A synthetic enzyme built from DNA flips 107 lipids per second in biological membranes Nat. Commun. (IF 12.124) Pub Date : 2018-06-21 Alexander Ohmann, Chen-Yu Li, Christopher Maffeo, Kareem Al Nahas, Kevin N. Baumann, Kerstin Göpfrich, Jejoong Yoo, Ulrich F. Keyser, Aleksei Aksimentiev
Mimicking enzyme function and increasing performance of naturally evolved proteins is one of the most challenging and intriguing aims of nanoscience. Here, we employ DNA nanotechnology to design a synthetic enzyme that substantially outperforms its biological archetypes. Consisting of only eight strands, our DNA nanostructure spontaneously inserts into biological membranes by forming a toroidal pore that connects the membrane’s inner and outer leaflets. The membrane insertion catalyzes spontaneous transport of lipid molecules between the bilayer leaflets, rapidly equilibrating the lipid composition. Through a combination of microscopic simulations and fluorescence microscopy we find the lipid transport rate catalyzed by the DNA nanostructure exceeds 107 molecules per second, which is three orders of magnitude higher than the rate of lipid transport catalyzed by biological enzymes. Furthermore, we show that our DNA-based enzyme can control the composition of human cell membranes, which opens new avenues for applications of membrane-interacting DNA systems in medicine.
Dual recognition of H3K4me3 and H3K27me3 by a plant histone reader SHL Nat. Commun. (IF 12.124) Pub Date : 2018-06-21 Shuiming Qian, Xinchen Lv, Ray N. Scheid, Li Lu, Zhenlin Yang, Wei Chen, Rui Liu, Melissa D. Boersma, John M. Denu, Xuehua Zhong, Jiamu Du
The ability of a cell to dynamically switch its chromatin between different functional states constitutes a key mechanism regulating gene expression. Histone mark “readers” display distinct binding specificity to different histone modifications and play critical roles in regulating chromatin states. Here, we show a plant-specific histone reader SHORT LIFE (SHL) capable of recognizing both H3K27me3 and H3K4me3 via its bromo-adjacent homology (BAH) and plant homeodomain (PHD) domains, respectively. Detailed biochemical and structural studies suggest a binding mechanism that is mutually exclusive for either H3K4me3 or H3K27me3. Furthermore, we show a genome-wide co-localization of SHL with H3K27me3 and H3K4me3, and that BAH-H3K27me3 and PHD-H3K4me3 interactions are important for SHL-mediated floral repression. Together, our study establishes BAH-PHD cassette as a dual histone methyl-lysine binding module that is distinct from others in recognizing both active and repressive histone marks.
IBD risk loci are enriched in multigenic regulatory modules encompassing putative causative genes Nat. Commun. (IF 12.124) Pub Date : 2018-06-21 Yukihide Momozawa, Julia Dmitrieva, Emilie Théâtre, Valérie Deffontaine, Souad Rahmouni, Benoît Charloteaux, François Crins, Elisa Docampo, Mahmoud Elansary, Ann-Stephan Gori, Christelle Lecut, Rob Mariman, Myriam Mni, Cécile Oury, Ilya Altukhov, Dmitry Alexeev, Yuri Aulchenko, Leila Amininejad, Gerd Bouma, Frank Hoentjen, Mark Löwenberg, Bas Oldenburg, Marieke J. Pierik, Andrea E. vander Meulen-de Jong, C. Janneke van der Woude, Marijn C. Visschedijk, Mark Lathrop, Jean-Pierre Hugot, Rinse K. Weersma, Martine De Vos, Denis Franchimont, Severine Vermeire, Michiaki Kubo, Edouard Louis, Michel Georges
GWAS have identified >200 risk loci for Inflammatory Bowel Disease (IBD). The majority of disease associations are known to be driven by regulatory variants. To identify the putative causative genes that are perturbed by these variants, we generate a large transcriptome data set (nine disease-relevant cell types) and identify 23,650 cis-eQTL. We show that these are determined by ∼9720 regulatory modules, of which ∼3000 operate in multiple tissues and ∼970 on multiple genes. We identify regulatory modules that drive the disease association for 63 of the 200 risk loci, and show that these are enriched in multigenic modules. Based on these analyses, we resequence 45 of the corresponding 100 candidate genes in 6600 Crohn disease (CD) cases and 5500 controls, and show with burden tests that they include likely causative genes. Our analyses indicate that ≥10-fold larger sample sizes will be required to demonstrate the causality of individual genes using this approach.
Conformational switching of the pseudokinase domain promotes human MLKL tetramerization and cell death by necroptosis Nat. Commun. (IF 12.124) Pub Date : 2018-06-21 Emma J. Petrie, Jarrod J. Sandow, Annette V. Jacobsen, Brian J. Smith, Michael D. W. Griffin, Isabelle S. Lucet, Weiwen Dai, Samuel N. Young, Maria C. Tanzer, Ahmad Wardak, Lung-Yu Liang, Angus D. Cowan, Joanne M. Hildebrand, Wilhelmus J. A. Kersten, Guillaume Lessene, John Silke, Peter E. Czabotar, Andrew I. Webb, James M. Murphy
Necroptotic cell death is mediated by the most terminal known effector of the pathway, MLKL. Precisely how phosphorylation of the MLKL pseudokinase domain activation loop by the upstream kinase, RIPK3, induces unmasking of the N-terminal executioner four-helix bundle (4HB) domain of MLKL, higher-order assemblies, and permeabilization of plasma membranes remains poorly understood. Here, we reveal the existence of a basal monomeric MLKL conformer present in human cells prior to exposure to a necroptotic stimulus. Following activation, toggling within the MLKL pseudokinase domain promotes 4HB domain disengagement from the pseudokinase domain αC helix and pseudocatalytic loop, to enable formation of a necroptosis-inducing tetramer. In contrast to mouse MLKL, substitution of RIPK3 substrate sites in the human MLKL pseudokinase domain completely abrogated necroptotic signaling. Therefore, while the pseudokinase domains of mouse and human MLKL function as molecular switches to control MLKL activation, the underlying mechanism differs between species.
High-veracity functional imaging in scanning probe microscopy via Graph-Bootstrapping Nat. Commun. (IF 12.124) Pub Date : 2018-06-21 Xin Li, Liam Collins, Keisuke Miyazawa, Takeshi Fukuma, Stephen Jesse, Sergei V. Kalinin
The key objective of scanning probe microscopy (SPM) techniques is the optimal representation of the nanoscale surface structure and functionality inferred from the dynamics of the cantilever. This is particularly pertinent today, as the SPM community has seen a rapidly growing trend towards simultaneous capture of multiple imaging channels and complex modes of operation involving high-dimensional information-rich datasets, bringing forward the challenges of visualization and analysis, particularly for cases where the underlying dynamic model is poorly understood. To meet this challenge, we present a data-driven approach, Graph-Bootstrapping, based on low-dimensional manifold learning of the full SPM spectra and demonstrate its successes for high-veracity mechanical mapping on a mixed polymer thin film and resolving irregular hydration structure of calcite at atomic resolution. Using the proposed methodology, we can efficiently reveal and hierarchically represent salient material features with rich local details, further enabling denoising, classification, and high-resolution functional imaging.
Mitotic polarization of transcription factors during asymmetric division establishes fate of forming cancer cells Nat. Commun. (IF 12.124) Pub Date : 2018-06-21 Yongqing Liu, Laura Siles, Xiaoqin Lu, Kevin C. Dean, Miriam Cuatrecasas, Antonio Postigo, Douglas C. Dean
A model of K-Ras-initiated lung cancer was used to follow the transition of precancerous adenoma to adenocarcinoma. In hypoxic, Tgf-β1-rich interiors of adenomas, we show that adenoma cells divide asymmetrically to produce cancer-generating cells highlighted by epithelial mesenchymal transition and a CD44/Zeb1 loop. In these cells, Zeb1 represses the Smad inhibitor Zeb2/Sip1, causing Pten loss and launching Tgf-β1 signaling that drives nuclear translocation of Yap1. Surprisingly, the nuclear polarization of transcription factors during mitosis establishes parent and daughter fates prior to cytokinesis in sequential asymmetric divisions that generate cancer cells from precancerous lesions. Mutation or knockdown of Zeb1 in the lung blocked the production of CD44hi, Zeb1hi cancer-generating cells from adenoma cells. A CD44/Zeb1 loop then initiates two-step transition of precancerous cells to cancer cells via a stable intermediate population of cancer-generating cells. We show these initial cancer-generating cells are independent of cancer stem cells generated in tumors by p53-regulated reprogramming of existing cancer cells.
Predictive modeling of battery degradation and greenhouse gas emissions from U.S. state-level electric vehicle operation Nat. Commun. (IF 12.124) Pub Date : 2018-06-21 Fan Yang, Yuanyuan Xie, Yelin Deng, Chris Yuan
Electric vehicles (EVs) are widely promoted as clean alternatives to conventional vehicles for reducing greenhouse gas (GHG) emissions from ground transportation. However, the battery undergoes a sophisticated degradation process during EV operations and its effects on EV energy consumption and GHG emissions are unknown. Here we show on a typical 24 kWh lithium-manganese-oxide–graphite battery pack that the degradation of EV battery can be mathematically modeled to predict battery life and to study its effects on energy consumption and GHG emissions from EV operations. We found that under US state-level average driving conditions, the battery life is ranging between 5.2 years in Florida and 13.3 years in Alaska under 30% battery degradation limit. The battery degradation will cause a 11.5–16.2% increase in energy consumption and GHG emissions per km driven at 30% capacity loss. This study provides a robust analytical approach and results for supporting policy making in prioritizing EV deployment in the U.S.
