Higher-Order Clustering of the Transmembrane Anchor of DR5 Drives Signaling.

Receptor clustering on the cell membrane is critical in the signaling of many immunoreceptors, and this mechanism has previously been attributed to the extracellular and/or the intracellular interactions. Here, we report an unexpected finding that for death receptor 5 (DR5), a receptor in the tumor necrosis factor receptor superfamily, the transmembrane helix (TMH) alone in the receptor directly assembles a higher-order structure to drive signaling and that this structure is inhibited by the unliganded ectodomain. Nuclear magnetic resonance structure of the TMH in bicelles shows distinct trimerization and dimerization faces, allowing formation of dimer-trimer interaction networks. Single-TMH mutations that disrupt either trimerization or dimerization abolish ligand-induced receptor activation. Surprisingly, proteolytic removal of the DR5 ectodomain can fully activate downstream signaling in the absence of ligand. Our data suggest a receptor activation mechanism in which binding of ligand or antibodies to overcome the pre-ligand autoinhibition allows TMH clustering and thus signaling.

CovEpiAb: a comprehensive database and analysis resource for immune epitopes and antibodies of human coronaviruses.

Coronaviruses have threatened humans repeatedly, especially COVID-19 caused by SARS-CoV-2, which has posed a substantial threat to global public health. SARS-CoV-2 continuously evolves through random mutation, resulting in a significant decrease in the efficacy of existing vaccines and neutralizing antibody drugs. It is critical to assess immune escape caused by viral mutations and develop broad-spectrum vaccines and neutralizing antibodies targeting conserved epitopes. Thus, we constructed CovEpiAb, a comprehensive database and analysis resource of human coronavirus (HCoVs) immune epitopes and antibodies. CovEpiAb contains information on over 60 000 experimentally validated epitopes and over 12 000 antibodies for HCoVs and SARS-CoV-2 variants. The database is unique in (1) classifying and annotating cross-reactive epitopes from different viruses and variants; (2) providing molecular and experimental interaction profiles of antibodies, including structure-based binding sites and around 70 000 data on binding affinity and neutralizing activity; (3) providing virological characteristics of current and past circulating SARS-CoV-2 variants and in vitro activity of various therapeutics; and (4) offering site-level annotations of key functional features, including antibody binding, immunological epitopes, SARS-CoV-2 mutations and conservation across HCoVs. In addition, we developed an integrated pipeline for epitope prediction named COVEP, which is available from the webpage of CovEpiAb. CovEpiAb is freely accessible at https://pgx.zju.edu.cn/covepiab/.

Superantigen-fused T cell engagers for tumor antigen-mediated robust T cell activation and tumor cell killing.

Inadequate T cell activation has severely limited the success of T cell engager (TCE) therapy, especially in solid tumors. Enhancing T cell activity while maintaining the tumor specificity of TCEs is the key to improving their clinical efficacy. However, currently, there needs to be more effective strategies in clinical practice. Here, we design novel superantigen-fused TCEs that display robust tumor antigen-mediated T cell activation effects. These innovative drugs are not only armed with the powerful T cell activation ability of superantigens but also retain the dependence of TCEs on tumor antigens, realizing the ingenious combination of the advantages of two existing drugs. Superantigen-fused TCEs have been preliminarily proven to have good (>30-fold more potent) and specific (>25-fold more potent) antitumor activity in vitro and in vivo. Surprisingly, they can also induce the activation of T cell chemotaxis signals, which may promote T cell infiltration and further provide an additional guarantee for improving TCE efficacy in solid tumors. Overall, this proof-of-concept provides a potential strategy for improving the clinical efficacy of TCEs.

Multi-dimensional cylindrical vector beam (de)multiplexing through cascaded wavelength- and polarization-sensitive metasurfaces.

