Growth hormone deficiency in megalencephaly-capillary malformation syndrome: An association with activating mutations in PIK3CA

Megalencephaly-capillary malformation syndrome (MCAP) is a brain overgrowth disorder characterized by cortical malformations (specifically polymicrogyria), vascular anomalies, and segmental overgrowth secondary to somatic activating mutations in the PI3K-AKT-MTOR pathway (PIK3CA). Cases of growth failure and hypoglycemia have been reported in patients with MCAP, raising the suspicion for unappreciated growth hormone (GH) deficiency. Here we report an observational multicenter study of children with MCAP and GH deficiency. Eleven participants were confirmed to have GH deficiency, all with very low or undetectable circulating concentrations of insulin-like growth factor-1 and insulin-like growth factor binding protein-3. Seven underwent GH stimulation testing and all had insufficient responses with a median GH peak of 3.7 ng/ml (range 1.1-8.6). Growth patterns revealed a drastic decline in length z-scores within the first year of life but then stabilized afterward. Five were treated with GH; one discontinued due to inconsolability. The other four participants continued on GH with improvement in linear growth velocity. Other endocrinopathies were identified in 7 of the 11 participants in this cohort. This study indicates that GH deficiency is associated with MCAP and that children with MCAP and hypoglycemia and/or postnatal growth failure should be evaluated for GH deficiency and other endocrinopathies

ERRγ enhances cardiac maturation with T-tubule formation in human iPSC-derived cardiomyocytes

ヒトのiPS細胞から新生児レベルまで成熟した心筋細胞を作製する. 京都大学プレスリリース. 2021-06-21.Lowering the cost of heart cell therapies. 京都大学プレスリリース. 2021-06-21.One of the earliest maturation steps in cardiomyocytes (CMs) is the sarcomere protein isoform switch between TNNI1 and TNNI3 (fetal and neonatal/adult troponin I). Here, we generate human induced pluripotent stem cells (hiPSCs) carrying a TNNI1[EmGFP] and TNNI3[mCherry] double reporter to monitor and isolate mature sub-populations during cardiac differentiation. Extensive drug screening identifies two compounds, an estrogen-related receptor gamma (ERRγ) agonist and an S-phase kinase-associated protein 2 inhibitor, that enhances cardiac maturation and a significant change to TNNI3 expression. Expression, morphological, functional, and molecular analyses indicate that hiPSC-CMs treated with the ERRγ agonist show a larger cell size, longer sarcomere length, the presence of transverse tubules, and enhanced metabolic function and contractile and electrical properties. Here, we show that ERRγ-treated hiPSC-CMs have a mature cellular property consistent with neonatal CMs and are useful for disease modeling and regenerative medicine

Measurement of the Lifetime Difference Between B_s Mass Eigenstates

We present measurements of the lifetimes and polarization amplitudes for B_s --> J/psi phi and B_d --> J/psi K*0 decays. Lifetimes of the heavy (H) and light (L) mass eigenstates in the B_s system are separately measured for the first time by determining the relative contributions of amplitudes with definite CP as a function of the decay time. Using 203 +/- 15 B_s decays, we obtain tau_L = (1.05 +{0.16}/-{0.13} +/- 0.02) ps and tau_H = (2.07 +{0.58}/-{0.46} +/- 0.03) ps. Expressed in terms of the difference DeltaGamma_s and average Gamma_s, of the decay rates of the two eigenstates, the results are DeltaGamma_s/Gamma_s = (65 +{25}/-{33} +/- 1)%, and DeltaGamma_s = (0.47 +{0.19}/-{0.24} +/- 0.01) inverse ps.Comment: 8 pages, 3 figures, 2 tables; as published in Physical Review Letters on 16 March 2005; revisions are for length and typesetting only, no changes in results or conclusion

Evidence for a Grooming Claw in a North American Adapiform Primate: Implications for Anthropoid Origins

