The effect of cellular context on miR-155-mediated gene regulation in four major immune cell types.

Numerous microRNAs and their target mRNAs are coexpressed across diverse cell types. However, it is unknown whether they are regulated in a manner independent of or dependent on cellular context. Here, we explored transcriptome-wide targeting and gene regulation by miR-155, whose activation-induced expression plays important roles in innate and adaptive immunity. Through mapping of miR-155 targets through differential iCLIP, mRNA quantification with RNA-seq, and 3' untranslated region (UTR)-usage analysis with poly(A)-seq in macrophages, dendritic cells, and T and B lymphocytes either sufficient or deficient in activated miR-155, we identified numerous targets differentially bound by miR-155. Whereas alternative cleavage and polyadenylation (ApA) contributed to differential miR-155 binding to some transcripts, in most cases, identical 3'-UTR isoforms were differentially regulated across cell types, thus suggesting ApA-independent and cellular-context-dependent miR-155-mediated gene regulation. Our study provides comprehensive maps of miR-155 regulatory networks and offers a valuable resource for dissecting context-dependent and context-independent miRNA-mediated gene regulation in key immune cell types.

A vaccine targeting resistant tumours by dual T cell plus NK cell attack.

Most cancer vaccines target peptide antigens, necessitating personalization owing to the vast inter-individual diversity in major histocompatibility complex (MHC) molecules that present peptides to T cells. Furthermore, tumours frequently escape T cell-mediated immunity through mechanisms that interfere with peptide presentation1. Here we report a cancer vaccine that induces a coordinated attack by diverse T cell and natural killer (NK) cell populations. The vaccine targets the MICA and MICB (MICA/B) stress proteins expressed by many human cancers as a result of DNA damage2. MICA/B serve as ligands for the activating NKG2D receptor on T cells and NK cells, but tumours evade immune recognition by proteolytic MICA/B cleavage3,4. Vaccine-induced antibodies increase the density of MICA/B proteins on the surface of tumour cells by inhibiting proteolytic shedding, enhance presentation of tumour antigens by dendritic cells to T cells and augment the cytotoxic function of NK cells. Notably, this vaccine maintains efficacy against MHC class I-deficient tumours resistant to cytotoxic T cells through the coordinated action of NK cells and CD4+ T cells. The vaccine is also efficacious in a clinically important setting: immunization following surgical removal of primary, highly metastatic tumours inhibits the later outgrowth of metastases. This vaccine design enables protective immunity even against tumours with common escape mutations.

High-Resolution In Vivo Identification of miRNA Targets by Halo-Enhanced Ago2 Pull-Down.

The identification of microRNA (miRNA) targets by Ago2 crosslinking-immunoprecipitation (CLIP) methods has provided major insights into the biology of this important class of non-coding RNAs. However, these methods are technically challenging and not easily applicable to an in vivo setting. To overcome these limitations and facilitate the investigation of miRNA functions in vivo, we have developed a method based on a genetically engineered mouse harboring a conditional Halo-Ago2 allele expressed from the endogenous Ago2 locus. By using a resin conjugated to the HaloTag ligand, Ago2-miRNA-mRNA complexes can be purified from cells and tissues expressing the endogenous Halo-Ago2 allele. We demonstrate the reproducibility and sensitivity of this method in mouse embryonic stem cells, developing embryos, adult tissues, and autochthonous mouse models of human brain and lung cancers. This method and the datasets we have generated will facilitate the characterization of miRNA-mRNA networks in vivo under physiological and pathological conditions.

A Single miRNA-mRNA Interaction Affects the Immune Response in a Context- and Cell-Type-Specific Manner.

MicroRNA (miRNA)-dependent regulation of gene expression confers robustness to cellular phenotypes and controls responses to extracellular stimuli. Although a single miRNA can regulate expression of hundreds of target genes, it is unclear whether any of its distinct biological functions can be due to the regulation of a single target. To explore in vivo the function of a single miRNA-mRNA interaction, we mutated the 3' UTR of a major miR-155 target (SOCS1) to specifically disrupt its regulation by miR-155. We found that under physiologic conditions and during autoimmune inflammation or viral infection, some immunological functions of miR-155 were fully or largely attributable to the regulation of SOCS1, whereas others could be accounted only partially or not at all by this interaction. Our data suggest that the role of a single miRNA-mRNA interaction is dependent on cell type and biological context.

Brainnetome atlas of preadolescent children based on anatomical connectivity profiles.

