Loss of epigenetic information as a cause of mammalian aging.

All living things experience an increase in entropy, manifested as a loss of genetic and epigenetic information. In yeast, epigenetic information is lost over time due to the relocalization of chromatin-modifying proteins to DNA breaks, causing cells to lose their identity, a hallmark of yeast aging. Using a system called "ICE" (inducible changes to the epigenome), we find that the act of faithful DNA repair advances aging at physiological, cognitive, and molecular levels, including erosion of the epigenetic landscape, cellular exdifferentiation, senescence, and advancement of the DNA methylation clock, which can be reversed by OSK-mediated rejuvenation. These data are consistent with the information theory of aging, which states that a loss of epigenetic information is a reversible cause of aging.

Notch signaling regulates macrophage-mediated inflammation in metabolic dysfunction-associated steatotic liver disease.

The liver macrophage population comprises resident Kupffer cells (KCs) and monocyte-derived macrophages with distinct pro- or anti-inflammatory properties that affect the severity and course of liver diseases. The mechanisms underlying macrophage differentiation and functions in metabolic dysfunction-associated steatotic liver disease and/or steatohepatitis (MASLD/MASH) remain mostly unknown. Using single-cell RNA sequencing (scRNA-seq) and fate mapping of hepatic macrophage subpopulations, we unraveled the temporal and spatial dynamics of distinct monocyte and monocyte-derived macrophage subsets in MASH. We revealed a crucial role for the Notch-Recombination signal binding protein for immunoglobulin kappa J region (RBPJ) signaling pathway in controlling the monocyte-to-macrophage transition, with Rbpj deficiency blunting inflammatory macrophages and monocyte-derived KC differentiation and conversely promoting the emergence of protective Ly6Clo monocytes. Mechanistically, Rbpj deficiency promoted lipid uptake driven by elevated CD36 expression in Ly6Clo monocytes, enhancing their protective interactions with endothelial cells. Our findings uncover the crucial role of Notch-RBPJ signaling in monocyte-to-macrophage transition and will aid in the design of therapeutic strategies for MASH treatment.

A subset of Kupffer cells regulates metabolism through the expression of CD36.

Tissue macrophages are immune cells whose phenotypes and functions are dictated by origin and niches. However, tissues are complex environments, and macrophage heterogeneity within the same organ has been overlooked so far. Here, we used high-dimensional approaches to characterize macrophage populations in the murine liver. We identified two distinct populations among embryonically derived Kupffer cells (KCs) sharing a core signature while differentially expressing numerous genes and proteins: a major CD206loESAM- population (KC1) and a minor CD206hiESAM+ population (KC2). KC2 expressed genes involved in metabolic processes, including fatty acid metabolism both in steady-state and in diet-induced obesity and hepatic steatosis. Functional characterization by depletion of KC2 or targeted silencing of the fatty acid transporter Cd36 highlighted a crucial contribution of KC2 in the liver oxidative stress associated with obesity. In summary, our study reveals that KCs are more heterogeneous than anticipated, notably describing a subpopulation wired with metabolic functions.

Durable CO2 conversion in the proton-exchange membrane system.

Electrolysis that reduces carbon dioxide (CO2) to useful chemicals can, in principle, contribute to a more sustainable and carbon-neutral future1-6. However, it remains challenging to develop this into a robust process because efficient conversion typically requires alkaline conditions in which CO2 precipitates as carbonate, and this limits carbon utilization and the stability of the system7-12. Strategies such as physical washing, pulsed operation and the use of dipolar membranes can partially alleviate these problems but do not fully resolve them11,13-15. CO2 electrolysis in acid electrolyte, where carbonate does not form, has therefore been explored as an ultimately more workable solution16-18. Herein we develop a proton-exchange membrane system that reduces CO2 to formic acid at a catalyst that is derived from waste lead-acid batteries and in which a lattice carbon activation mechanism contributes. When coupling CO2 reduction with hydrogen oxidation, formic acid is produced with over 93% Faradaic efficiency. The system is compatible with start-up/shut-down processes, achieves nearly 91% single-pass conversion efficiency for CO2 at a current density of 600 mA cm-2 and cell voltage of 2.2 V and is shown to operate continuously for more than 5,200 h. We expect that this exceptional performance, enabled by the use of a robust and efficient catalyst, stable three-phase interface and durable membrane, will help advance the development of carbon-neutral technologies.

Single electrons on solid neon as a solid-state qubit platform.

