Mimotopes and Proteome Analyses Using Human Genomic and cDNA Epitope Phage Display

In the post-genomic era, validation of candidate gene targets frequently requires proteinbased strategies. Phage display is a powerful tool to define protein-protein interactions by generating peptide binders against target antigens. Epitope phage display libraries have the potential to enrich coding exon sequences from human genomic loci. We evaluated genomic and cDNA phage display strategies to identify genes in the 5q31 Interleukin gene cluster and to enrich cell surface receptor tyrosine kinase genes from a breast cancer cDNA library. A genomic display library containing 2 × 10 6 clones with exon-sized inserts was selected with antibodies specific for human Interleukin-4 (IL-4) and Interleukin-13. The library was enriched significantly after two selection rounds and DNA sequencing revealed unique clones. One clone matched a cognate IL-4 epitope; however, the majority of clone insert sequences corresponded to E. coli genomic DNA. These bacterial sequences act as ‘mimotopes’ (mimetic sequences of the true epitope), correspond to open reading frames, generate displayed peptides, and compete for binding during phage selection. The specificity of these mimotopes for IL-4 was confirmed by competition ELISA. Other E. coli mimotopes were generated using additional antibodies. Mimotopes for a receptor tyrosine kinase gene were also selected using a breast cancer SKBR-3 cDNA phage display library, screened against an anti-erbB2 monoclonal antibody. Identification of mimotopes in genomic and cDNA phage libraries is essential for phage display-based protein validation assays and two-hybrid phage approaches that examine protein-protein interactions. The predominance of E. coli mimotopes suggests that the E. coli genome may be useful to generate peptide diversity biased towards protein coding sequences

K2-114b and K2-115b : two transiting warm Jupiters

A.C.C. acknowledges support from STFC consolidated grant number ST/M001296/1.We report the first results from a search for transiting warm Jupiter exoplanets—gas giant planets receiving stellar irradiation below about 108 erg−1 cm−2, equivalent to orbital periods beyond about 10 days around Sun-like stars. We have discovered two transiting warm Jupiter exoplanets initially identified as transiting candidates in K2 photometry. K2-114b has a mass of 1.85^(+0.23)_(-0.22) MJ, a radius of 0.942^(+0.032)_(-0.020) RJ, and an orbital period of 11.4 days. K2-115b has a mass of 0.84^(+0.18)_(-0.20) MJ, a radius of 1.115^(+0.057)_(-0.061) RJ, and an orbital period of 20.3 days. Both planets are among the longest-period transiting gas giant planets with a measured mass, and they are orbiting relatively old host stars. Both planets are not inflated, as their radii are consistent with theoretical expectations. Their position in the planet radius–stellar irradiation diagram is consistent with the scenario where the radius–irradiation correlation levels off below about 108 erg s−1 cm−2, suggesting that for warm Jupiters stellar irradiation does not play a significant role in determining the planet radius. We also report our identification of another K2 transiting warm Jupiter candidate, EPIC 212504617, as a false positive.Publisher PDFPeer reviewe

Aerosols implicated as a prime driver of twentieth-century North Atlantic climate variability

Systematic climate shifts have been linked to multidecadal variability in observed sea surface temperatures in the North Atlantic Ocean1. These links are extensive, influencing a range of climate processes such as hurricane activity2 and African Sahel3, 4, 5 and Amazonian5 droughts. The variability is distinct from historical global-mean temperature changes and is commonly attributed to natural ocean oscillations6, 7, 8, 9, 10. A number of studies have provided evidence that aerosols can influence long-term changes in sea surface temperatures11, 12, but climate models have so far failed to reproduce these interactions6, 9 and the role of aerosols in decadal variability remains unclear. Here we use a state-of-the-art Earth system climate model to show that aerosol emissions and periods of volcanic activity explain 76 per cent of the simulated multidecadal variance in detrended 1860–2005 North Atlantic sea surface temperatures. After 1950, simulated variability is within observational estimates; our estimates for 1910–1940 capture twice the warming of previous generation models but do not explain the entire observed trend. Other processes, such as ocean circulation, may also have contributed to variability in the early twentieth century. Mechanistically, we find that inclusion of aerosol–cloud microphysical effects, which were included in few previous multimodel ensembles, dominates the magnitude (80 per cent) and the spatial pattern of the total surface aerosol forcing in the North Atlantic. Our findings suggest that anthropogenic aerosol emissions influenced a range of societally important historical climate events such as peaks in hurricane activity and Sahel drought. Decadal-scale model predictions of regional Atlantic climate will probably be improved by incorporating aerosol–cloud microphysical interactions and estimates of future concentrations of aerosols, emissions of which are directly addressable by policy actions

