Wnt ligands influence tumour initiation by controlling the number of intestinal stem cells Nat. Commun. (IF 12.124) Pub Date : 2018-03-19 D. J. Huels, L. Bruens, M. C. Hodder, P. Cammareri, A. D. Campbell, R. A. Ridgway, D. M. Gay, M. Solar-Abboud, W. J. Faller, C. Nixon, L. B. Zeiger, M. E. McLaughlin, E. Morrissey, D. J. Winton, H. J. Snippert, J. van Rheenen, O. J. Sansom
Many epithelial stem cell populations follow a pattern of stochastic stem cell divisions called 'neutral drift'. It is hypothesised that neutral competition between stem cells protects against the acquisition of deleterious mutations. Here we use a Porcupine inhibitor to reduce Wnt secretion at a dose where intestinal homoeostasis is maintained despite a reduction of Lgr5+ stem cells. Functionally, there is a marked acceleration in monoclonal conversion, so that crypts become rapidly derived from a single stem cell. Stem cells located further from the base are lost and the pool of competing stem cells is reduced. We tested whether this loss of stem cell competition would modify tumorigenesis. Reduction of Wnt ligand secretion accelerates fixation of Apc-deficient cells within the crypt leading to accelerated tumorigenesis. Therefore, ligand-based Wnt signalling influences the number of stem cells, fixation speed of Apc mutations and the speed and likelihood of adenoma formation.
Biomimetic artificial organelles with in vitro and in vivo activity triggered by reduction in microenvironment Nat. Commun. (IF 12.124) Pub Date : 2018-03-19 T. Einfalt, D. Witzigmann, C. Edlinger, S. Sieber, R. Goers, A. Najer, M. Spulber, O. Onaca-Fischer, J. Huwyler, C. G. Palivan
Despite tremendous efforts to develop stimuli-responsive enzyme delivery systems, their efficacy has been mostly limited to in vitro applications. Here we introduce, by using an approach of combining biomolecules with artificial compartments, a biomimetic strategy to create artificial organelles (AOs) as cellular implants, with endogenous stimuli-triggered enzymatic activity. AOs are produced by inserting protein gates in the membrane of polymersomes containing horseradish peroxidase enzymes selected as a model for natures own enzymes involved in the redox homoeostasis. The inserted protein gates are engineered by attaching molecular caps to genetically modified channel porins in order to induce redox-responsive control of the molecular flow through the membrane. AOs preserve their structure and are activated by intracellular glutathione levels in vitro. Importantly, our biomimetic AOs are functional in vivo in zebrafish embryos, which demonstrates the feasibility of using AOs as cellular implants in living organisms. This opens new perspectives for patient-oriented protein therapy.
Phase nucleation through confined spinodal fluctuations at crystal defects evidenced in Fe-Mn alloys Nat. Commun. (IF 12.124) Pub Date : 2018-03-19 A. Kwiatkowski da Silva, D. Ponge, Z. Peng, G. Inden, Y. Lu, A. Breen, B. Gault, D. Raabe
Analysis and design of materials and fluids requires understanding of the fundamental relationships between structure, composition, and properties. Dislocations and grain boundaries influence microstructure evolution through the enhancement of diffusion and by facilitating heterogeneous nucleation, where atoms must overcome a potential barrier to enable the early stage of formation of a phase. Adsorption and spinodal decomposition are known precursor states to nucleation and phase transition; however, nucleation remains the less well-understood step in the complete thermodynamic sequence that shapes a microstructure. Here, we report near-atomic-scale observations of a phase transition mechanism that consists in solute adsorption to crystalline defects followed by linear and planar spinodal fluctuations in an Fe-Mn model alloy. These fluctuations provide a pathway for austenite nucleation due to the higher driving force for phase transition in the solute-rich regions. Our observations are supported by thermodynamic calculations, which predict the possibility of spinodal decomposition due to magnetic ordering.
Meridional heat transport variability induced by mesoscale processes in the subpolar North Atlantic Nat. Commun. (IF 12.124) Pub Date : 2018-03-19 Jian Zhao, Amy Bower, Jiayan Yang, Xiaopei Lin
The ocean’s role in global climate change largely depends on its heat transport. Therefore, understanding the oceanic meridional heat transport (MHT) variability is a fundamental issue. Prevailing observational and modeling evidence suggests that MHT variability is primarily determined by the large-scale ocean circulation. Here, using new in situ observations in the eastern subpolar North Atlantic Ocean and an eddy-resolving numerical model, we show that energetic mesoscale eddies with horizontal scales of about 10–100 km profoundly modulate MHT variability on time scales from intra-seasonal to interannual. Our results reveal that the velocity changes due to mesoscale processes produce substantial variability for the MHT regionally (within sub-basins) and the subpolar North Atlantic as a whole. The findings have important implications for understanding the mechanisms for poleward heat transport variability in the subpolar North Atlantic Ocean, a key region for heat and carbon sequestration, ice–ocean interaction, and biological productivity.
Peli1 negatively regulates noncanonical NF-κB signaling to restrain systemic lupus erythematosus Nat. Commun. (IF 12.124) Pub Date : 2018-03-19 Junli Liu, Xinfang Huang, Shumeng Hao, Yan Wang, Manman Liu, Jing Xu, Xingli Zhang, Tao Yu, Shucheng Gan, Dongfang Dai, Xuan Luo, Qingyan Lu, Chaoming Mao, Yanyun Zhang, Nan Shen, Bin Li, Mingzhu Huang, Xiaodong Zhu, Jin Jin, Xuhong Cheng, Shao-Cong Sun, Yichuan Xiao
Systemic lupus erythematosus (SLE) is characterized by uncontrolled secretion of autoantibodies by plasma cells. Although the functional importance of plasma cells and autoantibodies in SLE has been well established, the underlying molecular mechanisms of controlling autoantibody production remain poorly understood. Here we show that Peli1 has a B cell-intrinsic function to protect against lupus-like autoimmunity in mice. Peli1 deficiency in B cells induces autoantibody production via noncanonical NF-κB signaling. Mechanically, Peli1 functions as an E3 ligase to associate with NF-κB inducing kinase (NIK) and mediates NIK Lys48 ubiquitination and degradation. Overexpression of Peli1 inhibits noncanonical NF-κB activation and alleviates lupus-like disease. In humans, PELI1 levels negatively correlate with disease severity in SLE patients. Our findings establish Peli1 as a negative regulator of the noncanonical NF-κB pathway in the context of restraining the pathogenesis of lupus-like disease.
Nitrogen-rich organic soils under warm well-drained conditions are global nitrous oxide emission hotspots Nat. Commun. (IF 12.124) Pub Date : 2018-03-19 Jaan Pärn, Jos T. A. Verhoeven, Klaus Butterbach-Bahl, Nancy B. Dise, Sami Ullah, Anto Aasa, Sergey Egorov, Mikk Espenberg, Järvi Järveoja, Jyrki Jauhiainen, Kuno Kasak, Leif Klemedtsson, Ain Kull, Fatima Laggoun-Défarge, Elena D. Lapshina, Annalea Lohila, Krista Lõhmus, Martin Maddison, William J. Mitsch, Christoph Müller, Ülo Niinemets, Bruce Osborne, Taavi Pae, Jüri-Ott Salm, Fotis Sgouridis, Kristina Sohar, Kaido Soosaar, Kathryn Storey, Alar Teemusk, Moses M. Tenywa, Julien Tournebize, Jaak Truu, Gert Veber, Jorge A. Villa, Seint Sann Zaw, Ülo Mander
Nitrous oxide (N2O) is a powerful greenhouse gas and the main driver of stratospheric ozone depletion. Since soils are the largest source of N2O, predicting soil response to changes in climate or land use is central to understanding and managing N2O. Here we find that N2O flux can be predicted by models incorporating soil nitrate concentration (NO3−), water content and temperature using a global field survey of N2O emissions and potential driving factors across a wide range of organic soils. N2O emissions increase with NO3− and follow a bell-shaped distribution with water content. Combining the two functions explains 72% of N2O emission from all organic soils. Above 5 mg NO3−-N kg−1, either draining wet soils or irrigating well-drained soils increases N2O emission by orders of magnitude. As soil temperature together with NO3− explains 69% of N2O emission, tropical wetlands should be a priority for N2O management.
Spatially heterogeneous dynamics in a metallic glass forming liquid imaged by electron correlation microscopy Nat. Commun. (IF 12.124) Pub Date : 2018-03-19 Pei Zhang, Jason J. Maldonis, Ze Liu, Jan Schroers, Paul M. Voyles
Supercooled liquids exhibit spatial heterogeneity in the dynamics of their fluctuating atomic arrangements. The length and time scales of the heterogeneous dynamics are central to the glass transition and influence nucleation and growth of crystals from the liquid. Here, we report direct experimental visualization of the spatially heterogeneous dynamics as a function of temperature in the supercooled liquid state of a Pt-based metallic glass, using electron correlation microscopy with sub-nanometer resolution. An experimental four-point space-time correlation function demonstrates a growing dynamic correlation length, ξ, upon cooling of the liquid toward the glass transition temperature. ξ as a function of the relaxation time τ are in good agreement with Adam-Gibbs theory, inhomogeneous mode-coupling theory and random first-order transition theory of the glass transition. The same experiments demonstrate the existence of a nanometer thickness near-surface layer with order of magnitude shorter relaxation time than inside the bulk.
