Search

It is unclear how the mitochondrial fusion protein Optic atrophy 1 (OPA1), which inhibits cristae remodeling, protects from mitochondrial dysfunction. Here we identify the mitochondrial F1Fo-ATP synthase as the effector of OPA1 in mitochondrial protection. In OPA1 overexpressing cells, the loss of proton electrochemical gradient caused by respiratory chain complex III inhibition is blunted and this protection is abolished by the ATP synthase inhibitor oligomycin. Mechanistically, OPA1 and ATP synthase can interact, but recombinant OPA1 fails to promote oligomerization of purified ATP synthase reconstituted in liposomes, suggesting that OPA1 favors ATP synthase oligomerization and reversal activity by modulating cristae shape. When ATP synthase oligomers are genetically destabilized by silencing the key dimerization subunit e, OPA1 is no longer able to preserve mitochondrial function and cell viability upon complex III inhibition. Thus, OPA1 protects mitochondria from respiratory chain inhibition by stabilizing cristae shape and favoring ATP synthase oligomerization., R.Q.-C. was supported by an AIRC Postdoctoral Fellowship, a Fondazione Umberto Veronesi Postdoctoral Fellowship and is currently a recipient of a Juan de la Cierva-Incorporación fellowship from the Spanish Ministry of Economy, Industry and Competitiveness (IJCI-2015–26225). This work was supported by Telethon-Italy GPP10005, GGP14187, GGP15091; AIRC Italy IG-15748, ERC FP7-282280, FP7 CIG PCIG13-GA-2013-618697; Italian Ministry of Research FIRB RBAP11Z3YA_005 to L.S. C.Ge. is supported by JST, CREST Grant JPMJCR13M4 (to Genij Kurisu and C.Ge.), the Platform for Drug Design, Discovery and Development from MEXT, Japan and the Grants-in-Aid for Scientific Research (Kiban B: 17H03647) from MEXT, Japan. JAE is supported by Spanish Ministry of Economy, Industry and Competitiveness (SAF2015-65633-R; SAF2015-71521-REDC). The CNIC is supported by MINECO and Pro-CNIC Foundation and is a SO-MINECO (award SEV-2015-0505).

In germinal centres (GC) mature B cells undergo intense proliferation and immunoglobulin gene modification before they differentiate into memory B cells or long-lived plasma cells (PC). GC B-cell-to-PC transition involves a major transcriptional switch that promotes a halt in cell proliferation and the production of secreted immunoglobulins. Here we show that the CCCTC-binding factor (CTCF) is required for the GC reaction in vivo, whereas in vitro the requirement for CTCF is not universal and instead depends on the pathways used for B-cell activation. CTCF maintains the GC transcriptional programme, allows a high proliferation rate, and represses the expression of Blimp-1, the master regulator of PC differentiation. Restoration of Blimp-1 levels partially rescues the proliferation defect of CTCF-deficient B cells. Thus, our data reveal an essential function of CTCF in maintaining the GC transcriptional programme and preventing premature PC differentiation., Activated B cells differentiate into antibody-producing plasma cells in the germinal centre in secondary lymphoid organs. Here the authors show that this differentiation process and related transcription programs are modulated by the transcription factor CTCF, partly by suppressing the premature expression of Blimp-1.

The ideal magnetocaloric material would lay at the borderline of a first-order and a second-order phase transition. Hence, it is crucial to unambiguously determine the order of phase transitions for both applied magnetocaloric research as well as the characterization of other phase change materials. Although Ehrenfest provided a conceptually simple definition of the order of a phase transition, the known techniques for its determination based on magnetic measurements either provide erroneous results for specific cases or require extensive data analysis that depends on subjective appreciations of qualitative features of the data. Here we report a quantitative fingerprint of first-order thermomagnetic phase transitions: the exponent n from field dependence of magnetic entropy change presents a maximum of n > 2 only for first-order thermomagnetic phase transitions. This model-independent parameter allows evaluating the order of phase transition without any subjective interpretations, as we show for different types of materials and for the Bean–Rodbell model., Magnetocaloric materials often perform best when their magnetic transitions are at the boundary between first- and second-order behavior. Here the authors propose a simple criterion to determine the order of a transition, which may accelerate future magnetocaloric material searches.

During development, mesodermal progenitors from the first heart field (FHF) form a primitive cardiac tube, to which progenitors from the second heart field (SHF) are added. The contribution of FHF and SHF progenitors to the adult zebrafish heart has not been studied to date. Here we find, using genetic tbx5a lineage tracing tools, that the ventricular myocardium in the adult zebrafish is mainly derived from tbx5a+ cells, with a small contribution from tbx5a− SHF progenitors. Notably, ablation of ventricular tbx5a+-derived cardiomyocytes in the embryo is compensated by expansion of SHF-derived cells. In the adult, tbx5a expression is restricted to the trabeculae and excluded from the outer cortical layer. tbx5a-lineage tracing revealed that trabecular cardiomyocytes can switch their fate and differentiate into cortical myocardium during adult heart regeneration. We conclude that a high degree of cardiomyocyte cell fate plasticity contributes to efficient regeneration., Funding was through FPU12/03007 and BFU2014–56970–P (Plan Estatal de Investigación Científica y Técnica y de Innovación 2013–2016, Programa Estatal de I+D+i Orientada a los Retos de la Sociedad Retos Investigación: Proyectos I+D+i 2016, del Ministerio de Economía competitividad e Industria), and co-funding by Fondo Europeo de Desarrollo Regional (FEDER) (H.S. and N.M.); Swiss National Science Foundation grant 31003A_159721, ANR-SNF collaborative Project 320030E-164245, and the ERC starting grant 337703–zebra–Heart (N.M.). A.E. is enrolled into PhD specialization Cutting Edge Microscopy offered by the Graduate School for Cellular and Biomedical Sciences (GCB) and the Microscopy Imaging Center (MIC). The CNIC is supported by the Ministry of Economy, Industry and Competitiveness (MEIC) and the Pro CNIC Foundation, and is a Severo Ochoa Center of Excellence (MEIC award SEV-2015-0505). Further support was from the Canton of Zürich, project grant from the Swiss Heart Foundation (A.F. and C. Mosimann); the Swiss National Science Foundation (SNSF) professorship (PP00P3_139093) and a Marie Curie Career Integration Grant from the European Commission (CIG PCIG14-GA-2013-631984) (C. Mosimann).

Conflicts between replication and transcription machineries represent a major source of genomic instability and cells have evolved strategies to prevent such conflicts. However, little is known regarding how cells cope with sudden increases of transcription while replicating. Here, we report the existence of a general mechanism for the protection of genomic integrity upon transcriptional outbursts in S phase that is mediated by Mrc1. The N-terminal phosphorylation of Mrc1 blocked replication and prevented transcription-associated recombination (TAR) and genomic instability during stress-induced gene expression in S phase. An unbiased kinome screening identified several kinases that phosphorylate Mrc1 at the N terminus upon different environmental stresses. Mrc1 function was not restricted to environmental cues but was also required when unscheduled transcription was triggered by low fitness states such as genomic instability or slow growth. Our data indicate that Mrc1 integrates multiple signals, thereby defining a general safeguard mechanism to protect genomic integrity upon transcriptional outbursts., B.C. is a recipient of an FPI fellowship. The study was supported by grants from the Spanish Ministry of Economy and Competitiveness (BFU2015-64437-P and FEDER, BFU2014-52125-REDT, and BFU2014-51672-REDC to F.P.; BFU2014-52333-P and FEDER to E.N.; and BFU2013-42918 and FEDER to A.A.), the Andalusian Government (P12-BIO-1238), ERC2014-ADG669898 TARLOOP, and Worldwide Cancer Research 15–0098 to A.A. and the Catalan Government (2014 SGR 599), and the Fundación Botín, by Banco Santander through its Santander Universities Global Division to F.P. F.P. and E.d.N. are recipients of an ICREA Acadèmia (Generalitat de Catalunya).

Heatwaves exert disproportionately strong and sometimes irreversible impacts on forest ecosystems. These impacts remain poorly understood at the tree and species level and across large spatial scales. Here, we investigate the effects of the record-breaking 2018 European heatwave on tree growth and tree water status using a collection of high-temporal resolution dendrometer data from 21 species across 53 sites. Relative to the two preceding years, annual stem growth was not consistently reduced by the 2018 heatwave but stems experienced twice the temporary shrinkage due to depletion of water reserves. Conifer species were less capable of rehydrating overnight than broadleaves across gradients of soil and atmospheric drought, suggesting less resilience toward transient stress. In particular, Norway spruce and Scots pine experienced extensive stem dehydration. Our high-resolution dendrometer network was suitable to disentangle the effects of a severe heatwave on tree growth and desiccation at large-spatial scales in situ, and provided insights on which species may be more vulnerable to climate extremes., This work utilised the network of dendrometer observations established by the COST Action network STReESS (grant FP1106). We acknowledge the involved networks TreeNet, Swiss Long-term Forest Ecosystem Research Programme LWF, French National Network for Long-term FOrest ECOsystem Monitoring RENECOFOR, the German Long Term Ecosystem Research Network LTER-D, the Italian Long Term Ecosystem Research Network ILTER, the Integrated Carbon Observation System ICOS and Tree-Watch.net. R.L.S. acknowledges funding from the Special Research Fund (BOF) of Ghent University for Postdoctoral Fellowships and the Spanish Ministry of Science, Innovation, and Universities (Juan de la Cierva Programme, grant IJC2018-036123-I). R.L.P., R.Z., P.F., and G.v.A. acknowledge funding from the Federal Office for the Environment FOEN (00.0365.PZ I 0427-0562, 09.0064.PJ/R301-0223; project treenet.info) and the Swiss National Science Foundation SNF (20FI21_148992, 20FI_173691, P2BSP3_184475; project LOTFOR 150205 and Grant 20FI20_173691; project ICOS-CH). J.M.V. and M.M. acknowledge funding from the Spanish MINECO via competitive grants CGL2013-46808-R and CGL2017-89149-C2-1-R. R.P. acknowledges funding from the grant RTI2018-095297-J-I00 (Spain) and by a Humboldt Research Fellowship for Experienced Researchers (Germany).