Progress towards the realization of quantum computers requires persistent advances in their constituent building blocks-qubits. Novel qubit platforms that simultaneously embody long coherence, fast operation and large scalability offer compelling advantages in the construction of quantum computers and many other quantum information systems1-3. Electrons, ubiquitous elementary particles of non-zero charge, spin and mass, have commonly been perceived as paradigmatic local quantum information carriers. Despite superior controllability and configurability, their practical performance as qubits through either motional or spin states depends critically on their material environment3-5. Here we report our experimental realization of a qubit platform based on isolated single electrons trapped on an ultraclean solid neon surface in vacuum6-13. By integrating an electron trap in a circuit quantum electrodynamics architecture14-20, we achieve strong coupling between the motional states of a single electron and a single microwave photon in an on-chip superconducting resonator. Qubit gate operations and dispersive readout are implemented to measure the energy relaxation time T1 of 15 µs and phase coherence time T2 over 200 ns. These results indicate that the electron-on-solid-neon qubit already performs near the state of the art for a charge qubit21.

Heterodimensional superlattice with in-plane anomalous Hall effect.

Superlattices-a periodic stacking of two-dimensional layers of two or more materials-provide a versatile scheme for engineering materials with tailored properties1,2. Here we report an intrinsic heterodimensional superlattice consisting of alternating layers of two-dimensional vanadium disulfide (VS2) and a one-dimensional vanadium sulfide (VS) chain array, deposited directly by chemical vapour deposition. This unique superlattice features an unconventional 1T stacking with a monoclinic unit cell of VS2/VS layers identified by scanning transmission electron microscopy. An unexpected Hall effect, persisting up to 380 kelvin, is observed when the magnetic field is in-plane, a condition under which the Hall effect usually vanishes. The observation of this effect is supported by theoretical calculations, and can be attributed to an unconventional anomalous Hall effect owing to an out-of-plane Berry curvature induced by an in-plane magnetic field, which is related to the one-dimensional VS chain. Our work expands the conventional understanding of superlattices and will stimulate the synthesis of more extraordinary superstructures.

High-density switchable skyrmion-like polar nanodomains integrated on silicon.

Topological domains in ferroelectrics1-5 have received much attention recently owing to their novel functionalities and potential applications6,7 in electronic devices. So far, however, such topological polar structures have been observed only in superlattices grown on oxide substrates, which limits their applications in silicon-based electronics. Here we report the realization of room-temperature skyrmion-like polar nanodomains in lead titanate/strontium titanate bilayers transferred onto silicon. Moreover, an external electric field can reversibly switch these nanodomains into the other type of polar texture, which substantially modifies their resistive behaviours. The polar-configuration-modulated resistance is ascribed to the distinct band bending and charge carrier distribution in the core of the two types of polar texture. The integration of high-density (more than 200 gigabits per square inch) switchable skyrmion-like polar nanodomains on silicon may enable non-volatile memory applications using topological polar structures in oxides.

Queuosine-tRNA promotes sex-dependent learning and memory formation by maintaining codon-biased translation elongation speed.

Queuosine (Q) is a modified nucleoside at the wobble position of specific tRNAs. In mammals, queuosinylation is facilitated by queuine uptake from the gut microbiota and is introduced into tRNA by the QTRT1-QTRT2 enzyme complex. By establishing a Qtrt1 knockout mouse model, we discovered that the loss of Q-tRNA leads to learning and memory deficits. Ribo-Seq analysis in the hippocampus of Qtrt1-deficient mice revealed not only stalling of ribosomes on Q-decoded codons, but also a global imbalance in translation elongation speed between codons that engage in weak and strong interactions with their cognate anticodons. While Q-dependent molecular and behavioral phenotypes were identified in both sexes, female mice were affected more severely than males. Proteomics analysis confirmed deregulation of synaptogenesis and neuronal morphology. Together, our findings provide a link between tRNA modification and brain functions and reveal an unexpected role of protein synthesis in sex-dependent cognitive performance.

The visual effect of wind turbines on property values is small and diminishing in space and time.

Renewable power generation is the key to decarbonizing the electricity system. Wind power is the fastest-growing renewable source of electricity in the United States. However, expanding wind capacity often faces local opposition, partly due to a perceived visual disamenity from large wind turbines. Here, we provide a US-wide assessment of the externality costs of wind power generation through the visibility impact on property values. To this end, we create a database on wind turbine visibility, combining information on the site and height of each utility-scale turbine having fed power into the U.S. grid, with a high-resolution elevation map to account for the underlying topography of the landscape. Building on hedonic valuation theory, we statistically estimate the impact of wind turbine visibility on home values, informed by data from the majority of home sales in the United States since 1997. We find that on average, wind turbine visibility negatively affects home values in an economically and statistically significant way in close proximity ([Formula: see text]5 miles/8 km). However, the effect diminishes over time and in distance and is indistinguishable from zero for larger distances and toward the end of our sample.