Copper-surface-mediated synthesis of acetylenic carbon-rich nanofibers for active metal-free photocathodes Nat. Commun. (IF 12.124) Pub Date : 2018-03-19 Tao Zhang, Yang Hou, Volodymyr Dzhagan, Zhongquan Liao, Guoliang Chai, Markus Löffler, Davide Olianas, Alberto Milani, Shunqi Xu, Matteo Tommasini, Dietrich R. T. Zahn, Zhikun Zheng, Ehrenfried Zschech, Rainer Jordan, Xinliang Feng
The engineering of acetylenic carbon-rich nanostructures has great potential in many applications, such as nanoelectronics, chemical sensors, energy storage, and conversion, etc. Here we show the synthesis of acetylenic carbon-rich nanofibers via copper-surface-mediated Glaser polycondensation of 1,3,5-triethynylbenzene on a variety of conducting (e.g., copper, graphite, fluorine-doped tin oxide, and titanium) and non-conducting (e.g., Kapton, glass, and silicon dioxide) substrates. The obtained nanofibers (with optical bandgap of 2.51 eV) exhibit photocatalytic activity in photoelectrochemical cells, yielding saturated cathodic photocurrent of ca. 10 µA cm−2 (0.3–0 V vs. reversible hydrogen electrode). By incorporating thieno[3,2-b]thiophene units into the nanofibers, a redshift (ca. 100 nm) of light absorption edge and twofold of the photocurrent are achieved, rivalling those of state-of-the-art metal-free photocathodes (e.g., graphitic carbon nitride of 0.1–1 µA cm−2). This work highlights the promise of utilizing acetylenic carbon-rich materials as efficient and sustainable photocathodes for water reduction
The MerR-like protein BldC binds DNA direct repeats as cooperative multimers to regulate Streptomyces development Nat. Commun. (IF 12.124) Pub Date : 2018-03-19 Maria A. Schumacher, Chris D. Hengst, Matthew J. Bush, T. B. K. Le, Ngat T. Tran, Govind Chandra, Wenjie Zeng, Brady Travis, Richard G. Brennan, Mark J. Buttner
Streptomycetes are notable for their complex life cycle and production of most clinically important antibiotics. A key factor that controls entry into development and the onset of antibiotic production is the 68-residue protein, BldC. BldC is a putative DNA-binding protein related to MerR regulators, but lacks coiled-coil dimerization and effector-binding domains characteristic of classical MerR proteins. Hence, the molecular function of the protein has been unclear. Here we show that BldC is indeed a DNA-binding protein and controls a regulon that includes other key developmental regulators. Intriguingly, BldC DNA-binding sites vary significantly in length. Our BldC-DNA structures explain this DNA-binding capability by revealing that BldC utilizes a DNA-binding mode distinct from MerR and other known regulators, involving asymmetric head-to-tail oligomerization on DNA direct repeats that results in dramatic DNA distortion. Notably, BldC-like proteins radiate throughout eubacteria, establishing BldC as the founding member of a new structural family of regulators.
Publisher Correction: Anderson light localization in biological nanostructures of native silk Nat. Commun. (IF 12.124) Pub Date : 2018-03-19 Seung Ho Choi, Seong-Wan Kim, Zahyun Ku, Michelle A. Visbal-Onufrak, Seong-Ryul Kim, Kwang-Ho Choi, Hakseok Ko, Wonshik Choi, Augustine M. Urbas, Tae-Won Goo, Young L. Kim
The original PDF version of this Article contained errors in Equations 1 and 2. Both equations omitted all Γ terms. This has been corrected in the PDF version of the Article. The HTML version was correct from the time of publication.
Glycogen synthase kinase 3 controls migration of the neural crest lineage in mouse and Xenopus Nat. Commun. (IF 12.124) Pub Date : 2018-03-19 Sandra G. Gonzalez Malagon, Anna M. Lopez Muñoz, Daniel Doro, Triòna G. Bolger, Evon Poon, Elizabeth R. Tucker, Hadeel Adel Al-Lami, Matthias Krause, Christopher J. Phiel, Louis Chesler, Karen J. Liu
Neural crest migration is critical to its physiological function. Mechanisms controlling mammalian neural crest migration are comparatively unknown, due to difficulties accessing this cell population in vivo. Here we report requirements of glycogen synthase kinase 3 (GSK3) in regulating the neural crest in Xenopus and mouse models. We demonstrate that GSK3 is tyrosine phosphorylated (pY) in mouse neural crest cells and that loss of GSK3 leads to increased pFAK and misregulation of Rac1 and lamellipodin, key regulators of cell migration. Genetic reduction of GSK3 results in failure of migration. We find that pY-GSK3 phosphorylation depends on anaplastic lymphoma kinase (ALK), a protein associated with neuroblastoma. Consistent with this, neuroblastoma cells with increased ALK activity express high levels of pY-GSK3, and blockade of GSK3 or ALK can affect migration of these cells. Altogether, this work identifies a role for GSK3 in cell migration during neural crest development and cancer.
Predator-secreted sulfolipids induce defensive responses in C. elegans Nat. Commun. (IF 12.124) Pub Date : 2018-03-19 Zheng Liu, Maro J. Kariya, Christopher D. Chute, Amy K. Pribadi, Sarah G. Leinwand, Ada Tong, Kevin P. Curran, Neelanjan Bose, Frank C. Schroeder, Jagan Srinivasan, Sreekanth H. Chalasani
Animals respond to predators by altering their behavior and physiological states, but the underlying signaling mechanisms are poorly understood. Using the interactions between Caenorhabditis elegans and its predator, Pristionchus pacificus, we show that neuronal perception by C. elegans of a predator-specific molecular signature induces instantaneous escape behavior and a prolonged reduction in oviposition. Chemical analysis revealed this predator-specific signature to consist of a class of sulfolipids, produced by a biochemical pathway required for developing predacious behavior and specifically induced by starvation. These sulfolipids are detected by four pairs of C. elegans amphid sensory neurons that act redundantly and recruit cyclic nucleotide-gated (CNG) or transient receptor potential (TRP) channels to drive both escape and reduced oviposition. Functional homology of the delineated signaling pathways and abolishment of predator-evoked C. elegans responses by the anti-anxiety drug sertraline suggests a likely conserved or convergent strategy for managing predator threats.
Author Correction: Saturated palmitic acid induces myocardial inflammatory injuries through direct binding to TLR4 accessory protein MD2 Nat. Commun. (IF 12.124) Pub Date : 2018-03-19 Yi Wang, Yuanyuan Qian, Qilu Fang, Peng Zhong, Weixin Li, Lintao Wang, Weitao Fu, Yali Zhang, Zheng Xu, Xiaokun Li, Guang Liang
Author Correction: Saturated palmitic acid induces myocardial inflammatory injuries through direct binding to TLR4 accessory protein MD2
A supramolecular biomimetic skin combining a wide spectrum of mechanical properties and multiple sensory capabilities Nat. Commun. (IF 12.124) Pub Date : 2018-03-19 Zhouyue Lei, Peiyi Wu
Biomimetic skin-like materials, capable of adapting shapes to variable environments and sensing external stimuli, are of great significance in a wide range of applications, including artificial intelligence, soft robotics, and smart wearable devices. However, such highly sophisticated intelligence has been mainly found in natural creatures while rarely realized in artificial materials. Herein, we fabricate a type of biomimetic iontronics to imitate natural skins using supramolecular polyelectrolyte hydrogels. The dynamic viscoelastic networks provide the biomimetic skin with a wide spectrum of mechanical properties, including flexible reconfiguration ability, robust elasticity, extremely large stretchability, autonomous self-healability, and recyclability. Meanwhile, polyelectrolytes’ ionic conductivity allows multiple sensory capabilities toward temperature, strain, and stress. This work provides not only insights into dynamic interactions and sensing mechanism of supramolecular iontronics, but may also promote the development of biomimetic skins with sophisticated intelligence similar to natural skins.
An evolutionary hotspot defines functional differences between CRYPTOCHROMES Nat. Commun. (IF 12.124) Pub Date : 2018-03-19 Clark Rosensweig, Kimberly A. Reynolds, Peng Gao, Isara Laothamatas, Yongli Shan, Rama Ranganathan, Joseph S. Takahashi, Carla B. Green
Mammalian circadian clocks are driven by a transcription/translation feedback loop composed of positive regulators (CLOCK/BMAL1) and repressors (CRYPTOCHROME 1/2 (CRY1/2) and PER1/2). To understand the structural principles of regulation, we used evolutionary sequence analysis to identify co-evolving residues within the CRY/PHL protein family. Here we report the identification of an ancestral secondary cofactor-binding pocket as an interface in repressive CRYs, mediating regulation through direct interaction with CLOCK and BMAL1. Mutations weakening binding between CLOCK/BMAL1 and CRY1 lead to acceleration of the clock, suggesting that subtle sequence divergences at this site can modulate clock function. Divergence between CRY1 and CRY2 at this site results in distinct periodic output. Weaker interactions between CRY2 and CLOCK/BMAL1 at this pocket are strengthened by co-expression of PER2, suggesting that PER expression limits the length of the repressive phase in CRY2-driven rhythms. Overall, this work provides a model for the mechanism and evolutionary variation of clock regulatory mechanisms.
