Microenvironmental niche divergence shapes BRCA1-dysregulated ovarian cancer morphological plasticity Nat. Commun. (IF 12.353) Pub Date : 2018-09-25 Andreas Heindl, Adnan Mujahid Khan, Daniel Nava Rodrigues, Katherine Eason, Anguraj Sadanandam, Cecilia Orbegoso, Marco Punta, Andrea Sottoriva, Stefano Lise, Susana Banerjee, Yinyin Yuan
How tumor microenvironmental forces shape plasticity of cancer cell morphology is poorly understood. Here, we conduct automated histology image and spatial statistical analyses in 514 high grade serous ovarian samples to define cancer morphological diversification within the spatial context of the microenvironment. Tumor spatial zones, where cancer cell nuclei diversify in shape, are mapped in each tumor. Integration of this spatially explicit analysis with omics and clinical data reveals a relationship between morphological diversification and the dysregulation of DNA repair, loss of nuclear integrity, and increased disease mortality. Within the Immunoreactive subtype, spatial analysis further reveals significantly lower lymphocytic infiltration within diversified zones compared with other tumor zones, suggesting that even immune-hot tumors contain cells capable of immune escape. Our findings support a model whereby a subpopulation of morphologically plastic cancer cells with dysregulated DNA repair promotes ovarian cancer progression through positive selection by immune evasion.
Predicting nutrient content of ray-finned fishes using phylogenetic information Nat. Commun. (IF 12.353) Pub Date : 2018-09-25 Bapu Vaitla, David Collar, Matthew R. Smith, Samuel S. Myers, Benjamin L. Rice, Christopher D. Golden
Human food and nutrition security is dependent on marine ecosystems threatened by overfishing, climate change, and other processes. The consequences on human nutritional status are uncertain, in part because current methods of analyzing fish nutrient content are expensive. Here, we evaluate the possibility of predicting nutrient content of ray-finned fishes using existing phylogenetic and life history information. We focus on nutrients for which fish are important sources: protein, total fat, omega-3 and omega-6 fatty acids, iron, zinc, vitamin A, vitamin B12, and vitamin D. Our results show that life history traits are weak predictors of species nutrient content, but phylogenetic relatedness is associated with similar nutrient profiles. Further, we develop a method for predicting the nutrient content of 7500+ species based on phylogenetic relationships to species with known nutrient content. Our approach is a cost-effective means for estimating potential changes in human nutrient intake associated with altered access to ray-finned fishes.
Lnk/Sh2b3 deficiency restores hematopoietic stem cell function and genome integrity in Fancd2 deficient Fanconi anemia Nat. Commun. (IF 12.353) Pub Date : 2018-09-25 Joanna Balcerek, Jing Jiang, Yang Li, Qinqin Jiang, Nicholas Holdreith, Brijendra Singh, Vemika Chandra, Kaosheng Lv, Jian-gang Ren, Krasimira Rozenova, Weihua Li, Roger A. Greenberg, Wei Tong
Fanconi anemia (FA) is a bone marrow failure (BMF) syndrome that arises from mutations in a network of FA genes essential for DNA interstrand crosslink (ICL) repair and replication stress tolerance. While allogeneic stem cell transplantation can replace defective HSCs, interventions to mitigate HSC defects in FA do not exist. Remarkably, we reveal here that Lnk (Sh2b3) deficiency restores HSC function in Fancd2−/− mice. Lnk deficiency does not impact ICL repair, but instead stabilizes stalled replication forks in a manner, in part, dependent upon alleviating blocks to cytokine−mediated JAK2 signaling. Lnk deficiency restores proliferation and survival of Fancd2−/− HSCs, while reducing replication stress and genomic instability. Furthermore, deletion of LNK in human FA-like HSCs promotes clonogenic growth. These findings highlight a new role for cytokine/JAK signaling in promoting replication fork stability, illuminate replication stress as a major underlying origin of BMF in FA, and have strong therapeutic implications.
Analysis of extracellular mRNA in human urine reveals splice variant biomarkers of muscular dystrophies Nat. Commun. (IF 12.353) Pub Date : 2018-09-25 Layal Antoury, Ningyan Hu, Leonora Balaj, Sudeshna Das, Sofia Georghiou, Basil Darras, Tim Clark, Xandra O. Breakefield, Thurman M. Wheeler
Urine contains extracellular RNA (exRNA) markers of urogenital cancers. However, the capacity of genetic material in urine to identify systemic diseases is unknown. Here we describe exRNA splice products in human urine as a source of biomarkers for the two most common forms of muscular dystrophies, myotonic dystrophy (DM) and Duchenne muscular dystrophy (DMD). Using a training set, RT-PCR, droplet digital PCR, and principal component regression, we identify ten transcripts that are spliced differently in urine exRNA from patients with DM type 1 (DM1) as compared to unaffected or disease controls, form a composite biomarker, and develop a predictive model that is 100% accurate in our independent validation set. Urine also contains mutation-specific DMD mRNAs that confirm exon-skipping activity of the antisense oligonucleotide drug eteplirsen. Our results establish that urine mRNA splice variants can be used to monitor systemic diseases with minimal or no clinical effect on the urinary tract.
A germanium hole spin qubit Nat. Commun. (IF 12.353) Pub Date : 2018-09-25 Hannes Watzinger, Josip Kukučka, Lada Vukušić, Fei Gao, Ting Wang, Friedrich Schäffler, Jian-Jun Zhang, Georgios Katsaros
Holes confined in quantum dots have gained considerable interest in the past few years due to their potential as spin qubits. Here we demonstrate two-axis control of a spin 3/2 qubit in natural Ge. The qubit is formed in a hut wire double quantum dot device. The Pauli spin blockade principle allowed us to demonstrate electric dipole spin resonance by applying a radio frequency electric field to one of the electrodes defining the double quantum dot. Coherent hole spin oscillations with Rabi frequencies reaching 140 MHz are demonstrated and dephasing times of 130 ns are measured. The reported results emphasize the potential of Ge as a platform for fast and electrically tunable hole spin qubit devices.
Human hippocampal replay during rest prioritizes weakly learned information and predicts memory performance Nat. Commun. (IF 12.353) Pub Date : 2018-09-25 Anna C. Schapiro, Elizabeth A. McDevitt, Timothy T. Rogers, Sara C. Mednick, Kenneth A. Norman
The hippocampus replays experiences during quiet rest periods, and this replay benefits subsequent memory. A critical open question is how memories are prioritized for this replay. We used functional magnetic resonance imaging (fMRI) pattern analysis to track item-level replay in the hippocampus during an awake rest period after participants studied 15 objects and completed a memory test. Objects that were remembered less well were replayed more during the subsequent rest period, suggesting a prioritization process in which weaker memories—memories most vulnerable to forgetting—are selected for replay. In a second session 12 hours later, more replay of an object during a rest period predicted better subsequent memory for that object. Replay predicted memory improvement across sessions only for participants who slept during that interval. Our results provide evidence that replay in the human hippocampus prioritizes weakly learned information, predicts subsequent memory performance, and relates to memory improvement across a delay with sleep.
Plasmodium co-infection protects against chikungunya virus-induced pathologies Nat. Commun. (IF 12.353) Pub Date : 2018-09-25 Teck-Hui Teo, Fok-Moon Lum, Khairunnisa Ghaffar, Yi-Hao Chan, Siti Naqiah Amrun, Jeslin J. L. Tan, Cheryl Y. P. Lee, Tze-Kwang Chua, Guillaume Carissimo, Wendy W. L. Lee, Carla Claser, Ravisankar Rajarethinam, Laurent Rénia, Lisa F. P. Ng
Co-infection with Plasmodium and chikungunya virus (CHIKV) has been reported in humans, but the impact of co-infection on pathogenesis remains unclear. Here, we show that prior exposure to Plasmodium suppresses CHIKV-associated pathologies in mice. Mechanistically, Plasmodium infection induces IFNγ, which reduces viraemia of a subsequent CHIKV infection and suppresses tissue viral load and joint inflammation. Conversely, concomitant infection with both pathogens limits the peak of joint inflammation with no effect on CHIKV viraemia. Reduced peak joint inflammation is regulated by elevated apoptosis of CD4+ T-cells in the lymph nodes and disrupted CXCR3-mediated CD4+ T-cell migration that abolishes their infiltration into the joints. Virus clearance from tissues is delayed in both infection scenarios, and is associated with a disruption of B cell affinity-maturation in the spleen that reduces CHIKV-neutralizing antibody production.
One-step generation of multiple gene knock-outs in the diatom Phaeodactylum tricornutum by DNA-free genome editing Nat. Commun. (IF 12.353) Pub Date : 2018-09-25 Manuel Serif, Gwendoline Dubois, Anne-Laure Finoux, Marie-Ange Teste, Denis Jallet, Fayza Daboussi
Recently developed transgenic techniques to explore and exploit the metabolic potential of microalgae present several drawbacks associated with the delivery of exogenous DNA into the cells and its subsequent integration at random sites within the genome. Here, we report a highly efficient multiplex genome-editing method in the diatom Phaeodactylum tricornutum, relying on the biolistic delivery of CRISPR-Cas9 ribonucleoproteins coupled with the identification of two endogenous counter-selectable markers, PtUMPS and PtAPT. First, we demonstrate the functionality of RNP delivery by positively selecting the disruption of each of these genes. Then, we illustrate the potential of the approach for multiplexing by generating double-gene knock-out strains, with 65% to 100% efficiency, using RNPs targeting one of these markers and PtAureo1a, a photoreceptor-encoding gene. Finally, we created triple knock-out strains in one step by delivering six RNP complexes into Phaeodactylum cells. This approach could readily be applied to other hard-to-transfect organisms of biotechnological interest.
