Proc Natl Acad Sci U S A
· 2026 Jul · PMID 42384697
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The scientific world has lost one of its great architects with the passing of Pierre Chambon, a visionary French scientist, institution builder, and demanding yet inspiring mentor. He provided major insights into the fun...The scientific world has lost one of its great architects with the passing of Pierre Chambon, a visionary French scientist, institution builder, and demanding yet inspiring mentor. He provided major insights into the fundamental mechanisms governing gene expression and hormonal regulation that transformed modern biology and medicine. In addition, he developed groundbreaking mouse genetic techniques, and established Strasbourg as a leading European center for life sciences research. His death on May 5, 2026, at the age of 95, marks the end of an extraordinary era in science, yet his intellectual legacy will continue to shape generations of researchers across the world.
Liao J, Liu Q, Liu C
… +19 more, Liu G, Li X, Wang X, Wang Y, Liu R, Wu H, Wang C, Shi H, Zhao Y, Ke W, Ran Z, Wu Z, Tan B, Wang Q, Hua G, Zhang S, Xie Q, Liu G, He C
Proc Natl Acad Sci U S A
· 2026 Jul · PMID 42384696
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The corpus luteum (CL) arises from the luteinization of granulosa cells (GCs) and theca cells, marked by rapid progesterone elevation and angiogenesis. Intriguingly, angiogenesis lags behind progesterone elevation, creat...The corpus luteum (CL) arises from the luteinization of granulosa cells (GCs) and theca cells, marked by rapid progesterone elevation and angiogenesis. Intriguingly, angiogenesis lags behind progesterone elevation, creating an avascular phase during which luteal cells must fuel intensive steroidogenesis without perfusion. How the avascular CL meets this energetic demand remains a mystery. Here, we reveal a cellular adaptive mechanism-granulosa cell energy storage (GCES)-that resolves this enigma. We demonstrate that upon luteinization initiation, GCs enter a metabolically quiescent state yet enhance glucose uptake, converting the glucose into glycogen. Catabolism of this glycogen reserve supplies the energy required for the avascular CL, ensuring normal luteogenesis. Disruption of GCES induces luteal insufficiency, whereas timely glucose administration enhances GCES, improving luteal function and optimizing reproductive outcome in both mouse and ovine models. In human study, oral intake of glucose post-hCG significantly augments GCES and enhances progesterone production. These results advance our understanding of luteinization.
Wang X, Qin Y, Duong LD
… +17 more, Liang M, Chao A, Parrotta R, Li Y, Purohit PK, Fang Y, Liu G, He J, Wen J, Liu Y, Zhang Y, Zhao J, Barupala N, Schafer ZT, Lu X, Szegezdi E, Lu X
Proc Natl Acad Sci U S A
· 2026 Jul · PMID 42384695
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Clear cell renal cell carcinoma (ccRCC) is the most common and aggressive subtype of kidney cancer. Loss of von Hippel-Lindau (VHL) and the consequent activation of hypoxia-inducible factor-α (HIFα, especially HIF2α) pla...Clear cell renal cell carcinoma (ccRCC) is the most common and aggressive subtype of kidney cancer. Loss of von Hippel-Lindau (VHL) and the consequent activation of hypoxia-inducible factor-α (HIFα, especially HIF2α) plays an essential role in ccRCC initiation and progression. The VHL-HIF2α axis as the main driver for ccRCC may present specific opportunities to control the disease by cotargeting HIF2α with belzutifan and another vulnerability. This study elucidates the synthetic essentiality of TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) in VHL-deficient ccRCC. Upregulated in ccRCC in a VHL-HIF2α-dependent manner, TRAIL is selectively essential in ccRCC cells, promoting cell proliferation by activating the p38 MAPK pathway and facilitating G1/S phase transition. Depletion of endogenous TRAIL or inhibition of HIF2α with belzutifan sensitizes ccRCC cell and tumor models to recombinant TRAIL, presenting a promising avenue for combination therapy in ccRCC.