CtIP fusion to Cas9 enhances transgene integration by homology-dependent repair Nat. Commun. (IF 12.124) Pub Date : 2018-03-19 M. Charpentier, A. H. Y. Khedher, S. Menoret, A. Brion, K. Lamribet, E. Dardillac, C. Boix, L. Perrouault, L. Tesson, S. Geny, A. De Cian, J. M. Itier, I. Anegon, B. Lopez, C. Giovannangeli, J. P. Concordet
In genome editing with CRISPR–Cas9, transgene integration often remains challenging. Here, we present an approach for increasing the efficiency of transgene integration by homology-dependent repair (HDR). CtIP, a key protein in early steps of homologous recombination, is fused to Cas9 and stimulates transgene integration by HDR at the human AAVS1 safe harbor locus. A minimal N-terminal fragment of CtIP, designated HE for HDR enhancer, is sufficient to stimulate HDR and this depends on CDK phosphorylation sites and the multimerization domain essential for CtIP activity in homologous recombination. HDR stimulation by Cas9–HE, however, depends on the guide RNA used, a limitation that may be overcome by testing multiple guides to the locus of interest. The Cas9–HE fusion is simple to use and allows obtaining twofold or more efficient transgene integration than that with Cas9 in several experimental systems, including human cell lines, iPS cells, and rat zygotes.
HIV envelope V3 region mimic embodies key features of a broadly neutralizing antibody lineage epitope Nat. Commun. (IF 12.124) Pub Date : 2018-03-16 Daniela Fera, Matthew S. Lee, Kevin Wiehe, R. Ryan Meyerhoff, Alessandro Piai, Mattia Bonsignori, Baptiste Aussedat, William E. Walkowicz, Therese Ton, Jeffrey O. Zhou, Samuel Danishefsky, Barton F. Haynes, Stephen C. Harrison
HIV-1 envelope (Env) mimetics are candidate components of prophylactic vaccines and potential therapeutics. Here we use a synthetic V3-glycopeptide (“Man9-V3”) for structural studies of an HIV Env third variable loop (V3)-glycan directed, broadly neutralizing antibody (bnAb) lineage (“DH270”), to visualize the epitope on Env and to study how affinity maturation of the lineage proceeded. Unlike many previous V3 mimetics, Man9-V3 encompasses two key features of the V3 region recognized by V3-glycan bnAbs—the conserved GDIR motif and the N332 glycan. In our structure of an antibody fragment of a lineage member, DH270.6, in complex with the V3 glycopeptide, the conformation of the antibody-bound glycopeptide conforms closely to that of the corresponding segment in an intact HIV-1 Env trimer. An additional structure identifies roles for two critical mutations in the development of breadth. The results suggest a strategy for use of a V3 glycopeptide as a vaccine immunogen.
Intersubband plasmons in the quantum limit in gated and aligned carbon nanotubes Nat. Commun. (IF 12.124) Pub Date : 2018-03-16 Kazuhiro Yanagi, Ryotaro Okada, Yota Ichinose, Yohei Yomogida, Fumiya Katsutani, Weilu Gao, Junichiro Kono
Confined electrons collectively oscillate in response to light, resulting in a plasmon resonance whose frequency is determined by the electron density and the size and shape of the confinement structure. Plasmons in metallic particles typically occur in the classical regime where the characteristic quantum level spacing is negligibly small compared to the plasma frequency. In doped semiconductor quantum wells, quantum plasmon excitations can be observed, where the quantization energy exceeds the plasma frequency. Such intersubband plasmons occur in the mid- and far-infrared ranges and exhibit a variety of dynamic many-body effects. Here, we report the observation of intersubband plasmons in carbon nanotubes, where both the quantization and plasma frequencies are larger than those of typical quantum wells by three orders of magnitude. As a result, we observed a pronounced absorption peak in the near-infrared. Specifically, we observed the near-infrared plasmon peak in gated films of aligned single-wall carbon nanotubes only for probe light polarized perpendicular to the nanotube axis and only when carriers are present either in the conduction or valence band. Both the intensity and frequency of the peak were found to increase with the carrier density, consistent with the plasmonic nature of the resonance. Our observation of gate-controlled quantum plasmons in aligned carbon nanotubes will not only pave the way for the development of carbon-based near-infrared optoelectronic devices but also allow us to study the collective dynamic response of interacting electrons in one dimension.
Continuous-wave highly-efficient low-divergence terahertz wire lasers Nat. Commun. (IF 12.124) Pub Date : 2018-03-16 Simone Biasco, Katia Garrasi, Fabrizio Castellano, Lianhe Li, Harvey E. Beere, David A. Ritchie, Edmund H. Linfield, A. Giles Davies, Miriam S. Vitiello
Terahertz (THz) quantum cascade lasers (QCLs) have undergone rapid development since their demonstration, showing high power, broad-tunability, quantum-limited linewidth, and ultra-broadband gain. Typically, to address applications needs, continuous-wave (CW) operation, low-divergent beam profiles and fine spectral control of the emitted radiation, are required. This, however, is very difficult to achieve in practice. Lithographic patterning has been extensively used to this purpose (via distributed feedback (DFB), photonic crystals or microcavities), to optimize either the beam divergence or the emission frequency, or, both of them simultaneously, in third-order DFBs, via a demanding fabrication procedure that precisely constrains the mode index to 3. Here, we demonstrate wire DFB THz QCLs, in which feedback is provided by a sinusoidal corrugation of the cavity, defining the frequency, while light extraction is ensured by an array of surface holes. This new architecture, extendable to a broad range of far-infrared frequencies, has led to the achievement of low-divergent beams (10°), single-mode emission, high slope efficiencies (250 mW/A), and stable CW operation.
Thalamocortical dysrhythmia detected by machine learning Nat. Commun. (IF 12.124) Pub Date : 2018-03-16 Sven Vanneste, Jae-Jin Song, Dirk De Ridder
Thalamocortical dysrhythmia (TCD) is a model proposed to explain divergent neurological disorders. It is characterized by a common oscillatory pattern in which resting-state alpha activity is replaced by cross-frequency coupling of low- and high-frequency oscillations. We undertook a data-driven approach using support vector machine learning for analyzing resting-state electroencephalography oscillatory patterns in patients with Parkinson’s disease, neuropathic pain, tinnitus, and depression. We show a spectrally equivalent but spatially distinct form of TCD that depends on the specific disorder. However, we also identify brain areas that are common to the pathology of Parkinson’s disease, pain, tinnitus, and depression. This study therefore supports the validity of TCD as an oscillatory mechanism underlying diverse neurological disorders.
Monitoring ultrafast vibrational dynamics of isotopic molecules with frequency modulation of high-order harmonics Nat. Commun. (IF 12.124) Pub Date : 2018-03-16 Lixin He, Qingbin Zhang, Pengfei Lan, Wei Cao, Xiaosong Zhu, Chunyang Zhai, Feng Wang, Wenjing Shi, Muzi Li, Xue-Bin Bian, Peixiang Lu, André D. Bandrauk
Molecules constituted by different isotopes are different in vibrational modes, making it possible to elucidate the mechanism of a chemical reaction via the kinetic isotope effect. However, the real-time observation of the vibrational motion of isotopic nuclei in molecules is still challenging due to its ultrashort time scale. Here we demonstrate a method to monitor the nuclear vibration of isotopic molecules with the frequency modulation of high-order harmonic generation (HHG) during the laser-molecule interaction. In the proof-of-principle experiment, we report a red shift in HHG from H2 and D2. The red shift is ascribed to dominant HHG from the stretched isotopic molecules at the trailing edge of the laser pulse. By utilizing the observed frequency shift, the laser-driven nuclear vibrations of H2 and D2 are retrieved. These findings pave an accessible route toward monitoring the ultrafast nuclear dynamics and even tracing a chemical reaction in real time.
Author Correction: Efficient green light-emitting diodes based on quasi-two-dimensional composition and phase engineered perovskite with surface passivation Nat. Commun. (IF 12.124) Pub Date : 2018-03-16 Xiaolei Yang, Xingwang Zhang, Jinxiang Deng, Zema Chu, Qi Jiang, Junhua Meng, Pengyang Wang, Liuqi Zhang, Zhigang Yin, Jingbi You
The original version of this Article omitted an acknowledgement to the source of Fig. 1a. The following has been added to the end of the caption to Fig. 1: ‘Figure 1a adapted from ref. 13 (copyright 2016 Macmillan Publishers)’. This has been corrected in the PDF and HTML versions of the Article.
Scalable total synthesis and comprehensive structure–activity relationship studies of the phytotoxin coronatine Nat. Commun. (IF 12.124) Pub Date : 2018-03-16 Mairi M. Littleson, Christopher M. Baker, Anne J. Dalençon, Elizabeth C. Frye, Craig Jamieson, Alan R. Kennedy, Kenneth B. Ling, Matthew M. McLachlan, Mark G. Montgomery, Claire J. Russell, Allan J. B. Watson
Natural phytotoxins are valuable starting points for agrochemical design. Acting as a jasmonate agonist, coronatine represents an attractive herbicidal lead with novel mode of action, and has been an important synthetic target for agrochemical development. However, both restricted access to quantities of coronatine and a lack of a suitably scalable and flexible synthetic approach to its constituent natural product components, coronafacic and coronamic acids, has frustrated development of this target. Here, we report gram-scale production of coronafacic acid that allows a comprehensive structure–activity relationship study of this target. Biological assessment of a >120 member library combined with computational studies have revealed the key determinants of potency, rationalising hypotheses held for decades, and allowing future rational design of new herbicidal leads based on this template.
