Whole-genome sequencing is revolutionizing bacterial outbreak investigation, but its application to the clinic remains limited. In 2020, prospective and retrospective surveillance detected a Pseudomonas aeruginosa outbreak with 253 isolates collected from 82 patients in 26 wards of a hospital. Its origin was dated to the late 1990s, just after the facility opened, and patient-to-patient and environment-to-patient cases of transmission were inferred. Over time, two epidemic subclones evolved i...| eLife: latest articles
The intrinsic ability of injured neurons to degenerate and regenerate their axons facilitates nervous system repair; however, this ability is not engaged in all neurons and injury locations. Here, we investigate the regulation of a conserved axonal injury response pathway with respect to the location of damage in branched motoneuron (MN) axons in Drosophila larvae. The dileucine zipper kinase (DLK; also known as MAP3K12 in mammals and Wallenda (Wnd) in Drosophila) is a key regulator of divers...| eLife: latest articles
Training cognitive skills, such as remembering a list of words or navigating a new city, has important implications for everyday life. Yet, understanding what brain changes in humans underlies the acquisition of complex cognitive skills remains unresolved. Here, we developed and validated intensive multiweek interventions in which participants were randomly assigned training in either navigation or verbal memory. Healthy young participants (N=75) underwent structural and functional imaging pr...| eLife: latest articles
Here, we introduce a new endpoint ‘census population size’ to evaluate the epidemiology and control of Plasmodium falciparum infections, where the parasite, rather than the infected human host, is the unit of measurement. To calculate census population size, we rely on a definition of parasite variation known as multiplicity of infection (MOIvar), based on the hyper-diversity of the var multigene family. We present a Bayesian approach to estimate MOIvar from sequencing and counting the nu...| eLife: latest articles
Marsupials and placental mammals exhibit significant differences in reproductive and life history strategies. Marsupials are born highly underdeveloped after an extremely short period of gestation, leading to prioritized development of structures critical for post-birth survival in the pouch. Critically, they must undergo accelerated development of the orofacial region compared to placentals. Previously, we described the accelerated development of the orofacial region in the carnivorous Austr...| eLife: latest articles
In animal tissues, several cell types migrate along blood vessels, raising the possibility that blood flow influences cell migration. Here, we show that blood flow promotes the migration of new olfactory-bulb neurons in the adult mammalian brain. Neuronal migration is facilitated by blood flow, leading to accumulation of new neurons near blood vessels with abundant blood flow. Blood flow inhibition attenuates blood vessel-guided neuronal migration, suggesting that blood contains factors benef...| eLife: latest articles
Three-dimensional structured illumination microscopy (3D-SIM) doubles the resolution of fluorescence imaging in all directions and enables optical sectioning with increased image contrast. However, 3D-SIM has not been widely applied to imaging deep in thick tissues due to its sensitivity to sample-induced aberrations, making the method difficult to apply beyond 10 µm in depth. Furthermore, 3D-SIM has not been available in an upright configuration, limiting its use for live imaging while mani...| eLife: latest articles
The regional specificity of stem cell-derived astrocytes is believed to be an important prerequisite for their application in disease modelling and cell-based therapies. Due to the lack of subtype-defining markers for astrocytes in different regions of the brain, the regional identity of in vitro-derived astrocytes is often declared by the dominant positional characteristics of their antecedent neural progenitors, patterned to a fate of interest, with the assumption that the positional trait ...| eLife: latest articles
Various types of glycoproteins have been suggested to inhibit viral infection of cells via steric repulsion. However, it is difficult to evaluate such physical actions genetically, simply because they are nonspecific and can be caused by any molecule. Therefore, we investigated a method to compare this nonspecific action among cells with diverse membrane protein profiles. We found that a wide range of glycoproteins individually had a strong inhibitory effect on infection, while on the other h...| eLife: latest articles
Despite the current ubiquity of large language models (LLMs) across the medical domain, there is a surprising lack of studies which address their reasoning behaviour. We emphasise the importance of understanding reasoning behaviour as opposed to high-level prediction accuracies, since it is equivalent to explainable AI (XAI) in this context. In particular, achieving XAI in medical LLMs used in the clinical domain will have a significant impact across the healthcare sector. Therefore, in this ...| eLife: latest articles
Placebo and nocebo effects illustrate the profound influence of cognitive-affective processes on symptom perception and treatment outcomes, with the potential to significantly alter responses to medical interventions. Despite their clinical relevance, the question of how placebo and nocebo effects differ in strength and duration remains largely unexplored. Using a within-subject design in 104 healthy individuals, we investigated and directly compared the magnitude and persistence of placebo a...| eLife: latest articles
