Episodic memory involves encoding and remembering the order of events experienced over time. Previous work examining the mechanisms of temporal order memories has focused primarily on the hippocampus and prefrontal corti...Episodic memory involves encoding and remembering the order of events experienced over time. Previous work examining the mechanisms of temporal order memories has focused primarily on the hippocampus and prefrontal cortices, with comparatively less attention paid to population-level memory signals in the medial posterior parietal cortex (mPPC). Combining in vivo multi-unit electrophysiology and a temporal order judgment task with naturalistic cinematic material in macaques, we show that population activity in mPPC exhibits temporally structured dynamics during both encoding and retrieval. During encoding, mPPC neuronal ensembles exhibit gradually evolving activity patterns consistent with temporal context representations embedded in the unfolding video episodes, whereas during retrieval these neurons engage in coordinated, synchronous activity preceding memory-guided decisions. Moreover, trial-by-trial similarity between population activity patterns during encoding and retrieval predicts temporal order judgment performance. A separate control experiment further ruled out eye saccades, fixation patterns, and scan paths as confounding factors contributing to the observed neural dynamics. Together, these findings suggest that mPPC contributes to temporal order memory through population-level representations that integrate temporally extended experience with retrieval-related decision processes, rather than through simple sensory-driven or motor-related responses.
How the motor cortex controls movement remains a fundamental question in neuroscience. Although somatosensory input is thought to influence motor cortex activity and the execution of voluntary movements, its role in driv...How the motor cortex controls movement remains a fundamental question in neuroscience. Although somatosensory input is thought to influence motor cortex activity and the execution of voluntary movements, its role in driving motor cortex activity during voluntary behavior remains unclear. To address this, we performed whole-cell recordings from motor cortex neurons in mice during self-initiated, voluntary forelimb movements, either with intact somatosensory input or transection of the sensory nerves innervating the forelimb. In the absence of somatosensation, mice were still able to perform forelimb movements, including reaches, but these movements were significantly slower and more prolonged. Membrane potential recordings showed that cortical state changes were centrally generated, whereas external somatosensory input drives motor cortical activity before movement onset, curtails synaptic input during reaching to a hyperpolarized reversal potential value, and shapes membrane potential dynamics correlated with limb kinematics. Together, these findings demonstrate that somatosensory inputs play a central role in shaping motor cortex activity and its control of limb movement.
Non-spike changes driving SARS-CoV-2 fitness remain undercharacterized. Two PLOS Biology papers show that evolutionary N gene changes create a transcription-regulating sequence producing a truncated N protein that enhanc...Non-spike changes driving SARS-CoV-2 fitness remain undercharacterized. Two PLOS Biology papers show that evolutionary N gene changes create a transcription-regulating sequence producing a truncated N protein that enhances fitness by blocking antiviral responses.
The circadian clock and cellular metabolism are tightly coupled to maintain homeostasis. A new study in PLOS Biology leverages metabolic tracing to reveal time-of-day-dependent activities of glucose metabolic pathways in...The circadian clock and cellular metabolism are tightly coupled to maintain homeostasis. A new study in PLOS Biology leverages metabolic tracing to reveal time-of-day-dependent activities of glucose metabolic pathways in Drosophila that are disrupted in clock and sleep mutants.
Humans and other animals learn the value of candidate actions by interacting with their environment, which invariably requires the exertion of effort. Dopamine has been implicated in both effort and reward learning, but...Humans and other animals learn the value of candidate actions by interacting with their environment, which invariably requires the exertion of effort. Dopamine has been implicated in both effort and reward learning, but little is known about how these processes interact. In this double-blind study, healthy young adults (N = 42) were randomized to receive either high-dose sulpiride (a post-synaptic D2-receptor antagonist) or placebo. Participants then completed a novel two-armed bandit task, in which they weighed the effort costs associated with each option against their expected rewards. Overall, learning accuracy was lower on sulpiride compared to placebo. Computational modeling revealed that this was driven by the capacity of effort to significantly modulate learning rates on placebo but, critically, not on sulpiride. Simulations showed that the capacity of effort to modulate learning rates plays an adaptive role by improving performance in agents whose learning would otherwise be compromised by low motivation. Together, these data provide causal evidence that dopamine supports the relationship between effort and learning, and reveal a novel role for dopamine in shaping how humans learn from the consequences of their actions.