Lateralized hippocampal oscillations underlie distinct aspects of human spatial memory and navigation Nat. Commun. (IF 12.124) Pub Date : 2018-06-21 Jonathan Miller, Andrew J. Watrous, Melina Tsitsiklis, Sang Ah Lee, Sameer A. Sheth, Catherine A. Schevon, Elliot H. Smith, Michael R. Sperling, Ashwini Sharan, Ali Akbar Asadi-Pooya, Gregory A. Worrell, Stephen Meisenhelter, Cory S. Inman, Kathryn A. Davis, Bradley Lega, Paul A. Wanda, Sandhitsu R. Das, Joel M. Stein, Richard Gorniak, Joshua Jacobs
The hippocampus plays a vital role in various aspects of cognition including both memory and spatial navigation. To understand electrophysiologically how the hippocampus supports these processes, we recorded intracranial electroencephalographic activity from 46 neurosurgical patients as they performed a spatial memory task. We measure signals from multiple brain regions, including both left and right hippocampi, and we use spectral analysis to identify oscillatory patterns related to memory encoding and navigation. We show that in the left but not right hippocampus, the amplitude of oscillations in the 1–3-Hz “low theta” band increases when viewing subsequently remembered object–location pairs. In contrast, in the right but not left hippocampus, low-theta activity increases during periods of navigation. The frequencies of these hippocampal signals are slower than task-related signals in the neocortex. These results suggest that the human brain includes multiple lateralized oscillatory networks that support different aspects of cognition.
Author Correction: Dynamics enhanced by HCl doping triggers 60% Pauling entropy release at the ice XII–XIV transition Nat. Commun. (IF 12.124) Pub Date : 2018-06-20 K. W. Köster, V. Fuentes-Landete, A. Raidt, M. Seidl, C. Gainaru, T. Loerting, R. Böhmer
Author Correction: Dynamics enhanced by HCl doping triggers 60% Pauling entropy release at the ice XII–XIV transition
Brain-actuated functional electrical stimulation elicits lasting arm motor recovery after stroke Nat. Commun. (IF 12.124) Pub Date : 2018-06-20 A. Biasiucci, R. Leeb, I. Iturrate, S. Perdikis, A. Al-Khodairy, T. Corbet, A. Schnider, T. Schmidlin, H. Zhang, M. Bassolino, D. Viceic, P. Vuadens, A. G. Guggisberg, J. d. R. Millán
Brain-computer interfaces (BCI) are used in stroke rehabilitation to translate brain signals into intended movements of the paralyzed limb. However, the efficacy and mechanisms of BCI-based therapies remain unclear. Here we show that BCI coupled to functional electrical stimulation (FES) elicits significant, clinically relevant, and lasting motor recovery in chronic stroke survivors more effectively than sham FES. Such recovery is associated to quantitative signatures of functional neuroplasticity. BCI patients exhibit a significant functional recovery after the intervention, which remains 6–12 months after the end of therapy. Electroencephalography analysis pinpoints significant differences in favor of the BCI group, mainly consisting in an increase in functional connectivity between motor areas in the affected hemisphere. This increase is significantly correlated with functional improvement. Results illustrate how a BCI–FES therapy can drive significant functional recovery and purposeful plasticity thanks to contingent activation of body natural efferent and afferent pathways.
Intraamniotic Zika virus inoculation of pregnant rhesus macaques produces fetal neurologic disease Nat. Commun. (IF 12.124) Pub Date : 2018-06-20 Lark L. Coffey, Rebekah I. Keesler, Patricia A. Pesavento, Kevin Woolard, Anil Singapuri, Jennifer Watanabe, Christina Cruzen, Kari L. Christe, Jodie Usachenko, JoAnn Yee, Victoria A. Heng, Eliza Bliss-Moreau, J. Rachel Reader, Wilhelm von Morgenland, Anne M. Gibbons, Kenneth Jackson, Amir Ardeshir, Holly Heimsath, Sallie Permar, Paranthaman Senthamaraikannan, Pietro Presicce, Suhas G. Kallapur, Jeffrey M. Linnen, Kui Gao, Robert Orr, Tracy MacGill, Michelle McClure, Richard McFarland, John H. Morrison, Koen K. A. Van Rompay
Zika virus (ZIKV) infection of pregnant women can cause fetal microcephaly and other neurologic defects. We describe the development of a non-human primate model to better understand fetal pathogenesis. To reliably induce fetal infection at defined times, four pregnant rhesus macaques are inoculated intravenously and intraamniotically with ZIKV at gestational day (GD) 41, 50, 64, or 90, corresponding to first and second trimester of gestation. The GD41-inoculated animal, experiencing fetal death 7 days later, has high virus levels in fetal and placental tissues, implicating ZIKV as cause of death. The other three fetuses are carried to near term and euthanized; while none display gross microcephaly, all show ZIKV RNA in many tissues, especially in the brain, which exhibits calcifications and reduced neural precursor cells. Given that this model consistently recapitulates neurologic defects of human congenital Zika syndrome, it is highly relevant to unravel determinants of fetal neuropathogenesis and to explore interventions.
miR-143/145 differentially regulate hematopoietic stem and progenitor activity through suppression of canonical TGFβ signaling Nat. Commun. (IF 12.124) Pub Date : 2018-06-20 Jeffrey Lam, Marion van den Bosch, Joanna Wegrzyn, Jeremy Parker, Rawa Ibrahim, Kate Slowski, Linda Chang, Sergio Martinez-Høyer, Gianluigi Condorelli, Mark Boldin, Yu Deng, Patricia Umlandt, Megan Fuller, Aly Karsan
Expression of miR-143 and miR-145 is reduced in hematopoietic stem/progenitor cells (HSPCs) of myelodysplastic syndrome patients with a deletion in the long arm of chromosome 5. Here we show that mice lacking miR-143/145 have impaired HSPC activity with depletion of functional hematopoietic stem cells (HSCs), but activation of progenitor cells (HPCs). We identify components of the transforming growth factor β (TGFβ) pathway as key targets of miR-143/145. Enforced expression of the TGFβ adaptor protein and miR-145 target, Disabled-2 (DAB2), recapitulates the HSC defect seen in miR-143/145−/− mice. Despite reduced HSC activity, older miR-143/145−/− and DAB2-expressing mice show elevated leukocyte counts associated with increased HPC activity. A subset of mice develop a serially transplantable myeloid malignancy, associated with expansion of HPC. Thus, miR-143/145 play a cell context-dependent role in HSPC function through regulation of TGFβ/DAB2 activation, and loss of these miRNAs creates a preleukemic state.
Cultural conformity generates extremely stable traditions in bird song Nat. Commun. (IF 12.124) Pub Date : 2018-06-20 Robert F. Lachlan, Oliver Ratmann, Stephen Nowicki
Cultural traditions have been observed in a wide variety of animal species. It remains unclear, however, what is required for social learning to give rise to stable traditions: what level of precision and what learning strategies are required. We address these questions by fitting models of cultural evolution to learned bird song. We recorded 615 swamp sparrow (Melospiza georgiana) song repertoires, and compared syllable frequency distributions to the output of individual-based simulations. We find that syllables are learned with an estimated error rate of 1.85% and with a conformist bias in learning. This bias is consistent with a simple mechanism of overproduction and selective attrition. Finally, we estimate that syllable types could frequently persist for more than 500 years. Our results demonstrate conformist bias in natural animal behaviour and show that this, along with moderately precise learning, may support traditions whose stability rivals those of humans.
Unsupervised clustering and epigenetic classification of single cells Nat. Commun. (IF 12.124) Pub Date : 2018-06-20 Mahdi Zamanighomi, Zhixiang Lin, Timothy Daley, Xi Chen, Zhana Duren, Alicia Schep, William J. Greenleaf, Wing Hung Wong
Characterizing epigenetic heterogeneity at the cellular level is a critical problem in the modern genomics era. Assays such as single cell ATAC-seq (scATAC-seq) offer an opportunity to interrogate cellular level epigenetic heterogeneity through patterns of variability in open chromatin. However, these assays exhibit technical variability that complicates clear classification and cell type identification in heterogeneous populations. We present scABC, an R package for the unsupervised clustering of single-cell epigenetic data, to classify scATAC-seq data and discover regions of open chromatin specific to cell identity.
Assigning the absolute configuration of single aliphatic molecules by visual inspection Nat. Commun. (IF 12.124) Pub Date : 2018-06-20 Daniel Ebeling, Marina Šekutor, Marvin Stiefermann, Jalmar Tschakert, Jeremy E. P. Dahl, Robert M. K. Carlson, André Schirmeisen, Peter R. Schreiner
Deciphering absolute configuration of a single molecule by direct visual inspection is the next step in compound identification, with far-reaching implications for medicinal chemistry, pharmacology, and natural product synthesis. We demonstrate the feasibility of this approach utilizing low temperature atomic force microscopy (AFM) with a CO-functionalized tip to determine the absolute configuration and orientation of a single, adsorbed tetramantane molecule, the smallest chiral diamondoid. We differentiate between single enantiomers on Cu(111) by direct visual inspection, and furthermore identify molecular dimers and molecular clusters. The experimental results are confirmed by a computational study that allowed quantification of the corresponding intermolecular interactions. The unique toolset of absolute configuration determination combined with AFM tip manipulation opens a route for studying molecular nucleation, including chirality-driven assembly or reaction mechanisms.