Macroautophagy, a major self-degradation pathway in eukaryotic cells, utilizes autophagosomes to transport self-material to lysosomes for degradation. While microtubular transport is crucial for the proper function of autophagy, the exact roles of factors responsible for positioning autophagosomes remain incompletely understood. In this study, we performed a loss-of-function genetic screen targeting genes potentially involved in microtubular motility. A genetic background that blocks autophag...| eLife: latest articles
Previous studies based on layer specificity suggest that ascending signals from the thalamus to the sensory neocortex preserve spatially organized information, but it remains unknown whether sensory information descending from sensory neocortex to the thalamus also maintains such spatial organization pattern. By focusing on projection specificity, we mapped the tone response properties of two groups of cortical neurons in the primary auditory cortex (A1), based on the relationship between the...| eLife: latest articles
Endotherms increase the rate of metabolism in metabolic organs as one strategy to cope with a decline in the temperature of the external environment. However, an additional major contributor to maintenance of body temperature in a cold environment is contraction-based thermogenesis in skeletal muscle. Here, we show that impairment of hind limb muscle contraction by cast immobilization induced a loss of function of skeletal muscle and activated brown adipose tissue (BAT) thermogenesis as a com...| eLife: latest articles
Specific character traits of mineralized endoskeletal tissues need to be clearly defined and comprehensively examined among extant chondrichthyans (elasmobranchs, such as sharks and skates, and holocephalans, such as chimaeras) to understand their evolution. For example, tiles of mineralized polygonal structures called tesserae occur at cartilage surfaces in chondrichthyans, but recent studies showing trabecular mineralization at elasmobranch cartilage surfaces suggest that tesserae are not a...| eLife: latest articles
Extracellular matrices surrounding eggs in fish (chorion) and mammals (zona pellucida [ZP]) regulate gamete recognition before fertilization, though their mechanisms differ. Mouse sperm bind and cross the ZP at any site, while fish sperm cross the chorion through a funnel-shaped opening, the micropyle. To explore these divergent processes, we established cross-species insemination assays, mixing zebrafish eggs with mouse sperm. While mouse sperm could not bind to the chorion, a subpopulation ...| eLife: latest articles
Intravital microscopy (IVM) enables live imaging of animals at single-cell level, offering essential insights into cancer progression. This technique allows for the observation of single-cell behaviors within their natural 3D tissue environments, shedding light on how genetic and microenvironmental changes influence the complex dynamics of tumors. IVM generates highly complex datasets that often exceed the analytical capacity of traditional uni-parametric approaches, which can neglect single-...| eLife: latest articles
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Following prolonged activity blockade, amplitudes of miniature excitatory postsynaptic currents (mEPSCs) increase, a form of plasticity termed ‘homeostatic synaptic plasticity’. We previously showed that a presynaptic protein, the small GTPase Rab3a, is required for full expression of the increase in miniature endplate current amplitudes following prolonged blockade of action potential activity at the mouse neuromuscular junction (NMJ) in vivo, where an increase in postsynaptic receptors ...| eLife: latest articles
Human fertility is suboptimal in part by error-prone divisions during early cleavage stages, which frequently result in chromosomal aneuploidy. Most human pre-implantation embryos are mosaics of euploid and aneuploid cells, yet those with a low proportion of aneuploid cells can develop to term at rates similar to fully euploid embryos. How embryos manage aneuploidy during early development remains poorly understood – yet this knowledge is crucial for improving fertility outcomes and reducin...| eLife: latest articles
The resting primate brain is traversed by spontaneous functional connectivity patterns that show striking differences between conscious and unconscious states. Transcranial direct current stimulation (tDCS), a non-invasive neuromodulatory technique, can improve signs of consciousness in disorders of consciousness (DOCs); however, can it influence both conscious and unconscious dynamic functional connectivity? We investigated the modulatory effect of prefrontal cortex (PFC) tDCS on brain dynam...| eLife: latest articles
A study that monitored the expression and function of designer receptors called DREADDs in macaque monkeys for a period of three years demonstrates that they are effective in long-term studies of nonhuman primates.| eLife: latest articles
The pulvinar, the largest thalamic nucleus, is a highly interconnected structure supporting perception, visuospatial attention, and emotional processing. Such a central role relies on a precise topographical organization reflected in anatomical connectivity and neurochemical markers. Traditionally subdivided into distinct subnuclei, recent work shows that these divisions only partially explain its organization, which is better captured by continuous gradients of cortical connections along dor...| eLife: latest articles
Synchronous neuronal ensembles play a pivotal role in the consolidation of long-term memory in the hippocampus. However, their organization during the acquisition of spatial memory remains less clear. In this study, we used neuronal population voltage imaging to investigate the synchronization patterns of mice CA1 pyramidal neuronal ensembles during the exploration of a new environment, a critical phase for spatial memory acquisition. We found synchronous ensembles comprising approximately 40...| eLife: latest articles
