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[EN] Genomes contain rare guanine-rich sequences capable of assembling into four-stranded helical structures, termed G-quadruplexes, with potential roles in gene regulation and chromosome stability. Their mechanical unfolding has only been reported to date by all-atom simulations, which cannot dissect the major physical interactions responsible for their cohesion. Here, we propose a mesoscopic model to describe both the mechanical and thermal stability of DNA G-quadruplexes, where each nucleotide of the structure, as well as each central cation located at the inner channel, is mapped onto a single bead. In this framework we are able to simulate loading rates similar to the experimental ones, which are not reachable in simulations with atomistic resolution. In this regard, we present single-molecule force-induced unfolding experiments by a high-resolution optical tweezers on a DNA telomeric sequence capable of adopting a G-quadruplex conformation. Fitting the parameters of the model to the experiments we find a correct prediction of the rupture-force kinetics and a good agreement with previous near equilibrium measurements. Since G-quadruplex unfolding dynamics is halfway in complexity between secondary nucleic acids and tertiary protein structures, our model entails a nanoscale paradigm for non-equilibrium processes in the cell. ; Work supported by the Spanish Ministry of Economy and Competitiveness (MINECO), grant No. FIS2014-55867, co-financed by FEDER funds. We also thank the support of the Aragon Government and Fondo Social Europeo to FENOL group. Work in J.R.A.-G. laboratory was supported by a grant from MINECO, No. MAT2015-71806-R). ; Bergues-Pupo, A.; Gutiérrez, I.; Arias-Gonzalez, JR.; Falo, F.; Fiasconaro, A. (2017). Mesoscopic model for DNA G-quadruplex unfolding. Scientific Reports. 7:1-13. https://doi.org/10.1038/s41598-017-10849-2 ; S ; 1 ; 13 ; 7 ; Arias-Gonzalez, J. R. Single-molecule portrait of DNA and RNA double helices. Integr. Biol. 6, 904 (2014). ; Burge, S., Parkinson, G. N., Hazel, P., ...

Under the terms of the Creative Commons Attribution License 3.0 (CC-BY). ; We present a study of the DNA translocation of the bacteriophage P29 packaging molecular motor. From the available experimental information we present a model system based on a stochastic flashing potential, which reproduces the experimental observations such as detailed trajectories, steps and substeps, spatial correlation, and velocity. Moreover, the model allows the evaluation of the power and efficiency of this motor. We have found that the maximum power regime does not correspond with that of the maximum efficiency. This information can stimulate further experiments. © 2013 American Physical Society. ; This work has been partially supported by the Spanish DGICYT Projects No. FIS2011-25167 and No. FIS2012-37655-C2-2, cofinanced by FEDER funds, and Spanish government fellowship No. FPU-AP2007-00987 (R.P.C.). ; Peer Reviewed

Curaxins and especially the second-generation derivative curaxin CBL0137 have important antitumor activities in multiple cancers such as glioblastoma, melanoma and others. Although most of the authors suggest that their mechanism of action comes from the activation of p53 and inactivation of NF-kB by targeting FACT, there is evidence supporting the involvement of DNA binding in their antitumor activity. In this work, the DNA binding properties of curaxin CBL0137 with model quadruplex DNA oligomers were studied by 1H NMR, CD, fluorescence and molecular modeling. We provided molecular details of the interaction of curaxin with two G-quadruplex structures, the single repeat of human telomere d(TTAGGGT)4 and the c-myc promoter Pu22 sequence. We also performed 1H and 31P NMR experiments were also performed in order to investigate the interaction with duplex DNA models. Our data support the hypothesis that the interaction of curaxin with G-quadruplex may provide a novel insight into the DNA-binding properties of CBL0137, and it will be helpful for the design of novel selective DNA-targeting curaxin analogues. ; This research was funded by PIANO DI SOSTEGNO ALLA RICERCA 2020—Linea 2 azione B (DEFENS) and by the Spanish Ministerio de Ciencia e Innnvacion (PID2019-107158GB-I00) and recognition from the Autonomous Catalan government (2017SGR114). ; Peer reviewed