Archimedes’ law explains penetration of solids into granular media Nat. Commun. (IF 12.124) Pub Date : 2018-03-16 Wenting Kang, Yajie Feng, Caishan Liu, Raphael Blumenfeld
Understanding the response of granular matter to intrusion of solid objects is key to modelling many aspects of behaviour of granular matter, including plastic flow. Here we report a general model for such a quasistatic process. Using a range of experiments, we first show that the relation between the penetration depth and the force resisting it, transiently nonlinear and then linear, is scalable to a universal form. We show that the gradient of the steady-state part, K ϕ , depends only on the medium’s internal friction angle, ϕ, and that it is nonlinear in μ = tan ϕ, in contrast to an existing conjecture. We further show that the intrusion of any convex solid shape satisfies a modified Archimedes’ law and use this to: relate the zero-depth intercept of the linear part to K ϕ and the intruder’s cross-section; explain the curve’s nonlinear part in terms of the stagnant zone’s development.
Calcineurin-mediated IL-2 production by CD11chighMHCII+ myeloid cells is crucial for intestinal immune homeostasis Nat. Commun. (IF 12.124) Pub Date : 2018-03-16 Andrea Mencarelli, Hanif Javanmard Khameneh, Jan Fric, Maurizio Vacca, Sary El Daker, Baptiste Janela, Jing Ping Tang, Sabrina Nabti, Akhila Balachander, Tong Seng Lim, Florent Ginhoux, Paola Ricciardi-Castagnoli, Alessandra Mortellaro
The intestinal immune system can respond to invading pathogens yet maintain immune tolerance to self-antigens and microbiota. Myeloid cells are central to these processes, but the signaling pathways that underlie tolerance versus inflammation are unclear. Here we show that mice lacking Calcineurin B in CD11chighMHCII+ cells (Cnb1 CD11c mice) spontaneously develop intestinal inflammation and are susceptible to induced colitis. In these mice, colitis is associated with expansion of T helper type 1 (Th1) and Th17 cell populations and a decrease in the number of FoxP3+ regulatory T (Treg) cells, and the pathology is linked to the inability of intestinal Cnb1-deficient CD11chighMHCII+ cells to express IL-2. Deleting IL-2 in CD11chighMHCII+ cells induces spontaneous colitis resembling human inflammatory bowel disease. Our findings identify that the calcineurin–NFAT–IL-2 pathway in myeloid cells is a critical regulator of intestinal homeostasis by influencing the balance of inflammatory and regulatory responses in the mouse intestine.
Physiological and therapeutic regulation of glucose homeostasis by upper small intestinal PepT1-mediated protein sensing Nat. Commun. (IF 12.124) Pub Date : 2018-03-16 Helen J. Dranse, T. M. Zaved Waise, Sophie C. Hamr, Paige V. Bauer, Mona A. Abraham, Brittany A. Rasmussen, Tony K. T. Lam
High protein feeding improves glucose homeostasis in rodents and humans with diabetes, but the mechanisms that underlie this improvement remain elusive. Here we show that acute administration of casein hydrolysate directly into the upper small intestine increases glucose tolerance and inhibits glucose production in rats, independently of changes in plasma amino acids, insulin levels, and food intake. Inhibition of upper small intestinal peptide transporter 1 (PepT1), the primary oligopeptide transporter in the small intestine, reverses the preabsorptive ability of upper small intestinal casein infusion to increase glucose tolerance and suppress glucose production. The glucoregulatory role of PepT1 in the upper small intestine of healthy rats is further demonstrated by glucose homeostasis disruption following high protein feeding when PepT1 is inhibited. PepT1-mediated protein-sensing mechanisms also improve glucose homeostasis in models of early-onset insulin resistance and obesity. We demonstrate that preabsorptive upper small intestinal protein-sensing mechanisms mediated by PepT1 have beneficial effects on whole-body glucose homeostasis.
A b map implying the first eastern rupture of the Nankai Trough earthquakes Nat. Commun. (IF 12.124) Pub Date : 2018-03-16 K. Z. Nanjo, A. Yoshida
The Nankai Trough megathrust earthquakes inflicted catastrophic damage on Japanese society and more widely. Most research is aimed at identifying strongly coupled regions that are considered as a major source of future disastrous earthquakes. Here we present a b-value map for the entire Nankai Trough zone. The b value, which represents the rate of occurrence of small earthquakes relative to larger ones, is inversely dependent on differential stresses, and has been used to detect highly stressed areas on fault planes in various tectonic situations. A remarkable finding is that the b value is inversely correlated with the slip-deficit rate (SDR). Moreover, the b value for the areas of high SDR in the eastern part is lower than that in the western part, indicating that differential stress on asperities in the eastern part is higher than that in the western part. This may explain the history of the Nankai Trough earthquakes, in which the eastern part tends to rupture first.
Clathrin-adaptor ratio and membrane tension regulate the flat-to-curved transition of the clathrin coat during endocytosis Nat. Commun. (IF 12.124) Pub Date : 2018-03-16 Delia Bucher, Felix Frey, Kem A. Sochacki, Susann Kummer, Jan-Philip Bergeest, William J. Godinez, Hans-Georg Kräusslich, Karl Rohr, Justin W. Taraska, Ulrich S. Schwarz, Steeve Boulant
Although essential for many cellular processes, the sequence of structural and molecular events during clathrin-mediated endocytosis remains elusive. While it was long believed that clathrin-coated pits grow with a constant curvature, it was recently suggested that clathrin first assembles to form flat structures that then bend while maintaining a constant surface area. Here, we combine correlative electron and light microscopy and mathematical growth laws to study the ultrastructural rearrangements of the clathrin coat during endocytosis in BSC-1 mammalian cells. We confirm that clathrin coats initially grow flat and demonstrate that curvature begins when around 70% of the final clathrin content is acquired. We find that this transition is marked by a change in the clathrin to clathrin-adaptor protein AP2 ratio and that membrane tension suppresses this transition. Our results support the notion that BSC-1 mammalian cells dynamically regulate the flat-to-curved transition in clathrin-mediated endocytosis by both biochemical and mechanical factors.
SUMO targets the APC/C to regulate transition from metaphase to anaphase Nat. Commun. (IF 12.124) Pub Date : 2018-03-16 Karolin Eifler, Sabine A. G. Cuijpers, Edwin Willemstein, Jonne A. Raaijmakers, Dris El Atmioui, Huib Ovaa, René H. Medema, Alfred C. O. Vertegaal
Signal transduction by small ubiquitin-like modifier (SUMO) regulates a myriad of nuclear processes. Here we report on the role of SUMO in mitosis in human cell lines. Knocking down the SUMO conjugation machinery results in a delay in mitosis and defects in mitotic chromosome separation. Searching for relevant SUMOylated proteins in mitosis, we identify the anaphase-promoting complex/cyclosome (APC/C), a master regulator of metaphase to anaphase transition. The APC4 subunit is the major SUMO target in the complex, containing SUMO acceptor lysines at positions 772 and 798. SUMOylation is crucial for accurate progression of cells through mitosis and increases APC/C ubiquitylation activity toward a subset of its targets, including the newly identified target KIF18B. Combined, our findings demonstrate the importance of SUMO signal transduction for genome integrity during mitotic progression and reveal how SUMO and ubiquitin cooperate to drive mitosis.
A DHODH inhibitor increases p53 synthesis and enhances tumor cell killing by p53 degradation blockage Nat. Commun. (IF 12.124) Pub Date : 2018-03-16 Marcus J. G. W. Ladds, Ingeborg M. M. van Leeuwen, Catherine J. Drummond, Su Chu, Alan R. Healy, Gergana Popova, Andrés Pastor Fernández, Tanzina Mollick, Suhas Darekar, Saikiran K. Sedimbi, Marta Nekulova, Marijke C. C. Sachweh, Johanna Campbell, Maureen Higgins, Chloe Tuck, Mihaela Popa, Mireia Mayoral Safont, Pascal Gelebart, Zinayida Fandalyuk, Alastair M. Thompson, Richard Svensson, Anna-Lena Gustavsson, Lars Johansson, Katarina Färnegårdh, Ulrika Yngve, Aljona Saleh, Martin Haraldsson, Agathe C. A. D’Hollander, Marcela Franco, Yan Zhao, Maria Håkansson, Björn Walse, Karin Larsson, Emma M. Peat, Vicent Pelechano, John Lunec, Borivoj Vojtesek, Mar Carmena, William C. Earnshaw, Anna R. McCarthy, Nicholas J. Westwood, Marie Arsenian-Henriksson, David P. Lane, Ravi Bhatia, Emmet McCormack, Sonia Laín
The development of non-genotoxic therapies that activate wild-type p53 in tumors is of great interest since the discovery of p53 as a tumor suppressor. Here we report the identification of over 100 small-molecules activating p53 in cells. We elucidate the mechanism of action of a chiral tetrahydroindazole (HZ00), and through target deconvolution, we deduce that its active enantiomer (R)-HZ00, inhibits dihydroorotate dehydrogenase (DHODH). The chiral specificity of HZ05, a more potent analog, is revealed by the crystal structure of the (R)-HZ05/DHODH complex. Twelve other DHODH inhibitor chemotypes are detailed among the p53 activators, which identifies DHODH as a frequent target for structurally diverse compounds. We observe that HZ compounds accumulate cancer cells in S-phase, increase p53 synthesis, and synergize with an inhibitor of p53 degradation to reduce tumor growth in vivo. We, therefore, propose a strategy to promote cancer cell killing by p53 instead of its reversible cell cycle arresting effect.
