Anobile DP, Barbar L, Maucotel E
… +15 more, Cornec A, Manriquez V, Richer W, Denizeau J, Sedlik C, Bories C, Couderc E, Leclere R, Sobas J, Papillon E, Mena Osuna R, Tosello-Boari J, Burbage M, Piaggio E, Poirier EZ
One of the first-line treatments for advanced non-small cell lung cancer (NSCLC) are immune checkpoint inhibitors (ICI), which activate the antitumor immune response. Despite their success, ICI remain ineffective in many...One of the first-line treatments for advanced non-small cell lung cancer (NSCLC) are immune checkpoint inhibitors (ICI), which activate the antitumor immune response. Despite their success, ICI remain ineffective in many patients, highlighting the need for strategies to overcome resistance. Most efforts have focused on promoting immune cell infiltration into refractory tumors to improve ICI efficacy. In this work, we mobilize this approach by focusing on Argonaute 2 (Ago2), a pivotal member of the RNA interference pathway. Using two murine models of immunorefractory NSCLC, we demonstrate that tumoral Ago2 suppresses interferon signaling, leading to poor immunogenicity and failure of ICI therapy. Genetic deletion of Ago2 in cancer cells restores interferon signaling and supports immune infiltration of the tumor. Consequently, whereas wild-type tumors are resistant to ICI, tumors devoid of Ago2 become sensitive to treatment. In NSCLC patients treated with ICI, high Ago2 expression and a low interferon signature in tumors correlate with reduced survival. Ago2 is thus a driver of the immunorefractory phenotype observed in NSCLC and may represent a therapeutic target when aiming to sensitize patients to ICI.
Docampo-Seara A, Cosacak MI, Heilemann K
… +11 more, Kessel F, Oprişoreanu AM, Westphal M, Çark Ö, Zöller D, Arnold J, Bretschneider A, Hnatiuk A, Ninov N, Becker CG, Becker T
Zebrafish, in contrast to mammals, regenerate neurons after spinal cord injury, but little is known about the control mechanisms of this process. Here we use scRNA-seq and in vivo experiments to show that sema4ab, mainly...Zebrafish, in contrast to mammals, regenerate neurons after spinal cord injury, but little is known about the control mechanisms of this process. Here we use scRNA-seq and in vivo experiments to show that sema4ab, mainly expressed by lesion-reactive microglia, attenuates regenerative neurogenesis by changing the complex lesion environment. After spinal injury, disruption of sema4ab doubles the number of newly generated progenitor cells and neurons but attenuates axon regrowth and recovery of swimming function. Disruption of the plxnb1a/b receptors, selectively expressed by neural progenitor cells, increases regenerative neurogenesis. In addition, disruption of sema4ab alters activation state and cytokine expression of microglia, such that fibroblasts increase expression of the cytokine tgfb3, which strongly promotes regenerative neurogenesis. Hence, we propose that sema4ab expression in microglia attenuates regenerative neurogenesis in multiple ways, likely directly through plxnb1a/b receptors and indirectly, by controlling the inflammatory milieu and tgfb3 levels. Targeting Sema4A-dependent signaling in non-regenerating vertebrates may be a future strategy to improve regenerative outcomes.
