Mechanical Identities of RNA and DNA Double Helices Unveiled at the Single-Molecule Level

[EN] Double-stranded (ds) RNA is the genetic material of a variety of viruses and has been recently recognized as a relevant molecule in cells for its regulatory role. Despite that the elastic response of dsDNA has been thoroughly characterized in recent years in single-molecule stretching experiments, an equivalent study with dsRNA is still lacking. Here, we have engineered long dsRNA molecules for their individual characterization contrasting information with dsDNA molecules of the same sequence. It is known that dsRNA is an A-form molecule unlike dsDNA, which exhibits B-form in physiological conditions. These structural types are distinguished at the single-molecule level with atomic force microscopy (AFM) and are the basis to understand their different elastic response. Force¿extension curves of dsRNA with optical and magnetic tweezers manifest two main regimes of elasticity, an entropic regime whose end is marked by the A-form contour- length and an intrinsic regime that ends in a low-cooperative overstretching transition in which the molecule extends to 1.7 times its A-form contour-length. DsRNA does not switch between the A and B conformations in the presence of force. Finally, dsRNA presents both a lower stretch modulus and overstretching transition force than dsDNA, whereas the electrostatic and intrinsic contributions to the persistence length are larger.This work was supported by grants from the Spanish Ministry of Science and Innovation (BFU2011-29038 and BFU2010-15703) and the Comunidad de Madrid (S2009/MAT/1507). IRA.-G. acknowledges a Ramon y Cajal contract from the Spanish Ministry of Science and Innovation (RYC-2007-01765). Work in the F.M.-H. laboratory was supported by a Starting Grant from the European Research Council (no. 206117) and a grant from the Spanish Ministry of Science and Innovation (FIS2011-24638). We thank M. S. Dillingham for kindly providing the pSP73-JY0 plasmid, M. Menendez for access to a spectropolarimeter, A. Monserrate for polylysine-AFM control experiments, and B. Ibarra for fruitful discussions.Herrero-Galán, E.; Fuentes-Perez. M.E.; Carrasco, C.; Valpuesta, J.; Carrascosa, J.; Moreno-Herrero, F.; Arias-Gonzalez, JR. (2013). Mechanical Identities of RNA and DNA Double Helices Unveiled at the Single-Molecule Level. Journal of the American Chemical Society. 135(1):122-131. https://doi.org/10.1021/ja3054755S122131135

Family physicians' views on participating in prevention of major depression. The predictD-EVAL qualitative study

Background The predictD intervention, a multicomponent intervention delivered by family physicians (FPs), reduced the incidence of major depression by 21% versus the control group and was cost-effective. A qualitative methodology was proposed to identify the mechanisms of action of these complex interventions. Purpose To seek the opinions of these FPs on the potential successful components of the predictD intervention for the primary prevention of depression in primary care and to identify areas for improvement. Method Qualitative study with FPs who delivered the predictD intervention at 35 urban primary care centres in seven Spanish cities. Face-to-face semi-structured interviews adopting a phenomenological approach. The data was triangulated by three investigators using thematic analysis and respondent validation was carried out. Results Sixty-seven FPs were interviewed and they indicated strategies used to perform the predictD intervention, including specific communication skills such as empathy and the activation of patient resources. They perceived barriers such as lack of time and facilitators such as prior acquaintance with patients. FPs recognized the positive consequences of the intervention for FPs, patients and the doctor-patient relationship. They also identified strategies for future versions and implementations of the predictD intervention. Conclusions The FPs who carried out the predictD intervention identified factors potentially associated with successful prevention using this program and others that could be improved. Their opinions about the predictD intervention will enable development of a more effective and acceptable version and its implementation in different primary health care settings

A personalized intervention to prevent depression in primary care: cost-effectiveness study nested into a clustered randomized trial