Zhao C, Yuan S, You J
… +6 more, Bai C, Su Y, Cheng X, Shen S, Yan X, Zhang J
Proc Natl Acad Sci U S A
· 2026 Jul · PMID 42384694
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In the oxygen evolution reaction (OER), adherent gas bubbles are conventionally viewed as a major impediment that blocks ion and mass transport by covering active sites. Here, we show that for ionomer-based electrodes, t...In the oxygen evolution reaction (OER), adherent gas bubbles are conventionally viewed as a major impediment that blocks ion and mass transport by covering active sites. Here, we show that for ionomer-based electrodes, this prevailing view is oversimplified. Using a self-developed transparent on-chip electrolyzer that integrates multimodal in-situ characterization, including optical microscopy, spectroscopic analysis, and atomic force microscopy, we uncover complex intrabubble dynamics on ionomer-coated electrodes. During bubble growth, the three-phase contact line exhibits characteristic pinning-depinning behavior. Beyond a critical bubble size (~420 μm), free water molecules are evolved from the ionomer into the bubble-electrode contact area, forming microdroplets (<20 μm) that continuously coalesce. Inside these microdroplets, oxygen products further nucleate as pancake-shaped nanobubbles (~50 nm), revealing a previously unrecognized intrabubble process. We find that this coupled microdroplet-nanobubble evolution is enabled by the phase-separation behavior of ionomer. The ionomer also preserves local electrochemical activity even under substantial bubble coverage, unlike ionomer-free electrodes where bubble blockage leads to severe deactivation. By tailoring ionomer phase separation, we achieve intensified microdroplet-nanobubble evolution and measurable performance improvement at high current densities. This finding opens a route to mitigate bubble-induced activity loss in OER electrodes.
Alia AG, Hu X, Gu Y
… +10 more, Yau J, Tian G, Semmelhack JL, Saito K, Tanimoto H, Tsuyuzaki K, Naganos S, Miyashita T, Saitoe M, Hirano Y
Proc Natl Acad Sci U S A
· 2026 Jul · PMID 42384693
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Although fear conditioning has elucidated cue-evoked acute fear responses, the mechanisms by which stress experiences induce generalized internal states linked to anxiety or phobia are poorly understood. Here, we report...Although fear conditioning has elucidated cue-evoked acute fear responses, the mechanisms by which stress experiences induce generalized internal states linked to anxiety or phobia are poorly understood. Here, we report that robust stress induces a persistent behavioral change characterized by avoidance of a confined space, claustrophobia-like behavior (CLB) in . Unlike aversive memory formation, the development of CLB does not require dopamine receptors. Our neuronal screening determined that neuropeptide signaling via Allatostatin-A inactivates the downstream neurons via its receptor AstA-R1, causally inducing CLB. Moreover, gene expression profiling of individual fly heads revealed that innate immune response activation in the blood-brain barrier is involved in CLB. Our data demonstrate that stress-induced persistent behavioral change would not be related to a canonical mechanism of aversive memory formation, rather involves neuropeptidergic signaling and the blood-brain barrier, providing the mechanism determining internal states which persistently change into a phobia-like mode.
Proc Natl Acad Sci U S A
· 2026 Jul · PMID 42384692
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Nitrogen is an essential nutrient vital for plant health and productivity. How plants integrate nutrient signals and epigenome dynamics to modulate transcription and developmental transition remains largely unknown. Here...Nitrogen is an essential nutrient vital for plant health and productivity. How plants integrate nutrient signals and epigenome dynamics to modulate transcription and developmental transition remains largely unknown. Here, we uncover the crucial role of EARLY BOLTING IN SHORT DAYS (EBS) homeostasis in controlling floral transitions in response to nitrogen deficiency. EBS, a bivalent histone reader capable of recognizing both H3K27me3 and H3K4me3 histone marks, can switch its binding preference to regulate the vegetative-to-reproductive transition. We demonstrate that nitrogen and Target of Rapamycin (TOR) signaling regulate EBS protein abundance through a direct TOR-EBS interaction. TOR phosphorylates EBS at the S195 and S196 residues, which promotes EBS stability and represses the transcription of and other flowering genes, thereby preventing premature floral transition. Collectively, this study identifies EBS as a direct substrate of TOR and reveals a mechanistic link between nutrient signaling, epigenome dynamics, and plant developmental transition. Our findings provide important insights into complex nutrient-TOR-chromatin interplays and highlight the intricate mechanisms by which plants adapt their growth and developmental processes based on nutrient availability.