Adiponectin is the most abundant hormone in the circulation. Plasma adiponectin decreases in obesity but increases in leanness, including during caloric restriction (CR) in animals and humans. In obesity, adiponectin def...Adiponectin is the most abundant hormone in the circulation. Plasma adiponectin decreases in obesity but increases in leanness, including during caloric restriction (CR) in animals and humans. In obesity, adiponectin deficiency promotes cardiometabolic dysfunction. In contrast, the roles of adiponectin in CR, when it is at its highest, are largely unknown. To address this, we studied global adiponectin knockout (KO) in male and female mice fed either ad libitum (AL) or a 30% CR diet from 9-13 weeks of age. We show that adiponectin KO did not alter CR effects on body mass, body composition, or energy expenditure. However, KO unexpectedly decreased blood glucose levels during CR, both with fasting and following an oral glucose challenge. This is opposite to the effects of adiponectin deficiency during AL feeding or obesity and occurred without changes in insulin concentrations or sensitivity. Moreover, adiponectin KO augmented CR-induced increases in plasma fatty acids in both sexes and, in males only, impaired systemic triglyceride clearance on both AL and CR diets. These effects on lipid metabolism were associated with sex- and diet-specific KO effects on white adipose tissue, including altered adipocyte size and expression of key regulators of adipocyte lipid metabolism. Indirect calorimetry further revealed that adiponectin KO alters the shifts between carbohydrate and lipid utilization that occur during transitions between fed and fasted states. To determine potential molecular mechanisms, we investigated effects of adiponectin KO on the liver, a major adiponectin target that plays key roles entraining metabolism to nutritional state. Hepatic transcriptomics revealed that, in both sexes, adiponectin KO upregulates sterol and fatty acid synthesis genes under AL while increasing amino acid catabolic genes during CR. However, the latter occurred without altering plasma or hepatic amino acid concentrations. Together, our findings suggest that adiponectin exerts sexually dimorphic effects on glucose, lipid, and amino acid metabolism during CR, in whole or in part through effects on the liver. Thus, the roles adiponectin in CR differ markedly from its widely reported functions in obesity, insulin resistance, and other pathological states.
A population's ability to adapt is determined by its levels of additive genetic variance (VA), and while it is agreed that most organisms have genetic variation for most traits, the extent to which it varies between spec...A population's ability to adapt is determined by its levels of additive genetic variance (VA), and while it is agreed that most organisms have genetic variation for most traits, the extent to which it varies between species is poorly characterized. Here, we investigate this question by compiling 3,209 and 1,852 estimates of heritability and evolvability (the additive genetic variance divided by the square of the mean), respectively, for a variety of traits from 220 and 172 multicellular eukaryotic species. Using phylogenetic generalized linear mixed models, we find substantial and highly significant interspecific variation in evolvability. Much of the variation is explained by phylogenetic relatedness, with plants in our data having substantially higher evolvability than animals. While heritability also varies between species, the differences are more subtle, and plants are not exceptional. We investigate whether the variation in evolvability and heritability between species is due to variation in the mutation rate, effective population size, genome size, ploidy, and recombination rate, but find little evidence of any factor being important. However, the confidence intervals are large suggesting that we have little power to detect any associations between these factors and our estimates of VA.
Marine fungi were assumed to have a minor role in carbon cycling, unable to compete with bacteria. A new PLOS Biology study challenges this dogma, showing fungi can dominate labile dissolved organic matter assimilation,...Marine fungi were assumed to have a minor role in carbon cycling, unable to compete with bacteria. A new PLOS Biology study challenges this dogma, showing fungi can dominate labile dissolved organic matter assimilation, reshaping our understanding of ocean carbon retention and storage.
Crossover (CO) formation ensures accurate segregation of homologous chromosomes during the first meiotic division. The pro-crossover proteins are essential for crossover formation and undergo dynamic changes during meiot...Crossover (CO) formation ensures accurate segregation of homologous chromosomes during the first meiotic division. The pro-crossover proteins are essential for crossover formation and undergo dynamic changes during meiotic prophase I, although the underlying regulatory mechanism is largely unknown. Here, we found that the ubiquitin-proteasome system (UPS) plays a pivotal role in orchestrating pro-crossover protein dynamics and crossover patterning during meiosis in Caenorhabditis elegans. Knockdown of either the ubiquitin-activating enzyme E1 or the proteasome resulted in elevated pro-crossover protein levels and crossover designation. Impairing ubiquitination, but not proteasome activity, led to persistent association of pro-crossover proteins on meiotic chromosomes, a process mediated by the CDC-48UFD-1/NPL-4 segregase. Utilizing a hypomorphic allele of cosa-1, a well-characterized pro-crossover protein-encoding gene, we further demonstrate that the UPS restricts crossover formation. Collectively, our findings reveal a multilayered UPS-mediated regulatory network that maintains proper pro-crossover protein dynamics, thereby coordinating crossover formation with meiotic chromosome segregation.
