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Long noncoding RNAs are thought to regulate gene expression by organizing protein complexes through unclear mechanisms. XIST controls the inactivation of an entire X chromosome in female placental mammals. Here we develop and integrate several orthogonal structure-interaction methods to demonstrate that XIST RNA-protein complex folds into an evolutionarily conserved modular architecture. Chimeric RNAs and clustered protein binding in fRIP and eCLIP experiments align with long-range RNA secondary structure, revealing discrete XIST domains that interact with distinct sets of effector proteins. CRISPR-Cas9-mediated permutation of the Xist A-repeat location shows that A-repeat serves as a nucleation center for multiple Xist-associated proteins and m 6 A modification. Thus modular architecture plays an essential role, in addition to sequence motifs, in determining the specificity of RBP binding and m 6 A modification. Together, this work builds a comprehensive structure-function model for the XIST RNA-protein complex, and suggests a general strategy for mechanistic studies of large ribonucleoprotein assemblies. The long noncoding RNA XIST plays a central role in sex-specific gene expression in humans by silencing one of two X chromosomes in female cells. Here the authors show that higher order secondary structure creates the modular domain structure of XIST ribonucleoprotein complex and spatial separation of functions.

Lipid nanoparticles (LNPs) are currently the most commonly used non-viral gene delivery system. Their physiochemical attributes, encompassing size, charge and surface modifications, significantly affect their behaviors both in vivo and in vitro. Nevertheless, the effects of these properties on the transfection and distribution of LNPs after intramuscular injection remain elusive. In this study, LNPs with varying sizes, lipid-based charges and PEGylated lipids were formulated to study their transfection and in vivo distribution. Luciferase mRNA (mLuc) was entraped in LNPs as a model nucleic acid molecule. Results indicated that smaller-sized LNPs and those with neutral potential presented superior transfection efficiency after intramuscular injection. Surprisingly, the sizes and charges did not exert a notable influence on the in vivo distribution of the LNPs. Furthermore, PEGylated lipids with shorter acyl chains contributed to enhanced transfection efficiency due to their superior cellular uptake and lysosomal escape capabilities. Notably, the mechanisms underlying cellular uptake differed among LNPs containing various types of PEGylated lipids, which was primarily attributed to the length of their acyl chain. Together, these insights underscore the pivotal role of nanoparticle characteristics and PEGylated lipids in the intramuscular route. This study not only fills crucial knowledge gaps but also provides significant directions for the effective delivery of mRNA via LNPs. Graphical Abstract

Muscle stem cells （MuSCs, satellite cells） are the major contributor to muscle regeneration. Like most adult stem cells, long-term expansion of MuSCs in vitro is difficult. The in vivo muscle regeneration abilities of MuSCs are quickly lost after culturing in vitro, which prevents the potential applications of MuSCs in cell-based therapies. Here, we establish a system to serially expand MuSCs in vitro for over 20 passages by mimicking the endogenous microen- vironment. We identified that the combination of four pro-inflammatory cytoklnes, IL-1α, IL-13, TNF-α, and IFN-γ, secreted by T cells was able to stimulate MuSC proliferation in vivo upon injury and promote serial expansion of MuSCs in vitro. The expanded MuSCs can replenish the endogenous stem cell pool and are capable of repairing mul- tiple rounds of muscle injuries in vivo after a single transplantation. The establishment of the in vitro system provides us a powerful method to expand functional MuSCs to repair muscle injuries.

High-resolution contact maps of active enhancers and target genes generated by H3K27ac HiChIP in primary human cells provide rational guides to link noncoding disease-associated risk variants to candidate causal genes. Genes are validated by CRISPR activation and interference at connected enhancers and eQTL analysis, leading to a fourfold increase in the number of potential target genes for autoimmune and cardiovascular diseases. The challenge of linking intergenic mutations to target genes has limited molecular understanding of human diseases. Here we show that H3K27ac HiChIP generates high-resolution contact maps of active enhancers and target genes in rare primary human T cell subtypes and coronary artery smooth muscle cells. Differentiation of naive T cells into T helper 17 cells or regulatory T cells creates subtype-specific enhancer–promoter interactions, specifically at regions of shared DNA accessibility. These data provide a principled means of assigning molecular functions to autoimmune and cardiovascular disease risk variants, linking hundreds of noncoding variants to putative gene targets. Target genes identified with HiChIP are further supported by CRISPR interference and activation at linked enhancers, by the presence of expression quantitative trait loci, and by allele-specific enhancer loops in patient-derived primary cells. The majority of disease-associated enhancers contact genes beyond the nearest gene in the linear genome, leading to a fourfold increase in the number of potential target genes for autoimmune and cardiovascular diseases.

