Expansion of the CD8 memory T cells : implications for the self-renewal gene Hoxb4

Les cellules CD8 T mémoire (Tm) offrent une protection tout au long de la vie contre les infections récurrentes. Elles sont maintenues grâce à des mécanismes d'auto-renouvellement. Les cellules souches hématopoïétiques (CSH) peuvent aussi s'auto-renouveller lentement, en assurant leur maintenance à long terme. Les deux types de cellules utilisent la moelle osseuse comme principale niche de prolifération. CD8 Tm et CSH partagent partiellement un profil transcriptionnel, y compris certains gènes connus pour contrôler l'auto-renouvellement. Les gènes Hox, dont Hoxb4 qui est un activateur puissant de l’expansion des CSH in vitro et in vivo, sont exprimés par les CSH. Basé sur les similitudes entre les CSH et les cellules Tm, nous émettons l'hypothèse que les gènes impliqués dans l’auto-renouvellement des CSH, comme Hoxb4, favoriseront l'expansion des cellules CD8 Tm. Pour tester cette hypothèse, nous avons déterminé l'effet de la surexpression de Hoxb4 dans les cellules T à partir de souris transgéniques jeunes et âgées, et sur la prise de greffe et le maintien des cellules CD8 Tm après leur transplantation dans des souris immunocompétentes ou immunosupprimées. À l'état basal, la composition et le phénotype des cellules T naïves et mémoire n’ont pas été affectés par la surexpression de Hoxb4. Pour étudier le maintien des cellules CD8 Tm, les souris transgéniques Hoxb4 et OT-1 ont été croisées. Les cellules T des souris OT-1, entre autre, expriment un récepteur de lymphocyte T qui reconnaît le peptide d'ovalbumine (OVA), présenté par le complexe majeur d’histocompatibilité de classe I. En utilisant ce modèle, nous avons généré in vitro un grand nombre de cellules CD8 Tm pour les expériences du transfert adoptif. Ces cellules sont monoclonales et spécifiques pour la reconnaissance d’OVA. Le nombre et le phénotype des cellules CD8 Tm générées en culture n’ont pas été affectés par la surexpression de Hoxb4. Ces cellules ont été transplantées dans des souris de type sauvage afin d'évaluer leur prise de greffe et leur maintien à long terme. Après la transplantation chez des souris soit immunocompétentes ou immunosupprimées, la prise de greffe et le maintien des cellules CD8 Tm surexprimant Hoxb4 n'a pas été améliorée lorsque comparée aux cellules CD8 Tm de type sauvage. Ces résultats suggèrent que Hoxb4 ne favorise pas l’auto-renouvellement des cellules CD8 Tm. D'autres études vont essayer d'identifier les facteurs contrôlant l’auto-renouvellement des cellules CD8 Tm.CD8 memory T (Tm) cells provide life long protection against recurrent infections and are maintained through self-renewal mechanisms. Hematopoietic stem cells (HSC) also possess the capacity to slowly self-renew assuring their long-term maintenance. Both cell types use the bone marrow as their preferred proliferation niche. CD8 Tm and HSC partially share a transcriptional profile including some genes known to control self-renewal. Hox genes are expressed in HSCs, among them Hoxb4 is a potent enhancer of HSC expansion in vitro and in vivo. Based on the similarities between HSC and Tm cells, we hypothesize that genes involved in HSC self-renewal, like Hoxb4, will promote CD8 Tm cell expansion. To test this hypothesis, we have determined the effect of Hoxb4 overexpression in T cells from young and old transgenic mice, and on the engraftment and maintenance of CD8 Tm cells after transplantation into immunocompetent or immunodeficient mice. At the steady-state, the composition and phenotype of the naïve and memory T cells were not affected by Hoxb4 overexpression. To study CD8 Tm cell maintenance, the Hoxb4 and the OT-1 transgenic mice were crossed; the latter express a T cell receptor that recognizes the ovalbumin (OVA) peptide, presented by major histocompatibility complex class I. Using this model, we generated in vitro large numbers of monoclonal and OVA specific CD8 Tm cells for adoptive transfer experiments. The number and the phenotype of Tm cells generated in culture were not affected by Hoxb4 overexpression. These cells were transplanted into wild type mice to evaluate their engraftment and long-term maintenance. After transplantation in either immunocompetent or immunodeficient mice, Hoxb4 overexpressing Tm cell engraftment or maintenance was not enhanced when compare to wild-type Tm cells. These results demonstrate that Hoxb4 does not promote CD8 Tm cell self-renewal. Further studies will try to identify the factors controlling CD8 Tm cell self-renewal