Fungi serve as critical biological carbon storage reservoirs in soil ecosystems, but whether this fungal trait is also important for marine sediment carbon storage processes is poorly understood. Here, we quantify for th...Fungi serve as critical biological carbon storage reservoirs in soil ecosystems, but whether this fungal trait is also important for marine sediment carbon storage processes is poorly understood. Here, we quantify for the first time assimilation of dissolved free amino acids by fungi in marine sediments from a high Arctic fjord and show that a distinct community of marine fungi promoted the stabilization of assimilated carbon via a relatively high metabolic efficiency. This corresponded to higher in situ ratios of fungi:prokaryote biomass in the fjord benthos, indicating efficient fungal metabolism promotes increased retention of microbial biomass at the seafloor. Quantitative stable isotope probing linked this efficient assimilation of amino acids to more than 80 fungal taxa in the fjord sediments, primarily associated with aquatic hyphomycetes. An efficient assimilation of amino acids is shown here to be a trait of marine fungi that plays a role in retaining labile dissolved organic matter as microbial biomass in Arctic fjord benthic ecosystems, hotspots for carbon sequestration that are currently experiencing rapid change due to climate warming. Our results indicate that fungal metabolism and biomass in marine sediment should be considered as an important contributor to seafloor carbon storage.
The brain and body undergo coordinated changes throughout the life span, yet studies of aging have traditionally examined these systems as separate entities. Here we ask how brain health relates to aging and peripheral b...The brain and body undergo coordinated changes throughout the life span, yet studies of aging have traditionally examined these systems as separate entities. Here we ask how brain health relates to aging and peripheral biomarkers of metabolic and vascular function, including body mass index, blood pressure, and blood biochemistry. We use multivariate pattern learning to identify generalizable patterns of covariance between multi-modal neuroimaging data (structural, functional, diffusion, and arterial spin labeling MRI), demographic, and physiological markers in two large-scale deeply phenotyped datasets: the Human Connectome Project-Aging and UK Biobank. This data-driven approach isolates two principal axes of brain-body associations in both biological sexes. The first axis is driven by the dominant contribution of age. Across multiple brain measures, aging is associated with loss of brain structural integrity and cerebral vascular dysfunction. The second axis is driven by metabolic features, characterized by low high-density lipoprotein cholesterol, elevated body mass index, blood pressure, glycosylated hemoglobin, insulin, glucose, and alanine aminotransferase that predominantly converge on reduced cerebral perfusion. Importantly, the aging and the metabolic axes are independent of each other, meaning that age and metabolic dysfunction have separable influences on the brain. Finally, we show that deviations from a healthy metabolic profile are linked to cognitive deficits, particularly in females. Our study contributes to development of comprehensive translatable biomarkers for brain health assessment, and highlights the importance of metabolic health as a determinant of brain health in aging population.
In eukaryotes, transcription elongation factors (TEFs) associate with RNA Polymerase II (RNAPII) to facilitate gene expression and couple transcription to co-transcriptional processes, including chromatin regulation and...In eukaryotes, transcription elongation factors (TEFs) associate with RNA Polymerase II (RNAPII) to facilitate gene expression and couple transcription to co-transcriptional processes, including chromatin regulation and RNA processing. To further our understanding of TEF biology, we developed a domain-centric analysis pipeline to perform a broad survey of 10 TEF orthologs-Paf1, Ctr9, Cdc73, Rtf1, Leo1, Spt4, Spt5, Spt6, Spn1, and Elf1-across the Tree of Life and analyze their evolutionary patterns in a structural context. We report evidence for all 10 TEFs being present in the last eukaryotic common ancestor, indicating that mechanisms of TEF-mediated transcription regulation are both ancient and conserved. However, some early-diverging eukaryotic clades exhibit signs of altered TEF domain composition. A comparative phylogenetic analysis highlighted conserved regions of TEFs that are detected in both metazoans and fungi and other regions that appear clade-specific, detected only in metazoans. These observations, together with additional insights generated from evolutionary rate covariation analysis, shed light on under-characterized aspects of TEFs, including domains for which functions have yet to be dissected.
