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Article
| Open AccessSmall molecule induced STING degradation facilitated by the HECT ligase HERC4
In this paper, Mutlu et al. identifies a STING degrader, AK59, which inhibits downstream cGAS/STING activity through STING degradation employing a HECT-domain E3 ligase HERC4 and proteasomal ubiquitination pathway.
- Merve Mutlu
- , Isabel Schmidt
- & Danilo Guerini
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Article
| Open AccessLiver and pancreatic-targeted interleukin-22 as a therapeutic for metabolic dysfunction-associated steatohepatitis
Novel short-acting IL-22 bispecific biologics offer new hope for treating metabolic dysfunction-associated steatohepatitis (MASH), a global health concern with few treatment options. Here, the authors show these drugs significantly improve blood sugar control, liver fat, inflammation, and scarring.
- Haressh Sajiir
- , Sahar Keshvari
- & Sumaira Z. Hasnain
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Article
| Open AccessHaplotype-resolved gapless genome and chromosome segment substitution lines facilitate gene identification in wild rice
Genetic variation present in wild rice is a reservoir of useful genes for rice breeding. Here, the authors report the haplotype-resolved gapless genome assembly of wild rice, the development of two sets of chromosome segment substitution lines, and the cloning of a blast resistance gene originated from wild rice.
- Jingfen Huang
- , Yilin Zhang
- & Weihua Qiao
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Article
| Open AccessStochasticity, determinism, and contingency shape genome evolution of endosymbiotic bacteria
Endosymbionts often have small genomes that maintain minimal functions required to serve their hosts. This study examines cases of new endosymbiont acquisition and finds genome degeneration involves both stochastic and deterministic processes that shape gene content and organismal function.
- Bret M. Boyd
- , Ian James
- & Colin Dale
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Article
| Open AccessBinding of Akkermansia muciniphila to mucin is O-glycan specific
Intestinal mucus consists of densely O-glycosylated mucins, serving as a nutrient source for bacteria. Elzinga et al. show that mucin-degrading Akkermansia muciniphila selectively binds to O-glycan structures found on human colonic mucins.
- Janneke Elzinga
- , Yoshiki Narimatsu
- & Hanne L. P. Tytgat
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Article
| Open AccessG protein-specific mechanisms in the serotonin 5-HT2A receptor regulate psychosis-related effects and memory deficits
Here authors aim to understand the 5-HT2AR coupling signature in response to different signaling probes and their physiological impacts using computational modeling, in vitro and in vivo experiments, and analysis of human brain tissue.
- Elk Kossatz
- , Rebeca Diez-Alarcia
- & Jana Selent
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Article
| Open AccessMucus production, host-microbiome interactions, hormone sensitivity, and innate immune responses modeled in human cervix chips
Human cervical mucosa and its interactions with the microbiome play a central role in female reproductive tract health and disease. Here, the authors develop physiological models of the human cervix using Organ-on-a-Chip technology that produce mucus, and respond to hormonal, environmental, and microbial cues similar to the living cervix.
- Zohreh Izadifar
- , Justin Cotton
- & Donald E. Ingber
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Article
| Open AccessAn amphioxus neurula stage cell atlas supports a complex scenario for the emergence of vertebrate head mesoderm
The evolution of the vertebrate head mesoderm involved the emergence of new structures and cell types. Here the authors generated a cell atlas of the cephalochordate neurula to study the origins of these novelties and propose a revised scenario for the evolution of the vertebrate head muscles.
- Xavier Grau-Bové
- , Lucie Subirana
- & Hector Escriva
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Article
| Open AccessRapid response of fly populations to gene dosage across development and generations
While developmental phenotypes are often multigenic and involve environmental inputs, most research approaches involve perturbation of small numbers of genes. Here they use a synthetic evolution approach in Drosophila to show that adding extra copies of bicoid leads to rapid, system-wide phenotypic responses, potentiated by highly polygenic traits such as embryo size.
- Xueying C. Li
- , Lautaro Gandara
- & Justin Crocker
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Article
| Open AccessThe evolution of antibiotic resistance islands occurs within the framework of plasmid lineages
In their study, Wang and Dagan show that 84% of antibiotic resistance genes in multidrug resistance plasmids in Escherichia, Salmonella, and Klebsiella reside within resistance islands that evolve within the framework of plasmid lineages.