Vibrio parahaemolyticus RhsP represents a widespread group of pro-effectors for type VI secretion systems Nat. Commun. (IF 12.353) Pub Date : 2018-09-25 Nan Jiang, Le Tang, Ruiqiang Xie, Zhi Li, Brianne Burkinshaw, Xiaoye Liang, Dylan Sosa, L. Aravind, Tao Dong, Dapeng Zhang, Jun Zheng
Type VI secretion systems (T6SSs) translocate effector proteins, such as Rhs toxins, to eukaryotic cells or prokaryotic competitors. All T6SS Rhs-type effectors characterized thus far contain a PAAR motif or a similar structure. Here, we describe a T6SS-dependent delivery mechanism for a subset of Rhs proteins that lack a PAAR motif. We show that the N-terminal Rhs domain of protein RhsP (or VP1517) from Vibrio parahaemolyticus inhibits the activity of the C-terminal DNase domain. Upon auto-proteolysis, the Rhs fragment remains inside the cells, and the C-terminal region interacts with PAAR2 and is secreted by T6SS2; therefore, RhsP acts as a pro-effector. Furthermore, we show that RhsP contributes to the control of certain “social cheaters” (opaR mutants). Genes encoding proteins with similar Rhs and PAAR-interacting domains, but diverse C-terminal regions, are widely distributed among Vibrio species.
Caspase-1 inhibition alleviates cognitive impairment and neuropathology in an Alzheimer’s disease mouse model Nat. Commun. (IF 12.353) Pub Date : 2018-09-25 Joseph Flores, Anastasia Noël, Bénédicte Foveau, Jeffrey Lynham, Clotilde Lecrux, Andréa C. LeBlanc
Alzheimer's disease (AD) is an intractable progressive neurodegenerative disease characterized by cognitive decline and dementia. An inflammatory neurodegenerative pathway, involving Caspase-1 activation, is associated with human age-dependent cognitive impairment and several classical AD brain pathologies. Here, we show that the nontoxic and blood–brain barrier permeable small molecule Caspase-1 inhibitor VX-765 dose-dependently reverses episodic and spatial memory impairment, and hyperactivity in the J20 mouse model of AD. Cessation of VX-765 results in the reappearance of memory deficits in the mice after 1 month and recommencement of treatment re-establishes normal cognition. VX-765 prevents progressive amyloid beta peptide deposition, reverses brain inflammation, and normalizes synaptophysin protein levels in mouse hippocampus. Consistent with these findings, Caspase-1 null J20 mice are protected from episodic and spatial memory deficits, neuroinflammation and Aβ accumulation. These results provide in vivo proof of concept for Caspase-1 inhibition against AD cognitive deficits and pathologies.
The evolution of multiple active site configurations in a designed enzyme Nat. Commun. (IF 12.353) Pub Date : 2018-09-25 Nan-Sook Hong, Dušan Petrović, Richmond Lee, Ganna Gryn’ova, Miha Purg, Jake Saunders, Paul Bauer, Paul D. Carr, Ching-Yeh Lin, Peter D. Mabbitt, William Zhang, Timothy Altamore, Chris Easton, Michelle L. Coote, Shina C. L. Kamerlin, Colin J. Jackson
Developments in computational chemistry, bioinformatics, and laboratory evolution have facilitated the de novo design and catalytic optimization of enzymes. Besides creating useful catalysts, the generation and iterative improvement of designed enzymes can provide valuable insight into the interplay between the many phenomena that have been suggested to contribute to catalysis. In this work, we follow changes in conformational sampling, electrostatic preorganization, and quantum tunneling along the evolutionary trajectory of a designed Kemp eliminase. We observe that in the Kemp Eliminase KE07, instability of the designed active site leads to the emergence of two additional active site configurations. Evolutionary conformational selection then gradually stabilizes the most efficient configuration, leading to an improved enzyme. This work exemplifies the link between conformational plasticity and evolvability and demonstrates that residues remote from the active sites of enzymes play crucial roles in controlling and shaping the active site for efficient catalysis.
Publisher Correction: Hypermethylation of gene body CpG islands predicts high dosage of functional oncogenes in liver cancer Nat. Commun. (IF 12.353) Pub Date : 2018-09-25 Maria Arechederra, Fabrice Daian, Annie Yim, Sehrish K. Bazai, Sylvie Richelme, Rosanna Dono, Andrew J. Saurin, Bianca H. Habermann, Flavio Maina
In the original version of this Article, the sixth sentence of the abstract incorrectly read ‘Most of the genes upregulated and with hypermethylated CGIs in the Alb-R26Met HCC model undergo the same change.’, and should have read ‘Most of the genes upregulated and with hypermethylated CGIs in the Alb-R26Met HCC model undergo the same change in a large proportion of HCC patients.’. This has been corrected in both the PDF and HTML versions of the Article.
Quantifying climate sensitivity and climate-driven change in North American amphibian communities Nat. Commun. (IF 12.353) Pub Date : 2018-09-25 David A. W. Miller, Evan H. Campbell Grant, Erin Muths, Staci M. Amburgey, Michael J. Adams, Maxwell B. Joseph, J. Hardin Waddle, Pieter T. J. Johnson, Maureen E. Ryan, Benedikt R. Schmidt, Daniel L. Calhoun, Courtney L. Davis, Robert N. Fisher, David M. Green, Blake R. Hossack, Tracy A. G. Rittenhouse, Susan C. Walls, Larissa L. Bailey, Sam S. Cruickshank, Gary M. Fellers, Thomas A. Gorman, Carola A. Haas, Ward Hughson, David S. Pilliod, Steven J. Price, Andrew M. Ray, Walt Sadinski, Daniel Saenz, William J. Barichivich, Adrianne Brand, Cheryl S. Brehme, Rosi Dagit, Katy S. Delaney, Brad M. Glorioso, Lee B. Kats, Patrick M. Kleeman, Christopher A. Pearl, Carlton J. Rochester, Seth P. D. Riley, Mark Roth, Brent H. Sigafus
Changing climate will impact species’ ranges only when environmental variability directly impacts the demography of local populations. However, measurement of demographic responses to climate change has largely been limited to single species and locations. Here we show that amphibian communities are responsive to climatic variability, using >500,000 time-series observations for 81 species across 86 North American study areas. The effect of climate on local colonization and persistence probabilities varies among eco-regions and depends on local climate, species life-histories, and taxonomic classification. We found that local species richness is most sensitive to changes in water availability during breeding and changes in winter conditions. Based on the relationships we measure, recent changes in climate cannot explain why local species richness of North American amphibians has rapidly declined. However, changing climate does explain why some populations are declining faster than others. Our results provide important insights into how amphibians respond to climate and a general framework for measuring climate impacts on species richness.
Lineage dynamics of murine pancreatic development at single-cell resolution Nat. Commun. (IF 12.353) Pub Date : 2018-09-25 Lauren E. Byrnes, Daniel M. Wong, Meena Subramaniam, Nathaniel P. Meyer, Caroline L. Gilchrist, Sarah M. Knox, Aaron D. Tward, Chun J. Ye, Julie B. Sneddon
Organogenesis requires the complex interactions of multiple cell lineages that coordinate their expansion, differentiation, and maturation over time. Here, we profile the cell types within the epithelial and mesenchymal compartments of the murine pancreas across developmental time using a combination of single-cell RNA sequencing, immunofluorescence, in situ hybridization, and genetic lineage tracing. We identify previously underappreciated cellular heterogeneity of the developing mesenchyme and reconstruct potential lineage relationships among the pancreatic mesothelium and mesenchymal cell types. Within the epithelium, we find a previously undescribed endocrine progenitor population, as well as an analogous population in both human fetal tissue and human embryonic stem cells differentiating toward a pancreatic beta cell fate. Further, we identify candidate transcriptional regulators along the differentiation trajectory of this population toward the alpha or beta cell lineages. This work establishes a roadmap of pancreatic development and demonstrates the broad utility of this approach for understanding lineage dynamics in developing organs.
Sex and species specific hearing mechanisms in mosquito flagellar ears Nat. Commun. (IF 12.353) Pub Date : 2018-09-25 Matthew P. Su, Marta Andrés, Nicholas Boyd-Gibbins, Jason Somers, Joerg T. Albert
Hearing is essential for the courtship of one of the major carriers of human disease, the mosquito. Males locate females through flight-tone recognition and both sexes engage in mid-air acoustic communications, which can take place within swarms containing thousands of individuals. Despite the importance of hearing for mosquitoes, its mechanisms are still largely unclear. We here report a multilevel analysis of auditory function across three disease-transmitting mosquitoes (Aedes aegypti, Anopheles gambiae and Culex quinquefasciatus). All ears tested display transduction-dependent power gain. Quantitative analyses of mechanotransducer function reveal sex-specific and species-specific variations, including male-specific, highly sensitive transducer populations. Systemic blocks of neurotransmission result in large-amplitude oscillations only in male flagellar receivers, indicating sexually dimorphic auditory gain control mechanisms. Our findings identify modifications of auditory function as a key feature in mosquito evolution. We propose that intra-swarm communication has been a driving force behind the observed sex-specific and species-specific diversity.