Adolescence is a developmental period characterized by heightened plasticity. Yet, how ongoing development affects sensory processing and cognitive function is unclear. We investigated how adolescent (postnatal day 20–42) and adult (postnatal day 60–82) mice differ in performance on a pure tone Go/No-Go auditory discrimination task of varying difficulty. Using dense electrophysiological recordings, we measured spiking activity at single neuron resolution in the auditory cortex while mice ...| eLife: latest articles
Tumors with low expression of interferon-stimulated genes (ISG) and antigen presentation (AP) genes respond relatively poorly to current immunotherapies. One of the early hallmarks of cancer is DNA hypomethylation in genomic repeat regions that can result in the expression of normally silenced endogenous ‘viral’ elements. Such epigenetic changes have the potential to augment anti-tumor immune responses as well as reduce tumor cell fitness through the generation of aberrant nucleic acid sp...| eLife: latest articles
Frizzled (FZD) proteins are the principal receptors of the Wnt signaling pathway. However, whether Wnt ligands induce FZD endocytosis and degradation remains elusive. The transmembrane E3 ubiquitin ligases ZNRF3 and RNF43 promote the endocytosis and degradation of FZD receptors to inhibit Wnt signaling, and their function is antagonized by R-spondin (RSPO) proteins. However, the dependency of RSPO-ZNRF3/RNF43-mediated FZD endocytosis and degradation on Wnt stimulation, as well as the specific...| eLife: latest articles
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The immune system is one of the first lines of defence against cancer. When effector cells attempt to suppress tumour, cancer cells can evolve methods of escape or inhibition. Knowledge of this coevolutionary system can help to understand tumour–immune dynamics both during tumourigenesis and during immunotherapy treatments. Here, we present an individual-based model of mutation accumulation, where random mutations in cancer cells trigger specialised immune responses. Unlike previous researc...| eLife: latest articles
Innate immune cells possess memory-like properties. Exposure to infections or sterile inflammation can prime them, leading to either exacerbated inflammatory responses, a process called trained immunity, or reduced responsiveness to pro-inflammatory signals, a process termed immune tolerance. Microglia, the resident innate immune cells of the central nervous system, are central players in neurodegenerative diseases. Characterizing trained immunity and tolerance in microglia is necessary for a...| eLife: latest articles
Species interactions affect ecosystem productivity. Positive interactions (resource partitioning and facilitation) increase productivity while negative interactions (species interference) decrease productivity relative to the null expectations defined by monoculture yields. Effects of competitive interactions (resource competition) can be either positive or negative. Distinguishing effects of species interactions is therefore difficult, if not impossible, with current biodiversity experiments...| eLife: latest articles
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Impairments of locus coeruleus (LC) are implicated in anxiety/depression and Alzheimer’s disease (AD). Increases in cytosolic noradrenaline (NA) concentration and monoamine oxidase A (MAO-A) activity initiate the LC impairment through production of NA metabolite, 3,4-dihydroxyphenyl-glycolaldehyde (DOPEGAL), by MAO-A. However, how NA accumulates in soma/dendritic cytosol of LC neurons has never been addressed despite the fact that NA is virtually absent in cytosol while NA is produced exclu...| eLife: latest articles
Push-pull systems for sustainable pest management combine repellent stimuli from intercrops (‘push’) and attractive stimuli from border plants (‘pull’) to repel herbivorous insects from a main crop and attract the herbivores’ natural enemies. The most widespread implementation, intercropping the legume Desmodium with maize surrounded by border grass, reduces damage from the invasive fall armyworm (FAW) Spodoptera frugiperda. While initial research indicated that Desmodium volatiles ...| eLife: latest articles
It is currently impossible to non-invasively assess cerebellar cell structure during early development. Here, we propose a novel approach to non-invasively and longitudinally track cell-specific development using diffusion-weighted magnetic resonance spectroscopy (MRS) in combination with microstructural modelling. Tracking metabolite diffusion allows us to probe cell-specific developmental trajectories in the cerebellum and thalamus of healthy rat neonates from postnatal day (P) 5 to P30. Ad...| eLife: latest articles
Megakaryocytes, the progenitor cells of blood platelets, play a crucial role in hemostasis by residing in the bone marrow and ensuring continuous platelet production. Unlike other hematopoietic cells, megakaryocytes do not enter the blood circulation intact. They remain anchored within the bone marrow while extending cytoplasmic protrusions called proplatelets through the sinusoidal endothelial barrier. These proplatelets subsequently fragment into functional platelets. This unique process of...| eLife: latest articles
The active system consolidation theory suggests that information transfer between the hippocampus and cortex during sleep underlies memory consolidation in humans. Neural oscillations during sleep, including the temporal coupling between slow oscillations (SO) and sleep spindles (SP), may play a mechanistic role in memory consolidation. However, differences in analytical approaches and the presence of physiological and behavioral moderators have led to inconsistent conclusions. This meta-anal...| eLife: latest articles