Reading behavior and the effect of embedded selfies in role-playing picture e-books: An eye-tracking investigation

Digital and interactive media platforms, such as e-books, are becoming important tools in reading and education. In particular, picture e-books can embed multimedia effects such as sound, animation or personalized images, with potential benefits for learning and engagement. However, little is known about how such e-books are read, and most designs remain untested. In this study, an innovative type of role-playing picture e-book entitled “The Prank in the Forest” was designed which provides three different role-playing approaches: emotive selfies that allow the reader to appear as one of the main characters and were varied according to the story development, a fixed selfie that was the same on each page, or no selfie. Sixty-five students were randomly assigned to the emotive selfie, fixed selfie, and no selfie groups. To understand students’ online reading processes, their eye movements were tracked. The results showed that the emotive selfies attracted attention to the main character and also promoted scanning between text and pictures, indicating a better integration of the written and pictorial information. The selfie design led to distinct scanpaths, and this was particularly true when emotive selfies were embedded which responded to the context. Self-report questionnaires of reading motivation and engagement demonstrated that this condition was also the most engaging design for readers. We conclude that emotive selfies can boost reading engagement since they encourage the reader to observe the development of the story from the role he/she chose to play, and we discuss how embodying the reader within the graphics can enhance role-play activities with the potential for improved educational outcomes. We suggest this emotive selfie role-playing design could be applied in e-book user interfaces to create more interaction and personal meaning for the readers

Photogrammetry of blue whales with an unmanned hexacopter

Author Posting. © Society for Marine Mammalogy, 2016. This article is posted here by permission of Society for Marine Mammalogy for personal use, not for redistribution. The definitive version was published in Marine Mammal Science 32 (2016):1510–1515, doi:10.1111/mms.12328.Baleen whales are the largest animals ever to live on earth, and many populations were hunted close to extinction in the 20th century (Clapham et al. 1999). Their recovery is now a key international conservation goal, and they are important in marine ecosystems as massive consumers that can promote primary production through nutrient cycling (Roman et al. 2014). However, although abundance has been assessed to monitor the recovery of some large whale populations (e.g., Barlow et al. 2011, Laake et al. 2012) many populations are wide-ranging and pelagic, and this inaccessibility has generally impeded quantitative assessments of recovery (Peel et al. 2015). To augment traditional abundance monitoring, we suggest that photogrammetric measures of individual growth and body condition can also inform about population status, enabling assessment of individual health as well as population numbers. Photogrammetry from manned aircraft has used photographs taken from directly above whales to estimate individual lengths (Gilpatrick and Perryman 2008) and monitor growth trends (Fearnbach et al. 2011), and shape profiles can be measured to assess body condition to infer reproductive and nutritional status (e.g., Perryman and Lynn 2002, Miller et al. 2012). Recently, Durban et al. (2015) demonstrated the utility of an unmanned hexacopter for collecting aerial photogrammetry images of killer whales (Orcinus orca); this provided a noninvasive, cost-effective, and safe platform that could be deployed from a boat to obtain vertical images of whales. Here we describe the use of this small, unmanned aerial system (UAS) to measure length and condition of blue whales (Balaenoptera musculus), the largest of all whales.María Francisca Cortés Solari; Rafaela Landea Briones; MERI Foundation; Woods Hole Oceanographic Institution Acces

Fermi Large Area Telescope Constraints on the Gamma-ray Opacity of the Universe

The Extragalactic Background Light (EBL) includes photons with wavelengths from ultraviolet to infrared, which are effective at attenuating gamma rays with energy above ~10 GeV during propagation from sources at cosmological distances. This results in a redshift- and energy-dependent attenuation of the gamma-ray flux of extragalactic sources such as blazars and Gamma-Ray Bursts (GRBs). The Large Area Telescope onboard Fermi detects a sample of gamma-ray blazars with redshift up to z~3, and GRBs with redshift up to z~4.3. Using photons above 10 GeV collected by Fermi over more than one year of observations for these sources, we investigate the effect of gamma-ray flux attenuation by the EBL. We place upper limits on the gamma-ray opacity of the Universe at various energies and redshifts, and compare this with predictions from well-known EBL models. We find that an EBL intensity in the optical-ultraviolet wavelengths as great as predicted by the "baseline" model of Stecker et al. (2006) can be ruled out with high confidence.Comment: 42 pages, 12 figures, accepted version (24 Aug.2010) for publication in ApJ; Contact authors: A. Bouvier, A. Chen, S. Raino, S. Razzaque, A. Reimer, L.C. Reye

