Sleep plays a critical role in animal physiology, primarily governed by the brain, and its disruption is prevalent in various brain disorders. Mettl5 is associated with intellectual disability (ID), which often includes sleep disturbances. However, the mechanism underlying these sleep disruptions in ID remains poorly understood. In this study, we investigated the sleep phenotypes resulting from <i>Drosophila Mettl5</i> mutations. Rescue experiments revealed that <i>Mettl5</i> functions predominantly within neurons and glia marked by <i>Mettl5</i>-Gal4 to regulate sleep. Previous work established that Mettl5 forms a complex with Trmt112 to influence rRNA methylation. Notably, a mutation in <i>Trmt112</i> recapitulated these sleep disturbances, implicating translational regulation by the Mettl5/Trmt112 complex. Subsequent RNA-seq and Ribo-seq analyses of <i>Mettl5<sup>1bp</sup></i> mutants uncovered downstream effects, including altered expression of proteasome components and clock genes. Rescue experiments confirmed that the net increase in PERIOD protein underlies the sleep phenotype. This study illuminates the interplay between ribosome function, clock genes, and the proteasome in sleep regulation, highlighting the integrated roles of protein synthesis and degradation. These findings could potentially provide an example for in vivo study of rRNA methylation function, expand our understanding of protein homeostasis in sleep, and offer insights into the sleep phenotypes associated with ID.
Science Journals
<p>by Ying-Jun Dong, Kun Xi, Ya-Zhi Zhang, Jian-Heng Xue, Dan-Dan Shen, Shao-Kun Zang, Ruozhu Zhao, Hai Qi, Chunyou Mao, Wei-Wei Wang, Yan Zhang</p>
G protein-coupled receptor 174 (GPR174), a key modulator of autoimmune responses, maintains immune homeostasis through distinct G protein signaling pathways, particularly G<sub>s</sub> and G<sub>i</sub>. Although the structural mechanism of lysophosphatidylserine (LysoPS)-activated GPR174 in the G<sub>s</sub> pathway has been characterized, how hydration-mediated interactions influence GPR174 activation and signaling selectivity remains unclear. Here, we determined high-resolution cryo-electron microscopy (cryo-EM) structures of LysoPS-activated human GPR174 bound to G<sub>s</sub> (2.0 Å) and G<sub>i</sub> (3.4 Å), revealing a continuous hydration-mediated signal transduction network that bridges the sodium-binding pocket, the NPxxY and DRY motifs, and the G protein-binding interface. This network stabilizes the active-state conformation of GPR174 and dynamically reshapes the intracellular cavity, thereby enabling differential engagement of G<sub>s</sub> and G<sub>i</sub>. Molecular dynamics simulations and functional assays demonstrated that the hydration network is essential for receptor activation and selectively modulates G protein coupling. To evaluate its conservation, we performed sequence alignments and structural analyses across class A GPCRs, defining three hydration cavities: the conserved water cavity (CWC), the junctional water cavity (JWC), and the extended water cavity (EWC), whose hydration is determined by residue properties at position 5.58. Together, our study reveals a hydration-driven molecular mechanism that underlies the activation of GPR174 and its dual G protein selectivity. These findings advance the understanding of hydration-mediated signaling in GPR174 and provide a framework for investigating water-mediated regulation across class A GPCRs.
<p>by Kaisar Ahmad Lone, Amit Mahendra Karole, Geethanjali Ravindran, Shweta Tyagi</p>
Trimethylation of histone 3 lysine 4 (H3K4me3) is a mark of active transcription, and its regulatory role in RNA polymerase II-mediated transcription has been well-studied. However, if and how this mark regulates RNA polymerase I (RNA Pol I) is not known. Here, we used customized genome assemblies for rDNA to demonstrate that KMT2A and KMT2F bind to entire rDNA loci. The binding of these enzymes was mirrored by the binding of H3K4me2 and H3K4me3 marks. Using biochemical assays, we demonstrate the interaction of KMT2-specific subunits with RNA Pol I transcriptional machinery. Our findings reveal KMT2F as the primary KMT depositing the H3K4me3 on rDNA. Loss of H3K4me3 adversely affects the epigenetic landscape and leads to repression of the rDNA locus. Mechanistically, using mammalian cells as a model system, we demonstrate that KMT2F promotes the formation of the pre-initiation complex by RNA Pol I. Our findings highlight the thus far undiscovered role of H3K4me3 in the transcriptional initiation of rDNA genes.
