance in skeletal turnover. The cyclic adenosine monophosphate (cAMP) and the cyclic guanosine monophosphate (cGMP) are second messengers involved in a variety of cellular responses to such extracellular agents as hormones and neurotransmitters. In the hormonal regulation of bone metabolism, i.e. via parathyroid hormone (PTH), parathyroid hormone-related peptide (PTHrp) and prostaglandin E2 signal via cAMP. cAMP and cGMP are formed by adenylate and guanylate cyclases and are degraded by phosphodiesterases (PDEs). PDEs determine the amplitudes of cyclic nucleotide-mediated hormonal responses and modulate the duration of the signal. The activities of the PDEs are regulated by multiple inputs from other signalling systems and are crucial points of cross-talk between the pathways. Food-derived bioactive peptides are reported to express a variety of functions in vivo. The angiotensin-converting enzymes (ACEs) are involved in the regulation of the specific maturation or degradation of a number of mammalian bioactive peptides. The bioactive peptides offer also a nutriceutical and a nutrigenomic aspect to bone cell biology. The aim of this study was to investigate the influence of PDEs and bioactive peptides on the activation and the differentiation of human osteoblast cells. The profile of PDEs in human osteoblast-like cells and the effect of glucocorticoids on the function of cAMP PDEs, were investigated at the mRNA and enzyme levels. The effects of PDEs on bone formation and osteoblast gene expression were determined with chemical inhibitors and siRNAs (short interfering RNAs). The influence of bioactive peptides on osteoblast gene expression and proliferation was studied at the mRNA and cellular levels. This work provides information on how PDEs are involved in the function and the differentiation of osteoblasts. The findings illustrate that gene-specific silencing with an RNA interference (RNAi) method is useful in inhibiting, the gene expression of specific PDEs and further, PDE7 inhibition upregulates several osteogenic genes and increases bALP activity and mineralization in human mesenchymal stem cells-derived osteoblasts. PDEs appear to be involved in a mechanism by which glucocorticoids affect cAMP signaling. This may provide a potential route in the formation of glucocorticoid-induced bone loss, involving the down-regulation of cAMP-PDE. PDEs may play an important role in the regulation of osteoblastic differentiation. Isoleucine-proline-proline (IPP), a bioactive peptide, possesses the potential to increase osteoblast proliferation, differentiation and signalling.Monet luusairaudet, kuten osteoporoosi, johtuvat epätasapainosta luun uusiutumiskierrossa. Luusairauksien ehkäisemiseksi ja hoitamiseksi on tärkeää ymmärtää niitä tekijöitä, jotka säätelevät luukudoksen aineenvaihduntaa ja fysiologiaa. Osteoblastit ovat luuston soluja, jotka vastaavat luunmuodostuksesta. Solujen toimintaa ohjaavat solun sisäiset ja ulkoiset signaalit, jotka voivat tehostaa tai heikentää solun jakautumista, erilaistumista ja elinikää. Osteoblastien lukumäärä ja aktiivisuus vaikuttavat luukudoksen määrään ja laatuun, jolla on iso merkitys luun kestävyyteen ja murtuma-alttiuteen. Väitöskirjatyön osatöissä I-III tutkittiin luutamuodostavien solujen signaalivälitystä, toimintaa ja erilaistumista in vitro. Syklinen AMP (cAMP) on tärkeä luun aineenvaihduntaa säätelevä toisiolähetti mm. kilpirauhashormonin vaikutukset välittyvät sen kautta. Fosfodiesteraasit (PDE:t) ovat entsyymejä, jotka inaktivoivat cAMP:in. PDE perheitä on 11 ja niiden luustovaikutukset saattavat vaihdella. Väitöskirjatyössä kartoitettiin ihmisen luuta muodostavien solujen PDEiden ilmenemistä, selvitettiin PDE7 ja PDE8 geenien hiljentämisen luusoluvaikutuksia ja tutkittiin synteettisen glukokortikoidin vaikutusta osteoblastien cAMP:hen, fosfodiesteraasigeenien ilmenemiseen ja aktiivisuuteen. Osatyössä IV tutkittiin kolmen bioaktiivisen peptidin IPP, LKP ja VPP lyhytaikaisvaikutusta osteoblastien geenien ilmenemiseen ja solujen jakautumiseen. Proteiinien peptidit toimivat elimistön rakennusaineena, mutta ohjaavat myös solujen toimintaa. Vaikka PDE:t ovat tärkeä osa solun signaalivälitystä, niista tiedetään hyvin vähän luusoluissa. Fosfodiesteraasi-estäjistä on tullut tärkeitä terapeuttisia aineita monen sairauden, kuten sydämen vajaatoiminnan, masennuksen, astman ja impotenssin hoidossa. Tunnetuin fosfodiesteraasi-estäjistä lienee sildenafiilisitraatti (Viagra®). Väitöskirjatyö valaiseen osteoblastien fosfodiestraasientsyymien ilmenemistä ja estämisen seurauksia luuta muodostaviin soluihin. PDE7:n toiminnan estäminen lisää osteoblastien erilaistumista ja mineraalin muodostamista. Deksametasoni, kortisonijohdos vähentää PDE4:n entsyymi-aktiivisuutta luuta muodostavissa soluissa. Glukokortikoideja käytetään hillitsemään tulehdusreaktioita ja niiden pitkäaikaiskäytöllä on havaittu luustovaikutuksia. Luustoa heikentävä vaikutus saattaa osin välittyä PDE4:n toiminnan estämisen kautta. Fosfodiesteraasientsyymien aktiivisuuden hallittu ja kohdennettu säätely tarjoaa mahdollisuuden tehostaa osteoblastien erilaistumista ja toimintaa ja siten uuden luun muodostusta. IPP, yksi tutkituista bioaktiivisista peptideistä, lisäsi osteoblastisolujen jakautumista, ja erilaistumiseen, signaloitumiseen ja elinkykyyn vaikuttavien geenien ilmenemistä. Bioaktiivisten peptidien luusoluvaikutukset saattavat lisätä kiinnostusta funktionaalisia ja luustoaktiivisia peptidejä sisältävien ravintoaineiden kehittämiseen