Functional architecture of reward learning in mushroom body extrinsic neurons of larval Drosophila Nat. Commun. (IF 12.124) Pub Date : 2018-03-16 Timo Saumweber, Astrid Rohwedder, Michael Schleyer, Katharina Eichler, Yi-chun Chen, Yoshinori Aso, Albert Cardona, Claire Eschbach, Oliver Kobler, Anne Voigt, Archana Durairaja, Nino Mancini, Marta Zlatic, James W. Truman, Andreas S. Thum, Bertram Gerber
The brain adaptively integrates present sensory input, past experience, and options for future action. The insect mushroom body exemplifies how a central brain structure brings about such integration. Here we use a combination of systematic single-cell labeling, connectomics, transgenic silencing, and activation experiments to study the mushroom body at single-cell resolution, focusing on the behavioral architecture of its input and output neurons (MBINs and MBONs), and of the mushroom body intrinsic APL neuron. Our results reveal the identity and morphology of almost all of these 44 neurons in stage 3 Drosophila larvae. Upon an initial screen, functional analyses focusing on the mushroom body medial lobe uncover sparse and specific functions of its dopaminergic MBINs, its MBONs, and of the GABAergic APL neuron across three behavioral tasks, namely odor preference, taste preference, and associative learning between odor and taste. Our results thus provide a cellular-resolution study case of how brains organize behavior.
Asymmetric adhesion of rod-shaped bacteria controls microcolony morphogenesis Nat. Commun. (IF 12.124) Pub Date : 2018-03-16 Marie-Cécilia Duvernoy, Thierry Mora, Maxime Ardré, Vincent Croquette, David Bensimon, Catherine Quilliet, Jean-Marc Ghigo, Martial Balland, Christophe Beloin, Sigolène Lecuyer, Nicolas Desprat
Surface colonization underpins microbial ecology on terrestrial environments. Although factors that mediate bacteria–substrate adhesion have been extensively studied, their spatiotemporal dynamics during the establishment of microcolonies remains largely unexplored. Here, we use laser ablation and force microscopy to monitor single-cell adhesion during the course of microcolony formation. We find that adhesion forces of the rod-shaped bacteria Escherichia coli and Pseudomonas aeruginosa are polar. This asymmetry induces mechanical tension, and drives daughter cell rearrangements, which eventually determine the shape of the microcolonies. Informed by experimental data, we develop a quantitative model of microcolony morphogenesis that enables the prediction of bacterial adhesion strength from simple time-lapse measurements. Our results demonstrate how patterns of surface colonization derive from the spatial distribution of adhesive factors on the cell envelope.
Plasma dye coating as straightforward and widely applicable procedure for dye immobilization on polymeric materials Nat. Commun. (IF 12.124) Pub Date : 2018-03-16 Lieselot Smet, Gertjan Vancoillie, Peter Minshall, Kathleen Lava, Iline Steyaert, Ella Schoolaert, Elke Walle, Peter Dubruel, Karen Clerck, Richard Hoogenboom
Here, we introduce a novel concept for the fabrication of colored materials with significantly reduced dye leaching through covalent immobilization of the desired dye using plasma-generated surface radicals. This plasma dye coating (PDC) procedure immobilizes a pre-adsorbed layer of a dye functionalized with a radical sensitive group on the surface through radical addition caused by a short plasma treatment. The non-specific nature of the plasma-generated surface radicals allows for a wide variety of dyes including azobenzenes and sulfonphthaleins, functionalized with radical sensitive groups to avoid significant dye degradation, to be combined with various materials including PP, PE, PA6, cellulose, and PTFE. The wide applicability, low consumption of dye, relatively short procedure time, and the possibility of continuous PDC using an atmospheric plasma reactor make this procedure economically interesting for various applications ranging from simple coloring of a material to the fabrication of chromic sensor fabrics as demonstrated by preparing a range of halochromic materials.
Estrogen receptor α drives pro-resilient transcription in mouse models of depression Nat. Commun. (IF 12.124) Pub Date : 2018-03-16 Zachary S. Lorsch, Yong-Hwee Eddie Loh, Immanuel Purushothaman, Deena M. Walker, Eric M. Parise, Marine Salery, Michael E. Cahill, Georgia E. Hodes, Madeline L. Pfau, Hope Kronman, Peter J. Hamilton, Orna Issler, Benoit Labonté, Ann E. Symonds, Matthew Zucker, Tie Yuan Zhang, Michael J. Meaney, Scott J. Russo, Li Shen, Rosemary C. Bagot, Eric J. Nestler
Most people exposed to stress do not develop depression. Animal models have shown that stress resilience is an active state that requires broad transcriptional adaptations, but how this homeostatic process is regulated remains poorly understood. In this study, we analyze upstream regulators of genes differentially expressed after chronic social defeat stress. We identify estrogen receptor α (ERα) as the top regulator of pro-resilient transcriptional changes in the nucleus accumbens (NAc), a key brain reward region implicated in depression. In accordance with these findings, nuclear ERα protein levels are altered by stress in male and female mice. Further, overexpression of ERα in the NAc promotes stress resilience in both sexes. Subsequent RNA-sequencing reveals that ERα overexpression in NAc reproduces the transcriptional signature of resilience in male, but not female, mice. These results indicate that NAc ERα is an important regulator of pro-resilient transcriptional changes, but with sex-specific downstream targets.
PLK1 has tumor-suppressive potential in APC-truncated colon cancer cells Nat. Commun. (IF 12.124) Pub Date : 2018-03-16 Monika Raab, Mourad Sanhaji, Yves Matthess, Albrecht Hörlin, Ioana Lorenz, Christina Dötsch, Nils Habbe, Oliver Waidmann, Elisabeth Kurunci-Csacsko, Ron Firestein, Sven Becker, Klaus Strebhardt
The spindle assembly checkpoint (SAC) acts as a molecular safeguard in ensuring faithful chromosome transmission during mitosis, which is regulated by a complex interplay between phosphatases and kinases including PLK1. Adenomatous polyposis coli (APC) germline mutations cause aneuploidy and are responsible for familial adenomatous polyposis (FAP). Here we study the role of PLK1 in colon cancer cells with chromosomal instability promoted by APC truncation (APC-ΔC). The expression of APC-ΔC in colon cells reduces the accumulation of mitotic cells upon PLK1 inhibition, accelerates mitotic exit and increases the survival of cells with enhanced chromosomal abnormalities. The inhibition of PLK1 in mitotic, APC-∆C-expressing cells reduces the kinetochore levels of Aurora B and hampers the recruitment of SAC component suggesting a compromised mitotic checkpoint. Furthermore, Plk1 inhibition (RNAi, pharmacological compounds) promotes the development of adenomatous polyps in two independent Apc Min/+ mouse models. High PLK1 expression increases the survival of colon cancer patients expressing a truncated APC significantly.
Neural basis for categorical boundaries in the primate pre-SMA during relative categorization of time intervals Nat. Commun. (IF 12.124) Pub Date : 2018-03-15 Germán Mendoza, Juan Carlos Méndez, Oswaldo Pérez, Luis Prado, Hugo Merchant
Perceptual categorization depends on the assignment of different stimuli to specific groups based, in principle, on the notion of flexible categorical boundaries. To determine the neural basis of categorical boundaries, we record the activity of pre-SMA neurons of monkeys executing an interval categorization task in which the limit between short and long categories changes between blocks of trials within a session. A large population of cells encodes this boundary by reaching a constant peak of activity close to the corresponding subjective limit. Notably, the time at which this peak is reached changes according to the categorical boundary of the current block, predicting the monkeys’ categorical decision on a trial-by-trial basis. In addition, pre-SMA cells also represent the category selected by the monkeys and the outcome of the decision. These results suggest that the pre-SMA adaptively encodes subjective duration boundaries between short and long durations and contains crucial neural information to categorize intervals and evaluate the outcome of such perceptual decisions.