Biological clocks shape metabolism, but how circadian programs govern nutrient processing is unclear. Here, using human metabolomics and 13C6-glucose tracing in Drosophila, we delineate previously under characterized dai...Biological clocks shape metabolism, but how circadian programs govern nutrient processing is unclear. Here, using human metabolomics and 13C6-glucose tracing in Drosophila, we delineate previously under characterized daily oscillations in glucose-derived metabolic networks, providing a mechanistic framework for a purpose-built isotope-tracing approach. In flies, we reveal a pronounced "rush hour" of glucose utilization early in the light phase, with carbons directed to biosynthetic and energetic pathways. By contrast, a dopamine reuptake-deficient hyperactive mutant (fumin) with elevated metabolic rate shows phase-shifted and amplified metabolic peaks, indicating that altered neural signaling reshapes temporal glucose flux. Neither altered feeding schedules nor short-term fasting disrupt these intrinsic metabolic rhythms, strongly suggesting that circadian timing, rather than nutrient availability, orchestrates temporal homeostasis. By integrating human metabolite profiling with isotope-tracing in flies, we define a conserved temporal architecture of glucose utilization and demonstrate that metabolic flux is dynamically gated across the day. Our findings establish a framework for understanding how circadian misalignment contributes to metabolic dysfunction and disease.
Evidence-based solutions are needed to help improve reproducibility in research. This Consensus View presents a consensus-based list of core reproducibility items for research that has been developed by a multidisciplina...Evidence-based solutions are needed to help improve reproducibility in research. This Consensus View presents a consensus-based list of core reproducibility items for research that has been developed by a multidisciplinary group interested in research, open science, and reproducibility. The set of minimum requirements presented here outlines core expectations regarding planning, methods, data collection, management and analysis, and dissemination. This tool aims to improve the reproducibility of methods and results throughout all phases of the research process and, more generally, to promote a broader cultural shift toward transparent, reliable research.
While it is tempting to suppose that everything that happens inside our cells has a function, a recent study in PLOS Biology adds to the growing consensus that, for large-bodied species, the high diversity of transcripts...While it is tempting to suppose that everything that happens inside our cells has a function, a recent study in PLOS Biology adds to the growing consensus that, for large-bodied species, the high diversity of transcripts is down to the fact that accidents happen.
In eukaryotes, alternative transcription initiation (ATI), alternative splicing (AS), and alternative polyadenylation (APA) result in multiple different transcripts per gene, but the biological significance of the transc...In eukaryotes, alternative transcription initiation (ATI), alternative splicing (AS), and alternative polyadenylation (APA) result in multiple different transcripts per gene, but the biological significance of the transcript diversity produced remains controversial. Some suggested that this diversity is adaptive, while others contended that it is largely deleterious and arises from molecular errors in transcription and RNA processing. The error hypothesis makes a distinct prediction that is not expected under the adaptive hypothesis: transcript diversity declines with the effective population size (Ne) of the species because natural selection minimizing errors is more effective under larger Ne. By analyzing 166 transcriptomes from 75 metazoans, we report that transcript diversity measured by the percentage uses of minor ATI, AS, and APA sites decreases with Ne or its proxies. This observation supports the error hypothesis and suggests that metazoan transcript diversity is largely deleterious.