Molecular basis for the production of cyclic peptides by plant asparaginyl endopeptidases Nat. Commun. (IF 12.124) Pub Date : 2018-06-20 M. A. Jackson, E. K. Gilding, T. Shafee, K. S. Harris, Q. Kaas, S. Poon, K. Yap, H. Jia, R. Guarino, L. Y. Chan, T. Durek, M. A. Anderson, D. J. Craik
Asparaginyl endopeptidases (AEPs) are proteases that have crucial roles in plant defense and seed storage protein maturation. Select plant AEPs, however, do not function as proteases but as transpeptidases (ligases) catalyzing the intra-molecular ligation of peptide termini, which leads to peptide cyclization. These ligase-type AEPs have potential biotechnological applications ranging from in vitro peptide engineering to plant molecular farming, but the structural features enabling these enzymes to catalyze peptide ligation/cyclization rather than proteolysis are currently unknown. Here, we compare the sequences, structures, and functions of diverse plant AEPs by combining molecular modeling, sequence space analysis, and functional testing in planta. We find that changes within the substrate-binding pocket and an adjacent loop, here named the “marker of ligase activity”, together play a key role for AEP ligase efficiency. Identification of these structural determinants may facilitate the discovery of more ligase-type AEPs and the engineering of AEPs with tailored catalytic properties.
Urinary cell-free DNA is a versatile analyte for monitoring infections of the urinary tract Nat. Commun. (IF 12.124) Pub Date : 2018-06-20 Philip Burnham, Darshana Dadhania, Michael Heyang, Fanny Chen, Lars F. Westblade, Manikkam Suthanthiran, John Richard Lee, Iwijn De Vlaminck
Urinary tract infections are one of the most common infections in humans. Here we tested the utility of urinary cell-free DNA (cfDNA) to comprehensively monitor host and pathogen dynamics in bacterial and viral urinary tract infections. We isolated cfDNA from 141 urine samples from a cohort of 82 kidney transplant recipients and performed next-generation sequencing. We found that urinary cfDNA is highly informative about bacterial and viral composition of the microbiome, antimicrobial susceptibility, bacterial growth dynamics, kidney allograft injury, and host response to infection. These different layers of information are accessible from a single assay and individually agree with corresponding clinical tests based on quantitative PCR, conventional bacterial culture, and urinalysis. In addition, cfDNA reveals the frequent occurrence of pathologies that remain undiagnosed with conventional diagnostic protocols. Our work identifies urinary cfDNA as a highly versatile analyte to monitor infections of the urinary tract.
Advances in highly doped upconversion nanoparticles Nat. Commun. (IF 12.124) Pub Date : 2018-06-20 Shihui Wen, Jiajia Zhou, Kezhi Zheng, Artur Bednarkiewicz, Xiaogang Liu, Dayong Jin
Lanthanide-doped upconversion nanoparticles (UCNPs) are capable of converting near-infra-red excitation into visible and ultraviolet emission. Their unique optical properties have advanced a broad range of applications, such as fluorescent microscopy, deep-tissue bioimaging, nanomedicine, optogenetics, security labelling and volumetric display. However, the constraint of concentration quenching on upconversion luminescence has hampered the nanoscience community to develop bright UCNPs with a large number of dopants. This review surveys recent advances in developing highly doped UCNPs, highlights the strategies that bypass the concentration quenching effect, and discusses new optical properties as well as emerging applications enabled by these nanoparticles.
Double thermoelectric power factor of a 2D electron system Nat. Commun. (IF 12.124) Pub Date : 2018-06-20 Yuqiao Zhang, Bin Feng, Hiroyuki Hayashi, Cheng-Ping Chang, Yu-Miin Sheu, Isao Tanaka, Yuichi Ikuhara, Hiromichi Ohta
Two-dimensional electron systems have attracted attention as thermoelectric materials, which can directly convert waste heat into electricity. It has been theoretically predicted that thermoelectric power factor can be largely enhanced when the two-dimensional electron layer is far narrower than the de Broglie wavelength. Although many studies have been made, the effectiveness has not been experimentally clarified thus far. Here we experimentally clarify that an enhanced two-dimensionality is efficient to enhance thermoelectric power factor. We fabricated superlattices of [N unit cell SrTi1−xNb x O3|11 unit cell SrTiO3]10—there are two different de Broglie wavelength in the SrTi1−xNb x O3 system. The maximum power factor of the superlattice composed of the longer de Broglie wavelength SrTi1−xNb x O3 exceeded ∼5 mW m−1 K−2, which doubles the value of optimized bulk SrTi1−xNb x O3. The present approach—use of longer de Broglie wavelength—is epoch-making and is fruitful to design good thermoelectric materials showing high power factor.
C-terminal truncation of IFN-γ inhibits proinflammatory macrophage responses and is deficient in autoimmune disease Nat. Commun. (IF 12.124) Pub Date : 2018-06-20 Antoine Dufour, Caroline L. Bellac, Ulrich Eckhard, Nestor Solis, Theo Klein, Reinhild Kappelhoff, Nikolaus Fortelny, Parker Jobin, Jacob Rozmus, Jennifer Mark, Paul Pavlidis, Vincent Dive, Sean J. Barbour, Christopher M. Overall
Controlled macrophage differentiation and activation in the initiation and resolution of inflammation is crucial for averting progression to chronic inflammatory and autoimmune diseases. Here we show a negative feedback mechanism for proinflammatory IFN-γ activation of macrophages driven by macrophage-associated matrix metalloproteinase 12 (MMP12). Through C-terminal truncation of IFN-γ at 135Glu↓Leu136 the IFN-γ receptor-binding site was efficiently removed thereby reducing JAK-STAT1 signaling and IFN-γ activation of proinflammatory macrophages. In acute peritonitis this signature was absent in Mmp12 –/– mice and recapitulated in Mmp12 +/+ mice treated with a MMP12-specific inhibitor. Similarly, loss-of-MMP12 increases IFN-γ–dependent proinflammatory markers and iNOS+/MHC class II+ macrophage accumulation with worse lymphadenopathy, arthritic synovitis and lupus glomerulonephritis. In active human systemic lupus erythematosus, MMP12 levels were lower and IFN-γ higher compared to treated patients or healthy individuals. Hence, macrophage proteolytic truncation of IFN-γ attenuates classical activation of macrophages as a prelude for resolving inflammation.
Spatial maps of prostate cancer transcriptomes reveal an unexplored landscape of heterogeneity Nat. Commun. (IF 12.124) Pub Date : 2018-06-20 Emelie Berglund, Jonas Maaskola, Niklas Schultz, Stefanie Friedrich, Maja Marklund, Joseph Bergenstråhle, Firas Tarish, Anna Tanoglidi, Sanja Vickovic, Ludvig Larsson, Fredrik Salmén, Christoph Ogris, Karolina Wallenborg, Jens Lagergren, Patrik Ståhl, Erik Sonnhammer, Thomas Helleday, Joakim Lundeberg
Intra-tumor heterogeneity is one of the biggest challenges in cancer treatment today. Here we investigate tissue-wide gene expression heterogeneity throughout a multifocal prostate cancer using the spatial transcriptomics (ST) technology. Utilizing a novel approach for deconvolution, we analyze the transcriptomes of nearly 6750 tissue regions and extract distinct expression profiles for the different tissue components, such as stroma, normal and PIN glands, immune cells and cancer. We distinguish healthy and diseased areas and thereby provide insight into gene expression changes during the progression of prostate cancer. Compared to pathologist annotations, we delineate the extent of cancer foci more accurately, interestingly without link to histological changes. We identify gene expression gradients in stroma adjacent to tumor regions that allow for re-stratification of the tumor microenvironment. The establishment of these profiles is the first step towards an unbiased view of prostate cancer and can serve as a dictionary for future studies.
Giant intrinsic circular dichroism of prolinol-derived squaraine thin films Nat. Commun. (IF 12.124) Pub Date : 2018-06-20 Matthias Schulz, Jennifer Zablocki, Oliya S. Abdullaeva, Stefanie Brück, Frank Balzer, Arne Lützen, Oriol Arteaga, Manuela Schiek
Molecular chirality and the inherently connected differential absorption of circular polarized light (CD) combined with semiconducting properties offers great potential for chiral opto-electronics. Here we discuss the temperature-controlled assembly of enantiopure prolinol functionalized squaraines with opposite handedness into intrinsically circular dichroic, molecular J-aggregates in spincasted thin films. By Mueller matrix spectroscopy we accurately probe an extraordinary high excitonic circular dichroism, which is not amplified by mesoscopic ordering effects. At maximum, CD values of 1000 mdeg/nm are reached and, after accounting for reflection losses related to the thin film nature, we obtain a film thickness independent dissymmetry factor g = 0.75. The large oscillator strength of the corresponding absorption within the deep-red spectral range translates into a negative real part of the dielectric function in the spectral vicinity of the exciton resonance. Thereby, we provide a new small molecular benchmark material for the development of organic thin film based chiroptics.
Caffeine-inducible gene switches controlling experimental diabetes Nat. Commun. (IF 12.124) Pub Date : 2018-06-19 Daniel Bojar, Leo Scheller, Ghislaine Charpin-El Hamri, Mingqi Xie, Martin Fussenegger
Programming cellular behavior using trigger-inducible gene switches is integral to synthetic biology. Although significant progress has been achieved in trigger-induced transgene expression, side-effect-free remote control of transgenes continues to challenge cell-based therapies. Here, utilizing a caffeine-binding single-domain antibody we establish a caffeine-inducible protein dimerization system, enabling synthetic transcription factors and cell-surface receptors that enable transgene expression in response to physiologically relevant concentrations of caffeine generated by routine intake of beverages such as tea and coffee. Coffee containing different caffeine concentrations dose-dependently and reversibly controlled transgene expression by designer cells with this caffeine-stimulated advanced regulators (C-STAR) system. Type-2 diabetic mice implanted with microencapsulated, C-STAR-equipped cells for caffeine-sensitive expression of glucagon-like peptide 1 showed substantially improved glucose homeostasis after coffee consumption compared to untreated mice. Biopharmaceutical production control by caffeine, which is non-toxic, inexpensive and only present in specific beverages, is expected to improve patient compliance by integrating therapy with lifestyle.
