National Science Review

Structural-functional coupling (SFC) provides critical insights into how the brains structural architecture constrains functional organization for supporting higher-order cognition. Investigating evolutionary differences in SFC between humans and macaques may provide new insights into the neural basis of unique human cognitive abilities. In this study, we analyzed multimodal magnetic resonance imaging data from anesthetized and awake adult rhesus macaques and adult humans to examine cross-species divergences in SFC. Moreover, we integrated transcriptomic data to elucidate the molecular mechanisms underlying evolutionary differences in SFC patterns. We find that humans and macaques exhibit distinct SFC patterns: the human brain shows high SFC in the lateral and medial prefrontal cortex, whereas macaques show high SFC in the sensorimotor cortex. Notably, language-related regions in the human lateral temporal cortex exhibit relatively low SFC. Furthermore, the human whole-brain SFC pattern and the evolutionary differences in SFC between humans and macaques are negatively correlated with cortical evolutionary expansion. By integrating human and macaque transcriptomes, we reveal that the macaque SFC specifically associated genes are primarily involved in basic physiological functions, whereas the human SFC specifically associated genes exhibit evolutionary adaptations in synaptic function, neurotransmitter secretion, and other molecular processes. Moreover, the human-specific genes showing significant overlap with Human Accelerated Regions genes were mainly enriched in cell types of astrocyte and oligodendrocyte and in diseases of schizophrenia and Alzheimers diseases. Overall, these findings advance our understanding of the intricate relationships of SFC in human and macaque brains and provide novel insights in understanding evolutionary conservation and species specificity in cognitive function and gene regulation.

Insect olfaction is facilitated by a heterotetrameric odorant receptor-odorant receptor co-receptor (OR-Orco) complex, which is distinct from that of vertebrate ORs. However, extreme sequence divergence among insect ORs has hindered a unified understanding of their evolutionary history and ecological importance. In this study, we present a multiscale analysis of OR genes across 115 insect species. We overcome the limitations of traditional phylogenetic approaches by applying a protein similarity network-based strategy and introduce a "trunk-branch" framework to systematically describe the evolutionary trajectories of insect ORs across sequence, structural, and functional levels. Although they possess different sequences and structural communities, all the insect orders were found to contain fully functional OR repertoires. Notably, insects adapted to end-Permian mass extinction through shifts in their functional OR repertoires, and early- and late-diverging lineages exhibit distinct patterns of OR differentiation. The emergence of Orco represents a key evolutionary transition point, marking the shift from a homomeric to a heteromeric complex accompanied by specialization of the extracellular domain and binding pocket. Furthermore, we established robust associations between olfactory recognition breadth and ecological variables, including diet, circadian rhythm, and habitat. Our findings provide a comprehensive framework for the evolution of insect ORs, explaining the complex adaptive relationship between insect olfactory potential and diverse ecological environments.

The {gamma}- to {beta}-globin switch is intricately regulated during human ontogeny, and this process is manipulated for therapeutic approaches to treat {beta}-hemoglobinopathies by activating {gamma}-globin expression. Several genetic strategies to reactivate HbF have partially reversed the {gamma}- to {beta}-globin switch and ameliorated the clinical symptoms of {beta}-hemoglobinopathies. However, whether the {gamma}- to {beta}-globin switch can be completely reversed remains unknown. Completely reversing the {gamma}- to {beta}-globin switch requires a thorough redirection of the locus control region (LCR) from interacting with the {beta}-globin gene (HBB) to interacting with the {gamma}-globin gene (HBG). Here, we found that disrupting the KLF1-mediated HBB-LCR interaction by mutating the CACCC motif in HBB leads to the release of the LCR and its retargeting to other {beta}-like globin genes. Moreover, simultaneously disrupting the KLF1-mediated HBB-LCR interaction and the epigenetic repression of HBG by combined editing of the CACCC motif in HBB and the TGACCA motif in HBG reinforces the HBG-LCR interaction, resulting in almost exclusive {gamma}-globin expression while nearly absent {beta}-globin expression, achieving near complete reversal of the {gamma}- to {beta}-globin switch. This finding demonstrates the comprehensive regulation of the {gamma}- to {beta}-globin switch by gene competition and gene silencing mechanisms. This finding also suggests that silenced genes can be fully activated through the redirection of enhancer-promoter contacts and that the specificity of enhancer-promoter contact within chromosomal domains is achieved through the transcription factor clusters binding to enhancers and promoters. Combined editing of the CACCC&TGACCA motifs also offer a more optimal therapeutic strategy for {beta}-hemoglobinopathies.