- Yiqing Wang
- & Tal Dagan
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Article
| Open AccessA spatially localized DNA linear classifier for cancer diagnosis
Molecular computing is an emerging paradigm with a crucial role in clinical diagnosis. Here, authors develop a spatially localized, DNA-integrated circuits-based classifier, DNA IC-CLA, which enables accurate cancer diagnosis for clinical samples in a faster and more effective manner.
- Linlin Yang
- , Qian Tang
- & Da Han
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Article
| Open AccessAcute depletion of BRG1 reveals its primary function as an activator of transcription
Here, the authors generate a mouse line by knocking in the auxin-inducible degron tag to the SMARCA4 gene, which encodes BRG1. They suggest that BRG1 primarily contributes positively to chromatin accessibility, RNAP binding, and nascent RNA production.
- Gang Ren
- , Wai Lim Ku
- & Keji Zhao
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Article
| Open AccessPIF transcriptional regulators are required for rhythmic stomatal movements
Stomata function is essential for photosynthesis and the global carbon and oxygen cycles. Here, the authors report the regulatory framework that establishes rhythmic pore movements to prevent water loss at night and allow CO2 uptake during the day.
- Arnau Rovira
- , Nil Veciana
- & Elena Monte
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Article
| Open AccessGermline Cas9 promoters with improved performance for homing gene drive
High-performance promoters are needed for gene drives; these are currently lacking in Drosophila melanogaster. Here the authors tested eleven Drosophila melanogaster germline promoters in several configurations and show higher drive conversion efficiency with minimal embryo resistance.
- Jie Du
- , Weizhe Chen
- & Jackson Champer
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Article
| Open AccessBreast cancer cell-secreted miR-199b-5p hijacks neurometabolic coupling to promote brain metastasis
Breast cancer metastasis to the brain is rising in prevalence and is an increasingly lethal threat to the patients. Here, the authors show miR-199b-5p, secreted by some breast cancer cells and detected at a higher level in patients with brain metastases, impairs the metabolic coupling between neurons and astrocytes to facilitate development of brain metastasis.
- Xianhui Ruan
- , Wei Yan
- & Shizhen Emily Wang
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Article
| Open AccessTemporal interference stimulation disrupts spike timing in the primate brain
Whether and how temporal interference (TI) stimulation disrupt primate oscillatory brain activity are not fully understood. Here authors show TI stimulation can non-invasively disrupt oscillatory brain activity but three factors make it too weak to impose new rhythms on the primate brain. Thus, it may be a potential method for safely controlling pathological brain activity.
- Pedro G. Vieira
- , Matthew R. Krause
- & Christopher C. Pack
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Article
| Open AccessRemote sensing of emperor penguin abundance and breeding success
Emperor penguins colony occupancy is variable and chiefly estimated with remote sensing images at end of the breeding season. Here, the authors provide a phenological model that can extrapolate occupancy from sparse data and can predict phenological events, breeding pairs and fledging chicks.
- Alexander Winterl
- , Sebastian Richter
- & Daniel P. Zitterbart
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Article
| Open AccessPancreatic beta-cell IL-22 receptor deficiency induces age-dependent dysregulation of insulin biosynthesis and systemic glucose homeostasis
IL-22RA1 is highly expressed on pancreatic islets and absent on immune cells. Here, the authors investigate its role by generating animals that lack IL-22RA1 on beta cells and reveal IL22RA1 signalling is critical for insulin biosynthesis and beta-cell health, evidenced by its regulation of MHC II expression and its suppressive effect on inflammation and cellular stress.
- Haressh Sajiir
- , Kuan Yau Wong
- & Sumaira Z. Hasnain
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Article
| Open AccessGlucocorticoids paradoxically promote steroid resistance in B cell acute lymphoblastic leukemia through CXCR4/PLC signaling
Resistance to glucocorticoids (GC) is a major obstacle for the treatment of pediatric B-cell acute lymphoblastic leukemia (B-ALL). Here, the authors report that GC-triggered CXCR4 internalization promotes a phospholipase C (PLC)-mediated cell survival pathway, driving GC resistance in B-ALL.
