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The Warburg effect, which originally described increased production of lactate in cancer, is associated with diverse cellular processes such as angiogenesis, hypoxia, polarization of macrophages and activation of T cells. This phenomenon is intimately linked to several diseases including neoplasia, sepsis and autoimmune diseases 1 , 2 . Lactate, which is converted from pyruvate in tumour cells, is widely known as an energy source and metabolic by-product. However, its non-metabolic functions in physiology and disease remain unknown. Here we show that lactate-derived lactylation of histone lysine residues serves as an epigenetic modification that directly stimulates gene transcription from chromatin. We identify 28 lactylation sites on core histones in human and mouse cells. Hypoxia and bacterial challenges induce the production of lactate by glycolysis, and this acts as a precursor that stimulates histone lactylation. Using M1 macrophages that have been exposed to bacteria as a model system, we show that histone lactylation has different temporal dynamics from acetylation. In the late phase of M1 macrophage polarization, increased histone lactylation induces homeostatic genes that are involved in wound healing, including Arg1 . Collectively, our results suggest that an endogenous ‘lactate clock’ in bacterially challenged M1 macrophages turns on gene expression to promote homeostasis. Histone lactylation thus represents an opportunity to improve our understanding of the functions of lactate and its role in diverse pathophysiological conditions, including infection and cancer. The lactylation of lysine residues on histones in mammalian cells is stimulated by hypoxia and bacterial challenges, and increased histone lactylation induces genes involved in wound healing.

Metabolic regulation of histone marks is associated with diverse biological processes through dynamically modulating chromatin structure and functions. Here we report the identification and characterization of a histone mark, lysine benzoylation (K bz ). Our study identifies 22 K bz sites on histones from HepG2 and RAW cells. This type of histone mark can be stimulated by sodium benzoate (SB), an FDA-approved drug and a widely used chemical food preservative, via generation of benzoyl CoA. By ChIP-seq and RNA-seq analysis, we demonstrate that histone K bz marks are associated with gene expression and have physiological relevance distinct from histone acetylation. In addition, we demonstrate that SIRT2, a NAD + -dependent protein deacetylase, removes histone K bz both in vitro and in vivo. This study therefore reveals a new type of histone marks with potential physiological relevance and identifies possible non-canonical functions of a widely used chemical food preservative. Histone marks regulate chromatin structure and function. Here the authors identify and characterize lysine benzoylation, a histone mark that can be modulated by sodium benzoate, a widely used chemical food preservative, associated with specific regulation of gene expression.

Protein post-translational modifications (PTMs) in eukaryotic cells play important roles in the regulation of functionalities of the proteome and in the tempo-spatial control of cellular processes. Most PTMs enact their regulatory functions by affecting the biochemical properties of substrate proteins such as altering structural conformation, protein–protein interaction, and protein–nucleic acid interaction. Amid various PTMs, arginine methylation is widespread in all eukaryotic organisms, from yeasts to humans. Arginine methylation in many situations can drastically or subtly affect the interactions of substrate proteins with their partnering proteins or nucleic acids, thus impacting major cellular programs. Recently, arginine methylation has become an important regulator of the formation of membrane-less organelles inside cells, a phenomenon of liquid–liquid phase separation (LLPS), through altering π-cation interactions. Another unique feature of arginine methylation lies in its impact on cellular physiology through its downstream amino acid product, asymmetric dimethylarginine (ADMA). Accumulation of ADMA in cells and in the circulating bloodstream is connected with endothelial dysfunction and a variety of syndromes of cardiovascular diseases. Herein, we review the current knowledge and understanding of protein arginine methylation in regards to its canonical function in direct protein regulation, as well as the biological axis of protein arginine methylation and ADMA biology.

