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| Open AccessImmunotherapy with engineered bacteria by targeting the STING pathway for anti-tumor immunity
Synthetic biology can be used to create rationally designed living therapeutics. Here the authors engineer E. coli Nissle to target STING activation in antigen presenting cells for the treatment of solid tumors and demonstrate preclinical activity in murine models.
- Daniel S. Leventhal
- , Anna Sokolovska
- & Jose M. Lora
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Article
| Open AccessThe central amygdala recruits mesocorticolimbic circuitry for pursuit of reward or pain
Brain disorders can create maladaptive attractions, such as in addiction or self-harming. Here the authors use multiple valence modes of the central amygdala to create such attractions, arbitrarily making rats into ‘sucrose addicts' or ‘cocaine addicts', or causing maladaptive attraction to shocks.
- Shelley M. Warlow
- , Erin E. Naffziger
- & Kent C. Berridge
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Article
| Open AccessMachine learning uncovers cell identity regulator by histone code
Identification of genes that determine and regulate cell identity remains challenging. Here, the authors use machine learning to identify cell identity genes and master regulator transcription factors based on gene expression profiles and histone modifications.
- Bo Xia
- , Dongyu Zhao
- & Kaifu Chen
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Article
| Open AccessModel-based analysis of sample index hopping reveals its widespread artifacts in multiplexed single-cell RNA-sequencing
Sample index hopping results in various artefacts in multiplexed scRNA-seq experiments. Here, the authors introduce a statistical model to estimate sample index hopping rate in droplet-based scRNA-seq data and show that artifacts can be corrected by purging phantom molecules from the data.
- Rick Farouni
- , Haig Djambazian
- & Hamed S. Najafabadi
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Article
| Open AccessCo-evolution of primitive methane-cycling ecosystems and early Earth’s atmosphere and climate
Biology can profoundly influence the planet’s climate, but over Earth’s long history these effects are poorly constrained. Here the authors show that on early Earth, the evolution of microbes producing and consuming methane likely controlled warming and glacial events, and thus Earth’s habitability
- Boris Sauterey
- , Benjamin Charnay
- & Régis Ferrière
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Article
| Open AccessAnalysis of immune, microbiota and metabolome maturation in infants in a clinical trial of Lactobacillus paracasei CBA L74-fermented formula
Milk breastfeeding and prebiotic-supplemented formulas have varying effects on the infant gut microbiome. Here, in a randomized controlled clinical trial, the authors investigate the effects of a Lactobacillus paracasei-fermented formula on the immune defense mechanisms, microbiota and its metabolome in full term infants.
- Paola Roggero
- , Nadia Liotto
- & Maria Rescigno
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Article
| Open AccessThe TSPO-NOX1 axis controls phagocyte-triggered pathological angiogenesis in the eye
Age-related macular degeneration (AMD) is a major cause of blindness in the elderly. Here, the authors show that microglia-specific deletion of TSPO and chemical inhibition of TSPO prevent neuroinflammation and vascular damage in a mouse model of AMD.
- Anne Wolf
- , Marc Herb
- & Thomas Langmann
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Article
| Open AccessUrbanization and agricultural intensification destabilize animal communities differently than diversity loss
Environmental change and species diversity could jointly affect the stability of animal communities. Here the authors use citizen science data on bats, birds, and butterflies along urbanization and agricultural intensification gradients in France to show that both environmental change and diversity loss destabilise communities, but in different ways.
- Théophile Olivier
- , Elisa Thébault
- & Colin Fontaine
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Article
| Open AccessInformation can explain the dynamics of group order in animal collective behaviour
In animal groups, the degree of alignment of individuals could have different benefits and costs for individuals depending on their reliance on private or social information. Here the authors show that in shoals of three-spined sticklebacks, some individuals reach resources faster when groups are disordered, a state which favours reliance on privately acquired information, while other individuals reach resources faster when groups are ordered, allowing them to exploit social information more effectively.
- Hannah E. A. MacGregor
- , James E. Herbert-Read
- & Christos C. Ioannou
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Article
| Open AccessTriggering typical nemaline myopathy with compound heterozygous nebulin mutations reveals myofilament structural changes as pathomechanism
Nebulin-based nemaline myopathy is a heterogenous disease with unclear pathological mechanisms. Here, the authors generate a mouse model that mimics the most common genetic cause of the disease and demonstrate that muscle weakness in this model is associated with twisted actin filaments and altered tropomyosin and troponin behaviour.