Knot data analysis using multiscale Gauss link integral.

In the past decade, topological data analysis has emerged as a powerful algebraic topology approach in data science. Although knot theory and related subjects are a focus of study in mathematics, their success in practical applications is quite limited due to the lack of localization and quantization. We address these challenges by introducing knot data analysis (KDA), a paradigm that incorporates curve segmentation and multiscale analysis into the Gauss link integral. The resulting multiscale Gauss link integral (mGLI) recovers the global topological properties of knots and links at an appropriate scale and offers a multiscale geometric topology approach to capture the local structures and connectivities in data. By integration with machine learning or deep learning, the proposed mGLI significantly outperforms other state-of-the-art methods across various benchmark problems in 13 intricately complex biological datasets, including protein flexibility analysis, protein-ligand interactions, human Ether-à-go-go-Related Gene potassium channel blockade screening, and quantitative toxicity assessment. Our KDA opens a research area-knot deep learning-in data science.

Variants of the promoter of MYH6 gene in congenital isolated and sporadic patent ductus arteriosus: case-control study and cellular functional analyses.

Patent ductus arteriosus (PDA) is a common form of congenital heart disease. The MYH6 gene has important effects on cardiovascular growth and development, but the effect of variants in the MYH6 gene promoter on ductus arteriosus is unknown. DNA was extracted from blood samples of 721 subjects (428 patients with isolated and sporadic PDA and 293 healthy controls) and analyzed by sequencing for MYH6 gene promoter region variants. Cellular function experiments with three cell lines (HEK-293, HL-1, and H9C2 cells) and bioinformatics analyses were performed to verify their effects on gene expression. In the MYH6 gene promoter, 11 variants were identified. Four variants were found only in patients with PDA and 2 of them (g.3434G>C and g.4524C>T) were novel. Electrophoretic mobility shift assay showed that the transcription factors bound by the promoter variants were significantly altered in comparison to the wild-type in all three cell lines. Dual luciferase reporter showed that all the 4 variants reduced the transcriptional activity of the MYH6 gene promoter (P < 0.05). Prediction of transcription factors bound by the variants indicated that these variants alter the transcription factor binding sites. These pathological alterations most likely affect the contraction of the smooth muscle of ductus arteriosus, leading to PDA. This study is the first to focus on variants at the promoter region of the MYH6 gene in PDA patients with cellular function tests. Therefore, this study provides new insights to understand the genetic basis and facilitates further studies on the mechanism of PDA formation.

ECM dimensionality tunes actin tension to modulate endoplasmic reticulum function and spheroid phenotypes of mammary epithelial cells.

Patient-derived organoids and cellular spheroids recapitulate tissue physiology with remarkable fidelity. We investigated how engagement with a reconstituted basement membrane in three dimensions (3D) supports the polarized, stress resilient tissue phenotype of mammary epithelial spheroids. Cells interacting with reconstituted basement membrane in 3D had reduced levels of total and actin-associated filamin and decreased cortical actin tension that increased plasma membrane protrusions to promote negative plasma membrane curvature and plasma membrane protein associations linked to protein secretion. By contrast, cells engaging a reconstituted basement membrane in 2D had high cortical actin tension that forced filamin unfolding and endoplasmic reticulum (ER) associations. Enhanced filamin-ER interactions increased levels of PKR-like ER kinase effectors and ER-plasma membrane contact sites that compromised calcium homeostasis and diminished cell viability. Consequently, cells with decreased cortical actin tension had reduced ER stress and survived better. Consistently, cortical actin tension in cellular spheroids regulated polarized basement membrane membrane deposition and sensitivity to exogenous stress. The findings implicate cortical actin tension-mediated filamin unfolding in ER function and underscore the importance of tissue mechanics in organoid homeostasis.

Multiscale topology in interactomic network: from transcriptome to antiaddiction drug repurposing.