A modular transcriptional signature identifies phenotypic heterogeneity of human tuberculosis infection Nat. Commun. (IF 12.124) Pub Date : 2018-06-19 Akul Singhania, Raman Verma, Christine M. Graham, Jo Lee, Trang Tran, Matthew Richardson, Patrick Lecine, Philippe Leissner, Matthew P. R. Berry, Robert J. Wilkinson, Karine Kaiser, Marc Rodrigue, Gerrit Woltmann, Pranabashis Haldar, Anne O’Garra
Whole blood transcriptional signatures distinguishing active tuberculosis patients from asymptomatic latently infected individuals exist. Consensus has not been achieved regarding the optimal reduced gene sets as diagnostic biomarkers that also achieve discrimination from other diseases. Here we show a blood transcriptional signature of active tuberculosis using RNA-Seq, confirming microarray results, that discriminates active tuberculosis from latently infected and healthy individuals, validating this signature in an independent cohort. Using an advanced modular approach, we utilise the information from the entire transcriptome, which includes overabundance of type I interferon-inducible genes and underabundance of IFNG and TBX21, to develop a signature that discriminates active tuberculosis patients from latently infected individuals or those with acute viral and bacterial infections. We suggest that methods targeting gene selection across multiple discriminant modules can improve the development of diagnostic biomarkers with improved performance. Finally, utilising the modular approach, we demonstrate dynamic heterogeneity in a longitudinal study of recent tuberculosis contacts.
Nuclear PTEN safeguards pre-mRNA splicing to link Golgi apparatus for its tumor suppressive role Nat. Commun. (IF 12.124) Pub Date : 2018-06-19 Shao-Ming Shen, Yan Ji, Cheng Zhang, Shuang-Shu Dong, Shuo Yang, Zhong Xiong, Meng-Kai Ge, Yun Yu, Li Xia, Meng Guo, Jin-Ke Cheng, Jun-Ling Liu, Jian-Xiu Yu, Guo-Qiang Chen
Dysregulation of pre-mRNA alternative splicing (AS) is closely associated with cancers. However, the relationships between the AS and classic oncogenes/tumor suppressors are largely unknown. Here we show that the deletion of tumor suppressor PTEN alters pre-mRNA splicing in a phosphatase-independent manner, and identify 262 PTEN-regulated AS events in 293T cells by RNA sequencing, which are associated with significant worse outcome of cancer patients. Based on these findings, we report that nuclear PTEN interacts with the splicing machinery, spliceosome, to regulate its assembly and pre-mRNA splicing. We also identify a new exon 2b in GOLGA2 transcript and the exon exclusion contributes to PTEN knockdown-induced tumorigenesis by promoting dramatic Golgi extension and secretion, and PTEN depletion significantly sensitizes cancer cells to secretion inhibitors brefeldin A and golgicide A. Our results suggest that Golgi secretion inhibitors alone or in combination with PI3K/Akt kinase inhibitors may be therapeutically useful for PTEN-deficient cancers.
Covalent-supramolecular hybrid polymers as muscle-inspired anisotropic actuators Nat. Commun. (IF 12.124) Pub Date : 2018-06-19 Stacey M. Chin, Christopher V. Synatschke, Shuangping Liu, Rikkert J. Nap, Nicholas A. Sather, Qifeng Wang, Zaida Álvarez, Alexandra N. Edelbrock, Timmy Fyrner, Liam C. Palmer, Igal Szleifer, Monica Olvera de la Cruz, Samuel I. Stupp
Skeletal muscle provides inspiration on how to achieve reversible, macroscopic, anisotropic motion in soft materials. Here we report on the bottom-up design of macroscopic tubes that exhibit anisotropic actuation driven by a thermal stimulus. The tube is built from a hydrogel in which extremely long supramolecular nanofibers are aligned using weak shear forces, followed by radial growth of thermoresponsive polymers from their surfaces. The hierarchically ordered tube exhibits reversible anisotropic actuation with changes in temperature, with much greater contraction perpendicular to the direction of nanofiber alignment. We identify two critical factors for the anisotropic actuation, macroscopic alignment of the supramolecular scaffold and its covalent bonding to polymer chains. Using finite element analysis and molecular calculations, we conclude polymer chain confinement and mechanical reinforcement by rigid supramolecular nanofibers are responsible for the anisotropic actuation. The work reported suggests strategies to create soft active matter with molecularly encoded capacity to perform complex tasks.
Late-life targeting of the IGF-1 receptor improves healthspan and lifespan in female mice Nat. Commun. (IF 12.124) Pub Date : 2018-06-19 Kai Mao, Gabriela Farias Quipildor, Tahmineh Tabrizian, Ardijana Novaj, Fangxia Guan, Ryan O. Walters, Fabien Delahaye, Gene B. Hubbard, Yuji Ikeno, Keisuke Ejima, Peng Li, David B. Allison, Hossein Salimi-Moosavi, Pedro J. Beltran, Pinchas Cohen, Nir Barzilai, Derek M. Huffman
Diminished growth factor signaling improves longevity in laboratory models, while a reduction in the somatotropic axis is favorably linked to human aging and longevity. Given the conserved role of this pathway on lifespan, therapeutic strategies, such as insulin-like growth factor-1 receptor (IGF-1R) monoclonal antibodies (mAb), represent a promising translational tool to target human aging. To this end, we performed a preclinical study in 18-mo-old male and female mice treated with vehicle or an IGF-1R mAb (L2-Cmu, Amgen Inc), and determined effects on aging outcomes. Here we show that L2-Cmu preferentially improves female healthspan and increases median lifespan by 9% (P = 0.03) in females, along with a reduction in neoplasms and inflammation (P ≤ 0.05). Thus, consistent with other models, targeting IGF-1R signaling appears to be most beneficial to females. Importantly, these effects could be achieved at advanced ages, suggesting that IGF-1R mAbs could represent a promising therapeutic candidate to delay aging.
DNA methylation as a mediator of HLA-DRB1*15:01 and a protective variant in multiple sclerosis Nat. Commun. (IF 12.124) Pub Date : 2018-06-19 Lara Kular, Yun Liu, Sabrina Ruhrmann, Galina Zheleznyakova, Francesco Marabita, David Gomez-Cabrero, Tojo James, Ewoud Ewing, Magdalena Lindén, Bartosz Górnikiewicz, Shahin Aeinehband, Pernilla Stridh, Jenny Link, Till F. M. Andlauer, Christiane Gasperi, Heinz Wiendl, Frauke Zipp, Ralf Gold, Björn Tackenberg, Frank Weber, Bernhard Hemmer, Konstantin Strauch, Stefanie Heilmann-Heimbach, Rajesh Rawal, Ulf Schminke, Carsten O. Schmidt, Tim Kacprowski, Andre Franke, Matthias Laudes, Alexander T. Dilthey, Elisabeth G. Celius, Helle B. Søndergaard, Jesper Tegnér, Hanne F. Harbo, Annette B. Oturai, Sigurgeir Olafsson, Hannes P. Eggertsson, Bjarni V. Halldorsson, Haukur Hjaltason, Elias Olafsson, Ingileif Jonsdottir, Kari Stefansson, Tomas Olsson, Fredrik Piehl, Tomas J. Ekström, Ingrid Kockum, Andrew P. Feinberg, Maja Jagodic
The human leukocyte antigen (HLA) haplotype DRB1*15:01 is the major risk factor for multiple sclerosis (MS). Here, we find that DRB1*15:01 is hypomethylated and predominantly expressed in monocytes among carriers of DRB1*15:01. A differentially methylated region (DMR) encompassing HLA-DRB1 exon 2 is particularly affected and displays methylation-sensitive regulatory properties in vitro. Causal inference and Mendelian randomization provide evidence that HLA variants mediate risk for MS via changes in the HLA-DRB1 DMR that modify HLA-DRB1 expression. Meta-analysis of 14,259 cases and 171,347 controls confirms that these variants confer risk from DRB1*15:01 and also identifies a protective variant (rs9267649, p < 3.32 × 10−8, odds ratio = 0.86) after conditioning for all MS-associated variants in the region. rs9267649 is associated with increased DNA methylation at the HLA-DRB1 DMR and reduced expression of HLA-DRB1, suggesting a modulation of the DRB1*15:01 effect. Our integrative approach provides insights into the molecular mechanisms of MS susceptibility and suggests putative therapeutic strategies targeting a methylation-mediated regulation of the major risk gene.
Author Correction: Herbivorous turtle ants obtain essential nutrients from a conserved nitrogen-recycling gut microbiome Nat. Commun. (IF 12.124) Pub Date : 2018-06-19 Yi Hu, Jon G. Sanders, Piotr Łukasik, Catherine L. D’Amelio, John S. Millar, David R. Vann, Yemin Lan, Justin A. Newton, Mark Schotanus, Daniel J. C. Kronauer, Naomi E. Pierce, Corrie S. Moreau, John T. Wertz, Philipp Engel, Jacob A. Russell
The originally published version of the Supplementary Information file associated with this Article contained an error in Supplementary Figure 3. Panel b was inadvertently replaced with a duplicate of panel a. The error has now been fixed and the corrected version of the Supplementary Information PDF is available to download from the HTML version of the Article.