Characterized by the earliest use of pottery, the Jomon culture was a unique Neolithic culture that spread throughout the Japanese Archipelago. Previous archaeological evidence suggests that Jomon hunter-gatherers colonized the southernmost islands, the Ryukyu Archipelago, by approximately 7,000 years before present (YBP). However, genetic characteristics of the Ryukyu Jomon population and its contribution to the modern population have not been elucidated yet. In this study, we newly sequenced 273 modern and 25 ancient (6,700-900 YBP) whole genomes collected across the Ryukyu Archipelago. Our analysis demonstrated a genetic differentiation between the Hondo (Japanese mainland) and Ryukyu Jomon, dating back to [~]6,900 YBP. After the divergence from the Hondo Jomon, the Ryukyu Jomon experienced severe bottlenecks, with an effective population size of [~]2,000. Admixture between the Ryukyu Jomon and migrants from the historic Hondo population occurred [~]1,000 YBP, which corresponds to the widespread adoption of iron tools and agriculture in the Central Ryukyus. Different demographic histories between modern Hondo and Ryukyu populations resulted in different rates of Jomon ancestry in these populations. By providing a new perspective on the peopling of the Ryukyu Archipelago, this study significantly enhances our understanding of cultural transitions in the region.

Enhancer-regulating epigenetic modifiers play critical roles in normal physiological processes and human pathogenesis. The major enhancer regulator paralogs MLL3 and MLL4 (MLL3/4) belong to the lysine methyltransferase 2 (KMT2) family, which catalyzes the methylation of lysine 4 on histone H3 (H3K4me). MLL3/4 are required for enhancer activation and are essential for mammalian development and stem cell differentiation. Recent studies have linked MLL3/4 with different metabolic pathways in the context of stem cell self-renewal and cancer cell growth; however, the underlying mechanisms remain elusive. Here, we utilize Seahorse extracellular flux analysis, stable isotope tracing, stem cell biology techniques, and transcriptomic analysis to investigate the functional relationship of MLL3/4, cellular respiration, and stem cell differentiation. Our results indicate that the loss of MLL3/4 impairs glycolytic activity and mitochondrial respiration in murine embryonic stem cells by downregulating the rate-limiting glycolytic enzyme Hexokinase 2 (HK2) and impairing the function of the Alpha-ketoglutarate dehydrogenase (OGDH) complex. Furthermore, simultaneously overexpression of HK2 and OGDH rescues defects in both cellular respiration and differentiation caused by MLL3/4 loss. Taken together, our study reveals a novel mechanism by which epigenetic machineries such as MLL3/4 govern the differentiation of pluripotent stem cells and facilitates the understanding of disease pathogenesis driven by enhancer malfunction.

Neuromodulators influence critical functions of the developing human brain and regulate behavioral states. Dysfunction of neuromodulatory systems is often involved in neuropsychiatric disease and many drugs for these conditions act on these signaling pathways. Recent advances in stem cell biology have made it possible to derive a wide range of cells across the developing human nervous system in regionalized organoids and to functionally integrate them into assembloids, however they currently do not systematically incorporate neuromodulation. Here, we generated human midbrain-hindbrain organoids (hMHO) from human induced pluripotent stem (hiPS) cells and fused them with human cortical organoids (hCO) to form neuromodulatory assembloids (hNMA). We focus on serotonin (5-hydroxytryptamine, 5-HT) as one key neuromodulator and found characteristic gene expression patterns and electrophysiological properties of serotonergic neurons (5-HT neurons) in the hMHO. In hNMA, 5-HT neurons projected into hCO, released 5-HT and modulated cortical network activity. To explore the applicability of this system in human disease, we studied 22q11.2 deletion syndrome (22q11.2DS), a common microdeletion associated with high risk for neuropsychiatric disease and defects in 5-HT signaling. We found aberrant 5-HT dynamics in hNMA from patient hiPS cell lines that were rescued by administration of a selective serotonin reuptake inhibitor (SSRI). Taken together, hNMA can be used to study human 5-HT dynamics and uncover disease phenotypes which could facilitate therapeutic development.