<p>by Rong Bi, Jan Grohn, Patricia L. Lockwood, Miriam C. Klein-Flügge, Lilian Weber</p>
Humans show remarkable flexibility in adapting their behaviour to constantly changing environments. This flexibility relies on the ability to regulate motivation in response to changing motivational demands. Typically, the amount of effort required to achieve a certain goal is not precisely signalled by the environment but needs to be learnt from experience. By contrast, prior work examining motivated choices has usually directly instructed effort requirements. It therefore remains unclear how healthy individuals estimate and flexibly regulate effort and how they might achieve this in dynamically changing environments. In the current study, we examine how effort learning is shaped by different types of environmental uncertainty when motivational requirements are not explicitly instructed. Analogous to tasks in the reward learning domain, we designed a novel effort learning task that systematically manipulated two key sources of uncertainty: volatility and noise. Participants were asked to exert effort by squeezing hand-held dynamometers. We characterised effort learning across different stages of the effort production process (e.g., initiation of effort production, effort expectation, error-driven adjustment), which allowed us to capture the dynamics underlying effort estimation and regulation over time. Our findings reveal that humans are able to learn effort requirements by integrating both effort priors and sensorimotor feedback. We further show that effort learning is modulated by environmental statistics, with slower force initiation, weaker priors, slower learning, and faster within-trial force adjustments in high noise environments, but slower learning and slower within-trial force adjustments in high volatility environments. In summary, when effort information is not instructed, different sources of uncertainty about an action’s required effort are integrated into pa…
<p>by Sean P. Heighton, Jérôme Murienne, Mukesh Thakur, Alain Didier Missoup, Wirdateti Wirdateti, Chabi Sylvestre Djagoun, Sery Bi Gonedelé, Gabriel Ngua Ayecaba, Brice Roxan Momboua, Flobert Njiokou, Anne-Lise Chaber, Helen C. Nash, Barbora Černá Bolfíková, Sylvain Dufour, Guy T. Gembu, Ayodeji Olayemi, Jordi Salmona, Amaia Iribar, Yves Cuenot, Philippe Gaubert</p>
Pangolins have become emblematic of the global wildlife trade crisis due to intense trafficking for consumption and traditional medicine. Coupled with habitat loss, the illicit trade in pangolins has severely threatened wild populations. Genetic identification of distinct pangolin populations is an imperative step toward guiding effective and informed conservation management. These populations can serve as a reference for assigning seized individuals to their geographic origins, and thus tracing trafficking networks. However, pangolin population genetics studies have been hindered by limited sampling of geo-referenced individuals, largely due to the species’ elusive nature. To address this, we developed a tailored gene-capture approach targeting 671 loci totaling 627 kb with high evolutionary and adaptive value across all eight pangolin species. We optimized the approach for low-quality DNA, including samples from museum collections and wildlife trade, such as bushmeat and scale seizures. We reassessed range-wide population delineations for the three most traded species, the white-bellied (<i>Phataginus tricuspis</i>), Sunda (<i>Manis javanica</i>), and Chinese (<i>M. pentadactyla</i>) pangolins, highlighting the need for biogeographically consistent lineage nomenclature and spatially aware analyses to support coherent conservation planning. The unprecedented geo-referenced DNA database for the three species yielded snapshot insights into pangolin trafficking hotspots and trade dynamics of both domestic markets and global trade seizures, the former providing novel insights into bushmeat trade. Domes…
<p>by The PLOS Biology Staff </p>
Proceedings of the National Academy of Sciences, Volume 123, Issue 19, May 2026. SignificanceRibonucleotide reductases (RNRs) are ancient enzymes responsible for the synthesis of deoxyribonucleotides from ribonucleotides. RNRs catalyze this reaction via a long-range proton-coupled electron transfer (PCET) process, involving the ...
Proceedings of the National Academy of Sciences, Volume 123, Issue 19, May 2026. SignificanceThe ordered arrangement of mechanosensory hair cells in vertebrate auditory epithelia relies on mechanical interactions among multiple cell types. Yet, how local mechanical heterogeneity produces tissue-scale organization remains unresolved. ...
Proceedings of the National Academy of Sciences, Volume 123, Issue 19, May 2026. SignificanceThe light-harvesting complex 2 (LH2) antenna of purple bacteria is a model system for photosynthetic light harvesting. The discovery of its delocalized excited states established a picture in which delocalization and associated rapid energy ...
Proceedings of the National Academy of Sciences, Volume 123, Issue 19, May 2026. SignificanceLogistic regression is a statistical method used to model binary outcome variables, such as whether a patient recovers or not, using a set of predictors. There are many competing methods for addressing uncertainty when selecting predictors, ...
Proceedings of the National Academy of Sciences, Volume 123, Issue 19, May 2026. SignificanceA potent protein kinase A (PKA)-selective kinase inhibitor, BLU0588, stabilizes the PKA catalytic subunit in an unusual open conformation and also abolishes the synergistic high-affinity binding of the physiological pseudosubstrate inhibitor ...
Proceedings of the National Academy of Sciences, Volume 123, Issue 19, May 2026.
New England Journal of Medicine, Ahead of Print.