Systemic signaling contributes to the unfolded protein response of the plant endoplasmic reticulum Nat. Commun. (IF 12.353) Pub Date : 2018-09-25 Ya-Shiuan Lai, Giovanni Stefano, Starla Zemelis-Durfee, Cristina Ruberti, Lizzie Gibbons, Federica Brandizzi
The unfolded protein response (UPR) of the endoplasmic reticulum constitutes a conserved and essential cytoprotective pathway designed to survive biotic and abiotic stresses that alter the proteostasis of the endoplasmic reticulum. The UPR is typically considered cell-autonomous and it is yet unclear whether it can also act systemically through non-cell autonomous signaling. We have addressed this question using a genetic approach coupled with micro-grafting and a suite of molecular reporters in the model plant species Arabidopsis thaliana. We show that the UPR has a non-cell autonomous component, and we demonstrate that this is partially mediated by the intercellular movement of the UPR transcription factor bZIP60 facilitating systemic UPR signaling. Therefore, in multicellular eukaryotes such as plants, non-cell autonomous UPR signaling relies on the systemic movement of at least a UPR transcriptional modulator.
Fine mapping of MHC region in lung cancer highlights independent susceptibility loci by ethnicity Nat. Commun. (IF 12.353) Pub Date : 2018-09-25 Aida Ferreiro-Iglesias, Corina Lesseur, James McKay, Rayjean J. Hung, Younghun Han, Xuchen Zong, David Christiani, Mattias Johansson, Xiangjun Xiao, Yafang Li, David C. Qian, Xuemei Ji, Geoffrey Liu, Neil Caporaso, Ghislaine Scelo, David Zaridze, Anush Mukeriya, Milica Kontic, Simona Ognjanovic, Jolanta Lissowska, Małgorzata Szołkowska, Beata Swiatkowska, Vladimir Janout, Ivana Holcatova, Ciprian Bolca, Milan Savic, Miodrag Ognjanovic, Stig Egil Bojesen, Xifeng Wu, Demetrios Albanes, Melinda C. Aldrich, Adonina Tardon, Ana Fernandez-Somoano, Guillermo Fernandez-Tardon, Loic Le Marchand, Gadi Rennert, Chu Chen, Jennifer Doherty, Gary Goodman, Heike Bickeböller, H-Erich Wichmann, Angela Risch, Albert Rosenberger, Hongbing Shen, Juncheng Dai, John K. Field, Michael Davies, Penella Woll, M. Dawn Teare, Lambertus A. Kiemeney, Erik H. F. M. van der Heijden, Jian-Min Yuan, Yun-Chul Hong, Aage Haugen, Shanbeh Zienolddiny, Stephen Lam, Ming-Sound Tsao, Mikael Johansson, Kjell Grankvist, Matthew B. Schabath, Angeline Andrew, Eric Duell, Olle Melander, Hans Brunnström, Philip Lazarus, Susanne Arnold, Stacey Slone, Jinyoung Byun, Ahsan Kamal, Dakai Zhu, Maria Teresa Landi, Christopher I. Amos, Paul Brennan
The basis for associations between lung cancer and major histocompatibility complex genes is not completely understood. Here the authors further consider genetic variation within the MHC region in lung cancer patients and identify independent associations within HLA genes that explain MHC lung cancer associations in Europeans and Asian populations.
Neonatally imprinted stromal cell subsets induce tolerogenic dendritic cells in mesenteric lymph nodes Nat. Commun. (IF 12.353) Pub Date : 2018-09-25 Joern Pezoldt, Maria Pasztoi, Mangge Zou, Carolin Wiechers, Michael Beckstette, Guilhem R. Thierry, Ehsan Vafadarnejad, Stefan Floess, Panagiota Arampatzi, Manuela Buettner, Janina Schweer, Diana Fleissner, Marius Vital, Dietmar H. Pieper, Marijana Basic, Petra Dersch, Till Strowig, Mathias Hornef, André Bleich, Ulrike Bode, Oliver Pabst, Marc Bajénoff, Antoine-Emmanuel Saliba, Jochen Huehn
Gut-draining mesenteric lymph nodes (mLNs) are important for inducing peripheral tolerance towards food and commensal antigens by providing an optimal microenvironment for de novo generation of Foxp3+ regulatory T cells (Tregs). We previously identified microbiota-imprinted mLN stromal cells as a critical component in tolerance induction. Here we show that this imprinting process already takes place in the neonatal phase, and renders the mLN stromal cell compartment resistant to inflammatory perturbations later in life. LN transplantation and single-cell RNA-seq uncover stably imprinted expression signatures in mLN fibroblastic stromal cells. Subsetting common stromal cells across gut-draining mLNs and skin-draining LNs further refine their location-specific immunomodulatory functions, such as subset-specific expression of Aldh1a2/3. Finally, we demonstrate that mLN stromal cells shape resident dendritic cells to attain high Treg-inducing capacity in a Bmp2-dependent manner. Thus, crosstalk between mLN stromal and resident dendritic cells provides a robust regulatory mechanism for the maintenance of intestinal tolerance.
Simulation of slip transients and earthquakes in finite thickness shear zones with a plastic formulation Nat. Commun. (IF 12.353) Pub Date : 2018-09-25 Xinyue Tong, Luc L. Lavier
We perform numerical experiments of damped quasi-dynamic fault slip that include a rate-and-state behavior at steady state to simulate earthquakes and a plastic rheology to model permanent strain. The model shear zone has a finite width which represents a natural fault zone. Here we reproduce fast and slow events that follow theoretical and observational scaling relationships for earthquakes and slow slip events (SSEs). We show that the transition between fast and slow slip occurs when the friction drop in the shear zone is equal to a critical value, Δμc. With lower friction drops, SSEs use nearly all of mechanical work to accumulate inelastic strain, while with higher friction drops fast slips use some of the mechanical work to slip frictionally. Our new formulation replaces the state evolution of rate and state by the stress evolution concurrent with accumulation of permanent damage in and around a fault zone.
Patterns of polymorphism and selection in the subgenomes of the allopolyploid Arabidopsis kamchatica Nat. Commun. (IF 12.353) Pub Date : 2018-09-25 Timothy Paape, Roman V. Briskine, Gwyneth Halstead-Nussloch, Heidi E. L. Lischer, Rie Shimizu-Inatsugi, Masaomi Hatakeyama, Kenta Tanaka, Tomoaki Nishiyama, Renat Sabirov, Jun Sese, Kentaro K. Shimizu
Genome duplication is widespread in wild and crop plants. However, little is known about genome-wide selection in polyploids due to the complexity of duplicated genomes. In polyploids, the patterns of purifying selection and adaptive substitutions may be affected by masking owing to duplicated genes or homeologs as well as effective population size. Here, we resequence 25 accessions of the allotetraploid Arabidopsis kamchatica, which is derived from the diploid species A. halleri and A. lyrata. We observe a reduction in purifying selection compared with the parental species. Interestingly, proportions of adaptive non-synonymous substitutions are significantly positive in contrast to most plant species. A recurrent pattern observed in both frequency and divergence–diversity neutrality tests is that the genome-wide distributions of both subgenomes are similar, but the correlation between homeologous pairs is low. This may increase the opportunity of different evolutionary trajectories such as in the HMA4 gene involved in heavy metal hyperaccumulation.
An OB-fold complex controls the repair pathways for DNA double-strand breaks Nat. Commun. (IF 12.353) Pub Date : 2018-09-25 Shengxian Gao, Sumin Feng, Shaokai Ning, Jingyan Liu, Huayu Zhao, Yixi Xu, Jinfeng Shang, Kejiao Li, Qing Li, Rong Guo, Dongyi Xu
53BP1 with its downstream proteins, RIF1, PTIP and REV7, antagonizes BRCA1-dependent homologous recombination (HR) and promotes non-homologous end joining (NHEJ) in an unclear manner. Here we show that REV7 forms a complex with two proteins, FAM35A and C20ORF196. We demonstrate that FAM35A preferentially binds single-strand DNA (ssDNA) in vitro, and is recruited to DSBs as a complex with C20ORF196 and REV7 downstream of RIF1 in vivo. Epistasis analysis shows that both proteins act in the same pathway as RIF1 in NHEJ. The defects in HR pathway to repair DSBs and the reduction in resection of broken DNA ends in BRCA1-mutant cells can be largely suppressed by inactivating FAM35A or C20ORF196, indicating that FAM35A and C20ORF196 prevent end resection in these cells. Together, our data identified a REV7–FAM35A–C20ORF196 complex that binds and protects broken DNA ends to promote the NHEJ pathway for DSB repair.
Persistent repair intermediates induce senescence Nat. Commun. (IF 12.353) Pub Date : 2018-09-25 F. M. Feringa, J. A. Raaijmakers, M. A. Hadders, C. Vaarting, L. Macurek, L. Heitink, L. Krenning, R. H. Medema
Double-stranded DNA breaks activate a DNA damage checkpoint in G2 phase to trigger a cell cycle arrest, which can be reversed to allow for recovery. However, damaged G2 cells can also permanently exit the cell cycle, going into senescence or apoptosis, raising the question how an individual cell decides whether to recover or withdraw from the cell cycle. Here we find that the decision to withdraw from the cell cycle in G2 is critically dependent on the progression of DNA repair. We show that delayed processing of double strand breaks through HR-mediated repair results in high levels of resected DNA and enhanced ATR-dependent signalling, allowing p21 to rise to levels at which it drives cell cycle exit. These data imply that cells have the capacity to discriminate breaks that can be repaired from breaks that are difficult to repair at a time when repair is still ongoing.
