Biological carbon pump estimate based on multidecadal hydrographic data.

The transfer of photosynthetically produced organic carbon from surface to mesopelagic waters draws carbon dioxide from the atmosphere1. However, current observation-based estimates disagree on the strength of this biological carbon pump (BCP)2. Earth system models (ESMs) also exhibit a large spread of BCP estimates, indicating limited representations of the known carbon export pathways3. Here we use several decades of hydrographic observations to produce a top-down estimate of the strength of the BCP with an inverse biogeochemical model that implicitly accounts for all known export pathways. Our estimate of total organic carbon (TOC) export at 73.4 m (model euphotic zone depth) is 15.00 ± 1.12 Pg C year-1, with only two-thirds reaching 100 m depth owing to rapid remineralization of organic matter in the upper water column. Partitioned by sequestration time below the euphotic zone, τ, the globally integrated organic carbon production rate with τ > 3 months is 11.09 ± 1.02 Pg C year-1, dropping to 8.25 ± 0.30 Pg C year-1 for τ > 1 year, with 81% contributed by the non-advective-diffusive vertical flux owing to sinking particles and vertically migrating zooplankton. Nevertheless, export of organic carbon by mixing and other fluid transport of dissolved matter and suspended particles remains regionally important for meeting the respiratory carbon demand. Furthermore, the temperature dependence of the sequestration efficiency inferred from our inversion suggests that future global warming may intensify the recycling of organic matter in the upper ocean, potentially weakening the BCP.

Optimizing multicopy chromosomal integration for stable high-performing strains.

The copy number of genes in chromosomes can be modified by chromosomal integration to construct efficient microbial cell factories but the resulting genetic systems are prone to failure or instability from triggering homologous recombination in repetitive DNA sequences. Finding the optimal copy number of each gene in a pathway is also time and labor intensive. To overcome these challenges, we applied a multiple nonrepetitive coding sequence calculator that generates sets of coding DNA sequence (CDS) variants. A machine learning method was developed to calculate the optimal copy number combination of genes in a pathway. We obtained an engineered Yarrowia lipolytica strain for eicosapentaenoic acid biosynthesis in 6 months, producing the highest titer of 27.5 g l-1 in a 50-liter bioreactor. Moreover, the lycopene production in Escherichia coli was also greatly improved. Importantly, all engineered strains of Y. lipolytica, E. coli and Saccharomyces cerevisiae constructed with nonrepetitive CDSs maintained genetic stability.

DNA-protein cross-links between abasic DNA damage and mitochondrial transcription factor A (TFAM).

In higher eukaryotic cells, mitochondria are essential organelles for energy production, metabolism, and signaling. Mitochondrial DNA (mtDNA) encodes 13 protein subunits for oxidative phosphorylation and a set of tRNAs and rRNAs. mtDNA damage, sourced from endogenous chemicals and environmental factors, contributes to mitochondrial genomic instability, which has been associated with various mitochondrial diseases. DNA-protein cross-links (DPCs) are deleterious DNA lesions that threaten genomic integrity. Although much has been learned about the formation and repair of DPCs in the nucleus, little is known about DPCs in mitochondria. Here, we present in vitro and in cellulo data to demonstrate the formation of DPCs between a prevalent abasic (AP) DNA lesion and a DNA-packaging protein, mitochondrial transcription factor A (TFAM). TFAM cleaves AP-DNA and forms DPCs and single-strand breaks (SSB). Lys residues of TFAM are critical for the formation of TFAM-DPC and a reactive 3'-phospho-α,ß-unsaturated aldehyde (3'pUA) residue on SSB. The 3'pUA residue reacts with two Cys of TFAM and contributes to the stable TFAM-DPC formation. Glutathione reacts with 3'pUA and competes with TFAM-DPC formation, corroborating our cellular experiments showing the accumulation of TFAM-DPCs under limiting glutathione. Our data point to the involvement of TFAM in AP-DNA turnover and fill a knowledge gap regarding the protein factors in processing damaged mtDNA.

Thermal Stability of Skyrmion Tubes in Nanostructured Cuboids.

Magnetic skyrmions in bulk materials are typically regarded as two-dimensional structures. However, they also exhibit three-dimensional configurations, known as skyrmion tubes, that elongate and extend in-depth. Understanding the configurations and stabilization mechanism of skyrmion tubes is crucial for the development of advanced spintronic devices. However, the generation and annihilation of skyrmion tubes in confined geometries are still rarely reported. Here, we present direct imaging of skyrmion tubes in nanostructured cuboids of a chiral magnet FeGe using Lorentz transmission electron microscopy (TEM), while applying an in-plane magnetic field. It is observed that skyrmion tubes stabilize in a narrow field-temperature region near the Curie temperature (Tc). Through a field cooling process, metastable skyrmion tubes can exist in a larger region of the field-temperature diagram. Combining these experimental findings with micromagnetic simulations, we attribute these phenomena to energy differences and thermal fluctuations. Our results could promote topological spintronic devices based on skyrmion tubes.