During the preadolescent period, when the cerebral thickness, curvature, and myelin are constantly changing, the brain's regionalization patterns underwent persistent development, contributing to the continuous improvements of various higher cognitive functions. Using a brain atlas to study the development of these functions has attracted much attention. However, the brains of children do not always have the same topological patterns as those of adults. Therefore, age-specific brain mapping is particularly important, serving as a basic and indispensable tool to study the normal development of children. In this study, we took advantage of longitudinal data to create the brain atlas specifically for preadolescent children. The resulting human Child Brainnetome Atlas, with 188 cortical and 36 subcortical subregions, provides a precise period-specific and cross-validated version of the brain atlas that is more appropriate for adoption in the preadolescent period. In addition, we compared and illustrated for regions with different topological patterns in the child and adult atlases, providing a topologically consistent reference for subsequent research studying child and adolescent development.

Two subtypes of schizophrenia identified by an individual-level atypical pattern of tensor-based morphometric measurement.

Difficulties in parsing the multiaspect heterogeneity of schizophrenia (SCZ) based on current nosology highlight the need to subtype SCZ using objective biomarkers. Here, utilizing a large-scale multisite SCZ dataset, we identified and validated 2 neuroanatomical subtypes with individual-level abnormal patterns of the tensor-based morphometric measurement. Remarkably, compared with subtype 1, which showed moderate deficits of some subcortical nuclei and an enlarged striatum and cerebellum, subtype 2, which showed cerebellar atrophy and more severe subcortical nuclei atrophy, had a higher subscale score of negative symptoms, which is considered to be a core aspect of SCZ and is associated with functional outcome. Moreover, with the neuroimaging-clinic association analysis, we explored the detailed relationship between the heterogeneity of clinical symptoms and the heterogeneous abnormal neuroanatomical patterns with respect to the 2 subtypes. And the neuroimaging-transcription association analysis highlighted several potential heterogeneous biological factors that may underlie the subtypes. Our work provided an effective framework for investigating the heterogeneity of SCZ from multilevel aspects and may provide new insights for precision psychiatry.

Pseudocapacitive Potassium-Ion Intercalation Enabled by Topologically Defective Soft Carbon toward High-Rate, Large-Areal-Capacity, and Low-Temperature Potassium-Ion Batteries.

Carbonaceous materials are widely investigated as anodes for potassium-ion batteries (PIBs). However, the inferior rate capability, low areal capacity, and limited working temperature caused by sluggish K-ions diffusion kinetics are still primary challenges for carbon-based anodes. Herein, a simple temperature-programmed co-pyrolysis strategy is proposed for the efficient synthesis of topologically defective soft carbon (TDSC) based on inexpensive pitch and melamine. The skeletons of TDSC are optimized with shortened graphite-like microcrystals, enlarged interlayer spacing, and abundant topological defects (e.g., pentagons, heptagons, and octagons), which endow TDSC with fast pseudocapacitive K-ion intercalation behavior. Meanwhile, micrometer-sized structure can reduce the electrolyte degradation over particle surface and avoid unnecessary voids, ensuring a high initial Coulombic efficiency as well as high energy density. These synergistic structural advantages contribute to excellent rate capability (116 mA h g-1 at 20 C), impressive areal capacity (1.83 mA h cm-2 with a mass loading of 8.32 mg cm-2 ), long-term cycling stability (capacity retention of 91.8% after 1200 h cycling), and low working temperature (-10 °C) of TDSC anodes, demonstrating great potential for the practical application of PIBs.

Expression pattern analysis of m6A regulators reveals IGF2BP3 as a key modulator in osteoarthritis synovial macrophages.