Chirality amplification by desymmetrization of chiral ligand-capped nanoparticles to nanorods quantified in soft condensed matter Nat. Commun. (IF 12.353) Pub Date : 2018-09-25 Ahlam Nemati, Sasan Shadpour, Lara Querciagrossa, Lin Li, Taizo Mori, Min Gao, Claudio Zannoni, Torsten Hegmann
Induction, transmission, and manipulation of chirality in molecular systems are well known, widely applied concepts. However, our understanding of how chirality of nanoscale entities can be controlled, measured, and transmitted to the environment is considerably lacking behind. Future discoveries of dynamic assemblies engineered from chiral nanomaterials, with a specific focus on shape and size effects, require exact methods to assess transmission and amplification of nanoscale chirality through space. Here we present a remarkably powerful chirality amplification approach by desymmetrization of plasmonic nanoparticles to nanorods. When bound to gold nanorods, a one order of magnitude lower number of chiral molecules induces a tighter helical distortion in the surrounding liquid crystal–a remarkable amplification of chirality through space. The change in helical distortion is consistent with a quantification of the change in overall chirality of the chiral ligand decorated nanomaterials differing in shape and size as calculated from a suitable pseudoscalar chirality indicator.
LUBAC prevents lethal dermatitis by inhibiting cell death induced by TNF, TRAIL and CD95L Nat. Commun. (IF 12.353) Pub Date : 2018-09-25 Lucia Taraborrelli, Nieves Peltzer, Antonella Montinaro, Sebastian Kupka, Eva Rieser, Torsten Hartwig, Aida Sarr, Maurice Darding, Peter Draber, Tobias L. Haas, Ayse Akarca, Teresa Marafioti, Manolis Pasparakis, John Bertin, Peter J. Gough, Philippe Bouillet, Andreas Strasser, Martin Leverkus, John Silke, Henning Walczak
The linear ubiquitin chain assembly complex (LUBAC), composed of HOIP, HOIL-1 and SHARPIN, is required for optimal TNF-mediated gene activation and to prevent cell death induced by TNF. Here, we demonstrate that keratinocyte-specific deletion of HOIP or HOIL-1 (E-KO) results in severe dermatitis causing postnatal lethality. We provide genetic and pharmacological evidence that the postnatal lethal dermatitis in HoipE-KO and Hoil-1E-KO mice is caused by TNFR1-induced, caspase-8-mediated apoptosis that occurs independently of the kinase activity of RIPK1. In the absence of TNFR1, however, dermatitis develops in adulthood, triggered by RIPK1-kinase-activity-dependent apoptosis and necroptosis. Strikingly, TRAIL or CD95L can redundantly induce this disease-causing cell death, as combined loss of their respective receptors is required to prevent TNFR1-independent dermatitis. These findings may have implications for the treatment of patients with mutations that perturb linear ubiquitination and potentially also for patients with inflammation-associated disorders that are refractory to inhibition of TNF alone.
Skin color-specific and spectrally-selective naked-eye dosimetry of UVA, B and C radiations Nat. Commun. (IF 12.353) Pub Date : 2018-09-25 Wenyue Zou, Ana González, Deshetti Jampaiah, Rajesh Ramanathan, Mohammad Taha, Sumeet Walia, Sharath Sriram, Madhu Bhaskaran, José M. Dominguez-Vera, Vipul Bansal
Spectrally–selective monitoring of ultraviolet radiations (UVR) is of paramount importance across diverse fields, including effective monitoring of excessive solar exposure. Current UV sensors cannot differentiate between UVA, B, and C, each of which has a remarkably different impact on human health. Here we show spectrally selective colorimetric monitoring of UVR by developing a photoelectrochromic ink that consists of a multi-redox polyoxometalate and an e− donor. We combine this ink with simple components such as filter paper and transparency sheets to fabricate low-cost sensors that provide naked-eye monitoring of UVR, even at low doses typically encountered during solar exposure. Importantly, the diverse UV tolerance of different skin colors demands personalized sensors. In this spirit, we demonstrate the customized design of robust real-time solar UV dosimeters to meet the specific need of different skin phototypes. These spectrally–selective UV sensors offer remarkable potential in managing the impact of UVR in our day-to-day life.
Gender differences in individual variation in academic grades fail to fit expected patterns for STEM Nat. Commun. (IF 12.353) Pub Date : 2018-09-25 R. E. O’Dea, M. Lagisz, M. D. Jennions, S. Nakagawa
Fewer women than men pursue careers in science, technology, engineering and mathematics (STEM), despite girls outperforming boys at school in the relevant subjects. According to the ‘variability hypothesis’, this over-representation of males is driven by gender differences in variance; greater male variability leads to greater numbers of men who exceed the performance threshold. Here, we use recent meta-analytic advances to compare gender differences in academic grades from over 1.6 million students. In line with previous studies we find strong evidence for lower variation among girls than boys, and of higher average grades for girls. However, the gender differences in both mean and variance of grades are smaller in STEM than non-STEM subjects, suggesting that greater variability is insufficient to explain male over-representation in STEM. Simulations of these differences suggest the top 10% of a class contains equal numbers of girls and boys in STEM, but more girls in non-STEM subjects.
Loss of PRC1 induces higher-order opening of Hox loci independently of transcription during Drosophila embryogenesis Nat. Commun. (IF 12.353) Pub Date : 2018-09-25 Thierry Cheutin, Giacomo Cavalli
Polycomb-group proteins are conserved chromatin factors that maintain the silencing of key developmental genes, notably the Hox gene clusters, outside of their expression domains. Depletion of Polycomb repressive complex 1 (PRC1) proteins typically results in chromatin unfolding, as well as ectopic transcription. To disentangle these two phenomena, here we analyze the temporal function of two PRC1 proteins, Polyhomeotic (Ph) and Polycomb (Pc), on Hox gene clusters during Drosophila embryogenesis. We show that the absence of Ph or Pc affects the higher-order chromatin folding of Hox clusters prior to ectopic Hox gene transcription, demonstrating that PRC1 primary function during early embryogenesis is to compact its target chromatin. Moreover, the differential effects of Ph and Pc on Hox cluster folding match the differences in ectopic Hox gene expression observed in these two mutants. Our data suggest that PRC1 maintains gene silencing by folding chromatin domains and impose architectural layer to gene regulation.
RARα supports the development of Langerhans cells and langerin-expressing conventional dendritic cells Nat. Commun. (IF 12.353) Pub Date : 2018-09-25 Seika Hashimoto-Hill, Leon Friesen, Sungtae Park, Suji Im, Mark H. Kaplan, Chang H. Kim
Langerhans cells (LC) are the prototype langerin-expressing dendritic cells (DC) that reside specifically in the epidermis, but langerin-expressing conventional DCs also reside in the dermis and other tissues, yet the factors that regulate their development are unclear. Because retinoic acid receptor alpha (RARα) is highly expressed by LCs, we investigate the functions of RARα and retinoic acid (RA) in regulating the langerin-expressing DCs. Here we show that the development of LCs from embryonic and bone marrow-derived progenitors and langerin+ conventional DCs is profoundly regulated by the RARα-RA axis. During LC differentiation, RARα is required for the expression of a LC-promoting transcription factor Runx3, but suppresses that of LC-inhibiting C/EBPβ. RARα promotes the development of LCs and langerin+ conventional DCs only in hypo-RA conditions, a function effectively suppressed at systemic RA levels. Our findings identify positive and negative regulatory mechanisms to tightly regulate the development of the specialized DC populations.
An orbitally derived single-atom magnetic memory Nat. Commun. (IF 12.353) Pub Date : 2018-09-25 Brian Kiraly, Alexander N. Rudenko, Werner M. J. van Weerdenburg, Daniel Wegner, Mikhail I. Katsnelson, Alexander A. Khajetoorians
A magnetic atom epitomizes the scaling limit for magnetic information storage. Individual atomic spins have recently exhibited magnetic remanence, a requirement for magnetic memory. However, such memory has been only realized on thin insulating surfaces, removing potential tunability via electronic gating or exchange-driven magnetic coupling. Here, we show a previously unobserved mechanism for single-atom magnetic storage based on bistability in the orbital population, or so-called valency, of an individual Co atom on semiconducting black phosphorus (BP). Ab initio calculations reveal that distance-dependent screening from the BP surface stabilizes the two distinct valencies, each with a unique orbital population, total magnetic moment, and spatial charge density. Excellent correspondence between the measured and predicted charge densities reveal that such orbital configurations can be accessed and manipulated without a spin-sensitive readout mechanism. This orbital memory derives stability from the energetic barrier to atomic relaxation, demonstrating the potential for high-temperature single-atom information storage.
RNA editing derived epitopes function as cancer antigens to elicit immune responses Nat. Commun. (IF 12.353) Pub Date : 2018-09-25 Minying Zhang, Jens Fritsche, Jason Roszik, Leila J. Williams, Xinxin Peng, Yulun Chiu, Chih-Chiang Tsou, Franziska Hoffgaard, Valentina Goldfinger, Oliver Schoor, Amjad Talukder, Marie A. Forget, Cara Haymaker, Chantale Bernatchez, Leng Han, Yiu-Huen Tsang, Kathleen Kong, Xiaoyan Xu, Kenneth L. Scott, Harpreet Singh-Jasuja, Greg Lizee, Han Liang, Toni Weinschenk, Gordon B. Mills, Patrick Hwu
In addition to genomic mutations, RNA editing is another major mechanism creating sequence variations in proteins by introducing nucleotide changes in mRNA sequences. Deregulated RNA editing contributes to different types of human diseases, including cancers. Here we report that peptides generated as a consequence of RNA editing are indeed naturally presented by human leukocyte antigen (HLA) molecules. We provide evidence that effector CD8+ T cells specific for edited peptides derived from cyclin I are present in human tumours and attack tumour cells that are presenting these epitopes. We show that subpopulations of cancer patients have increased peptide levels and that levels of edited RNA correlate with peptide copy numbers. These findings demonstrate that RNA editing extends the classes of HLA presented self-antigens and that these antigens can be recognised by the immune system.