- Johan Lindqvist
- , Weikang Ma
- & Henk Granzier
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Article
| Open AccessFunctional reconstruction of injured corpus cavernosa using 3D-printed hydrogel scaffolds seeded with HIF-1α-expressing stem cells
Injury of corpus cavernosa results in erectile dysfunction, and repair leading to restoration of function is difficult. Here the authors construct 3D printed hydrogel constructs seeded with HIF-1α-expressing muscle derived stem cells to restore corpus function in a rabbit model.
- Geng An
- , Feixiang Guo
- & Chuanbin Mao
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Article
| Open AccessSkeletal muscle enhancer interactions identify genes controlling whole-body metabolism
Obesity and type 2 diabetes (T2D) are metabolic disorders characterized by insulin resistance in skeletal muscle. Here, the authors map skeletal muscle enhancer elements dynamically regulated after exposure to free fatty acid palmitate or inflammatory cytokine TNFα and identify target genes involved in metabolic dysfunction in skeletal muscle.
- Kristine Williams
- , Lars R. Ingerslev
- & Romain Barrès
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Article
| Open AccessDetection of air and surface contamination by SARS-CoV-2 in hospital rooms of infected patients
Here, the authors sample air and surfaces in hospital rooms of COVID-19 patients, detect SARS-CoV-2 RNA in air samples of two of three tested airborne infection isolation rooms, and find surface contamination in 66.7% of tested rooms during the first week of illness and 20% beyond the first week of illness.
- Po Ying Chia
- , Kristen Kelli Coleman
- & Daniela Moses
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Article
| Open AccessTrophic innovations fuel reef fish diversification
Both geography and ecology can drive the origins of new species. Siqueira et al. show how geological changes in the structure of Miocene reefs and the concurrent evolution of new feeding strategies combine to explain why coral reefs contain such a diversity of fish species.
- Alexandre C. Siqueira
- , Renato A. Morais
- & Peter F. Cowman
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Article
| Open AccessA genome-scale map of DNA methylation turnover identifies site-specific dependencies of DNMT and TET activity
Local activity of the DNA methylation machinery remains poorly understood. Here, the authors present a theoretical and experimental framework to infer methylation and demethylation rates at genome scale in mouse embryonic stem cells, finding that maintenance methylation activity is reduced at transcription factor binding sites, while methylation turnover is elevated in transcribed gene bodies.
- Paul Adrian Ginno
- , Dimos Gaidatzis
- & Dirk Schübeler
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Article
| Open AccessTRPV4 disrupts mitochondrial transport and causes axonal degeneration via a CaMKII-dependent elevation of intracellular Ca2+
Mutations in the TRPV4 channel cause inherited neurodegeneration syndromes, but the molecular mechanisms are unknown. Here the authors reveal that TRPV4 activation causes dose-dependent, CaMKII-mediated neuronal dysfunction and axonal degeneration via disruption of mitochondrial axonal transport.
- Brian M. Woolums
- , Brett A. McCray
- & Thomas E. Lloyd
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Article
| Open AccessThe netrin receptor UNC-40/DCC assembles a postsynaptic scaffold and sets the synaptic content of GABAA receptors
The netrin receptor UNC-40/DCC is required to recruit GABAAR at neuromuscular junctions in C. elegans. Here, the authors show that UNC-40/DCC assembles an intracellular synaptic scaffold, regulating the content of GABAAR and inhibitory neurotransmission.
- Xin Zhou
- , Marine Gueydan
- & Jean-Louis Bessereau
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Article
| Open AccessHuman ESCRT-III polymers assemble on positively curved membranes and induce helical membrane tube formation
ESCRT-III complexes assemble in vivo inside membrane structures with a negative Gaussian curvature, but how membrane shape influences ESCRT-III polymerization remains unclear. Here authors use structural and biophysical methods to show how human ESCRT-III polymers assemble on positively curved membranes and induce helical membrane tube formation.
- Aurélie Bertin
- , Nicola de Franceschi
- & Patricia Bassereau
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Article
| Open AccessStructural insight into the electron transfer pathway of a self-sufficient P450 monooxygenase
Self-sufficient cytochrome P450 monooxygenases, which contain all redox partners in a single polypeptide chain, are of interest for biotechnological applications. Here, the authors present the crystal structure of full-length Thermobispora bispora CYP116B46 and discuss the potential electron transfer pathway.
- Lilan Zhang
- , Zhenzhen Xie
- & Chun-Chi Chen
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Article
| Open AccessISG15 and ISGylation is required for pancreatic cancer stem cell mitophagy and metabolic plasticity
The ubiquitin-like modifier ISG15 exerts post-translational protein regulation through ISGylation. Here, the authors show that ISGylation is necessary for pancreatic cancer stem cell self-renewal and tumourigenesis by supporting the recycling of non-functional mitochondria.
