A second planet transiting LTT 1445A and a determination of the masses of both worlds

K.H. acknowledges support from STFC grant ST/R000824/1.LTT 1445 is a hierarchical triple M-dwarf star system located at a distance of 6.86 pc. The primary star LTT 1445A (0.257 M⊙) is known to host the transiting planet LTT 1445Ab with an orbital period of 5.36 days, making it the second-closest known transiting exoplanet system, and the closest one for which the host is an M dwarf. Using Transiting Exoplanet Survey Satellite data, we present the discovery of a second planet in the LTT 1445 system, with an orbital period of 3.12 days. We combine radial-velocity measurements obtained from the five spectrographs, Echelle Spectrograph for Rocky Exoplanets and Stable Spectroscopic Observations, High Accuracy Radial Velocity Planet Searcher, High-Resolution Echelle Spectrometer, MAROON-X, and Planet Finder Spectrograph to establish that the new world also orbits LTT 1445A. We determine the mass and radius of LTT 1445Ab to be 2.87 ± 0.25 M⊕ and 1.304-0.060+0.067 R⊕, consistent with an Earth-like composition. For the newly discovered LTT 1445Ac, we measure a mass of 1.54-0.19+0.20 M⊕ and a minimum radius of 1.15 R⊕, but we cannot determine the radius directly as the signal-to-noise ratio of our light curve permits both grazing and nongrazing configurations. Using MEarth photometry and ground-based spectroscopy, we establish that star C (0.161 M⊙) is likely the source of the 1.4 day rotation period, and star B (0.215 M⊙) has a likely rotation period of 6.7 days. We estimate a probable rotation period of 85 days for LTT 1445A. Thus, this triple M-dwarf system appears to be in a special evolutionary stage where the most massive M dwarf has spun down, the intermediate mass M dwarf is in the process of spinning down, while the least massive stellar component has not yet begun to spin down.Publisher PDFPeer reviewe

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

<i>PIK3CA</i> missense mutations promote glioblastoma pathogenesis, but do not enhance targeted PI3K inhibition

<div><p>Background</p><p>Glioblastoma (GBM) is the most common adult primary brain tumor. Multimodal treatment is empiric and prognosis remains poor. Recurrent <i>PIK3CA</i> missense mutations (<i>PIK3CA</i>^<i>mut</i>) in GBM are restricted to three functional domains: adaptor binding (ABD), helical, and kinase. Defining how these mutations influence gliomagenesis and response to kinase inhibitors may aid in the clinical development of novel targeted therapies in biomarker-stratified patients.</p><p>Methods</p><p>We used normal human astrocytes immortalized via expression of hTERT, E6, and E7 (NHA). We selected two <i>PIK3CA</i>^<i>mut</i> from each of 3 mutated domains and induced their expression in NHA with (NHA^RAS) and without mutant <i>RAS</i> using lentiviral vectors. We then examined the role of <i>PIK3CA</i>^<i>mut</i> in gliomagenesis <i>in vitro</i> and in mice, as well as response to targeted PI3K (PI3Ki) and MEK (MEKi) inhibitors <i>in vitro</i>.</p><p>Results</p><p><i>PIK3CA</i>^<i>mut</i>, particularly helical and kinase domain mutations, potentiated proximal PI3K signaling and migration of NHA and NHA^RAS<i>in vitro</i>. Only kinase domain mutations promoted NHA colony formation, but both helical and kinase domain mutations promoted NHA^RAS tumorigenesis <i>in vivo</i>. <i>PIK3CA</i>^<i>mut</i> status had minimal effects on PI3Ki and MEKi efficacy. However, PI3Ki/MEKi synergism was pronounced in NHA and NHA^RAS harboring ABD or helical mutations.</p><p>Conclusion</p><p><i>PIK3CA</i>^<i>mut</i> promoted differential gliomagenesis based on the mutated domain. While <i>PIK3CA</i>^<i>mut</i> did not influence sensitivity to single agent PI3Ki, they did alter PI3Ki/MEKi synergism. Taken together, our results demonstrate that a subset of <i>PIK3CA</i>^<i>mut</i> promote tumorigenesis and suggest that patients with helical domain mutations may be most sensitive to dual PI3Ki/MEKi treatment.</p></div

Helical and kinase <i>PIK3CA</i>^<i>mut</i> potentiate cellular transformation and tumorigenesis.

<p>Only H1047R increased colony formation compared to parental (*, P = 0.03) and <i>PIKCA</i>^<i>WT</i> (ǂ, P = 0.04) NHA (<b>A</b>). H1047R did not affect colony formation of NHA^RAS (P = 0.5). Orthotopic xenografts of GFP, <i>PIK3CA</i>^<i>WT</i>, and <i>PIK3CA</i>^<i>mut</i> NHA^RAS (<b>BC</b>). Median survival of mice with R88Q, E542K, or H1047R <i>PIK3CA</i>^<i>mut</i> NHA^RAS was decreased compared to GFP control tumors (*, P≤0.003). E542K and H1047R <i>PIK3CA</i>^<i>mut</i> also decreased survival compared to <i>PIK3CA</i>^<i>WT</i> (ǂ, P≤0.002) and R88Q <i>PIK3CA</i>^<i>mut</i> (P<0.0001). Fold changes in median survival relative to GFP and <i>PIK3CA</i>^<i>WT</i> NHA^RAS are shown as heatmaps.</p

MEKi inhibits growth and ablates MAPK regardless of <i>PIK3CA</i>^<i>mut</i> status.

<p>Selumetinib IC₅₀ were similar regardless of <i>PIK3CA</i>^<i>mut</i> status in NHA (<b>A</b>), but slightly higher in most <i>PIK3CA</i>^<i>mut</i> NHA^RAS compared to parental cells (*, P≤0.03) (<b>B</b>) (<b><a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0200014#pone.0200014.s011" target="_blank">S11 Fig</a></b>). Fold changes in IC₅₀ relative to parental and <i>PIK3CA</i>^<i>WT</i> lines are shown as heatmaps. Representative immunoblots of control and <i>PIK3CA</i>^<i>mut</i> NHA (<b>C</b>) and NHA^RAS (<b>F</b>) treated with selumetinib for 24 h. Immunoblot quantification (<b>DEGH</b>) demonstrated dose-dependent decreases in MAPK in NHA (<b>D</b>) and NHA^RAS (<b>G</b>) lines. Although proximal PI3K was induced in control and <i>PIK3CA</i>^<i>mut</i> NHA (<b>E</b>), it was only potentiated in GFP and parental NHA^RAS (<b>H</b>) (<b><a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0200014#pone.0200014.s012" target="_blank">S12 Fig</a></b>). Western blots were performed either 1 or 2 times per experiment (Mean = 1.8).</p