The population of kisspeptin neurons located in the rostral periventricular area of the third ventricle (RP3V) is thought to have a key role in generating the GnRH surge that triggers ovulation. Using a modified GCaMP fibre photometry procedure, we have been able to record the in vivo population activity of RP3V<sup>KISS</sup> neurons across the estrous cycle of female mice. A marked increase in GCaMP activity was detected beginning on the afternoon of proestrus that lasted in total for 13±1 hr. This was comprised of slow baseline oscillations with a period of 91±4 min associated with high-frequency rapid transients. Very little oscillating baseline or transient activity was detected at other stages of the estrous cycle. Concurrent blood sampling showed that the peak of the LH surge occurred 3.5±1.1 hr after the first baseline RP3V<sup>KISS</sup> neuron baseline oscillation on the afternoon of proestrus. The time of onset of RP3V<sup>KISS</sup> neuron oscillations varied between mice and across subsequent proestrous stages in the same mice. To assess the impact of estradiol on RP3V<sup>KISS</sup> neuron activity, mice were ovariectomized and given an incremental estradiol replacement regimen. Minimal patterned GCaMP activity was found in OVX mice, and this was not changed acutely by any of the estradiol treatments. However, on the afternoon of the expected LH surge, the same oscillating baseline activity with associated transients occurred for 7.1±0.5 hr. These observations reveal an unexpected prolonged oscillatory pattern of RP3V<sup>KISS</sup> neuron activity that is dependent on estrogen and underlies the preovulatory LH surge as well as potentially other facets of reproductive behavior.
The extraction of a phospholipid called phosphatidic acid from the mitochondrial outer membrane is regulated by the curvature of this membrane.
The liver is a complex organ responsible for multiple functions, including metabolism, energy storage, detoxification, bile secretion, and immune regulation. Its highly organized vascular system plays a crucial role in maintaining functional zonation and tissue homeostasis. Within the liver, the hepatic artery, portal vein, hepatic vein, bile duct, and nerve networks intertwine to form an intricate three-dimensional architecture; however, traditional two-dimensional imaging fails to reveal their true spatial relationships, and current three-dimensional imaging methods remain insufficient to capture fine structural details. To achieve comprehensive visualization of these multi-ductal systems, we established a high-resolution three-dimensional imaging platform that combines multicolor perfusion of metallic compound nanoparticles (MCNPs) with an optimized tissue-clearing protocol (Liver-CUBIC), enabling simultaneous 3D reconstruction of the portal vein, hepatic artery, bile duct, and hepatic vein in mouse livers. Based on these data, we identified and defined a previously unrecognized structure located in the outer layer of the portal vein, termed the periportal lamellar complex (PLC). The PLC encircles the portal vein between the vascular endothelium and the perisinusoidal region, exhibits low-permeability barrier characteristics, and contains a distinctive population of CD34<sup>+</sup>Sca-1<sup>+</sup> endothelial cells. During liver fibrosis, the PLC extends from the portal vein toward the hepatic lobule, forming a structural scaffold that guides bile duct and nerve migration.
Proceedings of the National Academy of Sciences, Volume 123, Issue 19, May 2026.
Proceedings of the National Academy of Sciences, Volume 123, Issue 19, May 2026. SignificanceThe prefrontal cortex (PFC) controls higher-order cognitive processes that define mammals and distinguish humans. Although timing actions are critical for cognitive function, it is unclear how the PFC exerts temporal control of action. We ...
Proceedings of the National Academy of Sciences, Volume 123, Issue 19, May 2026. SignificanceAchieving durable, broad-spectrum crop protection remains difficult because plant immunity models often rely on limited species and overlook natural genetic diversity. To understand how plant defense networks shift across diverse lineages, we ...
Proceedings of the National Academy of Sciences, Volume 123, Issue 19, May 2026. SignificanceThis study identifies a critical role for amino acid side chain chirality in low-complexity domain (LCD) self-association. Using synthetic protein chemistry, we introduce targeted L-to-D amino acid inversions in LCDs without altering side ...
Proceedings of the National Academy of Sciences, Volume 123, Issue 19, May 2026. SignificanceExtravillous trophoblast (EVT) cells are a specialized cell type of the placenta that possess transformative actions on the uterine environment critical for a successful pregnancy outcome. Understanding how trophoblast stem (TS) cells ...
Proceedings of the National Academy of Sciences, Volume 123, Issue 19, May 2026. SignificanceGenetic mutations often play different roles in cancer, driving or suppressing tumor growth depending on their molecular context. The protein Speckle-type POZ protein (SPOP) is a striking example that acts as either a tumor-suppressor or ...
Proceedings of the National Academy of Sciences, Volume 123, Issue 19, May 2026. SignificanceDirect visualization of carbon corrosion in liquid uncovers the dynamics of carbon degradation during oxidation. Carbon materials underpin technologies ranging from energy storage to sensing, yet their instability remains poorly resolved at ...
Proceedings of the National Academy of Sciences, Volume 123, Issue 19, May 2026. SignificanceEukaryotic algae enhance their carbon assimilation using an organelle called the pyrenoid, where concentrated CO2is supplied to the CO2-fixing enzyme Rubisco. In many algae, a starch sheath surrounding the pyrenoid is thought to enhance CO2...
Proceedings of the National Academy of Sciences, Volume 123, Issue 19, May 2026. SignificanceMolecular dynamics (MD) simulation is a key tool for studying the behavior of proteins and other biomolecules, but despite four decades of hardware and algorithm advances, MD cannot characterize the biomolecular behavior of most systems of ...