Cylindrical vector beams (CVBs) exhibit great potential for multiplexing communication, owing to their mode orthogonality and compatibility with conventional wavelength multiplexing techniques. However, the practical application of CVB multiplexing communication faces challenges due to the lack of effective spatial polarization manipulation technologies for (de)multiplexing multi-dimensional physical dimensions of CVBs. Herein, we introduce a wavelength- and polarization-sensitive cascaded phase modulation strategy that utilizes multiple coaxial metasurfaces for multi-dimensional modulation of CVBs. By leveraging the spin-dependent phase modulation mechanism, these metasurfaces enable the independent transformation of the two orthogonal polarization components of CVB modes. Combined with the wavelength sensitivity of Fresnel diffraction in progressive phase modulation, this approach establishes a high-dimensional mapping relationship among CVB modes, wavelengths, spatial positions, and Gaussian fundamental modes, thereby facilitating multi-dimensional (de)multiplexing involving CVB modes and wavelengths. As a proof of concept, we theoretically demonstrate a 9-channel multi-dimensional multiplexing system, successfully achieving joint (de)multiplexing of 3 CVB modes (1, 2, and 3) and 3 wavelengths (1550 nm, 1560 nm, and 1570 nm) with a diffraction efficiency exceeding 80%. Additionally, we show the transmission of 16-QAM signals across 9 channels with the bit-error-rates below 10-5. By combining the integrability of metasurfaces with the high-dimensional wavefront manipulation capabilities of multilevel modulation, our strategy can effectively address the diverse demands of different wavelengths and CVB modes in optical communication.

Cascaded partitioned phase modulation for cross-connection of orbital angular momentum mode and polarization multiplexing channels.

Multi-dimensional orbital angular momentum (OAM) mode multiplexing provides a promising route for enlarging communication capacity and establishing comprehensive networks. While multi-dimensional multiplexing has gained advancements, the cross-connection of these multiplexed channels, especially involving modes and polarizations, remains challenging due to the needs for multi-mode interconversion and on-demand polarization control. Herein, we propose an OAM mode-polarization cross-transformation solution via cascaded partitioned phase modulation, which enables the divergently separated OAM modes to be independently phase-imposed within distinct spatial regions, leading to the synergistic conversion operation of mode and polarization channels. In demonstrations, we implemented the cross-connection of three OAM modes and two polarization multiplexed channels, achieving the mode purity that exceeds 0.951 and polarization contrast up to 0.947. The measured mode insertion losses and polarization conversion losses are below 3.42 and 3.54 dB, respectively. Consequently, 1.2 Tbit/s quadrature phase shift keying signals were successfully exchanged, yielding the bit-error-rates close to 10-6. Incorporating with increased partitioned phase treatments, this approach shows promise in accommodating massive mode-polarization multiplexed channels, which hold the potential to augment networking capability of large-scale OAM mode multiplexing communication networks.

Cross-connection of multiplexed cylindrical vector beams using off-axis spin-decoupled metasurfaces.

Cylindrical vector beam (CVB) multiplexing communication demands effective mode cross-connection techniques to establish communication networks. While methods like polarized grating and coordinate transformation have been developed for (de)multiplexing CVB modes, challenges persist in the cross-connection of these multiplexed mode channels, including multi-mode conversion and inhomogeneous polarization control. Herein, we present an independent off-axis spin-orbit interaction strategy utilizing spin-decoupled metasurfaces. Cross-connection is achieved by encoding conjugated Dammann optical vortex grating phases onto the two orthogonal circularly polarized components of CVBs. Experimental results demonstrate the successful interconversion of four CVB modes (CVB+1 and CVB-2, CVB+2 and CVB-4) using a Si-based metasurface with a polarization conversion efficiency exceeding 85%. This facilitates the cross-connection of 200 Gbit/s quadrature phase-shift keying signals with bit-error-rates below 10-6. Offering advantages such as ultra-compact device size, flexible control of CVB modes, and multi-mode parallel processing, this approach shows promise in advancing the networking capabilities of CVB mode multiplexing communication networks.

Distributed Vibration Sensing Based on a Forward Transmission Polarization-Generated Carrier.

For distributed fiber-optic sensors, slowly varying vibration signals down to 5 mHz are difficult to measure due to low signal-to-noise ratios. We propose and demonstrate a forward transmission-based distributed sensing system, combined with a polarization-generated carrier for detection bandwidth reduction, and cross-correlation for vibration positioning. By applying a higher-frequency carrier signal using a fast polarization controller, the initial phase of the known carrier frequency is monitored and analyzed to demodulate the vibration signal. Only the polarization carrier needs to be analyzed, not the arbitrary-frequency signal, which can lead to hardware issues (reduced detection bandwidth and less noise). The difference in arrival time between the two detection ends obtained through cross-correlation can determine the vibration position. Our experimental results demonstrate a sensitivity of 0.63 mrad/µÎµ and a limit of detection (LoD) of 355.6 pε/Hz1/2 at 60 Hz. A lock-in amplifier can be used on the fixed carrier to achieve a minimal LoD. The sensing distance can reach 131.5 km and the positioning accuracy is 725 m (root-mean-square error) while the spatial resolution is 105 m. The tested vibration frequency range is between 0.005 Hz and 160 Hz. A low frequency of 5 mHz for forward transmission-based distributed sensing is highly attractive for seismic monitoring applications.