To solve the problem of lumbar spine injuries of tractor drivers, lumbar support devices were added to the tractor. The purpose of study is to design lumbar supports with different protrusion thicknesses to adjust the load on the operator's lumbar under whole-body vibration. Integrating pressure distribution measurement with subjective assessment, pressure distribution on the contact surface between ten male tractor drivers and the seat under conditions of different lumbar supports and driving speeds and the influence of the presence of lumbar supports and their thickness on the subjects' comfort were analyzed. The results demonstrated that there existed a certain correlation between the pressure distribution indexes and the drivers' subjective evaluation, and the pressure distribution indexes could reflect ride comfort objectively. The 3 cm thick lumbar support did not improve ride comfort significantly, while the 9 cm thick support exerted too much stress on the waist, causing the lumbar spine to lean forward excessively and aggravating lumbar fatigue. Most subjects in the study would prefer to increase the thickness of the lumbar supports to approximately 6 cm. Based on the pressure distribution test, this study conducted an analysis of the influence of lumbar supports in tractors, which could provide a reference design for tractor seats.

To solve the problem of lumbar spine injuries of tractor drivers, lumbar support devices were added to the tractor. The purpose of study is to design lumbar supports with different protrusion thicknesses to adjust the load on the operator’s lumbar under whole-body vibration. Integrating pressure distribution measurement with subjective assessment, pressure distribution on the contact surface between ten male tractor drivers and the seat under conditions of different lumbar supports and driving speeds and the influence of the presence of lumbar supports and their thickness on the subjects’ comfort were analyzed. The results demonstrated that there existed a certain correlation between the pressure distribution indexes and the drivers’ subjective evaluation, and the pressure distribution indexes could reflect ride comfort objectively. The 3 cm thick lumbar support did not improve ride comfort significantly, while the 9 cm thick support exerted too much stress on the waist, causing the lumbar spine to lean forward excessively and aggravating lumbar fatigue. Most subjects in the study would prefer to increase the thickness of the lumbar supports to approximately 6 cm. Based on the pressure distribution test, this study conducted an analysis of the influence of lumbar supports in tractors, which could provide a reference design for tractor seats.

Machine learning is the core of artificial intelligence. Using optical signals for training and converting them into electrical signals for inference, combines the strengths of both, and thus can greatly improve machine learning efficiency. Optoelectronic memories are the hardware foundation for this strategy. However, the existing optoelectronic memories cannot modulate a large number of non-volatile resistive states using ultra-short and ultra-dim light pulses, leading to low training accuracy, slow computing speed and high energy consumption. Here, we synthesized a van der Waals layered photoconductive material, (NH 4 )BiI 3 , with excellent photoconductivity and strong dielectric screening effect. We further employed it as the photosensitive control gate in a floating-gate transistor, replacing the commonly used metal control gate, to construct an optical floating gate transistor which achieves adjustable synaptic weights under ultra-dim light without gate voltage assistance. Moreover, it shows ultra-low training energy consumption to generate a non-volatile state and the largest resistive state numbers among the known non-volatile optoelectronic memories. These exceptional performances enable the construction of one-transistor-one-memory device arrays to achieve ~99% accuracy in Artificial Neural Networks. Moreover, the device arrays can match the performance of GPU in YOLOv8 while greatly reducing energy consumption. The authors synthesise a Bi-based halide and use it as a photosensitive control gate in a floating-gate transistor, enabling a non-volatile optoelectronic memory with ultra-low energy consumption and large resistive state numbers, for high-accuracy machine learning.

