Developmental plasticity allows organisms to adapt to environmental stress and improve reproductive fitness. Caenorhabditis elegans adapts to starvation and other stressors by transiting through an alternate developmental stage called dauer, which allows them to remain quiescent for several months, and yet fully retain reproductive fitness when they resume development. The AMP-activated protein kinase (AMPK) is essential for animals to passage through the dauer stage without reproductive consequence. The loss of AMPK leads to germline hyperplasia, dramatically reduced post-dauer fertility, and shortened dauer survival. We identified a putative RNA-binding helicase (HZL-1) that is targeted by AMPK. Disabling HZL-1 function rescues many dauer and post-dauer reproductive defects typical of the AMPK mutants. HZL-1 shares significant similarity with the conserved HELZ family of RNA helicases, possessing characteristic DEAH helicase motifs, a predicted ATP binding motif, and intrinsically disordered regions that are crucial for its localization and function. Curiously, HZL-1 is expressed and exerts its function in the intestine, yet its elimination suppresses the aberrant germ cell proliferation while restoring germline quiescence and subsequent post-dauer fertility in AMPK mutants. CLIP-seq data revealed that HZL-1 binds several mRNAs during the dauer stage, and thus when it is active in AMPK mutants, its regulation of these RNAs contributes to germline hyperplasia in the dauer germ line. The most enriched RNA bound and inhibited by HZL-1, argk-1, promotes fertility by suppressing TOR activity in the germ line of dauer larvae, thereby preserving germline quiescence. These findings underscore the intricate role of RNAs and RNA-binding helicases in the complex interplay of genetic signals that animals have acquired to ensure their effective transit through periods of environmental challenge.

S-adenosylmethionine (SAM), produced by SAM synthases, is critical for various cellular regulatory pathways and the synthesis of diverse metabolites. Humans and many other organisms express multiple SAM synthases. However, loss of different synthase activity can have distinct phenotypic effects. For instance, in Caenorhabditis elegans loss of sams-1 leads to enhanced heat shock survival and increased life span, but loss of sams-4 reduces heat stress survival. This provides a biological context to test the hypothesis that the enzymatic source of SAM impacts its function and to identify mechanistic connections. Here, we show that SAMS-1 contributes SAM to a variety of intermediary metabolic pathways, whereas SAMS-4 has a more limited role to support SAM-dependent protein transmethylation reactions. Mitochondria seem to be particularly impacted specifically by loss of sams-1; many mitochondrial metabolites are perturbed and there is an age-dependent decline of nuclear-encoded mitochondrial gene expression in these animals. We further demonstrate that reduced production of phosphatidylcholine in sams-1-deficient animals leads to mitochondrial fragmentation and subsequent loss of mitochondrial components. We propose that alterations in mitochondria are mechanistically linked to the increased survival in heat stress specific to sams-1-deficient animals.

Autism spectrum disorder (ASD) is a group of heterogeneous, behaviorally defined neurodevelopmental conditions influenced by both genetic and environmental factors. Here, we show that supplementation of multiple low-dose nutrients-an important environmental factor contributing to ASD-can modulate synaptic proteomes, reconfigure neural ensembles, and improve social behaviors in mice. First, we used Tbr1+/- mice, a well-established model of ASD, to investigate the effect of nutrient cocktails containing zinc, branched-chain amino acids (BCAA), and serine, all of which are known to regulate synapse formation and activity. Supplementation of nutrient cocktails for 7 days altered total proteomes by increasing synapse-related proteins. Our results further reveal that Tbr1 haploinsufficiency promotes hyperactivation and hyperconnectivity of basolateral amygdala (BLA) neurons, enhancing the activity correlation between individual neurons and their corresponding ensembles. Nutrient supplementation normalized the activity and connectivity of the BLA neurons in Tbr1+/- mice during social interactions. We further show that although a low dose of individual nutrients did not alter social behaviors, treatment with supplement mixtures containing low-dose individual nutrients improved social behaviors and associative memory of Tbr1+/- mice, implying a synergistic effect of combining low-dose zinc, BCAA, and serine. Moreover, the supplement cocktails also improved social behaviors in Nf1+/- and Cttnbp2+/M120I mice, two additional ASD mouse models. Thus, our findings reveal aberrant neural connectivity in the BLA of Tbr1+/- mice and indicate that dietary supplementation with zinc, BCAA, and/or serine offers a safe and accessible approach to mitigate neural connectivity and social behaviors across multiple ASD models.