BACKGROUND: Disruption of N6 methyl adenosine (m6A) modulation hampers gene expression and cellular functions, leading to various illnesses. However, the role of m6A modification in osteoarthritis (OA) synovitis remains unclear. This study aimed to explore the expression patterns of m6A regulators in OA synovial cell clusters and identify key m6A regulators that mediate synovial macrophage phenotypes. METHODS: The expression patterns of m6A regulators in the OA synovium were illustrated by analyzing bulk RNA-seq data. Next, we built an OA LASSO-Cox regression prediction model to identify the core m6A regulators. Potential target genes of these m6A regulators were identified by analyzing data from the RM2target database. A molecular functional network based on core m6A regulators and their target genes was constructed using the STRING database. Single-cell RNA-seq data were collected to verify the effects of m6A regulators on synovial cell clusters. Conjoint analyses of bulk and single-cell RNA-seq data were performed to validate the correlation between m6A regulators, synovial clusters, and disease conditions. After IGF2BP3 was screened as a potential modulator in OA macrophages, the IGF2BP3 expression level was tested in OA synovium and macrophages, and its functions were further tested by overexpression and knockdown in vitro. RESULTS: OA synovium showed aberrant expression patterns of m6A regulators. Based on these regulators, we constructed a well-fitting OA prediction model comprising six factors (FTO, YTHDC1, METTL5, IGF2BP3, ZC3H13, and HNRNPC). The functional network indicated that these factors were closely associated with OA synovial phenotypic alterations. Among these regulators, the m6A reader IGF2BP3 was identified as a potential macrophage mediator. Finally, IGF2BP3 upregulation was verified in the OA synovium, which promoted macrophage M1 polarization and inflammation. CONCLUSIONS: Our findings revealed the functions of m6A regulators in OA synovium and highlighted the association between IGF2BP3 and enhanced M1 polarization and inflammation in OA macrophages, providing novel molecular targets for OA diagnosis and treatment.

The human mediodorsal thalamus: Organization, connectivity, and function.

The human mediodorsal thalamic nucleus (MD) is crucial for higher cognitive functions, while the fine anatomical organization of the MD and the function of each subregion remain elusive. In this study, using high-resolution data provided by the Human Connectome Project, an anatomical connectivity-based method was adopted to unveil the topographic organization of the MD. Four fine-grained subregions were identified in each hemisphere, including the medial (MDm), central (MDc), dorsal (MDd), and lateral (MDl), which recapitulated previous cytoarchitectonic boundaries from histological studies. The subsequent connectivity analysis of the subregions also demonstrated distinct anatomical and functional connectivity patterns, especially with the prefrontal cortex. To further evaluate the function of MD subregions, partial least squares analysis was performed to examine the relationship between different prefrontal-subregion connectivity and behavioral measures in 1012 subjects. The results showed subregion-specific involvement in a range of cognitive functions. Specifically, the MDm predominantly subserved emotional-cognition domains, while the MDl was involved in multiple cognitive functions especially cognitive flexibility and inhibition. The MDc and MDd were correlated with fluid intelligence, processing speed, and emotional cognition. In conclusion, our work provides new insights into the anatomical and functional organization of the MD and highlights the various roles of the prefrontal-thalamic circuitry in human cognition.

BindSpace decodes transcription factor binding signals by large-scale sequence embedding.

The decoding of transcription factor (TF) binding signals in genomic DNA is a fundamental problem. Here we present a prediction model called BindSpace that learns to embed DNA sequences and TF labels into the same space. By training on binding data from hundreds of TFs and embedding over 1 M DNA sequences, BindSpace achieves state-of-the-art multiclass binding prediction performance, in vitro and in vivo, and can distinguish between signals of closely related TFs.

Asporin regulated by miR-26b-5p mediates chondrocyte senescence and exacerbates osteoarthritis progression via TGF-ß1/Smad2 pathway.

OBJECTIVES: This study aimed to investigate the role and mechanism of asporin in modulating chondrocyte senescence in OA pathology. METHODS: Asporin and senescence-related hallmark expression were examined in human and experimental OA mouse cartilage samples. Twelve-week-old male C57 mice were administered with recombinant protein (rm-asporin)- or asporin-siRNA-expressing lentiviruses via intra-articular injection once a week after destabilization of the medial meniscus (DMM) surgery to induce OA. Cartilage damage was measured using the Osteoarthritis Research Society International score. Senescence-associated ß-galactosidase (SA-ß-Gal) staining, γH2AX, p21 and p16INK4a were analysed by immunofluorescence staining and western blot to assess the specific role of asporin in chondrocyte senescence. The TGF-ß1-Smad2 signalling pathway and miR-26b-5p were further evaluated to explore the mechanism of asporin in OA. RESULTS: Asporin was upregulated in articular chondrocytes of OA patients and DMM mice and accompanied by accumulation of senescent cells. Asporin overexpression exaggerated OA progression, whereas silencing asporin restored chondrocyte homeostasis and deferred chondrocyte senescence, leading to markedly attenuated DMM-induced OA. Cellular and molecular analyses showed that asporin can be inhibited by miR-26b-5p, which was significantly downregulated in OA cartilage, leading to exacerbation of experimental OA partially through inhibition of TGF-ß1-Smad2 signalling in chondrocytes. CONCLUSIONS: Our findings indicate that asporin plays an essential role in chondrocyte senescence and OA pathogenesis. Upregulated by miR-26b-5p, asporin inhibits the TGF-ß1-Smad2 pathway to accelerate chondrocyte senescence and exacerbate cartilage degeneration. Targeting the miR-26b-5p-asporin-Smad2 axis may serve as a practical therapeutic strategy to delay chondrocyte senescence and OA development.