Evidence has shown that tumor progression is associated with the acquisition of growing autonomy and the creation of a complex signaling network through various signal pathways. Which particular signaling pathway is involved in the metastasis of a specific cancer is unclear. Here, we applied metastatic functional screening and identified that one-carbon and SSP metabolism pathways, as well as related genes, are associated with tumor metastasis inhibition. We engineered the cancer cells with poorly or highly metastatic potential to confirm the metabolism pathways regulating the ability to colonize different tissue sites. We also asked whether the restriction of the metabolism pathways by known inhibitors. We then identified three new compounds that can inhibit the expression of these genes and block tumor metastasis. Our findings uncovered a mechanism by which tumor cells reprogram their metabolism to promote migration, invasion, and survival at distant sites in tumor metastasis, offering a rational strategy to guide clinical treatment. The identified novel molecular proteins and pathways represent a promising therapeutic target for metastatic disease.

The impact of cellular activities on large-scale brain dynamics is thought to determine brain functioning and disease, yet the causal relationships of neural mechanisms across scales remain unclear. Recently, the cerebellum has been reported to affect whole-brain dynamics during sensorimotor integration. To disclose the underlying mechanisms, we have developed a multiscale digital brain co-simulator, in which a spiking neural network of the olivo-cerebellar microcircuit is embedded in a mouse virtual brain and wired with other nodes using an atlas-based long-range connectome. Parameters and bi-directional interfaces between the spiking olivo-cerebellar network and other rate-coded modules were tuned to match experimental data of primary sensory and motor cortex (M1 and S1) power spectral densities and neuronal spiking rates. Then, the role of the cerebellar circuitry on sensorimotor integration was analyzed by lesioning critical circuit connections in silico. Simulations showed that spike processing within the cerebellar circuit is key to explaining the gamma-band coherence between M1 and S1 during sensorimotor integration. These results provide a mechanistic explanation of how the cerebellum promotes the formation of sensorimotor contingencies in relevant cortical modules as the basis of its critical role in sensorimotor prediction. On a broader perspective, this modelling approach opens new perspectives for the multiscale investigation of brain physiological and pathological states in relation to specific cellular and microcircuit properties.

Brain-body interactions (BBIs) are fundamental to cognition and mental health, but their continuous multimodal dynamics remain difficult to extract. Previous approaches have been largely observational, and few frameworks enable these interacting processes to be modeled within an integrated generative system. Here, we applied a Predictive-Coding-Inspired Variational RNN (PV-RNN) to simultaneous EEG, ECG, and respiration recordings obtained from 33 participants during exteroceptive and interoceptive attention. The model learned a temporal hierarchy spanning modality-specific dynamics, multimodal associative integration, and sequence-level global states, and accurately reconstructed unseen physiological sequences. Specifically, the intermediate associative layer successfully captured the core complexities of BBI by extracting multiscale, nonlinear, and bidirectional coupling dynamics with variable temporal lags. Furthermore, the estimated precision (inverse variance) of latent variables representing BBI dynamics within this multimodal associative layer increased significantly during interoceptive attention. The magnitude of this condition-dependent precision enhancement correlated positively with subjective adaptive body controllability and negatively with psychiatric vulnerabilities, including rumination and trait anxiety. These findings identify a latent physiological signature of interoceptive attention and establish hierarchical generative modeling as an interpretable framework for extracting continuous BBI dynamics and linking multimodal physiology to cognitive and clinical characteristics.