Why do we observe some plant phenotypes but not others? The multivariate phenotypic space occupied by individuals or species often reveals both limits and phenotypes strikingly deviating from main syndromes. These observations are usually thought to indicate, respectively, inviable trait combinations and unique phenotypes adapted to specific environments. However, the evolutionary drivers underlying trait covariations often remain unclear. Here, we characterized the phenotypic space of Arabidopsis thaliana by comparing 713 wild accessions collected across the globe with 2,544 artificially-created recombinant individuals. This, combined with the detection of adaptive processes operating within species, allowed us to elucidate the roles of natural selection as a driver of phenotypic (co)variations within A. thaliana. We found that the phenotypic space of this species is constrained and driven by varying levels of divergent and stabilizing selection across different traits. Moreover, at the margins of the European geographic range, strong directional selection favored outlier phenotypes characterized by very late flowering and variation in a WRKY transcription factor gene. Genome analyses revealed that these extreme phenotypes may be explained by hybridization between ancestral and modern lineages of A. thaliana. Our findings demonstrate how interplays between population history and natural selection shape phenotypic diversity in a plant species.

Membrane nanotubes serve as critical cytoskeletal structures that facilitate intercellular communication and signal transmission across distances in both plants and animals. Here, we report the role of microtubule (MT) nanotubes in rendering the Drosophila micropyle functional, a structure essential for sperm entry during fertilization. Our study highlights that MT-nanotubes emanate from the apical end of the specialized epithelial cells called the polar cells in late oogenesis, forming a narrow channel through the eggshell. Utilizing a combination of fly genetics, live cell imaging, and tissue immunochemistry, our research elucidates the structural and functional characteristics of the polar cell nanotube. We show that tubulin is vital for the formation of these nanotubes, which are enriched in the lateral membrane marker, Fasciclin III. Moreover, the overall polarity of the migrating cell cluster is critical for the successful development of the micropyle. Notably, both lysosomal function and lysosomal trafficking within the polar cells are essential for the opening of the vitelline layer, further facilitating the micropyle's role in fertilization.

Lysosomes are critical hubs for both cellular degradation and signal transduction, yet their function declines with age. Aging is also associated with significant changes in lysosomal morphology, but the physiological significance of these alterations remains poorly understood. Here, we find that a subset of aged lysosomes undergo enlargement resulting from lysosomal dysfunction in C. elegans. Importantly, this enlargement is not merely a passive consequence of functional decline but represents an active adaptive response to preserve lysosomal degradation capacity. Blocking lysosomal enlargement exacerbates the impaired degradation of dysfunctional lysosomes. Mechanistically, lysosomal enlargement is a transcriptionally regulated process governed by the longevity transcription factor SKN-1, which responds to lysosomal dysfunction by restricting fission and thereby induces lysosomal enlargement. Furthermore, in long-lived germline-deficient animals, SKN-1 activation induces lysosomal enlargement, thereby promoting lysosomal degradation and contributing to longevity. These findings unveil a morphological adaptation that safeguards lysosomal homeostasis, with potential relevance for lysosomal aging and life span.

The prevalent strategy of conserving nonmegafauna charismatic species may be counterproductive, if conservation impact measures are oversimplistic and do not facilitate the restoration of long-term ecosystems and their functions.