Functional modulation of primary visual cortex by the superior colliculus in the mouse Nat. Commun. (IF 12.353) Pub Date : 2018-09-25 Mehran Ahmadlou, Larry S. Zweifel, J. Alexander Heimel
The largest targets of retinal input in mammals are the dorsal lateral geniculate nucleus (dLGN), a relay to the primary visual cortex (V1), and the superior colliculus. V1 innervates and influences the superior colliculus. Here, we find that, in turn, superior colliculus modulates responses in mouse V1. Optogenetically inhibiting the superior colliculus reduces responses in V1 to optimally sized stimuli. Superior colliculus could influence V1 via its strong projection to the lateral posterior nucleus (LP/Pulvinar) or its weaker projection to the dLGN. Inhibiting superior colliculus strongly reduces activity in LP. Pharmacologically silencing LP itself, however, does not remove collicular modulation of V1. The modulation is instead due to a collicular gain modulation of the dLGN. Surround suppression operating in V1 explains the different effects for differently sized stimuli. Computations of visual saliency in the superior colliculus can thus influence tuning in the visual cortex via a tectogeniculate pathway.
Microglial dopamine receptor elimination defines sex-specific nucleus accumbens development and social behavior in adolescent rats Nat. Commun. (IF 12.353) Pub Date : 2018-09-25 Ashley M. Kopec, Caroline J. Smith, Nathan R. Ayre, Sean C. Sweat, Staci D. Bilbo
Adolescence is a developmental period in which the mesolimbic dopaminergic “reward” circuitry of the brain, including the nucleus accumbens (NAc), undergoes significant plasticity. Dopamine D1 receptors (D1rs) in the NAc are critical for social behavior, but how these receptors are regulated during adolescence is not well understood. In this report, we demonstrate that microglia and complement-mediated phagocytic activity shapes NAc development by eliminating D1rs in male, but not female rats, during adolescence. Moreover, immune-mediated elimination of D1rs is required for natural developmental changes in male social play behavior. These data demonstrate for the first time that microglia and complement-mediated immune signaling (i) participate in adolescent brain development in a sex-specific manner, and (ii) are causally implicated in developmental changes in behavior. These data have broad implications for understanding the adolescent critical period of development, the molecular mechanisms underlying social behavior, and sex differences in brain structure and function.
Cortical modulation of sensory flow during active touch in the rat whisker system Nat. Commun. (IF 12.353) Pub Date : 2018-09-25 Shubhodeep Chakrabarti, Cornelius Schwarz
Sensory gating, where responses to stimuli during sensor motion are reduced in amplitude, is a hallmark of active sensing systems. In the rodent whisker system, sensory gating has been described only at the thalamic and cortical stages of sensory processing. However, does sensory gating originate at an even earlier synaptic level? Most importantly, is sensory gating under top-down or bottom-up control? To address these questions, we used an active touch task in behaving rodents while recording from the trigeminal sensory nuclei. First, we show that sensory gating occurs in the brainstem at the first synaptic level. Second, we demonstrate that sensory gating is pathway-specific, present in the lemniscal but not in the extralemniscal stream. Third, using cortical lesions resulting in the complete abolition of sensory gating, we demonstrate its cortical dependence. Fourth, we show accompanying decreases in whisking-related activity, which could be the putative gating signal.
Estimating sources and sinks of malaria parasites in Madagascar Nat. Commun. (IF 12.353) Pub Date : 2018-09-25 Felana Angella Ihantamalala, Vincent Herbreteau, Feno M. J. Rakotoarimanana, Jean Marius Rakotondramanga, Simon Cauchemez, Bienvenue Rahoilijaona, Gwenaëlle Pennober, Caroline O. Buckee, Christophe Rogier, C. J. E. Metcalf, Amy Wesolowski
In areas where malaria epidemiology is spatially and temporally heterogeneous, human-mediated parasite importation can result in non-locally acquired clinical cases and outbreaks in low-transmission areas. Using mobility estimates derived from the mobile phone data and spatial malaria prevalence data, we identify travel routes relevant to malaria transmission in Madagascar. We find that the primary hubs of parasite importation are in a spatially connected area of the central highlands. Surprisingly, sources of these imported infections are not spatially clustered. We then related these source locations directly to clinical cases in the low-transmission area of the capital. We find that in the capital, a major sink, the primary sources of infection are along the more populated coastal areas, although these sources are seasonally variable. Our results have implications for targeting interventions at source locations to achieve local or national malaria control goals.
Single cell molecular alterations reveal target cells and pathways of concussive brain injury Nat. Commun. (IF 12.353) Pub Date : 2018-09-25 Douglas Arneson, Guanglin Zhang, Zhe Ying, Yumei Zhuang, Hyae Ran Byun, In Sook Ahn, Fernando Gomez-Pinilla, Xia Yang
The complex neuropathology of traumatic brain injury (TBI) is difficult to dissect, given the convoluted cytoarchitecture of affected brain regions such as the hippocampus. Hippocampal dysfunction during TBI results in cognitive decline that may escalate to other neurological disorders, the molecular basis of which is hidden in the genomic programs of individual cells. Using the unbiased single cell sequencing method Drop-seq, we report that concussive TBI affects previously undefined cell populations, in addition to classical hippocampal cell types. TBI also impacts cell type-specific genes and pathways and alters gene co-expression across cell types, suggesting hidden pathogenic mechanisms and therapeutic target pathways. Modulating the thyroid hormone pathway as informed by the T4 transporter transthyretin Ttr mitigates TBI-associated genomic and behavioral abnormalities. Thus, single cell genomics provides unique information about how TBI impacts diverse hippocampal cell types, adding new insights into the pathogenic pathways amenable to therapeutics in TBI and related disorders.
Using both qualitative and quantitative data in parameter identification for systems biology models Nat. Commun. (IF 12.353) Pub Date : 2018-09-25 Eshan D. Mitra, Raquel Dias, Richard G. Posner, William S. Hlavacek
In systems biology, qualitative data are often generated, but rarely used to parameterize models. We demonstrate an approach in which qualitative and quantitative data can be combined for parameter identification. In this approach, qualitative data are converted into inequality constraints imposed on the outputs of the model. These inequalities are used along with quantitative data points to construct a single scalar objective function that accounts for both datasets. To illustrate the approach, we estimate parameters for a simple model describing Raf activation. We then apply the technique to a more elaborate model characterizing cell cycle regulation in yeast. We incorporate both quantitative time courses (561 data points) and qualitative phenotypes of 119 mutant yeast strains (1647 inequalities) to perform automated identification of 153 model parameters. We quantify parameter uncertainty using a profile likelihood approach. Our results indicate the value of combining qualitative and quantitative data to parameterize systems biology models.
Author Correction: An intercross population study reveals genes associated with body size and plumage color in ducks Nat. Commun. (IF 12.353) Pub Date : 2018-09-25 Zhengkui Zhou, Ming Li, Hong Cheng, Wenlei Fan, Zhengrong Yuan, Qiang Gao, Yaxi Xu, Zhanbao Guo, Yunsheng Zhang, Jian Hu, Hehe Liu, Dapeng Liu, Weihuang Chen, Zhuqing Zheng, Yong Jiang, Zhiguo Wen, Yongming Liu, Hua Chen, Ming Xie, Qi Zhang, Wei Huang, Wen Wang, Shuisheng Hou, Yu Jiang
In the original version of this Article, there was an error in the legend for Figure 2, whereby the descriptions of panels a, b and c were presented in a different order to the corresponding figure panels. The text ‘a GWAS of duck plumage color, including 76 colored ducks and 30 white Pekin ducks. The gray horizontal dashed lines indicate the Bonferroni significance threshold of the GWAS (1 × 10−9). b Fixation index (FST) of all SNPs along chromosome 13 between mallards and Pekin ducks. Red dots indicate fixed SNPs. c The nucleotide diversity (π) of mallards (blue line) and Pekin ducks (red line) from 16.0 to 17.0 Mb on chromosome 13.’ should have read ‘a Fixation index (FST) of all SNPs along chromosome 13 between mallards and Pekin ducks. Red dots indicate fixed SNPs. b The nucleotide diversity (π) of mallards (blue line) and Pekin ducks (red line) from 16.0 to 17.0 Mb on chromosome 13. c GWAS of duck plumage color, including 76 colored ducks and 30 white Pekin ducks. The gray horizontal dashed lines indicate the Bonferroni significance threshold of the GWAS (1 × 10−9).’ This has been corrected in both the PDF and HTML versions of the Article.