ZOLA-3D allows flexible 3D localization microscopy over an adjustable axial range Nat. Commun. (IF 12.124) Pub Date : 2018-06-19 Andrey Aristov, Benoit Lelandais, Elena Rensen, Christophe Zimmer
Single molecule localization microscopy can generate 3D super-resolution images without scanning by leveraging the axial variations of normal or engineered point spread functions (PSF). Successful implementation of these approaches for extended axial ranges remains, however, challenging. We present Zernike Optimized Localization Approach in 3D (ZOLA-3D), an easy-to-use computational and optical solution that achieves optimal resolution over a tunable axial range. We use ZOLA-3D to demonstrate 3D super-resolution imaging of mitochondria, nuclear pores and microtubules in entire nuclei or cells up to ~5 μm deep.
HEPATOKIN1 is a biochemistry-based model of liver metabolism for applications in medicine and pharmacology Nat. Commun. (IF 12.124) Pub Date : 2018-06-19 Nikolaus Berndt, Sascha Bulik, Iwona Wallach, Tilo Wünsch, Matthias König, Martin Stockmann, David Meierhofer, Hermann-Georg Holzhütter
The epidemic increase of non-alcoholic fatty liver diseases (NAFLD) requires a deeper understanding of the regulatory circuits controlling the response of liver metabolism to nutritional challenges, medical drugs, and genetic enzyme variants. As in vivo studies of human liver metabolism are encumbered with serious ethical and technical issues, we developed a comprehensive biochemistry-based kinetic model of the central liver metabolism including the regulation of enzyme activities by their reactants, allosteric effectors, and hormone-dependent phosphorylation. The utility of the model for basic research and applications in medicine and pharmacology is illustrated by simulating diurnal variations of the metabolic state of the liver at various perturbations caused by nutritional challenges (alcohol), drugs (valproate), and inherited enzyme disorders (galactosemia). Using proteomics data to scale maximal enzyme activities, the model is used to highlight differences in the metabolic functions of normal hepatocytes and malignant liver cells (adenoma and hepatocellular carcinoma).
Electron–electron interactions and the paired-to-nematic quantum phase transition in the second Landau level Nat. Commun. (IF 12.124) Pub Date : 2018-06-19 K. A. Schreiber, N. Samkharadze, G. C. Gardner, Y. Lyanda-Geller, M. J. Manfra, L. N. Pfeiffer, K. W. West, G. A. Csáthy
In spite of its ubiquity in strongly correlated systems, the competition of paired and nematic ground states remains poorly understood. Recently such a competition was reported in the two-dimensional electron gas at filling factor ν = 5/2. At this filling factor a pressure-induced quantum phase transition was observed from the paired fractional quantum Hall state to the quantum Hall nematic. Here we show that the pressure-induced paired-to-nematic transition also develops at ν = 7/2, demonstrating therefore this transition in both spin branches of the second orbital Landau level. However, we find that pressure is not the only parameter controlling this transition. Indeed, ground states consistent with those observed under pressure also develop in a sample measured at ambient pressure, but in which the electron–electron interaction was tuned close to its value at the quantum critical point. Our experiments suggest that electron–electron interactions play a critical role in driving the paired-to-nematic transition.
Immuno-detection by sequencing enables large-scale high-dimensional phenotyping in cells Nat. Commun. (IF 12.124) Pub Date : 2018-06-19 Jessie A. G. van Buggenum, Jan P. Gerlach, Sabine E. J. Tanis, Mark Hogeweg, Pascal W. T. C. Jansen, Jesse Middelwijk, Ruud van der Steen, Michiel Vermeulen, Hendrik G. Stunnenberg, Cornelis A. Albers, Klaas W. Mulder
Cell-based small molecule screening is an effective strategy leading to new medicines. Scientists in the pharmaceutical industry as well as in academia have made tremendous progress in developing both large-scale and smaller-scale screening assays. However, an accessible and universal technology for measuring large numbers of molecular and cellular phenotypes in many samples in parallel is not available. Here we present the immuno-detection by sequencing (ID-seq) technology that combines antibody-based protein detection and DNA-sequencing via DNA-tagged antibodies. We use ID-seq to simultaneously measure 70 (phospho-)proteins in primary human epidermal stem cells to screen the effects of ~300 kinase inhibitor probes to characterise the role of 225 kinases. The results show an association between decreased mTOR signalling and increased differentiation and uncover 13 kinases potentially regulating epidermal renewal through distinct mechanisms. Taken together, our work establishes ID-seq as a flexible solution for large-scale high-dimensional phenotyping in fixed cell populations.
Dispositional free riders do not free ride on punishment Nat. Commun. (IF 12.124) Pub Date : 2018-06-19 Till O. Weber, Ori Weisel, Simon Gächter
Strong reciprocity explains prosocial cooperation by the presence of individuals who incur costs to help those who helped them (‘strong positive reciprocity’) and to punish those who wronged them (‘strong negative reciprocity’). Theories of social preferences predict that in contrast to ‘strong reciprocators’, self-regarding people cooperate and punish only if there are sufficient future benefits. Here, we test this prediction in a two-stage design. First, participants are classified according to their disposition towards strong positive reciprocity as either dispositional conditional cooperators (DCC) or dispositional free riders (DFR). Participants then play a one-shot public goods game, either with or without punishment. As expected, DFR cooperate only when punishment is possible, whereas DCC cooperate without punishment. Surprisingly, dispositions towards strong positive reciprocity are unrelated to strong negative reciprocity: punishment by DCC and DFR is practically identical. The ‘burden of cooperation’ is thus carried by a larger set of individuals than previously assumed.
Optimization of the structural characteristics of CaO and its effective stabilization yield high-capacity CO2 sorbents Nat. Commun. (IF 12.124) Pub Date : 2018-06-19 Muhammad Awais Naeem, Andac Armutlulu, Qasim Imtiaz, Felix Donat, Robin Schäublin, Agnieszka Kierzkowska, Christoph R. Müller
Calcium looping, a CO2 capture technique, may offer a mid-term if not near-term solution to mitigate climate change, triggered by the yet increasing anthropogenic CO2 emissions. A key requirement for the economic operation of calcium looping is the availability of highly effective CaO-based CO2 sorbents. Here we report a facile synthesis route that yields hollow, MgO-stabilized, CaO microspheres featuring highly porous multishelled morphologies. As a thermal stabilizer, MgO minimized the sintering-induced decay of the sorbents’ CO2 capacity and ensured a stable CO2 uptake over multiple operation cycles. Detailed electron microscopy-based analyses confirm a compositional homogeneity which is identified, together with the characteristics of its porous structure, as an essential feature to yield a high-performance sorbent. After 30 cycles of repeated CO2 capture and sorbent regeneration, the best performing material requires as little as 11 wt.% MgO for structural stabilization and exceeds the CO2 uptake of the limestone-derived reference material by ~500%.
The synaptic receptor Lrp4 promotes peripheral nerve regeneration Nat. Commun. (IF 12.124) Pub Date : 2018-06-19 Katherine D. Gribble, Lauren J. Walker, Louis Saint-Amant, John Y. Kuwada, Michael Granato
Early during PNS regeneration, regenerating axons emerge from the proximal nerve stump, yet whether they extend simultaneously or whether pioneering axons establish a path for follower axons remains unknown. Moreover, the molecular mechanisms underlying robust regeneration are incompletely understood. Using live imaging, we demonstrate that in zebrafish pioneering axons establish a regenerative path for follower axons. We find this process requires the synaptic receptor lrp4, and in lrp4 mutants pioneers are unaffected while follower axons frequently stall at the injury gap, providing evidence for molecular diversity between pioneering and follower axons in regeneration. We demonstrate that Lrp4 promotes regeneration through an axon extrinsic mechanism and independent of membrane anchoring and MuSK co-receptor signaling essential for synaptic development. Finally, we show that Lrp4 coordinates the realignment of denervated Schwann cells with regenerating axons, consistent with a model by which Lrp4 is repurposed to promote sustained peripheral nerve regeneration via axon-glia interactions.
Out-of-equilibrium microcompartments for the bottom-up integration of metabolic functions Nat. Commun. (IF 12.124) Pub Date : 2018-06-19 Thomas Beneyton, Dorothee Krafft, Claudia Bednarz, Christin Kleineberg, Christian Woelfer, Ivan Ivanov, Tanja Vidaković-Koch, Kai Sundmacher, Jean-Christophe Baret
Self-sustained metabolic pathways in microcompartments are the corner-stone for living systems. From a technological viewpoint, such pathways are a mandatory prerequisite for the reliable design of artificial cells functioning out-of-equilibrium. Here we develop a microfluidic platform for the miniaturization and analysis of metabolic pathways in man-made microcompartments formed of water-in-oil droplets. In a modular approach, we integrate in the microcompartments a nicotinamide adenine dinucleotide (NAD)-dependent enzymatic reaction and a NAD-regeneration module as a minimal metabolism. We show that the microcompartments sustain a metabolically active state until the substrate is fully consumed. Reversibly, the external addition of the substrate reboots the metabolic activity of the microcompartments back to an active state. We therefore control the metabolic state of thousands of independent monodisperse microcompartments, a step of relevance for the construction of large populations of metabolically active artificial cells.
Scalable training of artificial neural networks with adaptive sparse connectivity inspired by network science Nat. Commun. (IF 12.124) Pub Date : 2018-06-19 Decebal Constantin Mocanu, Elena Mocanu, Peter Stone, Phuong H. Nguyen, Madeleine Gibescu, Antonio Liotta
Through the success of deep learning in various domains, artificial neural networks are currently among the most used artificial intelligence methods. Taking inspiration from the network properties of biological neural networks (e.g. sparsity, scale-freeness), we argue that (contrary to general practice) artificial neural networks, too, should not have fully-connected layers. Here we propose sparse evolutionary training of artificial neural networks, an algorithm which evolves an initial sparse topology (Erdős–Rényi random graph) of two consecutive layers of neurons into a scale-free topology, during learning. Our method replaces artificial neural networks fully-connected layers with sparse ones before training, reducing quadratically the number of parameters, with no decrease in accuracy. We demonstrate our claims on restricted Boltzmann machines, multi-layer perceptrons, and convolutional neural networks for unsupervised and supervised learning on 15 datasets. Our approach has the potential to enable artificial neural networks to scale up beyond what is currently possible.