Identifying unequivocal signs of life on Mars is one of the most important objectives for sending missions to the red planet. Here we report Red Stone, a 163-100 My alluvial fan–fan delta that formed under arid conditions in the Atacama Desert, rich in hematite and mudstones containing clays such as vermiculite and smectites, and therefore geologically analogous to Mars. We show that Red Stone samples display an important number of microorganisms with an unusual high rate of phylogenetic indeterminacy, what we refer to as “dark microbiome”, and a mix of biosignatures from extant and ancient microorganisms that can be barely detected with state-of-the-art laboratory equipment. Our analyses by testbed instruments that are on or will be sent to Mars unveil that although the mineralogy of Red Stone matches that detected by ground-based instruments on the red planet, similarly low levels of organics will be hard, if not impossible to detect in Martian rocks depending on the instrument and technique used. Our results stress the importance in returning samples to Earth for conclusively addressing whether life ever existed on Mars., The research leading to these results is a contribution from the Project “MarsFirstWater”, funded by the European Research Council, Consolidator Grant no 818602 to AGF, and by the Human Frontiers Science Program grant n° RGY0066/2018 to A.A.-B. Additional funding provided was provided by MINECO grant PID2019-107442RB-C32 (O.P.-B. and A.M.), Grants-in-Aid for Scientific Research from the Japan Society for Promotion of Science grant numbers 17H06458 and 21H04515 (K.F.), grant numbers 17H06456, 17H06458, 20H00195, and 21H04515 (K.F. and Y.S.), Consejería de Educación e Investigación, Comunidad Autónoma de Madrid/European Social Fund program (MAFM), grant n° ESP2017-87690-C3-3-R (DC), Ramón y Cajal grant n° RYC2018-023943-I (L.S.-G.), AEI grant MDM-2017-0737 and MCIN/AEI grant PID2019-107442RB-C32 (V.M.-I.), MCIU/AEI (Spain) and FEDER (UE) grant n° PGC2018-094076-B-I00 (J.W. and C.A.), Italian Space Agency agreement 2017-48-H.0 (T.F., J.R.B. and G.P.), the Ministry of Science of Spain grant PID2019-107442RB-C31 (J.A.M., M.V., G.L.R., A.A. and F.R.), María Zambrano’ excellence grant program (CA3/RSUE/2021-00405), funded by the Spanish Ministry of Universities (MFM), NASA Mars Exploration Program contracts NNH13ZDA018O, NNH15AZ24I, NNH13ZDA018O and LANL Laboratory Directed Research and Development (LDRD) funding XX5V (A.M.O, R.C.W., A.R. and S.M.C.), NASA-GSFC grant NNX17AJ68G (M.M. and S.S.J.), NES focused on Sample Analysis at Mars of the Mars Science Laboratory mission, and Mars Organic Molecules Analyzer of the Exomars 2022 mission (O.M., C.S., and C.F.), and grants RTI2018-094368-B-I00 and MDM-2017-0737 Unidad de Excelencia “Maria de Maeztu”- Centro de Astrobiología (INTA-CSIC) by the Spanish Ministry of Science and Innovation/State Agency of Research MCIN/AEI/ 10.13039/501100011033 and by “ERDF A way of making Europe” (C.E., M.G.V., M.M.-P., and V.P.). R.C.W. thanks Dot Delapp for performing pre-processing of the LIBS data., With funding from the Spanish government through the "Severo Ochoa Center of Excellence" accreditation MDM-2017-0737.

15 pags., 6 figs., The RNA binding protein TDP-43 forms cytoplasmic inclusions via its C-terminal prion-like domain in several neurodegenerative diseases. Aberrant TDP-43 aggregation arises upon phase de-mixing and transitions from liquid to solid states, following still unknown structural conversions which are primed by oxidative stress and chaperone inhibition. Despite the well-established protective roles for molecular chaperones against protein aggregation pathologies, knowledge on the determinants of chaperone recognition in disease-related prions is scarce. Here we show that chaperones and co-chaperones primarily recognize the structured elements in TDP-43´s prion-like domain. Significantly, while HSP70 and HSP90 chaperones promote TDP-43 phase separation, co-chaperones from the three classes of the large human HSP40 family (namely DNAJA2, DNAJB1, DNAJB4 and DNAJC7) show strikingly different effects on TDP-43 de-mixing. Dismantling of the second helical element in TDP-43 prion-like domain by methionine sulfoxidation impacts phase separation and amyloid formation, abrogates chaperone recognition and alters phosphorylation by casein kinase-1δ. Our results show that metamorphism in the post-translationally modified TDP-43 prion-like domain encodes determinants that command mechanisms with major relevance in disease., This work was supported by grants PID2019-109276RA-I00/AEI/ 10.13039/501100011033 (to J.O.), PID2019-103845RB-C21-AEI/10.13039/ 501100011033 (to M.G.) and SAF2016-76678-C2-2-R (MINECO/AEI/ FEDER UE to D.V.L.) from the Spanish AEI-Ministry of Science and Innovation and Enhanced New Staff Start-up Research Grant (The University of Hong Kong) to R.H. J.O. was a recipient of a Leonardo Grant from the Spanish BBVA Foundation (BBM_TRA_0203) and is a Ramón y Cajal Fellow of the Spanish AEI-Ministry of Science and Innovation (RYC2018-026042-I funded by MCIN/AEI/10.13039/501100011033 and by “ESF Investing in your future”). NMR experiments were performed in the “Manuel Rico” NMR Laboratory (LMR) of the Spanish National Research Council (CSIC), a node of the Spanish Large-Scale National Facility (ICTS R-LRB).

Y-family DNA polymerase κ (Pol κ) can replicate damaged DNA templates to rescue stalled replication forks. Access of Pol κ to DNA damage sites is facilitated by its interaction with the processivity clamp PCNA and is regulated by PCNA mono-ubiquitylation. Here, we present cryo-EM reconstructions of human Pol κ bound to DNA, an incoming nucleotide, and wild type or mono-ubiquitylated PCNA (Ub-PCNA). In both reconstructions, the internal PIP-box adjacent to the Pol κ Polymerase-Associated Domain (PAD) docks the catalytic core to one PCNA protomer in an angled orientation, bending the DNA exiting the Pol κ active site through PCNA, while Pol κ C-terminal domain containing two Ubiquitin Binding Zinc Fingers (UBZs) is invisible, in agreement with disorder predictions. The ubiquitin moieties are partly flexible and extend radially away from PCNA, with the ubiquitin at the Pol κ-bound protomer appearing more rigid. Activity assays suggest that, when the internal PIP-box interaction is lost, Pol κ is retained on DNA by a secondary interaction between the UBZs and the ubiquitins flexibly conjugated to PCNA. Our data provide a structural basis for the recruitment of a Y-family TLS polymerase to sites of DNA damage., This research was supported by King Abdullah University of Science and Technology through core funding (to S.M.H.) and the Competitive Research Award Grant CRG8 URF/1/4036‐01‐01 (to S.M.H. and A.D.B.), and by the Wellcome Trust (to A.D.B.). R.C. acknowledges funding from the MINECO (CTQ2016-78636-P) and to AGAUR, (2017 SGR 324). The MD project has been carried out using CSUC resources. We acknowledge The Midlands Regional Cryo-EM Facility at the Leicester Institute of Structural and Chemical Biology (LISCB), major funding from MRC (MC_PC_17136). We thank Christos Savva (LISCB, University of Leicester) for his help in cryo-EM data collection and advice on data processing.

If neutrinos are their own antiparticles the otherwise-forbidden nuclear reaction known as neutrinoless double beta decay can occur. The very long lifetime expected for these exceptional events makes its detection a daunting task. In order to conduct an almost background-free experiment, the NEXT collaboration is investigating novel synthetic molecular sensors that may capture the Ba dication produced in the decay of certain Xe isotopes in a high-pressure gas experiment. The use of such molecular detectors immobilized on surfaces must be explored in the ultra-dry environment of a xenon gas chamber. Here, using a combination of highly sensitive surface science techniques in ultra-high vacuum, we demonstrate the possibility of employing the so-called Fluorescent Bicolor Indicator as the molecular component of the sensor. We unravel the ion capture process for these molecular indicators immobilized on a surface and explain the origin of the emission fluorescence shift associated to the ion trapping., This material is based upon work supported by the following agencies and institutions: the European Research Council (ERC) under ERC-2020-SyG 951281; the MCIN/AEI/10.13039/501100011033 of Spain and ERDF A way of making Europe under grants PID2020-114252GB-I00, PID2019-107338RB-C63, PID2019-104772GB-I00, PID2019-111281GB-I00, and RTI2018-095979, the Severo Ochoa Program grant CEX2018-000867-S; the Basque Government (GV/EJ) under grants IT-1553-22, IT-1591-22. The NEXT Collaboration acknowledges support from the following agencies and institutions: the European Union’s Framework Programme for Research and Innovation Horizon 2020 (2014-2020) under Grant Agreement No. 957202-HIDDEN; the MCIN/AEI of Spain and ERDF A way of making Europe under grants RTI2018-095979 and PID2021-125475NB, the Severo Ochoa Program grant CEX2018-000867-S and the Ramón y Cajal program grant RYC-2015-18820; the Generalitat Valenciana of Spain under grants PROMETEO/2021/087 and CIDEGENT/2019/049; the Department of Education of the Basque Government of Spain under the predoctoral training program non-doctoral research personnel; the Portuguese FCT under project UID/FIS/04559/2020 to fund the activities of LIBPhys-UC; the Pazy Foundation (Israel) under grants 877040 and 877041; the US Department of Energy under contracts number DE-AC02-06CH11357 (Argonne National Laboratory), DE-AC02-07CH11359 (Fermi National Accelerator Laboratory), DE-FG02-13ER42020 (Texas A&M), DE-SC0019054 (Texas Arlington) and DE-SC0019223 (Texas Arlington); the US National Science Foundation under award number NSF CHE 2004111; the Robert A Welch Foundation under award number Y-2031-20200401. Finally, we are grateful to the Laboratorio Subterráneo de Canfranc for hosting and supporting the NEXT experiment.

Antibodies, and antibody derivatives such as nanobodies, contain immunoglobulin-like (Ig) β-sandwich scaffolds which anchor the hypervariable antigen-binding loops and constitute the largest growing class of drugs. Current engineering strategies for this class of compounds rely on naturally existing Ig frameworks, which can be hard to modify and have limitations in manufacturability, designability and range of action. Here, we develop design rules for the central feature of the Ig fold architecture—the non-local cross-β structure connecting the two β-sheets—and use these to design highly stable Ig domains de novo, confirm their structures through X-ray crystallography, and show they can correctly scaffold functional loops. Our approach opens the door to the design of antibody-like scaffolds with tailored structures and superior biophysical properties., This research was supported by grants from the Spanish Ministry of Science and Innovation (RYC2018-025295-I, EUR2020-112164, and PID2020-120098GA-I00). This study was also supported in part by grants from Spanish and Catalan public and private bodies (grant/fellowship references MCIN/AEI/10.13039/501100011033/PID2019-107725RG-I00, 2017SGR3 and Fundació “La Marató de TV3” 201815). S.R.M. acknowledges grant BES2016-076877 from the Spanish State Agency for Research (MCIN/AEI/10.13039/501100011033) and the European Social Fund “ESF invests in your future”. U.E. was funded by a Beatriu de Pinós post-doctoral fellowship (AGAUR-MSCA COFUND 2018BP00163. J.R.T. was supported by an EMBO postdoctoral fellowship (under grant agreement ALTF 145-2021). J.C.K. was supported by a National Science Foundation Graduate Research Fellowship (grant DGE-1256082). D.B. and T.M.C. acknowledge the Howard Hughes Medical Institute. We thank the Princess Margaret Cancer Centre for funding of the NMR facility. The Structural Genomics Consortium is a registered charity (no: 1097737) that receives funds from Bayer AG, Boehringer Ingelheim, Bristol Myers Squibb, Genentech, Genome Canada through Ontario Genomics Institute [OGI-196], EU/EFPIA/OICR/McGill/KTH/Diamond Innovative Medicines Initiative 2 Joint Undertaking [EUbOPEN grant 875510], Janssen, Merck KGaA (aka EMD in Canada and US), Pfizer and Takeda.

