High-throughput single-cell assays reveal data that defies discrete categorization. The 'cell cloud' model, grounded in established systems biology principles, offers a framework to navigate biological plasticity alongsi...High-throughput single-cell assays reveal data that defies discrete categorization. The 'cell cloud' model, grounded in established systems biology principles, offers a framework to navigate biological plasticity alongside technical variability.
Flexible behavior requires the ability to modulate sensory processing based on task context, yet the circuit-level mechanisms supporting this capacity remain poorly understood. Here, we combine recurrent neural network m...Flexible behavior requires the ability to modulate sensory processing based on task context, yet the circuit-level mechanisms supporting this capacity remain poorly understood. Here, we combine recurrent neural network modeling and neural recordings from mouse visual cortex to investigate how task context shapes sensory coding. Networks trained on an instruction-based discrimination task develop a disinhibitory interneuron-to-interneuron motif that dynamically gates task-relevant sensory information. Perturbation and lesion analyses show that this motif is necessary for task performance and for maintaining distinct sensory representations across contexts. We validate key predictions in mouse visual cortex, where interneuron activity patterns exhibit comparable task-dependent modulation. These results identify a biologically plausible circuit motif that supports flexible sensory processing and link recurrent connectivity structure to adaptive context integration in both artificial and biological systems.
Advances in artificial intelligence (AI)-driven bioinformatics promise democratized discovery, yet major inequities persist. Equitable adoption of bioinformatics tools will require sustained investment in infrastructure,...Advances in artificial intelligence (AI)-driven bioinformatics promise democratized discovery, yet major inequities persist. Equitable adoption of bioinformatics tools will require sustained investment in infrastructure, training, institutions, and global communities, not just access.
Cognitive control is believed to arise from task-dependent interactions among networks of brain regions. Although several debilitating neuropsychiatric disorders are characterized by cognitive network dysfunction, the ne...Cognitive control is believed to arise from task-dependent interactions among networks of brain regions. Although several debilitating neuropsychiatric disorders are characterized by cognitive network dysfunction, the neural circuit mechanisms supporting task-dependent network activity are largely unknown. External and internal task demands elicit opposing responses from key cognitive networks, and claustrum projections target regions associated with both network states. We tested if claustrum supports task-dependent network activity in humans using fMRI during tasks with externally and internally driven demands: working memory (n = 420) and autobiographical memory (n = 35). Claustrum activity increased in both tasks. Claustrum exhibited anatomical connectivity with regions representing all implicated networks, and claustrum effective connectivity suggested an excitatory influence on regions in multiple task-associated networks. Task response and connectivity measures differed between the claustrum and regions prominently implicated in directing network states-the anterior insula and pulvinar. These findings establish a role for the claustrum in supporting task-dependent network states subserving cognitive control.
Recombination suppression leads to genomic erosion through an accumulation of deleterious mutations. A new study in PLOS Biology reveals an outstanding increase in aberrant splicing in non-recombining genomic regions in...Recombination suppression leads to genomic erosion through an accumulation of deleterious mutations. A new study in PLOS Biology reveals an outstanding increase in aberrant splicing in non-recombining genomic regions in green algae.
Homeostasis is essential for hematopoiesis, and its dysregulation can lead to severe pathological conditions. Retinoic acid (RA) is a key regulator that exerts concentration-dependent effects on both embryonic and adult...Homeostasis is essential for hematopoiesis, and its dysregulation can lead to severe pathological conditions. Retinoic acid (RA) is a key regulator that exerts concentration-dependent effects on both embryonic and adult hematopoiesis. However, the mechanisms that modulate RA signaling in hematopoietic processes remain poorly understood. Using zebrafish as a model, we identified angiopoietin-like protein 5 (Angptl5) as a critical regulator of hematopoietic homeostasis. Loss of Angptl5 function resulted in myeloid hyperplasia in the anterior lateral plate mesoderm (ALPM) and anterior expansion of erythroid progenitors in the posterior lateral plate mesoderm (PLPM)-phenotypes consistent with attenuated RA signaling. Molecular analyses confirmed impaired RA signaling in angptl5Δ10/Δ10 mutants, and exogenous RA supplementation fully rescued the hematopoietic defects. Mechanistically, we found that Angptl5 transcriptionally activates retinol dehydrogenase dhrs9 through its interaction with Integrin α6lβ5. Our findings establish Angptl5 as a novel and essential regulator of embryonic hematopoiesis and reveal a previously unrecognized mechanism controlling hematopoietic homeostasis. These insights position Angptl5 as a potential therapeutic target for hematological disorders.