The Hubble Space Telescope Survey of M31 Satellite Galaxies. II. The Star Formation Histories of Ultrafaint Dwarf Galaxies

We present the lifetime star formation histories (SFHs) for six ultrafaint dwarf (UFD; M V > − 7.0, 4.9<log10(M*(z=0)/M⊙)<5.5 ) satellite galaxies of M31 based on deep color–magnitude diagrams constructed from Hubble Space Telescope imaging. These are the first SFHs obtained from the oldest main-sequence turnoff of UFDs outside the halo of the Milky Way (MW). We find that five UFDs formed at least 50% of their stellar mass by z = 5 (12.6 Gyr ago), similar to known UFDs around the MW, but that 10%–40% of their stellar mass formed at later times. We uncover one remarkable UFD, And xiii, which formed only 10% of its stellar mass by z = 5, and 75% in a rapid burst at z ∼ 2–3, a result that is robust to choices of underlying stellar model and is consistent with its predominantly red horizontal branch. This “young” UFD is the first of its kind and indicates that not all UFDs are necessarily quenched by reionization, which is consistent with predictions from several cosmological simulations of faint dwarf galaxies. SFHs of the combined MW and M31 samples suggest reionization did not homogeneously quench UFDs. We find that the least-massive MW UFDs (M *(z = 5) ≲ 5 × 104 M ⊙) are likely quenched by reionization, whereas more-massive M31 UFDs (M *(z = 5) ≳ 105 M ⊙) may only have their star formation suppressed by reionization and quench at a later time. We discuss these findings in the context of the evolution and quenching of UFDs

TESS Discovery of Twin Planets near 2:1 Resonance around Early M-Dwarf TOI 4342

With data from the Transiting Exoplanet Survey Satellite (TESS), we showcase improvements to the MIT Quick-Look Pipeline (QLP) through the discovery and validation of a multi-planet system around M-dwarf TOI 4342 ($T_{mag}=11.032$, $M_* = 0.63 M_\odot$, $R_* = 0.60 R_\odot$, $T_{eff} = 3900$ K, $d = 61.54$ pc). With updates to QLP, including a new multi-planet search, as well as faster cadence data from TESS' First Extended Mission, we discovered two sub-Neptunes ($R_b = 2.266_{-0.038}^{+0.038} R_\oplus$ and $R_c = 2.415_{-0.040}^{+0.043} R_\oplus$; $P_b$ = 5.538 days and $P_c$ = 10.689 days) and validated them with ground-based photometry, spectra, and speckle imaging. Both planets notably have high transmission spectroscopy metrics (TSMs) of 36 and 32, making TOI 4342 one of the best systems for comparative atmospheric studies. This system demonstrates how improvements to QLP, along with faster cadence Full-Frame Images (FFIs), can lead to the discovery of new multi-planet systems.Comment: accepted for publication in A

A Rogues’ Gallery of Andromeda's Dwarf Galaxies. I. A Predominance of Red Horizontal Branches

We present homogeneous, sub-horizontal branch photometry of twenty dwarf spheroidal satellite galaxies of M31 observed with the Hubble Space Telescope. Combining our new data for sixteen systems with archival data in the same filters for another four, we show that Andromeda dwarf spheroidal galaxies favor strikingly red horizontal branches or red clumps down to ~10^{4.2} Lsun (M_V ~ -5.8). The age-sensitivity of horizontal branch stars implies that a large fraction of the M31 dwarf galaxies have extended star formation histories (SFHs), and appear inconsistent with early star formation episodes that were rapidly shutdown. Systems fainter than ~10^{5.5} Lsun show the widest range in the ratios and morphologies of red and blue horizontal branches, indicative of both complex SFHs and a diversity in quenching timescales and/or mechanisms, which is qualitatively different from what is currently known for faint Milky Way (MW) satellites of comparable luminosities. Our findings bolster similar conclusions from recent deeper data for a handful of M31 dwarf galaxies. We discuss several sources for diversity of our data such as varying halo masses, patchy reionization, mergers/accretion, and the environmental influence of M31 and the Milky Way on the early evolution of their satellite populations. A detailed comparison between the histories of M31 and MW satellites would shed signifiant insight into the processes that drive the evolution of low-mass galaxies. Such a study will require imaging that reaches the oldest main sequence turnoffs for a significant number of M31 companions.Comment: 11 pages, 5 figures, 2 tables. ApJ in press. v2: small tweaks to the results and discussion sectio

On the need for an international effort to capture, share and use crystallization screening data

Development of an ontology for the description of crystallization experiments and results is proposed

Clinical resistance to crenolanib in acute myeloid leukemia due to diverse molecular mechanisms.