Mileo E, Piero A, Lojou E
… +3 more, Cheruzel L, Gray HB, Ivancich A
Proc Natl Acad Sci U S A
· 2026 Jul · PMID 42384691
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The bifunctional heme peroxidase from (BpKatG) utilizes heme and three tryptophans (Trp139, Trp153, and Trp330) as unique redox cofactors in the peroxidase-like catalytic cycle, as was shown previously by multifrequency...The bifunctional heme peroxidase from (BpKatG) utilizes heme and three tryptophans (Trp139, Trp153, and Trp330) as unique redox cofactors in the peroxidase-like catalytic cycle, as was shown previously by multifrequency Electron Paramagnetic Resonance (EPR) spectroscopy combined with isotope labeling and site-directed mutagenesis. In this work, we exploited the redox properties of a strategically attached nitroxide as a direct probe of the long-range multistep electron-tunneling pathway between Trp153 and the high-valent heme intermediate, thereby showing it is mediated by Trp94 and Trp95. We also demonstrated that the equilibrium between the [Fe = O Trp153] and [Fe = O Trp139] intermediates, which is observed in the absence of substrate, is preferentially shifted toward catalytic oxidation of isoniazid substrate by Trp139. Our EPR experimental data confirm that Trp139 oxidatively activates the isoniazid prodrug, in sharp contrast to the current view that [Fe = O Por] is the oxidant, as in canonical peroxidases.
Jose A, Braun A, Hong S
… +2 more, Gennis RB, Solomon EI
Proc Natl Acad Sci U S A
· 2026 Jul · PMID 42384690
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Heme-copper oxidases, the terminal respiratory complex in the electron transport chain, harness the energy from the reduction of dioxygen to water to pump protons across mitochondrial or bacterial membranes against a gra...Heme-copper oxidases, the terminal respiratory complex in the electron transport chain, harness the energy from the reduction of dioxygen to water to pump protons across mitochondrial or bacterial membranes against a gradient to power ATP synthesis. While proton pumping in heme-copper oxidases was discovered more than four decades ago, a molecular-level understanding of the proton pumping mechanism remains elusive. Particularly, the role of the heme-copper active site, including a unique tyrosine residue covalently crosslinked to a copper ligand, remained inaccessible due to intense overlapping spectroscopic features from other redox centers in these enzymes. Here, by leveraging site-selective spectroscopic methods, we show that the active site copper and its crosslinked tyrosine directly control the proton pumping, providing the molecular mechanism underlying this process. This was achieved by experimental elucidation of the key intermediate F, formed in the first proton pumping step in heme-copper oxidases. By performing variable-temperature, variable-field magnetic circular dichroism spectroscopy on the oxo-heme center and K-edge X-ray absorption spectroscopy on the copper center of F, we find that the iron(IV)-oxo in F is ferromagnetically coupled to an electron-delocalized copper/tyrosine radical. These results show that the copper(I)-tyrosyl radical character, triggered by protonation of the heme-copper center, enables proton pumping. Furthermore, we find that the copper-tyrosyl radical character is regenerated in all four proton pumping intermediates, completing the molecular mechanism for proton pumping by the respiratory oxidase family of enzymes.
