ADMIXTURE components of Argentinean Natives in a worldwide context.

<p>Populations are divided by six admixture proportions as K = 6 indicated the best fit for the data. The main proportions are derived from Yoruba (k3), Han Chinese (k4), Europeans (k6), Mexicans (Mixe/Pima, k2), Andean populations (k1) and Wichí (k5). Collas are indistinguishable from Aymara and Quechua, while Chilean Andeans mainly consist of Andean (k1) and Mixe/Pima (k2) characteristic admixture proportions. Gran Chaco populations (Kaingang, Chané, Guaraní and Toba) carry Wichí specific admixture proportions among others. The population name is displayed underneath the admixture plot while the sample origin is listed above (A: Argentina, B: Brazil, Bo: Bolivia, C: Colombia, Ch: Chile, G: Guatemala, M: Mexico, P:Paraguay) The population name is followed by a sign designating its study (°: HapMap, ∧: Reich <i>et al </i><a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0093314#pone.0093314-Reich1" target="_blank">[64]</a>, ‘: HGDP, “: Mao <i>et al </i><a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0093314#pone.0093314-Mao1" target="_blank">[63]</a>, *: this study).</p

Pathways determining hypoxia candidate genes for this study.

<p>Pathways determining hypoxia candidate genes for this study.</p

Hypoxia candidate genes in the 1% of iHS and XP-EHH results in Collas.

<p>Hypoxia candidate genes in the 1% of iHS and XP-EHH results in Collas.</p

Comparison of variables between Collas and Wichí.

<p>*values correspond to the Commission Internationald'Eclairage L*a*b* system.</p>a<p>p≤0.001,</p>b<p>p<0.05.</p>c<p>Equally significant after correction for further independent variables:</p><p>Weight: corrected for height, age and gender; BMI: corrected for age and gender;</p><p>Systolic blood pressure/Cardiac output: corrected for time since last meal, its caloric amount, age and gender;</p><p>Log (Change in thorax breadth/depth): corrected for age and gender.</p

Consensus maximum likelihood tree for a reduced number of populations with 10 migration events.

<p>Non-bold numbers are bootstrap estimates based on 100 iterations with a support greater than 70%. Quechua, Aymara and Collas form one clade and group with Chilean Andean speakers (Yaghan, Hulliche, Chono and Chilote). Gran Chaco populations (Toba, Wichí, Guaraní, Chané and Kaingang) form a clade with Brazilians (Suruí and Karitiana) and Colombians (Piapoco). Mixe and Pima from Mexico cluster outside all South Americans and Kaqchikel from Guatemala. Branch length refers to the amount of drift experienced but is also increased in populations with more individuals in the data set. Black arrows indicate migrations confirmed as significant by <i>f</i>4 test, while grey arrows indicate insignificant <i>f</i>4 results. Bold numbers represent admixture proportions for black arrows: Toba received 40% admixture proportion from Wichí. Gene flow among Chilean Andeans was strongly supported: Hulliche contributed 100% admixture to Chono and HA Andeans 16%. An ancestral population of Chilote and Chono contributed 37% to Chono and 20% to Chilote. Yaghan contributed 0.05% admixture proportion to Chono.</p

<i>VEGFB</i> haplotype characterised by EHH >0.3 in study populations.

<p><i>VEGFB</i> haplotype characterised by EHH >0.3 in study populations.</p

Clinical characteristics of index patients at diagnosis.

<p>Clinical characteristics of index patients at diagnosis.</p

Clinical characteristics of family members.

<p>*Mean is based on 16 individuals; while maximal blood pressure, peak VO₂, EqCO₂, VO₂ at anaerobic threshold and oxygen pulse are based on 10 individuals</p><p>EqCO₂: ventilatory equivalent for carbon dioxide, max: value at maximal workload, VO₂/kg: oxygen consumption/kg.</p><p>Clinical characteristics of family members.</p

Pedigree of Family 2.

<p>The index patient of Family 2 (III:1, arrow) carries the <i>BMPR2</i> promoter mutation c.-669G>A [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0133042#pone.0133042.ref021" target="_blank">21</a>] and a unclassified variant in the <i>ENG</i> gene (c.1633G>A, p.(G545S)). Mut: mutation, UV: unknown variant, UTR: untranslated region, WT: wild type, X 11: exon 11 <i>ENG</i>. The horizontal line separates the two loci in <i>BMPR2</i> promoter and <i>ENG</i> exon 11.</p

Image_2_Circulating MicroRNA Markers for Pulmonary Hypertension in Supervised Exercise Intervention and Nightly Oxygen Intervention.JPEG

<p>Rationale: Therapeutic exercise training has been shown to significantly improve pulmonary hypertension (PH), including 6-min walking distance and right heart function. Supplemental nightly oxygen also has therapeutic effects. A biomarker tool that could query critical gene networks would aid in understanding the molecular effects of the interventions.</p><p>Methods: Paired bio-banked serum (n = 31) or plasma (n = 21) samples from the exercise or oxygen intervention studies, respectively, and bio-banked plasma samples (n = 20) from high altitude induced PH in cattle were tested. MicroRNAs (miRNAs) markers were chosen for study because they regulate gene expression, control the function of specific gene networks, and are conserved across species.</p><p>Results: miRNAs that control muscle (miR-22-3p, miR-21-5p) or erythrocyte function (miR-451a) were chosen based on pilot experiments. Plasma samples from cattle that developed PH in high altitude had significantly higher miR-22-3p/(relative to) miR-451a values when compared to control cattle tolerant to high altitude. Measurements of miR-22-3p/miR-451a values in serum from patients receiving exercise training showed that the values were significantly decreased in 74.2% of the samples following intervention and significantly increased in the remainder (25.8%). In samples obtained after exercise intervention, a higher composite miRNA value, made of miR-22-3p and miR-21-5p/miR-451a and spike RNA, was significantly decreased in 65% of the samples and significantly increased in 35% of the samples. In the study of nightly oxygen intervention, when comparing placebo and oxygen, half of the samples showed a significant down-ward change and the other half a significant up-ward change measuring either of the miRNA markers. Samples that had a downward change in the miRNA marker following either intervention originated from patients who had a significantly higher 6-min-walking-distance at baseline (mean difference of 90 m or 80 m following exercise or oxygen intervention, respectively) when compared to samples that had an upward change in the miRNA marker.</p><p>Conclusion: These natural animal model and human sample studies further highlight the utility of miRNAs as future biomarkers. The different directional changes of the miRNA markers following supervised exercise training or nightly oxygen intervention could indicate different PAH molecular pathomechanisms (endotypes). Further studies are needed to test this idea.</p