Precise control over the size and shape of graphene nanostructures allows engineering spin-polarized edge and topological states, representing a novel source of non-conventional π-magnetism with promising applications in quantum spintronics. A prerequisite for their emergence is the existence of robust gapped phases, which are difficult to find in extended graphene systems. Here we show that semi-metallic chiral GNRs (chGNRs) narrowed down to nanometer widths undergo a topological phase transition. We fabricated atomically precise chGNRs of different chirality and size by on surface synthesis using predesigned molecular precursors. Combining scanning tunneling microscopy (STM) measurements and theory simulations, we follow the evolution of topological properties and bulk band gap depending on the width, length, and chirality of chGNRs. Our findings represent a new platform for producing topologically protected spin states and demonstrate the potential of connecting chiral edge and defect structure with band engineering., We gratefully acknowledge financial support from the Agencia Estatal de Investigación (AEI) through projects No MAT2016-78293, PID2019-107338RB, and FIS2017-83780-P, and the Maria de Maeztu Units of Excellence Programme MDM-2016-0618, from the Xunta de Galicia (Centro singular de investigación de Galicia, accreditation 2016–2019, ED431G/09), from the University of the Basque Country (Grant IT1246-19) and the Basque Departamento de Educación (PhD scholarship no. PRE_2019_2_0218 of S.S.), and from the European Regional Development Fund. We also acknowledge funding from the European Union (EU) H2020 program through the ERC (grant agreement No. 635919) and FET Open project SPRING (grant agreement No. 863098).

Coordinated chromatin interactions between enhancers and promoters are critical for gene regulation. The architectural protein CTCF mediates chromatin looping and is enriched at the boundaries of topologically associating domains (TADs), which are sub-megabase chromatin structures. In vitro CTCF depletion leads to a loss of TADs but has only limited effects over gene expression, challenging the concept that CTCF-mediated chromatin structures are a fundamental requirement for gene regulation. However, how CTCF and a perturbed chromatin structure impacts gene expression during development remains poorly understood. Here we link the loss of CTCF and gene regulation during patterning and organogenesis in a ctcf knockout zebrafish model. CTCF absence leads to loss of chromatin structure and affects the expression of thousands of genes, including many developmental regulators. Our results demonstrate the essential role of CTCF in providing the structural context for enhancer-promoter interactions, thus regulating developmental genes., J.L.G.-S. received funding from the ERC (Grant Agreement No. 740041), the Spanish Ministerio de Economía y Competitividad (Grant No. BFU2016-74961-P) and the institutional grant Unidad de Excelencia María de Maeztu (MDM-2016-0687). J.T. was funded by a 2019 Leonardo Grant for Researchers and Cultural Creators, BBVA Foundation. I.I.-A. acknowledges support from the Federation of European Biochemical Societies (FEBS Long-Term Fellowship). M.F. was funded by the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement [#800396] and a Juan de la Cierva-Formación fellow from the Spanish Ministry of Science and Innovation (FJC2018-038233-I). JMS-P was funded by a postdoctoral fellowship from Junta de Andalucía (DOC_00512).

A single-wall carbon nanotube can be viewed as a one-dimensional material created by rolling up a sheet of graphene. Its electronic band structure depends on the chirality, i.e., how the sheet has been rolled up, yet synthesizing the symmetry at will is rather challenging. We structure an artificial honeycomb lattice in both a zigzag and an armchair tube and explore their topological features for sound. Our findings reveal how armchair tubes remain gapless, whereas the zigzag counterparts host nontrivial edge states of non-zero quantized Zak phase, which are dictated by the circumferential number of units. Unlike man-made planar lattices whose underling symmetry must be broken to harvest quantum Hall and pseudospin phases, interestingly, the structured tubular lattice symmetry remains intact, while its nontrivial phase alone is governed by the chirality and the tube diameter. We foresee that our results, not only for sound, but also in photonics, mechanics and electronics will broaden future avenues for fundamental and applied sciences This work was supported by the National Basic Research Program of China (2017YFA0303702), NSFC (12074183, 11922407, 11834008, 11874215, 12104226, and 12225408), and the Fundamental Research Funds for the Central Universities (020414380181). Z.Z. acknowledges the support from the China National Postdoctoral Program for Innovative Talents (BX20200165), the China Postdoctoral Science Foundation (2020M681541), Jiangsu Planned Projects for Postdoctoral Research Funds (2021K054A), and Funds for Zijin Scholars of Nanjing University. J.C. acknowledges the support from the European Research Council (ERC) through the Starting Grant 714577 PHONOMETA and from the MINECO through a Ramón y Cajal grant (Grant No. RYC-2015-17156).

Transceiving ultra-weak sound typically relies on signal pre-amplification at the transmitting end via active electro-acoustic devices, which inherently perturbs the environment in the form of noise that inevitably leads to information leakage. Here we demonstrate a passive remote-whispering metamaterial (RWM) enabling weak airborne sound at audible frequencies to reach unprecedented signal enhancement without altering the detected ambient soundscape, which is based on the extraordinary scattering properties of a metamaterial formed by a pair of self-resonating subwavelength Mie meta-cavities, constituting the acoustic analogy of Förster resonance energy transfer. We demonstrate efficient non-radiative sound transfer over distances hundreds times longer than the radius of the meta-cavities, which enables the RWM to recover weak sound signals completely overwhelmed by strong noise with enhanced signal-to-noise ratio from −3 dB below the detection limit of 0 dB in free space to 17.7 dB., Typically, sending sound from transmitter to receiver requires pre-amplification and disturbs the surrounding sound environment. Here, the authors present a metamaterial designed to enable transmission of weak sound that can be recovered even in the presence of strong noise

W.D.V.H. acknowledges support from National Institutes of Health (Grant: R01GM112077). S.B.O. acknowledges support from the Gordon and Betty Moore Foundations and National Science Foundation (Awards: 1715591 and 1901709). J.M.S.R. acknowledges support from Spanish Ministry of Economy and Competitiveness/FEDER Funds (Grants BIO2015-66426-R and RTI2018-097142-B-100) and the Human Frontier Science Program (Grant RGP0041/2017). V.A.R. acknowledges support from FEDER/Junta de Andalucia-Consejeria de Economia y Conocimiento (Grant E.FQM.113.UGR18). We would like to thank the beamline staff of ID30B of the ESRF (European Synchrotron Radiation Facility, Grenoble, France) for their assistance during data collection and the ESRF for the provision of time through proposals MX-2064., TEM-1 β-lactamase degrades β-lactam antibiotics with a strong preference for penicillins. Sequence reconstruction studies indicate that it evolved from ancestral enzymes that degraded a variety of β-lactam antibiotics with moderate efficiency. This generalist to specialist conversion involved more than 100 mutational changes, but conserved fold and catalytic residues, suggesting a role for dynamics in enzyme evolution. Here, we develop a conformational dynamics computational approach to rationally mold a protein flexibility profile on the basis of a hinge-shift mechanism. By deliberately weighting and altering the conformational dynamics of a putative Precambrian β-lactamase, we engineer enzyme specificity that mimics the modern TEM-1 β-lactamase with only 21 amino acid replacements. Our conformational dynamics design thus re-enacts the evolutionary process and provides a rational allosteric approach for manipulating function while conserving the enzyme active site., United States Department of Health & Human Services National Institutes of Health (NIH) - USA R01GM112077, Gordon and Betty Moore Foundations, National Science Foundation (NSF) 1715591 1901709, Spanish Ministry of Economy and Competitiveness/FEDER Funds BIO2015-66426-R RTI2018-097142-B-100, Human Frontier Science Program RGP0041/2017, FEDER/Junta de Andalucia-Consejeria de Economia y Conocimiento E.FQM.113.UGR18

15 páginas, 7 figuras, 1 tabla, The arbitrium system is employed by phages of the SPbeta family to communicate with their progeny during infection to decide either to follow the lytic or the lysogenic cycle. The system is controlled by a peptide, AimP, that binds to the regulator AimR, inhibiting its DNA-binding activity and expression of aimX. Although the structure of AimR has been elucidated for phages SPβ and phi3T, there is still controversy regarding the molecular mechanism of AimR function, with two different proposed models for SPβ. In this study, we deepen our understanding of the system by solving the structure of an additional AimR that shows chimerical characteristics with the SPβ receptor. The crystal structures of this AimR (apo, AimP-bound and DNA-bound) together with in vitro and in vivo analyses confirm a mechanism of action by AimP-induced conformational restriction, shedding light on peptide specificity and cross regulation with relevant biological implications., This work was supported by grants BIO2016-78571-P and PID2019-108541GB-I00 from Spanish Government (Ministerio de Economía y Competitividad y Ministerio de Ciencia e Innovación) and PROMETEO/2020/012 by Valencian Government to A.M, and grant MR/M003876/1, MR/V000772/1 and MR/S00940X/1 from the Medical Research Council (UK), BB/N002873/1, BB/V002376/1 and BB/S003835/1 from the Biotechnology and Biological Sciences Research Council (BBSRC, UK), ERC-ADG-2014 Proposal n° 670932 Dut-signal (from EU), and Wellcome Trust 201531/Z/16/Z to J.R.P.

The chain–walking of terminal alkenes (also called migration or isomerization reaction) is currently carried out in industry with unselective and relatively costly processes, to give mixtures of alkenes with significant amounts of oligomerized, branched and reduced by–products. Here, it is shown that part–per–million amounts of a variety of commercially available and in–house made ruthenium compounds, supported or not, transform into an extremely active catalyst for the regioselective migration of terminal alkenes to internal positions, with yields and selectivity up to >99% and without any solvent, ligand, additive or protecting atmosphere required, but only heating at temperatures >150 °C. The resulting internal alkene can be prepared in kilogram quantities, ready to be used in nine different organic reactions without any further treatment., A.L.-P. thanks the financial support by IFF and MICIIN (PID2020–115100GB–I00). We also thank the funding for open access charge to the Universitat Politècnica de València. S.S.-N. thanks a fellowship from MINECO (project number CTQ 2017–86735–P).