Mapping of histone-binding sites in histone replacement-completed spermatozoa Nat. Commun. (IF 12.353) Pub Date : 2018-09-24 Keisuke Yoshida, Masafumi Muratani, Hiromitsu Araki, Fumihito Miura, Takehiro Suzuki, Naoshi Dohmae, Yuki Katou, Katsuhiko Shirahige, Takashi Ito, Shunsuke Ishii
The majority of histones are replaced by protamines during spermatogenesis, but small amounts are retained in mammalian spermatozoa. Since nucleosomes in spermatozoa influence epigenetic inheritance, it is important to know how histones are distributed in the sperm genome. Conflicting data, which may result from different conditions used for micrococcal nuclease (MNase) digestion, have been reported: retention of nucleosomes at either gene promoter regions or within distal gene-poor regions. Here, we find that the swim-up sperm used in many studies contain about 10% population of sperm which have not yet completed the histone-to-protamine replacement. We develop a method to purify histone replacement-completed sperm (HRCS) and to completely solubilize histones from cross-linked HRCS without MNase digestion. Our results indicate that histones are retained at specific promoter regions in HRCS. This method allows the study of epigenetic status in mature sperm.
Solution-processed perovskite light emitting diodes with efficiency exceeding 15% through additive-controlled nanostructure tailoring Nat. Commun. (IF 12.353) Pub Date : 2018-09-24 Muyang Ban, Yatao Zou, Jasmine P. H. Rivett, Yingguo Yang, Tudor H. Thomas, Yeshu Tan, Tao Song, Xingyu Gao, Dan Credington, Felix Deschler, Henning Sirringhaus, Baoquan Sun
Organometal halide perovskites (OHP) are promising materials for low-cost, high-efficiency light-emitting diodes. In films with a distribution of two-dimensional OHP nanosheets and small three-dimensional nanocrystals, an energy funnel can be realized that concentrates the excitations in highly efficient radiative recombination centers. However, this energy funnel is likely to contain inefficient pathways as the size distribution of nanocrystals, the phase separation between the OHP and the organic phase. Here, we demonstrate that the OHP crystallite distribution and phase separation can be precisely controlled by adding a molecule that suppresses crystallization of the organic phase. We use these improved material properties to achieve OHP light-emitting diodes with an external quantum efficiency of 15.5%. Our results demonstrate that through the addition of judiciously selected molecular additives, sufficient carrier confinement with first-order recombination characteristics, and efficient suppression of non-radiative recombination can be achieved while retaining efficient charge transport characteristics.
Microfluidic deposition for resolving single-molecule protein architecture and heterogeneity Nat. Commun. (IF 12.353) Pub Date : 2018-09-24 Francesco Simone Ruggeri, Jerome Charmet, Tadas Kartanas, Quentin Peter, Sean Chia, Johnny Habchi, Christopher M. Dobson, Michele Vendruscolo, Tuomas P. J. Knowles
Scanning probe microscopy provides a unique window into the morphology, mechanics, and structure of proteins and their complexes on the nanoscale. Such measurements require, however, deposition of samples onto substrates. This process can affect conformations and assembly states of the molecular species under investigation and can bias the molecular populations observed in heterogeneous samples through differential adsorption. Here, we show that these limitations can be overcome with a single-step microfluidic spray deposition platform. This method transfers biological solutions to substrates as microdroplets with subpicoliter volume, drying in milliseconds, a timescale that is shorter than typical diffusion times of proteins on liquid–solid interfaces, thus avoiding surface mass transport and change to the assembly state. Finally, the single-step deposition ensures the attachment of the full molecular content of the sample to the substrate, allowing quantitative measurements of different molecular populations within heterogeneous systems, including protein aggregates.
Acquired cancer resistance to combination immunotherapy from transcriptional loss of class I HLA Nat. Commun. (IF 12.353) Pub Date : 2018-09-24 K. G. Paulson, V. Voillet, M. S. McAfee, D. S. Hunter, F. D. Wagener, M. Perdicchio, W. J. Valente, S. J. Koelle, C. D. Church, N. Vandeven, H. Thomas, A. G. Colunga, J. G. Iyer, C. Yee, R. Kulikauskas, D. M. Koelle, R. H. Pierce, J. H. Bielas, P. D. Greenberg, S. Bhatia, R. Gottardo, P. Nghiem, A. G. Chapuis
Understanding mechanisms of late/acquired cancer immunotherapy resistance is critical to improve outcomes; cellular immunotherapy trials offer a means to probe complex tumor–immune interfaces through defined T cell/antigen interactions. We treated two patients with metastatic Merkel cell carcinoma with autologous Merkel cell polyomavirus specific CD8+ T cells and immune-checkpoint inhibitors. In both cases, dramatic remissions were associated with dense infiltration of activated CD8+s into the regressing tumors. However, late relapses developed at 22 and 18 months, respectively. Here we report single cell RNA sequencing identified dynamic transcriptional suppression of the specific HLA genes presenting the targeted viral epitope in the resistant tumor as a consequence of intense CD8-mediated immunologic pressure; this is distinguished from genetic HLA-loss by its reversibility with drugs. Transcriptional suppression of Class I loci may underlie resistance to other immunotherapies, including checkpoint inhibitors, and have implications for the design of improved immunotherapy treatments.
Electrical conductivity and magnetic dynamos in magma oceans of Super-Earths Nat. Commun. (IF 12.353) Pub Date : 2018-09-24 François Soubiran, Burkhard Militzer
Super-Earths are extremely common among the numerous exoplanets that have been discovered. The high pressures and temperatures in their interiors are likely to lead to long-lived magma oceans. If their electrical conductivity is sufficiently high, the mantles of Super-Earth would generate their own magnetic fields. With ab initio simulations, we show that upon melting, the behavior of typical mantle silicates changes from semi-conducting to semi-metallic. The electrical conductivity increases and the optical properties are substantially modified. Melting could thus be detected with high-precision reflectivity measurements during the short time scales of shock experiments. We estimate the electrical conductivity of mantle silicates to be of the order of 100 Ω−1 cm−1, which implies that a magnetic dynamo process would develop in the magma oceans of Super-Earths if their convective velocities have typical values of 1 mm/s or higher. We predict exoplanets with rotation periods longer than 2 days to have multipolar magnetic fields.
Towards exact molecular dynamics simulations with machine-learned force fields Nat. Commun. (IF 12.353) Pub Date : 2018-09-24 Stefan Chmiela, Huziel E. Sauceda, Klaus-Robert Müller, Alexandre Tkatchenko
Molecular dynamics (MD) simulations employing classical force fields constitute the cornerstone of contemporary atomistic modeling in chemistry, biology, and materials science. However, the predictive power of these simulations is only as good as the underlying interatomic potential. Classical potentials often fail to faithfully capture key quantum effects in molecules and materials. Here we enable the direct construction of flexible molecular force fields from high-level ab initio calculations by incorporating spatial and temporal physical symmetries into a gradient-domain machine learning (sGDML) model in an automatic data-driven way. The developed sGDML approach faithfully reproduces global force fields at quantum-chemical CCSD(T) level of accuracy and allows converged molecular dynamics simulations with fully quantized electrons and nuclei. We present MD simulations, for flexible molecules with up to a few dozen atoms and provide insights into the dynamical behavior of these molecules. Our approach provides the key missing ingredient for achieving spectroscopic accuracy in molecular simulations.
Gas-solid reaction based over one-micrometer thick stable perovskite films for efficient solar cells and modules Nat. Commun. (IF 12.353) Pub Date : 2018-09-24 Zonghao Liu, Longbin Qiu, Emilio J. Juarez-Perez, Zafer Hawash, Taehoon Kim, Yan Jiang, Zhifang Wu, Sonia R. Raga, Luis K. Ono, Shengzhong (Frank) Liu, Yabing Qi
Besides high efficiency, the stability and reproducibility of perovskite solar cells (PSCs) are also key for their commercialization. Herein, we report a simple perovskite formation method to fabricate perovskite films with thickness over 1 μm in ambient condition on the basis of the fast gas−solid reaction of chlorine-incorporated hydrogen lead triiodide and methylamine gas. The resultant thick and smooth chlorine-incorporated perovskite films exhibit full coverage, improved crystallinity, low surface roughness and low thickness variation. The resultant PSCs achieve an average power conversion efficiency of 19.1 ± 0.4% with good reproducibility. Meanwhile, this method enables an active area efficiency of 15.3% for 5 cm × 5 cm solar modules. The un-encapsulated PSCs exhibit an excellent T80 lifetime exceeding 1600 h under continuous operation conditions in dry nitrogen environment.
Spatiotemporal dynamics of homologous recombination repair at single collapsed replication forks Nat. Commun. (IF 12.353) Pub Date : 2018-09-24 Donna R. Whelan, Wei Ting C. Lee, Yandong Yin, Dylan M. Ofri, Keria Bermudez-Hernandez, Sarah Keegan, David Fenyo, Eli Rothenberg
Homologous recombination (HR) is a crucial pathway for the repair of DNA double-strand breaks. BRCA1/2 breast cancer proteins are key players in HR via their mediation of RAD51 nucleofilament formation and function; however, their individual roles and crosstalk in vivo are unknown. Here we use super-resolution (SR) imaging to map the spatiotemporal kinetics of HR proteins, revealing the interdependent relationships that govern the dynamic interplay and progression of repair events. We show that initial single-stranded DNA/RAD51 nucleofilament formation is mediated by RAD52 or, in the absence of RAD52, by BRCA2. In contrast, only BRCA2 can orchestrate later RAD51 recombinase activity during homology search and resolution. Furthermore, we establish that upstream BRCA1 activity is critical for BRCA2 function. Our analyses reveal the underlying epistatic landscape of RAD51 functional dependence on RAD52, BRCA1, and BRCA2 during HR and explain the phenotypic similarity of diseases associated with mutations in these proteins.
