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.

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.

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.

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.

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.

In most mammals, female sexual receptivity (estrus) closely coincides with ovulation, providing males with precise fertility signals. However, in some anthropoid primates living in multi-male societies, females display extended receptivity along with exaggerated sexual swellings that probabilistically indicate ovulation. This raises the question about how males successfully time mating, particularly when ovulation is difficult to predict from such signals. To address this question in bonobos, we combined daily variation in swelling size, hormonal profiles, and male mating behaviors. By estimating day-specific ovulation probabilities relative to the onset and subsidence (detumescence) of maximal swelling, we also examined how male efforts correlate with female fertility. Our results revealed that while ovulation probability was widely distributed and difficult to predict when aligned with the onset of the swelling phase, male behavior was closely aligned with the conception probability. Males concentrated mating efforts late in the phase and stopped after detumescence. High-ranking males intervened in copulations involving females with higher conception probabilities, specifically those with maximal swelling and older infants. When multiple females exhibited maximal swelling, males preferentially followed females whose maximal swelling started earlier and who had older infants. Male-male aggression increased when there were more females with maximal swelling. However, this tendency was reversed when male party size exceeded the average. Importantly, our results revealed that the low predictability of ovulation is best explained by inter- and intra-individual variation in the length of maximal swelling phase, rather than ovulation occurring randomly within that phase in bonobos. Males effectively manage such a noisy signal by prioritizing late-phase ovulatory cues and integrating reproductive history, thereby extracting usable timing information. This behavioral mechanism helps explain the persistence of conspicuous yet noisy ovulatory signals in bonobos. Since males are capable of inferring ovulation timing even under noisy conditions, selection may not favor highly precise female signals. Instead, it shifts more of the time and energy costs onto males, allowing conspicuous female traits to be maintained.

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.

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.

Zoonotic spillover of influenza A viruses represents a threat to human health. Emerging research suggests that some influenza A viruses can enter host cells via MHC-II across species, potentially increasing spillover risk.

The traditional pipeline view of academia no longer reflects the reality of scientific careers. Reframing success as a network of paths recognizes excellence in its many forms, fostering a more inclusive, resilient, and socially engaged research culture.

The hydroxycarboxylic acid receptors (HCAR2 and HCAR3), also known as prototypical metabolite-sensing receptors, are key targets for treating dyslipidemia and metabolic disorders. While HCAR2 activation, but not HCAR3 activation, is associated with side effects of cutaneous flushing, the structural features and ligand preferences of HCAR3 remain less understood. Here, we used Sf9 cells to express HCAR3-Gi and HCAR2-Gi complexes, and present cryo-EM structures of HCAR3-Gi complexes with agonists compound 6O (3.31 Å), D-phenyllactic acid (3.05 Å), IBC293 (3.26 Å), and acifran (3.18Å), as well as HCAR2-Gi complex with agonist acifran (2.72 Å). Our findings reveal the mechanism behind 6O's highest affinity to HCAR3, attributed to its full occupation of both R1 and R2 regions of the orthosteric binding pocket. Moreover, combined with cAMP assay in HEK-293 cells, we have elucidated that the ligand selectivity between HCAR3 and HCAR2 depended on π-π interaction with F1073.32 (L1073.32 in HCAR2) and ligand-binding pocket size difference, facilitated by key residues difference V/L832.60, Y/N862.63, and S/W9123.48. Collectively, these structural insights lay the groundwork for developing HCAR3-specific drugs, potentially avoiding HCAR2-induced adverse effects.

The breast and ovarian tumor suppressor BRCA1 is a cell cycle-regulated protein and tumors with reduced BRCA1 protein level may share molecular features of BRCA1-mutant tumor and respond to PARPi therapy. Here, we identify that BRCA1 protein stability is controlled through ubiquitin lysine 11 (K11)-linkage modification under the regulation of Cezanne deubiquitinating enzyme, APC/C E3 ligase, and Ube2S E2 conjugating enzyme in a cell cycle-dependent manner. Cezanne-deficiency leads to increased BRCA1 K11-ubiquitination, decreased BRCA1 protein level, and increased cellular sensitivity to PARPi. The BRCA1 K11-linked ubiquitination is carried out through a degron on BRCA1 that is recognized by APC/C cofactor Cdh1. Tumor expression and mutational analyses indicate that Cezanne low or Ube2S high expression is associated with "BRCAness" and correlated with poor prognosis in breast cancer patients. Thus, our study has demonstrated a ubiquitin K11-linked ubiquitination pathway that regulates BRCA1 protein stability, dysregulation of which predicts BRCA1-deficiency that may be effectively targeted with PARPi therapy.

Animals with lifelong growth adjust their growth rates to nutrient availability, yet the underlying cellular and molecular mechanisms remain poorly understood. Here, we studied how food supply and TOR signaling regulate the cell cycle in a multipotent population of Vasa2-/Piwi1-expressing cells in the sea anemone Nematostella vectensis. We discovered that starvation induces a reversible G1/G0 cell cycle arrest in Vasa2+/Piwi1+ cells and that cell cycle re-entry upon refeeding is dependent on TOR signaling. In addition, the length of the refeeding stimulus after starvation determines the proportion of cells that re-enter S-phase. Remarkably, prolonged starvation delayed both refeeding-induced TOR signaling activation and S-phase re-entry, and led to a global decrease in the active histone mark H3K27ac in Vasa2+/Piwi1+ cells. This strongly suggests that Nematostella Vasa2+/Piwi1+ cells undergo starvation-controlled quiescence deepening, a phenomenon previously described only in unicellular eukaryotes and mammalian cell culture. The nutritional control of quiescence and cell proliferation may thus be a fundamental, evolutionarily conserved strategy underlying the environmental regulation of indeterminate growth in animals.

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.

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.

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.

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

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.

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.

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.

Centrioles are polarized microtubule-based structures with appendages at their distal end that are essential for cilia formation and function. The protein C2CD3 is critical for distal appendage assembly, with mutations linked to orofaciodigital syndrome and other ciliopathies. However, its precise molecular role in appendage recruitment remains unclear. Using ultrastructure expansion microscopy (U-ExM) and iterative U-ExM on human cells, together with in situ cryo-electron tomography (cryo-ET) on mouse tissues, we reveal that C2CD3 adopts a radially symmetric 9-fold organization within the centriole's distal lumen. We show that the C-terminal region of C2CD3 localizes close to a ~100 nm luminal ring structure consisting of ~27 nodes, while its N-terminal region localizes close to a hook-like structure that attaches to the A-microtubule as it extends from the centriole interior to exterior. This hook structure is adjacent to the DISCO complex (MNR/CEP90/OFD1), which marks future appendage sites. C2CD3 depletion disrupts not only the recruitment of the DISCO complex via direct interaction with MNR but also destabilizes the luminal ring network composed of C2CD3/SFI1/centrin-2/CEP135/NA14, as well as the distal microtubule tip protein CEP162. This reveals an intricate "in-to-out" molecular hub connecting the centriolar lumen, distal microtubule cap, and appendages. Although C2CD3 loss results in shorter centrioles and appendage defects, key structural elements remain intact, permitting continued centriole duplication. We propose that C2CD3 forms the luminal ring structure and extends radially to the space between triplet microtubules, functioning as an architectural hub that scaffolds the distal end of the centriole, orchestrating its assembly and directing appendage formation.