- Souleymane Abdoul-Azize
- , Rihab Hami
- & Olivier Boyer
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Article
| Open AccessA polygenic score method boosted by non-additive models
Polygenic scores aggregate the effects of multiple genetic variants and can be used to predict disease risk. Here, the authors present a polygenic score method that incorporates non-additive inheritance modes (recessive, dominant, over-recessive, and over-dominant) and show that this can improve risk prediction for certain polygenic diseases.
- Rikifumi Ohta
- , Yosuke Tanigawa
- & Shinichi Morishita
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Article
| Open AccessControl of artificial membrane fusion in physiological ionic solutions beyond the limits of electroformation
Membrane fusion is crucial for fabricating artificial membranes. Here, the authors present an approach combining electric field with hydraulic pressure to physically control the fusion, enabling tuning of the shape and size of the 3D freestanding lipid bilayers in physiological solutions.
- Bong Kyu Kim
- , Dong-Hyun Kang
- & Tae Song Kim
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Article
| Open AccessGut microbiome remodeling and metabolomic profile improves in response to protein pacing with intermittent fasting versus continuous caloric restriction
Here, in a follow-up of a clinical study, the authors show that protein pacing and intermittent fasting improves gut symptomatology and microbial diversity, as well as reduces visceral fat compared to a heart-healthy, calorie-restricted diet matched for overall energy intake and expenditure in free-living humans.
- Alex E. Mohr
- , Karen L. Sweazea
- & Paul J. Arciero
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Article
| Open AccessLiquid foam improves potency and safety of gene therapy vectors
Gene therapy is a rapidly growing field, but is hindered by efficacy and safety concerns, including those related to delivery methods. Here, inspired by the use of foam in the delivery of pharmaceuticals, Dr. Stephan and colleagues formulated foam as a safe and effective delivery platform for gene therapy.
- K. Fitzgerald
- , S. B. Stephan
- & M. T. Stephan
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Article
| Open AccessDynamics underlie the drug recognition mechanism by the efflux transporter EmrE
Here, the authors reveal the protonation of a single membrane embedded glutamate residue within the homodimer of the efflux transporter EmrE modulates the structure and dynamics in an allosteric manner using NMR spectroscopy.
- Jianping Li
- , Ampon Sae Her
- & Nathaniel J. Traaseth
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Article
| Open AccessMemory CD8 T cells are vulnerable to chronic IFN-γ signals but not to CD4 T cell deficiency in MHCII-deficient mice
Memory CD8+ T cells persist poorly in MHCII-deficient mice. Here the authors show that this CD8+ T cell attrition is not caused by a lack of CD4+ T cell help, as previously proposed, but by chronic IFN-γ signals derived from endogenous colonic CD8+ T cells.
- Ruka Setoguchi
- , Tomoya Sengiku
- & Shohei Hori
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Article
| Open AccessNucleosomal DNA has topological memory
Here, the authors develop Topo-seq to measure the DNA topology (∆Lk) restrained by individual nucleosomes in vivo. They show that nucleosome DNA topology is imprinted by its native chromatin context and persists when the nucleosome is relocated.
- Joana Segura
- , Ofelia Díaz-Ingelmo
- & Joaquim Roca
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Article
| Open AccessMulti-omics in nasal epithelium reveals three axes of dysregulation for asthma risk in the African Diaspora populations
Here, the authors suggest that molecular dysregulation on three axes may play a critical role in asthma within the African Diaspora. RNASeq and DNA methylation data are generated from nasal epithelium including cases and controls from seven different geographic sites.
- Brooke Szczesny
- , Meher Preethi Boorgula
- & Rasika A. Mathias
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Article
| Open AccessA protein sequence-based deep transfer learning framework for identifying human proteome-wide deubiquitinase-substrate interactions
The specificity of protein deubiquitination relies on deubiquitinase-substrate interactions (DSIs). Here, authors leverage evolutionary information from the proteome to predict DSIs, even with an inadequate training dataset.
- Yuan Liu
- , Dianke Li
- & Dong Li
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Article
| Open AccessPhysiochemical interaction between osmotic stress and a bacterial exometabolite promotes plant disease
A single exometabolite produced by an opportunistic bacterial pathogen of the root microbiome enhances host susceptibility to salt stress and promotes plant disease in complex soil systems.