Shigella flexneri is a Gram-negative bacterial pathogen and causative agent of bacillary dysentery. S. flexneri is closely related to Escherichia coli but harbours a virulence plasmid that encodes a type III secretion system (T3SS) required for host cell invasion. Widely recognised as a paradigm for research in cellular microbiology, S. flexneri has emerged as important to study mechanisms of cell-autonomous immunity, including septin cage entrapment. Here, we use high-content high-resolution...| eLife: latest articles
Development of the mammalian visual system is thought to proceed in two stages. In the first stage, before birth in primates and before eye opening in altricial mammals, spontaneous activity generated by the retina and cortex shapes visual brain circuits in an activity-dependent but experience-independent manner. In the second stage, visual activity generated by sensory experience refines receptive fields. Here, we investigated the consequences of altering this sequence of events by premature...| eLife: latest articles
Phytopathogens secrete effector molecules to manipulate host immunity and metabolism. Recent advances in structural genomics have identified fungal effector families whose members adopt similar folds despite sequence divergence, highlighting their importance in virulence and immune evasion. To extend the scope of comparative structure-guided analysis to more evolutionarily distant phytopathogens with similar lifestyles, we used AlphaFold2 to predict the 3D structures of the secretome from sel...| eLife: latest articles
Social isolation generally increases aggression but decreases mating competition, resulting in an intricate and ambiguous relationship between social experience, aggression, and reproductive success. In male Drosophila, aggression is often characterized by lunging, a frequent and comparatively low-intensity combat behavior. Here, we provide a behavioral paradigm for studying a less frequent but more vigorous fighting form known as tussling. While social enrichment decreases lunging, aligning ...| eLife: latest articles
Cellular membranes differ across the tree of life. In most bacteria and eukaryotes, single-headed lipids self-assemble into flexible bilayer membranes. By contrast, thermophilic archaea tend to possess bilayer lipids together with double-headed, monolayer spanning bolalipids, which are thought to enable cells to survive in harsh environments. Here, using a minimal computational model for bolalipid membranes, we explore the trade-offs at play when forming membranes. We find that flexible bolal...| eLife: latest articles
In neural information processing, the nervous system transmits neuronal activity between layers of neural circuits, occasionally passing through small layers composed only of sparse neurons. Hippocampal hilar mossy cells (MCs) constitute such a typical bottleneck layer. However, how efficient information encoding is achieved within such constrained layers remains poorly understood. To address this, we focused on sharp wave-ripples (SWRs) – synchronous neural events originating in the CA3 re...| eLife: latest articles
The earliest growing mouse follicles, wave 1, rapidly develop in the ovarian medulla, while the great majority, wave 2, are stored for later use as resting primordial follicles in the cortex. Wave 1 follicles are known to mostly undergo atresia, a fate sometimes associated with the persistence of steroidogenic theca cells, but this connection is poorly understood. We characterized wave 1 follicle biology using tissue clearing, lineage tracing, and scRNA-seq to clarify their contributions to o...| eLife: latest articles
The dorsal vagal complex (DVC) is a region in the brainstem comprised of an intricate network of specialized cells responsible for sensing and propagating many appetite-related cues. Understanding the dynamics controlling appetite requires deeply exploring the cell types and transitory states harbored in this brain site. We generated a multi-species DVC cell atlas using single-nuclei RNA-sequencing, by curating and harmonizing mouse and rat data, which includes >180,000 cells and 123 cell ide...| eLife: latest articles
Intrinsically disordered proteins (IDPs) are now well-recognized as drug targets. Identifying drug-interacting residues is valuable for both optimizing compounds and elucidating the mechanism of action. Currently, NMR chemical shift perturbation and all-atom molecular dynamics (MD) simulations are the primary tools for this purpose. Here, we present DIRseq, a fast method for predicting drug-interacting residues from the amino-acid sequence. All residues contribute to the propensity of a parti...| eLife: latest articles
Manipulating the neuronal pathway responsible for the hypoxic stress response in the worm C. elegans leads to an increase in lifespan.| eLife: latest articles
Though the responses of the rich variety of retinal ganglion cells (RGCs) reflect the totality of visual processing in the retina and provide the sole conduit for those processed responses to the brain, we have much to learn about how the brain uses these signals to guide behavior. An impediment to developing a comprehensive understanding of the role of retinal circuits in behavior is the paucity of causal studies in the intact primate visual system. Here, we demonstrate the ability to optoge...| eLife: latest articles
Non-invasive brain stimulation techniques have the potential to improve memory functions. However, the results so far have been relatively modest and time-consuming. Here, we implemented a novel 3-min combination of personalized repetitive transcranial magnetic stimulation (intermittent theta burst, iTBS) coupled with simultaneous application of gamma transcranial alternating current stimulation (γtACS) over the precuneus, a brain area connected with the hippocampus, to modulate long-term me...| eLife: latest articles