Learning to Predict miRNA-mRNA Interactions from AGO CLIP Sequencing and CLASH Data.

Recent technologies like AGO CLIP sequencing and CLASH enable direct transcriptome-wide identification of AGO binding and miRNA target sites, but the most widely used miRNA target prediction algorithms do not exploit these data. Here we use discriminative learning on AGO CLIP and CLASH interactions to train a novel miRNA target prediction model. Our method combines two SVM classifiers, one to predict miRNA-mRNA duplexes and a second to learn a binding model of AGO's local UTR sequence preferences and positional bias in 3'UTR isoforms. The duplex SVM model enables the prediction of non-canonical target sites and more accurately resolves miRNA interactions from AGO CLIP data than previous methods. The binding model is trained using a multi-task strategy to learn context-specific and common AGO sequence preferences. The duplex and common AGO binding models together outperform existing miRNA target prediction algorithms on held-out binding data. Open source code is available at https://bitbucket.org/leslielab/chimiric.

Differential responses of the whitefly Bemisia tabaci symbionts to unfavorable low and high temperatures.

The whitefly Bemisia tabaci complex contains many cryptic species, of which the Middle East-Asia Minor 1 (MEAM1) and Mediterranean (MED) are notorious invasive pests. In our field-collected whitefly samples, MEAM1 harbors an obligate primary symbiont "Candidatus Portiera aleyrodidarum" and two secondary symbionts, "Candidatus Hamiltonella defensa" and Rickettsia sp., whereas MED has only "Ca. Portiera aleyrodidarum" and "Ca. Hamiltonella defensa." Both "Ca. Portiera aleyrodidarum" and "Ca. Hamiltonella defensa" are intracellular endosymbionts residing in the bacteriomes, whereas Rickettsia sp. has a scattered distribution throughout the host body cavity. We examined responses of these symbionts to adverse temperatures as well as survival of the host insects. After cold treatment at 5 or 10 °C or heat treatment at 35 or 40 °C for 24 h, respectively, the infection rates of all symbionts were not significantly decreased based on diagnosis PCR. However, quantitative PCR assays indicated significant reduction of "Ca. Hamiltonella defensa" at 40 °C, and the reduction became greater as the duration increased. Compared with "Ca. Hamiltonella defensa," "Ca. Portiera aleyrodidarum" was initially less affected in the first day but then showed more rapid reduction at days 3-5. The density of Rickettsia sp. fluctuated but was not reduced significantly at 40 °C. Meanwhile, the mortality rates of the host whiteflies elevated rapidly as the duration of exposure to heat treatment increased. The differential responses of various symbionts to adverse temperatures imply complex interactions among the symbionts inside the same host insect and highlight the importance of taking the whole bacterial community into account in studies of symbioses.

Multimodal Connectivity-based Individual Parcellation and Analysis for Humans and Rhesus Monkeys.

Individual brains vary greatly in morphology, connectivity and organization. Individualized brain parcellation is capable of precisely localizing subject-specific functional regions. However, most individualization approaches examined single modality of data and have not generalized to nonhuman primates. The present study proposed a novel multimodal connectivity-based individual parcellation (MCIP) method, which optimizes within-region homogeneity, spatial continuity and similarity to a reference atlas with the fusion of personal functional and anatomical connectivity. Comprehensive evaluation demonstrated that MCIP outperformed state-of-the-art multimodal individualization methods in terms of functional and anatomical homogeneity, predictability of cognitive measures, heritability, reproducibility and generalizability across species. Comparative investigation showed a higher topographic variability in humans than that in macaques. Therefore, MCIP provides improved accurate and reliable mapping of brain functional regions over existing methods at an individual level across species, and could facilitate comparative and translational neuroscience research.

N-Halaminated spermidine-containing polymeric coating enables titanium to achieve dual functions of antibacterial and osseointegration.