The escalating drug addiction crisis in the United States underscores the urgent need for innovative therapeutic strategies. This study embarked on an innovative and rigorous strategy to unearth potential drug repurposing candidates for opioid and cocaine addiction treatment, bridging the gap between transcriptomic data analysis and drug discovery. We initiated our approach by conducting differential gene expression analysis on addiction-related transcriptomic data to identify key genes. We propose a novel topological differentiation to identify key genes from a protein-protein interaction network derived from DEGs. This method utilizes persistent Laplacians to accurately single out pivotal nodes within the network, conducting this analysis in a multiscale manner to ensure high reliability. Through rigorous literature validation, pathway analysis and data-availability scrutiny, we identified three pivotal molecular targets, mTOR, mGluR5 and NMDAR, for drug repurposing from DrugBank. We crafted machine learning models employing two natural language processing (NLP)-based embeddings and a traditional 2D fingerprint, which demonstrated robust predictive ability in gauging binding affinities of DrugBank compounds to selected targets. Furthermore, we elucidated the interactions of promising drugs with the targets and evaluated their drug-likeness. This study delineates a multi-faceted and comprehensive analytical framework, amalgamating bioinformatics, topological data analysis and machine learning, for drug repurposing in addiction treatment, setting the stage for subsequent experimental validation. The versatility of the methods we developed allows for applications across a range of diseases and transcriptomic datasets.

A novel TOX3-WDR5-ABCG2 signaling axis regulates the progression of colorectal cancer by accelerating stem-like traits and chemoresistance.

The eradication of cancer stem cells (CSCs) with drug resistance confers the probability of local tumor control after chemotherapy or targeted therapy. As the main drug resistance marker, ABCG2 is also critical for colorectal cancer (CRC) evolution, in particular cancer stem-like traits expansion. Hitherto, the knowledge about the expression regulation of ABCG2, in particular its upstream transcriptional regulatory mechanisms, remains limited in cancer, including CRC. Here, ABCG2 was found to be markedly up-regulated in CRC CSCs (cCSCs) expansion and chemo-resistant CRC tissues and closely associated with CRC recurrence. Mechanistically, TOX3 was identified as a specific transcriptional factor to drive ABCG2 expression and subsequent cCSCs expansion and chemoresistance by binding to -261 to -141 segments of the ABCG2 promoter region. Moreover, we found that TOX3 recruited WDR5 to promote tri-methylation of H3K4 at the ABCG2 promoter in cCSCs, which further confers stem-like traits and chemoresistance to CRC by co-regulating the transcription of ABCG2. In line with this observation, TOX3, WDR5, and ABCG2 showed abnormal activation in chemo-resistant tumor tissues of in situ CRC mouse model and clinical investigation further demonstrated the comprehensive assessment of TOX3, WDR5, and ABCG2 could be a more efficient strategy for survival prediction of CRC patients with recurrence or metastasis. Thus, our study found that TOX3-WDR5/ABCG2 signaling axis plays a critical role in regulating CRC stem-like traits and chemoresistance, and a combination of chemotherapy with WDR5 inhibitors may induce synthetic lethality in ABCG2-deregulated tumors.

EGFR-Phosphorylated Platelet Isoform of Phosphofructokinase 1 Promotes PI3K Activation.

EGFR activates phosphatidylinositide 3-kinase (PI3K), but the mechanism underlying this activation is not completely understood. We demonstrated here that EGFR activation resulted in lysine acetyltransferase 5 (KAT5)-mediated K395 acetylation of the platelet isoform of phosphofructokinase 1 (PFKP) and subsequent translocation of PFKP to the plasma membrane, where the PFKP was phosphorylated at Y64 by EGFR. Phosphorylated PFKP binds to the N-terminal SH2 domain of p85α, which is distinct from binding of Gab1 to the C-terminal SH2 domain of p85α, and recruited p85α to the plasma membrane resulting in PI3K activation. PI3K-dependent AKT activation results in enhanced phosphofructokinase 2 (PFK2) phosphorylation and production of fructose-2,6-bisphosphate, which in turn promotes PFK1 activation. PFKP Y64 phosphorylation-enhanced PI3K/AKT-dependent PFK1 activation and GLUT1 expression promoted the Warburg effect, tumor cell proliferation, and brain tumorigenesis. These findings underscore the instrumental role of PFKP in PI3K activation and enhanced glycolysis through PI3K/AKT-dependent positive-feedback regulation.

Lost in translation: How neurons cope with tRNA decoding.

Post-transcriptional tRNA modifications contribute to the decoding efficiency of tRNAs by supporting codon recognition and tRNA stability. Recent work shows that the molecular and cellular functions of tRNA modifications and tRNA-modifying-enzymes are linked to brain development and neurological disorders. Lack of these modifications affects codon recognition and decoding rate, promoting protein aggregation and translational stress response pathways with toxic consequences to the cell. In this review, we discuss the peculiarity of local translation in neurons, suggesting a role for fine-tuning of translation performed by tRNA modifications. We provide several examples of tRNA modifications involved in physiology and pathology of the nervous system, highlighting their effects on protein translation and discussing underlying mechanisms, like the unfolded protein response (UPR), ribosome quality control (RQC), and no-go mRNA decay (NGD), which could affect neuronal functions. We aim to deepen the understanding of the roles of tRNA modifications and the coordination of these modifications with the protein translation machinery in the nervous system.

