Molecule mapping of HR8799b using OSIRIS on Keck: Strong detection of water and carbon monoxide, but no methane

Context. In 2015, Barman et al. (ApJ, 804, 61) presented detections of absorption from water, carbon monoxide, and methane in the atmosphere of the directly imaged exoplanet HR8799b using integral field spectroscopy (IFS) with OSIRIS on the Keck II telescope. We recently devised a new method to analyse IFU data, called molecule mapping, searching for high-frequency signatures of particular molecules in an IFU data cube. Aims. The aim of this paper is to use the molecule mapping technique to search for the previously detected spectral signatures in HR8799b using the same data, allowing a comparison of molecule mapping with previous methods. Methods. The medium-resolution H- and K-band pipeline-reduced archival data were retrieved from the Keck archive facility. Telluric and stellar lines were removed from each spectrum in the data cube, after which the residuals were cross-correlated with model spectra of carbon monoxide, water, and methane. Results. Both carbon monoxide and water are clearly detected at high signal-to-noise, however, methane is not retrieved. Conclusions. Molecule mapping works very well on the OSIRIS data of exoplanet HR8799b. However, it is not evident why methane is detected in the original analysis, but not with the molecule mapping technique. Possible causes could be the presence of telluric residuals, different spectral filtering techniques, or the use of different methane models. We do note that in the original analysis methane was only detected in the K-band, while the H-band methane signal could be expected to be comparably strong. More sensitive observations with the JWST will be capable of confirming or disproving the presence of methane in this planet at high confidence.Comment: 5 pages, 5 figures and 2 tables, accepted by A&

Efecto del suministro reducido de leche en la crianza de terneros utilizando leche entera y un reemplazador.

En ganado de leche es necesario investigar diferentes sistemas de crianza artificial de terneros con el fin de reducir los costos de alimentación y liberar mas leche para consumo humano en la medida que se incremente el uso de lacto-reemplazadores. En este trabajo se comparó el sistema Tibaitatá (170 litros de leche en 56 días), suministrados a diferentes niveles según edad con un nivel único de leche desde el 4o. día de nacido hasta los 56 días, contra el efecto biológico de suministro de un lacto-reemplazador en la cría de terneros de razas lecheras (Holstein). Se utilizaron 24 terneros (12 machos y 12 hembras) distribuidos en 3 grupos de 8 terneros. Los tratamientos fueron: 170 l,itros de leche entera suministrados de acuerdo a la edad del ternero, 170 litros de leche entera suministrados en nivel único de 3 litros/día y 170 litros de un lacto-reemplazador en niveles según edad. Además se les suministró concentrado a voluntad y pasto de una mezcla de raigrases (Lolium hibrydum) y tréboles (Trifolium repens), manejando los animales por el sistema de estaca en pastoreo y cambiándolos cada 24 horas. Los resultados mostraron que no hubo diferencias significativas entre tratamientos en peso, alzada y perímetro tonácico. Por lo tanto se recomienda criar terneros con lacto-reemplazador como sustituto total de la leche, con el fin de disminuir gástos en este período y suministrar un nivel único de leche desde el nacimiento hasta la época del destete, para simplificar el manejo de los terneros en esta etap

Biharmonic pattern selection

A new model to describe fractal growth is discussed which includes effects due to long-range coupling between displacements $u$. The model is based on the biharmonic equation $\nabla^{4}u =0$ in two-dimensional isotropic defect-free media as follows from the Kuramoto-Sivashinsky equation for pattern formation -or, alternatively, from the theory of elasticity. As a difference with Laplacian and Poisson growth models, in the new model the Laplacian of $u$ is neither zero nor proportional to $u$. Its discretization allows to reproduce a transition from dense to multibranched growth at a point in which the growth velocity exhibits a minimum similarly to what occurs within Poisson growth in planar geometry. Furthermore, in circular geometry the transition point is estimated for the simplest case from the relation $r_{\ell}\approx L/e^{1/2}$ such that the trajectories become stable at the growing surfaces in a continuous limit. Hence, within the biharmonic growth model, this transition depends only on the system size $L$ and occurs approximately at a distance $60 \%$ far from a central seed particle. The influence of biharmonic patterns on the growth probability for each lattice site is also analysed.Comment: To appear in Phys. Rev. E. Copies upon request to [email protected]

Utilizing TAPBPR to promote exogenous peptide loading onto cell surface MHC I molecules.

