Fetal growth restriction (FGR) is a major cause of perinatal morbidity and mortality, yet its underlying mechanism remains elusive. Here, we show that growth differentiation factor 15 (GDF15) levels are significantly reduced in the placenta and fetal circulation in mouse and pig FGR models and correlate positively with fetal weight. Placenta-specific GDF15 deficiency causes FGR, while placenta-specific Gdf15 mRNA delivery through targeted lipid nanoparticle (LNP) effectively alleviates FGR. Mechanistically, placental GDF15 is a major contributor to the fetal circulating GDF15 pool and enters the fetal compartment, where it activates the hepatic STAT3 signaling pathway to stimulate IGF2 production during pregnancy. Placental GDF15 deficiency decreases hepatic STAT3 phosphorylation and IGF2 levels in fetuses. Inhibition of STAT3 in primary mouse fetal hepatocytes blocks GDF15-induced IGF2 upregulation. Placenta-specific Gdf15 mRNA-LNP administration rescues the decreased hepatic p-STAT3 and IGF2 levels in FGR fetuses. Collectively, our findings identify a placenta-fetal liver metabolic axis where placental GDF15 promotes fetal growth by activating the fetal hepatic STAT3-IGF2 pathway, revealing a potential therapeutic target for FGR.

Neuroinflammation and vascular dysfunction are hallmarks of most neurodegenerative diseases. For organoids intended to model neurodegeneration, immune, and vascular cells should therefore be considered fundamental components, rather than optional additions.

Barrier epithelia are shielded from the external environment by their apical extracellular matrices (aECMs). The molecular complexity of aECMs has challenged understanding of their organization in vivo. To define the molecular architecture of a model aECM we generated a toolkit of 105 fluorescently tagged aECM components using gene editing in C. elegans, focusing on proteins secreted by the epidermis to form the collagen-rich cuticle. We developed efficient pipelines for modular protein tagging and rapid fluorophore swapping. Most tagged collagens were functional and exhibited exquisitely specific patterning across stages, cell types, and matrix substructures. We define multiple reference markers for key substructures including the little-understood cortical layer, as well as the helical crossed fiber arrays that function as a hydrostatic skeleton to maintain organismal shape. We further tagged 30 members of key aECM protein classes including proteases, protease inhibitors, and lipid transporters. Our standardized markers will allow dissection of the mechanistic basis of aECM spatiotemporal patterning in vivo.

Social learning is a fundamental adaptive strategy that critically shapes decision-making and feeding behaviors. Through the social transmission of food preference (STFP), animals acquire information about food safety via social interactions, forming a food-odor memory that overrides innate preferences and guides subsequent food preferences. However, the neural mechanisms through which social cues durably influence feeding preferences remain unclear. Here, we identify the lateral septum (LS) as a key node in STFP. We show that LS neuronal activity increases following social learning and reliably distinguishes between socially cued and uncued foods. Chemogenetic inhibition of the dorsal LS (dLS), but not the ventral LS (vLS), abolishes STFP-driven food preference, revealing subregional specificity within the LS. Furthermore, oxytocin receptor (OXTR) signaling within the dLS is required for STFP in mice, where it enhances neuronal excitability through PLC pathway activation. Together, our results reveal a subregion-specific circuit mechanism through which the dLS integrates social information with feeding motivation, and highlight oxytocinergic modulation as a key mediator of socially guided food preferences.

Human cognition is capacity-limited, requiring strategies to actively structure information. Eye movements offer a natural mechanism for sequential sampling, but whether such sequences reflect memory organization is unknown. We developed a working-memory task where color-frequency pairings created a latent ordinal structure to optimally reduce memory load. Across two experiments, gaze patterns spontaneously aligned with this structure. Participants sampled items following this sequence during encoding and revisited them during maintenance. Critically, the expression of this structure depended on cognitive demand. In a 3-item task, high performers showed robust sequential sampling during encoding, whereas lower performers compensated with replay-like revisitation during maintenance. Under higher demand (4 items), encoding-based organization was disrupted, and structured revisitation emerged primarily during maintenance. These findings suggest that eye movements provide an overt expression of an internally generated organizational process that flexibly adapts to cognitive demands, revealing a behavioral analogue to neural replay when encoding resources are strained.