- Sonia Alcalá
- , Patricia Sancho
- & Bruno Sainz Jr
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Article
| Open AccessAnisotropic ESCRT-III architecture governs helical membrane tube formation
ESCRT-III proteins assemble into ubiquitous membrane-remodeling polymers during many cellular processes. Here, the authors use cryo-ET, cryo-EM and mathematical modeling to reveal how the shape of the helical membrane tube arises from the assembly of two distinct bundles of helical filaments.
- Joachim Moser von Filseck
- , Luca Barberi
- & Aurélien Roux
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Article
| Open AccessA network of RNA-binding proteins controls translation efficiency to activate anaerobic metabolism
mRNA translation efficiency is regulated in response to stimuli. Here the authors employ mass spectrometry analysis of ribosome fractions and show that under hypoxia, oxygen-sensitive RNA binding proteins enhance the translation efficiency of glycolysis pathway transcripts.
- J. J. David Ho
- , Nathan C. Balukoff
- & Stephen Lee
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Article
| Open AccessWeaker neural suppression in autism
Sensory hypersensitivity is common in autism spectrum disorders. Using functional MRI, psychophysics, and computational modeling, Schallmo et al. show that differences in visual motion perception in ASD are accompanied by weaker neural suppression in visual cortex.
- Michael-Paul Schallmo
- , Tamar Kolodny
- & Scott O. Murray
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Article
| Open AccessEvolution and structure of clinically relevant gene fusions in multiple myeloma
Multiple myeloma is characterised by frequent gene fusions. Here, the authors use data from the Multiple Myeloma Research Foundation CoMMpass Study to further investigate fusion genes in this disease and their clinical relevance.
- Steven M. Foltz
- , Qingsong Gao
- & Ravi Vij
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Article
| Open AccessHomologous recombination DNA repair deficiency and PARP inhibition activity in primary triple negative breast cancer
Defects in homologous recombination (HR) are found in some triple negative breast cancers, suggesting they may be sensitive to PARP inhibitors. In this phase II clinical trial of the PARP inhibitor rucaparib, changes in Ki67 levels did not correlate with markers of HR deficiency but HR deficiency was detected in 69% of tumours, indicating that PARP inhibitors may be a useful treatment.
- Neha Chopra
- , Holly Tovey
- & Nicholas C. Turner
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Article
| Open AccessThe neuropeptide substance P regulates aldosterone secretion in human adrenals
Adrenal aldosterone production is regulated by plasma angiotensin and potassium levels. Here the authors report that the neuropeptide substance P stimulates aldosterone production via neurokinin type 1 receptors (NK1R), and report a proof-of-concept placebo controlled clinical trial showing that a NK1R antagonist decreases aldosterone levels.
- Julien Wils
- , Céline Duparc
- & Hervé Lefebvre
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Article
| Open AccessLandscape of multi-nucleotide variants in 125,748 human exomes and 15,708 genomes
Multi-nucleotide variants (MNV) are genetic variants in close proximity of each other on the same haplotype whose functional impact is difficult to predict if they reside in the same codon. Here, Wang et al. use the gnomAD dataset to assemble a catalogue of MNVs and estimate their global mutation rate.
- Qingbo Wang
- , Emma Pierce-Hoffman
- & Daniel G. MacArthur
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Article
| Open AccessHigh-resolution annotation of the mouse preimplantation embryo transcriptome using long-read sequencing
Until now, the transcriptome of preimplantation mouse embryos has only been analysed by short-read sequencing. Here, the authors perform long-read sequencing to provide a more detailed transcriptome of the preimplantation mouse embryo, identifying various novel transcripts, for example Kdm4dl.
- Yunbo Qiao
- , Chao Ren
- & Wenjie Shu
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Article
| Open AccessCharacterising the loss-of-function impact of 5’ untranslated region variants in 15,708 individuals
Upstream open reading frames (uORFs), located in 5’ untranslated regions, are regulators of downstream protein translation. Here, Whiffin et al. use the genomes of 15,708 individuals in the Genome Aggregation Database (gnomAD) to systematically assess the deleteriousness of variants creating or disrupting uORFs.
- Nicola Whiffin
- , Konrad J. Karczewski
- & James S. Ware
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Article
| Open AccesshnRNP H/F drive RNA G-quadruplex-mediated translation linked to genomic instability and therapy resistance in glioblastoma
RNA G-quadruplexes (RG4s) have been functionally linked to cancer gene expression. Here, Herviou, Le Bras et al. have identified the protein machinery modulating RG4s and reveal the role and mechanism of hnRNP H/F and DHX36 in RG4-mediated translational regulation affecting cancer treatment in glioblastoma.