Background: Depression is viewed as a major and increasing public health issue, as it causes high distress in the people experiencing it and considerable financial costs to society. Efforts are being made to reduce this burden by preventing depression. A critical component of this strategy is the ability to assess the individual level and profile of risk for the development of major depression. This paper presents the cost-effectiveness of a personalized intervention based on the risk of developing depression carried out in primary care, compared with usual care. Methods: Cost-effectiveness analyses are nested within a multicentre, clustered, randomized controlled trial of a personalized intervention to prevent depression. The study was carried out in 70 primary care centres from seven cities in Spain. Two general practitioners (GPs) were randomly sampled from those prepared to participate in each centre (i.e. 140 GPs), and 3326 participants consented and were eligible to participate. The intervention included the GP communicating to the patient his/her individual risk for depression and personal risk factors and the construction by both GPs and patients of a psychosocial programme tailored to prevent depression. In addition, GPs carried out measures to activate and empower the patients, who also received a leaflet about preventing depression. GPs were trained in a 10- to 15-h workshop. Costs were measured from a societal and National Health care perspective. Qualityadjustedlife years were assessed using the EuroQOL five dimensions questionnaire. The time horizon was 18 months. Results: With a willingness-to-pay threshold of (sic)10, 000 ((sic)8568) the probability of cost-effectiveness oscillated from 83% (societal perspective) to 89% (health perspective). If the threshold was increased to (sic)30, 000 ((sic)25, 704), the probability of being considered cost-effective was 94% (societal perspective) and 96%, respectively (health perspective). The sensitivity analysis confirmed these results. Conclusions: Compared with usual care, an intervention based on personal predictors of risk of depression implemented by GPs is a cost-effective strategy to prevent depression. This type of personalized intervention in primary care should be further developed and evaluated

Relative validity of a semi-quantitative food-frequency questionnaire in an elderly Mediterranean population of Spain

The aim of the present study was to assess reproducibility and relative validity of a self-administered FFQ used in the PREDIMED Study, a clinical trial for primary prevention of CVD by Mediterranean diet in a population at high cardiovascular risk. The FFQ was administered twice (FFQ1 and FFQ2) to explore reproducibility at 1 year. Four 3d dietary records (DR) were used as reference to explore validity; participants therefore recorded their food intake over 12 d in the course of 1 year. The degree of misclassification in the FFQ was also evaluated by a contingency table of quintiles comparing the information from the FFQ2 and the DR. A total of 158 men and women (aged 55-80 years) were asked not to modify their dietary habits during the study period. Reproducibility for food groups, energy and nutrient intake, explored by the Pearson correlation coefficient (r) raneed 0.50-0.82, and the intraclass correlation coefficient ([CC) ranged from 0.63 to 0.90. The FFQ2 tended to report higher energy and nutrient intake than the DR. The validity indices of the FFQ in relation to the DR for food groups and energy and nutrient intake ranged (r) from 0.24 to 0.72, while the ranee of the ICC: was between 0.40 and 0.84. With regard to food groups, 68-83 % of individuals were in the same or adjacent quintile in both methods, a figure which decreased to 55-75 % for enemy and nutrient intake. We concluded that FFQ measurements had :good reproducibility and a relative validity similar to those of FFQ used in other prospective studies

Temperature chaos is present in off-equilibrium spin-glass dynamics

Experiments featuring non-equilibrium glassy dynamics under temperature changes still await interpretation. There is a widespread feeling that temperature chaos (an extreme sensitivity of the glass to temperature changes) should play a major role but, up to now, this phenomenon has been investigated solely under equilibrium conditions. In fact, the very existence of a chaotic effect in the non-equilibrium dynamics is yet to be established. In this article, we tackle this problem through a large simulation of the 3D Edwards-Anderson model, carried out on the Janus II supercomputer. We find a dynamic effect that closely parallels equilibrium temperature chaos. This dynamic temperature-chaos effect is spatially heterogeneous to a large degree and turns out to be controlled by the spin-glass coherence length ¿. Indeed, an emerging length-scale ¿* rules the crossover from weak (at ¿ « ¿*) to strong chaos (¿ » ¿*). Extrapolations of ¿* to relevant experimental conditions are provided. © 2021, The Author(s)

Evolution of CRISPR-associated endonucleases as inferred from resurrected proteins