Deep Integration of Fiber-Optic Communication and Sensing Systems Using Forward-Transmission Distributed Vibration Sensing and on-off Keying.

The deep integration of communication and sensing technology in fiber-optic systems has been highly sought after in recent years, with the aim of rapid and cost-effective large-scale upgrading of existing communication cables in order to monitor ocean activities. As a proof-of-concept demonstration, a high-degree of compatibility was shown between forward-transmission distributed fiber-optic vibration sensing and an on-off keying (OOK)-based communication system. This type of deep integration allows distributed sensing to utilize the optical fiber communication cable, wavelength channel, optical signal and demodulation receiver. The addition of distributed sensing functionality does not have an impact on the communication performance, as sensing involves no hardware changes and does not occupy any bandwidth; instead, it non-intrusively analyzes inherent vibration-induced noise in the data transmitted. Likewise, the transmission of communication data does not affect the sensing performance. For data transmission, 150 Mb/s was demonstrated with a BER of 2.8 × 10-7 and a QdB of 14.1. For vibration sensing, the forward-transmission method offers distance, time, frequency, intensity and phase-resolved monitoring. The limit of detection (LoD) is 8.3 pε/Hz1/2 at 1 kHz. The single-span sensing distance is 101.3 km (no optical amplification), with a spatial resolution of 0.08 m, and positioning accuracy can be as low as 10.1 m. No data averaging was performed during signal processing. The vibration frequency range tested is 10-1000 Hz.

Comprehensive modular analyses of scar subtypes illuminate underlying molecular mechanisms and potential therapeutic targets.

Pathological scarring resulting from traumas and wounds, such as hypertrophic scars and keloids, pose significant aesthetic, functional and psychological challenges. This study provides a comprehensive transcriptomic analysis of these conditions, aiming to illuminate underlying molecular mechanisms and potential therapeutic targets. We employed a co-expression and module analysis tool to identify significant gene clusters associated with distinct pathophysiological processes and mechanisms, notably lipid metabolism, sebum production, cellular energy metabolism and skin barrier function. This examination yielded critical insights into several skin conditions including folliculitis, skin fibrosis, fibrosarcoma and congenital ichthyosis. Particular attention was paid to Module Cluster (MCluster) 3, encompassing genes like BLK, TRPV1 and GABRD, all displaying high expression and potential implications in immune modulation. Preliminary immunohistochemistry validation supported these findings, showing elevated expression of these genes in non-fibrotic samples rich in immune activity. The complex interplay of different cell types in scar formation, such as fibroblasts, myofibroblasts, keratinocytes and mast cells, was also explored, revealing promising therapeutic strategies. This study underscores the promise of targeted gene therapy for pathological scars, paving the way for more personalised therapeutic approaches. The results necessitate further research to fully ascertain the roles of these identified genes and pathways in skin disease pathogenesis and potential therapeutics. Nonetheless, our work forms a strong foundation for a new era of personalised medicine for patients suffering from pathological scarring.

CanDriS: posterior profiling of cancer-driving sites based on two-component evolutionary model.

Current cancer genomics databases have accumulated millions of somatic mutations that remain to be further explored. Due to the over-excess mutations unrelated to cancer, the great challenge is to identify somatic mutations that are cancer-driven. Under the notion that carcinogenesis is a form of somatic-cell evolution, we developed a two-component mixture model: while the ground component corresponds to passenger mutations, the rapidly evolving component corresponds to driver mutations. Then, we implemented an empirical Bayesian procedure to calculate the posterior probability of a site being cancer-driven. Based on these, we developed a software CanDriS (Cancer Driver Sites) to profile the potential cancer-driving sites for thousands of tumor samples from the Cancer Genome Atlas and International Cancer Genome Consortium across tumor types and pan-cancer level. As a result, we identified that approximately 1% of the sites have posterior probabilities larger than 0.90 and listed potential cancer-wide and cancer-specific driver mutations. By comprehensively profiling all potential cancer-driving sites, CanDriS greatly enhances our ability to refine our knowledge of the genetic basis of cancer and might guide clinical medication in the upcoming era of precision medicine. The results were displayed in a database CandrisDB (http://biopharm.zju.edu.cn/candrisdb/).

MODIG: integrating multi-omics and multi-dimensional gene network for cancer driver gene identification based on graph attention network model.