Precise, site-specific integration of large DNA sequences into plant genomes is a long-standing goal of crop biotechnology and synthetic biology, yet remains constrained by random insertion, inefficient homologous recombination, and gene targeting. Here, we present PrimeStack, a DSB-independent platform that integrates PE with the unidirectional large serine integrase Bxb1, leveraging evolved variants for enhanced activity, to achieve the programmable insertion of multigene, multikilobase cargos at predefined genomic safe harbors (GSH) in rice (Oryza sativa). Optimized prime editors first install attP landing sites with high fidelity and heritability followed by Bxb1-mediated recombination that generates irreversible integration of genetic information. PrimeStack enabled targeted large-cargo integration in regenerated rice plants with efficiencies of up to 45%, as determined by junction-specific PCR analyses. No obvious morphological differences from WT plants were observed at 5 weeks after transfer to soil under the evaluated conditions. We validate its utility by achieving targeted insertion of a carotenoid cassette at an experimentally confirmed genomic safe harbor. PrimeStack delivers a modular, site-specific gene stacking platform that enables predictable, multigene trait pyramiding and pathway construction at GSH, thereby accelerating the development of improved and resilient crop varieties, as well as scalable plant-based biomanufacturing and a powerful chassis for synthetic biology.

Nutrient sensing and utilization are critical for microbes to adapt to their environment and evade predators. The encapsuled yeast Cryptococcus neoformans has a unique ability to sense and utilize the sugar inositol as both a signaling molecule and as a carbon source. This trait is advantageous not only in the natural environment but also to promote its pathogenesis, including invasion of the central nervous system. In this study, we have identified a novel inositol transporter-like receptor (transceptor) Itr4 that coordinates inositol and glucose metabolism by regulating inositol transporters (ITRs) and glucose sensor Hxs1. Itr4 binds inositol and regulates the function of other ITRs and its loss leads to a significant decrease in inositol uptake activity, resulting in a lack of mating, reduced capsule size, reduced blood-brain barrier (BBB) penetration, and virulence attenuation. Mutagenesis analysis of Itr4 protein identified an essential N-terminal tail and two amino acids, Q388 and Q389, as sites of functional importance. The ITR4Q388A, Q389A allele showed a dominant phenotype with increased inositol uptake, enlarged capsule and significantly attenuated virulence. In summary, we identify a new C. neoformans inositol transceptor, Itr4, the first such example in eukaryotes, with novel regulatory roles in both inositol and glucose metabolism and fungal virulence.

Many traits divert resources from reproduction and are costly due to the physiological trade-offs organisms face. These traits might require the allocation of different resources, e.g., energy expenditure or production of macromolecules, and it is unclear how their costs can be compared given their different units. Moreover, the effect of environmental conditions and genetic background on the cost of traits is not well understood. Two different frameworks have been proposed to quantify the resource costs of traits, focusing on either energy allocation or proteome allocation. These frameworks implicitly assume energy provisioning or protein production limits growth, respectively, but the connection between the two limitations has been underexplored. To better connect these frameworks, we develop a framework that considers limitations in energy provisioning and macromolecule biosynthesis simultaneously to quantify and compare the cost of traits that require different resources. Using this model, we explore how environmental quality and genetic background affect the cost of traits. Notably, our model predicts that increasing food quality increases the cost of traits that require the production of new structures, while decreasing the cost of traits requiring energy expenditure. Moreover, our model makes novel predictions about the effect of degradation, recycling, and energetic demands for maintenance on the relationship between the macromolecular composition of the cells and growth rate (also known as bacterial growth laws).