Titanium (Ti) and its alloys have been widely employed in the treatment of orthopedics and other hard tissue diseases. However, Ti-based implants are bioinert and suffer from bacterial infections and poor osseointegration in clinical applications. Herein, we successfully modified Ti with a porous N-halaminated spermidine-containing polymeric coating (Ti-SPD-Cl) through alkali-heat treatment, surface grafting and chlorination, and it has both excellent antibacterial and osteogenic abilities to significantly enhance osseointegration. The as-obtained Ti-SPD-Cl contains abundant N-Cl groups and demonstrates effective antibacterial ability against S. aureus and E. coli. Meanwhile, due to the presence of the spermidine component and construction of a porous hydrophilic surface, Ti-SPD-Cl is also beneficial for maintaining cell membrane homeostasis and promoting cell adhesion, exhibiting good biocompatibility and osteogenic ability. The rat osteomyelitis model demonstrates that Ti-SPD-Cl can effectively suppress bacterial infection and enhance bone-implant integration. Thus, Ti-SPD-Cl shows promising clinical applicability in the prevention of orthopedic implant infections and poor osseointegration.

Comparative Analysis of Human-Chimpanzee Divergence in Brain Connectivity and its Genetic Correlates.

Chimpanzees (Pan troglodytes) are humans' closest living relatives, making them the most directly relevant comparison point for understanding human brain evolution. Zeroing in on the differences in brain connectivity between humans and chimpanzees can provide key insights into the specific evolutionary changes that might have occured along the human lineage. However, conducting comparisons of brain connectivity between humans and chimpanzees remains challenging, as cross-species brain atlases established within the same framework are currently lacking. Without the availability of cross-species brain atlases, the region-wise connectivity patterns between humans and chimpanzees cannot be directly compared. To address this gap, we built the first Chimpanzee Brainnetome Atlas (ChimpBNA) by following a well-established connectivity-based parcellation framework. Leveraging this new resource, we found substantial divergence in connectivity patterns across most association cortices, notably in the lateral temporal and dorsolateral prefrontal cortex between the two species. Intriguingly, these patterns significantly deviate from the patterns of cortical expansion observed in humans compared to chimpanzees. Additionally, we identified regions displaying connectional asymmetries that differed between species, likely resulting from evolutionary divergence. Genes associated with these divergent connectivities were found to be enriched in cell types crucial for cortical projection circuits and synapse formation. These genes exhibited more pronounced differences in expression patterns in regions with higher connectivity divergence, suggesting a potential foundation for brain connectivity evolution. Therefore, our study not only provides a fine-scale brain atlas of chimpanzees but also highlights the connectivity divergence between humans and chimpanzees in a more rigorous and comparative manner and suggests potential genetic correlates for the observed divergence in brain connectivity patterns between the two species. This can help us better understand the origins and development of uniquely human cognitive capabilities.

RPL35 downregulated by mechanical overloading promotes chondrocyte senescence and osteoarthritis development via Hedgehog-Gli1 signaling.

Objectives: To investigate the potential role of Ribosomal protein L35 (RPL35) in regulating chondrocyte catabolic metabolism and to examine whether osteoarthritis (OA) progression can be delayed by overexpressing RPL35 in a mouse compression loading model. Methods: RNA sequencing analysis was performed on chondrocytes treated with or without 20 % elongation strain loading for 24 h. Experimental OA in mice was induced by destabilization of the medial meniscus and compression loading. Mice were randomly assigned to a sham group, an intra-articular adenovirus-mediated overexpression of the negative group, and an intra-articular adenovirus-mediated overexpression of the RPL35 operated group. The Osteoarthritis Research Society International score was used to evaluate cartilage degeneration. Immunostaining and western blot analyses were conducted to detect relative protein levels. Primary mouse chondrocytes were treated with 20 % elongation strain loading for 24 h to investigate the role of RPL35 in modulating chondrocyte catabolic metabolism and regulating cellular senescence in chondrocytes. Results: The protein expression of RPL35 in mouse chondrocytes was significantly reduced when excessive mechanical loading was applied, while elevated protein levels of RPL35 protected articular chondrocytes from degeneration. In addition, the RPL35 knockdown alone induced chondrocyte senescence, decreased the expression of anabolic markers, and increased the expression of catabolic markers in vitro in part through the hedgehog (Hh) pathway. Conclusions: These findings demonstrated a functional pathway important for OA development and identified intra-articular injection of RPL35 as a potential therapy for OA prevention and treatment. The translational potential of this article: It is necessary to develop new targeted drugs for OA due to the limitations of conventional pharmacotherapy. Our study explores and demonstrates the protective effect of RPL35 against excessive mechanical stress in OA models in vivo and in vitro in animals. These findings might provide novel insights into OA pathogenesis and show its translational potential for OA therapy.