The intrinsic dynamic nature of chromosomes is emerging as a fundamental component in regulating DNA transcription, replication, and damage-repair among other nuclear functions. With this increased awareness, reinforced over the last ten years, many new experimental techniques, mainly based on microscopy and chromosome conformation capture, have been introduced to study the genome in space and time. Owing to the increasing complexity of these cutting-edge techniques, computational approaches have become of paramount importance to interpret, contextualize, and complement such experiments with new insights. Hence, it is becoming crucial for experimental biologists to have a clear understanding of the diverse theoretical modeling approaches available and the biological information each of them can provide. ; M.A.M-R. acknowledges support from the European Union's Seventh Framework Programme through the ERC (grant agreement 609989), European Union's Horizon 2020 research and innovation programme (grant agreement 676556), and the Spanish Ministerio de Ciencia, Innovación y Universidades (BFU2017-85926-P). M.D.S. acknowledges support from the ORION project that has received funding from the European Union's Horizon 2020 research and innovation programme under grant agreement (grant agreement 741527). D.J. acknowledges Agence Nationale de la Recherche (ANR-18-CE12-0006-03, ANR-18-CE45-0022-01) for funding. CRG acknowledges support from 'Centro de Excelencia Severo Ochoa 2013-2017', SEV-2012-0208 and the CERCA Programme/Generalitat de Catalunya as well as support of the Spanish Ministry of Science and Innovation through the Instituto de Salud Carlos III and the EMBL partnership, the Generalitat de Catalunya through Departament de Salut and Departament d'Empresa i Coneixement, and the Co-financing with funds from the European Regional Development Fund (ERDF) by the Spanish Ministery of Science and Innovation coresponding to the Programa Opertaivo FEDER Plurirregional de España (POPE) 2014-2020 and by the Secretaria d'Universitats i Recerca, Departament d'Empresa i Coneixement of the Generalitat de Catalunya corresponding to the programa Operatiu FEDER Catalunya 2014-2020. Open Access fees paid from COST Action INC (CA18127), supported by COST (European Cooperation in Science and Technology)

We propose that peptides are highly versatile platforms for the precise design of supramolecular metal architectures, and particularly, for the controlled assembly of helicates. In this context, we show that the bacteriophage T4 Fibritin foldon (T4Ff) can been engineered on its N-terminus with metal-chelating 2,2′-bipyridine units that stereoselectively assemble in the presence of Fe(II) into parallel, three-stranded peptide helicates with preferred helical orientation. Modeling studies support the proposed self-assembly and the stability of the final helicate. Furthermore, we show that these designed mini-metalloproteins selectively recognize three-way DNA junctions over double-stranded DNA ; Financial support from the Spanish grants CTQ2015-70698-R, CTQ2017-87889-P, the Xunta de Galicia (Centro singular de investigación de Galicia accreditation 2016–2019, ED431G/09) and the European Union (European Regional Development Fund - ERDF), is gratefully acknowledged. JG-G, thanks the Spanish MINECO for his FPI fellowship, GB thanks the ERC for her EU METALIC-II 2013-2442/001-001-EMA2 mobility scheme fellowship, and GS. thanks the Universitat Autònoma de Barcelona for its support to his PhD. J-DM and GS are thankful for the support given by the Generalitat de Catalunya 2017SGR1323. Support of COST Action CM1306 is kindly acknowledged. MEV, also wish to acknowledge the generous support by the Fundación Asociación Española Contra el Cáncer AECC (IDEAS197VAZQ grant) ; SI

The propensity of 5-formyluracil and 5-formylcytosine, i.e. oxidative lesions and epigenetic intermediates, in acting as intrinsic DNA photosensitizers is unraveled by using a combination of molecular modeling, simulation and spectroscopy. Exploration of potential energy surfaces and non-adiabatic dynamics confirm a higher intersystem crossing rate for 5-formyluracil, whereas the kinetic models evidence different equilibria in the excited states for both compounds. ; Support from the Université de Lorraine, CNRS and Spanish Government (PGC2018-096684-B-I00) is kindly acknowledged. A. F.-M. is grateful to Generalitat Valenciana (CTQ2017-87054-C2-2-P) and the European Social Fund for a postdoctoral contract (APOSTD/2019/149), M. L.-R. acknowledges the Universitat Politècnica de València for the FPI grant. Calculations have been performed on the local LPCT computer center and on the Explor regional center in the framework of the project "Dancing under the light".