Advancing quantitative PCR with color cycle multiplex amplification.

Quantitative PCR (qPCR) is the gold standard for detection and quantitation of known DNA targets, but the scarcity of spectrally distinct fluorophores and filter sets limits the number of detectable targets. Here, we introduce color cycle multiplex amplification (CCMA) to significantly increase the number of detectable DNA targets in a single qPCR reaction using standard instrumentation. In CCMA, presence of one DNA target species results in a pre-programmed pattern of fluorescence increases. This pattern is distinguished by cycle thresholds (Cts) through rationally designed delays in amplification. For example, we design an assay wherein Staphylococcus aureus sequentially induces FAM, then Cy5.5, then ROX fluorescence increases with more than 3 cycles between each signal. CCMA offers notably higher potential for multiplexing because it uses fluorescence permutation rather than combination. With 4 distinct fluorescence colors, CCMA theoretically allows the detection of up to 136 distinct DNA target sequences using fluorescence permutation. Experimentally, we demonstrated a single-tube qPCR assay screening 21 sepsis-related bacterial DNA targets in samples of blood, sputum, pleural effusion and bronchoalveolar lavage fluid, with 89% clinical sensitivity and 100% clinical specificity, showing its potential as a powerful tool for advanced quantitative screening in molecular diagnostics.

Dynamic phase evolution of MoS3 accompanied by organodiselenide mediation enables enhanced performance rechargeable lithium battery.

Considerable efforts have been devoted to Li-S batteries, typically the soluble polysulfides shuttling effect. As a typical transition metal sulfide, MoS2 is a magic bullet for addressing the issues of Li-S batteries, drawing increasing attention. In this study, we introduce amorphous MoS3 as analogous sulfur cathode material and elucidate the dynamic phase evolution in the electrochemical reaction. The metallic 1T phase incorporated 2H phase MoS2 with sulfur vacancies (SVs-1T/2H-MoS2) decomposed from amorphous MoS3 achieves refined mixing with the "newborn" sulfur at the molecular level and supplies continuous conduction pathways and controllable physical confinement. Meanwhile, the in situ-generated SVs-1T/2H-MoS2 allows lithium intercalation in advance at high discharge voltage (≥1.8 V) and enables fast electron transfer. Moreover, aiming at the unbonded sulfur, diphenyl diselenide (PDSe), as a model redox mediator is applied, which can covalently bond sulfur atoms to form conversion-type organoselenosulfides, changing the original redox pathway of "newborn" sulfur in MoS3, and suppressing the polysulfides shuttling effect. It also significantly lowers the activation energy and thus accelerates the sulfur reduction kinetics. Thus, the in situ-formed intercalation-conversion hybrid electrode of SVs-1T/2H-MoS2 and organoselenosulfides realizes enhanced rate capability and superior cycling stability. This work provides a novel concept for designing high-energy-density electrode materials.

High sensitivity top-down proteomics captures single muscle cell heterogeneity in large proteoforms.

Single-cell proteomics has emerged as a powerful method to characterize cellular phenotypic heterogeneity and the cell-specific functional networks underlying biological processes. However, significant challenges remain in single-cell proteomics for the analysis of proteoforms arising from genetic mutations, alternative splicing, and post-translational modifications. Herein, we have developed a highly sensitive functionally integrated top-down proteomics method for the comprehensive analysis of proteoforms from single cells. We applied this method to single muscle fibers (SMFs) to resolve their heterogeneous functional and proteomic properties at the single-cell level. Notably, we have detected single-cell heterogeneity in large proteoforms (>200 kDa) from the SMFs. Using SMFs obtained from three functionally distinct muscles, we found fiber-to-fiber heterogeneity among the sarcomeric proteoforms which can be related to the functional heterogeneity. Importantly, we detected multiple isoforms of myosin heavy chain (~223 kDa), a motor protein that drives muscle contraction, with high reproducibility to enable the classification of individual fiber types. This study reveals single muscle cell heterogeneity in large proteoforms and establishes a direct relationship between sarcomeric proteoforms and muscle fiber types, highlighting the potential of top-down proteomics for uncovering the molecular underpinnings of cell-to-cell variation in complex systems.