搜索结果：uncover

The atomic-scale structure of a metal catalyst surface controls its catalytic performance. Through a combination of high-pressure scanning tunneling microscopy (HP-STM), ambient-pressure X-ray photoelectron spectroscopy (AP-XPS), and machine learning-accelerated computational studies, we uncovered that Pt nanoclusters, formed by restructuring of hex-Pt(100) under reaction conditions involving CO, experience major structural evolution when exposed to increasing CO pressure in the range of 2 × 10-8-750 Torr. Atom-resolved images and simulations demonstrate that CO binds strongly on these nanoclusters, leading to a CO coverage of one molecule per Pt atom, while the lateral CO-CO repulsion is released by tilting CO molecules outward at the nanocluster edge. Metal nanoclusters break down along as CO pressure is increased from 2 × 10-8 to 1 Torr with the average size decreasing from 3.2 ± 1.5 to 2.3 ± 1.0 nm, consistent with Pt 4f7/2 photoemission feature evolution observed with AP-XPS. In contrast, in the pressure range of 1-750 Torr at 25 °C, HP-STM observed a decrease of nanocluster density by 4-5 times, consistent with the growth of the average nanocluster size from 2.3 ± 1.0 nm in 1 Torr CO to 4.6 ± 1.8 nm in 750 Torr. This uncovers a reactant pressure-driven coalescence of nanoclusters even at room temperature. Nanoclusters formed at 25 °C in 750 Torr CO require annealing to 100-130 °C to reach equilibrium size, indicating akinetic control of nanocluster growth at low preparation temperatures, such as room temperature. Our neural network potential (NNP) coupled with basin-hopping (BH) simulations determined the optimal CO coverage and configuration at various CO pressures and showed, in agreement with experiments, an optimum nanocluster size resulting from a competition between the size-dependent energy cost of nanocluster formation and the energy gain through CO adsorption. The formation of Pt nanoclusters, followed by their breakdown with increasing CO pressure from 2 × 10-8 to 1 Torr and coalescence in CO pressure from 1 to 750 Torr highlights the significance of imaging catalyst nanoparticle surfaces in gas phase at a specific reactant pressure toward establishing a direct structure-catalytic performance correlation.

Niemann-Pick disease type C (NPC) is a neurovisceral lysosomal storage disorder comprising two clinically indistinguishable but genetically distinct subtypes caused by mutations in NPC1 , or NPC2 . The specific impact of each deficiency on cellular homeostasis remains poorly defined due to the phenotypic heterogeneity of patient-derived models and a lack of isogenic platforms for comparative study. Here we established isogenic ARPE19 models of NPC1 and NPC2 deficiency that faithfully recapitulate hallmark pathologies, including homogeneous lysosomal expansion and lipid sequestration. Direct comparison of these isogenic lines revealed a fundamental divergence in organelle crosstalk: while both genotypes exhibit comparable lipid accumulation, expanded mitochondria-lysosome contact sites (MLCs) are observed exclusively in NPC1 -/- cells. Using StARD3-targeted proximity labelling and quantitative proteomics, we identified the mitochondrial protein HKDC1 as an MLC regulator. We demonstrate that HKDC1 is markedly upregulated in NPC1 -/- cells and that its overexpression drives MLC expansion in wild-type cells. Thus our study uncovers a homeostatic role for HKDC1-mediated organelle remodelling and demonstrates the power of isogenic modelling for identifying novel regulators of organelle architecture and potential therapeutic targets.

Histone proteins are critical for regulating functions that occur at DNA, such as gene expression. Certain mutations in histone genes were characterized to drive oncogenesis, termed oncohistones, and one of the first identified oncohistones is H3K36M. While humans have a high copy number of H3 genes, making genetic engineering in cell lines challenging, budding yeast only have two H3 genes. Additionally, histone H3 shares 90% sequence identity between budding yeast and humans, making it a great model for studying H3K36M. We had previously identified the catalytic subunit of the NuA4 lysine acetyltransferase complex as a suppressor of growth defects in H3K36 mutant yeast cells. Here, we expand upon our initial finding by discovering that the NuA4 scaffold Eaf1 is an even stronger suppressor of mutant H3K36 growth defects. We uncover that this suppression by Eaf1 is dependent on its HSA domain. We also created H4-4K→A and H4-4K→R mutants that eliminated the potential for acetylation at mutant H4, on their own and in combination with H3K36 mutants, and found that these H4 mutants have reduced viability and disrupted global H4 acetylation. Importantly, we discover that Eaf1 is unable to suppress growth defects in these H4 mutants, suggesting its suppression is dependent on acetylation at histone H4 N-terminal tails. Lastly, we discovered that inhibiting NuA4 activity in H3K36M human cells limits their oncogenic potential. Together, this work further characterizes the connection between H3K36 and H4 N-terminal tails in the context of a cancer-causing mutation.

