Translating the Game: Ribosomes as Active Players

Ribosomes have been long considered as executors of the translational program. The fact that ribosomes can control the translation of specific mRNAs or entire cellular programs is often neglected. Ribosomopathies, inherited diseases with mutations in ribosomal factors, show tissue specific defects and cancer predisposition. Studies of ribosomopathies have paved the way to the concept that ribosomes may control translation of specific mRNAs. Studies in Drosophila and mice support the existence of heterogeneous ribosomes that differentially translate mRNAs to coordinate cellular programs. Recent studies have now shown that ribosomal activity is not only a critical regulator of growth but also of metabolism. For instance, glycolysis and mitochondrial function have been found to be affected by ribosomal availability. Also, ATP levels drop in models of ribosomopathies. We discuss findings highlighting the relevance of ribosome heterogeneity in physiological and pathological conditions, as well as the possibility that in rate-limiting situations, ribosomes may favor some translational programs. We discuss the effects of ribosome heterogeneity on cellular metabolism, tumorigenesis and aging. We speculate a scenario in which ribosomes are not only executors of a metabolic program but act as modulators

Cross Disciplinary Overtures with Interview Data: Integrating Digital Practices and Tools in the Scholarly Workflow

There is much talk about the need for multidisciplinary approaches to research and the opportunities that have been created by digital technologies. A good example of this is the CLARIN Portal, that promotes and supports such research by offering a large suite of tools for working with textual and audio-visual data. Yet scholars who work with interview material are largely unaware of this resource and are still predominantly oriented towards familiar traditional research methods. To reach out to these scholars and assess the potential for integration of these new technologies a multidisciplinary international community of experts set out to test CLARIN-type approaches and tools on different scholars by eliciting and documenting their feedback. This was done through a series of workshops held from 2016 to 2019, and funded by CLARIN and affiliated EU funding. This paper presents the goals, the tools that were tested and the evaluation of how they were experienced. It concludes by setting out envisioned pathways for a better use of the CLARIN family of approaches and tools in the area of qualitative and oral history data analysi

po 130 ser235 residue drives eif6 oncogenic activity in npm alk induced t cell lymphomagenesis

Introduction Dysregulation of mRNA translational control in cancer leads to cell transformation, metabolic reprogramming and angiogenesis. eIF6 is an oncogenic translation factor, which regulates the initiation phase of translation acting on 60S availability in the cytoplasm and controlling active 80S complex formation. eIF6 activation is mTORC1-independent and driven by PKCβ mediated phosphorylation on Ser235. An increment of eIF6 expression is reported in several cancer cell lines and human tumours, due to amplification or overexpression. In mice, eIF6 haploinsufficiency blocks Myc-driven lymphomagenesis. Intriguingly, high levels of PKC and eIF6 are found in T-cell lymphomas. In particular, in Anaplastic Large Cell Lymphoma (ALCL) eIF6 is overexpressed and hyperactivated. Material and methods Here, we aimed to define the role of eIF6 phosphorylation in NPM-ALK mediated T-cell lymphomagenesis, combining multidisciplinary studies on murine and cellular models. We used a conditional eIF6 SA KI mouse model in which Ser235 is replaced by an Ala. Results and discussions First, we addressed the effect of eIF6 mutated protein expression in all tissues: homozygosity is lethal after gastrulation while heterozygous mice are viable but resistant to NPM-ALK driven lymphomagenesis. Then, we investigated the role of Ser235 phosphorylation specifically in T-cell lineage, crossing eIF6 SA KI mice with CD4-Cre mice. Physiological T-cell development and subsets composition are not affected by the eIF6 mutated protein. In cancer, eIF6 SA/SA CD4-Cre NPM-ALK mice have a significant increase in survival time, compared to wt with a delay in the appearance of lymphoma up to 6 months. Histological analysis and ex vivo cultures confirm the delay in disease development. eIF6 SA/SA CD4-Cre NPM-ALK thymocytes are smaller respect to wt counterparts and show a striking senescence-like phenotype in vitro . Similarly, in vitro generated eIF6 SA/SA MEFs show a markedly reduced proliferation and increased SA β-gal positivity. This phenotype is completely rescued by transducing eIF6 wild-type, but not by eIF6 SA . Currently, we are investigating the molecular mechanisms by which eIF6 phosphorylation affects ALK-induced malignancy and whether it may modulate premature cell senescence, thus establishing an effective barrier to T-cell lymphomagenesis. Conclusion Our work demonstrates for the first time that eIF6 phosphorylation plays an essential role in mammals development, cell homeostasis and is rate-limiting for T-cell lymphomagenesis in vivo

Effect of the ethinylestradiol/norelgestromin contraceptive patch on body composition. Results of bioelectrical impedance analysis in a population of Italian women

<p>Abstract</p> <p>Background</p> <p>As weight gain is one of the most frequently cited reasons for not using and for discontinuing hormonal contraceptives, in an open-label, single-arm, multicentre clinical study we evaluated the effect of the ethinylestradiol/norelgestromin contraceptive patch (EVRA, Janssen-Cilag International, Belgium) on body composition using bioelectrical impedance analysis (BIA).</p> <p>Methods</p> <p>Body weight and impedance vector components (resistance (R) and reactance (Xc), at 50 kHz frequency, Akern-RJL Systems analyzer) were recorded before entry, after 1, 3 and 6 months in 182 Italian healthy women aged 29 yr (18 to 45), and with BMI 21.8 kg/m²(16 to 31). Total body water (TBW) was estimated with a BIA regression equation. Vector BIA was performed with the RXc mean graph method and the Hotelling's T²test for paired and unpaired data.</p> <p>Results</p> <p>After 6 months body weight increased by 0.64 kg (1.1%) and TBW increased by 0.51 L (1.7%). The pattern of impedance vector displacement indicated a small increase in soft tissue hydration (interstitial gel fluid). Body composition changes did not significantly differ among groups of previous contraceptive methods. Arterial blood pressure did not significantly change over time.</p> <p>Conclusion</p> <p>After 6 months of treatment with the ethinylestradiol/norelgestromin contraceptive patch we found a minimal, clinically not relevant, increase in body weight less than 1 kg that could be attributed to an adaptive interstitial gel hydration. This fluctuation is physiological as confirmed by the lack of any effect on blood pressure. This could be useful in increasing women's choice, acceptability and compliance of the ethinylestradiol/norelgestromin contraceptive patch.</p

CryoSat instrument performance and ice product quality status

Over the past 20 years, satellite radar altimetry has shown its ability to revolutionise our understanding of the ocean and climate. Previously, these advances were largely limited to ice-free regions, neglecting large portions of the Polar Regions. Launched in 2010, the European Space Agency’s (ESA) polar-orbiting CryoSat satellite was specifically designed to measure changes in the thickness of polar sea ice and the elevation of the ice sheets and mountain glaciers. To reach this goal, the CryoSat products have to meet the highest performance standards, achieved through continual improvements of the associated Instrument Processing Facilities. Since April 2015, the CryoSat ice products are generated with Baseline-C, which represented a major processor upgrade. Several improvements were implemented in this new Baseline, most notably the release of freeboard data within the Level 2 products. The Baseline-C upgrade has brought significant improvements to the quality of Level-1B and Level-2 products relative to the previous Baseline-B products, which in turn is expected to have a positive impact on the scientific exploitation of CryoSat measurements over land ice and sea ice. This paper provides an overview of the CryoSat ice data quality assessment and evolutions, covering all quality control and calibration activities performed by ESA and its partners. Also discussed are the forthcoming evolutions of the processing chains and improvements anticipated in the next processing Baseline