Macaque Brainnetome Atlas: A multifaceted brain map with parcellation, connection, and histology.

The rhesus macaque (Macaca mulatta) is a crucial experimental animal that shares many genetic, brain organizational, and behavioral characteristics with humans. A macaque brain atlas is fundamental to biomedical and evolutionary research. However, even though connectivity is vital for understanding brain functions, a connectivity-based whole-brain atlas of the macaque has not previously been made. In this study, we created a new whole-brain map, the Macaque Brainnetome Atlas (MacBNA), based on the anatomical connectivity profiles provided by high angular and spatial resolution ex vivo diffusion MRI data. The new atlas consists of 248 cortical and 56 subcortical regions as well as their structural and functional connections. The parcellation and the diffusion-based tractography were evaluated with invasive neuronal-tracing and Nissl-stained images. As a demonstrative application, the structural connectivity divergence between macaque and human brains was mapped using the Brainnetome atlases of those two species to uncover the genetic underpinnings of the evolutionary changes in brain structure. The resulting resource includes: (1) the thoroughly delineated Macaque Brainnetome Atlas (MacBNA), (2) regional connectivity profiles, (3) the postmortem high-resolution macaque diffusion and T2-weighted MRI dataset (Brainnetome-8), and (4) multi-contrast MRI, neuronal-tracing, and histological images collected from a single macaque. MacBNA can serve as a common reference frame for mapping multifaceted features across modalities and spatial scales and for integrative investigation and characterization of brain organization and function. Therefore, it will enrich the collaborative resource platform for nonhuman primates and facilitate translational and comparative neuroscience research.

Determination of trace tellurium by photochemical vapor generation-atomic fluorescence spectrometry using bifunctional Co-MOF-74 for preconcentration and sensitization.

The determination of trace tellurium in real samples with complicated matrix can be rather challenging due to the low abundance and interferences. Herein, we report a new method for the highly sensitive detection of Te(IV) by photochemical vapor generation-atomic fluorescence spectrometry (PVG-AFS), utilizing Co-MOF-74 as an adsorbent and a precursor of Co2+ ion sensitizer for preconcentration and enhanced PVG efficiency. The synthesized Co-MOF-74 can completely adsorb Te(IV) within 10 min in a wide pH range. Following filtration and re-suspension in a dilute solution of formic and acetic acid, the adsorbed Te(IV) was converted to volatile compounds under the UV irradiation and swept to AFS for detection. A limit of detection of 0.08 ng/mL for Te(IV) was obtained after a 50-fold preconcentration. The proposed method was used for analysis of various natural water samples for trace Te(IV), with satisfactory spike recoveries achieved.

Rough Endoplasmic Reticulum Inspired Polystyrene-Brush-Based Superhigh Sulfur Content Cathodes Enable Lithium-Sulfur Cells with High Mass and Capacity Loading.

The development of highly sophisticated biomimetic models is significant yet remains challenging in the electrochemical energy storage field. Lithium-sulfur (Li-S) cells with high sulfur content and high-sulfur-loading cathodes are urgently required to meet the fast-growing demand for electronic devices. Nevertheless, such cathode materials generally suffer from large sulfur agglomeration, nonporous structure, and insufficient conductivity, leading to rapid capacity decay and low sulfur utilization. Herein, inspired by rough endoplasmic reticulum, a 2D polystyrene (PS)-brush-based (G-g-PS) superhigh-sulfur-content (96 wt%) composite(G-g-sPS@S) is fabricated via the vulcanization reaction. The vulcanized PS side-chains and their S8 composites on the nanosheet surface can efficiently provide sulfur species, and the intersheet interstitial pores can provide rapid mass-transfer channels for redox reactions of sulfur species. Furthermore, the highly sulfophilic vulcanized PS side-chains are able to effectively inhibit the shuttle effect of polysulfides and regulate their redox process. With these merits, the cells with G-g-sPS@S cathodes exhibit an ultralow decay rate of 0.02% per cycle over 400 cycles at 2 C and deliver a superior areal capacity of 12.6 mAh cm-2 even with a high sulfur loading of 10.5 mg cm-2 .