MOTIVATION: Identifying genes that play a causal role in cancer evolution remains one of the biggest challenges in cancer biology. With the accumulation of high-throughput multi-omics data over decades, it becomes a great challenge to effectively integrate these data into the identification of cancer driver genes. RESULTS: Here, we propose MODIG, a graph attention network (GAT)-based framework to identify cancer driver genes by combining multi-omics pan-cancer data (mutations, copy number variants, gene expression and methylation levels) with multi-dimensional gene networks. First, we established diverse types of gene relationship maps based on protein-protein interactions, gene sequence similarity, KEGG pathway co-occurrence, gene co-expression patterns and gene ontology. Then, we constructed a multi-dimensional gene network consisting of approximately 20 000 genes as nodes and five types of gene associations as multiplex edges. We applied a GAT to model within-dimension interactions to generate a gene representation for each dimension based on this graph. Moreover, we introduced a joint learning module to fuse multiple dimension-specific representations to generate general gene representations. Finally, we used the obtained gene representation to perform a semi-supervised driver gene identification task. The experiment results show that MODIG outperforms the baseline models in terms of area under precision-recall curves and area under the receiver operating characteristic curves. AVAILABILITY AND IMPLEMENTATION: The MODIG program is available at https://github.com/zjupgx/modig. The code and data underlying this article are also available on Zenodo, at https://doi.org/10.5281/zenodo.7057241. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

High-order orbital angular momentum mode-based phase shift-keying communication using phase difference modulation.

Orbital angular momentum (OAM) mode offers a promising modulation dimension for high-order shift-keying (SK) communication due to its mode orthogonality. However, the expansion of modulation order through superposing OAM modes is constrained by the mode-field mismatch resulting from the rapidly increased divergence with mode orders. Herein, we address this problem by propose a phase-difference modulation strategy that breaks the limitation of modulation orders via introducing a phase-difference degree of freedom (DoF) beyond OAM modes. Phase-difference modulation exploits the sensitivity of mode interference to phase differences, thereby providing distinct tunable parameters. This enables the generation of a series of codable spatial modes with continuous variation within the same superposed OAM modes by manipulating the interference state. Due to the inherent independence between OAM mode and phase-difference DoF, the number of codable modes increases exponentially, which facilitates establishing ultra-high-order phase shift-keying by discretizing the continuous phase difference and establishing a one-to-one mapping between coding symbols and constructed modes. We show that a phase shift-keying communication link with a modulation order of up to 4 × 104 is achieved by employing only 3 OAM modes (+1, + 2 and +3), and the decode accuracy reaches 99.9%. Since the modulation order is exponentially correlated with the OAM modes and phase differences, the order can be greatly improved by further increasing the superimposed OAM modes, which may provide new insight for high-order OAM-based SK communication.

Full-duplex cylindrical vector beam multiplexing communication using spin-dependent phase modulation metasurfaces.

Cylindrical vector beam (CVB) has recently gained attention as a promising carrier for signal multiplexing owing to its mode orthogonality. However, the full-duplex multiplexing communication has not been previously explored for the lack of effective technologies to parallelly couple and separate CVB modes. Herein, we present a full-duplex solution for CVB multiplexing communication that utilizes spin-dependent phase modulation metasurfaces. By independently phase-modulating the two spin eigenstates of CVBs with the metasurface via spin-dependent orbital interactions, and loading two binary Dammann vortex gratings, we enabled an independent and reciprocal wave vector manipulation of CVBs for full-duplex (de)multiplexing operation. To demonstrate this concept, we constructed a 16-channel (including 4 CVB modes and 4 wavelengths) full-duplex CVB multiplexing communication system and achieved the bidirectional transmission of 800 Gbit/s quadrature-phase shift-keying (QPSK) signals over a 5 km few-mode fiber. Our results demonstrate the successful multiplexing and demultiplexing of 2 radial CVB modes and 2 azimuthal CVB modes in full-duplex communication with the bit-error-rates approaching 1.87 × 10-5.

Improving the tumor selectivity of T cell engagers by logic-gated dual tumor-targeting.