Identifying the causes of human diseases requires deconvolution of abnormal molecular phenotypes spanning DNA accessibility, gene expression and protein abundance1–3. We present a single-cell framework that integrates highly multiplexed protein quantification, transcriptome profiling and analysis of chromatin accessibility. Using this approach, we establish a normal epigenetic baseline for healthy blood development, which we then use to deconvolve aberrant molecular features within blood from patients with mixed-phenotype acute leukemia4,5. Despite widespread epigenetic heterogeneity within the patient cohort, we observe common malignant signatures across patients as well as patient-specific regulatory features that are shared across phenotypic compartments of individual patients. Integrative analysis of transcriptomic and chromatin-accessibility maps identified 91,601 putative peak-to-gene linkages and transcription factors that regulate leukemia-specific genes, such as RUNX1-linked regulatory elements proximal to the marker gene CD69. These results demonstrate how integrative, multiomic analysis of single cells within the framework of normal development can reveal both distinct and shared molecular mechanisms of disease from patient samples.

The human long non-coding RNA TINCR binds to STAU1 and controls epidermal differentiation by stabilizing key differentiation mRNAs, by means of a TINCR-binding motif found enriched in epidermal differentiation genes. An lncRNA required for tissue differentiation The human genome codes for thousands of long non-coding RNAs (lncRNAs), but their biological functions are mostly unknown. This study reports the identification and characterization of a 3.7-kilobase lncRNA, named TINCR (for terminal differentiation-induced ncRNA). TINCR controls epidermal differentiation by stabilizing the mRNA of an array of differentiation genes. A 25-nucleotide TINCR-binding motif is enriched in these epidermal differentiation genes. TINCR also combines with the RNA-binding protein staufen1 to form a complex that stabilizes differentiation transcripts via direct binding and other mechanisms yet to be identified. Several of the thousands of human long non-coding RNAs (lncRNAs) have been functionally characterized 1 , 2 , 3 , 4 ; however, potential roles for lncRNAs in somatic tissue differentiation remain poorly understood. Here we show that a 3.7-kilobase lncRNA, terminal differentiation-induced ncRNA (TINCR), controls human epidermal differentiation by a post-transcriptional mechanism. TINCR is required for high messenger RNA abundance of key differentiation genes, many of which are mutated in human skin diseases, including FLG, LOR, ALOXE3, ALOX12B, ABCA12, CASP14 and ELOVL3 . TINCR-deficient epidermis lacked terminal differentiation ultrastructure, including keratohyalin granules and intact lamellar bodies. Genome-scale RNA interactome analysis revealed that TINCR interacts with a range of differentiation mRNAs. TINCR–mRNA interaction occurs through a 25-nucleotide ‘TINCR box’ motif that is strongly enriched in interacting mRNAs and required for TINCR binding. A high-throughput screen to analyse TINCR binding capacity to approximately 9,400 human recombinant proteins revealed direct binding of TINCR RNA to the staufen1 (STAU1) protein. STAU1-deficient tissue recapitulated the impaired differentiation seen with TINCR depletion. Loss of UPF1 and UPF2 , both of which are required for STAU1-mediated RNA decay, however, did not have differentiation effects. Instead, the TINCR–STAU1 complex seems to mediate stabilization of differentiation mRNAs, such as KRT80 . These data identify TINCR as a key lncRNA required for somatic tissue differentiation, which occurs through lncRNA binding to differentiation mRNAs to ensure their expression.

The use of surface plasmons, charge density oscillations of conduction electrons of metallic nanostructures, to boost the efficiency of light-harvesting devices through increased light-matter interactions could drastically alter how sunlight is converted into electricity or fuels. These excitations can decay directly into energetic electron–hole pairs, useful for photocurrent generation or photocatalysis. However, the mechanisms behind plasmonic carrier generation remain poorly understood. Here we use nanowire-based hot-carrier devices on a wide-bandgap semiconductor to show that plasmonic carrier generation is proportional to internal field-intensity enhancement and occurs independently of bulk absorption. We also show that plasmon-induced hot electrons have higher energies than carriers generated by direct excitation and that reducing the barrier height allows for the collection of carriers from plasmons and direct photoexcitation. Our results provide a route to increasing the efficiency of plasmonic hot-carrier devices, which could lead to more efficient devices for converting sunlight into usable energy. Plasmonic excitations of electrons in metallic nanostructures are promising for the enhanced conversion of light in semiconductor solar cells. Here, the authors are able to experimentally distinguish the absorption phenomena of plasmonic carrier generation and excitation of carriers by light absorption.