© The Author(s) 2020, Pancreatic ductal adenocarcinoma (PDAC), the fourth leading cause of cancer death, has a 5-year survival rate of approximately 7–9%. The ineffectiveness of anti-PDAC therapies is believed to be due to the existence of a subpopulation of tumor cells known as cancer stem cells (CSCs), which are functionally plastic, and have exclusive tumorigenic, chemoresistant and metastatic capacities. Herein, we describe a 2D in vitro system for long-term enrichment of pancreatic CSCs that is amenable to biological and CSC-specific studies. By changing the carbon source from glucose to galactose in vitro, we force PDAC cells to utilize OXPHOS, resulting in enrichment of CSCs defined by increased CSC biomarker and pluripotency gene expression, greater tumorigenic potential, induced but reversible quiescence, increased OXPHOS activity, enhanced invasiveness, and upregulated immune evasion properties. This CSC enrichment method can facilitate the discovery of new CSC-specific hallmarks for future development into targets for PDAC-based therapies., We acknowledge and thank Dr. Nuria Malats and Jaime Villarreal from the Spanish National Cancer Research Center (CNIO) for RNA sequencing and analysis, funded by Fondo de Investigaciones Sanitarias (FIS) grant PI18/01347. We thank Patricia Sánchez-Tomero and Marina Ochando-Garmendia for technical assistance and support and Dr. Raúl Sánchez Lanzas for assistance with autophagy experiments. We want to particularly acknowledge the patients and the BioBank Hospital Ramón y Cajal-IRYCIS (PT13/0010/0002) integrated in the Spanish National Biobanks Network for its collaboration and, in particular, Adrián Povo Retana for macrophage isolation. We would also like to thank the Transmission Electron Microscopy Unit Laboratory, part of the UAM Interdepartmental Investigation Service (SIdI); Coral Pedrero for exceptional help with in vivo experiments; and the laboratories of Dr. Amparo Cano and Dr. José González Castaño for reagents and helpful discussions. S.V. was a recipient of an Ayuda de Movilidad del Personal Investigador del IRYCIS, a mobility grant from the Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain, and a pre-doctoral fellowship from the Comunidad de Madrid, Ayudas Para La Contratación De Investigadores Predoctorales Y Posdoctorales (PEJD-2017-PRE/BMD-5062), Madrid, Spain. This study was supported by a Rámon y Cajal Merit Award (RYC-2012-12104) from the Ministerio de Economía y Competitividad, Spain (to B.S.); funding from la Beca Carmen Delgado/Miguel Pérez-Mateo from AESPANC-ACANPAN Spain (to B.S.); a Conquer Cancer Now Grant from the Concern Foundation (Los Angeles, CA, USA) (to B.S.); a Coordinated grant (GC16173694BARB) from the Fundación Asociación Española Contra el Cáncer (AECC) (to B.S.); FIS grants PI18/00757 (to B.S.), PI16/00789 (to M.A.F.-M.), PI18/00267 (to L.G.-B.; co-financed through Fondo Europeo de Desarrollo Regional (FEDER) “Una manera de hacer Europa”); a Miguel Servet award (CP16/00121) (to P.S.); a Max Eder Fellowship of the German Cancer Aid (111746) (to P.C.H.); and the German Research Foundation (DFG, CRC 1279 “Exploiting the human peptidome for Novel Antimicrobial and Anticancer Agents”; to P.C.H.).

Atomically sharp heterojunctions in lateral two-dimensional heterostructures can provide the narrowest one-dimensional functionalities driven by unusual interfacial electronic states. For instance, the highly controlled growth of patchworks of graphene and hexagonal boron nitride (h-BN) would be a potential platform to explore unknown electronic, thermal, spin or optoelectronic property. However, to date, the possible emergence of physical properties and functionalities monitored by the interfaces between metallic graphene and insulating h-BN remains largely unexplored. Here, we demonstrate a blue emitting atomic-resolved heterojunction between graphene and h-BN. Such emission is tentatively attributed to localized energy states formed at the disordered boundaries of h-BN and graphene. The weak blue emission at the heterojunctions in simple in-plane heterostructures of h-BN and graphene can be enhanced by increasing the density of the interface in graphene quantum dots array embedded in the h-BN monolayer. This work suggests that the narrowest, atomically resolved heterojunctions of in-plane two-dimensional heterostructures provides a future playground for optoelectronics., This work was supported by the research funds (NRF-2017R1E1A1A01074493 and NRF-2019R1A4A1027934) and the grant (CASE-2013M3A6A5073173) from the centre for Advanced Soft Electronics under the Global Frontier Research Program through the National Research Foundation by the Ministry of Science and ICT, Korea. H.S.S. and K.S. thank the A3 foresight program for their collaboration. Y.S., Y.-C.L. and K.S. acknowledge JSPS KAKENHI Grant Numbers JP19K05223, JP18K14119 and JP16H06333, respectively. S.R. acknowledges the European Union’s Horizon 2020 research and innovation programme under Grant Agreement No. 881603 (Graphene Flagship). ICN2 is funded by the CERCA Programme/Generalitat de Catalunya, and is supported by the Severo Ochoa program from Spanish MINECO (Grant No. SEV-2017-0706). J.E.B.-V. acknowledges funding from PAIP Facultad de Química, UNAM (Grant No. 5000-9173).

Integrating and manipulating the nano-optoelectronic properties of Van der Waals heterostructures can enable unprecedented platforms for photodetection and sensing. The main challenge of infrared photodetectors is to funnel the light into a small nanoscale active area and efficiently convert it into an electrical signal. Here, we overcome all of those challenges in one device, by efficient coupling of a plasmonic antenna to hyperbolic phonon-polaritons in hexagonal-BN to highly concentrate mid-infrared light into a graphene pn-junction. We balance the interplay of the absorption, electrical and thermal conductivity of graphene via the device geometry. This approach yields remarkable device performance featuring room temperature high sensitivity (NEP of 82 pW/Hz−−−√) and fast rise time of 17 nanoseconds (setup-limited), among others, hence achieving a combination currently not present in the state-of-the-art graphene and commercial mid-infrared detectors. We also develop a multiphysics model that shows very good quantitative agreement with our experimental results and reveals the different contributions to our photoresponse, thus paving the way for further improvement of these types of photodetectors even beyond mid-infrared range., F.H.L.K. acknowledges financial support from the Spanish Ministry of Economy and Competitiveness, through the “Severo Ochoa” Programme for Centres of Excellence in R& D (SEV-2015-0522), support by Fundacio Cellex Barcelona, Generalitat de Catalunya through the CERCA program, and the Agency for Management of University and Research Grants (AGAUR) 2017 SGR 1656. Furthermore, the research leading to these results has received funding from the European Union Seventh Framework Programme under grant agreement no. 785219 and no. 881603 Graphene Flagship for Core2 and Core3. ICN2 is supported by the Severo Ochoa program from Spanish MINECO (Grant No. SEV-2017-0706). K.J.T. acknowledges funding from the European Union’s Horizon 2020 research and innovation programme under Grant Agreement No. 804349. R.H. acknowledges financial support from the Spanish Ministry of Science, Innovation and Universities (national project RTI2018-094830-B-100 and the project MDM-2016-0618 of the Marie de Maeztu Units of Excellence Program) and the Basque Government (grant No. IT1164-19). S.C. acknowledges financial support from the Barcelona Institute of Science and Technology (BIST), the Secretaria d’Universitats i Recerca del Departament d’Empresa i Coneixement de la Generalitat de Catalunya and the European Social Fund (L’FSE inverteix en el teu futur)—FEDER. D.E. acknowledges partial support from the Army Research Office MURI “Ab-Initio Solid-State Quantum Materials” Grant No. W911NF18-1-0431. J.G. was supported by the ARL-MIT Institute for Soldier Nanotechnologies (ISN). T.S. and L.M.M. acknowledge support by Spain’s MINECO under Grant No. MAT2017-88358-C3-1-R and the Aragon Government through project Q-MAD.

© The Author(s) 2020., Regenerative proliferation capacity and poor differentiation are histological features usually linked to poor prognosis in head and neck squamous cell carcinoma (hnSCC). However, the pathways that regulate them remain ill-characterized. Here, we show that those traits can be triggered by the RHO GTPase activator VAV2 in keratinocytes present in the skin and oral mucosa. VAV2 is also required to maintain those traits in hnSCC patient-derived cells. This function, which is both catalysis- and RHO GTPase-dependent, is mediated by c-Myc- and YAP/TAZ-dependent transcriptomal programs associated with regenerative proliferation and cell undifferentiation, respectively. High levels of VAV2 transcripts and VAV2-regulated gene signatures are both associated with poor hnSCC patient prognosis. These results unveil a druggable pathway linked to the malignancy of specific SCC subtypes., We thank M. Blázquez and CIC facilities’ personnel for lab work and core unit technical assistance, respectively. X.R.B. is supported by grants from Worldwide Cancer Research (14-1248), the Castilla-León Government (CSI049U16, CLC-2017-01), the Spanish Ministry of Science and Innovation (MSI) (SAF2015-64556-R, RTI2018-096481-B-I00), the Ramón Areces Foundation, and the Spanish Association against Cancer (GC16173472GARC). X.R.B.’s institution is supported by the Programa de Apoyo a Planes Estratégicos de Investigación de Estructuras de Investigación de Excelencia of the Ministry of Education of the Castilla-León Government (CLC-2017-01). J.M.P. is supported by MSI grants (SAF2015-66015-R, PIE15/00076). S.A.B. was supported by the European Research Council, the Spanish MSIU, and the IRB-Barcelona. S.R.-F. and L.F. L.-M. contracts have been supported by funding from the MSI (BES-2013-063573) and the Spanish Ministry of Education, Culture, and Sports (L.F.L.-M., FPU13/02923), respectively. Both Spanish and Castilla-León government-associated funding is partially supported by the European Regional Development Fund.