Human vocal tracts, like other physical traits, exhibit extensive interindividual variation. However, little is known about how this variation translates into phonetic diversity between speakers, and ultimately, across languages. Here we develop a biocultural model of phonetic evolution, analogous to Russell Lande's model of multivariate phenotypic evolution. We show that individual vocal tract morphologies and associated articulatory strategies leave consistent acoustic signatures, resulting in a characteristic pattern of phonetic variation within speaker groups that correlates with the pattern observed between groups. Recalling a central tenet of evolutionary biology-that within-group variation feeds between-group diversification-our findings suggest that phonologically similar vowel systems can attain phonetically diverse realizations according to a neutral-like evolutionary process. Our model serves as a null hypothesis for disentangling the biological versus cultural mechanisms underlying phonetic diversification, where deviations from the neutral expectation may indicate culturally mediated language change.

The ratio of nonsynonymous to synonymous substitutions (dN/dS) encodes important information about the selection pressures acting on protein-coding genes. In bacterial populations, dN/dS often declines with the sequence divergence between strains, but the mechanisms responsible for this broad empirical trend are still debated. Existing models have primarily focused on de novo mutations, overlooking the older genetic variants that are continually introduced through horizontal gene transfer and recombination. Here we introduce a phenomenological model of dN/dS in recombining populations of bacteria, which allows us to disentangle the effects of recombination among pairs of closely related strains. We find that clonally inherited regions of the genome exhibit consistently higher dN/dS ratios, and that the accumulation of recombined segments can quantitatively explain the majority of the decline in dN/dS. We use these observations to re-examine models of purifying selection and adaptive reversion in human gut bacteria, and uncover evidence for widespread weak selection at a large fraction of protein-coding sites. Our findings show that horizontal gene transfer can be an important factor in shaping genome-wide patterns of selective constraint, and raise new questions about the effectiveness of natural selection in complex bacterial populations.

Fungal morphogenesis is a major driver of disease outcome. For the opportunistic fungal pathogen Cryptococcus neoformans, extreme morphological heterogeneity within the lung environment drives dissemination, immune evasion, and drug resistance. One such cell type is the small, oval, titanide (2-4 µm). This poorly understood cell type is prevalent in lung histology as well as host-relevant in vitro conditions. In conditions that generate cellular heterogeneity, titanides comprise 4%-10% of cells 24 hours post-induction and by 72 hours are the dominant cell type. Despite their prevalence and the significance of cryptococcal morphogenesis for virulence, key questions pertaining to their origin, fate, and underlying biology remain unstudied. Using TEM, SEM, and fluorescence microscopy we demonstrate that titanides display distinct morphological features; they possess thin cell walls, single birth scars, and capsules, with reduced Pathogen-Associated Molecular Pattern exposure and altered distribution. These features distinguish titanides from previously described C. neoformans 'small cells' such as in vivo seed cells (6 µm, high cell-wall mannan content) and micro cells (round, <1 μm, with thick cell walls) among others. Using microfluidics, we reveal that titanides arise from yeast-like 'typical' mothers, highlighting the morphological plasticity of typical cells in host-relevant conditions. Upon birth, titanides have compact nuclei and do not immediately proliferate, but transfer to fresh media results in rapid swelling and cell division. Consistent with this, titanides are more resistant to some cell wall/membrane stressors and are an effective infectious propagule in a murine model. Together, these findings establish a definition and essential characterisation of the titanide cell type and provide new insight into a key player in C. neoformans cell biology and pathogenesis.

The consequences of oligodendrocyte involvement in Alzheimer's disease are poorly understood. Could a key role of gray-matter oligodendrocytes-activity-dependent adaptive myelination to sustain changes in activity-be perturbed, leading to cognitive loss?