The suprachiasmatic nucleus (SCN), the central circadian pacemaker, orchestrates daily metabolic rhythms, yet its role in substrate selection and thermogenic adaptation under stress remains insufficiently understood. Here, we show that SCN lesioning abolishes the adaptive suppression of brown adipose tissue (BAT) thermogenesis typically observed during time-restricted feeding in subthermoneutral environments (TRF-STE), a paradigm that imposes concurrent nutrient and thermal stress. Contrary to wild-type responses, SCN-lesioned mice maintain elevated BAT thermogenic activity, despite impaired lipolysis, instead shifting toward glucose-driven heat production. This phenotype is accompanied by sustained sympathetic tone and β3-adrenergic receptor (ADRB3) signaling in BAT. Mechanistically, we identify a SCN-regulated ADRB3-S100B signaling axis underlying this metabolic reprogramming. S100B, a nutrient-sensitive calcium-binding protein, is upregulated in BAT following SCN disruption, where it promotes thermogenesis by stimulating brown adipocyte proliferation and suppressing senescence. Functional studies reveal that S100B is both necessary and sufficient for sustaining BAT thermogenesis under TRF-STE. Furthermore, diverse SCN disruption models, including light-induced circadian arrhythmia, N-Methyl-D-aspartic acid (NMDA) excitotoxicity, and Caspase-3-mediated ablation, consistently elevate S100B expression in BAT, reinforcing its role as a convergent effector of SCN-regulated metabolic adaptation. Thus, in intact animal, the SCN restrains the ADRB3-S100B module, gating BAT thermogenic output in accordance with energetic availability. Disruption of SCN output lifts this restraint, unmasking a latent ADRB3-S100B program that preserves thermogenesis when lipid fuel is limited. These findings reveal a previously unrecognized role of the SCN in governing thermogenic flexibility and fuel partitioning, and position the ADRB3-S100B axis as a potential target for mitigating circadian misalignment and metabolic disease.

Mitochondrial function and dynamics are essential for maintaining cellular homeostasis and overall health. Disruptions in these processes can contribute to various diseases, including cancer. The Hippo signaling pathway, a key regulator of tissue growth, plays a central role in cancer through its main effector, the Yes-associated protein (YAP), known as Yorkie (Yki) in Drosophila. In this model organism, Yki upregulation drives benign tissue overgrowth in imaginal discs. Our research demonstrates that the conserved metabolic regulator dPGC1 restricts Yki-driven tissue hyperplasia and helps maintain epithelial integrity in vivo. Combined Yki upregulation and dPGC1 depletion results in tumors characterized by enlarged mitochondria and the upregulation of genes promoting mitochondrial fusion, a condition that is both necessary and sufficient for Yki-driven oncogenic growth. We further demonstrate that mitochondrial enlargement is associated with increased levels of the cell cycle regulator Cyclin E, which plays a critical role in tumor development. These findings identify dPGC1 as a context-dependent tumor suppressor that coordinates mitochondrial dynamics and cell cycle regulation in response to oncogene activation, with implications for understanding cancer development in humans.

Bacteria encode for gene regulatory networks crucial for sensing and repairing DNA damage. Upon exposure to genotoxic stress, these transcriptional networks are induced in a temporally structured manner. A case in point is of the highly conserved SOS response that is regulated by the LexA repressor. Studies have proposed that affinity of LexA towards promoters of SOS response genes is the primary determinant of its expression dynamics. Here, we describe an additional level of regulation beyond LexA box properties that modulates the SOS response gene expression pattern. Using transcriptomic analyses, we reveal a distinct temporal hierarchy in the induction of SOS-regulated genes in Caulobacter crescentus. We observe that LexA box properties are insufficient in predicting the temporal hierarchy of these genes. Instead, we find that intrinsic promoter strength underlies the order of gene activation, with differential sigma factor association as one of the factors modulating gene expression timing. Our findings highlight a novel regulatory layer in SOS dynamics and underscore the importance of promoter properties in shaping bacterial stress responses.

Patient and carer perspectives, methodological rigor, and ethical considerations can all be successfully integrated into the biomedical funding process. Drawing on experiences with ERA-NET NEURON, we present a structured, scalable, and transferable model for funders to follow.

[This corrects the article DOI: 10.1371/journal.pbio.3003361.].

How does the visual system process dynamic inputs? Perception and neural activity are shaped by the spatial and temporal context of sensory input, which has been modeled by divisive normalization over space or time. However, theoretical work has largely treated normalization separately within these dimensions and has not explained how future stimuli can suppress past ones. Here, we introduce a dynamic spatiotemporal normalization model (DSTN) with a unified spatiotemporal receptive field structure that implements normalization across both space and time and ask whether this model captures the bidirectional effects of temporal context on neural responses and behavior. DSTN implements temporal normalization through excitatory and suppressive drives that depend on the recent history of stimulus input, controlled by separate temporal windows. We found that biphasic temporal receptive fields emerged from this normalization computation, consistent with empirical observations. The model also reproduced several neural response properties, including surround suppression, nonlinear response dynamics, subadditivity, response adaptation, and backwards masking. Further, spatiotemporal normalization captured bidirectional temporal suppression that depended on stimulus contrast, consistent with human behavior. Thus, DSTN captured a wide range of neural and behavioral effects, demonstrating that a unified spatiotemporal normalization computation could underlie dynamic stimulus processing and perception.

