Quantitative principles of cis-translational control by general mRNA sequence features in eukaryotes.

BackgroundGeneral translational cis-elements are present in the mRNAs of all genes and affect the recruitment, assembly, and progress of preinitiation complexes and the ribosome under many physiological states. These elements include mRNA folding, upstream open reading frames, specific nucleotides flanking the initiating AUG codon, protein coding sequence length, and codon usage. The quantitative contributions of these sequence features and how and why they coordinate to control translation rates are not well understood.ResultsHere, we show that these sequence features specify 42-81% of the variance in translation rates in Saccharomyces cerevisiae, Schizosaccharomyces pombe, Arabidopsis thaliana, Mus musculus, and Homo sapiens. We establish that control by RNA secondary structure is chiefly mediated by highly folded 25-60 nucleotide segments within mRNA 5' regions, that changes in tri-nucleotide frequencies between highly and poorly translated 5' regions are correlated between all species, and that control by distinct biochemical processes is extensively correlated as is regulation by a single process acting in different parts of the same mRNA.ConclusionsOur work shows that general features control a much larger fraction of the variance in translation rates than previously realized. We provide a more detailed and accurate understanding of the aspects of RNA structure that directs translation in diverse eukaryotes. In addition, we note that the strongly correlated regulation between and within cis-control features will cause more even densities of translational complexes along each mRNA and therefore more efficient use of the translation machinery by the cell

Promotoras as Mental Health Practitioners in Primary Care: A Multi-Method Study of an Intervention to Address Contextual Sources of Depression

We assessed the role of promotoras—briefly trained community health workers—in depression care at community health centers. The intervention focused on four contextual sources of depression in underserved, low-income communities: underemployment, inadequate housing, food insecurity, and violence. A multi-method design included quantitative and ethnographic techniques to study predictors of depression and the intervention’s impact. After a structured training program, primary care practitioners (PCPs) and promotoras collaboratively followed a clinical algorithm in which PCPs prescribed medications and/or arranged consultations by mental health professionals and promotoras addressed the contextual sources of depression. Based on an intake interview with 464 randomly recruited patients, 120 patients with depression were randomized to enhanced care plus the promotora contextual intervention, or to enhanced care alone. All four contextual problems emerged as strong predictors of depression (chi square, p < .05); logistic regression revealed housing and food insecurity as the most important predictors (odds ratios both 2.40, p < .05). Unexpected challenges arose in the intervention’s implementation, involving infrastructure at the health centers, boundaries of the promotoras’ roles, and “turf” issues with medical assistants. In the quantitative assessment, the intervention did not lead to statistically significant improvements in depression (odds ratio 4.33, confidence interval overlapping 1). Ethnographic research demonstrated a predominantly positive response to the intervention among stakeholders, including patients, promotoras, PCPs, non-professional staff workers, administrators, and community advisory board members. Due to continuing unmet mental health needs, we favor further assessment of innovative roles for community health workers

Identification of Host Genes Involved in Geminivirus Infection Using a Reverse Genetics Approach

Geminiviruses, like all viruses, rely on the host cell machinery to establish a successful infection, but the identity and function of these required host proteins remain largely unknown. Tomato yellow leaf curl Sardinia virus (TYLCSV), a monopartite geminivirus, is one of the causal agents of the devastating Tomato yellow leaf curl disease (TYLCD). The transgenic 2IRGFP N. benthamiana plants, used in combination with Virus Induced Gene Silencing (VIGS), entail an important potential as a tool in reverse genetics studies to identify host factors involved in TYLCSV infection. Using these transgenic plants, we have made an accurate description of the evolution of TYLCSV replication in the host in both space and time. Moreover, we have determined that TYLCSV and Tobacco rattle virus (TRV) do not dramatically influence each other when co-infected in N. benthamiana, what makes the use of TRV-induced gene silencing in combination with TYLCSV for reverse genetic studies feasible. Finally, we have tested the effect of silencing candidate host genes on TYLCSV infection, identifying eighteen genes potentially involved in this process, fifteen of which had never been implicated in geminiviral infections before. Seven of the analyzed genes have a potential anti-viral effect, whereas the expression of the other eleven is required for a full infection. Interestingly, almost half of the genes altering TYLCSV infection play a role in postranslational modifications. Therefore, our results provide new insights into the molecular mechanisms underlying geminivirus infections, and at the same time reveal the 2IRGFP/VIGS system as a powerful tool for functional reverse genetics studies

