Royal Society Scientific Meeting: Extracellular vesicles in the tumour microenvironment

Cancer cells do not grow as an isolated homogeneous mass; tumours are, in fact, complex and heterogeneous collections of cancer and surrounding stromal cells, collectively termed the tumour microenvironment. The interaction between cancer cells and stromal cells in the tumour microenvironment has emerged as a key concept in the regulation of cancer progression. Understanding the intercellular dialogue in the tumour microenvironment is therefore an important goal. One aspect of this dialogue which has not been appreciated until recently is the role of extracellular vesicles (EVs). EVs are small vesicles released by cells under both normal and pathological conditions; they can transfer biological molecules between cells leading to changes in phenotype. EVs have emerged as important regulators of biological processes and can be dysregulated in diseases such as cancer; rapidly growing interest in their biology and therapeutic potential led to the Royal Society hosting a Scientific Meeting to explore the roles of EVs in the tumour microenvironment. This cross-disciplinary meeting explored examples of how aberrant cross-talk between tumour and stromal cells can promote cancer progression, and how such signalling can be targeted for diagnostic, prognostic and therapeutic benefit. In this review, and the special edition of Philosophical Transactions of the Royal Society B that follows, we will provide an overview of the content and outcomes of this exciting meeting

The barium isotopic mixture for the metal-poor subgiant star HD140283

Current theory regarding heavy element nucleosynthesis in metal-poor environments states that the r-process would be dominant. The star HD140283 has been the subject of debate after it appeared in some studies to be dominated by the s-process. We provide an independent measure of the Ba isotope mixture in HD140283 using an extremely high quality spectrum and an extensive chi^2 analysis. We exploit hyperfine splitting of the BaII 4554 \AA\ and 4934 \AA\ resonance lines in an effort to constrain the isotope ratio in 1D LTE. Using the code ATLAS in conjunction with KURUCZ06 model atmospheres we analyse 93 Fe lines to determine the star's macroturbulence. With this information we construct a grid of Ba synthetic spectra and, using a \chi^2 code, fit these to our observed data to determine the isotopic ratio, fodd, which represents the ratio of odd to even isotopes. We also analyse the Eu lines. We set a new upper limit of the rotation of HD140283 at vsin{i}\leq3.9\kms, a new upper limit on [Eu/H] < -2.80 and abundances [Fe/H] = -2.59\pm0.09, [Ba/H] = -3.46\pm0.11. This leads to a new lower limit on [Ba/Eu] > -0.66. We find that, in the framework of a 1D LTE analysis, the isotopic ratios of Ba in HD140283 indicate fodd=0.02\pm0.06, a purely s-process signature. This implies that observations and analysis do not validate currently accepted theory. We speculate that a 1D code, due to simplifying assumptions, is not adequate when dealing with observations with high levels of resolution and S/N because of the turbulent motions associated with a 3D stellar atmosphere. New approaches to analysing isotopic ratios, in particular 3D hydrodynamics, need to be considered when dealing with the levels of detail required to properly determine them. However published 3D results exacerbate the disagreement between theory and observation.Comment: 16 pages, 10 figures, 7 tables, 1 online appendix Accepted by A&

Exploring the Structures and Substructures of the Andromeda Satellite Dwarf Galaxies Cassiopeia III, Perseus I, and Lacerta I

We present results from wide-field imaging of the resolved stellar populations of the dwarf spheroidal galaxies Cassiopeia III (And XXXII) and Perseus I (And XXXIII), two satellites in the outer stellar halo of the Andromeda galaxy (M31). Our WIYN pODI photometry traces the red giant star population in each galaxy to ~2.5-3 half-light radii from the galaxy center. We use the Tip of the Red Giant Branch (TRGB) method to derive distances of (m-M)_0 = 24.62+/-0.12 mag (839 (+48,-450) kpc, or 156 (+16,-13) kpc from M31) for Cas III and 24.47+/-0.13 mag (738 (+48,-45) kpc, or 351 (+17,-16) kpc from M31) for Per I. These values are consistent within the errors with TRGB distances derived from a deeper Hubble Space Telescope study of the galaxies' inner regions. For each galaxy, we derive structural parameters, total magnitude, and central surface brightness. We also place upper limits on the ratio of neutral hydrogen gas mass to optical luminosity, confirming the gas-poor nature of both galaxies. We combine our data set with corresponding data for the M31 satellite galaxy Lacerta I (And XXXI) from earlier work, and search for substructure within the RGB star populations of Cas III, Per I, and Lac I. We find an overdense region on the west side of Lac I at a significance level of 2.5-3-sigma and a low-significance filament extending in the direction of M31. In Cas III, we identify two modestly significant overdensities near the center of the galaxy and another at two half-light radii. Per I shows no evidence for substructure in its RGB star population, which may reflect this galaxy's isolated nature.Comment: 26 pages, 15 figures, 5 tables. Accepted for publication in The Astronomical Journa

Srf1 Is a Novel Regulator of Phospholipase D Activity and Is Essential to Buffer the Toxic Effects of C16:0 Platelet Activating Factor