Patient derived organoids to model rare prostate cancer phenotypes Nat. Commun. (IF 12.124) Pub Date : 2018-06-19 Loredana Puca, Rohan Bareja, Davide Prandi, Reid Shaw, Matteo Benelli, Wouter R. Karthaus, Judy Hess, Michael Sigouros, Adam Donoghue, Myriam Kossai, Dong Gao, Joanna Cyrta, Verena Sailer, Aram Vosoughi, Chantal Pauli, Yelena Churakova, Cynthia Cheung, Lesa Dayal Deonarine, Terra J. McNary, Rachele Rosati, Scott T. Tagawa, David M. Nanus, Juan Miguel Mosquera, Charles L. Sawyers, Yu Chen, Giorgio Inghirami, Rema A. Rao, Carla Grandori, Olivier Elemento, Andrea Sboner, Francesca Demichelis, Mark A. Rubin, Himisha Beltran
A major hurdle in the study of rare tumors is a lack of existing preclinical models. Neuroendocrine prostate cancer is an uncommon and aggressive histologic variant of prostate cancer that may arise de novo or as a mechanism of treatment resistance in patients with pre-existing castration-resistant prostate cancer. There are few available models to study neuroendocrine prostate cancer. Here, we report the generation and characterization of tumor organoids derived from needle biopsies of metastatic lesions from four patients. We demonstrate genomic, transcriptomic, and epigenomic concordance between organoids and their corresponding patient tumors. We utilize these organoids to understand the biologic role of the epigenetic modifier EZH2 in driving molecular programs associated with neuroendocrine prostate cancer progression. High-throughput organoid drug screening nominated single agents and drug combinations suggesting repurposing opportunities. This proof of principle study represents a strategy for the study of rare cancer phenotypes.
A phosphorylation switch turns a positive regulator of phototropism into an inhibitor of the process Nat. Commun. (IF 12.124) Pub Date : 2018-06-19 Paolo Schumacher, Emilie Demarsy, Patrice Waridel, Laure Allenbach Petrolati, Martine Trevisan, Christian Fankhauser
Phototropins are light-activated protein kinases, which contribute to photosynthesis optimization both through enhancement of photon absorption when light is limiting and avoidance responses in high light. This duality is in part endowed by the presence of phototropins with different photosensitivity (phot1 and phot2). Here we show that phot1, which senses low light to promote positive phototropism (growth towards the light), also limits the response in high light. This response depends in part on phot1-mediated phosphorylation of Phytochrome Kinase Substrate 4 (PKS4). This light-regulated phosphorylation switch changes PKS4 from a phototropism enhancer in low light to a factor limiting the process in high light. In such conditions phot1 and PKS4 phosphorylation prevent phototropic responses to shallow light gradients and limit phototropism in a natural high light environment. Hence, by modifying PKS4 activity in high light the phot1-PKS4 regulon enables appropriate physiological adaptations over a range of light intensities.
Thermodynamic and structural anomalies of water nanodroplets Nat. Commun. (IF 12.124) Pub Date : 2018-06-19 Shahrazad M. A. Malek, Peter H. Poole, Ivan Saika-Voivod
Liquid water nanodroplets are important in earth’s climate, and are valuable for studying supercooled water because they resist crystallisation well below the bulk freezing temperature. Bulk liquid water has well-known thermodynamic anomalies, such as a density maximum, and when supercooled is hypothesised to exhibit a liquid–liquid phase transition (LLPT) at elevated pressure. However, it is not known how these bulk anomalies might manifest themselves in nanodroplets. Here we show, using simulations of the TIP4P/2005 water model, that bulk anomalies occur in nanodroplets as small as 360 molecules. We also show that the Laplace pressure inside small droplets reaches 220 MPa at 180 K, conditions close to the LLPT of TIP4P/2005. While the density and pressure inside nanodroplets coincide with bulk values at moderate supercooling, we show that deviations emerge at lower temperature, as well as significant radial density gradients, which arise from and signal the approach to the LLPT.
Single-walled carbon-nanohorns improve biocompatibility over nanotubes by triggering less protein-initiated pyroptosis and apoptosis in macrophages Nat. Commun. (IF 12.124) Pub Date : 2018-06-19 Bing He, Yujie Shi, Yanqin Liang, Anpu Yang, Zhipu Fan, Lan Yuan, Xiajuan Zou, Xin Chang, Hua Zhang, Xueqing Wang, Wenbin Dai, Yiguang Wang, Qiang Zhang
Single-walled carbon-nanohorns (SNH) exhibit huge application prospects. Notably, spherical SNH possess different morphology from conventional carbon nanotubes (CNT). However, there is a tremendous lack of studies on the nanotoxicity and mechanism of SNH, and their comparison with nanotubes. Here, the dissimilarity between SNH and CNT is found in many aspects including necrosis, pyroptosis, apoptosis, protein expression, hydrolases leakage, lysosome stress, membrane disturbance and the interaction with membrane proteins. The improved biocompatibility of SNH over four types of established CNT is clearly demonstrated in macrophages. Importantly, a key transmembrane protein, glycoprotein nonmetastatic melanoma protein B (GPNMB) is discovered to initiate the nanotoxicity. Compared to CNT, the weaker nano-GPNMB interaction in SNH group induces lower degree of cascade actions from nano/membrane interplay to final cell hypotoxicity. In conclusion, the geometry of single-construct unit, but not that of dispersive forms or intracellular levels of nanocarbons make the most difference.
Enhanced ocean-atmosphere carbon partitioning via the carbonate counter pump during the last deglacial Nat. Commun. (IF 12.124) Pub Date : 2018-06-19 Stéphanie Duchamp-Alphonse, Giuseppe Siani, Elisabeth Michel, Luc Beaufort, Yves Gally, Samuel L. Jaccard
Several synergistic mechanisms were likely involved in the last deglacial atmospheric pCO2 rise. Leading hypotheses invoke a release of deep-ocean carbon through enhanced convection in the Southern Ocean (SO) and concomitant decreased efficiency of the global soft-tissue pump (STP). However, the temporal evolution of both the STP and the carbonate counter pump (CCP) remains unclear, thus preventing the evaluation of their contributions to the pCO2 rise. Here we present sedimentary coccolith records combined with export production reconstructions from the Subantarctic Pacific to document the leverage the SO biological carbon pump (BCP) has imposed on deglacial pCO2. Our data suggest a weakening of BCP during the phases of carbon outgassing, due in part to an increased CCP along with higher surface ocean fertility and elevated [CO2aq]. We propose that reduced BCP efficiency combined with enhanced SO ventilation played a major role in propelling the Earth out of the last ice age.
Improving formaldehyde consumption drives methanol assimilation in engineered E. coli Nat. Commun. (IF 12.124) Pub Date : 2018-06-19 Benjamin M. Woolston, Jason R. King, Michael Reiter, Bob Van Hove, Gregory Stephanopoulos
Due to volatile sugar prices, the food vs fuel debate, and recent increases in the supply of natural gas, methanol has emerged as a promising feedstock for the bio-based economy. However, attempts to engineer Escherichia coli to metabolize methanol have achieved limited success. Here, we provide a rigorous systematic analysis of several potential pathway bottlenecks. We show that regeneration of ribulose 5-phosphate in E. coli is insufficient to sustain methanol assimilation, and overcome this by activating the sedoheptulose bisphosphatase variant of the ribulose monophosphate pathway. By leveraging the kinetic isotope effect associated with deuterated methanol as a chemical probe, we further demonstrate that under these conditions overall pathway flux is kinetically limited by methanol dehydrogenase. Finally, we identify NADH as a potent kinetic inhibitor of this enzyme. These results provide direction for future engineering strategies to improve methanol utilization, and underscore the value of chemical biology methodologies in metabolic engineering.
Efficient and self-adaptive in-situ learning in multilayer memristor neural networks Nat. Commun. (IF 12.124) Pub Date : 2018-06-19 Can Li, Daniel Belkin, Yunning Li, Peng Yan, Miao Hu, Ning Ge, Hao Jiang, Eric Montgomery, Peng Lin, Zhongrui Wang, Wenhao Song, John Paul Strachan, Mark Barnell, Qing Wu, R. Stanley Williams, J. Joshua Yang, Qiangfei Xia
Memristors with tunable resistance states are emerging building blocks of artificial neural networks. However, in situ learning on a large-scale multiple-layer memristor network has yet to be demonstrated because of challenges in device property engineering and circuit integration. Here we monolithically integrate hafnium oxide-based memristors with a foundry-made transistor array into a multiple-layer neural network. We experimentally demonstrate in situ learning capability and achieve competitive classification accuracy on a standard machine learning dataset, which further confirms that the training algorithm allows the network to adapt to hardware imperfections. Our simulation using the experimental parameters suggests that a larger network would further increase the classification accuracy. The memristor neural network is a promising hardware platform for artificial intelligence with high speed-energy efficiency.
