Alveolar epithelial CNGA1 channels mediate cGMP-stimulated, amiloride-insensitive, lung liquid absorption.

Impairment of lung liquid absorption can lead to severe respiratory symptoms, such as those observed in pulmonary oedema. In the adult lung, liquid absorption is driven by cation transport through two pathways: a well-established amiloride-sensitive Na(+) channel (ENaC) and, more controversially, an amiloride-insensitive channel that may belong to the cyclic nucleotide-gated (CNG) channel family. Here, we show robust CNGA1 (but not CNGA2 or CNGA3) channel expression principally in rat alveolar type I cells; CNGA3 was expressed in ciliated airway epithelial cells. Using a rat in situ lung liquid clearance assay, CNG channel activation with 1 mM 8Br-cGMP resulted in an approximate 1.8-fold stimulation of lung liquid absorption. There was no stimulation by 8Br-cGMP when applied in the presence of either 100 μM L: -cis-diltiazem or 100 nM pseudechetoxin (PsTx), a specific inhibitor of CNGA1 channels. Channel specificity of PsTx and amiloride was confirmed by patch clamp experiments showing that CNGA1 channels in HEK 293 cells were not inhibited by 100 μM amiloride and that recombinant αβγ-ENaC were not inhibited by 100 nM PsTx. Importantly, 8Br-cGMP stimulated lung liquid absorption in situ, even in the presence of 50 μM amiloride. Furthermore, neither L: -cis-diltiazem nor PsTx affected the β(2)-adrenoceptor agonist-stimulated lung liquid absorption, but, as expected, amiloride completely ablated it. Thus, transport through alveolar CNGA1 channels, located in type I cells, underlies the amiloride-insensitive component of lung liquid reabsorption. Furthermore, our in situ data highlight the potential of CNGA1 as a novel therapeutic target for the treatment of diseases characterised by lung liquid overload.

Talent o educació: el cas Mozart

Aquest article pretén analitzar la influència de Leopold Mozart en l'educació musical i la formació integral de W.A.Mozart, mitjançant les seves cartes i escrits, així com de l'estil de les seves primeres obres i llur semblança amb el quadern que Leopold va recopilar per a Wolfgang en 1762 i que va servir de mètode d'aprenentatge de piano durant els seus viatges i estades a l'estranger.

Seventy-five genetic loci influencing the human red blood cell.

Anaemia is a chief determinant of global ill health, contributing to cognitive impairment, growth retardation and impaired physical capacity. To understand further the genetic factors influencing red blood cells, we carried out a genome-wide association study of haemoglobin concentration and related parameters in up to 135,367 individuals. Here we identify 75 independent genetic loci associated with one or more red blood cell phenotypes at P < 10(-8), which together explain 4-9% of the phenotypic variance per trait. Using expression quantitative trait loci and bioinformatic strategies, we identify 121 candidate genes enriched in functions relevant to red blood cell biology. The candidate genes are expressed preferentially in red blood cell precursors, and 43 have haematopoietic phenotypes in Mus musculus or Drosophila melanogaster. Through open-chromatin and coding-variant analyses we identify potential causal genetic variants at 41 loci. Our findings provide extensive new insights into genetic mechanisms and biological pathways controlling red blood cell formation and function.

Biological, clinical and population relevance of 95 loci for blood lipids.

Plasma concentrations of total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides are among the most important risk factors for coronary artery disease (CAD) and are targets for therapeutic intervention. We screened the genome for common variants associated with plasma lipids in >100,000 individuals of European ancestry. Here we report 95 significantly associated loci (P < 5 x 10(-8)), with 59 showing genome-wide significant association with lipid traits for the first time. The newly reported associations include single nucleotide polymorphisms (SNPs) near known lipid regulators (for example, CYP7A1, NPC1L1 and SCARB1) as well as in scores of loci not previously implicated in lipoprotein metabolism. The 95 loci contribute not only to normal variation in lipid traits but also to extreme lipid phenotypes and have an impact on lipid traits in three non-European populations (East Asians, South Asians and African Americans). Our results identify several novel loci associated with plasma lipids that are also associated with CAD. Finally, we validated three of the novel genes-GALNT2, PPP1R3B and TTC39B-with experiments in mouse models. Taken together, our findings provide the foundation to develop a broader biological understanding of lipoprotein metabolism and to identify new therapeutic opportunities for the prevention of CAD.

Hundreds of variants clustered in genomic loci and biological pathways affect human height.

Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P < 0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16% of phenotypic variation (approximately 20% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways.

Genome-wide association study identifies loci influencing concentrations of liver enzymes in plasma.