A novel MYT1L mutation in a patient with severe early-onset obesity and intellectual disability

The genetic background of severe early-onset obesity is still incompletely understood. Deletions at 2p25.3 associate with early-onset obesity and variable intellectual disability. Myelin-transcriptor-factor-1-like (MYT1L) gene in this locus has been proposed a candidate gene for obesity. We report on a 13-year-old boy presenting with overweight already at 1 year of age (body mass index [BMI] Z-score +2.3) and obesity at 2 years of age (BMI Z-score +3.8). The patient had hyperphagia and delayed neurological, cognitive and motor development. He also had speech delay, strabismus, hyperactivity and intellectual disability. Brain MRI was normal. The parents and sister had normal BMI. Whole-genome sequencing identified in the index patient a novel de novo frameshift deletion that introduces a premature termination of translation NM_015025.2(MYT1L): c.2215_2224delACGCGCTGCC, p.(Thr739Alafs*7) in MYT1L. The frameshift variant was confirmed by Sanger sequencing. Our finding supports the association of MYT1L mutations with early-onset syndromic obesity. The identification of novel monogenic forms of childhood-onset obesity will provide insights to the involved genetic and biologic pathways.Peer reviewe

GNAS, PDE4D, and PRKAR1A Mutations and GNAS Methylation Changes Are Not a Common Cause of Isolated Early-Onset Severe Obesity Among Finnish Children

Context: Pseudohypoparathyroidism type Ia (PHP1A) is caused by inactivating mutations involving GNAS exons 1–13, encoding the alpha-subunit of the stimulatory G protein (Gsα). Particularly PHP1A, but also other disorders involving the Gsα-cAMP-signaling pathway, have been associated with early-onset obesity. Thus, patients with mutations in the genes encoding PDE4D and PRKAR1A can also be obese. Furthermore, epigenetic GNAS changes, as in pseudohypoparathyroidism type Ib (PHP1B), can lead to excessive weight.Objective: Search for genetic variants in GNAS, PDE4D, and PRKAR1A and for methylation alterations at the GNAS locus in Finnish subjects with isolated severe obesity before age 10 years.Methods: Next generation sequencing to identify pathogenic variants in the coding exons of GNAS, PDE4D, and PRKAR1A; Multiplex Ligation-dependent Probe Amplification (MLPA) and methylation-sensitive MLPA (MS-MLPA) to search for deletions in GNAS and STX16, and for epigenetic changes at the four differentially methylated regions (DMR) within GNAS.Results: Among the 88 subjects (median age 13.8 years, median body mass index Z-score +3.9), we identified one rare heterozygous missense variant of uncertain significance in the XL exon of GNAS in a single patient. We did not identify clearly pathogenic variants in PDE4D and PRKAR1A, and no GNAS methylation changes were detected by MS-MLPA.Conclusions: Our results suggest that coding GNAS mutations or methylation changes at the GNAS DMRs, or coding mutations in PDE4D and PRKAR1A are not common causes of isolated childhood obesity in Finland.Peer reviewe

Targeted Exome Sequencing of Genes Involved in Rare CNVs in Early-Onset Severe Obesity

Context: Rare copy number variants (CNVs) have been associated with the development of severe obesity. However, the potential disease-causing contribution of individual genes within the region of CNVs is often not known.Objective: Screening of rare variants in genes involved in CNVs in Finnish patients with severe early-onset obesity to find candidate genes linked to severe obesity.Methods: Custom-made targeted exome sequencing panel to search for rare (minor allele frequencyPeer reviewe