Observed outcomes of our movements sometimes differ from our expectations. These sensory prediction errors recalibrate the brain's internal models for motor control, reflected in alterations to subsequent movements that...Observed outcomes of our movements sometimes differ from our expectations. These sensory prediction errors recalibrate the brain's internal models for motor control, reflected in alterations to subsequent movements that counteract these errors (motor adaptation). While leading theories suggest that all forms of motor adaptation are driven by learning from sensory prediction errors, dominant models of speech adaptation argue that adaptation results from integrating time-advanced copies of corrective feedback commands into feedforward motor programs. Here, we tested these competing theories of speech adaptation by inducing planned, but not executed, speech. Human speakers were prompted to speak a word and, on a subset of trials, were rapidly cued to withhold the prompted speech. On standard trials, speakers were exposed to real-time playback of their own speech with an auditory perturbation of the first formant to induce single-trial speech adaptation. Speakers experienced a similar sensory error on movement cancellation trials, hearing a perturbation applied to a recording of their speech from a previous trial at the time they would have spoken. Speakers adapted to auditory prediction errors in both contexts, altering the spectral content of spoken vowels to counteract formant perturbations even when no actual produced speech coincided with the perturbed feedback. Such adaptation was not observed when participants passively listened to perturbed feedback without the intention to speak, ruling out observational learning as the cause of adaptation in movement cancellation trials. These results suggest that prediction errors, rather than corrective motor commands, drive audiomotor adaptation in speech, building on recent findings in reaching.
Bacterial pathogens commonly become drug resistant via horizontal acquisition of antimicrobial resistance genes (ARGs), which are often encoded on mobile genetic elements (MGEs). Although bacterial defence systems are ty...Bacterial pathogens commonly become drug resistant via horizontal acquisition of antimicrobial resistance genes (ARGs), which are often encoded on mobile genetic elements (MGEs). Although bacterial defence systems are typically considered barriers to horizontal gene transfer (HGT), previous studies revealed that bacteria with more restriction-modification (RM) systems (the most abundant bacterial defences) frequently carry more MGEs. It was suggested that this counterintuitive relationship might result from stronger selection for RM systems when exposure to costly MGEs increases. Here, we test this hypothesis using a combination of modeling and bioinformatics analysis of >40,000 bacterial genomes to better understand how eco-evolutionary feedbacks between selection for RM and acquisition of MGEs shape bacterial genome evolution. Our model predicts negative associations between HGT and RM, but only if RM diversity is high. By contrast, at low RM diversity, eco-evolutionary feedbacks drive the emergence of positive associations between HGT and RM. Consistent with these predictions, we identified negative relationships between acquired ARG counts and RM counts across species but positive relationships within individual species. Collectively, our work helps to understand how RM systems shape patterns of HGT of ARGs, which may offer opportunities for targeted surveillance of strains at higher risk of horizontally acquiring novel drug resistance alleles.
The integration between biogeography and ecology has been historically limited due to the lack of data on biotic interactions across large spatial scales. The emergence of new methods and high-quality ecological network...The integration between biogeography and ecology has been historically limited due to the lack of data on biotic interactions across large spatial scales. The emergence of new methods and high-quality ecological network data at biogeographical scales are paving the way for a deeper integration of biogeography and ecology. This Essay examines this integration through three interconnected research areas: the effects of biotic interactions on species distributions; the influence of environmental gradients on biotic interactions; and the effects of biotic interactions on the environment. Recent progress and primary challenges are discussed, and suggestions provided on how to advance understanding of biodiversity patterns and processes across scales.