Concentrations of liver enzymes in plasma are widely used as indicators of liver disease. We carried out a genome-wide association study in 61,089 individuals, identifying 42 loci associated with concentrations of liver enzymes in plasma, of which 32 are new associations (P = 10(-8) to P = 10(-190)). We used functional genomic approaches including metabonomic profiling and gene expression analyses to identify probable candidate genes at these regions. We identified 69 candidate genes, including genes involved in biliary transport (ATP8B1 and ABCB11), glucose, carbohydrate and lipid metabolism (FADS1, FADS2, GCKR, JMJD1C, HNF1A, MLXIPL, PNPLA3, PPP1R3B, SLC2A2 and TRIB1), glycoprotein biosynthesis and cell surface glycobiology (ABO, ASGR1, FUT2, GPLD1 and ST3GAL4), inflammation and immunity (CD276, CDH6, GCKR, HNF1A, HPR, ITGA1, RORA and STAT4) and glutathione metabolism (GSTT1, GSTT2 and GGT), as well as several genes of uncertain or unknown function (including ABHD12, EFHD1, EFNA1, EPHA2, MICAL3 and ZNF827). Our results provide new insight into genetic mechanisms and pathways influencing markers of liver function.

Alveolar epithelial CNGA1 channels mediate cGMP-stimulated, amiloride-insensitive, lung liquid absorption.

Impairment of lung liquid absorption can lead to severe respiratory symptoms, such as those observed in pulmonary oedema. In the adult lung, liquid absorption is driven by cation transport through two pathways: a well-established amiloride-sensitive Na(+) channel (ENaC) and, more controversially, an amiloride-insensitive channel that may belong to the cyclic nucleotide-gated (CNG) channel family. Here, we show robust CNGA1 (but not CNGA2 or CNGA3) channel expression principally in rat alveolar type I cells; CNGA3 was expressed in ciliated airway epithelial cells. Using a rat in situ lung liquid clearance assay, CNG channel activation with 1 mM 8Br-cGMP resulted in an approximate 1.8-fold stimulation of lung liquid absorption. There was no stimulation by 8Br-cGMP when applied in the presence of either 100 μM L: -cis-diltiazem or 100 nM pseudechetoxin (PsTx), a specific inhibitor of CNGA1 channels. Channel specificity of PsTx and amiloride was confirmed by patch clamp experiments showing that CNGA1 channels in HEK 293 cells were not inhibited by 100 μM amiloride and that recombinant αβγ-ENaC were not inhibited by 100 nM PsTx. Importantly, 8Br-cGMP stimulated lung liquid absorption in situ, even in the presence of 50 μM amiloride. Furthermore, neither L: -cis-diltiazem nor PsTx affected the β(2)-adrenoceptor agonist-stimulated lung liquid absorption, but, as expected, amiloride completely ablated it. Thus, transport through alveolar CNGA1 channels, located in type I cells, underlies the amiloride-insensitive component of lung liquid reabsorption. Furthermore, our in situ data highlight the potential of CNGA1 as a novel therapeutic target for the treatment of diseases characterised by lung liquid overload.

Porstuan kautta keittiöön, ehkä jopa olohuoneeseen

Arvostellun teoksen nimeke artikkelissa virheellisesti: "Du är finsk, eller...?".

Genetic studies of body mass index yield new insights for obesity biology

Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in up to 339,224 individuals. This analysis identifies 97 BMI-associated loci (P < 5 × 10(-8)), 56 of which are novel. Five loci demonstrate clear evidence of several independent association signals, and many loci have significant effects on other metabolic phenotypes. The 97 loci account for ∼2.7% of BMI variation, and genome-wide estimates suggest that common variation accounts for >20% of BMI variation. Pathway analyses provide strong support for a role of the central nervous system in obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis.

FTO genetic variants, dietary intake and body mass index: insights from 177,330 individuals.

FTO is the strongest known genetic susceptibility locus for obesity. Experimental studies in animals suggest the potential roles of FTO in regulating food intake. The interactive relation among FTO variants, dietary intake and body mass index (BMI) is complex and results from previous often small-scale studies in humans are highly inconsistent. We performed large-scale analyses based on data from 177,330 adults (154 439 Whites, 5776 African Americans and 17 115 Asians) from 40 studies to examine: (i) the association between the FTO-rs9939609 variant (or a proxy single-nucleotide polymorphism) and total energy and macronutrient intake and (ii) the interaction between the FTO variant and dietary intake on BMI. The minor allele (A-allele) of the FTO-rs9939609 variant was associated with higher BMI in Whites (effect per allele = 0.34 [0.31, 0.37] kg/m(2), P = 1.9 × 10(-105)), and all participants (0.30 [0.30, 0.35] kg/m(2), P = 3.6 × 10(-107)). The BMI-increasing allele of the FTO variant showed a significant association with higher dietary protein intake (effect per allele = 0.08 [0.06, 0.10] %, P = 2.4 × 10(-16)), and relative weak associations with lower total energy intake (-6.4 [-10.1, -2.6] kcal/day, P = 0.001) and lower dietary carbohydrate intake (-0.07 [-0.11, -0.02] %, P = 0.004). The associations with protein (P = 7.5 × 10(-9)) and total energy (P = 0.002) were attenuated but remained significant after adjustment for BMI. We did not find significant interactions between the FTO variant and dietary intake of total energy, protein, carbohydrate or fat on BMI. Our findings suggest a positive association between the BMI-increasing allele of FTO variant and higher dietary protein intake and offer insight into potential link between FTO, dietary protein intake and adiposity.