Targeting single tumor antigens makes it difficult to provide sufficient tumor selectivity for T cell engagers (TCEs), leading to undesirable toxicity and even treatment failure, which is particularly serious in solid tumors. Here, we designed novel trispecific TCEs (TriTCEs) to improve the tumor selectivity of TCEs by logic-gated dual tumor-targeting. TriTCE can effectively redirect and activate T cells to kill tumor cells (∼18 pM EC50) by inducing the aggregation of dual tumor antigens, which was ∼70- or 750- fold more effective than the single tumor-targeted isotype controls, respectively. Further in vivo experiments indicated that TriTCE has the ability to accumulate in tumor tissue and can induce circulating T cells to infiltrate into tumor sites. Hence, TriTCE showed a stronger tumor growth inhibition ability and significantly prolonged the survival time of the mice. Finally, we revealed that this concept of logic-gated dual tumor-targeted TriTCE can be applied to target different tumor antigens. Cumulatively, we reported novel dual tumor-targeted TriTCEs that can mediate a robust T cell response by simultaneous recognition of dual tumor antigens at the same cell surface. TriTCEs allow better selective T cell activity on tumor cells, resulting in safer TCE treatment.

Regulation of olfactory-based sex behaviors in the silkworm by genes in the sex-determination cascade.

Insect courtship and mating depend on integration of olfactory, visual, and tactile cues. Compared to other insects, Bombyx mori, the domesticated silkworm, has relatively simple sexual behaviors as it cannot fly. Here by using CRISPR/Cas9 and electrophysiological techniques we found that courtship and mating behaviors are regulated in male silk moths by mutating genes in the sex determination cascade belonging to two conserved pathways. Loss of Bmdsx gene expression significantly reduced the peripheral perception of the major pheromone component bombykol by reducing expression of the product of the BmOR1 gene which completely blocked courtship in adult males. Interestingly, we found that mating behavior was regulated independently by another sexual differentiation gene, Bmfru. Loss of Bmfru completely blocked mating, but males displayed normal courtship behavior. Lack of Bmfru expression significantly reduced the perception of the minor pheromone component bombykal due to the down regulation of BmOR3 expression; further, functional analysis revealed that loss of the product of BmOR3 played a key role in terminating male mating behavior. Our results suggest that Bmdsx and Bmfru are at the base of the two primary pathways that regulate olfactory-based sexual behavior.

Orbital angular momentum mode diversity gain in optical communication.

Vortex beams carrying orbital angular momentum (OAM) modes show superior multiplexing abilities in enhancing communication capacity. However, the signal fading induced by turbulence noise severely degrades the communication performance and even leads to communication interruption. Herein, we propose a diversity gain strategy to mitigate signal fading in OAM multiplexing communication and investigate the gain combination and channel assignment to optimize the diversity efficiency and communication capacity. Endowing signals with distinct channel matrices and superposing them with designed channel weights, we perform the diversity gain with an optimal gain efficiency, and the signal fading is mitigated by equalizing the turbulence noise. For the tradeoff between turbulence noise tolerance and communication capacity, multiplexed channels are algorithm-free assigned for diversity and multiplexing according to bit-error-rate and outage probability. As a proof of concept, we demonstrate a 6-channel multiplexing communication, where 3 OAM modes are assigned for diversity gain and 24 Gbit/s QPSK-OFDM signals are transmitted. After diversity gain, the bit-error-rate decreases from 1.41 × 10-2 to 1.63 × 10-4 at -14 dBm, and the outage probability of 86.7% is almost completely suppressed.

Orbital angular momentum deep multiplexing holography via an optical diffractive neural network.

Orbital angular momentum (OAM) mode multiplexing provides a new strategy for reconstructing multiple holograms, which is compatible with other physical dimensions involving wavelength and polarization to enlarge information capacity. Conventional OAM multiplexing holography usually relies on the independence of physical dimensions, and the deep holography involving spatial depth is always limited for the lack of spatiotemporal evolution modulation technologies. Herein, we introduce a depth-controllable imaging technology in OAM deep multiplexing holography via designing a prototype of five-layer optical diffractive neural network (ODNN). Since the optical propagation with dimensional-independent spatiotemporal evolution offers a unique linear modulation to light, it is possible to combine OAM modes with spatial depths to realize OAM deep multiplexing holography. Exploiting the multi-plane light conversion and in-situ optical propagation principles, we simultaneously modulate both the OAM mode and spatial depth of incident light via unitary transformation and linear modulations, where OAM modes are encoded independently for conversions among holograms. Results show that the ODNN realized light field conversion and evolution of five multiplexed OAM modes in deep multiplexing holography, where the mean square error and structural similarity index measure are 0.03 and 86%, respectively. Our demonstration explores a depth-controllable spatiotemporal evolution technology in OAM deep multiplexing holography, which is expected to promote the development of OAM mode-based optical holography and storage.