The Mycobacterium tuberculosis RNA polymerase (MtbRNAP) is the target of the first-line anti-tuberculosis inhibitor rifampin; however, the emergence of rifampin resistance necessitates the development of new antibiotics. Here, we communicate the first single-molecule characterization of MtbRNAP elongation and its inhibition by three diverse small-molecule inhibitors: N(α)-aroyl-N-aryl-phenylalaninamide (D-IX216), streptolydigin (Stl), and pseudouridimycin (PUM) using high-resolution optical ...| eLife: latest articles
The ability to sense and adapt to adverse food conditions is essential for survival across species, but the detailed mechanisms of neuron-digestive crosstalk in food sensing and adaptation remain poorly understood. Here, we identify a novel mechanism by which Caenorhabditis elegans detect unfavorable food sources through neurons and initiate a systemic response to shut down digestion, thus safeguarding against potential harm. Specifically, we demonstrate that NSY-1, expressed in AWC neurons, ...| eLife: latest articles
Complex diseases often exhibit sex dimorphism in morbidity and prognosis, many of which are age-related. However, the underlying mechanisms of sex-dimorphic aging remain foggy, with limited studies across multiple tissues. We systematically analyzed ~17,000 transcriptomes from 35 human tissues to quantitatively evaluate the individual and combined contributions of sex and age to transcriptomic variations. We discovered extensive sex dimorphisms during aging with distinct patterns of change in...| eLife: latest articles
The skin is frequently subjected to minor mechanical insults that may compromise its barrier integrity and permit the entry of pathogens. Therefore, the immune system of the skin needs to rapidly balance antimicrobial defense with tissue repair. To maintain homeostasis, the skin relies both on acute immune defenses and on mechanisms of innate memory or trained immunity. This enhanced inflammatory response to a second challenge has been well characterized in bone marrow cells, such as monocyte...| eLife: latest articles
The power of electrophysiologically measured cortical activity decays with an approximately 1 /fX function. The slope of this decay (i.e. the spectral exponent, X) is modulated by various factors such as age, cognitive states or psychiatric/neurological disorders. Interestingly, a mostly parallel line of research has also uncovered similar effects for the spectral slope in the electrocardiogram (ECG). This raises the question of whether these bodywide changes in spectral slopes are (in-)depen...| eLife: latest articles
Artemisinin partial resistance (ART-R) in Plasmodium falciparum is a major challenge to malaria control globally. Over the last two decades, ART-R has spread widely across Southeast Asia, undermining public health strategies and hindering elimination. As of 2024, ART-R has now emerged in East Africa, with the potential to dramatically impact current efforts to control malaria in the region. Mitigating its spread requires detailed genomic surveillance of point mutations in the kelch13 gene, th...| eLife: latest articles
The assembly and operation of neural circuits in the brain rely on the coordination and balance of excitatory and inhibitory activities. Inhibitory synapses are key regulators of the functional balance of neural circuits. However, due to the diversity of inhibitory presynaptic neurons, the complex composition of postsynaptic receptor subunits, and the lack of typical postsynaptic dense structure, there are relatively few studies on the regulatory mechanisms for inhibitory synaptic structure a...| eLife: latest articles
A quarter of the human population is infected with Mycobacterium tuberculosis, but less than 10% of those infected develop pulmonary TB. We developed a genetically defined sst1-susceptible mouse model that uniquely reproduces a defining feature of human TB: the development of necrotic lung granulomas and determined that the sst1-susceptible phenotype was driven by the aberrant macrophage activation. This study demonstrates that the aberrant response of the sst1-susceptible macrophages to prol...| eLife: latest articles
Mammalian genomes are organized by multi-level folding; yet how this organization contributes to cell-type-specific transcription remains unclear. SATB1 forms a nuclear substructure that resists high-salt extraction. SATB1 binds base-unpairing regions (BURs), genomic elements with high unwinding propensities. In mouse thymocytes, we found that SATB1 establishes a two-tiered chromatin organization: one through indirect binding to transcriptionally active DNase 1-accessible chromatin and anothe...| eLife: latest articles
The safety-efficiency dilemma describes the problem of maintaining safety during efficient exploration and is a special case of the exploration-exploitation dilemma in the face of potential dangers. Conventional exploration-exploitation solutions collapse punishment and reward into a single feedback signal, whereby early losses can be overcome by later gains. However, the brain has a separate system for Pavlovian fear learning, suggesting a possible computational advantage to maintaining a sp...| eLife: latest articles
Differences in the activity of an enzyme called CARM1 influence the timing of blastomere polarization and whether they become part of the embryo or the placenta.| eLife: latest articles
Past sensory experiences influence perception of the present. Multiple research subfields have emerged to study this phenomenon at different temporal scales. These phenomena fall into three categories: the influence of immediately preceding sensory events (micro), expectations established by short sequences of events (meso), and regularities over long sequences of events (macro). In a single paradigm, we examined the influence of temporal context on human perception at each scale. By integrat...| eLife: latest articles