Sensitive and frequent identification of high avidity neo-epitope specific CD8+ T cells in immunotherapy-naive ovarian cancer Nat. Commun. (IF 12.124) Pub Date : 2018-03-15 Sara Bobisse, Raphael Genolet, Annalisa Roberti, Janos L. Tanyi, Julien Racle, Brian J. Stevenson, Christian Iseli, Alexandra Michel, Marie-Aude Bitoux, Philippe Guillaume, Julien Schmidt, Valentina Bianchi, Denarda Dangaj, Craig Fenwick, Laurent Derré, Ioannis Xenarios, Olivier Michielin, Pedro Romero, Dimitri S. Monos, Vincent Zoete, David Gfeller, Lana E. Kandalaft, George Coukos, Alexandre Harari
Immunotherapy directed against private tumor neo-antigens derived from non-synonymous somatic mutations is a promising strategy of personalized cancer immunotherapy. However, feasibility in low mutational load tumor types remains unknown. Comprehensive and deep analysis of circulating and tumor-infiltrating lymphocytes (TILs) for neo-epitope specific CD8+ T cells has allowed prompt identification of oligoclonal and polyfunctional such cells from most immunotherapy-naive patients with advanced epithelial ovarian cancer studied. Neo-epitope recognition is discordant between circulating T cells and TILs, and is more likely to be found among TILs, which display higher functional avidity and unique TCRs with higher predicted affinity than their blood counterparts. Our results imply that identification of neo-epitope specific CD8+ T cells is achievable even in tumors with relatively low number of somatic mutations, and neo-epitope validation in TILs extends opportunities for mutanome-based personalized immunotherapies to such tumors.
A common mechanism of proteasome impairment by neurodegenerative disease-associated oligomers Nat. Commun. (IF 12.124) Pub Date : 2018-03-15 Tiffany A. Thibaudeau, Raymond T. Anderson, David M. Smith
Protein accumulation and aggregation with a concomitant loss of proteostasis often contribute to neurodegenerative diseases, and the ubiquitin–proteasome system plays a major role in protein degradation and proteostasis. Here, we show that three different proteins from Alzheimer’s, Parkinson’s, and Huntington’s disease that misfold and oligomerize into a shared three-dimensional structure potently impair the proteasome. This study indicates that the shared conformation allows these oligomers to bind and inhibit the proteasome with low nanomolar affinity, impairing ubiquitin-dependent and ubiquitin-independent proteasome function in brain lysates. Detailed mechanistic analysis demonstrates that these oligomers inhibit the 20S proteasome through allosteric impairment of the substrate gate in the 20S core particle, preventing the 19S regulatory particle from injecting substrates into the degradation chamber. These results provide a novel molecular model for oligomer-driven impairment of proteasome function that is relevant to a variety of neurodegenerative diseases, irrespective of the specific misfolded protein that is involved.
A comprehensive evaluation of module detection methods for gene expression data Nat. Commun. (IF 12.124) Pub Date : 2018-03-15 Wouter Saelens, Robrecht Cannoodt, Yvan Saeys
A critical step in the analysis of large genome-wide gene expression datasets is the use of module detection methods to group genes into co-expression modules. Because of limitations of classical clustering methods, numerous alternative module detection methods have been proposed, which improve upon clustering by handling co-expression in only a subset of samples, modelling the regulatory network, and/or allowing overlap between modules. In this study we use known regulatory networks to do a comprehensive and robust evaluation of these different methods. Overall, decomposition methods outperform all other strategies, while we do not find a clear advantage of biclustering and network inference-based approaches on large gene expression datasets. Using our evaluation workflow, we also investigate several practical aspects of module detection, such as parameter estimation and the use of alternative similarity measures, and conclude with recommendations for the further development of these methods.
How RNA transcripts coordinate DNA recombination and repair Nat. Commun. (IF 12.124) Pub Date : 2018-03-15 Shane McDevitt, Timur Rusanov, Tatiana Kent, Gurushankar Chandramouly, Richard T. Pomerantz
Genetic studies in yeast indicate that RNA transcripts facilitate homology-directed DNA repair in a manner that is dependent on RAD52. The molecular basis for so-called RNA−DNA repair, however, remains unknown. Using reconstitution assays, we demonstrate that RAD52 directly cooperates with RNA as a sequence-directed ribonucleoprotein complex to promote two related modes of RNA−DNA repair. In a RNA-bridging mechanism, RAD52 assembles recombinant RNA−DNA hybrids that coordinate synapsis and ligation of homologous DNA breaks. In an RNA-templated mechanism, RAD52-mediated RNA−DNA hybrids enable reverse transcription-dependent RNA-to-DNA sequence transfer at DNA breaks that licenses subsequent DNA recombination. Notably, we show that both mechanisms of RNA−DNA repair are promoted by transcription of a homologous DNA template in trans. In summary, these data elucidate how RNA transcripts cooperate with RAD52 to coordinate homology-directed DNA recombination and repair in the absence of a DNA donor, and demonstrate a direct role for transcription in RNA−DNA repair.
Voltage gating of mechanosensitive PIEZO channels Nat. Commun. (IF 12.124) Pub Date : 2018-03-15 Mirko Moroni, M. Rocio Servin-Vences, Raluca Fleischer, Oscar Sánchez-Carranza, Gary R. Lewin
Mechanosensitive PIEZO ion channels are evolutionarily conserved proteins whose presence is critical for normal physiology in multicellular organisms. Here we show that, in addition to mechanical stimuli, PIEZO channels are also powerfully modulated by voltage and can even switch to a purely voltage-gated mode. Mutations that cause human diseases, such as xerocytosis, profoundly shift voltage sensitivity of PIEZO1 channels toward the resting membrane potential and strongly promote voltage gating. Voltage modulation may be explained by the presence of an inactivation gate in the pore, the opening of which is promoted by outward permeation. Older invertebrate (fly) and vertebrate (fish) PIEZO proteins are also voltage sensitive, but voltage gating is a much more prominent feature of these older channels. We propose that the voltage sensitivity of PIEZO channels is a deep property co-opted to add a regulatory mechanism for PIEZO activation in widely different cellular contexts.
Apolipoprotein AI prevents regulatory to follicular helper T cell switching during atherosclerosis Nat. Commun. (IF 12.124) Pub Date : 2018-03-15 Dalia E. Gaddis, Lindsey E. Padgett, Runpei Wu, Chantel McSkimming, Veronica Romines, Angela M. Taylor, Coleen A. McNamara, Mitchell Kronenberg, Shane Crotty, Michael J. Thomas, Mary G. Sorci-Thomas, Catherine C. Hedrick
Regulatory T (Treg) cells contribute to the anti-inflammatory response during atherogenesis. Here we show that during atherogenesis Treg cells lose Foxp3 expression and their immunosuppressive function, leading to the conversion of a fraction of these cells into T follicular helper (Tfh) cells. We show that Tfh cells are pro-atherogenic and that their depletion reduces atherosclerosis. Mechanistically, the conversion of Treg cells to Tfh cells correlates with reduced expression of IL-2Rα and pSTAT5 levels and increased expression of IL-6Rα. In vitro, incubation of naive T cells with oxLDL prevents their differentiation into Treg cells. Furthermore, injection of lipid-free Apolipoprotein AI (ApoAI) into ApoE−/− mice reduces intracellular cholesterol levels in Treg cells and prevents their conversion into Tfh cells. Together our results suggest that ApoAI, the main protein in high-density lipoprotein particles, modulates the cellular fate of Treg cells and thus influences the immune response during atherosclerosis.
Amplification of heat extremes by plant CO2 physiological forcing Nat. Commun. (IF 12.124) Pub Date : 2018-03-15 Christopher B. Skinner, Christopher J. Poulsen, Justin S. Mankin
Plants influence extreme heat events by regulating land-atmosphere water and energy exchanges. The contribution of plants to changes in future heat extremes will depend on the responses of vegetation growth and physiology to the direct and indirect effects of elevated CO2. Here we use a suite of earth system models to disentangle the radiative versus vegetation effects of elevated CO2 on heat wave characteristics. Vegetation responses to a quadrupling of CO2 increase summer heat wave occurrence by 20 days or more—30–50% of the radiative response alone—across tropical and mid-to-high latitude forests. These increases are caused by CO2 physiological forcing, which diminishes transpiration and its associated cooling effect, and reduces clouds and precipitation. In contrast to recent suggestions, our results indicate CO2-driven vegetation changes enhance future heat wave frequency and intensity in most vegetated regions despite transpiration-driven soil moisture savings and increases in aboveground biomass from CO2 fertilization.
Light-triggered enzymatic reactions in nested vesicle reactors Nat. Commun. (IF 12.124) Pub Date : 2018-03-15 James W. Hindley, Yuval Elani, Catriona M. McGilvery, Simak Ali, Charlotte L. Bevan, Robert V. Law, Oscar Ces
Cell-sized vesicles have tremendous potential both as miniaturised pL reaction vessels and in bottom-up synthetic biology as chassis for artificial cells. In both these areas the introduction of light-responsive modules affords increased functionality, for example, to initiate enzymatic reactions in the vesicle interior with spatiotemporal control. Here we report a system composed of nested vesicles where the inner compartments act as phototransducers, responding to ultraviolet irradiation through diacetylene polymerisation-induced pore formation to initiate enzymatic reactions. The controlled release and hydrolysis of a fluorogenic β-galactosidase substrate in the external compartment is demonstrated, where the rate of reaction can be modulated by varying ultraviolet exposure time. Such cell-like nested microreactor structures could be utilised in fields from biocatalysis through to drug delivery.