The Rossiter-McLaughlin effect in Exoplanet Research

The Rossiter-McLaughlin effect occurs during a planet's transit. It provides the main means of measuring the sky-projected spin-orbit angle between a planet's orbital plane, and its host star's equatorial plane. Observing the Rossiter-McLaughlin effect is now a near routine procedure. It is an important element in the orbital characterisation of transiting exoplanets. Measurements of the spin-orbit angle have revealed a surprising diversity, far from the placid, Kantian and Laplacian ideals, whereby planets form, and remain, on orbital planes coincident with their star's equator. This chapter will review a short history of the Rossiter-McLaughlin effect, how it is modelled, and will summarise the current state of the field before describing other uses for a spectroscopic transit, and alternative methods of measuring the spin-orbit angle.Comment: Review to appear as a chapter in the "Handbook of Exoplanets", ed. H. Deeg & J.A. Belmont

36-month clinical outcomes of patients with venous thromboembolism:GARFIELD-VTE

Background: Venous thromboembolism (VTE), encompassing both deep vein thrombosis (DVT) and pulmonary embolism (PE), is a leading cause of morbidity and mortality worldwide. Methods: GARFIELD-VTE is a prospective, non-interventional observational study of real-world treatment practices. We aimed to capture the 36-month clinical outcomes of 10,679 patients with objectively confirmed VTE enrolled between May 2014 and January 2017 from 415 sites in 28 countries. Findings: A total of 6582 (61.6 %) patients had DVT alone, 4097 (38.4 %) had PE ± DVT. At baseline, 98.1 % of patients received anticoagulation (AC) with or without other modalities of therapy. The proportion of patients on AC therapy decreased over time: 87.6 % at 3 months, 73.0 % at 6 months, 54.2 % at 12 months and 42.0 % at 36 months. At 12-months follow-up, the incidences (95 % confidence interval [CI]) of all-cause mortality, recurrent VTE and major bleeding were 6.5 (7.0–8.1), 5.4 (4.9–5.9) and 2.7 (2.4–3.0) per 100 person-years, respectively. At 36-months, these decreased to 4.4 (4.2–4.7), 3.5 (3.2–2.7) and 1.4 (1.3–1.6) per 100 person-years, respectively. Over 36-months, the rate of all-cause mortality and major bleeds were highest in patients treated with parenteral therapy (PAR) versus oral anti-coagulants (OAC) and no OAC, and the rate of recurrent VTE was highest in patients on no OAC versus those on PAR and OAC. The most frequent cause of death after 36-month follow-up was cancer (n = 565, 48.6 %), followed by cardiac (n = 94, 8.1 %), and VTE (n = 38, 3.2 %). Most recurrent VTE events were DVT alone (n = 564, 63.3 %), with the remainder PE, (n = 236, 27.3 %), or PE in combination with DVT (n = 63, 7.3 %). Interpretation: GARFIELD-VTE provides a global perspective of anticoagulation patterns and highlights the accumulation of events within the first 12 months after diagnosis. These findings may help identify treatment gaps for subsequent interventions to improve patient outcomes in this patient population.</p

Sex differences in the neuroanatomy of alcohol dependence: hippocampus and amygdala subregions in a sample of 966 people from the ENIGMA Addiction Working Group

Males and females with alcohol dependence have distinct mental health and cognitive problems. Animal models of addiction postulate that the underlying neurobiological mechanisms are partially distinct, but there is little evidence of sex differences in humans with alcohol dependence as most neuroimaging studies have been conducted in males. We examined hippocampal and amygdala subregions in a large sample of 966 people from the ENIGMA Addiction Working Group. This comprised 643 people with alcohol dependence (225 females), and a comparison group of 323 people without alcohol dependence (98 females). Males with alcohol dependence had smaller volumes of the total amygdala and its basolateral nucleus than male controls, that exacerbated with alcohol dose. Alcohol dependence was also associated with smaller volumes of the hippocampus and its CA1 and subiculum subfield volumes in both males and females. In summary, hippocampal and amygdalar subregions may be sensitive to both shared and distinct mechanisms in alcohol-dependent males and females