OCP–FRP protein complex topologies suggest a mechanism for controlling high light tolerance in cyanobacteria Nat. Commun. (IF 12.353) Pub Date : 2018-09-24 Nikolai N. Sluchanko, Yury B. Slonimskiy, Evgeny A. Shirshin, Marcus Moldenhauer, Thomas Friedrich, Eugene G. Maksimov
In cyanobacteria, high light photoactivates the orange carotenoid protein (OCP) that binds to antennae complexes, dissipating energy and preventing the destruction of the photosynthetic apparatus. At low light, OCP is efficiently deactivated by a poorly understood action of the dimeric fluorescence recovery protein (FRP). Here, we engineer FRP variants with defined oligomeric states and scrutinize their functional interaction with OCP. Complemented by disulfide trapping and chemical crosslinking, structural analysis in solution reveals the topology of metastable complexes of OCP and the FRP scaffold with different stoichiometries. Unable to tightly bind monomeric FRP, photoactivated OCP recruits dimeric FRP, which subsequently monomerizes giving 1:1 complexes. This could be facilitated by a transient OCP–2FRP–OCP complex formed via the two FRP head domains, significantly improving FRP efficiency at elevated OCP levels. By identifying key molecular interfaces, our findings may inspire the design of optically triggered systems transducing light signals into protein–protein interactions.
Identifying the missing link in catalyst transfer polymerization Nat. Commun. (IF 12.353) Pub Date : 2018-09-24 Weiying He, Brian O. Patrick, Pierre Kennepohl
Nickel-catalyzed catalyst transfer polycondensation (CTP) of thiophenes is an efficient strategy for the controlled synthesis of polythiophenes. However, a detailed view of its reaction mechanism has remained elusive with unresolved questions regarding the geometry and bonding of critical Ni(0) thiophene intermediates. Herein, we provide experimental and computational evidence of structurally characterized square planar η2-Ni(0)–thiophene species and their relevance to the mechanism of CTP. These results confirm the viability of C,C-η2 bound intermediates in CTP of thiophenes, providing an electronic rationale for the stability of such species, and thus that such processes can proceed as living polymerizations. We further show that C,S-κ2 species may also be relevant in nickel-catalyzed CTP of thiophenes, providing new avenues for exploitation and optimization.
Modulating the hierarchical fibrous assembly of Au nanoparticles with atomic precision Nat. Commun. (IF 12.353) Pub Date : 2018-09-24 Qi Li, Jake C. Russell, Tian-Yi Luo, Xavier Roy, Nathaniel L. Rosi, Yan Zhu, Rongchao Jin
The ability to modulate nanoparticle (NP) assemblies with atomic precision is still lacking, which hinders us from creating hierarchical NP organizations with desired properties. In this work, a hierarchical fibrous (1D to 3D) assembly of Au NPs (21-gold atom, Au21) is realized and further modulated with atomic precision via site-specific tailoring of the surface hook (composed of four phenyl-containing ligands with a counteranion). Interestingly, tailoring of the associated counterion significantly changes the electrical transport properties of the NP-assembled solids by two orders of magnitude due to the altered configuration of the interacting π–π pairs of the surface hooks. Overall, our success in atomic-level modulation of the hierarchical NP assembly directly evidences how the NP ligands and associated counterions can function to guide the 1D, 2D, and 3D hierarchical self-assembly of NPs in a delicate manner. This work expands nanochemists’ skills in rationally programming the hierarchical NP assemblies with controllable structures and properties.
Natural variation at XND1 impacts root hydraulics and trade-off for stress responses in Arabidopsis Nat. Commun. (IF 12.353) Pub Date : 2018-09-24 Ning Tang, Zaigham Shahzad, Fabien Lonjon, Olivier Loudet, Fabienne Vailleau, Christophe Maurel
Soil water uptake by roots is a key component of plant performance and adaptation to adverse environments. Here, we use a genome-wide association analysis to identify the XYLEM NAC DOMAIN 1 (XND1) transcription factor as a negative regulator of Arabidopsis root hydraulic conductivity (Lpr). The distinct functionalities of a series of natural XND1 variants and a single nucleotide polymorphism that determines XND1 translation efficiency demonstrate the significance of XND1 natural variation at species-wide level. Phenotyping of xnd1 mutants and natural XND1 variants show that XND1 modulates Lpr through action on xylem formation and potential indirect effects on aquaporin function and that it diminishes drought stress tolerance. XND1 also mediates the inhibition of xylem formation by the bacterial elicitor flagellin and counteracts plant infection by the root pathogen Ralstonia solanacearum. Thus, genetic variation at XND1, and xylem differentiation contribute to resolving the major trade-off between abiotic and biotic stress resistance in Arabidopsis.
Targeting PFKFB3 radiosensitizes cancer cells and suppresses homologous recombination Nat. Commun. (IF 12.353) Pub Date : 2018-09-24 Nina M. S. Gustafsson, Katarina Färnegårdh, Nadilly Bonagas, Anna Huguet Ninou, Petra Groth, Elisee Wiita, Mattias Jönsson, Kenth Hallberg, Jemina Lehto, Rosa Pennisi, Jessica Martinsson, Carina Norström, Jessica Hollers, Johan Schultz, Martin Andersson, Natalia Markova, Petra Marttila, Baek Kim, Martin Norin, Thomas Olin, Thomas Helleday
The glycolytic PFKFB3 enzyme is widely overexpressed in cancer cells and an emerging anti-cancer target. Here, we identify PFKFB3 as a critical factor in homologous recombination (HR) repair of DNA double-strand breaks. PFKFB3 rapidly relocates into ionizing radiation (IR)-induced nuclear foci in an MRN-ATM-γH2AX-MDC1-dependent manner and co-localizes with DNA damage and HR repair proteins. PFKFB3 relocalization is critical for recruitment of HR proteins, HR activity, and cell survival upon IR. We develop KAN0438757, a small molecule inhibitor that potently targets PFKFB3. Pharmacological PFKFB3 inhibition impairs recruitment of ribonucleotide reductase M2 and deoxynucleotide incorporation upon DNA repair, and reduces dNTP levels. Importantly, KAN0438757 induces radiosensitization in transformed cells while leaving non-transformed cells unaffected. In summary, we identify a key role for PFKFB3 enzymatic activity in HR repair and present KAN0438757, a selective PFKFB3 inhibitor that could potentially be used as a strategy for the treatment of cancer.
Neurogenetic profiles delineate large-scale connectivity dynamics of the human brain Nat. Commun. (IF 12.353) Pub Date : 2018-09-24 Ibai Diez, Jorge Sepulcre
Experimental and modeling work of neural activity has described recurrent and attractor dynamic patterns in cerebral microcircuits. However, it is still poorly understood whether similar dynamic principles exist or can be generalizable to the large-scale level. Here, we applied dynamic graph theory-based analyses to evaluate the dynamic streams of whole-brain functional connectivity over time across cognitive states. Dynamic connectivity in local networks is located in attentional areas during tasks and primary sensory areas during rest states, and dynamic connectivity in distributed networks converges in the default mode network (DMN) in both task and rest states. Importantly, we find that distinctive dynamic connectivity patterns are spatially associated with Allen Human Brain Atlas genetic transcription levels of synaptic long-term potentiation and long-term depression-related genes. Our findings support the neurobiological basis of large-scale attractor-like dynamics in the heteromodal cortex within the DMN, irrespective of cognitive state.
Maternal gut and breast milk microbiota affect infant gut antibiotic resistome and mobile genetic elements Nat. Commun. (IF 12.353) Pub Date : 2018-09-24 Katariina Pärnänen, Antti Karkman, Jenni Hultman, Christina Lyra, Johan Bengtsson-Palme, D. G. Joakim Larsson, Samuli Rautava, Erika Isolauri, Seppo Salminen, Himanshu Kumar, Reetta Satokari, Marko Virta
The infant gut microbiota has a high abundance of antibiotic resistance genes (ARGs) compared to adults, even in the absence of antibiotic exposure. Here we study potential sources of infant gut ARGs by performing metagenomic sequencing of breast milk, as well as infant and maternal gut microbiomes. We find that fecal ARG and mobile genetic element (MGE) profiles of infants are more similar to those of their own mothers than to those of unrelated mothers. MGEs in mothers’ breast milk are also shared with their own infants. Termination of breastfeeding and intrapartum antibiotic prophylaxis of mothers, which have the potential to affect microbial community composition, are associated with higher abundances of specific ARGs, the composition of which is largely shaped by bacterial phylogeny in the infant gut. Our results suggest that infants inherit the legacy of past antibiotic consumption of their mothers via transmission of genes, but microbiota composition still strongly impacts the overall resistance load.
Regulation of the terminal maturation of iNKT cells by mediator complex subunit 23 Nat. Commun. (IF 12.353) Pub Date : 2018-09-24 Yu Xu, Yang Sun, Hao Shen, Yuling Dai, Haifeng Liu, Ronghong Li, Hongdao Zhang, Ligang Wu, Xiaoyan Zhu, Xiaolong Liu
Invariant natural killer T cells (iNKT cells) are a specific subset of T cells that recognize glycolipid antigens and upon activation rapidly exert effector functions. This unique function is established during iNKT cell development; the detailed mechanisms of this process, however, remain to be elucidated. Here the authors show that deletion of the mediator subunit Med23 in CD4+CD8+ double positive (DP) thymocytes completely blocks iNKT cell development at stage 2. This dysregulation is accompanied by a bias in the expression of genes related to the regulation of transcription and metabolism, and functional impairment of the cells including the loss of NK cell characteristics, reduced ability to secrete cytokines and attenuated recruitment capacity upon activation. Moreover, Med23-deficient iNKT cells exhibit impaired anti-tumor activity. Our study identifies Med23 as an essential transcriptional regulator that controls iNKT cell differentiation and terminal maturation.