Modulation of sensory prediction error in Purkinje cells during visual feedback manipulations Nat. Commun. (IF 12.124) Pub Date : 2018-03-15 Martha L. Streng, Laurentiu S. Popa, Timothy J. Ebner
It is hypothesized that the cerebellum implements a forward internal model that transforms motor commands into predictions about upcoming movements. The predictions are compared with sensory feedback to generate sensory prediction errors critical to controlling movements. The simple spike firing of cerebellar Purkinje cells both lead and lag movement consistent with representations of motor predictions and sensory feedback. This study tests whether this leading and lagging modulation provides the prediction and sensory feedback necessary to compute sensory prediction errors. Two manipulations of the visual feedback are used in rhesus monkeys performing pseudo-random tracking. Consistent with a forward model, delaying the visual feedback demonstrates that the leading simple spike modulation with position error is time-locked to the hand movement. Reducing the feedback shows that the lagged modulation is directly driven by visual inputs. Therefore, Purkinje cell discharge carries both the motor predictions and sensory feedback required of a forward internal model.
Dark zone of the Greenland Ice Sheet controlled by distributed biologically-active impurities Nat. Commun. (IF 12.124) Pub Date : 2018-03-14 Jonathan C. Ryan, Alun Hubbard, Marek Stibal, Tristram D. Irvine-Fynn, Joseph Cook, Laurence C. Smith, Karen Cameron, Jason Box
Albedo—a primary control on surface melt—varies considerably across the Greenland Ice Sheet yet the specific surface types that comprise its dark zone remain unquantified. Here we use UAV imagery to attribute seven distinct surface types to observed albedo along a 25 km transect dissecting the western, ablating sector of the ice sheet. Our results demonstrate that distributed surface impurities—an admixture of dust, black carbon and pigmented algae—explain 73% of the observed spatial variability in albedo and are responsible for the dark zone itself. Crevassing and supraglacial water also drive albedo reduction but due to their limited extent, explain just 12 and 15% of the observed variability respectively. Cryoconite, concentrated in large holes or fluvial deposits, is the darkest surface type but accounts for <1% of the area and has minimal impact. We propose that the ongoing emergence and dispersal of distributed impurities, amplified by enhanced ablation and biological activity, will drive future expansion of Greenland's dark zone.
The preprophase band-associated kinesin-14 OsKCH2 is a processive minus-end-directed microtubule motor Nat. Commun. (IF 12.124) Pub Date : 2018-03-14 Kuo-Fu Tseng, Pan Wang, Yuh-Ru Julie Lee, Joel Bowen, Allison M. Gicking, Lijun Guo, Bo Liu, Weihong Qiu
In animals and fungi, cytoplasmic dynein is a processive minus-end-directed motor that plays dominant roles in various intracellular processes. In contrast, land plants lack cytoplasmic dynein but contain many minus-end-directed kinesin-14s. No plant kinesin-14 is known to produce processive motility as a homodimer. OsKCH2 is a plant-specific kinesin-14 with an N-terminal actin-binding domain and a central motor domain flanked by two predicted coiled-coils (CC1 and CC2). Here, we show that OsKCH2 specifically decorates preprophase band microtubules in vivo and transports actin filaments along microtubules in vitro. Importantly, OsKCH2 exhibits processive minus-end-directed motility on single microtubules as individual homodimers. We find that CC1, but not CC2, forms the coiled-coil to enable OsKCH2 dimerization. Instead, our results reveal that removing CC2 renders OsKCH2 a nonprocessive motor. Collectively, these results show that land plants have evolved unconventional kinesin-14 homodimers with inherent minus-end-directed processivity that may function to compensate for the loss of cytoplasmic dynein.
Magnon detection using a ferroic collinear multilayer spin valve Nat. Commun. (IF 12.124) Pub Date : 2018-03-14 Joel Cramer, Felix Fuhrmann, Ulrike Ritzmann, Vanessa Gall, Tomohiko Niizeki, Rafael Ramos, Zhiyong Qiu, Dazhi Hou, Takashi Kikkawa, Jairo Sinova, Ulrich Nowak, Eiji Saitoh, Mathias Kläui
Information transport and processing by pure magnonic spin currents in insulators is a promising alternative to conventional charge-current-driven spintronic devices. The absence of Joule heating and reduced spin wave damping in insulating ferromagnets have been suggested for implementing efficient logic devices. After the successful demonstration of a majority gate based on the superposition of spin waves, further components are required to perform complex logic operations. Here, we report on magnetization orientation-dependent spin current detection signals in collinear magnetic multilayers inspired by the functionality of a conventional spin valve. In Y3Fe5O12|CoO|Co, we find that the detection amplitude of spin currents emitted by ferromagnetic resonance spin pumping depends on the relative alignment of the Y3Fe5O12 and Co magnetization. This yields a spin valve-like behavior with an amplitude change of 120% in our systems. We demonstrate the reliability of the effect and identify its origin by both temperature-dependent and power-dependent measurements.
Predicting the spatiotemporal diversity of seizure propagation and termination in human focal epilepsy Nat. Commun. (IF 12.124) Pub Date : 2018-03-14 Timothée Proix, Viktor K. Jirsa, Fabrice Bartolomei, Maxime Guye, Wilson Truccolo
Recent studies have shown that seizures can spread and terminate across brain areas via a rich diversity of spatiotemporal patterns. In particular, while the location of the seizure onset area is usually invariant across seizures in an individual patient, the source of traveling (2–3 Hz) spike-and-wave discharges during seizures can either move with the slower propagating ictal wavefront or remain stationary at the seizure onset area. Furthermore, although many focal seizures terminate synchronously across brain areas, some evolve into distinct ictal clusters and terminate asynchronously. Here, we introduce a unifying perspective based on a new neural field model of epileptic seizure dynamics. Two main mechanisms, the co-existence of wave propagation in excitable media and coupled-oscillator dynamics, together with the interaction of multiple time scales, account for the reported diversity. We confirm our predictions in seizures and tractography data obtained from patients with pharmacologically resistant epilepsy. Our results contribute toward patient-specific seizure modeling.
Chemo-photothermal therapy combination elicits anti-tumor immunity against advanced metastatic cancer Nat. Commun. (IF 12.124) Pub Date : 2018-03-14 Jutaek Nam, Sejin Son, Lukasz J. Ochyl, Rui Kuai, Anna Schwendeman, James J. Moon
Photothermal therapy (PTT) is a promising cancer treatment modality, but PTT generally requires direct access to the source of light irradiation, thus precluding its utility against disseminated, metastatic tumors. Here, we demonstrate that PTT combined with chemotherapy can trigger potent anti-tumor immunity against disseminated tumors. Specifically, we have developed polydopamine-coated spiky gold nanoparticles as a new photothermal agent with extensive photothermal stability and efficiency. Strikingly, a single round of PTT combined with a sub-therapeutic dose of doxorubicin can elicit robust anti-tumor immune responses and eliminate local as well as untreated, distant tumors in >85% of animals bearing CT26 colon carcinoma. We also demonstrate their therapeutic efficacy against TC-1 submucosa-lung metastasis, a highly aggressive model for advanced head and neck squamous cell carcinoma (HNSCC). Our study sheds new light on a previously unrecognized, immunological facet of chemo-photothermal therapy and may lead to new therapeutic strategies against advanced cancer.
Micro-scale fusion in dense relativistic nanowire array plasmas Nat. Commun. (IF 12.124) Pub Date : 2018-03-14 Alden Curtis, Chase Calvi, James Tinsley, Reed Hollinger, Vural Kaymak, Alexander Pukhov, Shoujun Wang, Alex Rockwood, Yong Wang, Vyacheslav N. Shlyaptsev, Jorge J. Rocca
Nuclear fusion is regularly created in spherical plasma compressions driven by multi-kilojoule pulses from the world’s largest lasers. Here we demonstrate a dense fusion environment created by irradiating arrays of deuterated nanostructures with joule-level pulses from a compact ultrafast laser. The irradiation of ordered deuterated polyethylene nanowires arrays with femtosecond pulses of relativistic intensity creates ultra-high energy density plasmas in which deuterons (D) are accelerated up to MeV energies, efficiently driving D–D fusion reactions and ultrafast neutron bursts. We measure up to 2 × 106 fusion neutrons per joule, an increase of about 500 times with respect to flat solid targets, a record yield for joule-level lasers. Moreover, in accordance with simulation predictions, we observe a rapid increase in neutron yield with laser pulse energy. The results will impact nuclear science and high energy density research and can lead to bright ultrafast quasi-monoenergetic neutron point sources for imaging and materials studies.
Shallow very-low-frequency earthquakes accompany slow slip events in the Nankai subduction zone Nat. Commun. (IF 12.124) Pub Date : 2018-03-14 Masaru Nakano, Takane Hori, Eiichiro Araki, Shuichi Kodaira, Satoshi Ide
Recent studies of slow earthquakes along plate boundaries have shown that tectonic tremor, low-frequency earthquakes, very-low-frequency events (VLFEs), and slow-slip events (SSEs) often accompany each other and appear to share common source faults. However, the source processes of slow events occurring in the shallow part of plate boundaries are not well known because seismic observations have been limited to land-based stations, which offer poor resolution beneath offshore plate boundaries. Here we use data obtained from seafloor observation networks in the Nankai trough, southwest of Japan, to investigate shallow VLFEs in detail. Coincident with the VLFE activity, signals indicative of shallow SSEs were detected by geodetic observations at seafloor borehole observatories in the same region. We find that the shallow VLFEs and SSEs share common source regions and almost identical time histories of moment release. We conclude that these slow events arise from the same fault slip and that VLFEs represent relatively high-frequency fluctuations of slip during SSEs.