Whole-genome duplication (WGD) is a major evolutionary event that drives molecular and species diversification. However, few studies have traced how WGD has shaped the long-term functional evolution of individual genes. Here, we investigated the olfactory marker protein (omp) genes duplicated by the teleost-specific WGD ([~]300 million years ago) through phylogenetic, syntenic, expression, and promoter analyses. Our results suggest that the duplicated omp gene pair has retained redundancy over an extended evolutionary period, leading to both non- and sub-functionalization, thereby generating molecular diversity. Moreover, evolutionary analyses of the olfactory signal transduction cascade revealed prolonged redundancy across its components, likely constrained by gene dosage balance. These findings imply that WGD may have introduced unexpected diversity into the entire olfactory signaling machinery of teleosts through dosage-constrained functional divergence. HighlightsO_LITeleost-specific WGD generated duplicated omp genes that persisted for [~]300 million years. C_LIO_LIExtended redundancy in ompa/ompb led to both non- and sub-functionalization. C_LIO_LIOlfactory transduction genes also show long-term redundancy shaped by dosage constraints. C_LIO_LIWGD likely introduced diversification into teleost olfactory signaling via dosage constraints. C_LI

The temporal stability and spatial heterogeneity of global marine ecosystems under changing climates reveal how biodiversity persists or collapses. However, the deep-time evolution of these phenomena remains poorly understood. We reconstructed the stability landscape of pelagic plankton from the Cretaceous-Paleogene extinction to the present. We find that the Cenozoic was a period of punctuated volatility with high turnover post-extinction and during the Late Neogene cooling. Spatially resolved analysis revealed latitude-dependent trends: equatorial regions stabilized over time, whereas polar communities, especially in the Southern Ocean, destabilized. Equatorial regions homogenized from initially high heterogeneity, whereas polar communities showed the opposite pattern, including a latitudinal seesaw of spatial heterogeneity over the past 30 million years. These findings illuminate temporal stability and spatial heterogeneity dynamics across geologic timescales.

Impaired mucosal barrier function is a pathological hallmark of ulcerative colitis (UC), yet current clinical therapeutic strategies primarily rely on anti-inflammatory agents or surgery, lacking strategies to repair mucosal damage1,2. Here, through a systematic screen of our established library of deanticoagulated heparins3, we found that the nonanticoagulant low-molecular-weight heparin NALHP (average Mw, 6400 Da; PDI=2.23) and its separated representative fine fragment S6 (average Mw, 4200 Da; PDI=1.1) significantly ameliorated dextran sulfate sodium (DSS)-induced UC in mice by restoring intestinal integrity. Both compounds promoted crypt stem cell differentiation into goblet cells, thereby repairing the colonic mucosal barrier. Notably, in human UC patient-derived organoids, NALHP and S6 enhanced goblet cell differentiation, increased MUC2 secretion, and modulated Wnt and Notch signaling to optimize epithelial composition. Our study is the first to reveal the therapeutic mechanism of deanticoagulated heparin derivatives in UC through the regulation of epithelial mucosal regeneration via the mediation of goblet cell differentiation, providing crucial insights for the development of novel UC therapeutics capable of targeting the mucosal barrier repair process.

Although the causes of Tau aggregates vary, once Tau aggregates are formed, their neurotoxicity significantly contributes to neuronal death and cognitive decline in tauopathies, with Alzheimers disease (AD) being the most well-known example. Despite its central pathogenic role, however, effective therapeutic strategies targeting neurotoxicity of Tau remain poor. Here we demonstrate the pathogenic role of neuronal cell death in Tau-related neurodegeneration. Tau-expressing neurons undergo cell death through Z-DNA-binding protein 1 (ZBP1) activation triggered by endogenous Z-RNAs. These Z-RNAs are derived from reactivated transposable elements (TEs) that are typically silenced within heterochromatin. Tau aggregates show a strong affinity for H3K9me3-modified chromatin, effectively sequestering these epigenetic marks from Heterochromatin Protein 1 (HP1), thereby disrupting the condensation of constitutive heterochromatin. Clinically, an inverse correlation between ZBP1 expression levels in excitatory neurons and cognitive performance in AD patients was observed. Importantly, Zbp1 haploinsufficiency significantly ameliorated cognitive deficits in aged Tau-transgenic mice (24-month-old), highlighting the therapeutic potential of ZBP1 inhibition to strive against neurodegeneration in tauopathies.