Neutrophil extracellular traps (NETs) are increasingly recognized as key regulators of tumor progression, yet the molecular circuitry that governs their induction in cancer remains elusive. Here, we identify the RNA-binding protein RBFOX2 as a tumor suppressor that curtails glioma growth by coordinately restraining tumor cell proliferation and NETosis. RBFOX2 expression is markedly reduced in glioma and positively correlates with patient survival. Mechanistically, RBFOX2 binds to 5-hydroxymethylcytidine (5hmC)-modified sites within PDGFB mRNA and promotes its decay, thereby dampening AKT-SP1 signaling and repressing CSF3 transcription. This repression limits neutrophil-mediated NET formation in the tumor microenvironment, as confirmed in PAD4-/- mice and upon CSF3 neutralization. Collectively, our study uncovers a 5hmC-dependent post-transcriptional mechanism linking RBFOX2 to NETosis control and glioma suppression, revealing RBFOX2 as a potential biomarker and therapeutic lever and establishing a broader paradigm in which RNA-binding proteins couple post-transcriptional RNA modification and immune regulation in tumor evolution.

Brain disorders characterized by progressive neurodegeneration, such as Alzheimer's disease (AD) and frontotemporal dementia (FTD), represent an increasing medical and societal challenge. While genome‑wide studies have uncovered numerous susceptibility loci, these efforts have largely focused on common variants and leave a substantial portion of genetic liability unresolved. Variants of low frequency, often associated with stronger biological effects, remain insufficiently characterized, particularly in heterogeneous populations. Genetically isolated populations offer an effective strategy to overcome these limitations. Finland, shaped by historical demographic events, harbors a distinctive spectrum of enriched rare variants that can facilitate gene discovery. The FinnGen initiative capitalizes on this setting by combining extensive genotyping with nationwide health registry data through a coordinated network of Finnish biobanks. With half a million participants analyzed, FinnGen supports highly powered analyses across a broad array of clinical outcomes and registry data. Recent comprehensive analyses have reported thousands of significant genotype-phenotype associations, including novel protein‑altering variants. Importantly, the FinnGen cohort structure favors older individuals and hospital‑derived samples, increasing representation of brain disorders, such as AD and idiopathic normal pressure hydrocephalus (iNPH), a disorder frequently accompanied by AD‑like pathological features. In this expert review, we summarize FinnGen‑based investigations relevant to neurodegenerative diseases and iNPH, highlighting insights into genetic susceptibility, disease overlap, and protective factors, and discuss how integration with recall studies as well as biomarker and clinical data accelerates translational applications in brain disorders.

Interleukin 23 receptor (IL-23R) signaling is critical for the generation of pro-inflammatory CD4+ IL-17-producing T helper cells (Th17) that can drive autoimmune tissue inflammation, but the underlying mechanisms are not clear. We integrated phosphoproteomic and transcriptomic data downstream of IL-23R and IL-12 receptor (IL-12R), which share a common subunit, to identify mechanisms engaged specifically by IL-23. We identified chromodomain helicase DNA-binding protein 1 (CHD1), an epigenetic regulator, and the glucocorticoid receptor (GR), a transcription factor (TF), as mediators of IL-23R signaling. IL-23R activation promoted CHD1 interaction with TF STAT3 and co-binding at the TF RORγt locus to enforce a pro-inflammatory Th17 state. Conversely, IL-23R signaling altered phosphorylation of the GR, thereby preventing its activation and nuclear translocation, ultimately impairing GR-driven inhibition of pro-inflammatory Th17 gene programs. Our findings uncover two mechanisms by which IL-23 promotes a pro-inflammatory Th17 cell state, offering potential therapeutic targets for treating Th17-driven autoimmune tissue inflammation and restoring homeostasis.

Naringenin, a chiral flavonoid, contains a chiral center and exists as (R)- and (S)-enantiomers, yet its enantiomer-specific metabolism has remained largely unexplored. Herein, high-purity (R)- and (S)-naringenin were isolated via chiral semipreparative chromatography, and their racemization kinetics under near-physiological conditions were systematically quantified. Incubation with rat liver microsomes revealed pronounced stereoselectivity: the (R)-enantiomer was metabolized significantly faster than the (S)-enantiomer. Mechanistic studies identified the CYP3A subfamily as the key mediator of this stereoselectivity. Notably, this stereoselective profile was completely absent in human liver microsomes, uncovering a critical species difference. These findings provide direct evidence for enzyme-level chiral recognition in naringenin metabolism and highlight species-specific disparities in its metabolic pathway.

Parental care, a key step in the evolution of sociality, has evolved multiple times in insects, yet the molecular mechanisms underlying its emergence remain poorly understood. Weevils (Curculionidae) exhibit diverse parental care behaviours, from nest building to egg and larval attendance, making them an ideal system to investigate genomic changes associated with social behaviour. We analysed 13 high-quality weevil genomes, encompassing independent origins of egg and larval attendance, to test two predictions: (1) the sheltering hypothesis, where parental care relaxes selection on traits critical for independent larval survival, and (2) the regulatory hypothesis, where behavioural shifts are driven by changes in transcriptional regulation. In support of hypothesis 1, we identified over 400 genes with evidence of significantly relaxed selection on the branches where egg and larval attendance evolved. In further support, we uncovered a significant number of convergent gene losses that coincided with both origins of larval attendance, particularly in genes linked to transcriptional regulation, metabolism and development. In contrast, positive selection and intensified selection were rare but contained multiple genes regulating gene expression, consistent with hypothesis 2. Together, these results suggest that parental care in weevils drives both simplification of larval traits through relaxed selection and convergent gene loss, and innovation in caregiving behaviours via adaptive changes in gene regulation.