Circuit quantum electrodynamics of granular aluminum resonators Nat. Commun. (IF 12.353) Pub Date : 2018-09-24 N. Maleeva, L. Grünhaupt, T. Klein, F. Levy-Bertrand, O. Dupre, M. Calvo, F. Valenti, P. Winkel, F. Friedrich, W. Wernsdorfer, A. V. Ustinov, H. Rotzinger, A. Monfardini, M. V. Fistul, I. M. Pop
Granular aluminum (grAl) is a promising high kinetic inductance material for detectors, amplifiers, and qubits. Here we model the grAl structure, consisting of pure aluminum grains separated by thin aluminum oxide barriers, as a network of Josephson junctions, and we calculate the dispersion relation and nonlinearity (self-Kerr and cross-Kerr coefficients). To experimentally study the electrodynamics of grAl thin films, we measure microwave resonators with open-boundary conditions and test the theoretical predictions in two limits. For low frequencies, we use standard microwave reflection measurements in a low-loss environment. The measured low-frequency modes are in agreement with our dispersion relation model, and we observe self-Kerr coefficients within an order of magnitude from our calculation starting from the grAl microstructure. Using a high-frequency setup, we measure the plasma frequency of the film around 70 GHz, in agreement with the analytical prediction.
PAXX and its paralogs synergistically direct DNA polymerase λ activity in DNA repair Nat. Commun. (IF 12.353) Pub Date : 2018-09-24 Andrew Craxton, Deeksha Munnur, Rebekah Jukes-Jones, George Skalka, Claudia Langlais, Kelvin Cain, Michal Malewicz
PAXX is a recently identified component of the nonhomologous end joining (NHEJ) DNA repair pathway. The molecular mechanisms of PAXX action remain largely unclear. Here we characterise the interactomes of PAXX and its paralogs, XLF and XRCC4, to show that these factors share the ability to interact with DNA polymerase λ (Pol λ), stimulate its activity and are required for recruitment of Pol λ to laser-induced DNA damage sites. Stimulation of Pol λ activity by XRCC4 paralogs requires a direct interaction between the SP/8 kDa domain of Pol λ and their N-terminal head domains to facilitate recognition of the 5′ end of substrate gaps. Furthermore, PAXX and XLF collaborate with Pol λ to promote joining of incompatible DNA ends and are redundant in supporting Pol λ function in vivo. Our findings identify Pol λ as a novel downstream effector of PAXX function and show XRCC4 paralogs act in synergy to regulate polymerase activity in NHEJ.
Plant neighbor detection and allelochemical response are driven by root-secreted signaling chemicals Nat. Commun. (IF 12.353) Pub Date : 2018-09-24 Chui-Hua Kong, Song-Zhu Zhang, Yong-Hua Li, Zhi-Chao Xia, Xue-Fang Yang, Scott J. Meiners, Peng Wang
Plant neighbor detection and response strategies are important mediators of interactions among species. Despite increasing knowledge of neighbor detection and response involving plant volatiles, less is known about how soil-borne signaling chemicals may act belowground in plant–plant interactions. Here, we experimentally demonstrate neighbor detection and allelopathic responses between wheat and 100 other plant species via belowground signaling. Wheat can detect both conspecific and heterospecific neighbors and responds by increasing allelochemical production. Furthermore, we show that (-)-loliolide and jasmonic acid are present in root exudates from a diverse range of species and are able to trigger allelochemical production in wheat. These findings suggest that root-secreted (-)-loliolide and jasmonic acid are involved in plant neighbor detection and allelochemical response and may be widespread mediators of belowground plant-plant interactions.
Structure of Type-I Mycobacterium tuberculosis fatty acid synthase at 3.3 Å resolution Nat. Commun. (IF 12.353) Pub Date : 2018-09-24 Nadav Elad, Szilvia Baron, Yoav Peleg, Shira Albeck, Jacob Grunwald, Gal Raviv, Zippora Shakked, Oren Zimhony, Ron Diskin
Tuberculosis (TB) is a devastating and rapidly spreading disease caused by Mycobacterium tuberculosis (Mtb). Therapy requires prolonged treatment with a combination of multiple agents and interruptions in the treatment regimen result in emergence and spread of multi-drug resistant (MDR) Mtb strains. MDR Mtb poses a significant global health problem, calling for urgent development of novel drugs to combat TB. Here, we report the 3.3 Å resolution structure of the ~2 MDa type-I fatty acid synthase (FAS-I) from Mtb, determined by single particle cryo-EM. Mtb FAS-I is an essential enzymatic complex that contributes to the virulence of Mtb, and thus a prime target for anti-TB drugs. The structural information for Mtb FAS-I we have obtained enables computer-based drug discovery approaches, and the resolution achieved by cryo-EM is sufficient for elucidating inhibition mechanisms by putative small molecular weight inhibitors.
Griffithsin carrageenan fast dissolving inserts prevent SHIV HSV-2 and HPV infections in vivo Nat. Commun. (IF 12.353) Pub Date : 2018-09-24 Nina Derby, Manjari Lal, Meropi Aravantinou, Larisa Kizima, Patrick Barnable, Aixa Rodriguez, Manshun Lai, Asa Wesenberg, Shweta Ugaonkar, Keith Levendosky, Olga Mizenina, Kyle Kleinbeck, Jeffrey D. Lifson, M. Melissa Peet, Zachary Lloyd, Michael Benson, Walid Heneine, Barry R O’Keefe, Melissa Robbiani, Elena Martinelli, Brooke Grasperge, James Blanchard, Agegnehu Gettie, Natalia Teleshova, José A. Fernández-Romero, Thomas M. Zydowsky
Human immunodeficiency virus (HIV) pre-exposure prophylaxis (PrEP) strategies with proven in vivo efficacy rely on antiretroviral drugs, creating the potential for drug resistance and complicated treatment options in individuals who become infected. Moreover, on-demand products are currently missing from the PrEP development portfolio. Griffithsin (GRFT) is a non-antiretroviral HIV entry inhibitor derived from red algae with an excellent safety profile and potent activity in vitro. When combined with carrageenan (CG), GRFT has strong activity against herpes simplex virus-2 (HSV-2) and human papillomavirus (HPV) in vitro and in vivo. Here, we report that GRFT/CG in a freeze-dried fast dissolving insert (FDI) formulation for on-demand use protects rhesus macaques from a high dose vaginal SHIV SF162P3 challenge 4 h after FDI insertion. Furthermore, the GRFT/CG FDI also protects mice vaginally against HSV-2 and HPV pseudovirus. As a safe, potent, broad-spectrum, on-demand non-antiretroviral product, the GRFT/CG FDI warrants clinical development.
Contrasting effects on deep convective clouds by different types of aerosols Nat. Commun. (IF 12.353) Pub Date : 2018-09-24 Jonathan H. Jiang, Hui Su, Lei Huang, Yuan Wang, Steven Massie, Bin Zhao, Ali Omar, Zhien Wang
Convective clouds produce a significant proportion of the global precipitation and play an important role in the energy and water cycles. We quantify changes of the convective cloud ice mass-weighted altitude centroid (ZIWC) as a function of aerosol optical thickness (AOT). Analyses are conducted in smoke, dust and polluted continental aerosol environments over South America, Central Africa and Southeast Asia, using the latest measurements from the CloudSat and CALIPSO satellites. We find aerosols can inhibit or invigorate convection, depending on aerosol type and concentration. On average, smoke tends to suppress convection and results in lower ZIWC than clean clouds. Polluted continental aerosol tends to invigorate convection and promote higher ZIWC. The dust aerosol effects are regionally dependent and their signs differ from place to place. Moreover, we find that the aerosol inhibition or invigoration effects do not vary monotonically with AOT and the variations depend strongly on aerosol type. Our observational findings indicate that aerosol type is one of the key factors in determining the aerosol effects on convective clouds.
A room-temperature sodium–sulfur battery with high capacity and stable cycling performance Nat. Commun. (IF 12.353) Pub Date : 2018-09-24 Xiaofu Xu, Dong Zhou, Xianying Qin, Kui Lin, Feiyu Kang, Baohua Li, Devaraj Shanmukaraj, Teofilo Rojo, Michel Armand, Guoxiu Wang
High-temperature sodium–sulfur batteries operating at 300–350 °C have been commercially applied for large-scale energy storage and conversion. However, the safety concerns greatly inhibit their widespread adoption. Herein, we report a room-temperature sodium–sulfur battery with high electrochemical performances and enhanced safety by employing a “cocktail optimized” electrolyte system, containing propylene carbonate and fluoroethylene carbonate as co-solvents, highly concentrated sodium salt, and indium triiodide as an additive. As verified by first-principle calculation and experimental characterization, the fluoroethylene carbonate solvent and high salt concentration not only dramatically reduce the solubility of sodium polysulfides, but also construct a robust solid-electrolyte interface on the sodium anode upon cycling. Indium triiodide as redox mediator simultaneously increases the kinetic transformation of sodium sulfide on the cathode and forms a passivating indium layer on the anode to prevent it from polysulfide corrosion. The as-developed sodium–sulfur batteries deliver high capacity and long cycling stability.
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