Biofluid Biomarkers in Huntington's Disease

Huntington's disease (HD) is a chronic progressive neurodegenerative condition where new markers of disease progression are needed. So far no disease-modifying interventions have been found, and few interventions have been proven to alleviate symptoms. This may be partially explained by the lack of reliable indicators of disease severity, progression, and phenotype.Biofluid biomarkers may bring advantages in addition to clinical measures, such as reliability, reproducibility, price, accuracy, and direct quantification of pathobiological processes at the molecular level; and in addition to empowering clinical trials, they have the potential to generate useful hypotheses for new drug development.In this chapter we review biofluid biomarker reports in HD, emphasizing those we feel are likely to be closest to clinical applicability

Multi-messenger observations of a binary neutron star merger

On 2017 August 17 a binary neutron star coalescence candidate (later designated GW170817) with merger time 12:41:04 UTC was observed through gravitational waves by the Advanced LIGO and Advanced Virgo detectors. The Fermi Gamma-ray Burst Monitor independently detected a gamma-ray burst (GRB 170817A) with a time delay of ~1.7 s with respect to the merger time. From the gravitational-wave signal, the source was initially localized to a sky region of 31 deg2 at a luminosity distance of 40+8-8 Mpc and with component masses consistent with neutron stars. The component masses were later measured to be in the range 0.86 to 2.26 Mo. An extensive observing campaign was launched across the electromagnetic spectrum leading to the discovery of a bright optical transient (SSS17a, now with the IAU identification of AT 2017gfo) in NGC 4993 (at ~40 Mpc) less than 11 hours after the merger by the One- Meter, Two Hemisphere (1M2H) team using the 1 m Swope Telescope. The optical transient was independently detected by multiple teams within an hour. Subsequent observations targeted the object and its environment. Early ultraviolet observations revealed a blue transient that faded within 48 hours. Optical and infrared observations showed a redward evolution over ~10 days. Following early non-detections, X-ray and radio emission were discovered at the transient’s position ~9 and ~16 days, respectively, after the merger. Both the X-ray and radio emission likely arise from a physical process that is distinct from the one that generates the UV/optical/near-infrared emission. No ultra-high-energy gamma-rays and no neutrino candidates consistent with the source were found in follow-up searches. These observations support the hypothesis that GW170817 was produced by the merger of two neutron stars in NGC4993 followed by a short gamma-ray burst (GRB 170817A) and a kilonova/macronova powered by the radioactive decay of r-process nuclei synthesized in the ejecta

Performance of the upgraded PreProcessor of the ATLAS Level-1 Calorimeter Trigger