Hailey-Hailey disease (HHD) is a rare autosomal dominant genodermatosis characterized by skin blistering and erosions in intertriginous regions, frequently complicated by secondary infections leading to substantial impairment in quality of life. No targeted mechanism-based therapies are currently available. Here, we applied a multiomics approach to define the molecular and cellular landscape of HHD. Bulk transcriptomics and proteomics uncovered a striking interferon (IFN) signature in HHD skin lesions. Single cell and spatial transcriptomics analyses revealed inflammatory niches, where immune, epithelial, vascular and stromal cells create a multi-compartment IFN-driven signaling network, that sustains a feed-forward amplification loop essential for chronic inflammation. Crucially, in nine patients with refractory HHD, topical treatment with the JAK1/2 inhibitor ruxolitinib led to rapid and durable re-epithelialization with drastic reduction in pain, itching, oozing and skin inflammation, significantly improving patient quality of life. Collectively, our findings identify IFN signaling as a key pathogenic driver in HHD and support topical JAK inhibition as an effective therapy, redefining the standard of care for individuals living with HHD.

Mutant KRAS-driven control of protein synthesis remains poorly defined. Here, we define KRAS-dependent translational programs and their acute remodeling upon KRAS inhibition. We find that mutant KRAS controls the translation of a subset of mRNAs and affects the production of proteins of the mRNA translation apparatus. Interestingly, these specific subsets of mRNAs have short, weakly folded 5'UTRs and harbor low folding energy consensus RNA sequences. We observe ribosome accumulation on selective mRNAs. Our findings clarify the indispensable role of mutant KRAS in regulating mRNA translation, setting it apart from the other previously known mechanisms that depend on mTOR and EIF4E-EIF4A signals. Our findings uncover a mechanism by which mutant KRAS selectively uncouples the translation of mRNAs for protein synthetic machinery from the broader mRNA pool, redefining our understanding of the oncogenic regulation of mRNA translation in cancer.

Iron homeostasis is regulated by bone morphogenetic protein (BMP) signaling which induces hepcidin to negatively regulate serum iron levels and iron import. After a major blood loss event, developing erythroblasts produce erythroferrone (ERFE) which inhibits hepatocyte BMP signaling to increase serum iron levels and drive their maturation to erythrocytes. While ERFE was recently shown to contain a heparin binding motif (HBM), its mechanistic significance remains poorly understood. Here, we establish that the ERFE HBM is essential for BMP inhibition and uncover a novel ternary mechanism for ligand antagonism. Using biophysical assays and molecular dynamics (MD) simulations, we show that heparin/heparan sulfate (HS) simultaneously engages with the HBM of both ERFE and BMP6 to stabilize a high-order inhibitory complex. This complex exerts far greater affinity for HS in the extracellular matrix than ERFE alone, supporting potent, ligand-dependent localization to the cell surface. Importantly, we demonstrate that ERFE preferentially engages the BMP6:HS complex over other BMP ligands, suggesting modes of ligand-HS interactions are key determinants for selectivity. Together, these findings reframe ERFE as a matrix-assisted antagonist that exploits HS as a structural co-factor for BMP antagonism and gives insight into the mechanism for tissue-restricted BMP antagonism of ERFE.

The cellular cytosol is a crowded environment. Biomolecular Förster resonance energy transfer (FRET) sensors have been developed to measure crowding in cytosol mimics composed of synthetic polymers such as polyethylene glycol (PEG) and Ficoll that impart an excluded volume effect. We investigate the PEG-driven phase separation of a protein crowding sensor, AcGFP1/mCherry-FRET crowding helix 2 (CrH2), into fluorescent puncta compared to a DNA-based crowding sensor (CrD) with an Alexa488/Cy5 FRET pair that did not form observable puncta under the same crowding conditions of 100-400 mg/mL 8 kDa PEG. Using fluorescence recovery after photobleaching imaging, we uncover the liquid-like physical properties of the PEG-induced puncta. Two-color fluorescence microscopy imaging reveals crowder-induced inhomogeneity, concentration variations, and partition coefficients across the dilute and dense phases of the liquid puncta, which remain largely underexplored in bulk fluorometry measurements. Thus, the average crowding sensor response may originate from an aqueous biphasic system, reporting an erroneous average response instead of distinct levels of crowdedness. A comparison of excluded volume effects conferred by Ficoll and PEGs of various molecular weights shows the influence of size, concentration, excluded volume, and chemical composition on the CrH2 sensor response. We demonstrate that ≥18% PEG (w/v) was sufficient to enable the phase separation of CrH2 and alter sensor response through a mechanism that may be driven by polymer interactions with the flexible hinge region. We also show that CrD can form fluorescence puncta upon charge-neutralization with poly-l-lysine. Thus, our study emphasizes the need to probe crowding environments with orthogonal sensors.