Among fossil primates, the Eocene adapiforms have been suggested as the closest relatives of living anthropoids (monkeys, apes, and humans). Central to this argument is the form of the second pedal digit. Extant strepsirrhines and tarsiers possess a grooming claw on this digit, while most anthropoids have a nail. While controversial, the possible presence of a nail in certain European adapiforms has been considered evidence for anthropoid affinities. Skeletons preserved well enough to test this idea have been lacking for North American adapiforms. Here, we document and quantitatively analyze, for the first time, a dentally associated skeleton of Notharctus tenebrosus from the early Eocene of Wyoming that preserves the complete bones of digit II in semi-articulation. Utilizing twelve shape variables, we compare the distal phalanges of Notharctus tenebrosus to those of extant primates that bear nails (n = 21), tegulae (n = 4), and grooming claws (n = 10), and those of non-primates that bear claws (n = 7). Quantitative analyses demonstrate that Notharctus tenebrosus possessed a grooming claw with a surprisingly well-developed apical tuft on its second pedal digit. The presence of a wide apical tuft on the pedal digit II of Notharctus tenebrosus may reflect intermediate morphology between a typical grooming claw and a nail, which is consistent with the recent hypothesis that loss of a grooming claw occurred in a clade containing adapiforms (e.g. Darwinius masillae) and anthropoids. However, a cladistic analysis including newly documented morphologies and thorough representation of characters acknowledged to have states constituting strepsirrhine, haplorhine, and anthropoid synapomorphies groups Notharctus tenebrosus and Darwinius masillae with extant strepsirrhines rather than haplorhines suggesting that the form of pedal digit II reflects substantial homoplasy during the course of early primate evolution

CD151 expression marks atrial- and ventricular- differentiation from human induced pluripotent stem cells

Abstract Current differentiation protocols for human induced pluripotent stem cells (hiPSCs) produce heterogeneous cardiomyocytes (CMs). Although chamber-specific CM selection using cell surface antigens enhances biomedical applications, a cell surface marker that accurately distinguishes between hiPSC-derived atrial CMs (ACMs) and ventricular CMs (VCMs) has not yet been identified. We have developed an approach for obtaining functional hiPSC-ACMs and -VCMs based on CD151 expression. For ACM differentiation, we found that ACMs are enriched in the CD151low population and that CD151 expression is correlated with the expression of Notch4 and its ligands. Furthermore, Notch signaling inhibition followed by selecting the CD151low population during atrial differentiation leads to the highly efficient generation of ACMs as evidenced by gene expression and electrophysiology. In contrast, for VCM differentiation, VCMs exhibiting a ventricular-related gene signature and uniform action potentials are enriched in the CD151high population. Our findings enable the production of high-quality ACMs and VCMs appropriate for hiPSC-derived chamber-specific disease models and other applications

Genome-wide association study and meta-analysis identify loci associated with ventricular and supraventricular ectopy

Abstract The genetic basis of supraventricular and ventricular ectopy (SVE, VE) remains largely uncharacterized, despite established genetic mechanisms of arrhythmogenesis. To identify novel genetic variants associated with SVE/VE in ancestrally diverse human populations, we conducted a genome-wide association study of electrocardiographically identified SVE and VE in five cohorts including approximately 43,000 participants of African, European and Hispanic/Latino ancestry. In thirteen ancestry-stratified subgroups, we tested multivariable-adjusted associations of SVE and VE with single nucleotide polymorphism (SNP) dosage. We combined subgroup-specific association estimates in inverse variance-weighted, fixed-effects and Bayesian meta-analyses. We also combined fixed-effects meta-analytic t-test statistics for SVE and VE in multi-trait SNP association analyses. No loci reached genome-wide significance in trans-ethnic meta-analyses. However, we found genome-wide significant SNPs intronic to an apoptosis-enhancing gene previously associated with QRS interval duration (FAF1; lead SNP rs7545860; effect allele frequency = 0.02; P = 2.0 × 10−8) in multi-trait analysis among European ancestry participants and near a locus encoding calcium-dependent glycoproteins (DSC3; lead SNP rs8086068; effect allele frequency = 0.17) in meta-analysis of SVE (P = 4.0 × 10−8) and multi-trait analysis (P = 2.9 × 10−9) among African ancestry participants. The novel findings suggest several mechanisms by which genetic variation may predispose to ectopy in humans and highlight the potential value of leveraging pleiotropy in future studies of ectopy-related phenotypes