Carbon costs and benefits of Indonesian rainforest conversion to plantations Nat. Commun. (IF 12.124) Pub Date : 2018-06-19 Thomas Guillaume, Martyna M. Kotowska, Dietrich Hertel, Alexander Knohl, Valentyna Krashevska, Kukuh Murtilaksono, Stefan Scheu, Yakov Kuzyakov
Land-use intensification in the tropics plays an important role in meeting global demand for agricultural commodities but generates high environmental costs. Here, we synthesize the impacts of rainforest conversion to tree plantations of increasing management intensity on carbon stocks and dynamics. Rainforests in Sumatra converted to jungle rubber, rubber, and oil palm monocultures lost 116 Mg C ha−1, 159 Mg C ha−1, and 174 Mg C ha−1, respectively. Up to 21% of these carbon losses originated from belowground pools, where soil organic matter still decreases a decade after conversion. Oil palm cultivation leads to the highest carbon losses but it is the most efficient land use, providing the lowest ratio between ecosystem carbon storage loss or net primary production (NPP) decrease and yield. The imbalanced sharing of NPP between short-term human needs and maintenance of long-term ecosystem functions could compromise the ability of plantations to provide ecosystem services regulating climate, soil fertility, water, and nutrient cycles.
Co-regulatory activity of hnRNP K and NS1-BP in influenza and human mRNA splicing Nat. Commun. (IF 12.124) Pub Date : 2018-06-19 Matthew G. Thompson, Raquel Muñoz-Moreno, Prasanna Bhat, Renat Roytenberg, John Lindberg, Matthew R. Gazzara, Michael J. Mallory, Ke Zhang, Adolfo García-Sastre, Beatriz M. A. Fontoura, Kristen W. Lynch
Three of the eight RNA segments encoded by the influenza A virus (IAV) undergo alternative splicing to generate distinct proteins. Previously, we found that host proteins hnRNP K and NS1-BP regulate IAV M segment splicing, but the mechanistic details were unknown. Here we show NS1-BP and hnRNP K bind M mRNA downstream of the M2 5′ splice site (5′ss). NS1-BP binds most proximal to the 5′ss, partially overlapping the U1 snRNP binding site, while hnRNP K binds further downstream and promotes U1 snRNP recruitment. Mutation of either or both the hnRNP K and NS1-BP-binding sites results in M segment mis-splicing and attenuated IAV replication. Additionally, we show that hnRNP K and NS1-BP regulate host splicing events and that viral infection causes mis-splicing of some of these transcripts. Therefore, our proposed mechanism of hnRNP K/NS1-BP mediated IAV M splicing provides potential targets of antiviral intervention and reveals novel host functions for these proteins.
Nanoscale electrical conductivity imaging using a nitrogen-vacancy center in diamond Nat. Commun. (IF 12.124) Pub Date : 2018-06-19 Amila Ariyaratne, Dolev Bluvstein, Bryan A. Myers, Ania C. Bleszynski Jayich
The electrical conductivity of a material can feature subtle, non-trivial, and spatially varying signatures with critical insight into the material’s underlying physics. Here we demonstrate a conductivity imaging technique based on the atom-sized nitrogen-vacancy (NV) defect in diamond that offers local, quantitative, and non-invasive conductivity imaging with nanoscale spatial resolution. We monitor the spin relaxation rate of a single NV center in a scanning probe geometry to quantitatively image the magnetic fluctuations produced by thermal electron motion in nanopatterned metallic conductors. We achieve 40-nm scale spatial resolution of the conductivity and realize a 25-fold increase in imaging speed by implementing spin-to-charge conversion readout of a shallow NV center. NV-based conductivity imaging can probe condensed-matter systems in a new regime not accessible to existing technologies, and as a model example, we project readily achievable imaging of nanoscale phase separation in complex oxides.
Tailoring exciton and excimer emission in an exfoliated ultrathin 2D metal-organic framework Nat. Commun. (IF 12.124) Pub Date : 2018-06-19 Wei-Ming Liao, Jian-Hua Zhang, Shao-Yun Yin, He Lin, Xingmin Zhang, Jihong Wang, Hai-Ping Wang, Kai Wu, Zheng Wang, Ya-Nan Fan, Mei Pan, Cheng-Yong Su
Two-dimensional (2D) metal–organic frameworks have exhibited a range of fascinating attributes, of interest to numerous fields. Here, a calcium-based metal-organic framework with a 2D layered structure has been designed. Dual emissions relating to intralayer excimers and interlayer trapped excitons are produced, showing excitation-dependent shifting tendency, characteristic of a low dimensional semiconductor nature. Furthermore, the layer stacking by weak van der Waals forces among dynamically coordinated DMF molecules enables exfoliation and morphology transformation, which can be achieved by ultrasound in different ratios of DMF/H2O solvents, or grinding under appropriate humidity conditions, leading to nano samples including ultrathin nanosheets with single or few coordination layers. The cutting down of layer numbers engenders suppression of interlayer exciton-related emission, resulting in modulation of the overall emitting color and optical memory states. This provides a rare prototypical model with switchable dual-channel emissions based on 2D-MOFs, in which the interlayer excitation channel can be reversibly tuned on/off by top-down exfoliation and morphology transformation.
Neural mechanisms for selectively tuning in to the target speaker in a naturalistic noisy situation Nat. Commun. (IF 12.124) Pub Date : 2018-06-19 Bohan Dai, Chuansheng Chen, Yuhang Long, Lifen Zheng, Hui Zhao, Xialu Bai, Wenda Liu, Yuxuan Zhang, Li Liu, Taomei Guo, Guosheng Ding, Chunming Lu
The neural mechanism for selectively tuning in to a target speaker while tuning out the others in a multi-speaker situation (i.e., the cocktail-party effect) remains elusive. Here we addressed this issue by measuring brain activity simultaneously from a listener and from multiple speakers while they were involved in naturalistic conversations. Results consistently show selectively enhanced interpersonal neural synchronization (INS) between the listener and the attended speaker at left temporal–parietal junction, compared with that between the listener and the unattended speaker across different multi-speaker situations. Moreover, INS increases significantly prior to the occurrence of verbal responses, and even when the listener’s brain activity precedes that of the speaker. The INS increase is independent of brain-to-speech synchronization in both the anatomical location and frequency range. These findings suggest that INS underlies the selective process in a multi-speaker situation through neural predictions at the content level but not the sensory level of speech.
In situ architecture of the algal nuclear pore complex Nat. Commun. (IF 12.124) Pub Date : 2018-06-18 Shyamal Mosalaganti, Jan Kosinski, Sahradha Albert, Miroslava Schaffer, Daniela Strenkert, Patrice A. Salomé, Sabeeha S. Merchant, Jürgen M. Plitzko, Wolfgang Baumeister, Benjamin D. Engel, Martin Beck
Nuclear pore complexes (NPCs) span the nuclear envelope and mediate nucleocytoplasmic exchange. They are a hallmark of eukaryotes and deeply rooted in the evolutionary origin of cellular compartmentalization. NPCs have an elaborate architecture that has been well studied in vertebrates. Whether this architecture is unique or varies significantly in other eukaryotic kingdoms remains unknown, predominantly due to missing in situ structural data. Here, we report the architecture of the algal NPC from the early branching eukaryote Chlamydomonas reinhardtii and compare it to the human NPC. We find that the inner ring of the Chlamydomonas NPC has an unexpectedly large diameter, and the outer rings exhibit an asymmetric oligomeric state that has not been observed or predicted previously. Our study provides evidence that the NPC is subject to substantial structural variation between species. The divergent and conserved features of NPC architecture provide insights into the evolution of the nucleocytoplasmic transport machinery.
High-resolution crossover mapping reveals similarities and differences of male and female recombination in maize Nat. Commun. (IF 12.124) Pub Date : 2018-06-18 Penny M. A. Kianian, Minghui Wang, Kristin Simons, Farhad Ghavami, Yan He, Stefanie Dukowic-Schulze, Anitha Sundararajan, Qi Sun, Jaroslaw Pillardy, Joann Mudge, Changbin Chen, Shahryar F. Kianian, Wojciech P. Pawlowski
Meiotic crossovers (COs) are not uniformly distributed across the genome. Factors affecting this phenomenon are not well understood. Although many species exhibit large differences in CO numbers between sexes, sex-specific aspects of CO landscape are particularly poorly elucidated. Here, we conduct high-resolution CO mapping in maize. Our results show that CO numbers as well as their overall distribution are similar in male and female meioses. There are, nevertheless, dissimilarities at local scale. Male and female COs differ in their locations relative to transcription start sites in gene promoters and chromatin marks, including nucleosome occupancy and tri-methylation of lysine 4 of histone H3 (H3K4me3). Our data suggest that sex-specific factors not only affect male–female CO number disparities but also cause fine differences in CO positions. Differences between male and female CO landscapes indicate that recombination has distinct implications for population structure and gene evolution in male and in female meioses.
The 3.3 Å structure of a plant geminivirus using cryo-EM Nat. Commun. (IF 12.124) Pub Date : 2018-06-18 Emma L. Hesketh, Keith Saunders, Chloe Fisher, Joran Potze, John Stanley, George P. Lomonossoff, Neil A. Ranson
Geminiviruses are major plant pathogens that threaten food security globally. They have a unique architecture built from two incomplete icosahedral particles, fused to form a geminate capsid. However, despite their importance to agricultural economies and fundamental biological interest, the details of how this is realized in 3D remain unknown. Here we report the structure of Ageratum yellow vein virus at 3.3 Å resolution, using single-particle cryo-electron microscopy, together with an atomic model that shows that the N-terminus of the single capsid protein (CP) adopts three different conformations essential for building the interface between geminate halves. Our map also contains density for ~7 bases of single-stranded DNA bound to each CP, and we show that the interactions between the genome and CPs are different at the interface than in the rest of the capsid. With additional mutagenesis data, this suggests a central role for DNA binding-induced conformational change in directing the assembly of geminate capsids.