- Felix Getzke
- , Lei Wang
- & Stéphane Hacquard
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Article
| Open AccessSmall body size is associated with increased evolutionary lability of wing skeleton proportions in birds
Birds vary in body mass by many orders of magnitude, but how this effects the evolution of their skeletal proportions is unclear. This study shows that small body size is associated with decreased evolutionary integration between wing bone sizes, facilitating increased evolutionary lability.
- Andrew Orkney
- & Brandon P. Hedrick
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Article
| Open AccessCrykey: Rapid identification of SARS-CoV-2 cryptic mutations in wastewater
Wastewater surveillance has the potential to be used for early detection of new SARS-CoV-2 lineages. Here, the authors present Crykey, a computational method for detecting cryptic SARS-CoV-2 mutations in wastewater that co-occur on the same sequencing read, potentially representing new lineages.
- Yunxi Liu
- , Nicolae Sapoval
- & Lauren B. Stadler
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Article
| Open AccessRegiodivergent biosynthesis of bridged bicyclononanes
Hypericum plants contain complex compounds with promising medicinal properties. Here, the authors report a pair of enzymes catalyzing prenylation and regiodivergent cyclization. The forged scaffolds are characteristic of hyperforin analogs.
- Lukas Ernst
- , Hui Lyu
- & Benye Liu
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Article
| Open AccessLong-read sequencing for 29 immune cell subsets reveals disease-linked isoforms
This paper unveils the complexity of human immune cell splicing, highlighting cell-specific isoforms and establishing connections between alternative splicing and complex traits. These findings have implications for understanding diseases and the evolution of the genome.
- Jun Inamo
- , Akari Suzuki
- & Yuta Kochi
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Article
| Open AccessTAD border deletion at the Kit locus causes tissue-specific ectopic activation of a neighboring gene
Research on the Kit locus shows TAD boundary deletion may or may not trigger ectopic gene activation in different cell types, influenced by active enhancers’ position relative gene promoters.
- Evelyn Kabirova
- , Anastasiya Ryzhkova
- & Nariman Battulin
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Article
| Open AccessAssociations of semaglutide with incidence and recurrence of alcohol use disorder in real-world population
Anecdotal reports from patients prescribed semaglutide describe a reduced desire to drink. Here, the authors show that semaglutide is associated with a 50%-56% reduced risk for both the incidence and recurrence of alcohol use disorder in real-world populations.
- William Wang
- , Nora D. Volkow
- & Rong Xu
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Article
| Open AccessStructure prediction of protein-ligand complexes from sequence information with Umol
Here the authors report the AI system Umol that predicts flexible all-atom structures of protein-ligand complexes from sequence information, advancing AI-driven drug discovery: accurate structures and affinity can be selected from predicted confidence metrics (plDDT).
- Patrick Bryant
- , Atharva Kelkar
- & Frank Noé
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Article
| Open AccessAn isoform quantitative trait locus in SBNO2 links genetic susceptibility to Crohn’s disease with defective antimicrobial activity
Genetic variants in the SBNO2 locus are associated with Crohns’s disease. Here the authors show that those variants cause a cell type and isoform specific effect were transcription of SBNO2 isoform 2 impacts on antimicrobial activity in macrophages providing a plausible gene-mechanism-phenotype model.
- Dominik Aschenbrenner
- , Isar Nassiri
- & Holm H. Uhlig
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Article
| Open AccessStructure and distinct supramolecular organization of a PSII-ACPII dimer from a cryptophyte alga Chroomonas placoidea
The authors report structure of PSII-ACPII from a cryptophyte alga Chroomonas placoidea, providing insights into a distinct supramolecular organization and assembly of antennas in the supercomplex and possible excitation energy transfer pathways.
- Zhiyuan Mao
- , Xingyue Li
- & Guangye Han
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Article
| Open AccessThe low-density lipoprotein receptor and apolipoprotein E associated with CCHFV particles mediate CCHFV entry into cells
This study shows that Crimean-Congo hemorrhagic fever virus (CCHFV) recruits apoE, an exchangeable apolipoprotein that mediates LDL/LDL-R interaction, to promote virion entry via the LDLR. Molecules that down-regulate LDL-R inhibit CCHFV infection.