The lysine acetyltransferases type 3 (KAT3) family members CBP and p300 are important transcriptional co-activators, but their specific functions in adult post-mitotic neurons remain unclear. Here, we show that the combined elimination of both proteins in forebrain excitatory neurons of adult mice resulted in a rapidly progressing neurological phenotype associated with severe ataxia, dendritic retraction and reduced electrical activity. At the molecular level, we observed the downregulation of neuronal genes, as well as decreased H3K27 acetylation and pro-neural transcription factor binding at the promoters and enhancers of canonical neuronal genes. The combined deletion of CBP and p300 in hippocampal neurons resulted in the rapid loss of neuronal molecular identity without de- or transdifferentiation. Restoring CBP expression or lysine acetylation rescued neuronal-specific transcription in cultured neurons. Together, these experiments show that KAT3 proteins maintain the excitatory neuron identity through the regulation of histone acetylation at cell type-specific promoter and enhancer regions., M.L. is recipient of a Santiago Grisolia fellowship given by the Generalitat Valenciana, J.M.C. is recipient of a fellowship from the Spanish Ministry of Education, Culture and Sport (MECD), J.F.-A. and C.M.N. are recipients of fellowships from the Spanish Ministry of Science and Innovation (MICINN). The ultrastructure research was supported by the Polish National Science Center Grant UMO-2014/15/N/NZ3/04468 and by the European Regional Development Fund POIG 01.01.02-00-008/08. J.P.L.-A. research is supported by Grants RYC-2015-18056 and RTI2018-102260-B-I00 from MICINN co-financed by ERDF. A.B. research is supported by Grants SAF2017-87928-R, PCIN-2015-192-C02-01, and SEV-2017-0723 from MICINN co-financed by ERDF, PROMETEO/2016/026 from the Generalitat Valenciana, and RGP0039/2017 from the Human Frontiers Science Program Organization (HFSPO). The Instituto de Neurociencias is a “Centre of Excellence Severo Ochoa”.

Symmetry breaking and the emergence of self-organized patterns is the hallmark of complexity. Here, we demonstrate that a sessile drop, containing titania powder particles with negligible self-propulsion, exhibits a transition to collective motion leading to self-organized flow patterns. This phenomenology emerges through a novel mechanism involving the interplay between the chemical activity of the photocatalytic particles, which induces Marangoni stresses at the liquid–liquid interface, and the geometrical confinement provided by the drop. The response of the interface to the chemical activity of the particles is the source of a significantly amplified hydrodynamic flow within the drop, which moves the particles. Furthermore, in ensembles of such active drops long-ranged ordering of the flow patterns within the drops is observed. We show that the ordering is dictated by a chemical communication between drops, i.e., an alignment of the flow patterns is induced by the gradients of the chemicals emanating from the active particles, rather than by hydrodynamic interactions., Complex systems exhibit unique properties like spontaneous symmetry breaking and self-organization. Singh et al. show that catalytically active, non-propelling particles can induce steady vortical flows within a drop, as well as flow alignment between neighboring drops.

Telomerase deficiency leads to age-related diseases and shorter lifespans. Inhibition of the mechanistic target of rapamycin (mTOR) delays aging and age-related pathologies. Here, we show that telomerase deficient mice with short telomeres (G2-Terc−/−) have an hyper-activated mTOR pathway with increased levels of phosphorylated ribosomal S6 protein in liver, skeletal muscle and heart, a target of mTORC1. Transcriptional profiling confirms mTOR activation in G2-Terc−/− livers. Treatment of G2-Terc−/− mice with rapamycin, an inhibitor of mTORC1, decreases survival, in contrast to lifespan extension in wild-type controls. Deletion of mTORC1 downstream S6 kinase 1 in G3-Terc−/− mice also decreases longevity, in contrast to lifespan extension in single S6K1−/− female mice. These findings demonstrate that mTOR is important for survival in the context of short telomeres, and that its inhibition is deleterious in this setting. These results are of clinical interest in the case of human syndromes characterized by critically short telomeres., Telomerase deficiency leads to age-related diseases and shortened lifespan, while inhibition of the mTOR pathway delays aging. Here, the authors show that inhibition of mTORC1 signaling shortens the lifespan of telomerase deficient mice.

Eukaryotic transcription factors (TF) function by binding to short 6-10 bp DNA recognition sites located near their target genes, which are scattered through vast genomes. Such process surmounts enormous specificity, efficiency and celerity challenges using a molecular mechanism that remains poorly understood. Combining biophysical experiments, theory and bioinformatics, we dissect the interplay between the DNA-binding domain of Engrailed, a Drosophila TF, and the regulatory regions of its target genes. We find that Engrailed binding affinity is strongly amplified by the DNA regions flanking the recognition site, which contain long tracts of degenerate recognition-site repeats. Such DNA organization operates as an antenna that attracts TF molecules in a promiscuous exchange among myriads of intermediate affinity binding sites. The antenna ensures a local TF supply, enables gene tracking and fine control of the target site’s basal occupancy. This mechanism illuminates puzzling gene expression data and suggests novel engineering strategies to control gene expression., To carry out their function, transcription factors must efficiently recognize specific DNA sequence targets, a complex problem in the context of eukaryotic chromatin. Here the authors use single-molecule biophysical experiments, statistical mechanical theory and bioinformatics analyses to conclude that interactions with non-target sequences near promoters serve to increase overall affinity and targeting efficiency.

This Open Access article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder., Narrow bipolar events (NBEs) are signatures in radio signals from thunderstorms observed by ground-based receivers. NBEs may occur at the onset of lightning, but the discharge process is not well understood. Here, we present spectral measurements by the Atmosphere‐Space Interactions Monitor (ASIM) on the International Space Station that are associated with nine negative and three positive NBEs observed by a ground‐based array of receivers. We found that both polarities NBEs are associated with emissions at 337 nm with weak or no detectable emissions at 777.4 nm, suggesting that NBEs are associated with streamer breakdown. The rise times of the emissions for negative NBEs are about 10 μs, consistent with source locations at cloud tops where photons undergo little scattering by cloud particles, and for positive NBEs are ~1 ms, consistent with locations deeper in the clouds. For negative NBEs, the emission strength is almost linearly correlated with the peak current of the associated NBEs. Our findings suggest that ground-based observations of radio signals provide a new means to measure the occurrences and strength of cloud-top discharges near the tropopause. © 2021, The Author(s)., The authors would acknowledge financial support from the National Key Research & Development Program (2017YFC1501501), the Project of Stable Support for Youth Team in Basic Research Field, CAS (YSBR-018), the B-type Strategic Priority Program of the Chinese Academy of Sciences (XDB41000000), National Natural Science Foundation of China (41775004, 41831070, 41875006, 41974181, 42005068, and U1938115), and the Open Research Project of Large Research Infrastructures of CAS—“Study on the interaction between low/mid-latitude atmosphere and ionosphere based on the Chinese Meridian Project”. F.F.L is also supported by Fundamental Research Funds for the Central Universities (WK2080000134). A.L. and D.L. is supported by the European Research Council (ERC) under the European Union H2020 programme/ERC Grant Agreement 681257. F.J.G.V. acknowledges funding by the Spanish Ministry of Science and Innovation (AEI) under project PID2019‐109269RB‐C43 and the FEDER program. F.J.G.V., A.L., and D.L. acknowledge financial support from the Spanish AEI through the Center of Excellence “Severo Ochoa” award for the Instituto de Astrofísica de Andalucía (SEV‐2017‐0709). ASIM and the ASIM Science Data Centre are funded by ESA and by national grants of Denmark, Norway and Spain. We thank Vaisala for the GLD360 lightning data.

© The Author(s) 2021., BRCA2 and its interactors are required for meiotic homologous recombination (HR) and fertility. Loss of HSF2BP, a BRCA2 interactor, disrupts HR during spermatogenesis. We test the model postulating that HSF2BP localizes BRCA2 to meiotic HR sites, by solving the crystal structure of the BRCA2 fragment in complex with dimeric armadillo domain (ARM) of HSF2BP and disrupting this interaction in a mouse model. This reveals a repeated 23 amino acid motif in BRCA2, each binding the same conserved surface of one ARM domain. In the complex, two BRCA2 fragments hold together two ARM dimers, through a large interface responsible for the nanomolar affinity — the strongest interaction involving BRCA2 measured so far. Deleting exon 12, encoding the first repeat, from mBrca2 disrupts BRCA2 binding to HSF2BP, but does not phenocopy HSF2BP loss. Thus, results herein suggest that the high-affinity oligomerization-inducing BRCA2-HSF2BP interaction is not required for RAD51 and DMC1 recombinase localization in meiotic HR., AP: Ministry of Economy and Competitiveness of Spain (BFU2015–71371-R), the Instituto de Salud Carlos III through CIBERONC, Junta de Castilla y León (CSI146P20), the Scientific Foundation of the Spanish Association Against Cancer (AECC), ALMOM, ACMUMA and the CRIS Cancer Foundation. JCM is funded by the Instituto de Salud Carlos III through a Miguel Servet program (CP12/03073 and CPII17/00015) and receives research support from the same institution (PI18/00796). LGS is recipient of a predoctoral contract (BES-2016-077748). IRP is recipient of a predoctoral contract (CSI030–18). SGA is recipient of a predoctoral contract from the MINECO (BES-2013-065223). Work carried out in our laboratory receives support from the European Community through the Regional Development Funding Program (FEDER).

13 pags., 9 figs. -- Open Access funded by Creative Commons Atribution Licence 4.0, SPOR domains are widely present in bacterial proteins that recognize cell-wall peptidoglycan strands stripped of the peptide stems. This type of peptidoglycan is enriched in the septal ring as a product of catalysis by cell-wall amidases that participate in the separation of daughter cells during cell division. Here, we document binding of synthetic denuded glycan ligands to the SPOR domain of the lytic transglycosylase RlpA from Pseudomonas aeruginosa (SPOR-RlpA) by mass spectrometry and structural analyses, and demonstrate that indeed the presence of peptide stems in the peptidoglycan abrogates binding. The crystal structures of the SPOR domain, in the apo state and in complex with different synthetic glycan ligands, provide insights into the molecular basis for recognition and delineate a conserved pattern in other SPOR domains. The biological and structural observations presented here are followed up by molecular-dynamics simulations and by exploration of the effect on binding of distinct peptidoglycan modifications., The work in Spain was supported by grants from the Spanish Ministry of Science, Innovation and Universities (BFU2014-59389-P and BFU2017-90030-P to JAH) and in the USA by grants from the NIH (GM131685 and GM61629 to SM). D.A.D. is a Fellow of the Chemistry-Biochemistry-Biology Interface Program (NIH Training Grant T32GM075762) and a Fellow of the ECK Institute of Global Health at the University of Notre Dame. We thank Dr. We thank the staff from ALBA synchrotron facility (Barcelona, Spain) for help during crystallographic data collection. We thank the Center for Research Computing of the University of Notre Dame for the computing resources.