A CD4-mimetic compound enhances vaccine efficacy against stringent immunodeficiency virus challenge Nat. Commun. (IF 12.124) Pub Date : 2018-06-18 Navid Madani, Amy M. Princiotto, Linh Mach, Shilei Ding, Jérémie Prevost, Jonathan Richard, Bhavna Hora, Laura Sutherland, Connie A. Zhao, Brandon P. Conn, Todd Bradley, M. Anthony Moody, Bruno Melillo, Andrés Finzi, Barton F. Haynes, Amos B. Smith III, Sampa Santra, Joseph Sodroski
The envelope glycoprotein (Env) trimer ((gp120/gp41)3) mediates human immunodeficiency virus (HIV-1) entry into cells. The “closed,” antibody-resistant Env trimer is driven to more open conformations by binding the host receptor, CD4. Broadly neutralizing antibodies that recognize conserved elements of the closed Env are potentially protective, but are elicited inefficiently. HIV-1 has evolved multiple mechanisms to evade readily elicited antibodies against more open Env conformations. Small-molecule CD4-mimetic compounds (CD4mc) bind the HIV-1 gp120 Env and promote conformational changes similar to those induced by CD4, exposing conserved Env elements to antibodies. Here, we show that a CD4mc synergizes with antibodies elicited by monomeric HIV-1 gp120 to protect monkeys from multiple high-dose intrarectal challenges with a heterologous simian-human immunodeficiency virus (SHIV). The protective immune response persists for at least six months after vaccination. CD4mc should increase the protective efficacy of any HIV-1 Env vaccine that elicits antibodies against CD4-induced conformations of Env.
Global probabilistic projections of extreme sea levels show intensification of coastal flood hazard Nat. Commun. (IF 12.124) Pub Date : 2018-06-18 Michalis I. Vousdoukas, Lorenzo Mentaschi, Evangelos Voukouvalas, Martin Verlaan, Svetlana Jevrejeva, Luke P. Jackson, Luc Feyen
Global warming is expected to drive increasing extreme sea levels (ESLs) and flood risk along the world’s coastlines. In this work we present probabilistic projections of ESLs for the present century taking into consideration changes in mean sea level, tides, wind-waves, and storm surges. Between the year 2000 and 2100 we project a very likely increase of the global average 100-year ESL of 34–76 cm under a moderate-emission-mitigation-policy scenario and of 58–172 cm under a business as usual scenario. Rising ESLs are mostly driven by thermal expansion, followed by contributions from ice mass-loss from glaciers, and ice-sheets in Greenland and Antarctica. Under these scenarios ESL rise would render a large part of the tropics exposed annually to the present-day 100-year event from 2050. By the end of this century this applies to most coastlines around the world, implying unprecedented flood risk levels unless timely adaptation measures are taken.
PreDicta chip-based high resolution diagnosis of rhinovirus-induced wheeze Nat. Commun. (IF 12.124) Pub Date : 2018-06-18 Katarzyna Niespodziana, Katarina Stenberg-Hammar, Spyridon Megremis, Clarissa R. Cabauatan, Kamila Napora-Wijata, Phyllis C. Vacal, Daniela Gallerano, Christian Lupinek, Daniel Ebner, Thomas Schlederer, Christian Harwanegg, Cilla Söderhäll, Marianne van Hage, Gunilla Hedlin, Nikolaos G. Papadopoulos, Rudolf Valenta
Rhinovirus (RV) infections are major triggers of acute exacerbations of severe respiratory diseases such as pre-school wheeze, asthma and chronic obstructive pulmonary disease (COPD). The occurrence of numerous RV types is a major challenge for the identification of the culprit virus types and for the improvement of virus type-specific treatment strategies. Here, we develop a chip containing 130 different micro-arrayed RV proteins and peptides and demonstrate in a cohort of 120 pre-school children, most of whom had been hospitalized due to acute wheeze, that it is possible to determine the culprit RV species with a minute blood sample by serology. Importantly, we identify RV-A and RV-C species as giving rise to most severe respiratory symptoms. Thus, we have generated a chip for the serological identification of RV-induced respiratory illness which should be useful for the rational development of preventive and therapeutic strategies targeting the most important RV types.
The Wave2 scaffold Hem-1 is required for transition of fetal liver hematopoiesis to bone marrow Nat. Commun. (IF 12.124) Pub Date : 2018-06-18 Lijian Shao, Jianhui Chang, Wei Feng, Xiaoyan Wang, Elizabeth A. Williamson, Ying Li, Amir Schajnovitz, David Scadden, Luke J. Mortensen, Charles P. Lin, Linheng Li, Ariel Paulson, James Downing, Daohong Zhou, Robert A. Hromas
The transition of hematopoiesis from the fetal liver (FL) to the bone marrow (BM) is incompletely characterized. We demonstrate that the Wiskott–Aldrich syndrome verprolin-homologous protein (WAVE) complex 2 is required for this transition, as complex degradation via deletion of its scaffold Hem-1 causes the premature exhaustion of neonatal BM hematopoietic stem cells (HSCs). This exhaustion of BM HSC is due to the failure of BM engraftment of Hem-1−/− FL HSCs, causing early death. The Hem-1−/− FL HSC engraftment defect is not due to the lack of the canonical function of the WAVE2 complex, the regulation of actin polymerization, because FL HSCs from Hem-1−/− mice exhibit no defects in chemotaxis, BM homing, or adhesion. Rather, the failure of Hem-1−/− FL HSC engraftment in the marrow is due to the loss of c-Abl survival signaling from degradation of the WAVE2 complex. However, c-Abl activity is dispensable for the engraftment of adult BM HSCs into the BM. These findings reveal a novel function of the WAVE2 complex and define a mechanism for FL HSC fitness in the embryonic BM niche.
Yu–Shiba–Rusinov screening of spins in double quantum dots Nat. Commun. (IF 12.124) Pub Date : 2018-06-18 K. Grove-Rasmussen, G. Steffensen, A. Jellinggaard, M. H. Madsen, R. Žitko, J. Paaske, J. Nygård
A magnetic impurity coupled to a superconductor gives rise to a Yu–Shiba–Rusinov (YSR) state inside the superconducting energy gap. With increasing exchange coupling the excitation energy of this state eventually crosses zero and the system switches to a YSR ground state with bound quasiparticles screening the impurity spin by ħ/2. Here we explore indium arsenide (InAs) nanowire double quantum dots tunnel coupled to a superconductor and demonstrate YSR screening of spin-1/2 and spin-1 states. Gating the double dot through nine different charge states, we show that the honeycomb pattern of zero-bias conductance peaks, archetypal of double dots coupled to normal leads, is replaced by lines of zero-energy YSR states. These enclose regions of YSR-screened dot spins displaying distinctive spectral features, and their characteristic shape and topology change markedly with tunnel coupling strengths. We find excellent agreement with a simple zero-bandwidth approximation, and with numerical renormalization group calculations for the two-orbital Anderson model.
Biosynthesis of thiocarboxylic acid-containing natural products Nat. Commun. (IF 12.124) Pub Date : 2018-06-18 Liao-Bin Dong, Jeffrey D. Rudolf, Dingding Kang, Nan Wang, Cyndi Qixin He, Youchao Deng, Yong Huang, K. N. Houk, Yanwen Duan, Ben Shen
Thiocarboxylic acid-containing natural products are rare and their biosynthesis and biological significance remain unknown. Thioplatensimycin (thioPTM) and thioplatencin (thioPTN), thiocarboxylic acid congeners of the antibacterial natural products platensimycin (PTM) and platencin (PTN), were recently discovered. Here we report the biosynthetic origin of the thiocarboxylic acid moiety in thioPTM and thioPTN. We identify a thioacid cassette encoding two proteins, PtmA3 and PtmU4, responsible for carboxylate activation by coenzyme A and sulfur transfer, respectively. ThioPTM and thioPTN bind tightly to β-ketoacyl-ACP synthase II (FabF) and retain strong antibacterial activities. Density functional theory calculations of binding and solvation free energies suggest thioPTM and thioPTN bind to FabF more favorably than PTM and PTN. Additionally, thioacid cassettes are prevalent in the genomes of bacteria, implicating that thiocarboxylic acid-containing natural products are underappreciated. These results suggest that thiocarboxylic acid, as an alternative pharmacophore, and thiocarboxylic acid-containing natural products may be considered for future drug discovery.
Recurrent intragenic rearrangements of EGFR and BRAF in soft tissue tumors of infants Nat. Commun. (IF 12.124) Pub Date : 2018-06-18 Jenny Wegert, Christian Vokuhl, Grace Collord, Martin Del Castillo Velasco-Herrera, Sarah J. Farndon, Charlotte Guzzo, Mette Jorgensen, John Anderson, Olga Slater, Catriona Duncan, Sabrina Bausenwein, Heike Streitenberger, Barbara Ziegler, Rhoikos Furtwängler, Norbert Graf, Michael R. Stratton, Peter J. Campbell, David TW Jones, Christian Koelsche, Stefan M. Pfister, William Mifsud, Neil Sebire, Monika Sparber-Sauer, Ewa Koscielniak, Andreas Rosenwald, Manfred Gessler, Sam Behjati
Soft tissue tumors of infancy encompass an overlapping spectrum of diseases that pose unique diagnostic and clinical challenges. We studied genomes and transcriptomes of cryptogenic congenital mesoblastic nephroma (CMN), and extended our findings to five anatomically or histologically related soft tissue tumors: infantile fibrosarcoma (IFS), nephroblastomatosis, Wilms tumor, malignant rhabdoid tumor, and clear cell sarcoma of the kidney. A key finding is recurrent mutation of EGFR in CMN by internal tandem duplication of the kinase domain, thus delineating CMN from other childhood renal tumors. Furthermore, we identify BRAF intragenic rearrangements in CMN and IFS. Collectively these findings reveal novel diagnostic markers and therapeutic strategies and highlight a prominent role of isolated intragenic rearrangements as drivers of infant tumors.
Some contents have been Reproduced by permission of The Royal Society of Chemistry.
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