Understanding where a cell sits along developmental time is as important as identifying its type. While single-cell transcriptomics has catalogued the diversity of neural cell types, aligning them along a shared temporal...Understanding where a cell sits along developmental time is as important as identifying its type. While single-cell transcriptomics has catalogued the diversity of neural cell types, aligning them along a shared temporal axis across studies, species, and model systems remains a fundamental challenge. Here, we develop a single-cell transcriptomic 'clock' that predicts true developmental age, enabling standardized, cross-context comparisons of neural maturation. Through a meta-analysis of over 2.8 million cells from the developing human brain, we identify robust tissue-level and cell-autonomous predictors of developmental age. We find that bulk tissue composition predicts age within individual studies but lacks generalizability, whereas specific cell type proportions, particularly astrocytes and progenitors, track age reliably across studies. Using machine learning, we develop a cell type-agnostic predictor based on 462 genes that robustly tracks developmental dynamics across diverse cell types and datasets (error = 2.6 weeks). Our model accurately estimates developmental age in human neural organoids and detects disease-associated shifts. Model predictions further generalize across species, revealing 10-fold accelerated neurodevelopment in mice relative to humans. Our approach provides a robust framework to assess neural maturation across contexts, with broad relevance for developmental biology and disease modeling.
The circadian clock is an internal timekeeping system that enables organisms to adapt to daily environmental changes. A defining property of this clock is temperature compensation, whereby the circadian period remains re...The circadian clock is an internal timekeeping system that enables organisms to adapt to daily environmental changes. A defining property of this clock is temperature compensation, whereby the circadian period remains relatively constant despite fluctuations in temperature. Although this phenomenon has been extensively studied in cultured cells and tissues, how the mammalian circadian clock responds to hypothermia in vivo remains largely unknown. Here, we examined circadian dynamics in a hibernation-like state in mice, termed Q neuron-induced hypometabolic and hypothermic state (QIH), which lowers core and brain temperatures to approximately 25 °C for extended periods. We found that free-running behavioral and body temperature rhythms were preserved after QIH, exhibiting only minor phase changes. In vivo recordings further revealed that neuronal firing rhythms in the suprachiasmatic nucleus (SCN) and molecular rhythms of PER2::Luc bioluminescence in peripheral tissues persisted during QIH with dampened amplitudes but largely unaltered circadian periods. In contrast, SCN and kidney slice cultures maintained at the same temperature displayed strongly attenuated or reset PER2::Luc oscillations. Together, these findings demonstrate that the circadian period is robustly temperature compensated in vivo, likely supported by systemic regulatory mechanisms beyond cell-autonomous clockwork. Our results provide new insight into the fundamental biology of circadian robustness and establish a framework for understanding clock function during hibernation and potential medical hypothermia.
Mycobacterium tuberculosis (Mtb) is a human bacterial pathogen that establishes chronic infection in the lung. Although the genome of Mtb was sequenced nearly 25 years ago, the genetic basis of Mtb's success as a human p...Mycobacterium tuberculosis (Mtb) is a human bacterial pathogen that establishes chronic infection in the lung. Although the genome of Mtb was sequenced nearly 25 years ago, the genetic basis of Mtb's success as a human pathogen remains to be fully elucidated. Large-scale mutation-based genetic approaches to understanding gene function are hindered by the limited throughput of traditional transposon sequencing strategies used in mycobacteria. To create a resource for determining the function of genes, we generated a pooled random barcode transposon-site sequencing (RB-TnSeq) library in Mtb. A unique 20-nucleotide barcode in the transposon allows for rapid, high-throughput genetic screening without the laborious protocol of standard bacterial TnSeq screens. We performed 95 RB-TnSeq screens on an array of carbon sources, nitrogen sources, stressors, and antibiotics. Using the resulting dataset, we examined phenotypes of pe and ppe genes, a mycobacterial gene family whose function has long been elusive, uncovering 187 novel phenotypes across 37 genes in this family. We propose a pathway for lactate utilization in which the ESX-5 type VII secretion system may export PPE3, facilitating the import of D- and L-lactate into the bacterial cell. Notably, we identify a candidate D-lactate dehydrogenase that may mediate this metabolic capability. Additionally, we find that the proton-pumping NADH dehydrogenase Nuo is required for utilization of propionate, highlighting the metabolic flexibility of Mtb. Lastly, we characterize a novel mutant that confers resistance to the new tuberculosis antibiotic pretomanid. Results from these genetic screens will facilitate the development of additional new hypotheses about the function of uncharacterized genes and will expand our knowledge of Mtb metabolism and resistance to stress.