Cells remodel their structure in response to mechanical strain. However, how mechanical forces are translated into biochemical signals that coordinate the structural changes observed at the plasma membrane (PM) and the underlying cytoskeleton during mechanoadaptation is unclear. Here, we show that PM mechanoadaptation is controlled by a tension-sensing pathway composed of c-Abl tyrosine kinase and membrane curvature regulator FBP17. FBP17 is recruited to caveolae to induce the formation of caveolar rosettes. FBP17 deficient cells have reduced rosette density, lack PM tension buffering capacity under osmotic shock, and cannot adapt to mechanical strain. Mechanistically, tension is transduced to the FBP17 F-BAR domain by direct phosphorylation mediated by c-Abl, a mechanosensitive molecule. This modification inhibits FBP17 membrane bending activity and releases FBP17-controlled inhibition of mDia1-dependent stress fibers, favoring membrane adaptation to increased tension. This mechanoprotective mechanism adapts the cell to changes in mechanical tension by coupling PM and actin cytoskeleton remodeling., Mechanical forces are sensed by cells and can alter plasma membrane properties, but biochemical changes underlying this are not clear. Here the authors show tension is sensed by c-Abl and FBP17, which couples changes in mechanical tension to remodelling of the plasma membrane and actin cytoskeleton.

A wide variety of social, biological or technological systems can be described as processes taking place on networked structures in continuous interaction with other networks. We propose here a new methodology to describe, anticipate and manage, in real time, the out-of-equilibrium dynamics of processes that evolve on interconnected networks. This goal is achieved through the full analytical treatment of the phenomenology and its reduction to a two-dimensional flux diagram, allowing us to predict at every time step the dynamical consequences of modifying the links between the different ensembles. Our results are consistent with real data and the methodology can be translated to clustered networks and/or interconnected networks of any size, topology or origin, from the struggle for knowledge on innovation structures to international economic relations or disease spreading on social groups., Network properties can be modified when they interact with other networks, yet most previous results have focused on equilibrium states exclusively. Here the authors introduce a framework to examine the out-of-equilibrium dynamics of evolutionary processes to mimic real-world interconnected networks.

Genome stability involves accurate replication and DNA repair. Broken replication forks, such as those encountering a nick, lead to double strand breaks (DSBs), which are preferentially repaired by sister-chromatid recombination (SCR). To decipher the role of chromatin in eukaryotic DSB repair, here we analyze a collection of yeast chromatin-modifying mutants using a previously developed system for the molecular analysis of repair of replication-born DSBs by SCR based on a mini-HO site. We confirm the candidates through FLP-based systems based on a mutated version of the FLP flipase that causes nicks on either the leading or lagging DNA strands. We demonstrate that Rpd3L and Hda1 histone deacetylase (HDAC) complexes contribute to the repair of replication-born DSBs by facilitating cohesin loading, with no effect on other types of homology-dependent repair, thus preventing genome instability. We conclude that histone deacetylation favors general sister chromatid cohesion as a necessary step in SCR., Double strand breaks (DSBs) are preferentially repaired by sister-chromatid recombination (SCR) to maintain genome stability. Here, the authors reveal a role for histone deacetylate (HDAC) complexes favouring the repair of replication related DSBs by facilitating cohesin loading.

Overinhibition is assumed one of the main causes of cognitive deficits (e.g. memory impairment) in mouse models of Down syndrome (DS). Yet the mechanisms that drive such exaggerated synaptic inhibition and their behavioral effects remain unclear. Here we report the existence of bidirectional alterations to the synaptic inhibition on CA1 pyramidal cells in the Ts2Cje mouse model of DS which are associated to impaired spatial memory. Furthermore, we identify triplication of the kainate receptor (KAR) encoding gene Grik1 as the cause of these phenotypes. Normalization of Grik1 dosage in Ts2Cje mice specifically restored spatial memory and reversed the bidirectional alterations to CA1 inhibition, but not the changes in synaptic plasticity or the other behavioral modifications observed. We propose that modified information gating caused by disturbed inhibitory tone rather than generalized overinhibition underlies some of the characteristic cognitive deficits in DS., The authors gratefully acknowledge the financial support received from the Spanish Agency of Research (AEI) under the grant BFU2015-64656-R (to J.L.), co-financed by the European Regional Development Fund (ERDF), and the “Severo Ochoa” Program for Centres of Excellence in R&D (SEV-2013-0317 and SEV-2017-0723). This work was also supported by the Generalitat Valenciana through the program PrometeoII/2015/012 (to J.L.), the FPI fellowship program (to S.V. and A.G.), and the SyMBaD – Marie Curie ITN (agreement # 238608) (to W.M.)

11 páginas, 6 figuras., The Mycobacterium tuberculosis complex (MTBC) members display different host-specificities and virulence phenotypes. Here, we have performed a comprehensive RNAseq and methylome analysis of the main clades of the MTBC and discovered unique transcriptional profiles. The majority of genes differentially expressed between the clades encode proteins involved in host interaction and metabolic functions. A significant fraction of changes in gene expression can be explained by positive selection on single mutations that either create or disrupt transcriptional start sites (TSS). Furthermore, we show that clinical strains have different methyltransferases inactivated and thus different methylation patterns. Under the tested conditions, differential methylation has a minor direct role on transcriptomic differences between strains. However, disruption of a methyltransferase in one clinical strain revealed important expression differences suggesting indirect mechanisms of expression regulation. Our study demonstrates that variation in transcriptional profiles are mainly due to TSS mutations and have likely evolved due to differences in host characteristics., This project has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programmes 638553 (TB-ACCELERATE to I.C.) and 637730 (MtbTransReg to T.C.). M.B. was funded by the National Institute of Health grant AI119573. W.R.J. was funded by the National Institutes of Health grant AI26170. In addition, this work was funded by projects SAF2016-77346-R from Ministerio de Economía y Competitividad (Spanish Government) and AICO/2018/113 from Generalitat Valenciana (to I.C.), BFU2014-58656-R, BFU2017-89594-R from Ministerio de Economía y Competitividad (Spanish Government), PROMETEO/2016/122 from Generalitat Valenciana (to FGC), Wellcome Trust grant 098051 to the Sanger Institute. A.C.O. is recipient of a FPU fellowship from Ministerio de Educación y Ciencia FPU13/00913 (Spanish Government).

© The Author(s) 2019., Understanding urothelial stem cell biology and differentiation has been limited by the lack of methods for their unlimited propagation. Here, we establish mouse urothelial organoids that can be maintained uninterruptedly for >1 year. Organoid growth is dependent on EGF and Wnt activators. High CD49f/ITGA6 expression features a subpopulation of organoid-forming cells expressing basal markers. Upon differentiation, multilayered organoids undergo reduced proliferation, decreased cell layer number, urothelial program activation, and acquisition of barrier function. Pharmacological modulation of PPARγ and EGFR promotes differentiation. RNA sequencing highlighted genesets enriched in proliferative organoids (i.e. ribosome) and transcriptional networks involved in differentiation, including expression of Wnt ligands and Notch components. Single-cell RNA sequencing (scRNA-Seq) analysis of the organoids revealed five clusters with distinct gene expression profiles. Together with the use of γ-secretase inhibitors, scRNA-Seq confirms that Notch signaling is required for differentiation. Urothelial organoids provide a powerful tool to study cell regeneration and differentiation., This work was supported, in part, by grants from Spanish Ministry of Economy, Industry and Competitiveness (SAF2016-76377-R), CIBERONC (CB16/12/00453 and CB16/12/00273), and Fundación Científica de la Asociación Española Contra el Cáncer. CNIO is supported by Ministerio de Ciencia, Innovación y Universidades as a Centro de Excelencia Severo Ochoa SEV-2015–0510.

NMDA receptor-dependent long-term depression (LTD) in the hippocampus is a well-known form of synaptic plasticity that has been linked to different cognitive functions. The core mechanism for this form of plasticity is thought to be entirely neuronal. However, we now demonstrate that astrocytic activity drives LTD at CA3-CA1 synapses. We have found that LTD induction enhances astrocyte-to-neuron communication mediated by glutamate, and that Ca2+ signaling and SNARE-dependent vesicular release from the astrocyte are required for LTD expression. In addition, using optogenetic techniques, we show that low-frequency astrocytic activation, in the absence of presynaptic activity, is sufficient to induce postsynaptic AMPA receptor removal and LTD expression. Using cell-type-specific gene deletion, we show that astrocytic p38α MAPK is required for the increased astrocytic glutamate release and astrocyte-to-neuron communication during low-frequency stimulation. Accordingly, removal of astrocytic (but not neuronal) p38α abolishes LTD expression. Finally, this mechanism modulates long-term memory in vivo., How astrocytes influence neuronal plasticity remains unclear, as they are typically considered as modulators of core mechanisms driven by neuronal components. Here, authors show that Long-term depression (LTD) induction in the hippocampus triggers calcium signaling in the astrocyte and enhances SNARE-dependent astrocytic glutamate release, which is then responsible for the activation of postsynaptic NMDA receptors and synaptic depression.

© The Author(s) 2019., Sterols and hopanoids are chemically and structurally related lipids mostly found in eukaryotic and bacterial cell membranes. Few bacterial species have been reported to produce sterols and this anomaly had originally been ascribed to lateral gene transfer (LGT) from eukaryotes. In addition, the functions of sterols in these bacteria are unknown and the functional overlap between sterols and hopanoids is still unclear. Gemmata obscuriglobus is a bacterium from the Planctomycetes phylum that synthesizes sterols, in contrast to its hopanoid-producing relatives. Here we show that sterols are essential for growth of G. obscuriglobus, and that sterol depletion leads to aberrant membrane structures and defects in budding cell division. This report of sterol essentiality in a prokaryotic species advances our understanding of sterol distribution and function, and provides a foundation to pursue fundamental questions in evolutionary cell biology., E.R.-M., C.S.-M., and D. P.D. were supported by BFU2013-40866-P and BFU-2016-7826-P. S.S., E.Y.G., M.H., F. B., and N.L.W. were supported by the US National Science Foundation awards MCB0920667 and IOS-1656637. S.S. and E.Y.G. were additionally supported by the US National Institutes of Health awards NCRR-P20RR016474 and NIGMS-P20GM103432. The acquisition of the GC-MS was made possible by the US National Science Foundation award CHE-0844694 to F.B.

13 p.-9 fig.-1 tab., Dynamic combinatorial chemistry (DCC) has proven its potential in drug discovery speedingthe identification of modulators of biological targets. However, the exchange chemistriestypically take place under specific reaction conditions, with limited tools capable of operatingunder physiological parameters. Here we report a catalyzed protein-directed DCC working atlow temperatures that allows the calcium sensor NCS-1 tofind the best ligands in situ.Ultrafast NMR identifies the reaction intermediates of the acylhydrazone exchange, tracingthe molecular assemblies and getting a real-time insight into the essence of DCC processesat physiological pH. Additionally, NMR, X-ray crystallography and computational methods areemployed to elucidate structural and mechanistic aspects of the molecular recognition event.The DCC approach leads us to the identification of a compound stabilizing the NCS-1/Ric8acomplex and whose therapeutic potential is proven in aDrosophilamodel of disease withsynaptic alterations., This work was supported by differentfunding agencies: the Spanish Ministry of Economy and Competitiveness (MINECO)with Grants CTQ2015-69643-R (R.P.F), SAF2015-74507-JIN (A. Mansilla) andBIO2017-89523-R (M.J.S.-B.), and European Cooperation in Science and Technology(COST) action CMI304 Emergence and evolution of complex chemical systems (R.P.-F.),and a 2017 Leonardo Grant for Researchers and Cultural Creators from the BBVAFoundation (M.J.S.-B) and a 2018 CaixaImpulse program from La Caixa Foundation(A.Mansilla). M.J.S.-B. was supported by a Ramón y Cajal Contract RYC-2008-03449from MINECO.