Gamma-ray and radio properties of six pulsars detected by the fermi large area telescope

We report the detection of pulsed γ-rays for PSRs J0631+1036, J0659+1414, J0742-2822, J1420-6048, J1509-5850, and J1718-3825 using the Large Area Telescope on board the Fermi Gamma-ray Space Telescope (formerly known as GLAST). Although these six pulsars are diverse in terms of their spin parameters, they share an important feature: their γ-ray light curves are (at least given the current count statistics) single peaked. For two pulsars, there are hints for a double-peaked structure in the light curves. The shapes of the observed light curves of this group of pulsars are discussed in the light of models for which the emission originates from high up in the magnetosphere. The observed phases of the γ-ray light curves are, in general, consistent with those predicted by high-altitude models, although we speculate that the γ-ray emission of PSR J0659+1414, possibly featuring the softest spectrum of all Fermi pulsars coupled with a very low efficiency, arises from relatively low down in the magnetosphere. High-quality radio polarization data are available showing that all but one have a high degree of linear polarization. This allows us to place some constraints on the viewing geometry and aids the comparison of the γ-ray light curves with high-energy beam models

Detection of High-Energy Gamma-Ray Emission from the Globular Cluster 47 Tucanae with Fermi

Gamma-Ray Pulsar Bonanza Most of the pulsars we know about were detected through their radio emission; a few are known to pulse gamma rays but were first detected at other wavelengths (see the Perspective by Halpern ). Using the Fermi Gamma-Ray Space Telescope, Abdo et al. (p. 840 , published online 2 July; see the cover) report the detection of 16 previously unknown pulsars based on their gamma-ray emission alone. Thirteen of these coincide with previously unidentified gamma-ray sources, solving the 30-year-old mystery of their identities. Pulsars are fast-rotating neutron stars. With time they slow down and cease to radiate; however, if they are in a binary system, they can have their spin rates increased by mass transfer from their companion stars, starting a new life as millisecond pulsars. In another study, Abdo et al. (p. 845 ) report the detection of gamma-ray emission from the globular cluster 47 Tucanae, which is coming from an ensemble of millisecond pulsars in the cluster's core. The data imply that there are up to 60 millisecond pulsars in 47 Tucanae, twice as many as predicted by radio observations. In a further companion study, Abdo et al. (p. 848 , published online 2 July) searched Fermi Large Area Telescope data for pulsations from all known millisecond pulsars outside of stellar clusters, finding gamma-ray pulsations for eight of them. Their properties resemble those of other gamma-ray pulsars, suggesting that they share the same basic emission mechanism. Indeed, both sets of pulsars favor emission models in which the gamma rays are produced in the outer magnetosphere of the neutron star

Targeting DNA Damage Response and Replication Stress in Pancreatic Cancer

Background and aims: Continuing recalcitrance to therapy cements pancreatic cancer (PC) as the most lethal malignancy, which is set to become the second leading cause of cancer death in our society. The study aim was to investigate the association between DNA damage response (DDR), replication stress and novel therapeutic response in PC to develop a biomarker driven therapeutic strategy targeting DDR and replication stress in PC. Methods: We interrogated the transcriptome, genome, proteome and functional characteristics of 61 novel PC patient-derived cell lines to define novel therapeutic strategies targeting DDR and replication stress. Validation was done in patient derived xenografts and human PC organoids. Results: Patient-derived cell lines faithfully recapitulate the epithelial component of pancreatic tumors including previously described molecular subtypes. Biomarkers of DDR deficiency, including a novel signature of homologous recombination deficiency, co-segregates with response to platinum (P &lt; 0.001) and PARP inhibitor therapy (P &lt; 0.001) in vitro and in vivo. We generated a novel signature of replication stress with which predicts response to ATR (P &lt; 0.018) and WEE1 inhibitor (P &lt; 0.029) treatment in both cell lines and human PC organoids. Replication stress was enriched in the squamous subtype of PC (P &lt; 0.001) but not associated with DDR deficiency. Conclusions: Replication stress and DDR deficiency are independent of each other, creating opportunities for therapy in DDR proficient PC, and post-platinum therapy