Proc Natl Acad Sci U S A
· 2026 Jul · PMID 42384689
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Fungi frequently transition between pathogenic, endophytic, and saprophytic lifestyles, yet the functional traits enabling these ecological shifts remain unclear. Comparative analyses of early and recently diverged linea...Fungi frequently transition between pathogenic, endophytic, and saprophytic lifestyles, yet the functional traits enabling these ecological shifts remain unclear. Comparative analyses of early and recently diverged lineages of reveal contrasting life-history strategies. Early diverged strains exhibit limited plant root association, slower insect lethality, extensive within-host proliferation, and high sporulation, whereas recently diverged strains display rapid germination on insect cuticle and plant roots, accelerated host killing, and hyphal growth from cadavers to plant roots; most also exhibit destruxin activity. Carbon utilization profiling across 95 substrates demonstrates that expanded metabolic breadth strongly predicts cuticle and plant-responsive germination, virulence across multiple insect hosts, and root colonization efficiency, linking cross-kingdom performance to nutritional breadth. Host immune activation further modulates strain-specific virulence but does not obscure the central role of metabolic flexibility. Collectively, these findings identify metabolic capacity as a functional axis coupling nutrient acquisition to ecological diversification, providing a mechanistic framework for understanding ecological plasticity in host-associated fungi.
Fu W, Qiao P, Bai H
… +11 more, Shi K, Dong X, Zhang J, Du Z, Kong J, Yang H, Zhang X, Zhang K, Su L, Nishinari K, Mao HK
Proc Natl Acad Sci U S A
· 2026 Jul · PMID 42384688
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Hydrogels have been widely used in biomedical and environmental applications, yet precise control of mechanical properties (quantified by elastic modulus, G') over a broad range remains essential for expanding their func...Hydrogels have been widely used in biomedical and environmental applications, yet precise control of mechanical properties (quantified by elastic modulus, G') over a broad range remains essential for expanding their functionality. While pressure treatment typically enhances hydrogel strength through pressure-induced crosslinking, we report a counterintuitive phenomenon in locust bean gum (LBG) hydrogels: High-pressure processing induces softening rather than stiffening. Under repeated compression-decompression cycles up to 1.2 GPa, LBG hydrogels undergo progressive softening, with elastic modulus decreasing to approximately 31% of the initial value. Conversely, repeated freeze-thaw cycles enhance the modulus by approximately 2.3-fold. Scanning electron microscopy reveals a structural transition from a porous network to a flocculent morphology, corresponding to substantial alterations in elastic modulus and viscoelastic behavior. Mechanistic analysis suggests that pressure-induced disruption of hydrogen bonding, water redistribution, and structural rearrangement drive these changes. These findings demonstrate that pressure modulation can serve as a complementary method to conventional freeze-thaw treatment, offering precise control over hydrogel mechanical properties across a wide range.
Cheng CC, Li CC, Wang YS
… +2 more, Lin CW, Chiang YW
Proc Natl Acad Sci U S A
· 2026 Jul · PMID 42384687
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Proton-coupled ion transport is a fundamental chemical process underlying membrane physiology, yet how local electrostatics are transduced into gated Ca permeation remains poorly defined. Here, we combine single-channel...Proton-coupled ion transport is a fundamental chemical process underlying membrane physiology, yet how local electrostatics are transduced into gated Ca permeation remains poorly defined. Here, we combine single-channel planar bilayer electrophysiology, nanodisc-based double electron-electron resonance spectroscopy, atomistic modeling, and a nanodisc nano-delivery strategy that enables direct functional insertion of purified membrane proteins into live mammalian cells. Applying this integrated toolkit to the bacterial transmembrane Bax-inhibitor-1-containing motif prototype YetJ, we resolve a hierarchical electrostatic gating mechanism governed by two salt bridges with distinct physical roles. A periplasmic E49-R205 interaction functions as a proton-sensitive latch that drives transmembrane helix 2 displacement and controls opening probability, while a cytoplasmic E182-R15 pair operates as a local electrostatic determinant of Ca self-block that tunes conductance and selectivity without large-scale conformational change. Quantitative separation of these effects reveals how protonation reshapes the energy landscape of ion permeation. Live-cell Ca imaging following nano-delivery recapitulates this gating logic in a cellular membrane setting. Together, this work establishes dual salt-bridge electrostatics as a chemical principle for graded Ca leak and introduces nano-delivery as a powerful platform for connecting molecular electrostatics to cellular ion transport.