[EN] The propensity of 5-formyluracil and 5-formylcytosine, i.e. oxidative lesions and epigenetic intermediates, in acting as intrinsic DNA photosensitizers is unraveled by using a combination of molecular modeling, simulation and spectroscopy. Exploration of potential energy surfaces and non-adiabatic dynamics confirm a higher intersystem crossing rate for 5-formyluracil, whereas the kinetic models evidence different equilibria in the excited states for both compounds. ; Support from the Universite de Lorraine, CNRS and Spanish Government (PGC2018-096684-B-I00) is kindly acknowledged. A. F.-M. is grateful to Generalitat Valenciana (CTQ2017-87054-C2-2-P) and the European Social Fund for a postdoctoral contract (APOSTD/2019/149), M. L.-R. acknowledges the Universitat Politecnica de Valencia for the FPI grant. Calculations have been performed on the local LPCT computer center and on the Explor regional center in the framework of the project "Dancing under the light''. ; Francés-Monerris, A.; Lineros-Rosa, M.; Miranda Alonso, MÁ.; Lhiaubet, VL.; Monari, A. (2020). Photoinduced intersystem crossing in DNA oxidative lesions and epigenetic intermediates. Chemical Communications. 56(32):4404-4407. https://doi.org/10.1039/d0cc01132k ; S ; 4404 ; 4407 ; 56 ; 32 ; Madabhushi, R., Pan, L., & Tsai, L.-H. (2014). DNA Damage and Its Links to Neurodegeneration. Neuron, 83(2), 266-282. doi:10.1016/j.neuron.2014.06.034 ; Sage, E. (1993). DISTRIBUTION AND REPAIR OF PHOTOLESIONS IN DNA: GENETIC CONSEQUENCES AND THE ROLE OF SEQUENCE CONTEXT. Photochemistry and Photobiology, 57(1), 163-174. doi:10.1111/j.1751-1097.1993.tb02273.x ; Cadet, J., Sage, E., & Douki, T. (2005). Ultraviolet radiation-mediated damage to cellular DNA. Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis, 571(1-2), 3-17. doi:10.1016/j.mrfmmm.2004.09.012 ; G. T. Wondrak , Skin stress response pathways: Environmental factors and molecular opportunities , Springer , 2016 ; Nakamura, J., Mutlu, E., Sharma, V., Collins, L., Bodnar, W., Yu, ...

14 páginas, 4 figuras, 3 tablas. ; [EN]: In northwest Africa some species from Sahelian origin appear with relict populations and apparently isolated by the extreme aridity of the Sahara desert. However very tolerant to aridity species could maintain continuous populations as might be the case for Echis leucogaster as indicated by results from genetic analysis and bioclimatic models. ; [CA]: Al nord-oest d'àfrica apareixen un grup d'espècies d'origen sahelià en poblacions relictes i aparentment aïllades pel desert del Sàhara. No obstant això espècies molt tolerants a l"aridesa podrien mantenir poblacions contínues, com podria ser el cas de Echis leucogaster segons indiquen els resultats de l'anàlisi genètica i els models bioclimàtics. ; This work was carried out under a permit from the Moroccan Government (Department of Water and Forestry resources) to David Donaire. ; Peer reviewed

Formaldehyde induced squamous‐cell carcinomas in the nasal passages of F344 rats in two inhalation bioassays at exposure levels of 6 ppm and above. Increases in rates of cell proliferation were measured by T. M. Monticello and colleagues at exposure levels of 0.7 ppm and above in the same tissues from which tumors arose. A risk assessment for formaldehyde was conducted at the CIIT Centers for Health Research, in collaboration with investigators from Toxicological Excellence in Risk Assessment (TERA) and the U.S. Environmental Protection Agency (U.S. EPA) in 1999. Two methods for dose‐response assessment were used: a full biologically based modeling approach and a statistically oriented analysis by benchmark dose (BMD) method. This article presents the later approach, the purpose of which is to combine BMD and pharmacokinetic modeling to estimate human cancer risks from formaldehyde exposure. BMD analysis was used to identify points of departure (exposure levels) for low‐dose extrapolation in rats for both tumor and the cell proliferation endpoints. The benchmark concentrations for induced cell proliferation were lower than for tumors. These concentrations were extrapolated to humans using two mechanistic models. One model used computational fluid dynamics (CFD) alone to determine rates of delivery of inhaled formaldehyde to the nasal lining. The second model combined the CFD method with a pharmacokinetic model to predict tissue dose with formaldehyde‐induced DNA‐protein cross‐links (DPX) as a dose metric. Both extrapolation methods gave similar results, and the predicted cancer risk in humans at low exposure levels was found to be similar to that from a risk assessment conducted by the U.S. EPA in 1991. Use of the mechanistically based extrapolation models lends greater certainty to these risk estimates than previous approaches and also identifies the uncertainty in the measured dose‐response relationship for cell proliferation at low exposure levels, the dose‐response relationship for DPX in monkeys, and the choice between linear and nonlinear methods of extrapolation as key remaining sources of uncertainty.