The PreProcessor of the ATLAS Level-1 Calorimeter Trigger prepares the analogue trigger signals sent from the ATLAS calorimeters by digitising, synchronising, and calibrating them to reconstruct transverse energy deposits, which are then used in further processing to identify event features. During the first long shutdown of the LHC from 2013 to 2014, the central components of the PreProcessor, the Multichip Modules, were replaced by upgraded versions that feature modern ADC and FPGA technology to ensure optimal performance in the high pile-up environment of LHC Run 2. This paper describes the features of the newMultichip Modules along with the improvements to the signal processing achieved.ANPCyTYerPhI, ArmeniaAustralian Research CouncilBMWFW, AustriaAustrian Science Fund (FWF)Azerbaijan National Academy of Sciences (ANAS)SSTC, BelarusNational Council for Scientific and Technological Development (CNPq)Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP)Natural Sciences and Engineering Research Council of CanadaCanada Foundation for InnovationNational Natural Science Foundation of China (NSFC)Departamento Administrativo de Ciencia, Tecnología e Innovación ColcienciasMinistry of Education, Youth & Sports - Czech Republic Czech Republic GovernmentCzech Republic GovernmentDNRF, DenmarkDanish Natural Science Research CouncilCentre National de la Recherche Scientifique (CNRS)CEA-DRF/IRFU, FranceFederal Ministry of Education & Research (BMBF)Max Planck SocietyGreek Ministry of Development-GSRTRGC and Hong Kong SAR, ChinaIsrael Science FoundationBenoziyo Center, IsraelIstituto Nazionale di Fisica Nucleare (INFN)Ministry of Education, Culture, Sports, Science and Technology, Japan (MEXT)Ministry of Education, Culture, Sports, Science and Technology, Japan (MEXT) Japan Society for the Promotion of ScienceCNRST, MoroccoRCN, NorwayPortuguese Foundation for Science and TechnologyMNE/IFA, RomaniaMES of RussiaMESTD, SerbiaMSSR, SlovakiaSlovenian Research Agency - SloveniaMIZS, SloveniaSpanish GovernmentSRC, SwedenWallenberg Foundation, SwedenSNSF Geneva, SwitzerlandMinistry of Science and Technology, TaiwanMinistry of Energy & Natural Resources - TurkeyScience & Technology Facilities Council (STFC)United States Department of Energy (DOE)National Science Foundation (NSF)BCKDF, CanadaCANARIE, CanadaCRC, CanadaEuropean Research Council (ERC)European Union (EU)French National Research Agency (ANR)German Research Foundation (DFG)Alexander von Humboldt FoundationGreek NSRF, GreeceBSF-NSF, IsraelGerman-Israeli Foundation for Scientific Research and DevelopmentLa Caixa Banking Foundation, SpainCERCA Programme Generalitat de Catalunya, SpainPROMETEO, SpainGenT Programmes Generalitat Valenciana, SpainGoran Gustafssons Stiftelse, SwedenRoyal Society of LondonLeverhulme TrustNRC, CanadaCERNANID, ChileChinese Academy of SciencesMinistry of Science and Technology, ChinaSRNSFG, GeorgiaHGF, GermanyNetherlands Organization for Scientific Research (NWO) Netherlands GovernmentMinistry of Science and Higher Education, PolandNCN, PolandNRCKI, Russia FederationJINRDST/NRF, South AfricaSERI, Geneva, SwitzerlandCantons of Bern and Geneva, SwitzerlandCompute Canada, CanadaHorizon 2020Marie Sklodowska-Curie ActionsEuropean Cooperation in Science and Technology (COST)EU-ESF, Greec

Measurement of the tt¯tt¯ production cross section in pp collisions at √s=13 TeV with the ATLAS detector

A measurement of four-top-quark production using proton-proton collision data at a centre-of-mass energy of 13 TeV collected by the ATLAS detector at the Large Hadron Collider corresponding to an integrated luminosity of 139 fb−1 is presented. Events are selected if they contain a single lepton (electron or muon) or an opposite-sign lepton pair, in association with multiple jets. The events are categorised according to the number of jets and how likely these are to contain b-hadrons. A multivariate technique is then used to discriminate between signal and background events. The measured four-top-quark production cross section is found to be 26+17−15 fb, with a corresponding observed (expected) significance of 1.9 (1.0) standard deviations over the background-only hypothesis. The result is combined with the previous measurement performed by the ATLAS Collaboration in the multilepton final state. The combined four-top-quark production cross section is measured to be 24+7−6 fb, with a corresponding observed (expected) signal significance of 4.7 (2.6) standard deviations over the background-only predictions. It is consistent within 2.0 standard deviations with the Standard Model expectation of 12.0 ± 2.4 fb