Zhu J, Wang GZ, Pinto HD
… +4 more, Healton SE, Mishra LN, Skoultchi AI, Goff SP
Proc Natl Acad Sci U S A
· 2026 Jul · PMID 42384686
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In eukaryotic cells, genomic DNA is packaged into chromatin with nucleosomes formed by core histones H2A, H2B, H3, and H4, and further stabilized by the linker histone H1. During the early stages of retroviral infection,...In eukaryotic cells, genomic DNA is packaged into chromatin with nucleosomes formed by core histones H2A, H2B, H3, and H4, and further stabilized by the linker histone H1. During the early stages of retroviral infection, such as with murine leukemia virus (MLV) and human immunodeficiency virus type 1 (HIV-1), host core and H1 histones are rapidly deposited onto unintegrated viral DNAs upon nuclear entry. These unintegrated viral DNAs are transcriptionally silenced through histone posttranslational modifications (PTMs), including high levels of H3K9 trimethylation and low levels of H3 acetylation. Linker histone H1 is closely associated with chromatin compaction and histone PTMs, suggesting a potential role in regulating retroviral DNA fate. In this study, we demonstrate that simultaneous knockdown of four somatic H1 variants (H1.2, H1.3, H1.4, and H1.5) in K562 cells reverses the silencing of unintegrated HIV-1 DNA, resulting in increased viral expression. Notably, this effect was specific to HIV-1, as the same H1 depletion did not alter the silencing of MLV unintegrated DNA. Furthermore, inhibition of H3K9 methylation also relieved HIV-1 silencing, and H1 depletion reduced H3K9me3 deposition on HIV-1 unintegrated DNA. These findings indicate that H1 regulates HIV-1 unintegrated DNA expression by promoting H3K9me3 deposition, a mechanism that appears distinct from that of MLV.
Hu X, Liu X, Wang Y
… +11 more, Liu K, Gao H, Zhu G, Wang S, Fang X, Sun H, Zhou F, Ji S, Zhou C, Zhang Y, Xu X
Proc Natl Acad Sci U S A
· 2026 Jul · PMID 42384685
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Cell differentiation and Turing-like patterning are tightly associated in a group of filamentous cyanobacteria that differentiate specialized N-fixing cells, called heterocysts. Based on systematic genetic analyses, in p...Cell differentiation and Turing-like patterning are tightly associated in a group of filamentous cyanobacteria that differentiate specialized N-fixing cells, called heterocysts. Based on systematic genetic analyses, in particular genome-wide identification of recognized promoters and assays with a reconstituted transcription system in , we established HetZ as the central activator of the gene regulatory network of heterocyst differentiation. Biochemical and cryo-EM analyses further established HetZ as a σ factor (σ). Unique domain insertions in σ are involved in promoter DNA recognition-unwinding and interaction with the inhibitor PatU3. σ-PatU3 and the master regulator-diffusible inhibitor constitute the minimal core regulatory circuit (CRC) for cell fate determination and patterning. σ activates not only genes of the CRC but also downstream regulator/effector genes involved in morphological and functional development. The gene regulatory network and the structure-function relationship of σ depict how cell differentiation and patterning are coordinated in this group of multicellular cyanobacteria.
Aguilar P, Andrade P, Brejcha J
… +15 more, Pereira P, Arbore R, Abalos J, Afonso S, Afonso R, Badiane A, Font E, Simbula G, Bosakova Z, While GM, Uller T, Pinho C, Andersson L, Pérez I de Lanuza G, Carneiro M
Proc Natl Acad Sci U S A
· 2026 Jul · PMID 42384684
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The way organisms perceive the world influences their evolution. Many animals detect ultraviolet (UV) light invisible to humans, creating sensory contexts that alter the selective landscape for coloration. Here, we disse...The way organisms perceive the world influences their evolution. Many animals detect ultraviolet (UV) light invisible to humans, creating sensory contexts that alter the selective landscape for coloration. Here, we dissected the molecular basis of a UV-reflecting color morph in common wall lizards, uncovering its association with a noncoding region upstream of the transcription factor . Our results suggest that variation at this locus alters dermal architecture by modifying the cellular composition, exposing structures within specialized cells that generate UV structural coloration. We further demonstrate that the locus acts epistatically on other color genes to suppress pigment deposition, revealing a genetic interaction between pigmentary and structural pathways that underlie color production. Across populations, the frequency of the UV morph was not predicted by environmental variation, arguing against climate-driven selection. Inferred frequencies of the UV-associated allele across sampled populations exhibited weaker spatial structure than expected from genome-wide variation, suggesting this polymorphism may be maintained by balancing selection. Our findings reveal mechanisms of phenotypic evolution beyond human perception and a genetic link between pigmentary and structural coloration.