Glioma is the most common primary malignant tumor of the brain, and accumulating evidence indicates that neuronal activity plays a pivotal role in tumor progression. In this study, neuronal activity is modulated in vitro using potassium chloride (KCl)-induced depolarization and midazolam (MDZ)-mediated suppression. MDZ is a neuronal activity modulation medication, commonly used for sedation, anxiolysis, and amnesia in clinics. After treatment, conditioned media derived from these neuronal cultures are subsequently co-cultured with glioma cells. EdU incorporation assays demonstrate that MDZ significantly inhibits glioma cell proliferation in vitro. Furthermore, an orthotopic xenograft glioma model is established to assess the anti-tumor efficacy of MDZ in vivo, as evaluated by tumor volume and Ki-67 immunostaining. Mechanistically, insulin-like growth factor 1 (IGF1) is identified as the neuronal-activity-regulated factor that promotes glioma growth through activation of the PI3K/AKT signaling pathway. Moreover, transcriptomic profiling of brain tissues reveals that MDZ attenuates neuronal activity and downregulates neuron-derived growth factors in both glioma and non-tumor regions, thereby exerting anti-tumor effects in vivo. Collectively, these findings demonstrate that MDZ suppresses glioma progression by suppressing neuronal activity and inhibiting neuron-derived trophic factors, providing new insights into the development of therapeutic strategies for glioma.

The evolution of the water-conducting xylem and sugar-conducting phloem tissues were key innovations in land plant evolution, enabling the origin of long-distance transport networks1. In extant vascular plants, phloem and xylem are linked functionally and always occur together2, though their evolutionary origin is unclear. This uncertainty is owed to the greater fossilisation potential of lignified xylem tracheids compared to thin-walled phloem cells3, 4, 5. Therefore, the fossil record of xylem is far more extensive than that of phloem, with the first definitive record of xylem being around 40 million years earlier6 than phloem7. This bias in the fossil record obscures characterisation of the origins of plant vasculature. In this study, this limitation is overcome by re-describing the "phloem-like" tissues of exceptionally preserved plants from the 407-million-year-old Rhynie chert8-15. We report that this tissue differs markedly from the phloem of extant plants, and propose its identification as a tissue of food-conducting cells (FCCs). Major histological differences were observed in the fossil plants, including no evidence for a pericycle, which in extant species delimits vascular from ground tissues, and the FCCs of the Rhynie chert plants were significantly larger in diameter than phloem cells. These differences suggest that early vascular plants lacked true phloem. However, putative sieve pores in the FCCs of Asteroxylon mackiei were identified. This represents to our knowledge the earliest record of sieve pores in the fossil record. Our results suggest an evolutionary scenario in which phloem features assembled gradually within FCCs, asynchronous to the evolution of xylem.

Single-cell sequencing has reshaped the research paradigm of Alzheimers Disease (AD) by revealing the heterogeneous transcriptional states of brain cells. Large single-cell cohort datasets, such as ROSMAP and SEA-AD, provide valuable atlases but primarily focus on RNA expression and chromatin accessibility, often overlooking the roles of RNA secondary structures. Although RNA G-quadruplexes (rG4s) are increasingly recognized as regulators of neurodegeneration, their interacting RNA-binding proteins (RBPs) remain poorly understood. We analyzed multiple independent scRNA-seq datasets to investigate rG4-associated biological functions across AD-relevant cell types and transcriptional states. We discovered that rG4-binding RBPs (RG4BPs) directly regulate essential glial cell functions, which are frequently impaired in AD. At the transcriptional state level, distinct sets of dysregulated RG4BPs correspond to the impaired state-specific biological features of astrocytes and microglia during AD progression, including a shift from an acute protective state to a chronic stress-associated state. This progressive state transition is accompanied by glial exhaustion and accumulated rG4s, which ultimately compromise glial support functions. We report several RG4BPs that are known regulators, including CIRBP, HSP90AA1, VIM, and PICALM, whose altered expression is associated with either pathological activation or severe functional impairment. These dysregulated RG4BPs provide a lens to examine the mechanism of rG4 accumulation in AD and position RG4BPs as novel targets for understanding and potentially intervening in AD progression.