Antimicrobial resistance (AMR) is a substantial and growing global health burden. Understanding, and predicting, its evolution in specific pathogens will help responses across scales from individual patient cases to larg...Antimicrobial resistance (AMR) is a substantial and growing global health burden. Understanding, and predicting, its evolution in specific pathogens will help responses across scales from individual patient cases to large-scale policy. Here, we use global data on AMR features, predicted from 47k Klebsiella pneumoniae genomes, with hypercubic transition path sampling to infer the evolutionary pathways by which AMR features in K. pneumoniae (KpAMR) are acquired across 102 countries, territories, and areas. We identify "globally consistent" evolutionary behaviors that hold across countries, and "globally divergent" behaviors including carbapenem and fluoroquinolone resistance that vary across countries. We show how these divergent dynamics covary both with public health superregion and drug use policy, and reveal competing evolutionary pathways within and between countries. Using newly sequenced data across several decades from sub-Saharan Africa, we show that this inferred global roadmap of KpAMR evolution successfully predicts prospective evolutionary dynamics. Together, we hope that the ability to characterize and predict evolutionary dynamics of AMR acquisition, connected to socio-economic and drug policy predictors, will help strengthen our understanding of AMR evolution worldwide.
Expansion microscopy (ExM) has revolutionized super-resolution imaging in cell biology due to its simple and inexpensive workflow. The use of ExM has revealed several novel insights into the nanoscale architectures of ce...Expansion microscopy (ExM) has revolutionized super-resolution imaging in cell biology due to its simple and inexpensive workflow. The use of ExM has revealed several novel insights into the nanoscale architectures of cellular protein complexes, especially the microtubule cytoskeleton in model and non-model systems. Despite tremendous progress in expansion microscopy protocols that preserve cellular ultrastructure (U-ExM), compatible probes for imaging actin isoforms with U-ExM are still lacking and have hindered the study of diverse actin isoforms and networks across model systems. Here, we use IntAct, an internally tagged actin that incorporates into cellular actin networks, to develop and optimize U-ExM for diverse actin structures in yeast, mammalian cells, and primary neurons. Using ALFA-tagged IntAct variants, we achieve robust visualization of actin patches, cables, and rings in yeast, as well as diverse actin architectures including the cortex, stress fibers, filopodia, and lamellipodia in mammalian cells at improved resolution. In primary hippocampal neurons, IntAct efficiently labels actin throughout the soma and neuronal projections, revealing strong enrichment at dendritic spines and synaptic boutons. Notably, we observe a periodic organization of F-actin along axons consistent with the membrane-associated periodic cytoskeleton, thereby resolving the periodic, sub-diffraction actin ring organization. We also detect transient nuclear actin filaments using IntAct-U-ExM underscoring the advantages offered by our approach to image understudied actin structures. Overall, we demonstrate the effectiveness of IntAct-U-ExM for performing super-resolution imaging of various actin structures in an isoform-specific manner and highlight the potential of IntAct to study the nanoscale organization of diverse actin cytoskeletal networks across species.
Hedgehog (HH) signaling in vertebrates is dependent on the primary cilium, an organelle that scaffolds signal transduction. HH signals induce ciliary enrichment of Smoothened (SMO) and ciliary departure of the G protein-...Hedgehog (HH) signaling in vertebrates is dependent on the primary cilium, an organelle that scaffolds signal transduction. HH signals induce ciliary enrichment of Smoothened (SMO) and ciliary departure of the G protein-coupled receptor (GPCR) GPR161 to trigger GLI activation of the HH transcriptional program. Recently, SMO has been shown to inhibit protein kinase A (PKA). To test the hypothesis that SMO inhibits PKA at cilia to activate the HH signal transduction pathway, we developed a ciliary PKA reporter. Ciliary PKA activity was graded during zebrafish development. Activation of the HH signal transduction pathway by either Sonic hedgehog (SHH) or SMO agonist (SAG) inhibited ciliary PKA activity. Blocking SMO phosphorylation by GRK2/3 prevented ciliary SMO from inhibiting ciliary PKA activity. Converting the SMO C-terminal PKA pseudosubstrate site into a consensus PKA substrate blocked SMO-mediated inhibition of ciliary PKA activity. A ciliary GPCR, SSTR3, activated ciliary PKA and induced HH transcriptional responses in NIH/3T3 cells via a different mechanism: activation of Gαi/o. A different ciliary GPCR, GPR161, possesses an A-Kinase Anchoring Protein (AKAP), which we found was critical for the ciliary localization of the catalytic subunit of PKA (PKA-C) to promote ciliary PKA activity. We propose that HH signal transduction is inhibited by GPR161-mediated ciliary enrichment of PKA-C, and activated by GRK2/3-phosphorylated SMO inhibition of ciliary PKA activity.