George EA, Motes-Rodrigo A, Keller L
… +1 more, Frank ET
Proc Natl Acad Sci U S A
· 2026 Jul · PMID 42384683
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In social animals, open wounds pose a risk not only for the injured individual but also for its wider social context, especially when the probability of infection transmission is high. To mitigate this danger, different...In social animals, open wounds pose a risk not only for the injured individual but also for its wider social context, especially when the probability of infection transmission is high. To mitigate this danger, different strategies have evolved across species, with ants representing one of the few taxa beyond humans that engage in social wound care. Yet, who provides this care and what drives care provision remains unexplored. To answer these questions, we combined controlled injury experiments with automated behavioral tracking and simulations across six colonies of the ant . Our results demonstrate that caregivers are workers in a transitional state between nursing and foraging roles, characterized by elevated activity and broad nest coverage. Being in this transitional state, however, is required but not sufficient to explain the temporal dynamics of individual care provision. Instead, care provisioning is best explained by preinjury spatial overlap, encounter rates, and social interactions, which together constitute an affinity index that predicts both the frequency and duration of subsequent wound care events. We further show that the treatment of open wounds is not the result of a generalized increase in social behaviors directed to the injured ants but part of a care response toward injuries that also involves an increase in allogrooming. Taken together, our findings reveal the necessary conditions for an individual to act as a caregiver and highlight affinity-driven dyadic interactions as an underexplored mechanism for the behavioral coordination of social immunity strategies in decentralized caste-based insect societies.
Zentner A, Halingstad EV, Chalk C
… +4 more, Brenner MP, Murugan A, Winfree E, Shrinivas K
Proc Natl Acad Sci U S A
· 2026 Jul · PMID 42384681
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Living organisms rely on molecular networks, such as gene circuits and signaling pathways, for information processing and robust decision-making in crowded, noisy environments. Recent advances show that interacting biomo...Living organisms rely on molecular networks, such as gene circuits and signaling pathways, for information processing and robust decision-making in crowded, noisy environments. Recent advances show that interacting biomolecules self-organize by phase transitions into coexisting spatial compartments called condensates, often on cellular surfaces such as chromatin and membranes. In this paper, we demonstrate that multicomponent fluids can be designed to recruit distinct condensates to surfaces with differing compositions, performing a form of surface classification by condensation. We draw an analogy to multidimensional classification in machine learning and explore how hidden species, analogous to hidden nodes, expand the expressivity and capacity of these interacting ensembles to facilitate complex decision boundaries. By simply changing levels of individual species, we find that the same molecular repertoire can be reprogrammed to solve new tasks. Together, our findings suggest that the physical processes underlying biomolecular condensates can encode and drive adaptive information processing beyond compartmentalization.
van Beers JJ, Scheffer M, Solanki P
… +3 more, van de Leemput IA, van Nes EH, de Visser CC
Proc Natl Acad Sci U S A
· 2026 Jul · PMID 42384680
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Maintaining stability in feedback systems, from aircraft and autonomous robots to biological and physiological systems, relies on monitoring their behavior and continuously adjusting their inputs. Incremental damage can...Maintaining stability in feedback systems, from aircraft and autonomous robots to biological and physiological systems, relies on monitoring their behavior and continuously adjusting their inputs. Incremental damage can make such control fragile. This tends to go unnoticed until a small perturbation induces instability (i.e., loss of control). Traditional methods in the field of engineering rely on accurate system models to compute a safe set of operating instructions, which become invalid when the, possibly damaged, system diverges from its model. Here we demonstrate that the approach of such a feedback system toward instability can nonetheless be monitored through dynamical indicators of resilience. This holistic system safety monitor does not rely on a system model and is based on the generic phenomenon of critical slowing down, shown to occur in the climate, biology, and other complex nonlinear systems approaching criticality. Our findings for engineered devices opens up a wide range of applications involving real-time early warning systems as well as an empirical guidance of resilient system design exploration, or "tinkering." While we demonstrate the validity using drones, the generic nature of the underlying principles suggest that these indicators could apply across a wider class of controlled systems including reactors, aircraft, and self-driving cars.