The repertoire of peptides displayed at the cell surface by MHC I molecules is shaped by two intracellular peptide editors, tapasin and TAPBPR. While cell-free assays have proven extremely useful in identifying the function of both of these proteins, here we explored whether a more physiological system could be developed to assess TAPBPR-mediated peptide editing on MHC I. We reveal that membrane-associated TAPBPR targeted to the plasma membrane retains its ability to function as a peptide editor and efficiently catalyzes peptide exchange on surface-expressed MHC I molecules. Additionally, we show that soluble TAPBPR, consisting of the luminal domain alone, added to intact cells, also functions as an effective peptide editor on surface MHC I molecules. Thus, we have established two systems in which TAPBPR-mediated peptide exchange on MHC class I can be interrogated. Furthermore, we could use both plasma membrane-targeted and exogenous soluble TAPBPR to display immunogenic peptides on surface MHC I molecules and consequently induce T cell receptor engagement, IFN-γ secretion, and T cell-mediated killing of target cells. Thus, we have developed an efficient way to by-pass the natural antigen presentation pathway of cells and load immunogenic peptides of choice onto cells. Our findings highlight a potential therapeutic use for TAPBPR in increasing the immunogenicity of tumors in the future

Overview of the oncogenic signaling pathways in colorectal cancer: Mechanistic insights.

Colorectal cancer is a multifaceted disease which is therapeutically challenging. Based on insights gleaned from almost a quarter century of research, it is obvious that deregulation of spatio-temporally controlled signaling pathways play instrumental role in development and progression of colorectal cancer. High-throughput technologies have helped to develop a sharper and broader understanding of the wide ranging signal transduction cascades which also contribute to development of drug resistance, loss of apoptosis and, ultimately, of metastasis. In this review, we have set the spotlight on role of JAK/STAT, TGF/SMAD, Notch, WNT/β-Catenin, SHH/GLI and p53 pathways in the development and progression of colorectal cancer. We have also highlighted recent reports on TRAIL-mediated pathways and molecularly distinct voltage-gated sodium channels in colorectal cancer

Telomere lengths in human oocytes, cleavage stage embryos and blastocysts

Telomeres are repeated sequences that protect the ends of chromosomes and harbour DNA-repair proteins. Telomeres shorten during each cell division in the absence of telomerase. When telomere length becomes critically short, cell senescence occurs. Telomere length therefore reflects both cellular ageing and capacity for division. We have measured telomere length in human germinal vesicle (GV) oocytes and pre-implantation embryos, by quantitative fluorescence in-situ hybridisation (Q-FISH), providing baseline data towards our hypothesis that telomere length is a marker of embryo quality. The numbers of fluorescent foci suggest that extensive clustering of telomeres occurs in mature GV stage oocytes, and in pre-implantation embryos. When calculating average telomere length by assuming that each signal presents one telomere, the calculated telomere length decreased from the oocyte to the cleavage stages, and increased between the cleavage stages and the blastocyst (11.12 vs 8.43 vs 12.22kb respectively, p<0.001). Other methods of calculation, based upon expected maximum and minimum numbers of telomeres, confirm that telomere length in blastocysts is significantly longer than cleavage stages. Individual blastomeres within an embryo showed substantial variation in calculated average telomere length. This study implies that telomere length changes according to the stage of pre-implantation embryo development

Engineering mono- and multi-valent inhibitors on a modular scaffold.

Here we exploit the simple, ultra-stable, modular architecture of consensus-designed tetratricopeptide repeat proteins (CTPRs) to create a platform capable of displaying both single as well as multiple functions and with diverse programmable geometrical arrangements by grafting non-helical short linear binding motifs (SLiMs) onto the loops between adjacent repeats. As proof of concept, we built synthetic CTPRs to bind and inhibit the human tankyrase proteins (hTNKS), which play a key role in Wnt signaling and are upregulated in cancer. A series of mono-valent and multi-valent hTNKS binders was assembled. To fully exploit the modular scaffold and to further diversify the multi-valent geometry, we engineered the binding modules with two different formats, one monomeric and the other trimeric. We show that the designed proteins are stable, correctly folded and capable of binding to and inhibiting the cellular activity of hTNKS leading to downregulation of the Wnt pathway. Multivalency in both the CTPR protein arrays and the hTNKS target results in the formation of large macromolecular assemblies, which can be visualized both in vitro and in the cell. When delivered into the cell by nanoparticle encapsulation, the multivalent CTPR proteins displayed exceptional activity. They are able to inhibit Wnt signaling where small molecule inhibitors have failed to date. Our results point to the tremendous potential of the CTPR platform to exploit a range of SLiMs and assemble synthetic binding molecules with built-in multivalent capabilities and precise, pre-programmed geometries.BBSRC Doctoral Training Programme (DTP) scholarship Oliver Gatty Studentship AstraZeneca PhD studentship. UK Medical Research Foundation. CRUK Pioneer Award (C17838/A22676) CRUK BTERP Award (C17838/A27225) Leverhulme Trust (RPG-2014-089) Cambridge Newton Trust BBSRC project grant (BB/T002697/1)

Primary Cilia Mediate Diverse Kinase Inhibitor Resistance Mechanisms in Cancer.