- Pauline Herviou
- , Morgane Le Bras
- & Stefania Millevoi
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Article
| Open AccessGenome and single-cell RNA-sequencing of the earthworm Eisenia andrei identifies cellular mechanisms underlying regeneration
The mechanisms regulating regeneration of the earthworm are unclear. Here, the authors use genomic and transcriptomic analysis of the earthworm Eisenia andrei together with Hi-C analysis to identify genes involved and show activation of LINE2 transposable elements on regeneration.
- Yong Shao
- , Xiao-Bo Wang
- & Dong-Dong Wu
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Article
| Open AccessHippocampal seed connectome-based modeling predicts the feeling of stress
Although the feeling of being stressed is ubiquitous and clinically significant, the underlying neural mechanisms are unclear. Using a novel predictive modeling approach, the authors show that functional hippocampal networks specifically and consistently predict the feeling of stress.
- Elizabeth V. Goldfarb
- , Monica D. Rosenberg
- & Rajita Sinha
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Article
| Open AccessAssessing the origin of high-grade serous ovarian cancer using CRISPR-modification of mouse organoids
The relative contribution of fallopian tube (FT) or ovarian surface epithelium (OSE) to high-grade serous ovarian cancer (HG-SOC) development is unclear. Here, the authors establish organoid models from murine oviductal and OSE tissues that allow cancer modeling via CRISPR-Cas9 genome editing, and report a dual origin of murine HG-SOC.
- Kadi Lõhmussaar
- , Oded Kopper
- & Hans Clevers
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Article
| Open AccessVulnerabilities in coronavirus glycan shields despite extensive glycosylation
Glycosylation plays a key role in shielding of immunogenic epitopes on viral spike (S) proteins. Here Watanabe et al. report that glycans of coronavirus SARS and MERS S proteins are heterogeneously distributed and do not form an efficacious high-density global shield which would ensure efficient immune evasion.
- Yasunori Watanabe
- , Zachary T. Berndsen
- & Max Crispin
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Article
| Open AccessThe DNA methylation landscape of giant viruses
DNA methylation is an epigenetic marker in all domains of life. Here, Jeudy et al., using single-molecule realtime sequencing, determine DNA methylation patterns in giant viruses and evolutionary analysis of virus encoded DNA methyltransferases suggests that they affect viral fitness.
- Sandra Jeudy
- , Sofia Rigou
- & Matthieu Legendre
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Article
| Open AccessIntegrative analysis of reference epigenomes in 20 rice varieties
Comprehensive epigenomic maps of various rice varieties are still unavailable. Here, the authors report the development of eChIP as a fast and low-input upgrade of regular plant ChIP-seq protocol for epigenome analysis of 20 rice varieties and annotate over 80% of the genome with different epigenome properties for transcriptional regulation.
- Lun Zhao
- , Liang Xie
- & Xingwang Li
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Article
| Open AccessPrc1-rich kinetochores are required for error-free acentrosomal spindle bipolarization during meiosis I in mouse oocytes
Oocyte meiosis must achieve spindle bipolarization without predefined spatial cues. Yoshida et al. demonstrate that spindle bipolarization during meiosis I in mouse oocytes requires kinetochores to prevent chromosome segregation errors, a phenomenon that does not occur in error-prone human oocytes.
- Shuhei Yoshida
- , Sui Nishiyama
- & Tomoya S. Kitajima
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Article
| Open AccessThe stability of mutualism
Mutualism is typically portrayed as a destabilizing process in community ecology. Here, via a random matrix model that considers species density, the author shows that mutualistic interactions can, in fact, enhance population density at equilibrium and increase community resilience to perturbation.
- Lewi Stone
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Article
| Open AccessPregnancy reprograms the epigenome of mammary epithelial cells and blocks the development of premalignant lesions
Mammary epithelial cells are epigenetically modified during pregnancy, these changes can influence the pre-disposition to cancer. Here, the authors examine the epigenetic landscape of mammary epithelial cells pre and post pregnancy and identify changes to the epigenetic landscape, which can protect mice from Myc induced cancer.
- Mary J. Feigman
- , Matthew A. Moss
- & Camila O. dos Santos
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Article
| Open AccessPermissive microbiome characterizes human subjects with a neurovascular disease cavernous angioma
Gut microbiome has been linked to cavernous angioma (CA), a common vascular disease, but the role in humans remains unclear. Here, the authors combine 16S rRNA sequencing and shotgun metagenomics to profile the microbiome in a large cohort of human subjects with and without CA, and among subjects with different CA clinical features.