Proc Natl Acad Sci U S A
· 2026 Jul · PMID 42384679
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Prussian Blue is not only the oldest synthetic pigment, but also an electrochemically active material with modern technological relevance for its electrochromic properties and applications in energy storage. In this work...Prussian Blue is not only the oldest synthetic pigment, but also an electrochemically active material with modern technological relevance for its electrochromic properties and applications in energy storage. In this work, we study the fundamental mechanism of electron transport processes in this material, and how it varies as the material is progressively oxidized from Prussian White to Prussian Blue. Recently developed methods in spectroelectrochemical ultrafast 2D infrared spectroscopy allow us to measure the electron transfer rate within a film of Prussian Blue deposited onto the working electrode in an electrochemical cell as a function of applied bias potential. The intrinsic CN stretching modes serve as a local probe of the Fe oxidation state and as a measure for the solvation dynamics induced by water molecules incorporated into the subcells of the zeolitic lattice. We observe a fast, ps-scale electron transfer process with a rate that varies with the state of the material, revealing the intrinsic mobility of electrons decoupled from the slow diffusion of K+ ions. By correlating these observations to changes in the local structural distributions of FeIII sites, K+ ions and water molecules with the aid of a lattice model, we obtain insight into the mechanism of electron transport in this material. These results demonstrate a method for observing fast electron transfer and correlating them with nuclear motions, and provide a way to study chemical transformations at the electrochemical interface.
Lawrence J, Kulkarni VV, Tan CL
… +5 more, Callow M, Juste Y, Sangaraju D, Costa M, Bingol B
Proc Natl Acad Sci U S A
· 2026 Jul · PMID 42384678
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Mutations in the gene, which encodes the lysosomal glucocerebrosidase enzyme GCase, cause the lysosomal storage disorder Gaucher disease and represent the most common genetic risk factor for Parkinson's disease (PD). Th...Mutations in the gene, which encodes the lysosomal glucocerebrosidase enzyme GCase, cause the lysosomal storage disorder Gaucher disease and represent the most common genetic risk factor for Parkinson's disease (PD). These mutations deplete lysosomal GCase activity and cause accumulation of GCase substrate, glucosylceramide, and its pathological metabolite, glucosylsphingosine. Impaired GCase activity then drives immune and neuronal dysfunction in Gaucher disease and promotes pathogenic aggregation of α-Synuclein in PD. As such, boosting the lysosomal activity of GCase is a therapeutic strategy to ameliorate substrate accumulation and prevent associated neurotoxicity. To identify the regulators of GCase activity in lysosomes, we conducted a genome-wide screen in primary mouse macrophages using a fluorescent enzyme activity reporter. By validating the screen hits in cellular biochemical and profiling assays, we identified pathways that promote or inhibit lysosomal GCase activity. Our screen identified PLCG2 as a regulator of lysosomal GCase activity. Mechanistically, PLCG2 depletion accumulates Golgi-associated phosphatidylinositols, promoting the transport of mutant GCase into lysosomes while reducing its Golgi-associated pool. Functionally, PLCG2 depletion boosts the activity of lysosomal mutant GCase, the cellular flux of glucosylceramide, and the clearance of pathogenic GCase substrates. In summary, our screen has uncovered the regulators of GCase abundance and trafficking at a whole-genome scale and identified potential pathways for future therapeutic interventions in Gaucher and Parkinson's to boost the activity of this enzyme in lysosomes.