Primary cilia are microtubule-based organelles that detect mechanical and chemical stimuli. Although cilia house a number of oncogenic molecules (including Smoothened, KRAS, EGFR, and PDGFR), their precise role in cancer remains unclear. We have interrogated the role of cilia in acquired and de novo resistance to a variety of kinase inhibitors, and found that, in several examples, resistant cells are distinctly characterized by an increase in the number and/or length of cilia with altered structural features. Changes in ciliation seem to be linked to differences in the molecular composition of cilia and result in enhanced Hedgehog pathway activation. Notably, manipulating cilia length via Kif7 knockdown is sufficient to confer drug resistance in drug-sensitive cells. Conversely, targeting of cilia length or integrity through genetic and pharmacological approaches overcomes kinase inhibitor resistance. Our work establishes a role for ciliogenesis and cilia length in promoting cancer drug resistance and has significant translational implications.This research was partly funded by the Institute of Cancer Research and by grants from Sarcoma UK (to B.E.T. [14.2014] and P.H.H. [3.2014]), Kent Cancer Trust (to M.M.), Hilfe fuer Krebskranke Kinder Frankfurt e.V. and Frankfurter Stiftung fuer Krebskranke Kinder (to J.C.), CRUK-CI Core Grant (C14303/A17197), and S.H.D. Fellowship (Wellcome Trust/Royal Society [107609]) (to M.D.R.). B.E.T. was supported by an ICR fellowship

SILAC-based proteomic quantification of chemoattractant-induced cytoskeleton dynamics on a second to minute timescale

Cytoskeletal dynamics during cell behaviours ranging from endocytosis and exocytosis to cell division and movement is controlled by a complex network of signalling pathways, the full details of which are as yet unresolved. Here we show that SILAC-based proteomic methods can be used to characterize the rapid chemoattractant-induced dynamic changes in the actin–myosin cytoskeleton and regulatory elements on a proteome-wide scale with a second to minute timescale resolution. This approach provides novel insights in the ensemble kinetics of key cytoskeletal constituents and association of known and novel identified binding proteins. We validate the proteomic data by detailed microscopy-based analysis of in vivo translocation dynamics for key signalling factors. This rapid large-scale proteomic approach may be applied to other situations where highly dynamic changes in complex cellular compartments are expected to play a key role

Determinants of initial inhaled corticosteroid use in patients with GOLD A/B COPD:a retrospective study of UK general practice

Initial use of inhaled corticosteroid therapy is common in patients with Global Initiative for Chronic Obstructive Lung Disease (GOLD) A or B chronic obstructive pulmonary disease, contrary to GOLD guidelines. We investigated UK prescribing of inhaled corticosteroid therapy in these patients, to identify predictors of inhaled corticosteroid use in newly diagnosed chronic obstructive pulmonary disease patients. A cohort of newly diagnosed GOLD A/B chronic obstructive pulmonary disease patients was identified from the UK Clinical Practice Research Datalink (June 2005–June 2015). Patients were classified by prescribed treatment, with those receiving inhaled corticosteroid-containing therapy compared with those receiving long-acting bronchodilators without inhaled corticosteroid. In all, 29,815 patients with spirometry-confirmed chronic obstructive pulmonary disease were identified. Of those prescribed maintenance therapy within 3 months of diagnosis, 63% were prescribed inhaled corticosteroid-containing therapy vs. 37% prescribed non-inhaled corticosteroid therapy. FEV1% predicted, concurrent asthma diagnosis, region, and moderate exacerbation were the strongest predictors of inhaled corticosteroid use in the overall cohort. When concurrent asthma patients were excluded, all other co-variates remained significant predictors. Other significant predictors included general practitioner practice, younger age, and co-prescription with short-acting bronchodilators. Trends over time showed that initial inhaled corticosteroid prescriptions reduced throughout the study, but still accounted for 47% of initial prescriptions in 2015. These results suggest that inhaled corticosteroid prescribing in GOLD A/B patients is common, with significant regional variation that is independent of FEV1% predicted