During fieldwork in Thailand, we observed nearly identical tempos of co-located flashing fireflies and chirping crickets. Motivated by this, we survey published data showing that an abundance of evolutionarily distinct s...During fieldwork in Thailand, we observed nearly identical tempos of co-located flashing fireflies and chirping crickets. Motivated by this, we survey published data showing that an abundance of evolutionarily distinct species communicate isochronously at ~0.5-4 Hz, suggesting that this might be a tempo "hotspot." We hypothesize that this timescale may have a universal basis in the biophysics of the receiver's neurons. We test this by demonstrating that small receiver circuits constructed from elements representing typical neurons will be most responsive in the observed tempo range.
Gruner HN, Pickett CJ, Bao JY
… +19 more, Garcia R, Hozumi A, Scully TD, Popsuj S, Ning S, Gao M, Bautista G, Maze K, Lim HK, Osugi T, Collins-Doijode M, Cairns O, Levis G, Chen SY, Gong T, Satake H, Moshe Klein A, Sasakura Y, Davidson B
Neurons contribute to the complex interplay of signals that mediate heart development and homeostasis. Although a limited set of studies suggest that neuronal peptides impact vertebrate heart growth, the specific contrib...Neurons contribute to the complex interplay of signals that mediate heart development and homeostasis. Although a limited set of studies suggest that neuronal peptides impact vertebrate heart growth, the specific contributions of these peptides to cardiomyocyte progenitor differentiation or proliferation have not been elucidated. Here, we show that the neuropeptide tachykinin along with canonical Wnt signaling regulate cardiomyocyte progenitor proliferation in the chordate model Ciona robusta. In C. robusta, the heart continues to grow throughout adulthood and classic histological studies indicate that a line of undifferentiated cells may serve as a reserve progenitor lineage. We found that this line of cardiomyocyte progenitors consists of distinct distal and midline populations. Our analysis indicates that distal progenitors divide asymmetrically to produce distal and midline daughters while midline progenitors divide asymmetrically to produce myocardial precursors. Through single-cell RNA sequencing (scRNA-seq) of adult C. robusta hearts, we delineated the cardiomyocyte progenitor expression profile. Based on this data, we investigated the role of Wnt signaling in cardiomyocyte progenitor proliferation and found that canonical Wnt signaling is required to suppress excessive progenitor proliferation. The scRNA-seq data also identified a number of presumptive cardiac neural-like cells. Strikingly, we found that a subset of these neuronal cells appears to innervate the distal cardiomyocyte progenitors. Based on tachykinin receptor expression in these neural-like cells, we blocked tachykinin signaling using pharmacological inhibitors and found that this led to reduced proliferation in the distal progenitor pool. Through targeted CRISPR-Cas9 knockdown, we then demonstrated that both extrinsic tachykinin and intrinsic cardiac tachykinin receptors are required for formation of the myocardial heart tube. This work provides valuable insights regarding the deployment of neural signals to regulate organ growth in response to environmental or homeostatic inputs.