Marine organisms exhibit 12.4-hour rhythms of gene expression, physiology and behavior synchronized by tidal cues. The mechanism underlying these circatidal rhythms, and its overlap with the circadian clockwork, has remained elusive. However, recent studies showed that the core circadian gene BMAL1 sustains circatidal behavior in crustaceans. Therefore, we mutagenized the other three core circadian clock genes (PhCry2, PhPer and PhClk) in P. hawaiensis, a marine amphipod. We found that they are necessary for both circadian and circatidal behaviors. Moreover, all four core circadian genes are critical for 24-h oscillations of mRNA levels in circadian brain neurons and 12.4-h mRNA rhythms in circatidal neurons. Unexpectedly, the mutants indicate that PhCLK represses PhPer expression independently of PhBMAL1 specifically in circatidal neurons. Our study thus reveals that circadian and circatidal clocks share four core molecular components, but their transcriptional wiring differs.

Trypanosoma cruzi is the causative agent of Chagas disease, a neglected illness with outdated treatments. Bromodomain factors (BDFs) are essential proteins that recognize acetylated lysines and have strong therapeutic potential. They form part of epigenetic complexes that regulate chromatin accessibility and, therefore, gene expression. However, little is known about their structure in trypanosomatids. Here, we used a combination of experimental and bioinformatic approaches to infer the stoichiometry and structure of T. cruzi bromodomain-containing complexes. By reconstructing the proximity networks of five BDFs using TurboID-directed proximity labeling, we identified highly interconnected components that assemble into the CRKT and NuA4 complexes. Using novel structure prediction strategies that systematically explore the stoichiometric space, we inferred that CRKT assembles into three distinct modules and NuA4 in two, with different degrees of interaction dynamics. The core module of CRKT contains two copies of each component, including BDF3, BDF5, and BDF8, arranged in a subcomplex with central symmetry. The catalytic module of CRKT has three subunits, including the histone acetyltransferase 2 (HAT2), while the BET (bromodomain and extra-terminal) module has one unit of both BDF4 and BDF1. The catalytic module of NuA4 closely resembles the yeast piccolo-NuA4 module and contains HAT1, while the TINTIN module associates with the catalytic module via the C-terminal domain of BDF6. These insights shed light on the structure and composition of epigenetic complexes in trypanosomatids, opening new avenues for rational drug design aimed at disrupting their function.

O_LIThe N-terminal signal sequences of plant cytochrome P450 enzymes are recognized as critical determinants for subcellular localization and functional diversification, yet their evolutionary drivers and mechanisms remain largely unresolved. C_LIO_LIIn this study, the evolutionary trajectories of these signals were systematically decoded through the integration of the protein language model ESM-2 with phylogenetic and selection analyses. A conserved functional fingerprint was identified. This region may serve as the essential endoplasmic reticulum targeting signal and be evolutionarily decoupled from adjacent surfaces under positive selection during lineage-specific expansions. C_LIO_LIA functional-adaptive decoupling model is proposed to explain this pattern, wherein a conserved functional core is maintained while surrounding interfaces diversify. This evolutionary architecture is interpreted as the outcome of a two-step cycle: an initial phase of positive selection driving functional innovation, followed by pervasive neutral evolution that facilitates structural exploration and potentiates future adaptations. C_LIO_LIThis work demonstrates how interpretable machine learning can be integrated with evolutionary theory to reconcile neutralist and selectionist perspectives on protein evolution. A novel framework is thus provided for understanding the layered evolution of protein modules, where structural constraint, adaptive innovation, and neutral drift operate on distinct tiers to generate functional diversity. C_LI

Sleep benefits learning and memory. Fundamental questions remain regarding whether and how sleep transfers memories for adaptive behavior in humans. We demonstrate that declarative to procedural memory transfer occurs through rapid network reorganization and memory stability shifts in human participants. Following local processing in motor circuit during slow wave-spindle coupling in nonrapid eye movement (NREM) sleep, multiregional communication during phasic rapid-eye movement (REM) sleep enables transfer. By leveraging a newly developed time-resolved simultaneous ultrahigh-field magnetic resonance spectroscopy and polysomnography, we further reveal that memory state becomes instantaneously unstable during slow wave-spindle coupling then enters a hyperstable state during phasic-REM sleep. Thus, sleep bridges memory systems, utilizing increased instability in NREM sleep, and transferring memory through hyperstabilization in REM sleep for knowledge integration.