Diplonemids are among the most diverse and abundant protists in the deep ocean, have extremely complex and ancient cellular systems, and exhibit unique metabolic capacities. Despite this, we know very little about this major group of eukaryotes. To establish a model organism for comprehensive investigation, we performed subcellular proteomics on Paradiplonema papillatum and localized 4,870 proteins to 22 cellular compartments. We additionally confirmed the predicted location of several proteins by epitope tagging and fluorescence microscopy. To probe the metabolic capacities of P. papillatum, we explored the proteins predicted to the cell membrane compartment in our subcellular proteomics dataset. Our data revealed an accumulation of many carbohydrate-degrading enzymes (CDZymes). Our predictions suggest that these CDZymes are exposed to extracellular space, supporting proposals that diplonemids may specialize in breaking down carbohydrates in plant and algal cell walls. Further exploration of carbohydrate metabolism revealed an evolutionary divergence in the function of glycosomes (modified peroxisomes) in diplonemids versus kinetoplastids. Our subcellular proteome provides a resource for future investigations into the unique cell biology of diplonemids.

Synapse connectivity is optimized in response to environmental input in critical periods, characterized by experience-dependent, temporally-restricted, and transiently-reversible synapse pruning by glial phagocytes. This precise, targeted synaptic elimination process requires glial serotonergic intercellular signaling. We discover glia-to-glia communication between different glial classes is essential for experience-dependent synaptic pruning in a well-defined Drosophila juvenile brain olfactory critical period. We find ensheathing glia infiltrate specific target synaptic glomeruli in response to guiding odorant experience via 5-HT2A receptor (5-HT2AR) signaling. Using cell-targeted tryptophan hydroxylase (Trhn) RNAi to block serotonin production, we discover serotonin signaling from ensheathing glia is required for experience-dependent synapse pruning. Using cell-targeted 5-HT2AR RNAi, we find the serotonin receptor is required exclusively in astrocyte-like glia (ALG). Using cell-targeted 5-HT2AR rescue in 5-HT2AR null mutants, we discover the serotonin receptor mediates experience-dependent synapse pruning. Thus, glia-to-glia serotonin signaling between different glial classes mediated by 5-HT2A receptors is necessary and sufficient for synapse elimination. We discover that ALG-targeted conditional 5-HT2AR in mature adults induces experience-dependent synapse pruning indistinguishable from the critical period mechanism. Thus, astrocyte 5-HT2AR signaling is sufficient to 're-open' this characteristic critical period remodeling capability at maturity. We find astrocytic matrix metalloproteinase-1 (MMP-1) induced by critical period odorant experience is required for experience-dependent synapse pruning downstream of 5HT2AR activation. We discover that ALG-targeted MMP-1 induction restores synapse pruning in the absence of 5HT2AR signaling. Taken together, we conclude that glia-to-glia serotonergic 5HT2AR signaling drives MMP-1 for experience-dependent infiltration phagocytosis synapse pruning, and can rekindle this remodeling capacity at adult maturity.

Neuronal activity and sensory experience regulate the subunit stoichiometry of synaptic N-methyl-D-aspartate subtype glutamate receptors (NMDARs), a critical determinant for brain development, synaptic plasticity, and a line of neurological disorders. Here we found that Ras and Rab interactor 1 (RIN1), a neuron-specific protein in the brain, played an important role in dictating synaptic NMDAR subunit composition in spinal cord somatostatin-positive (SOM+) neuron, a key component in the spinal circuit transmitting mechanical pain in mice. Our data showed that the protein level of RIN1 was low early after birth, which progressively increased with synapse maturation and promoted the switch from synaptic GluN2B- to GluN2A-containing NMDARs. In adult mice, the nerve injury-induced pathological pain paralleled a significant increase of RIN1 protein in spinal SOM+ neurons, which drove a new round of GluN2B-to-GluN2A switching at mature synapses. Our data revealed the molecular mechanisms by which RIN1 differentially regulated the synaptic trafficking of GluN2B and GluN2A receptors, and implied that RIN1-mediated pathological switch of NMDAR subunit composition strikingly altered the analgesic efficacy of distinct NMDAR subunit antagonists with the development of neuropathic pain.