Adding/dropping polarization multiplexed cylindrical vector beams with local polarization-matched plasmonic metasurface.

Here we propose a polarization-dependent gradient phase modulation strategy and fabricate a local polarization-matched metasurface to add/drop polarization multiplexed cylindrical vector beams (CVBs). The two orthogonal linear polarization states in CVB multiplexing will represent as radial- and azimuthal-polarized CVBs, which means that we must introduce independent wave vectors to them for adding/dropping the polarization channels. By designing the rotation angle and geometric sizes of a meta-atom, a local polarization-matched propagation phase plasmonic metasurface is constructed, and the polarization-dependent gradient phases were loaded to perform this operation. As a proof of concept, the polarization multiplexed CVBs, carrying 150-Gbit/s quadrature phase shift keying signals, are successfully added and dropped, and the bit error rates approach 1 × 10-6. In addition to representing a route for adding/dropping polarization multiplexed CVBs, other functional phase modulation of arbitrary orthogonal linear polarization bases is expected, which might find potential applications in polarization encryption imaging, spatial polarization shaping, etc.

Optimization strategies for expression of a novel bifunctional anti-PD-L1/TGFBR2-ECD fusion protein.

The novel anti-PD-L1/TGFBR2-ECD fusion protein (BR102) comprises an anti-PD-L1 antibody (HS636) which is fused at the C terminus of the heavy chain to a TGF-ß1 receptor Ⅱ ectodomain (TGFBR2-ECD), and which can sequester the PD-1/PD-L1 pathway and TGF-ß bioactivity in the immunosuppressive tumor microenvironment. In the expression of TGFBR2-ECD wild-type fused protein (BR102-WT), a 50 kDa clipped species was confirmed to be induced by proteolytic cleavage at a "QKS" site located in the N-terminus of the ectodomain, which resulted in the formation of IgG-like clipping. The matrix metalloproteinase-9 was determined to be associated with BR102-WT digestion. In addition, it was observed that the N-glycosylation modifications of the fusion protein were tightly involved in regulating proteolytic activity and the levels of cleavage could be significantly suppressed by MMP-inhibitors. To avoid proteolytic degradation, eliminating protease-sensitive amino acid motifs and introducing potential glycosylation were performed. Three sensitive motifs were mutated, and the levels of clipping were strongly restrained. The mutant candidates exhibited similar binding affinities to hPD-L1 and hTGF-ß1 as well as highly purified BR102-WT2. Furthermore, the mutants displayed more significant proteolytic resistance than that of BR102-WT2 in the lysate incubation reaction and the plasma stability test. Moreover, the bifunctional candidate Mu3 showed an additive antitumor effect in MC38/hPD-L1 bearing models as compared to that of with anti-PD-L1 antibody alone. In conclusion, in this study, the protease-sensitive features of BR102-WT were well characterized and efficient optimization was performed. The candidate BR102-Mutants exhibited advanced druggability in drug stability and displayed desirable antitumor activity.

Impact of serum uric acid on subclinical myocardial injury in general population.

BACKGROUND AND AIMS: Hyperuricemia is widely thought as a risk factor for myocardial infarction (MI) and all-cause mortality; however, the relation of serum uric acid (sUA) and subclinical myocardial injury (SCeMI) remains unclear. We hypothesize that sUA is associated with subclinical myocardial injury. METHODS AND RESULTS: A total of 5880 adult individuals (57.9 ± 13.0 years, 54.23% women) without known cardiovascular disease from National Health and Nutrition Examination Survey (NHANES) III were included. Determined by Cardiac Infarction Injury Score (CIIS) from 12-lead electrocardiogram, SCeMI was defined by CIIS ≥10 units. The relationship between sUA and SCeMI was analyzed by using logistic regression models and the smooth curve fitting. Subgroup analyses were conducted. After adjusting for potential confounding variables, the smooth curve fitting revealed a non-linear relationship between sUA level and SCeMI. When sUA was above the inflection point 266.5 µmol/L, each 100 unit increase in sUA increase the risk of SCeMI by 15%. In women group, when sUA>340.3 µmol/L, each 100 unit increase in sUA increase the risk of SCeMI by 71%, but no significant correlation was observed in men group. CONCLUSIONS: Our findings confirm that sUA is an independent risk factor for subclinical myocardial injury after adjusting for potential confounding variables, and existence of such an association in women only, which require more random control trials to confirm the strategy of cardiovascular disease prevention based on sUA reduction in female.