Successful mammalian development normally requires contributions from both maternal and paternal genomes, yet how these parental components jointly shape organismal development remains incompletely understood. Using engi...Successful mammalian development normally requires contributions from both maternal and paternal genomes, yet how these parental components jointly shape organismal development remains incompletely understood. Using engineered bipaternal mice generated from androgenetic embryonic stem cells carrying extensive imprinting-region modifications and produced through tetraploid complementation, we examined developmental and physiological consequences of development supported exclusively by paternal genomes. Placental analyses revealed partial normalization of placental growth but persistent differences among conceptuses. Transcriptomic profiling across embryos and postnatal tissues similarly showed broad alterations in gene expression states involving both imprinted and non-imprinted genes. Despite these differences during development, adult physiology showed a more coherent endpoint: integrated transcriptomic and metabolomic analyses revealed that adult livers converge toward an altered metabolic configuration characterized by coordinated perturbations of the tricarboxylic acid cycle and associated lipid metabolism, accompanied by hepatic lipid accumulation and increased systemic fat mass. These findings indicate that paternal-only mammalian development can proceed across multiple stages but follows altered developmental trajectories that culminate in distinct physiological states, providing insight into how maternal and paternal genomic contributions interact to shape mammalian development and physiology.
Rapid information processing in complex organisms depends on myelin, which consists of a multilamellar membrane that tightly adheres to the axonal surface along the internode and at paranodal loops, where specialized adh...Rapid information processing in complex organisms depends on myelin, which consists of a multilamellar membrane that tightly adheres to the axonal surface along the internode and at paranodal loops, where specialized adhesion proteins maintain axon-glial contact. Because the decision to myelinate an axon profoundly influences neuronal transmission, this process must be precisely regulated. Yet, it remains unclear which specific molecules enable oligodendrocytes to select appropriate axonal substrates for myelination. Several key myelin-associated adhesion systems have been identified, including Myelin-associated glycoprotein (Mag) and Cell Adhesion Molecule 4 (Cadm4) at the internode, as well as Contactin1 (Cntn1) at the paranode; however, these three adhesion molecules have not previously been deleted in combination. Here, using zebrafish, we systematically disrupted all three myelin-associated adhesion systems. We found that the combined loss of Mag, Cadm4, and Cntn1 severely impairs myelin initiation and destabilizes the few nascent sheaths that do form, resulting in a phenotype characterized by oligodendrocytes exhibiting membrane "stubs". The failure to form myelin triggered cell death of early myelinating oligodendrocytes and resulted in profound hypomyelination. Our findings reveal that axonal target selection and myelin formation depend on a redundant set of adhesion molecules, and that their simultaneous loss largely abolishes myelin biogenesis.
Splicing deficiency may represent a critical yet underexplored form of genomic erosion in non-recombining regions. Across four phytoplankton species diverged ~333-639 million years ago, genes within U (female) and V (mal...Splicing deficiency may represent a critical yet underexplored form of genomic erosion in non-recombining regions. Across four phytoplankton species diverged ~333-639 million years ago, genes within U (female) and V (male) "UV" mating-type regions-non-recombining chromosomal regions that determine mating compatibility-show strikingly elevated intron retention relative to genes in other genomic regions. Long-read data reveal abundant aberrant, likely non-functional mRNA isoforms despite preserved coding potential. This preservation suggests that splicing defects arose early in UV evolution and have persisted over deep time. We propose that these defects arise from evolutionary changes in sequence composition and chromatin organization that accompany recombination suppression, such as reduced GC content, altered nucleosome occupancy, and disrupted methylation, that collectively compromise splicing fidelity. Unlike sex chromosomes, which often degenerate through gene loss, splicing-deficient UV regions in green algae retain hundreds of genes, indicating that transcript-level dysfunction provides an alternative route to functional decay. Our results identify chromatin-mediated splicing deficiency as a novel axis of genomic erosion and position algal UV systems as models for studying how recombination suppression reshapes RNA processing fidelity in essential, non-recombining genomes.