During Alzheimer's Disease, sustained exposure to amyloid-β42 oligomers perturbs metabolism of ether-linked glycerophospholipids defined by a saturated 16 carbon chain at the sn-1 position. The intraneuronal accumulation of 1-O-hexadecyl-2-acetyl-sn-glycerophosphocholine (C16:0 PAF), but not its immediate precursor 1-O-hexadecyl-sn-glycerophosphocholine (C16:0 lyso-PAF), participates in signaling tau hyperphosphorylation and compromises neuronal viability. As C16:0 PAF is a naturally occurring lipid involved in cellular signaling, it is likely that mechanisms exist to protect cells against its toxic effects. Here, we utilized a chemical genomic approach to identify key processes specific for regulating the sensitivity of Saccharomyces cerevisiae to alkyacylglycerophosphocholines elevated in Alzheimer's Disease. We identified ten deletion mutants that were hypersensitive to C16:0 PAF and five deletion mutants that were hypersensitive to C16:0 lyso-PAF. Deletion of YDL133w, a previously uncharacterized gene which we have renamed SRF1 (Spo14 Regulatory Factor 1), resulted in the greatest differential sensitivity to C16:0 PAF over C16:0 lyso-PAF. We demonstrate that Srf1 physically interacts with Spo14, yeast phospholipase D (PLD), and is essential for PLD catalytic activity in mitotic cells. Though C16:0 PAF treatment does not impact hydrolysis of phosphatidylcholine in yeast, C16:0 PAF does promote delocalization of GFP-Spo14 and phosphatidic acid from the cell periphery. Furthermore, we demonstrate that, similar to yeast cells, PLD activity is required to protect mammalian neural cells from C16:0 PAF. Together, these findings implicate PLD as a potential neuroprotective target capable of ameliorating disruptions in lipid metabolism in response to accumulating oligomeric amyloid-β42

Longitudinal Assessment of Growth in Hypoplastic Left Heart Syndrome: Results From the Single Ventricle Reconstruction Trial

Background: We sought to characterize growth between birth and age 3 years in infants with hypoplastic left heart syndrome who underwent the Norwood procedure. Methods and Results: We performed a secondary analysis using the Single Ventricle Reconstruction Trial database after excluding patients 2 SD below normal). Failure to find consistent risk factors supports the strategy of tailoring nutritional therapies to patient‐ and stage‐specific targets. Clinical Trial Registration URL: http://clinicaltrials.gov/. Unique identifier: NCT00115934

TOI-5375 B: A Very Low Mass Star at the Hydrogen-Burning Limit Orbiting an Early M-type Star

The TESS mission detected a companion orbiting TIC 71268730, categorized it as a planet candidate, and designated the system TOI-5375. Our follow-up analysis using radial velocity data from the Habitable-zone Planet Finder (HPF), photometric data from Red Buttes Observatory (RBO), and speckle imaging with NN-EXPLORE Exoplanet Stellar Speckle Imager (NESSI) determined that the companion is a very low mass star (VLMS) near the hydrogen-burning mass limit with a mass of 0.080\pm{0.002} M_{\Sun} ($83.81\pm{2.10} M_{J}$), a radius of 0.1114^{+0.0048}_{-0.0050} R_{\Sun} (1.0841$^{0.0467}_{0.0487} R_{J}$), and brightness temperature of $2600\pm{70}$ K. This object orbits with a period of 1.721553$\pm{0.000001}$ days around an early M dwarf star (0.62\pm{0.016}M_{\Sun}). TESS photometry shows regular variations in the host star's TESS light curve, which we interpreted as activity-induced variation of $\sim$2\%, and used this variability to measure the host star's stellar rotation period of 1.9716$^{+0.0080}_{-0.0083}$ days. The TOI-5375 system provides tight constraints on stellar models of low-mass stars at the hydrogen-burning limit and adds to the population in this important region.Comment: 15 pages, 8 figures, Accepted to the Astronomical Journa

Galactic chemical abundance evolution in the solar neighborhood up to the Iron peak

We have developed a detailed standard chemical evolution model to study the evolution of all the chemical elements up to the iron peak in the solar vicinity. We consider that the Galaxy was formed through two episodes of exponentially decreasing infall, out of extragalactic gas. In a first infall episode, with a duration of $\sim$ 1 Gyr, the halo and the thick disk were assembled out of primordial gas, while the thin disk formed in a second episode of infall of slightly enriched extragalactic gas, with much longer timescale. The model nicely reproduces the main observational constraints of the solar neighborhood, and the calculated elemental abundances at the time of the solar birth are in excellent agreement with the solar abundances. By the inclusion of metallicity dependent yields for the whole range of stellar masses we follow the evolution of 76 isotopes of all the chemical elements between hydrogen and zinc. Those results are confronted with a large and recent body of observational data, and we discuss in detail the implications for stellar nucleosynthesis.Comment: 19 pages, 14 figures, submitted to A&

Correction: Computationally guided discovery of a reactive, hydrophilic: Trans -5-oxocene dienophile for bioorthogonal labeling:(Organic and Biomolecular Chemistry (2017) 15 (6640-6644) DOI: 10.1039/C7OB01707C)

Correction for ‘Computationally guided discovery of a reactive, hydrophilic trans-5-oxocene dienophile for bioorthogonal labeling’ by William D. Lambert et al., Org. Biomol. Chem., 2017, 15, 6640–6644