Mammary stroma is essential for epithelial morphogenesis and development. Indeed, postnatal mammary gland (MG) development is controlled locally by the repetitive and bi-directional cross-talk between the epithelial and the stromal compartment. However, the signalling pathways involved in stromal–epithelial communication are not entirely understood. Here, we identify Sfrp3 as a mediator of the stromal–epithelial communication that is required for normal mouse MG development. Using Drosophila wing imaginal disc, we demonstrate that Sfrp3 functions as an extracellular transporter of Wnts that facilitates their diffusion, and thus, their levels in the boundaries of different compartments. Indeed, loss of Sfrp3 in mice leads to an increase of ductal invasion and branching mirroring an early pregnancy state. Finally, we observe that loss of Sfrp3 predisposes for invasive breast cancer. Altogether, our study shows that Sfrp3 controls MG morphogenesis by modulating the stromal-epithelial cross-talk during pubertal development., The signalling pathways regulating how the mammary gland stroma interacts with the epithelia to then regulate gland development are unclear. Here, the authors identify Sfrp3 as regulating stroma communication via Wnts, on deletion, this increases ductal invasion and initiates an early pregnancy state.

© The Author(s) 2019., Metastasis underlies the majority of cancer-related deaths yet remains poorly understood due, in part, to the lack of models in vivo. Here we show that expression of the EMT master inducer Snail in primary adult Drosophila intestinal tumors leads to the dissemination of tumor cells and formation of macrometastases. Snail drives an EMT in tumor cells, which, although retaining some epithelial markers, subsequently break through the basal lamina of the midgut, undergo a collective migration and seed polyclonal metastases. While metastases re-epithelialize over time, we found that early metastases are remarkably mesenchymal, discarding the requirement for a mesenchymal-to-epithelial transition for early stages of metastatic growth. Our results demonstrate the formation of metastases in adult flies, and identify a key role for partial-EMTs in driving it. This model opens the door to investigate the basic mechanisms underlying metastasis, in a powerful in vivo system suited for rapid genetic and drug screens., This study was supported by grants from the Ministerio de Economía y competitividad (Grant Numbers BFU2014–59781-P (to A.C.), BFU2015–73494-JIN (to K.C.), BFU2015–66488-P (to J.C.)). This work was also supported by the Joseph Steiner Foundation (to E.B.) and a Wellcome Trust/Royal Society Sir Henry Dale Award to K.C. (Grant number R/148777–11–1).

7 pags., 6 figs., -- Open Access funded by Creative Commons Atribution Licence 4.0, The design of achromatic optical components requires materials with high transparency and low dispersion. We show that although metals are highly opaque, densely packed arrays of metallic nanoparticles can be more transparent to infrared radiation than dielectrics such as germanium, even when the arrays are over 75% metal by volume. Such arrays form effective dielectrics that are virtually dispersion-free over ultra-broadband ranges of wavelengths from microns up to millimeters or more. Furthermore, the local refractive indices may be tuned by altering the size, shape, and spacing of the nanoparticles, allowing the design of gradient-index lenses that guide and focus light on the microscale. The electric field is also strongly concentrated in the gaps between the metallic nanoparticles, and the simultaneous focusing and squeezing of the electric field produces strong ‘doubly-enhanced’ hotspots which could boost measurements made using infrared spectroscopy and other non-linear processes over a broad range of frequencies., S.J.P. would like to acknowledge his studentship from the Centre for Doctoral Training on Theory and Simulation of Materials at Imperial College London funded by EPSRC Grant No. EP/L015579/1. R.A.A.-P., N.P.-P., L.G., and M.A.C.-D. thank the MINECO-Spain (CTM2014-58481R, CTM2017-84050R, CTQ2017-88648R, RYC-2015-19107 and RYC2016-20331), Xunta de Galicia (Centro Singular de Investigacion de Galicia, Acc. 2016-19 and EM2014/035), Generalitat de Cataluña (2017SGR883), URV (2017PFR-URV_B2-02), URV and Banco Santander (2017EXIT-08) and European Union (ERDF). X.X. acknowledges the Lee Family Scholarship. S.A.M. and R.V.C. acknowledge the EPSRC Mathematical Fundamentals of Metamaterials programme grant (EP/L024926/1) and the US Air Force Office of Scientific Research/EOARD (FA9550-17-1-0300). S.A.M. additionally acknowledges the Lee-Lucas Chair in Physics and DFG Cluster of Excellence Nanoinitiative Munich, and the Bavarian “Solar Technologies Go Hybrid” (SolTech) programme. R.V.C. thanks the Leverhulme Trust for their support. V.G. acknowledges the Consejo Superior de Investigaciones Cientficas (INTRAMURALES 201750I039).

10 pags., 3 figs., 2 tabs. -- Open Access funded by Creative Commons Atribution Licence 4.0, Fungal cell wall synthesis is achieved by a balance of glycosyltransferase, hydrolase and transglycosylase activities. Transglycosylases strengthen the cell wall by forming a rigid network of crosslinks through mechanisms that remain to be explored. Here we study the function of the Aspergillus fumigatus family of five Crh transglycosylases. Although crh genes are dispensable for cell viability, simultaneous deletion of all genes renders cells sensitive to cell wall interfering compounds. In vitro biochemical assays and localisation studies demonstrate that this family of enzymes functions redundantly as transglycosylases for both chitin-glucan and chitin-chitin cell wall crosslinks. To understand the molecular basis of this acceptor promiscuity, we solved the crystal structure of A. fumigatus Crh5 (AfCrh5) in complex with a chitooligosaccharide at the resolution of 2.8 Å, revealing an extensive elongated binding cleft for the donor (−4 to −1) substrate and a short acceptor (+1 to +2) binding site. Together with mutagenesis, the structure suggests a “hydrolysis product assisted” molecular mechanism favouring transglycosylation over hydrolysis., We thank the European Synchrotron Radiation Facility beamlines ID29 and ID30A-1, Grenoble, France. This work was funded by MRC Programme Grant (M004139) to D.M.F.v.A., Research Start-up Funding of Guangxi Academy of Sciences (2017YJJ025) and Guangxi Natural Science Foundation (2018GXNSFAA138012) to W.F., ARAID to R.H-G., Ministerio de Economía (MINECO) to both R.H-G. and J.A. (CTQ2013-44367- C2-2-P and BFU2016-75633-P to R.H-G., and BIO2016-79289-P to J.A.), DGA to R.H-G. (E34_R17), and Comunidad de Madrid (FSE, FEDER) (S2017/BMD-3691 InGEMICS-CM) to J.A. A.B.S. was supported by contract from Comunidad de Madrid (FSE, FEDER).

The recent thinning and retreat of Antarctic ice shelves has been attributed to both atmosphere and ocean warming. However, the lack of continuous, multi-year direct observations as well as limitations of climate and ice shelf models prevent a precise assessment on how the ocean forcing affects the fluctuations of a grounded and floating ice cap. Here we show that a +0.3–1.5 °C increase in subsurface ocean temperature (50–400 m) in the northeastern Antarctic Peninsula has driven to major collapse and recession of the regional ice shelf during both the instrumental period and the last 9000 years. Our projections following the representative concentration pathway 8.5 emission scenario from the Fifth Assessment Report of the Intergovernmental Panel on Climate Change reveal a +0.3 °C subsurface ocean temperature warming within the coming decades that will undoubtedly accelerate ice shelf melting, including the southernmost sector of the eastern Antarctic Peninsula., J.E. and C.E. are financially supported by the Spanish Ministerio de Economia y Competitividad (CTM2014–60451-C2–1-P) co-funded by the European Union through FEDER funds. J.-H.K. was supported by the grants funded by the Korea Polar Research Institute (KOPRI, NRF-2015M1A5A1037243 and PE19010). S.S. and J.S.S.D. are supported by the Netherlands Earth System Science Center funded by the Dutch Ministry of Education and Science (OCW). G.S. and D.S. were funded by the EMBRACE project (European Union’s FP7, Grant Number: 282672). We also acknowledge funding from the French ANR CLIMICE, ERC ICEPROXY 203441, ESF PolarClimate, HOLOCLIP 625 and FP7 Past4Future as well as the Netherlands Organisation of Scientific Research (NWO) through a VICI grant to S.S. The HOLOCLIP Project, a joint research project of ESF PolarCLIMATE programme, is funded by national contributions from Italy, France, Germany, Spain, Netherlands, Belgium and the United Kingdom. The research leading to these results has also received support from the European Union’s Seventh Framework programme (FP7/2007–2013) under Grant Agreement No. 243908, “Past4Future, Climate change – Learning from the past climate”. This is HOLOCLIP Contribution No. 32. We also thank J. Giraudeau for his constructive suggestions on the manuscript.

Precise cis-regulatory control of gene expression is essential for normal embryogenesis and tissue development. The BMP antagonist Gremlin1 (Grem1) is a key node in the signalling system that coordinately controls limb bud development. Here, we use mouse reverse genetics to identify the enhancers in the Grem1 genomic landscape and the underlying cis-regulatory logics that orchestrate the spatio-temporal Grem1 expression dynamics during limb bud development. We establish that transcript levels are controlled in an additive manner while spatial regulation requires synergistic interactions among multiple enhancers. Disrupting these interactions shows that altered spatial regulation rather than reduced Grem1 transcript levels prefigures digit fusions and loss. Two of the enhancers are evolutionary ancient and highly conserved from basal fishes to mammals. Analysing these enhancers from different species reveal the substantial spatial plasticity in Grem1 regulation in tetrapods and basal fishes, which provides insights into the fin-to-limb transition and evolutionary diversification of pentadactyl limbs., This research was initiated with support from the Bonus-of-Excellence SNF grant 310030B_166685 (to A.Z. and R.Z.) and then supported by the ERC advanced grant INTEGRAL ERC-2015-AdG; Project ID 695032 (to R.Z.) and the University of Basel provided core funding (to A.Z. and R.Z.). Additional funding support was provided by the National Institutes of Health grant R01 GM124251 (to K.A.P.). The research of J.L.R. is supported by MICINN grants BFU2017-82974-P and MDM-2016-0687. K.O. is supported by the Special Postdoctoral Researcher Program of RIKEN.