A new study in PLOS Biology shows that neuronal firing is selectively tuned to oscillatory frequency in human intracranial recordings, complementary to phase tuning, suggesting an additional dimension in how brain rhythm...A new study in PLOS Biology shows that neuronal firing is selectively tuned to oscillatory frequency in human intracranial recordings, complementary to phase tuning, suggesting an additional dimension in how brain rhythms may organize neural activity.
Understanding and predicting how communities assemble is a paramount challenge in ecology. Here we address these questions normatively by comparing the observed species abundance distribution to a game-theoretically fair...Understanding and predicting how communities assemble is a paramount challenge in ecology. Here we address these questions normatively by comparing the observed species abundance distribution to a game-theoretically fair distribution based on each species' Shapley value. By analyzing in total 56 distinct community outcomes, we assess how fairly biomass is distributed in microbial communities displaying both competitive and cooperative interactions in different growth conditions. We find examples of fair communities that closely follow their Shapley value across all environments as well as counterexamples where the true abundances deviate from the species' objective contribution to community biomass. Next, we develop a fair assembly rule based on the recursive definition of Shapley value and show that also unfair community compositions are consistent with the principles of fair assembly after the lower-level competitive outcomes are known. Our results give unique empirical insights into the distributive function of ecological dynamics and lay down the theoretical foundations of what might become a normative community assembly theory.
The dynamics of stem cell maintenance and proliferative patterns are key determinants of tissue aging in multicellular organisms. Leveraging our previously developed SMALT system with enhanced sequencing compatibility, w...The dynamics of stem cell maintenance and proliferative patterns are key determinants of tissue aging in multicellular organisms. Leveraging our previously developed SMALT system with enhanced sequencing compatibility, we performed longitudinal lineage tracing of the adult Drosophila melanogaster midgut across different developmental stages. Using ubiquitous Tubulin-GAL4-driven labeling, we first profiled midgut-wide clonal dynamics during early adulthood (3-33 days post-eclosion). Phylogenetic reconstruction revealed that clonal diversity peaked immediately after eclosion and began to decline earlier than anticipated, accompanied by a reduction in effective population size. To further investigate stem cell-specific dynamics during late adulthood, we employed intestinal stem cell (ISC)-specific Dl-GAL4-driven labeling (33-63 days post-eclosion) and observed sustained clonal attrition in the posterior midgut. This progressive loss of diversity was consistent with an age-associated change in effective proliferative behavior and reduced lineage maintenance capacity, as reflected by a decline in net proliferative output inferred from lineage topology. Remarkably, ISC lineages emerging within the first 10 days post-eclosion exhibited sustained clonal dominance in aging populations, with a single lineage comprising over 63% of sampled cells by Day 63. Bayesian survival modeling confirmed that these early-origin lineages have the highest probabilities of long-term persistence, while a graph neural network model accurately predicted their structural evolution across successive stages. Together, we delineate a timeline for clonal attrition and deliver topology-driven predictors of clone survival and structural change, enabling prospective identification of dominant and failing clones during aging.
Web-based modeling platforms can enhance collaboration between modelers and experimentalists during early model development. Drawing on two interdisciplinary case studies, we provide guiding principles on how to build in...Web-based modeling platforms can enhance collaboration between modelers and experimentalists during early model development. Drawing on two interdisciplinary case studies, we provide guiding principles on how to build interactive agile modeling tools.