The sensorimotor system is continuously adjusted to minimize error. Current theories assume that this adaptation process entails the operation of multiple learning systems, with a key division between implicit and explicit components. Recent studies have revealed several inconsistencies regarding the characteristics and constraints of the implicit system, suggesting that the current framework is incomplete. Here, we propose that these conflicting findings can be understood by recognizing that there are multiple implicit subcomponents, each with distinct computational goals. One well-studied component is implicit recalibration, a process critical for action execution which uses sensory-prediction errors to automatically refine the sensorimotor map. In the current study, we describe a second, novel component, implicit aiming, a process which contributes to action selection to achieve specific goals. Through a series of studies using human participants, we find compelling evidence that those two implicit processes show a clear separation in their temporal stabilities and contextual modulations. These distinct properties correspond to different computational frameworks attributing learning dynamics to either contextual inference or cancellation of competing neural populations, respectively. Together, these findings suggest an alternative framework for sensorimotor adaptation based on the computational goals of the system rather than phenomenology.

The cation channel of sperm, CatSper, is a sperm-specific calcium channel essential for male fertility across metazoans. CatSper is activated by intracellular alkalinization, membrane depolarization, and elevated temperature, which together ensure maximal current generation. However, the structural mechanisms by which these physiological stimuli jointly regulate channel activation remain poorly understood, in part because CatSper is an unusually complex ~15-subunit assembly organized in zigzag supramolecular arrays along the sperm flagellum. Here, we combine comparative genomics across 47 species with AlphaFold3-based modeling and evolutionary sequence-structure analyses to investigate a mechanism underlying temperature and pH sensitivity of CatSper. Phylogenetic analysis shows that N-terminal length and histidine enrichment of the pore-forming subunit CatSper1 strongly correlate with species-specific fertilization temperatures, suggesting evolutionary adaptation of temperature and pH sensitivity. Structural modeling further revealed conserved surface-exposed histidine clusters that form predicted contact interfaces between adjacent CatSper assemblies, with this contact interface positioned near the dominant voltage-sensing module. Functional validation using electrophysiology and calcium imaging in mouse sperm shows that capacitation-associated partial removal of the CatSper1 N-terminus selectively impairs temperature-dependent activation. Together, these findings support a model in which temperature-dependent histidine deprotonation functionally couples neighboring CatSper complexes within the supramolecular assembly, thereby promoting synchronized channel activation.

The ability to monitor the proliferative status of live cells both in vitro and in vivo over time has revolutionised our understanding of development, growth and disease. This was first made possible by fluorescent ubiquitination-based cell cycle indicator (Fucci) technology, which distinguishes specific cell cycle phases through the reciprocal degradation of fluorescently tagged, truncated forms of human CDT1 and GMNN proteins. Fucci genetic systems have been successfully implemented in transgenic mice, zebrafish, and axolotls. To date, no viable, stably expressing Fucci line has been developed in an avian species. Although a range of continuously improving Fucci constructs have been developed in recent years, existing in vivo Fucci models remain limited because they rely on older reporter technology that fails to distinguish cells in S, G2, and M phases or to label cells in early G1. As a result, these models can be challenging to interpret and their utility for continuous cell tracking and precise analysis of cell-cycle dynamics is limited. Here, we introduce FuChi, a multicistronic Fucci-expressing chicken line incorporating a newly optimised reporter construct composed of an mCerulean-tagged histone H1.0 linker protein fused via a self-cleaving 2A peptide to the tandem Fucci(CA)2 cell cycle biosensor, with additional epitope tags included for detection in fixed tissues. We show that this system accurately discriminates and permits tracking of cells in G1, S, G2, and M phases both in vitro and in vivo, enabling faithful visualisation of cell cycle status in intact tissues and organs. Using FuChi embryos, we mapped proliferation dynamics across developing tissues, analysed cell cycle states of migrating cells, and performed live imaging of early embryos. These latter experiments revealed that transition from S phase may be a key morphogenetic event during gastrulation as mesendoderm cells egress from the primitive streak to form embryonic structures including the prechordal plate. Pairing this advanced reporter with the intrinsic experimental advantages of the chicken embryo positions FuChi as a premier in vivo system for studying cell-cycle kinetics in development, delivering clear technological improvements over current Fucci models. FuChi chickens provide a powerful new resource for studying embryonic development, organ growth, tissue homeostasis, disease processes, and infection responses.