Refraction between isotropic media is characterized by light bending towards the normal to the boundary when passing from a low- to a high-refractive-index medium. However, refraction between anisotropic media is a more exotic phenomenon which remains barely investigated, particularly at the nanoscale. Here, we visualize and comprehensively study the general case of refraction of electromagnetic waves between two strongly anisotropic (hyperbolic) media, and we do it with the use of nanoscale-confined polaritons in a natural medium: α-MoO3. The refracted polaritons exhibit non-intuitive directions of propagation as they traverse planar nanoprisms, enabling to unveil an exotic optical effect: bending-free refraction. Furthermore, we develop an in-plane refractive hyperlens, yielding foci as small as λp/6, being λp the polariton wavelength (λ0/50 compared to the wavelength of free-space light). Our results set the grounds for planar nano-optics in strongly anisotropic media, with potential for effective control of the flow of energy at the nanoscale., G.Á.-P. and J.T.-G. acknowledge support through the Severo Ochoa Program from the Government of the Principality of Asturias (nos. PA-20-PF-BP19-053 and PA-18-PF-BP17-126, respectively). S.X. acknowledges the support from Independent Research Fund Denmark (Project No. 9041-00333B). B.C. acknowledges the support from VILLUM FONDEN (No. 00027987). The Center for Nanostructured Graphene is sponsored by the Danish National Research Foundation (Project No. DNRF103.) K.V.V. and V.S.V. gratefully acknowledge the financial support from the Ministry of Science and Higher Education of the Russian Federation (Agreement No. 075-15-2021-606). J.M.-S. acknowledges financial support through the Ramón y Cajal Program from the Government of Spain (RYC2018-026196-I). A.Y.N. and J.I.M. acknowledge the Spanish Ministry of Science, Innovation and Universities (national projects MAT201788358-C3-3-R and PID2019-104604RB/AEI/10.13039/501100011033). R.H. acknowledges financial support from the Spanish Ministry of Science, Innovation and Universities (national project RTI2018-094830-B-100 and the project MDM-2016-0618 of the Marie de Maeztu Units of Excellence Program) and the Basque Government (grant No. IT1164-19). A.Y.N. also acknowledges the Basque Department of Education (grant no. PIBA-2020-1-0014). P.A.-G. acknowledges support from the European Research Council under starting grant no. 715496, 2DNANOPTICA and the Spanish Ministry of Science and Innovation (State Plan for Scientific and Technical Research and Innovation grant number PID2019-111156GB-I00).

The implementation of Boolean logic circuits in cells have become a very active field within synthetic biology. Although these are mostly focussed on the genetic components alone, the context in which the circuit performs is crucial for its outcome. We characterise 20 genetic NOT logic gates in up to 7 bacterial-based contexts each, to generate 135 different functions. The contexts we focus on are combinations of four plasmid backbones and three hosts, two Escherichia coli and one Pseudomonas putida strains. Each gate shows seven different dynamic behaviours, depending on the context. That is, gates can be fine-tuned by changing only contextual parameters, thus improving the compatibility between gates. Finally, we analyse portability by measuring, scoring, and comparing gate performance across contexts. Rather than being a limitation, we argue that the effect of the genetic background on synthetic constructs expands functionality, and advocate for considering context as a fundamental design parameter., This work was funded by the SETH (RTI2018-095584-B-C42) (MINECO/FEDER), SYCOLIM (PCI2019-111859-2 ERA-COBIOTECH 2018) Project of the Spanish Ministry of Science and Innovation. MADONNA (H2020-FET-OPEN-RIA-2017-1-766975), BioRoboost (H2020-NMBP-BIO-CSA-2018/ 820699), SYNBIO4FLAV (H2020-NMBP/0500) and MIX-UP (H2020-Grant 870294) Contracts of the European Union, the InGEMICS-CM (S2017/BMD-3691) Project of the Comunidad de Madrid - European Structural and Investment Funds - (FSE, FECER), and the SynBio3D project of the UK Engineering and Physical Sciences Research Council (EP/R019002/1). G-M was also supported by grants from Comunidad de Madrid (Atracción de Talento Program, grant 2019-T1/BIO-14053) and the Severo Ochoa Program for Centres of Excellence in R&D from the Agencia Estatal de Investigación of Spain, grant SEV-2016-0672 (2017-2021).

The pancreas is a central organ for human diseases. Most alleles uncovered by genome-wide association studies of pancreatic dysfunction traits overlap with non-coding sequences of DNA. Many contain epigenetic marks of cis-regulatory elements active in pancreatic cells, suggesting that alterations in these sequences contribute to pancreatic diseases. Animal models greatly help to understand the role of non-coding alterations in disease. However, interspecies identification of equivalent cis-regulatory elements faces fundamental challenges, including lack of sequence conservation. Here we combine epigenetic assays with reporter assays in zebrafish and human pancreatic cells to identify interspecies functionally equivalent cis-regulatory elements, regardless of sequence conservation. Among other potential disease-relevant enhancers, we identify a zebrafish ptf1a distal-enhancer whose deletion causes pancreatic agenesis, a phenotype previously found to be induced by mutations in a distal-enhancer of PTF1A in humans, further supporting the causality of this condition in vivo. This approach helps to uncover interspecies functionally equivalent cis-regulatory elements and their potential role in human disease., This study was supported by the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (ERC-2015-StG-680156-ZPR and ERC-2016-AdG-740041-EvoLand to J.L.G.-S.). J.B. is supported by an FCT CEEC grant (CEECIND/03482/2018). J.L.G.-S. is supported by the Spanish Ministerio de Economía y Competitividad (BFU2016-74961-P), the Marató TV3 Fundacion (Grant 201611) and the institutional grant Unidad de Excelencia María de Maeztu (MDM-2016-0687). R.B.C. was funded by FCT (ON2201403-CTO-BPD), IBMC (BIM/04293-UID991520-BPD) and EMBO (Short-Term Fellowship). J.Tx. (SFRH/BD/126467/2016), M.D. (SFRH/BD/135957/2018), A.E. (SFRH/BD/147762/2019), and F.J.F. (PD/BD/105745/2014) are PhD fellows from FCT. M.G. was supported by the EnvMetaGen project via the European Union’s Horizon 2020 research and innovation programme (grant 668981). This work was funded by National Funds through FCT—Fundação para a Ciência e a Tecnologia, I.P., under the project UIDB/04293/2020”.

Open Access Article. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/., Emitted from the oceans, iodine-bearing molecules are ubiquitous in the atmosphere and a source of new atmospheric aerosol particles of potentially global significance. However, its inclusion in atmospheric models is hindered by a lack of understanding of the first steps of the photochemical gas-to-particle conversion mechanism. Our laboratory results show that under a high humidity and low HOx regime, the recently proposed nucleating molecule (iodic acid, HOIO2) does not form rapidly enough, and gas-to-particle conversion proceeds by clustering of iodine oxides (IxOy), albeit at slower rates than under dryer conditions. Moreover, we show experimentally that gas-phase HOIO2 is not necessary for the formation of HOIO2-containing particles. These insights help to explain new particle formation in the relatively dry polar regions and, more generally, provide for the first time a thermochemically feasible molecular mechanism from ocean iodine emissions to atmospheric particles that is currently missing in model calculations of aerosol radiative forcing. © 2020, The Author(s)., This study has received funding from the European Research Council Executive Agency under the European Union’s Horizon 2020 Research and Innovation programme (Project “ERC-2016-COG 726349 CLIMAHAL”). J.C.G.M. acknowledges financial support from the State Agency for Research of the Spanish MCIU through the “Center of Excellence Severo Ochoa” award to the Instituto de Astrofísica de Andalucía (SEV-2017-0709), the Ramon y Cajal Program (RYC-2016-19570) and the National I + D + i Program (RTI2018-095330-B-100). We thank the Holland Computing Center of the University of Nebraska—Lincoln for providing computing resources.

While neurons principally mediate brain function, astrocytes are emerging as cells with important neuromodulatory actions in brain physiology. In addition to homeostatic roles, astrocytes respond to neurotransmitters with calcium transients stimulating the release of gliotransmitters that regulate synaptic and neuronal functions. We investigated astrocyte-neuronal network interactions in vivo by combining two-photon microscopy to monitor astrocyte calcium and electrocorticogram to record neuronal network activity in the somatosensory cortex during sensory stimulation. We found astrocytes respond to sensory stimuli in a stimulus-dependent manner. Sensory stimuli elicit a surge of neuronal network activity in the gamma range (30–50 Hz) followed by a delayed astrocyte activity that dampens the steady-state gamma activity. This sensory-evoked gamma activity increase is enhanced in transgenic mice with impaired astrocyte calcium signaling and is decreased by pharmacogenetic stimulation of astrocytes. Therefore, cortical astrocytes respond to sensory inputs and regulate sensory-evoked neuronal network activity maximizing its dynamic range., This work was supported by National Institutes of Health-NINDS (R01NS097312), National Institutes of Health-NIDA (R01DA048822) and National Institutes of HealthMH (R01MH119355) to A.A.; NIH-NIA (1F31AG057155) and the University of Minnesota Doctoral Dissertation Fellowship to J.L.; Salvador de Madariaga Program (PRX19/ 00646) and Ministerio de Ciencia, Innovación y Universidades (BFU2017-88393-P), Spain, and AEI/FEDER, EU, to E.D.M.; National Institutes of Health-MH (R01MH119355) to P.K.; Ministerio de Economía y Competitividad (BFU2016-80665-P), Spain, Ayudas para la Movilidad de Investigadores M-BAE (BA15/00078) del Instituto de Salud Carlos III, Spain, and co-funded by FEDER (“A way to make Europe”) to J.A.

We report a detailed analysis of the electrical resistivity exponent of thin films of NdNiO3 as a function of epitaxial strain. Thin films under low strain conditions show a linear dependence of the resistivity versus temperature, consistent with a classical Fermi gas ruled by electron-phonon interactions. In addition, the apparent temperature exponent, n, can be tuned with the epitaxial strain between n = 1 and n = 3. We discuss the critical role played by quenched random disorder in the value of n. Our work shows that the assignment of Fermi/Non-Fermi liquid behaviour based on experimentally obtained resistivity exponents requires an in-depth analysis of the degree of disorder in the material., Qikai Guo and Saeedeh Farokhipoor acknowledge financial support from a China Scholarship Council (CSC) grant and a VENI grant (016.veni.179.053) of the Netherlands Organisation for Scientific Research (NWO), respectively. Francisco Rivadulla acknowledges support by the Ministry of Science of Spain (Project No. MAT2016-80762-R), the Conselleria de Cultura, Educacion e Ordenacion Universitaria. Xunta de Galicia (ED431F 2016/008, and Centro singular de investigación de Galicia accreditation 2016–2019, ED431G/09), the European Union (European Regional Development Fund (ERDF)) and the European Commission through the project 734187- SPI-COLOST (H2020-MSCA-RISE-2016).