The Xist lncRNA mediates X chromosome inactivation (XCI). Here we show that Spen, an Xist-binding repressor protein essential for XCI , binds to ancient retroviral RNA, performing a surveillance role to recruit chromatin silencing machinery to these parasitic loci. Spen loss activates a subset of endogenous retroviral (ERV) elements in mouse embryonic stem cells, with gain of chromatin accessibility, active histone modifications, and ERV RNA transcription. Spen binds directly to ERV RNAs that show structural similarity to the A-repeat of Xist, a region critical for Xist-mediated gene silencing. ERV RNA and Xist A-repeat bind the RRM domains of Spen in a competitive manner. Insertion of an ERV into an A-repeat deficient Xist rescues binding of Xist RNA to Spen and results in strictly local gene silencing in cis. These results suggest that Xist may coopt transposable element RNA-protein interactions to repurpose powerful antiviral chromatin silencing machinery for sex chromosome dosage compensation. The genetic material inside cells is often packaged into thread-like structures called chromosomes. In humans, mice and other mammals, a pair of sex chromosomes determines the genetic or chromosomal sex of each individual. Those who inherit two “X” chromosomes are said to be chromosomally female, while chromosomal males have one “X” and one “Y” chromosome. This means females have twice as many copies of genes on the X chromosome as a male does, which turns out to be double the number that the body needs. To solve this problem, mammals have developed a strategy known as dosage compensation. The second X chromosome in females becomes “silent”: its DNA remains unchanged, but none of the genes are active. A long noncoding RNA molecule called Xist is responsible for switching off the extra X genes in female cells. It does this by coating the entirety of the second X chromosome. Normally, RNA molecules transmit the coded instructions in genes to the cellular machinery that manufactures proteins. “Noncoding” RNAs like Xist, however, are RNAs that have taken on different jobs inside the cell. Researchers believe that the ancestral Xist gene may have once encoded a protein but changed over time to produce only a noncoding RNA. Carter, Xu et al. therefore set out to find out how exactly this might have happened, and also how Xist might have acquired its ability to switch genes off. Initial experiments used mouse cells grown in the laboratory, in which a protein called Spen was deleted. Spen is known to help Xist silence the X chromosome. In female cells lacking Spen, the second X chromosome remained active. Other chromosomes in male and female cells also had stretches of DNA that became active upon Spen’s removal. These DNA sequences, termed endogenous retroviruses, were remnants of ancestral viral infections. In other words, Spen normally acted as an antiviral defense. Analysis of genetic sequences showed that Spen recognized endogenous retrovirus sequences resembling a key region in Xist, a region which was needed for Xist to work properly. Inserting fragments of endogenous retroviruses into a defective version of Xist lacking this region also partially restored its ability to inactivate genes, suggesting that X chromosome silencing might work by hijacking cellular defenses against viruses. That is, female cells essentially ‘pretend’ there is a viral infection on the second X chromosome by coating it with Xist (which mimics endogenous retroviruses), thus directing Spen to shut it down. This research is an important step towards understanding how female cells carry out dosage compensation in mammals. More broadly, it sheds new light on how ancient viruses may have shaped the evolution of noncoding RNAs in the human genome.

Here we introduce Protein-indexed Assay of Transposase Accessible Chromatin with sequencing (Pi-ATAC) that combines single-cell chromatin and proteomic profiling. In conjunction with DNA transposition, the levels of multiple cell surface or intracellular protein epitopes are recorded by index flow cytometry and positions in arrayed microwells, and then subject to molecular barcoding for subsequent pooled analysis. Pi-ATAC simultaneously identifies the epigenomic and proteomic heterogeneity in individual cells. Pi-ATAC reveals a casual link between transcription factor abundance and DNA motif access, and deconvolute cell types and states in the tumor microenvironment in vivo. We identify a dominant role for hypoxia, marked by HIF1α protein, in the tumor microvenvironment for shaping the regulome in a subset of epithelial tumor cells. Cellular heterogeneity in cancer is complex and difficult to study. Here, the authors introduce Protein-indexed Assay of Transposase Accessible Chromatin (Pi-ATAC), which combines single cell chromatin and proteomic profiling to provide deep insight into the tumor microenvironment, and reveal the role of hypoxia in shaping the regulome of a subset of breast cancer cells in vivo.

Ambient solution-processed conductive materials with a sufficient low work function are essential to facilitate electron injection in electronic and optoelectronic devices but are challenging. Here, we design an electrically conducting and ambient-stable polymer electrolyte with an ultralow work function down to 2.2 eV, which arises from heavy n-doping of dissolved salts to polymer matrix. Such materials can be solution processed into uniform and smooth films on various conductors including graphene, conductive metal oxides, conducting polymers and metals to substantially improve their electron injection, enabling high-performance blue light-emitting diodes and transparent light-emitting diodes. This work provides a universal strategy to design a wide range of stable charge injection materials with tunable work function. As an example, we also synthesize a high-work-function polymer electrolyte material for high-performance solar cells. Ambient-stable solution-processed conductive materials with a low work function are essential to facilitate electron injection. Here, the authors design and synthesise polymer electrolyte with work function down to 2.2 eV for applications in high-performance light-emitting diodes and solar cells.