Clustered regularly interspaced short palindromic repeats (CRISPR)-associated Cas9 is an effector protein that targets invading DNA and plays a major role in the prokaryotic adaptive immune system. Although Streptococcus pyogenes CRISPR–Cas9 has been widely studied and repurposed for applications including genome editing, its origin and evolution are poorly understood. Here, we investigate the evolution of Cas9 from resurrected ancient nucleases (anCas) in extinct firmicutes species that last lived 2.6 billion years before the present. We demonstrate that these ancient forms were much more flexible in their guide RNA and protospacer-adjacent motif requirements compared with modern-day Cas9 enzymes. Furthermore, anCas portrays a gradual palaeoenzymatic adaptation from nickase to double-strand break activity, exhibits high levels of activity with both single-stranded DNA and single-stranded RNA targets and is capable of editing activity in human cells. Prediction and characterization of anCas with a resurrected protein approach uncovers an evolutionary trajectory leading to functionally flexible ancient enzymes.This work has been supported by grant nos. PID2019-109087RB-I00 (to R.P.-J.) and RTI2018-101223-B-I00 and PID2021-127644OB-I00 (to L.M.) from the Spanish Ministry of Science and Innovation. This project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement no. 964764 (to R.P.-J.). The content presented in this document represents the views of the authors, and the European Commission has no liability in respect to the content. We acknowledge financial support from the Spanish Foundation for the Promotion of Research of Amyotrophic Lateral Sclerosis. A.F. acknowledges Spanish Center for Biomedical Network Research on Rare Diseases (CIBERE) intramural funds (no. ER19P5AC756/2021). F.J.M.M. acknowledges research support by Conselleria d’Educació, Investigació, Cultura i Esport from Generalitat Valenciana, research project nos. PROMETEO/2017/129 and PROMETEO/2021/057. M.M. acknowledges funding from CIBERER (grant no. ER19P5AC728/2021). The work has received funding from the Regional Government of Madrid (grant no. B2017/BMD3721 to M.A.M.-P.) and from Instituto de Salud Carlos III, cofounded with the European Regional Development Fund ‘A way to make Europe’ within the National Plans for Scientific and Technical Research and Innovation 2017–2020 and 2021–2024 (nos. PI17/1659, PI20/0429 and IMP/00009; to M.A.M.-P. B.P.K. was supported by an MGH ECOR Howard M. Goodman Award and NIH P01 HL142494

FGF receptor genes and breast cancer susceptibility: results from the Breast Cancer Association Consortium

Background:Breast cancer is one of the most common malignancies in women. Genome-wide association studies have identified FGFR2 as a breast cancer susceptibility gene. Common variation in other fibroblast growth factor (FGF) receptors might also modify risk. We tested this hypothesis by studying genotyped single-nucleotide polymorphisms (SNPs) and imputed SNPs in FGFR1, FGFR3, FGFR4 and FGFRL1 in the Breast Cancer Association Consortium. Methods:Data were combined from 49 studies, including 53 835 cases and 50 156 controls, of which 89 050 (46 450 cases and 42 600 controls) were of European ancestry, 12 893 (6269 cases and 6624 controls) of Asian and 2048 (1116 cases and 932 controls) of African ancestry. Associations with risk of breast cancer, overall and by disease sub-type, were assessed using unconditional logistic regression. Results:Little evidence of association with breast cancer risk was observed for SNPs in the FGF receptor genes. The strongest evidence in European women was for rs743682 in FGFR3; the estimated per-allele odds ratio was 1.05 (95 confidence interval=1.02-1.09, P=0.0020), which is substantially lower than that observed for SNPs in FGFR2. Conclusion:Our results suggest that common variants in the other FGF receptors are not associated with risk of breast cancer to the degree observed for FGFR2. © 2014 Cancer Research UK

Observation of a new chi_b state in radiative transitions to Upsilon(1S) and Upsilon(2S) at ATLAS

The chi_b(nP) quarkonium states are produced in proton-proton collisions at the Large Hadron Collider (LHC) at sqrt(s) = 7 TeV and recorded by the ATLAS detector. Using a data sample corresponding to an integrated luminosity of 4.4 fb^-1, these states are reconstructed through their radiative decays to Upsilon(1S,2S) with Upsilon->mu+mu-. In addition to the mass peaks corresponding to the decay modes chi_b(1P,2P)->Upsilon(1S)gamma, a new structure centered at a mass of 10.530+/-0.005 (stat.)+/-0.009 (syst.) GeV is also observed, in both the Upsilon(1S)gamma and Upsilon(2S)gamma decay modes. This is interpreted as the chi_b(3P) system.Comment: 5 pages plus author list (18 pages total), 2 figures, 1 table, corrected author list, matches final version in Physical Review Letter

Search for displaced vertices arising from decays of new heavy particles in 7 TeV pp collisions at ATLAS

We present the results of a search for new, heavy particles that decay at a significant distance from their production point into a final state containing charged hadrons in association with a high-momentum muon. The search is conducted in a pp-collision data sample with a center-of-mass energy of 7 TeV and an integrated luminosity of 33 pb^-1 collected in 2010 by the ATLAS detector operating at the Large Hadron Collider. Production of such particles is expected in various scenarios of physics beyond the standard model. We observe no signal and place limits on the production cross-section of supersymmetric particles in an R-parity-violating scenario as a function of the neutralino lifetime. Limits are presented for different squark and neutralino masses, enabling extension of the limits to a variety of other models.Comment: 8 pages plus author list (20 pages total), 8 figures, 1 table, final version to appear in Physics Letters