UNLABELLED: Sleep is essential for synaptic homeostasis, a proposed mechanism whereby wakefulness leads to synaptic potentiation and sleep facilitates synaptic down-selection. Synaptic vesicle glycoprotein 2A (SV2A), who...UNLABELLED: Sleep is essential for synaptic homeostasis, a proposed mechanism whereby wakefulness leads to synaptic potentiation and sleep facilitates synaptic down-selection. Synaptic vesicle glycoprotein 2A (SV2A), whose availability is quantifiable by [¹⁸F]SynVesT-1 positron emission tomography (PET), is commonly interpreted as a proxy for synaptic density. In this randomized study, we examined 40 healthy adults (mean age 27.5 ± 6.5 years) who underwent two [¹⁸F]SynVesT-1 PET scans on consecutive days. Half of the participants were assigned to the normal sleep (i.e., control) condition and half to the sleep deprivation condition. Scans were performed at the same circadian time point, approximately 4 h after awakening in the control group and during baseline in the sleep deprivation group or after ~28 h of continuous wakefulness in the sleep deprivation group after sleep deprivation. Sleep deprivation led to significant increases in synaptic vesicle glycoprotein 2A binding in multiple brain regions, including the thalamus (+4.6%), hippocampus (+5.6%), and parietal cortex (+3.2%), whereas no changes were observed in controls. The degree of increase in synaptic vesicle glycoprotein 2A positively correlated with elevated slow wave activity during recovery sleep, a physiological marker of sleep pressure. These findings provide in vivo support for the synaptic homeostasis hypothesis in humans and suggest that synaptic vesicle glycoprotein 2A PET imaging is sensitive to sleep-wake dependent synaptic plasticity. TRIAL REGISTRATION: The study was prospectively registered on 19.01.2022 here: German Clinical Trials Registry: DRKS # DRKS00027867, https://drks.de/search/en/trial/DRKS00027867.
Neural oscillations play a critical role in shaping neuronal firing patterns. While phase-locked neuronal firing ("phase tuning") has been extensively studied in animal models and human invasive recordings, much less is...Neural oscillations play a critical role in shaping neuronal firing patterns. While phase-locked neuronal firing ("phase tuning") has been extensively studied in animal models and human invasive recordings, much less is known about whether neurons show preferential firing at specific oscillatory frequencies, termed frequency tuning. Here, we employ human intracranial recordings across several brain regions including hippocampus, entorhinal cortex, anterior and posterior cingulate cortex, and orbitofrontal cortex to test the hypothesis that neurons exhibit frequency-specific firing. We analyzed 357 single units recorded simultaneously with local field potentials in 19 neurosurgical patients during awake resting. We estimated the instantaneous frequency of the LFP using adaptive spectral decomposition and assessed frequency tuning of each neuron while controlling for changes in firing rate unrelated to frequency changes. We found 27% of neurons exhibited increased or decreased firing within specific frequencies, most commonly within the low-frequency range (<10 Hz). Neurons exhibiting frequency tuning were distinct from those displaying phase tuning, and both types of tuning were observed across multiple brain regions with no anatomical preference. Together, our results demonstrate that the instantaneous frequency of neural oscillations modulates neuronal firing which may serve as an additional mechanism for information processing in the human brain, opening new avenues for frequency-targeted neural stimulation.
The human endocrine system orchestrates critical physiological processes, yet a systematic quantitative synthesis of clinically relevant circulating hormones has been lacking. Here, we present a comprehensive, integrativ...The human endocrine system orchestrates critical physiological processes, yet a systematic quantitative synthesis of clinically relevant circulating hormones has been lacking. Here, we present a comprehensive, integrative analysis of circulating human hormones, leveraging clinically validated reference intervals across major endocrine subsystems. We use clinically validated reference intervals that we further validate using published datasets. Our analysis reveals that the total mass of circulating hormones is approximately 40 ± 2 mg. We find that this mass in healthy young adults is dominated by Adiponectin and DHEAS, which constitute over 90% of both total hormone weight and copy number. We show there are on the order of a million hormone molecules per cell in the human body. Females have about half the number of circulating hormone molecules compared to males. Across 56 hormones with curated affinity data, free (receptor-available) concentration correlates with receptor binding affinity, with class-specific scaling. Bioavailability mechanisms segregate by chemical class, consistent with chemical structure constraining available buffering strategies. Together, these data provide a quantitative reference for the human endocrine system and highlight relationships linking receptor affinity, bioavailability, and chemical class.