Decreased telomere length in children with cartilage-hair hypoplasia

Background Cartilage-hair hypoplasia (CHH) is an autosomal recessive chondrodysplasia caused by RMRP (RNA component of mitochondrial RNA processing endoribonuclease) gene mutations. Manifestations include short stature, variable immunodeficiency, anaemia and increased risk of malignancies, all of which have been described also in telomere biology disorders. RMRP interacts with the telomerase RT (TERT) subunit, but the influence of RMRP mutations on telomere length is unknown. We measured relative telomere length (RTL) in patients with CHH, their first-degree relatives and healthy controls and correlated RTL with clinical and laboratory features. Methods The study cohort included 48 patients with CHH with homozygous (n=36) or compound heterozygous RMRP mutations (median age 38.2 years, range 6.0-70.8 years), 86 relatives (74 with a heterozygous RMRP mutation) and 94 unrelated healthy controls. We extracted DNA from peripheral blood, sequenced the RMRP gene and measured RTL by qPCR. Results Compared with age-matched and sex-matched healthy controls, median RTL was significantly shorter in patients with CHH (n=40 pairs, 1.05 vs 1.21, p=0.017), but not in mutation carriers (n=48 pairs, 1.16 vs 1.10, p=0.224). RTL correlated significantly with age in RMRP mutation carriers (r=-0.482, p <0.001) and non-carriers (r=-0.498, p Conclusions Telomere length was decreased in children with CHH. We found no correlation between RTL and clinical or laboratory parameters.Peer reviewe

FGF23 gene variation and its association with phosphate homeostasis and bone mineral density in Finnish children and adolescents

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Vitamin D Is a Major Determinant of Bone Mineral Density at School Age

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Variation in the fibroblast growth factor 23 (FGF23) gene associates with serum FGF23 and bone strength in infants

Introduction: The effects of genetic variation in fibroblast growth factor 23 (FGF23) are unclear. This study explores the associations of single-nucleotide polymorphisms (SNPs) of FGF23 with phosphate and vitamin D metabolism and bone strength in early childhood.Methods: The study is part of the vitamin D intervention in infant (VIDI) trial (2013–2016), in which healthy term infants born to mothers of Northern European origin received vitamin D3 supplementation of 10 or 30 μg/day from 2 weeks to 24 months of age (ClinicalTrials.gov NCT01723852). Intact and C-terminal FGF23 (cFGF23), 25-hydroxyvitamin D (25-OHD), parathyroid hormone, phosphate, and peripheral quantitative computed tomography (pQCT)-derived bone strength parameters were analyzed at 12 and 24 months. The study included 622 VIDI participants with genotyping data on FGF23 SNPs rs7955866, rs11063112, and rs13312770.Results: Rs7955866 minor allele homozygotes had lowest cFGF23 at both time-points (mixed model for repeated measurements, pvariant = 0.009). Minor alleles of rs11063112 were associated with a greater age-related decrease in phosphate concentration (pinteraction = 0.038) from 12 to 24 months. Heterozygotes of rs13312770 had the greatest total bone mineral content (total BMC), cross-sectional area (total CSA), and polar moment of inertia (PMI) at 24 months (ANOVA p = 0.005, 0.037, and 0.036, respectively). Rs13312770 minor alleles were associated with a greater increase of total BMC, but a smaller increase of total CSA and PMI, during follow-up (pinteraction &lt;0.001, 0.043, and 0.012, respectively). Genotype of FGF23 did not modify 25-OHD.Conclusion: The study finds that genetic variation in FGF23 modifies cFGF23, phosphate, and pQCT-derived bone strength parameters from 12 to 24 months of age. These findings potentially promote an understanding of the regulation of FGF23 and its role in bone metabolism and temporal changes thereof during early childhood

Genetic variation in GC and CYP2R1 affects 25-hydroxyvitamin D concentration and skeletal parameters: A genome-wide association study in 24-month-old Finnish children

Author summary The effect of vitamin D continues to be highly debated in various health outcomes, including bone health. In this first study of children this young we searched for genes that modify vitamin D metabolism in early childhood using a genome-wide analysis of almost 700,000 genetic variants in a cohort of 761 healthy children participating in a vitamin D intervention study. We show that genetic variation in the genes coding for Vitamin D binding protein (GC) and Vitamin D 25-hydroxylase (CYP2R1) are important determinants for serum 25-hydroxyvitamin D concentration in 2-year-old children. Genetic variants within the GC gene also affect how the child responds to vitamin D supplementation. Moreover, our findings suggest that in 2-year-old children vitamin D concentration, even when within the normal range, influences bone strength as children with genetic constellations associating with lower vitamin D concentration and poorer response to vitamin D supplementation also have weaker bones.Peer reviewe