How does the tempo of animal communication signals evolve? This Primer explores two recent reports published in PLOS Biology, identifying a hotspot of signal tempos between 0.5-4 Hz and independently hypothesizing that d...How does the tempo of animal communication signals evolve? This Primer explores two recent reports published in PLOS Biology, identifying a hotspot of signal tempos between 0.5-4 Hz and independently hypothesizing that delta waves in the receivers' brains may drive the evolution of this pattern.
Investigating the integrity of published scientific papers is key to the scientific process, but the necessary knowledge is in short supply. We present COSIG, an open collection of meta-scientific guides enabling anyone...Investigating the integrity of published scientific papers is key to the scientific process, but the necessary knowledge is in short supply. We present COSIG, an open collection of meta-scientific guides enabling anyone to perform forensic peer review.
Acoustic communication is crucial for survival across the animal kingdom, with acoustic signals being shaped by the interaction of producer and receiver selective pressures. While spectral features' variation reflects sp...Acoustic communication is crucial for survival across the animal kingdom, with acoustic signals being shaped by the interaction of producer and receiver selective pressures. While spectral features' variation reflects species-specific selection, the evolutionary history of acoustic communication rhythms, i.e., the rhythmic modulations of acoustic signals, remains unknown. Using data from 98 species spanning primarily mammals and birds, with additional representation from amphibians, reptiles, fishes, and insects, we investigate the origins of acoustic communication rhythms, notably whether they are shaped by the producer's anatomical characteristics, environmental constraints, or social complexity. Regression models which controlled for phylogenetic relatedness did not support an influence of these species-specific selective forces; instead, explicit phylogenetic models of trait evolution showed that most species' rhythms are conserved around an evolutionary optimum of 2.7 Hz that falls within the neural delta range (1-4 Hz) and predates mammalian divergence. Given the known conserved brain oscillations across species and delta involvement in active sensing, we propose that, unlike spectral features, acoustic rhythm could be governed by a universal neural mechanism facilitating effective intra and interspecific communication via a shared channel that has persisted through evolutionary times.
Mutations in the innate immune receptor NOD2 are the greatest single genetic risk factor for Crohn's disease, yet the mechanisms by which NOD2 regulates intestinal homeostasis remain unclear. We used a CRISPR-generated z...Mutations in the innate immune receptor NOD2 are the greatest single genetic risk factor for Crohn's disease, yet the mechanisms by which NOD2 regulates intestinal homeostasis remain unclear. We used a CRISPR-generated zebrafish model to determine the impacts of NOD2 deficiency on intestinal health. In cellular, molecular, and transcriptomic studies, we uncovered substantial effects of NOD2 deficiency on epithelial and immune compartments, including deregulated expression of developmental pathways that establish and maintain the gut epithelium, and an unexpected increase in the expression of multiple estrogen-response genes. In functional assays, we uncovered a mechanistic link between estrogenic signals and NOD2-deficiency phenotypes, whereby exposure to estrogen alone replicated the effects of NOD2-deficiency, and treatment with the estrogen receptor modulator tamoxifen reverted the epithelial defects observed in nod2 mutants. Our findings identify a NOD2-estrogen regulatory axis that supports intestinal homeostasis and suggest that hormonal signaling may contribute to sex-specific aspects of Crohn's disease.