This study examines the patterns and predictors of post-traumatic stress disorder (PTSD) symptom trajectories among adolescent survivors following the Wenchuan earthquake in China. A total of 1573 adolescent survivors were followed up at 6, 12, 18 and 24 months post-earthquake. Participants completed the Posttraumatic Stress Disorder Self-Rating Scale (PTSD-SS), Adolescent Self-Rating Life Events Checklist, Social Support Rate Scale, and the Simplified Coping Style Questionnaire. Distinct patterns of PTSD symptom trajectories were established through grouping participants based on time-varying changes of developing PTSD (i.e. reaching the clinical cut-off on the PTSD-SS). Multivariate logistic regressions were used to examine predictors for trajectory membership. PTSD prevalence rates at 6, 12, 18 and 24 months were 21.0, 23.3, 13.5 and 14.7%, respectively. Five PTSD symptom trajectories were observed: resistance (65.3% of the sample), recovery (20.0%), relapsing/remitting (3.3%), delayed dysfunction (4.2%) and chronic dysfunction (7.2%). Female gender and senior grade were related to higher risk of developing PTSD symptoms in at least one time point, whereas being an only child increased the possibility of recovery relative to chronic dysfunction. Family members' injury/loss and witness of traumatic scenes could also cause PTSD chronicity. More negative life events, less social support, more negative coping and less positive coping were also common predictors for not developing resistance or recovery. Adolescents' PTSD symptoms showed an anniversary reaction. Although many adolescents remain euthymic or recover over time, some adolescents, especially those with the risk factors noted above, exhibit chronic, delayed or relapsing symptoms. Thus, the need for individualized intervention with these adolescents is indicated.

The Eulipotyphla (true insectivores) is the third largest mammalian order, comprising over 500 species, and could be an important source of human infectious diseases. However, relatively little is known about the microbial diversity in insectivores and their contribution to virus transmission among wild hosts. In this study, we compile a comprehensive dataset containing over 400,000 records of insectivores and their associated microbes from 1903 to 2023 from multiple public databases. Meta-analyses show that insectivores host 941 unique microbes, 60% of which are viruses; these are predominantly found in shrews and hedgehogs. Human-associated viruses harbored by shrews and hedgehogs are phylogenetically closely related to those in humans, suggesting potential bidirectional transmission between insectivores and humans. Moreover, virus-sharing networks reveal that insectivores hold the second-most central position for virus sharing, second to bats, among all mammalian orders. Insectivores have a high proportion of cross-order transmitted viruses, including many human-associated viruses. Dietary diversity, habitat diversity, and distributional traits emerge as the key ecological factors contributing to cross-species virus transmission. Our findings highlight the microbial diversity in insectivores, indicating this order may serve as potential incubators for viruses capable of infecting mammals and spreading viruses of public health concern. Here, using a meta-analysis approach the authors compile a database of microbes hosted by insectivores, showing that a majority of them are viruses, that shrews and hedgehogs particularly contribute to the global virus sharing networks and that insectivores may spread of viruses of potential public health concern.

Understanding object representations requires a broad, comprehensive sampling of the objects in our visual world with dense measurements of brain activity and behavior. Here, we present THINGS-data, a multimodal collection of large-scale neuroimaging and behavioral datasets in humans, comprising densely sampled functional MRI and magnetoencephalographic recordings, as well as 4.70 million similarity judgments in response to thousands of photographic images for up to 1,854 object concepts. THINGS-data is unique in its breadth of richly annotated objects, allowing for testing countless hypotheses at scale while assessing the reproducibility of previous findings. Beyond the unique insights promised by each individual dataset, the multimodality of THINGS-data allows combining datasets for a much broader view into object processing than previously possible. Our analyses demonstrate the high quality of the datasets and provide five examples of hypothesis-driven and data-driven applications. THINGS-data constitutes the core public release of the THINGS initiative ( https://things-initiative.org ) for bridging the gap between disciplines and the advancement of cognitive neuroscience.