The ability of Mycobacterium tuberculosis (Mtb) to dynamically adjust its growth behavior in response to host environments is critical for survival under immune and drug stress, but how these behaviors shift at the singl...The ability of Mycobacterium tuberculosis (Mtb) to dynamically adjust its growth behavior in response to host environments is critical for survival under immune and drug stress, but how these behaviors shift at the single-cell level remains poorly understood. Here, using high-resolution single-cell analysis, we show that Mtb adapts to acidic conditions by increasing the proportion of bacteria in a growth-arrested state, rather than uniformly slowing the growth rate of the entire population. This nongrowing subpopulation exhibits enhanced tolerance to ethambutol, highlighting its role in drug survival. Clinical strains displayed higher proportions of growth-arrested cells under both neutral and acidic conditions, suggesting that growth arrest may serve as one of the strategies for persistence during infection. While the PhoPR two-component system partially regulates this state, our RNA sequencing analysis revealed additional transcriptional regulators that are upregulated following acidic adaptation and may contribute to entry into the growth-arrested state and increased tolerance to ethambutol. Our study demonstrates that increasing the proportion of nongrowing subpopulations is an active adaptive strategy that can influence antibiotic susceptibility under acidic conditions, offering new perspectives for targeting bacterial heterogeneity in tuberculosis therapy.
Fluctuations in single-neuron activity in the sensory cortex often correlate with perceptual decisions. This kind of correlation is often hypothesized to reflect a causal influence of sensory signals on decisions, but it...Fluctuations in single-neuron activity in the sensory cortex often correlate with perceptual decisions. This kind of correlation is often hypothesized to reflect a causal influence of sensory signals on decisions, but it can be attributed to various noncausal factors as well. To disentangle these different possibilities, we have examined local field potentials (LFPs) recorded from the middle temporal (MT) area and area V4 of nonhuman primates (Macaca mulatta) while they performed two different perceptual decision-making tasks. Compared to single-neuron spiking, LFPs have the advantage of being decomposable into frequency bands that are associated with different anatomical sources of input. More importantly, they persist when spiking activity is inactivated, which precludes a causal influence of the corresponding neural activity on behavior. We found that high-gamma frequency (70-150 Hz) LFP power was correlated with perceptual decisions and that this correlation disappeared when spikes were inactivated, consistent with a causal role for this frequency band in decision-making. These signals overlapped in time with decision signals in the lower gamma band (30-70 Hz), which persisted after spiking inactivation, suggesting a noncausal input. Interestingly, lower-frequency LFP signals (5-30 Hz) reflected both impending perceptual decisions and the outcome of preceding trials, suggesting a modulatory influence of recent experience on neural dynamics. Our results, therefore, reveal that neural activity multiplexes different sources of information about perceptual decisions and that these types of information can be estimated reliably from different LFP frequencies.
Structural neuroplasticity supports learning, development, and shapes vulnerability to brain disorders, making it a central priority in neuroscience research. However, progress in humans has remained limited by the inabi...Structural neuroplasticity supports learning, development, and shapes vulnerability to brain disorders, making it a central priority in neuroscience research. However, progress in humans has remained limited by the inability to probe cellular processes in vivo, leaving mechanistic insight largely dependent on animal models. To address this gap, here we combined the sub-voxel sensitivity of ultra-high-gradient diffusion MRI with the cell-compartment specificity of the Soma and Neurite Density Imaging (SANDI) model to probe structural plasticity directly in the living human brain. By tracking how learning modulates the temporal dynamics of cell bodies and cell processes, we aimed to distinguish plastic from nonplastic biological processes driving changes in microstructure. We found that learning a motor skill triggered two distinct temporal responses: a transient expansion of cell bodies across all brain regions engaged by the task, consistent with a short-lived homeostatic mechanism, and a sustained increase in cell-process density restricted to key motor regions, consistent with structural plasticity. Our approach provides a mechanistic window into human neuroplasticity and marks a significant step toward bridging the gap between animal and human neuroscience.