Large-scale patterns of species richness have been attributed to ecological limits, variation in diversification rates, and differences in evolutionary time, yet the relative importance of these drivers remains debated....Large-scale patterns of species richness have been attributed to ecological limits, variation in diversification rates, and differences in evolutionary time, yet the relative importance of these drivers remains debated. Here, we present a unifying framework distinguishing four richness-generating scenarios, defined by contrasting roles of evolutionary time and speciation rates, which yields explicit and testable predictions for how evolutionary time, speciation, and environmental factors influence species richness. We applied this framework by analyzing 129 distinct, nonoverlapping clades spanning amphibians, reptiles, birds, and mammals. For each clade, we integrated historical biogeographic reconstructions, multiple estimates of speciation rates, and GIS-based environmental data. Using structural equation modeling, we quantified the direct and indirect effects of evolutionary time, speciation rates, and environmental conditions (productivity, temperature, and precipitation) on species richness. We further tested whether these effects varied systematically with clade-level traits, including age, physiology, diversity, and geographic extent. Productivity emerged as the dominant predictor of species richness, exerting strong and consistent direct effects that were largely invariant to clade traits. In contrast, speciation rates contributed little to species richness, while the influence of evolutionary time was highly context-dependent and most pronounced in younger clades. Temperature showed consistent direct effects not mediated by productivity, evolutionary time, or speciation rates, whereas precipitation influenced richness primarily via productivity. Together, our results support a productivity-driven equilibrium view of species richness, in which diversity reflects a balance between speciation and extinction regulated by energy availability. Deviations from equilibrium dynamics, particularly in younger clades, highlight the role of evolutionary history on biodiversity gradients.
Cognitive flexibility supports efficient switching between mental sets and contributes to the preservation of general cognition in aging. It relies on the integration between brain functional dynamics and structural arch...Cognitive flexibility supports efficient switching between mental sets and contributes to the preservation of general cognition in aging. It relies on the integration between brain functional dynamics and structural architecture. However, how this structure-function integration changes with age and contributes to cognitive flexibility decline in older adults remains unclear. In this study, we investigated longitudinal aging-related changes in multimodal structure-function integration, quantified as functional signal alignment (i.e., coupling) versus liberality (i.e., decoupling) relative to individual structural connectomes, which represent distinct spectral components, and tested their longitudinal associations with cognitive flexibility. Resting-state fMRI signals were decomposed based on diffusion MRI-derived structural networks using a graph signal processing framework. We focused on subnetworks within three core large-scale cognitive systems: the executive control network (ECN), default mode network (DMN), and salience network (SN). Across two independent datasets, the task-positive SN-A subnetwork, which includes core SN regions such as the anterior insula and dorsal anterior cingulate cortex, exhibited decreased coupling and increased decoupling with aging. Importantly, these changes were associated with a greater decline in cognitive flexibility (measured by the Trail Making Test and Color Trails Test) over time. In contrast, task-negative DMN-A (centered in the medial prefrontal and posterior cingulate cortex) showed aging-related changes in the opposite direction, with increased coupling and decreased decoupling over time. Together, these findings reveal network-specific trajectories of intrinsic structure-function integration in normal aging and indicate that preserved structure-function integration within the SN may be particularly important for maintaining cognitive flexibility in older adults.
Ranking-a ubiquitous relational structure-enables humans to organize complex information and overcome cognitive load, yet in real-world settings it is often inferred from sparse, few-shot learning of local pairwise relat...Ranking-a ubiquitous relational structure-enables humans to organize complex information and overcome cognitive load, yet in real-world settings it is often inferred from sparse, few-shot learning of local pairwise relationships. How the human brain performs relational inference under such limited evidence remains unknown. We hypothesized that under few-shot learning, relational inference is shaped by inductive biases, such that individuals actively impose structured global relationships-often idiosyncratic-to constrain and unify limited local information. In a preregistered behavioral study combined with magnetoencephalography (MEG) recordings, we show that even after identical few-shot local pair learning, individuals construct stable and self-consistent, yet idiosyncratic, global rankings that diverge from the ground-truth order-a phenomenon not readily explained by classical computational models of transitive inference. MEG recordings further reveal that frontoparietal neural representations are reorganized to reflect each individual's subjective ranking rather than those of others. Together, these findings highlight the constructive and generative nature of human cognition: under sparse samples and limited computational resources, the human brain actively infers and imposes relational structure.