Spiny projection neurons (SPNs) in the dorsal striatum play crucial roles in locomotion control and value-based decision-making. SPNs, which include both direct-pathway striatonigral and indirect-pathway striatopallidal neurons, can be further classified into subtypes based on distinct transcriptomic profiles and cell body distribution patterns. However, how these SPN subtypes regulate spontaneous locomotion in the context of environmental valence remains unclear. Using Sepw1-Cre transgenic m...| eLife: latest articles
The extracellular matrix (ECM) supports blood vessel architecture and functionality and undergoes active remodelling during vascular repair and atherogenesis. Vascular smooth muscle cells (VSMCs) are essential for vessel repair and, via their secretome, can invade from the vessel media into the intima to mediate ECM remodelling. Accumulation of fibronectin (FN) is a hallmark of early vascular repair and atherosclerosis. Here, we show that FN stimulates human VSMCs to secrete small extracellul...| eLife: latest articles
The function of the human telomerase reverse transcriptase (referred hereafter as TERT) in the synthesis and maintenance of chromosome ends, or telomeres, is widely understood. Whether and how telomeres, on the other hand, influence TERT regulation is relatively less studied. We found TERT was transcriptionally altered depending on telomere length (TL). This resulted from TL-dependent binding of TRF2 between telomeres and the TERT promoter. TERT promoter-bound TRF2 was non-telomeric and did n...| eLife: latest articles
Dense microbial communities, like the gut and soil microbiomes, are dynamic societies. Bacteria can navigate these environments by deploying proteins that alter foreign cells’ behavior, such as interbacterial effectors. Current models suggest that adjacent sibling cells are protected by an immunity protein, as compared to toxin-antitoxin systems that act only within the effector-producing cell. A prevailing hypothesis is that immunity proteins binding to specific (cognate) protein partners ...| eLife: latest articles
Most phylogenetic trees are inferred using time-reversible evolutionary models that assume that the relative rates of substitution for any given pair of nucleotides are the same regardless of the direction of the substitutions. However, there is no reason to assume that the underlying biochemical mutational processes that cause substitutions are similarly symmetrical. We consider two non-reversible nucleotide substitution models: (1) a 6-rate non-reversible model (NREV6) that is applicable to...| eLife: latest articles
Neural activity in the primate brain correlates with both sensory evaluation and action selection aspects of decision-making. However, the intricate interaction between these distinct neural processes and their impact on decision behaviors remains unexplored. Here, we examined the interplay of these decision processes in posterior parietal cortex (PPC) when monkeys performed a flexible decision task. We found that the PPC activity related to monkeys’ abstract decisions about visual stimuli ...| eLife: latest articles
Transcription factors (TFs) are proteins crucial for regulating gene expression. Effective regulation requires the TFs to rapidly bind to their correct target, enabling the cell to respond efficiently to stimuli such as nutrient availability or the presence of toxins. However, the search process is hindered by slow diffusive movement and the presence of ‘false’ targets – DNA segments that are similar to the true target. In eukaryotic cells, most TFs contain an intrinsically disordered r...| eLife: latest articles
Most behaviors result from integration of external and internal inputs. For example, social behavior requires information about conspecifics and internal physiological states. Like many other mammals, female mice undergo a reproductive cycle during which their physiology and behavioral responses to males change dramatically: during estrus, they are more receptive to male mating attempts. A critical element in reproductive behavior is the investigative stage, which in mice and many other speci...| eLife: latest articles
Drug repurposing screens reveal several epigenetic inhibitors as active against P. vivax hypnozoites demonstrating that epigenetic pathways play a central role in hypnozoite quiescence.| eLife
The epigenetic adaptation of innate immune cells to inflammatory stimuli, or trained immunity, represents an evolutionarily conserved feature of host defense. Recent advances have revealed that such adaptations can occur at the level of hematopoietic stem and progenitor cells, resulting in long-lasting epigenetic reprogramming of the immune system. However, a comprehensive mechanistic understanding of these processes remains incomplete, limiting our capacity to predict or therapeutically mani...| eLife: latest articles
The blood-brain barrier (BBB) interferes with the treatment of central nervous system disorders owing to the complexity of its structure and restrictive function. Thus, it is challenging to develop central nervous system drug delivery strategies. Specific mode electroacupuncture (EA) stimulation can effectively open the BBB in rats. Here, we used single-cell RNA sequencing (scRNA-seq) to comprehensively map the cell population in the Sprague-Dawley rat cerebral cortex. We identified 23 cell s...| eLife: latest articles
The transition from prebiotic chemistry to living systems requires the emergence of a scheme for enzyme-free genetic replication. Here, we analyze a recently proposed prebiotic replication scenario, the so-called Virtual Circular Genome (VCG) [Zhou et al., RNA 27, 1-11 (2021)]: Replication takes place in a pool of oligomers, where each oligomer contains a subsequence of a circular genome, such that the oligomers encode the full genome collectively. While the sequence of the circular genome ma...| eLife: latest articles