Geographiske chartor öfver Sverige - Charta öfver... Finland - 4 : Storfurstendömet Finland

Stockholm 1799, Graverad af Fr. Akrel

Sosiaalityö ja maahanmuuttajat. Lastensuojelun ammattilaisten ja asiakkaiden vuorovaikutus ja tulkinnat

Tutkimuksen tavoitteena oli tuottaa tietoa siitä, mitä maahanmuuttajia koskevat erityiskysymykset suomalaisessa lastensuojelun sosiaalityössä ovat ja miten näitä kysymyksiä lastensuojelussa käsitellään. Teoreettismetodologisena viitekehyksenä on sosiaalinen konstruktionismi. Etnisten suhteiden tutkimusperinteessä työ paikantuu keskusteluun, jossa kulttuuri ja etnisyys nähdään sosiaalisesti rakentuvina ja muuntuvina. Analyysissä sovelletaan diskurssianalyyttistä metodologiaa. Tutkimus rakentuu yhteenveto-osiosta ja nelj��stä artikkelista. Maahanmuuttajasosiaalityötä ja lastensuojelua tarkastellaan sosiaalityöntekij��iden, muiden ammattilaisten ja asiakkaiden kielenkäytön kautta. Aineisto koostuu 11 lastensuojelun asiakaskeskustelusta ja niiden j��lkeen keskustelun osapuolille tehdyistä haastatteluista, joita on yhteensä 35. Tutkimuksessa analysoidaan seuraavia kysymyksiä: Miten sosiaalityöntekij��t tulkitsevat maahanmuuttajasosiaalityön erityisyyttä oman ammatillisen tehtävänsä näkökulmasta? Minkälaisia ominaisuuksia sosiaalityöntekij��t rakentavat maahanmuuttaja-asiakkaille? Miten lastensuojelun keskusteluissa puhutaan monikulttuurisuuteen liittyvistä teemoista, kuten erilaisuudesta ja samanlaisuudesta sekä kulttuuri- ja rasismikysymyksistä? Miten maahanmuuttajalasten ja -nuorten osallisuus lastensuojelun asiakaskeskusteluissa rakentuu aikuisten ja lasten itsensä tuottamana? Mitä ja miten maahanmuuttajalapset ja -nuoret puhuvat kokemuksistaan lastensuojelussa ja suomalaisessa yhteiskunnassa? Maahanmuuttajien erityiskysymyksiä ovat kieleen, kulttuuriin ja valtayhteiskunnan toimintaan liittyvät ymmärtämisvaikeudet, kokemukset arkipäivän rasismista sekä perheen ja yhteisön merkittävä, osin ristiriitainen rooli. Lapsilla ja nuorilla kulttuuri on muuntuvaa ja jatkuvien neuvottelujen kohteena. Aineiston lastensuojelutilanteiden taustalla on usein kouluympäristöön liittyviä vaikeuksia. Haastatteluissa lapset kertovat kokemuksistaan ja toimijuudestaan perheeseen, yhteisöön ja kouluun paikantuvissa tilanteissa. Asiakaskeskusteluissa lasten puhuja-asema on usein heikko, jos aikuiset eivät aktiivisesti vahvista sitä. Jotkut lapset ottavat itse vahvan puhuja-aseman. Asiakaskeskusteluissa maahanmuuttajien erityiskysymyksistä puhutaan harvoin eksplisiittisesti. Haastatteluissa sosiaalityöntekij��t enemmän tai vähemmän tietoisesti paikantavat maahanmuuttajasosiaalityötä vieraannuttavaan, sopeuttavaan, tasa-arvoistavaan, kulttuuritietoiseen, rasismitietoiseen ja osallistavaan kehykseen. Kehykset nostavat sosiaalityön tavoitteista, menetelmistä ja asiakkaasta keskeisiksi erilaisia asioita. Tulkinnat ovat muuntuvia, vaikka osoittavat myös tiettyä säännönmukaisuutta. Kulttuuri on keskeinen käsite erilaisuuden ja samanlaisuuden ymmärtämiseksi. Sekä työntekij��t että asiakkaat perustelevat toivottavia elämäntapoja "omalla kulttuurillaan" ja selittävät ongelmia ”erilaisella kulttuurilla���. Kulttuurin käsitettä voidaan myös käyttää työvälineenä asiakaskeskusteluissa avattaessa asiakkaan omaa näkökulmaa korostavaa dialogia. Perheen ja kulttuurisen yhteisön merkitys on tärke��ä arvioida lapsen ja nuoren hyvinvoinnin ja kulttuurisen identiteetin kehittymisen näkökulmasta. Sosiaalityöntekij��illä on merkittävä välittäj��n rooli yhtäältä valtayhteiskunnan ja maahanmuuttaja-asiakkaiden, toisaalta vanhempien, yhteisöjen sekä lasten ja nuorten välillä. Lastensuojelussa haasteena on arkipäivän rasismin tiedostaminen sekä siihen pureutuvien työmenetelmien kehittäminen.