- Sean P. Polster
- , Anukriti Sharma
- & Issam A. Awad
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Article
| Open AccessThe bromodomain containing protein BRD-9 orchestrates RAD51–RAD54 complex formation and regulates homologous recombination-mediated repair
The bromodomain containing protein BRD9 has been reported to regulate chromatin remodeling and transcription. Here the authors reveal a role for BRD9 in homologous recombination by facilitating RAD51–RAD54 interaction.
- Qin Zhou
- , Jinzhou Huang
- & Jian Yuan
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Article
| Open AccessThe Perlman syndrome DIS3L2 exoribonuclease safeguards endoplasmic reticulum-targeted mRNA translation and calcium ion homeostasis
The DIS3L2 exonuclease degrades aberrant 7SL RNAs tagged by an oligouridine 3′-tail. Here the authors analyze DIS3L2 knockout mouse embryonic stem cells and suggest that DIS3L2-mediated quality control of 7SL RNA is important for ER-mediated translation and calcium ion homeostasis.
- Mehdi Pirouz
- , Chih-Hao Wang
- & Richard I. Gregory
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Article
| Open AccessSpread of pathological tau proteins through communicating neurons in human Alzheimer’s disease
The tau protein is theorized to spread transneuronally in Alzheimers disease, though this theory remains unproven in humans. Our simulations of epidemic-like protein spreading across human brain networks support this theory, and suggest the spreading dynamics are modified by β-amyloid
- Jacob W. Vogel
- , Yasser Iturria-Medina
- & Per Wollmer
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Article
| Open AccessSingle cell transcriptomics reveals opioid usage evokes widespread suppression of antiviral gene program
Over 100 million of opioid prescriptions are issued yearly in the USA alone, but the impact of opioid use on the immune system is barely characterized. Here the authors report antiviral immune response is blunted in several types of blood cells from opioid-dependent individuals, and when healthy donor cells are exposed to morphine in a dish.
- Tanya T. Karagiannis
- , John P. Cleary Jr
- & Christine S. Cheng
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Article
| Open AccessSources of path integration error in young and aging humans
Path integration abilities, important for spatial navigation, vary widely across individuals and deteriorate in old age. This work shows that path integration errors in general, as well as age-related path integration deficits, are mainly caused by accumulating noise in people’s velocity estimation.
- Matthias Stangl
- , Ingmar Kanitscheider
- & Thomas Wolbers
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Article
| Open AccessGenomic adaptations to aquatic and aerial life in mayflies and the origin of insect wings
Genomic studies of paleopteran insects, such as mayflies, are needed to reconstruct early insect evolution. Here, Almudi and colleagues present the genome of the mayfly Cloeon dipterum and use transcriptomics to characterize its adaptations to distinct habitats and the origin of insect wings.
- Isabel Almudi
- , Joel Vizueta
- & Fernando Casares
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Article
| Open AccessCryo-EM structures provide insight into how E. coli F1Fo ATP synthase accommodates symmetry mismatch
F1Fo ATP synthase consists of two coupled rotary molecular motors: the soluble ATPase F1 and the transmembrane Fo. Here, the authors present cryo-EM structures of E. coli ATP synthase in four discrete rotational sub-states at 3.1-3.4 Å resolution and observe a rotary sub-step of the Fo motor cring that reveals the mechanism of elastic coupling between the two rotary motors, which is essential for effective ATP synthesis.
- Meghna Sobti
- , James L. Walshe
- & Alastair G. Stewart
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Article
| Open AccessGlobal priorities for conservation of reptilian phylogenetic diversity in the face of human impacts
In addition to species richness, evolutionary measures of biodiversity are important considerations for conservation. Here, Gumbs et al. develop new biodiversity metrics incorporating phylogenetic diversity and human pressure and highlight conservation priorities in a global analysis of reptiles.
- Rikki Gumbs
- , Claudia L. Gray
- & James Rosindell
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Article
| Open AccessAccumulation of ambient phosphate into the periplasm of marine bacteria is proton motive force dependent
The ubiquitous oceanic bacteria harbour an external phosphate buffer for modulating phosphate (Pi) uptake. Here, using both oceanic SAR11, Prochlorococcus and Synechococcus strains as a model, the authors show that the Pi buffer accumulation in the periplasm is proton motive force-dependent and can be enhanced by light energy.
- Nina A. Kamennaya
- , Kalotina Geraki
- & Mikhail V. Zubkov
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