The choroid plexus is an important circadian clock component Nat. Commun. (IF 12.124) Pub Date : 2018-03-14 Jihwan Myung, Christoph Schmal, Sungho Hong, Yoshiaki Tsukizawa, Pia Rose, Yong Zhang, Michael J. Holtzman, Erik De Schutter, Hanspeter Herzel, Grigory Bordyugov, Toru Takumi
Mammalian circadian clocks have a hierarchical organization, governed by the suprachiasmatic nucleus (SCN) in the hypothalamus. The brain itself contains multiple loci that maintain autonomous circadian rhythmicity, but the contribution of the non-SCN clocks to this hierarchy remains unclear. We examine circadian oscillations of clock gene expression in various brain loci and discovered that in mouse, robust, higher amplitude, relatively faster oscillations occur in the choroid plexus (CP) compared to the SCN. Our computational analysis and modeling show that the CP achieves these properties by synchronization of “twist” circadian oscillators via gap-junctional connections. Using an in vitro tissue coculture model and in vivo targeted deletion of the Bmal1 gene to silence the CP circadian clock, we demonstrate that the CP clock adjusts the SCN clock likely via circulation of cerebrospinal fluid, thus finely tuning behavioral circadian rhythms.
Author Correction: Liquid crystal elastomer coatings with programmed response of surface profile Nat. Commun. (IF 12.124) Pub Date : 2018-03-14 Greta Babakhanova, Taras Turiv, Yubing Guo, Matthew Hendrikx, Qi-Huo Wei, Albert P. H. J. Schenning, Dirk J. Broer, Oleg D. Lavrentovich
The original version of this Article contained errors in Figs. 1a, 2a, 3a, and 4b, in which the units on the scale bars incorrectly read ‘µm’ rather than the correct ‘nm.’ This has been corrected in both the PDF and HTML versions of the Article.
Improving atomic displacement and replacement calculations with physically realistic damage models Nat. Commun. (IF 12.124) Pub Date : 2018-03-14 Kai Nordlund, Steven J. Zinkle, Andrea E. Sand, Fredric Granberg, Robert S. Averback, Roger Stoller, Tomoaki Suzudo, Lorenzo Malerba, Florian Banhart, William J. Weber, Francois Willaime, Sergei L. Dudarev, David Simeone
Atomic collision processes are fundamental to numerous advanced materials technologies such as electron microscopy, semiconductor processing and nuclear power generation. Extensive experimental and computer simulation studies over the past several decades provide the physical basis for understanding the atomic-scale processes occurring during primary displacement events. The current international standard for quantifying this energetic particle damage, the Norgett−Robinson−Torrens displacements per atom (NRT-dpa) model, has nowadays several well-known limitations. In particular, the number of radiation defects produced in energetic cascades in metals is only ~1/3 the NRT-dpa prediction, while the number of atoms involved in atomic mixing is about a factor of 30 larger than the dpa value. Here we propose two new complementary displacement production estimators (athermal recombination corrected dpa, arc-dpa) and atomic mixing (replacements per atom, rpa) functions that extend the NRT-dpa by providing more physically realistic descriptions of primary defect creation in materials and may become additional standard measures for radiation damage quantification.
Intermembrane crosstalk drives inner-membrane protein organization in Escherichia coli Nat. Commun. (IF 12.124) Pub Date : 2018-03-14 Patrice Rassam, Kathleen R. Long, Renata Kaminska, David J. Williams, Grigorios Papadakos, Christoph G. Baumann, Colin Kleanthous
Gram-negative bacteria depend on energised protein complexes that connect the two membranes of the cell envelope. However, β-barrel outer-membrane proteins (OMPs) and α-helical inner-membrane proteins (IMPs) display quite different organisation. OMPs cluster into islands that restrict their lateral mobility, while IMPs generally diffuse throughout the cell. Here, using live cell imaging of Escherichia coli, we demonstrate that when transient, energy-dependent transmembrane connections are formed, IMPs become subjugated by the inherent organisation of OMPs and that such connections impact IMP function. We show that while establishing a translocon for import, the colicin ColE9 sequesters the IMPs of the proton motive force (PMF)-linked Tol-Pal complex into islands mirroring those of colicin-bound OMPs. Through this imposed organisation, the bacteriocin subverts the outer-membrane stabilising role of Tol-Pal, blocking its recruitment to cell division sites and slowing membrane constriction. The ordering of IMPs by OMPs via an energised inter-membrane bridge represents an emerging functional paradigm in cell envelope biology.
Next generation histology methods for three-dimensional imaging of fresh and archival human brain tissues Nat. Commun. (IF 12.124) Pub Date : 2018-03-14 Hei Ming Lai, Alan King Lun Liu, Harry Ho Man Ng, Marc H. Goldfinger, Tsz Wing Chau, John DeFelice, Bension S. Tilley, Wai Man Wong, Wutian Wu, Steve M. Gentleman
Modern clearing techniques for the three-dimensional (3D) visualisation of neural tissue microstructure have been very effective when used on rodent brain but very few studies have utilised them on human brain material, mainly due to the inherent difficulties in processing post-mortem tissue. Here we develop a tissue clearing solution, OPTIClear, optimised for fresh and archival human brain tissue, including formalin-fixed paraffin-embedded material. In light of practical challenges with immunostaining in tissue clearing, we adapt the use of cresyl violet for visualisation of neurons in cleared tissue, with the potential for 3D quantification in regions of interest. Furthermore, we use lipophilic tracers for tracing of neuronal processes in post-mortem tissue, enabling the study of the morphology of human dendritic spines in 3D. The development of these different strategies for human tissue clearing has wide applicability and, we hope, will provide a baseline for further technique development.
Structures of Teneurin adhesion receptors reveal an ancient fold for cell-cell interaction Nat. Commun. (IF 12.124) Pub Date : 2018-03-14 Verity A. Jackson, Dimphna H. Meijer, Maria Carrasquero, Laura S. Bezouwen, Edward D. Lowe, Colin Kleanthous, Bert J. C. Janssen, Elena Seiradake
Teneurins are ancient cell–cell adhesion receptors that are vital for brain development and synapse organisation. They originated in early metazoan evolution through a horizontal gene transfer event when a bacterial YD-repeat toxin fused to a eukaryotic receptor. We present X-ray crystallography and cryo-EM structures of two Teneurins, revealing a ~200 kDa extracellular super-fold in which eight sub-domains form an intricate structure centred on a spiralling YD-repeat shell. An alternatively spliced loop, which is implicated in homophilic Teneurin interaction and specificity, is exposed and thus poised for interaction. The N-terminal side of the shell is ‘plugged’ via a fibronectin-plug domain combination, which defines a new class of YD proteins. Unexpectedly, we find that these proteins are widespread amongst modern bacteria, suggesting early metazoan receptor evolution from a distinct class of proteins, which today includes both bacterial proteins and eukaryotic Teneurins.
Internal climate variability and projected future regional steric and dynamic sea level rise Nat. Commun. (IF 12.124) Pub Date : 2018-03-14 Aixue Hu, Susan C. Bates
Observational evidence points to a warming global climate accompanied by rising sea levels which impose significant impacts on island and coastal communities. Studies suggest that internal climate processes can modulate projected future sea level rise (SLR) regionally. It is not clear whether this modulation depends on the future climate pathways. Here, by analyzing two sets of ensemble simulations from a climate model, we investigate the potential reduction of SLR, as a result of steric and dynamic oceanographic affects alone, achieved by following a lower emission scenario instead of business-as-usual one over the twenty-first century and how it may be modulated regionally by internal climate variability. Results show almost no statistically significant difference in steric and dynamic SLR on both global and regional scales in the near-term between the two scenarios, but statistically significant SLR reduction for the global mean and many regions later in the century (2061–2080). However, there are regions where the reduction is insignificant, such as the Philippines and west of Australia, that are associated with ocean dynamics and intensified internal variability due to external forcing.
The underappreciated potential of peatlands in global climate change mitigation strategies Nat. Commun. (IF 12.124) Pub Date : 2018-03-14 J. Leifeld, L. Menichetti
Soil carbon sequestration and avoidable emissions through peatland restoration are both strategies to tackle climate change. Here we compare their potential and environmental costs regarding nitrogen and land demand. In the event that no further areas are exploited, drained peatlands will cumulatively release 80.8 Gt carbon and 2.3 Gt nitrogen. This corresponds to a contemporary annual greenhouse gas emission of 1.91 (0.31–3.38) Gt CO2-eq. that could be saved with peatland restoration. Soil carbon sequestration on all agricultural land has comparable mitigation potential. However, additional nitrogen is needed to build up a similar carbon pool in organic matter of mineral soils, equivalent to 30–80% of the global fertilizer nitrogen application annually. Restoring peatlands is 3.4 times less nitrogen costly and involves a much smaller land area demand than mineral soil carbon sequestration, calling for a stronger consideration of peatland rehabilitation as a mitigation measure.
Some contents have been Reproduced by permission of The Royal Society of Chemistry.
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