- Maureen Ritter
- , Lola Canus
- & Solène Denolly
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Perspective
| Open AccessAlternative protein sources: science powered startups to fuel food innovation
Harnessing the potential of considerable food security efforts requires the ability to translate them into commercial applications. In this Perspective, the author explores the alternative protein source start-up landscape.
- Elena Lurie-Luke
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Article
| Open AccessHuman movement and environmental barriers shape the emergence of dengue
Here, using a dynamic modelling approach, the authors find that the spread of dengue through Mexico and Brazil is shaped by specific interactions between human mobility, climate, and the environment. Their models can also be applied to predict future spread in these geographic areas.
- Vinyas Harish
- , Felipe J. Colón-González
- & Oliver J. Brady
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Article
| Open AccessGlioblastoma disrupts cortical network activity at multiple spatial and temporal scales
The precise onset, temporal progression and spatial extent of neuron-tumor crosstalk in brain with Glioblastoma (GBM) are not fully understood. Here authors, using a genetic GBM mouse model, show widespread glutamate accumulation, chronic neural activity disruption between cells and brain areas, depending on tumor expansion rate and genotype with altered tumor and neural activity dynamics when adding glypican6.
- Jochen Meyer
- , Kwanha Yu
- & Jeffrey Noebels
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Article
| Open AccessDynamic movement of the Golgi unit and its glycosylation enzyme zones
The structure of the Golgi and the localization of glycosylation enzymes remain largely elusive. Here, the authors use super-resolution microscopy to show that the Golgi is composed of small dynamic units which have rapidly moving zones of glycosylation enzymes.
- Akihiro Harada
- , Masataka Kunii
- & Akihiko Nakano
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Article
| Open AccessEnhanced surface colonisation and competition during bacterial adaptation to a fungus
Bacterial-fungal interactions can stimulate the production of specialised microbial metabolites. Here, Richter et al. use co-culture experimental evolution to show that the presence of a fungus selects for increased surfactin production in the bacterium Bacillus subtilis, which inhibits fungal growth and facilitates the competitive success of the bacterium.
- Anne Richter
- , Felix Blei
- & Ákos T. Kovács
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Article
| Open AccessProximal protein landscapes of the type I interferon signaling cascade reveal negative regulation by PJA2
Type I IFN is vital for antiviral defense. Here, the authors use TurboID-based proximity labeling to comprehensively map the protein landscapes surrounding core IFN signaling members. Among factors uncovered, PJA2 emerged as a negative regulator of IFN signaling that ubiquitinates the Janus kinases.
- Samira Schiefer
- & Benjamin G. Hale
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Article
| Open AccessHairpin protein partitioning from the ER to lipid droplets involves major structural rearrangements
Lipid droplet (LD) function relies on protein partitioning between the endoplasmic reticulum (ER) and LD. The authors show that UBXD8 adopts distinct conformations in both membranes and undergoes structural rearrangements during ER-to-LD partitioning.
- Ravi Dhiman
- , Rehani S. Perera
- & Bianca Schrul
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Article
| Open AccessProton-coupled transport mechanism of the efflux pump NorA
Efflux pumps confer antibiotic resistance by coupling proton import with drug export. In this work, the authors uncover the proton-coupled transport mechanism for the clinically relevant efflux pump NorA from the pathogenic bacterium S. aureus.
- Jianping Li
- , Yan Li
- & Nathaniel J. Traaseth
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Article
| Open AccessOsSRF8 interacts with OsINP1 and OsDAF1 to regulate pollen aperture formation in rice
At the tetrad stage, OsSRF8 interacts with OsINP1 to promote the formation of aperture plasma membrane protrusion (APMP). Then, the OsINP1-OsSRF8 protein complex recruits OsDAF1 to the APMP site and co-regulate pollen aperture formation in rice.
- Keyi Chen
- , Qiming Wang
- & Jianmin Wan
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Article
| Open AccessShifts in evolutionary lability underlie independent gains and losses of root-nodule symbiosis in a single clade of plants
Kates et al. propose that nitrogen-fixing symbiosis between bacteria and angiosperms has been gained and lost multiple times, based on ancestral reconstructions of nodulation across a deeply sampled, 13,000-species phylogeny, in contrast to a single origin with many losses.
- Heather R. Kates
- , Brian C. O’Meara
- & Ryan A. Folk
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