FLT3 mutations are prevalent in AML patients and confer poor prognosis. Crenolanib, a potent type I pan-FLT3 inhibitor, is effective against both internal tandem duplications and resistance-conferring tyrosine kinase domain mutations. While crenolanib monotherapy has demonstrated clinical benefit in heavily pretreated relapsed/refractory AML patients, responses are transient and relapse eventually occurs. Here, to investigate the mechanisms of crenolanib resistance, we perform whole exome sequencing of AML patient samples before and after crenolanib treatment. Unlike other FLT3 inhibitors, crenolanib does not induce FLT3 secondary mutations, and mutations of the FLT3 gatekeeper residue are infrequent. Instead, mutations of NRAS and IDH2 arise, mostly as FLT3-independent subclones, while TET2 and IDH1 predominantly co-occur with FLT3-mutant clones and are enriched in crenolanib poor-responders. The remaining patients exhibit post-crenolanib expansion of mutations associated with epigenetic regulators, transcription factors, and cohesion factors, suggesting diverse genetic/epigenetic mechanisms of crenolanib resistance. Drug combinations in experimental models restore crenolanib sensitivity.This work was supported in part by The Leukemia & Lymphoma Society Beat AML Program, the V Foundation for Cancer Research, the Gabrielle’s Angel Foundation for Cancer Research and the National Cancer Institute (1R01CA183947–01; 1U01CA217862–01; 1U54CA224019-01; 3P30CA069533-18S5). H.Z. received a Collins Medical Trust research grant. S.D.B. was supported by the National Cancer Institute (5R01CA138744-08)

The LHS 1678 system : two earth-sized transiting planets and an astrometric companion orbiting an M dwarf near the convective boundary at 20 pc

Funding: The MEarth Team gratefully acknowledges funding from the David and Lucile Packard Fellowship for Science and Engineering (awarded to D.C.). This material is based upon work supported by the National Science Foundation under grants AST-0807690, AST-1109468, AST-1004488 (Alan T. Waterman Award), and AST-1616624, and upon work supported by the National Aeronautics and Space Administration under Grant No. 80NSSC18K0476 issued through the XRP Program. This work is made possible by a grant from the John Templeton Foundation. N. A.-D. acknowledges the support of FONDECYT project 3180063. TD acknowledges support from MIT’s Kavli Institute as a Kavli postdoctoral fellow. KH acknowledges support from STFC grant ST/R000824/1. E.A.G. thanks the LSSTC Data Science Fellowship Program, which is funded by LSSTC, NSF Cybertraining Grant #1829740, the Brinson Foundation, and the Moore Foundation; The material is based upon work supported by NASA under award number 80GSFC21M0002. This work was supported by the lead author’s appointment to the NASA Postdoctoral Program at the Goddard Space Flight Center, administered by Universities Space Research Association under contract with NASAWe present the Transiting Exoplanet Survey Satellite (TESS) discovery of the LHS 1678 (TOI-696) exoplanet system, comprised of two approximately Earth-sized transiting planets and a likely astrometric brown dwarf orbiting a bright (VJ = 12.5, Ks = 8.3) M2 dwarf at 19.9 pc. The two TESS-detected planets are of radius 0.70 ± 0.04 R⊕ and 0.98 ± 0.06 R⊕ in 0.86 day and 3.69 day orbits, respectively. Both planets are validated and characterized via ground-based follow-up observations. High Accuracy Radial Velocity Planet Searcher RV monitoring yields 97.7 percentile mass upper limits of 0.35 M⊕ and 1.4 M⊕ for planets b and c, respectively. The astrometric companion detected by the Cerro Tololo Inter-American Observatory/Small and Moderate Aperture Telescope System 0.9 m has an orbital period on the order of decades and is undetected by other means. Additional ground-based observations constrain the companion to being a high-mass brown dwarf or smaller. Each planet is of unique interest; the inner planet has an ultra-short period, and the outer planet is in the Venus zone. Both are promising targets for atmospheric characterization with the James Webb Space Telescope and mass measurements via extreme-precision radial velocity. A third planet candidate of radius 0.9 ± 0.1 R⊕ in a 4.97 day orbit is also identified in multicycle TESS data for validation in future work. The host star is associated with an observed gap in the lower main sequence of the Hertzsprung–Russell diagram. This gap is tied to the transition from partially to fully convective interiors in M dwarfs, and the effect of the associated stellar astrophysics on exoplanet evolution is currently unknown. The culmination of these system properties makes LHS 1678 a unique, compelling playground for comparative exoplanet science and understanding the formation and evolution of small, short-period exoplanets orbiting low-mass stars.Publisher PDFPeer reviewe