Signatures of consciousness are found in spectral and temporal properties of neuronal activity. Among these, spatiotemporal complexity after a perturbation has recently emerged as a robust metric to infer levels of consciousness. Perturbation paradigms remain, however, difficult to perform routinely. To discover alternative paradigms and metrics, we systematically explore brain stimulation and resting-state activity in a whole-brain model. We find that perturbational complexity only occurs wh...| eLife: latest articles
The evolutionary expansion of extracellular matrix (ECM) molecules has been crucial for the establishment of cell adhesion and the transition from unicellular to multicellular life. Members of the early diverging metazoan phylum Cnidaria offer an exceptionally rich perspective into the metazoan core adhesome and its original function in developmental and morphogenetic processes. Here, we present the ensemble of ECM proteins and associated factors for the starlet sea anemone Nematostella vecte...| eLife: latest articles
Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) offer a powerful means for reversible control of neuronal activity through systemic administration of inert actuators. Because chemogenetic control relies on DREADD expression levels, understanding and quantifying the temporal dynamics of their expression is crucial for planning long-term experiments in monkeys. In this study, we longitudinally quantified in vivo DREADD expression in macaque monkeys using positron emission t...| eLife: latest articles
In humans, new-born infants can regenerate their heart during early life. This is modelled in the mouse, where regenerative capacity is maintained for the first week after birth but lost thereafter. Reactivation of this process holds great therapeutic potential; however, the molecular pathways that might be targeted to extend neonatal regeneration remain elusive. Here, we explored a role for hypoxia and HIF signalling on the regulation of epicardial activity in the developing mouse heart and ...| eLife: latest articles
Blood pressure variability (BPV) has emerged as a significant risk factor for cognitive decline and dementia, independent of alterations in average blood pressure (BP). However, the impact of large BP fluctuations on neurovascular function remains poorly understood. In this study, we developed a novel murine model of BPV in middle-aged mice using intermittent angiotensin II infusions. Radio telemetry confirmed that 24 hr BP averages in BPV mice remained comparable to controls, demonstrating B...| eLife: latest articles
Maintenance of pluripotency is a multifactorial process in which NF-κB is a negative regulator. Our previous work identified a chromatin role for IκBα, the master regulator of NF-κB signaling, that is critical for the proper regulation of various tissue stem cells. Here, we found that IκBα accumulates specifically in the chromatin fraction of mouse pluripotent stem cells. IκBα depletion does not affect NF-kB-dependent transcription, but causes a profound epigenetic rewiring in pluripo...| eLife: latest articles
Relevant prospective moments arise intermittently, while most of the time is filled with irrelevant events, or noise, that constantly bombard our sensory systems. Thus, anticipating a few key moments necessitates disregarding what lies between the present and the future – the noise. Here, through examining how the brain and recurrent neural networks (RNNs) anticipate a sequence of prospective moments without relying on any external timing cues, we provided a reinterpretation of temporal ant...| eLife: latest articles
Evolutionary changes in RNA binding and antiviral activity result in diverse IFIT1 functions across mammals, even among closely related species.| eLife
With support from the COAR Notify Initiative, partners eLife and PREreview will strengthen connections between preprint review and curation services for authors, journals and the wider scientific community.| eLife
The striatal direct and indirect pathways constitute the core for basal ganglia function in action control. Although both striatal D1- and D2-spiny projection neurons (SPNs) receive excitatory inputs from the cerebral cortex, whether or not they share inputs from the same cortical neurons, and how pathway-specific corticostriatal projections control behavior remain largely unknown. Here using a G-deleted rabies system in mice, we found that more than two-thirds of excitatory inputs to D2-SPNs...| eLife: latest articles
NOMPC, a tethered mechanosensitive ion channel belonging to the transient receptor potential (TRP) family, converts mechanical stimuli into ionic electric signals that excite neuronal cells (Yan et al., 2013). Previous investigations have demonstrated that a pushing force applied to the linker helix domain or the compression of NOMPC’s ankyrin repeat (AR) domain can trigger channel opening (Wang et al., 2021). In this study, we explored the direct mechanical causes of NOMPC channel opening ...| eLife: latest articles
Bacterial growth characteristics intrinsic to each strain can impact and influence gene expression, antibiotic susceptibility, and disease pathogenesis. However, little is known about specific genomic variations that influence these bacterial growth features. Here, we investigate the impact of Streptococcus pneumoniae genetics on its in vitro growth features to shed light on genes that may be important targets in the development of vaccines and therapeutics. We use statistical models to estim...| eLife: latest articles
In cancer cells, ATR signaling is crucial to tolerate the intrinsically high damage levels that normally block replication fork progression. Assembly of TopBP1, a multifunctional scaffolding protein, into condensates is required to amplify ATR kinase activity to the levels needed to coordinate the DNA damage response and manage DNA replication stress. Many ATR inhibitors are tested for cancer treatment in clinical trials, but their overall effectiveness is often compromised by the emergence o...| eLife: latest articles