Cell assemblies are considered fundamental units of brain activity, underlying diverse functions ranging from perception to memory and decision-making. Cell assemblies have generally been studied in relation to specific stimuli or actions, but this approach does not readily extend to more abstract constructs. An alternative approach is to assess cell assemblies without making reference to external variables, and instead focus on internal brain processes-by assessing assemblies by their endogenous ability to effectively elicit specific responses in downstream ("reader") neurons. However, this compelling idea currently lacks experimental support. Here, we provide evidence for assembly-reader communication. Large-scale cross-structural recordings in rats revealed that reader activation was genuinely collective, functionally selective, yet flexible, implementing both pattern separation and completion. These processes occurred at the time scale of membrane integration, synaptic plasticity, and gamma oscillations. Finally, assembly-reader couplings were selectively modified upon associative learning, indicating that they were plastic and could become bound to behaviorally relevant variables. These results support cell assemblies as an endogenous mechanism for brain function.

Intraneuronal aggregates of the microtubule-associated protein tau play a pivotal role in Alzheimer's disease and several other neurodegenerative syndromes. Anti-tau antibodies can reduce pathology in mouse models of neurodegeneration and are currently being tested in humans. Here, we performed a large-scale seroepidemiological search for anti-tau IgG autoantibodies (ατ) on 40,497 human plasma samples. High-titer ατ+ individuals were surprisingly prevalent, with hospital patients being three times more likely to be ατ+ (EC50 ≥ 26; a nominal dilution of >1/64) than healthy blood donors (4.8% versus 1.6%). The prevalence increased with age over 70 years-old (RR 1.26, 95% CI 1.11-1.43, P < 0.001) and was higher for women (RR 1.20, 95% CI 1.07-1.39, P = 0.002). The autoantibodies bound selectively to tau, inhibited tau aggregation in vitro, and interfered with tau detection in plasma samples. No association was found between ατ autoantibodies and neurological disorders. Instead, tau autoreactivity showed a significant association with kidney and urinary disorders (adjusted RR 1.27, 95% CI 1.10-1.45, P = 0.001 and 1.40, 95% CI 1.20-1.63, P < 0.001, respectively). These results suggest a previously unrecognized association between ατ autoimmunity and extraneural diseases.

In the model gram-negative bacterium Escherichia coli, three of the four Type VII ATP-binding cassette (ABC) transporter systems have been well characterized structurally and functionally. A new study reports the cryo-EM structures of the fourth Type VII ABC system, YbbAP-TesA, and provides evidence for its role in extracting hydrophobic compounds from the bacterial inner membrane and their subsequent hydrolytic transformation.

The spinal cord is the key bridge between the brain and the body. However, scientific understanding of healthy spinal cord function has historically been limited because noninvasive measures of its neural activity have proven exceptionally challenging. In this work, we describe an enhanced recording and analysis approach, Electrical Spinal Imaging (ESI), to obtain noninvasive, high-resolution images of the spinal cord electrical activity in humans. ESI is analytically simple, easy to implement, and data-driven: it does not involve template-based strategies prone to produce spurious signals. Using this approach, we provide a detailed description and physiological characterization of the spatiotemporal dynamics of the peripheral, spinal, and cortical activity elicited by somatosensory stimulation. We also demonstrate that attention modulates postsynaptic activity at spinal cord level. Our method has enabled five important insights regarding spinal cord activity. (1) We identified three distinct responses in the time domain: sP9, sN13, and sP22. (2) The sP9 is a traveling wave reflecting the afferent volley entering the spinal cord through the dorsal root. (3) In contrast, the sN13 and sP22 reflect segmental postsynaptic activity. (4) While the sP9 response is first seen on the dorsal electrodes ipsilateral to the stimulated side, the sN13 and sP22 were not lateralized with respect to the side of stimulation. (5) Unimodal attention strongly modulates the amplitude of the sP22, but not that of the sP9 and sN13 components. The proposed method offers critical insights into the spatiotemporal dynamics of somatosensory processing within the spinal cord, paving the way for precise noninvasive functional monitoring of the spinal cord in basic and clinical neurophysiology.