The hippocampal-entorhinal system represents relations between states in spatial and nonspatial cognitive maps. Critical to understanding how these memory representations are used for cognition is to determine whether th...The hippocampal-entorhinal system represents relations between states in spatial and nonspatial cognitive maps. Critical to understanding how these memory representations are used for cognition is to determine whether the actions underlying state transitions are incorporated in entorhinal cognitive maps. Participants learned to transition between states using different actions, operationalized as mathematical operations. We found that the entorhinal cortex represented the afforded actions across the states. This action representation was not explained by other properties of the task space, such as link distance between the states or reaction times. Furthermore, gaze behavior reflected the direction of afforded actions in the horizontal axis, and the strength of this lateralization predicted both performance and entorhinal pattern similarities, suggesting a link between gaze behavior and neurocognitive mechanisms for navigating conceptual spaces. In sum, this study provides first evidence for the integration of action information into ocular and entorhinal representations of conceptual spaces, suggesting that these may not just map out experiences, but provide information about how to explore knowledge.
Protein kinases play a crucial role in regulating cellular processes, and their dysregulation is frequently implicated in various diseases, including cancer. Targeting protein kinases represents a promising therapeutic s...Protein kinases play a crucial role in regulating cellular processes, and their dysregulation is frequently implicated in various diseases, including cancer. Targeting protein kinases represents a promising therapeutic strategy for cancer treatment. Esophageal squamous cell carcinoma (ESCC) constitutes over 90% of esophageal cancer cases in high-incidence regions, with a global five-year survival rate below 20%. Here, we report that CK2 is aberrantly activated in ESCC, identified through kinase-substrate enrichment analysis (KSEA) of large-scale proteomic and phosphoproteomic data. Functional enrichment revealed the splicing factor SF3B3 as a clinically relevant CK2 substrate. We demonstrated that CK2-mediated phosphorylation of SF3B3 T1200 plays a pivotal role in ESCC progression. Mechanistically, CK2-mediated phosphorylation of SF3B3 enhances its affinity for the deubiquitinase USP7, leading to SF3B3 deubiquitination and subsequent protein stabilization. This stabilization drives ESCC progression by regulating alternative splicing (AS) events, including a critical event involving the inclusion of exon 4 in the EXOSC2 transcript. Furthermore, we demonstrated that SF3B3 T1200 phosphorylation specifically facilitates its incorporation into the U2 snRNP complex, directly promoting the aforementioned EXOSC2 exon 4 inclusion. Crucially, targeting CK2 or USP7, either individually or in combination, effectively suppressed ESCC progression. Our findings uncover a key molecular mechanism underlying SF3B3 stabilization and AS regulation, offering novel therapeutic opportunities for ESCC.
Bacteria, both individually and as symbionts of other organisms, significantly influence ecosystems by providing nutrients and metabolizing exogenous compounds. Some bacteria polymerize small organic acids such as lactat...Bacteria, both individually and as symbionts of other organisms, significantly influence ecosystems by providing nutrients and metabolizing exogenous compounds. Some bacteria polymerize small organic acids such as lactate, pyruvate, and β-or 3-hydroxybutyrate when there is an excess of carbon relative to other elements. One such polymer, poly-β-hydroxybutyrate (PHB) is a biodegradable bioplastic. While the role of PHB as energy/carbon-storage in bacteria is well documented, the effects of PHB on interactions between bacteria and their hosts remain unclear. Here, we discover that PHB-producing bacteria can kill the nematode Caenorhabditis elegans. Death results from a combination of pharyngeal deformation, intestinal distention, disruption of the intestinal barrier, and defecation defects. Remarkably, mutations in C. elegans nuc-1, which encodes DNAse II, partially alleviate PHB-induced lethality. Altogether, our findings illustrate that PHB-producing bacteria can affect host-physiology and survival.