Directional tongue movements are crucial for feeding and speech, ensuring proper food positioning for chewing and swallowing, as well as accurate sound production. While directional tuning in the arm region of the sensorimotor cortex during reaching tasks is well studied, little is known about how three-dimensional (3D) tongue direction is encoded in the orofacial sensorimotor cortex (OSMCx) during natural behaviors. Understanding this neural representation has important implications for reha...| eLife: latest articles
Volume electron microscopy (vEM) datasets such as those generated for connectome studies allow nanoscale quantifications and comparisons of the cell biological features underpinning circuit architectures. Quantifying cell biological relationships in the connectome yields rich, multidimensional datasets that benefit from data science approaches, including dimensionality reduction and integrated graphical representations of neuronal relationships. We developed NeuroSC (also known as NeuroSCAN,h...| eLife: latest articles
In the Drosophila olfactory system, most odorants are encoded in the antennal lobe in a combinatory way, activating several glomerular circuits. However, odorants of particular ecological role for the fly are encoded through activation of a single specialized olfactory pathway. Comparative analyses of densely reconstructed connectomes of one broadly tuned glomerulus (DL5) and one narrowly tuned glomerulus (DA2) gained detailed insight into the variations of synaptic circuitries of glomeruli w...| eLife: latest articles
Mutations in EGLN1, the gene encoding for hypoxia-inducible factor (HIF) prolyl-4-hydroxylase 2 (PHD2), cause erythrocytosis and in rare cases the development of neuroendocrine tumors. In the presence of oxygen, PHD2 hydroxylates one or both conserved prolines in the oxygen-dependent degradation domain (ODD) of HIFα subunits, sufficiently marking HIFα for binding and ubiquitylation via the von Hippel-Lindau (VHL) tumor suppressor protein-containing E3 ubiquitin ligase and subsequent degrada...| eLife: latest articles
Innate immune memory, or trained innate immunity (TII), represents a form of immunological adaptation in which innate immune cells, including myeloid and lymphoid cells, retain a trained state following prior exposure to immunological stimuli. This long-lasting modification either enhances or reduces the innate immune response to subsequent heterologous infections or inflammatory insults. While TII often provides protective benefits, including enhanced protection against pathogens and tumors,...| eLife: latest articles
Sound encoding depends on the precise and reliable neurotransmission at the afferent synapses between the sensory inner hair cells (IHCs) and spiral ganglion neurons (SGNs). The molecular mechanisms contributing to the formation, as well as interplay between the pre- and postsynaptic components, remain largely unclear. Here, we tested the role of the synaptic adhesion molecule and Nogo/RTN4 receptor homolog RTN4RL2 (also referred to as NgR2) in the development and function of afferent IHC–S...| eLife: latest articles
Conserved sequence motifs within intrinsically disordered protein regions act as evolutionary units that support phase separation and membraneless organelle formation.| eLife
Blood flow and a hormone called ghrelin help new neurons travel to where they are meant to be in the brain of adult mice.| eLife
Loss of ZDHHC9, a protein acyltransferase that is highly expressed in oligodendrocytes, does not grossly impact myelination but markedly alters oligodendrocyte morphology and myelination at the micro/nano-scale.| eLife
In brain regions featuring ongoing plasticity, the task of quickly encoding new information without overwriting old memories presents a significant challenge. In the rodent olfactory bulb, which is renowned for substantial structural plasticity driven by adult neurogenesis and persistent turnover of dendritic spines, we show that by synergistically combining both types of plasticity, this flexibility-stability dilemma can be overcome. To do so, we develop a computational model for structural ...| eLife: latest articles
There is a growing understanding of how alternative splicing contributes to functional specialization and adaptation, especially in well-studied model organisms. However, its large-scale evolutionary dynamics remain poorly understood. Through a comparative analysis of alternative splicing across 1494 species spanning the entire tree of life, this study integrates numerous lines of prior evidence to provide a unified view of alternative splicing. We propose a novel genome-scale metric designed...| eLife: latest articles
The rearrangement of TCR germline V(D)J genes during T cell development, including allelic exclusion and tolerance selection, ensures the clonal selection theory, which states that ‘a lymphocyte expresses only one type of antigen receptor’. This forms the basis for T cell-specific responses. However, the existence of ‘dual TCR T cells’ has consistently been supported by specific experimental evidence. Detailed reports on the origin, proportion, tissue distribution, and CDR3 characteri...| eLife: latest articles
Development of robotic device for pain and somatosensory assays in rodents allows remote, quantitative, and reproducible delivery of mechanical stimuli.| eLife
Effective mucosal immunity in the intestine involves a fine balance between tolerance of the microbiome, recognition, and elimination of pathogens, and inflammatory tissue injury. The anti-inflammatory cytokine IL10 regulates these processes in the intestines of mice and humans; the anti-inflammatory activity of IL10 is also conserved in birds. To determine the function of IL10 in avian mucosal immunity, we generated germ line modifications of the chicken IL10 locus to abolish or reduce IL10 ...| eLife: latest articles