We investigate, through modeling, the impact of interindividual heterogeneity in the metabolism of 4‐aminobiphenyl (ABP) and in physiological factors on human cancer risk: A physiological pharmacokinetic model was used to quantify the time course of the formation of the proximate carcinogen, N‐hydroxy‐4‐ABP and the DNA‐binding of the active species in the bladder. The metabolic and physiologic model parameters were randomly varied, via Monte Carlo simulations, to reproduce interindividual variability. The sampling means for most parameters were scaled from values developed by Kadlubar et al. (Cancer Res., 51: 4371, 1991) for dogs; variances were obtained primarily from published human data (e.g., measurements of ABP N‐oxidation, and arylamine N‐acetylation in human liver tissue). In 500 simulations, theoretically representing 500 humans, DNA‐adduct levels in the bladder of the most susceptible individuals are ten thousand times higher than for the least susceptible, and the 5th and 95th percentiles differ by a factor of 160. DNA binding for the most susceptible individual (with low urine pH, low N‐acetylation and high N‐oxidation activities) is theoretically one million‐fold higher than for the least susceptible (with high urine pH, high N‐acetylation and low N‐oxidation activities). The simulations also suggest that the four factors contributing most significantly to interindividual differences in DNA‐binding of ABP in human bladder are urine pH, ABP N‐oxidation, ABP N‐acetylation and urination frequency.

Movement as a constant? Envisioning a migration-centered worldview of human history / Megan J. Daniels -- Toward a new prehistory: re-theorizing genes, culture, and migratory expansions / Kristian Kristiansen -- Migration, ancient DNA, and Bronze Age pastoralists from the Eurasian steppes / David W. Anthony -- The conceptual impacts of genomics to the archaeology of movement / Omer Gokcumen -- New data and old narratives: migrants and the conjoining of the cultures and economies of the pre-Roman Western Mediterranean / Franco De Angelis -- The invisible migrant / Catherine M. Cameron -- The in/visibility of migration / Elena Isayev -- A harbor scene: reassessing mobility in the Bronze Age Eastern Mediterranean following the archaeological science revolution / Assaf Yasur-Landau -- Surfing with the alien: simulating and testing the spread of early farming across the Adriatic basin / Marc Vander Linden, Cornelis Drost, Jane Gasstra, Ivana Jovanović, Sébastien Manem, Anne de Vareilles -- The settlement record, paleodemography, and evidence for migrations in eneolithic Ukraine / Thomas K. Harper -- N site continuous model for migration: parameter and prehistoric tests / Ezra B. W. Zubrow, Aleksandr Diachenko, Jay Leavitt -- Toward a social archaeology of forced migration: rebuilding landscapes of memory in medieval Armenian Cilicia / Aurora E. Camańo -- Macro- and micro-mobilities and the creation of identity in the ancient near east / Anne Porter -- Wandering ports on the Datça peninsula: exploring regional mobility in a maritime landscape / Elizabeth S. Greene and Justin Leidwanger -- Assessing the possibility of trans-maritime mobility in archaic hominins: does Afro-Eurasian coastal palaeogeography support sweepstakes dispersal in homo? / Thomas P. Leppard -- Homo mobilis: interactions, consciousness, and the anthropocene / Hans Barnard

Numerous efforts are underway to determine gene regulatory networks that describe physical relationships between transcription factors (TFs) and their target DNA sequences. Members of paralogous TF families typically recognize similar DNA sequences. Knowledge of the molecular determinants of protein–DNA recognition by paralogous TFs is of central importance for understanding how small differences in DNA specificities can dictate target gene selection. Previously, we determined the in vitro DNA binding specificities of 19 Caenorhabditis elegans basic helix-loop-helix (bHLH) dimers using protein binding microarrays. These TFs bind E-box (CANNTG) and E-box-like sequences. Here, we combine these data with logics, bHLH–DNA co-crystal structures and computational modeling to infer which bHLH monomer can interact with which CAN E-box half-site and we identify a critical residue in the protein that dictates this specificity. Validation experiments using mutant bHLH proteins provide support for our inferences. Our study provides insights into the mechanisms of DNA recognition by bHLH dimers as well as a blueprint for system-level studies of the DNA binding determinants of other TF families in different model organisms and humans. ; National Institute of General Medical Sciences (U.S.) (DK068429) ; National Institute of General Medical Sciences (U.S.) (HG003985) ; European Union (PROSPECTS HEALTH-F4-2008-201648)

Clustered regularly interspaced palindromic repeats (CRISPR) with the associated (Cas) nuclease complexes have democratized genetic engineering through their precision and ease-of-use. We have applied a variation of this technology, known as CRISPR-directed mutagenesis (CDM), to reconstruct genetic profiles within the FLT3 gene of AML patients. We took advantage of the versatility of CDM and built expression vectors that, in combination with a specifically designed donor DNA fragment, recapitulate simple and complex mutations within the FLT3 gene. We generate insertions and point mutations including combinations of these mutations originating from individual patient samples. We then analyze how these complex genetic profiles modulate transformation of Ba/F3 cells. Our results show that FLT3 expression plasmids bearing patient-specific single or multiple mutations recapitulate cellular transformation properties induced by FLT3 ITDs and modify their sensitivity or resistance in response to established AML drugs as a function of these complex mutations.