Freeprotmap: waiting-free prediction method for protein distance map.

BACKGROUND: Protein residue-residue distance maps are used for remote homology detection, protein information estimation, and protein structure research. However, existing prediction approaches are time-consuming, and hundreds of millions of proteins are discovered each year, necessitating the development of a rapid and reliable prediction method for protein residue-residue distances. Moreover, because many proteins lack known homologous sequences, a waiting-free and alignment-free deep learning method is needed. RESULT: In this study, we propose a learning framework named FreeProtMap. In terms of protein representation processing, the proposed group pooling in FreeProtMap effectively mitigates issues arising from high-dimensional sparseness in protein representation. In terms of model structure, we have made several careful designs. Firstly, it is designed based on the locality of protein structures and triangular inequality distance constraints to improve prediction accuracy. Secondly, inference speed is improved by using additive attention and lightweight design. Besides, the generalization ability is improved by using bottlenecks and a neural network block named local microformer. As a result, FreeProtMap can predict protein residue-residue distances in tens of milliseconds and has higher precision than the best structure prediction method. CONCLUSION: Several groups of comparative experiments and ablation experiments verify the effectiveness of the designs. The results demonstrate that FreeProtMap significantly outperforms other state-of-the-art methods in accurate protein residue-residue distance prediction, which is beneficial for lots of protein research works. It is worth mentioning that we could scan all proteins discovered each year based on FreeProtMap to find structurally similar proteins in a short time because the fact that the structure similarity calculation method based on distance maps is much less time-consuming than algorithms based on 3D structures.

Streptomyces albipurpureus sp. nov., a novel actinobacterium with antimicrobial activity isolated from the rhizospheric soil of Fritillaria cirrhosa D. Don.

A novel actinobacterium, designated strain CWNU-1T, was isolated from the rhizospheric soil of Fritillaria cirrhosa D. Don and examined using a polyphasic taxonomic approach. The organism developed pale blue aerial mycelia that was simply branched and terminated in open or closed coils of three or more volutions on International Streptomyces Project 3 agar. Spores were ellipsoidal to cylindrical with wrinkled surfaces. The strain showed high 16S rRNA gene sequence similarity to Streptomyces kurssanovii NBRC 13192T (98.8 %), Streptomyces xantholiticus NBRC 13354T (98.7 %) and Streptomyces peucetius JCM 9920T (98.6 %). The phylogenetic result based on 16S rRNA gene and genome sequences clearly demonstrated that strain CWNU-1T formed an independent phylogenetic lineage. On the basis of orthologous average nucleotide identity, CWNU-1T was most closely related to Streptomyces inusitatus NBRC 13601T with 79.3 % identity. The results of the digital DNA-DNA hybridization analysis also indicated low levels of relatedness with other species, as the highest value was observed with S. inusitatus NBRC 13601T (25.3 %). With reference to phenotypic characteristics, phylogenetic data, orthologous average nucleotide identity and digital DNA-DNA hybridization results, strain CWNU-1T was readily distinguished from its most closely related strains and classified as representing a novel species, for which the name Streptomyces albipurpureus sp. nov. is proposed. The type strain is CWNU-1T (=CGMCC 4.7758T=MCCC 1K07402T=JCM 35391T).

Development and clinical application of loop-mediated isothermal amplification combined with lateral flow assay for rapid diagnosis of SARS-CoV-2.

BACKGROUND: The diagnostic assay leveraging multiple reverse transcription loop-mediated isothermal amplification (RT-LAMP) could meet the requirements for rapid nucleic acid detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). METHODS: The devised assay merged the lateral flow assay with the RT-LAMP technology and designed specific primers for the simultaneous detection of the target and human-derived internal reference genes within a single reaction. An inquiry into the assay's limit of detection (LOD), sensitivity, and specificity was carried out. The effectiveness of this assay was validated using 498 clinical specimens. RESULTS: This LOD of the assay was determined to be 500 copies/mL, and there was no observed cross-reaction with other respiratory pathogens. The detection results derived from clinical specimens showed substantial concordance with those from real-time reverse transcription-polymerase chain reaction (RT-qPCR) (Cohen's kappa, 0.876; 95% CI: 0.833-0.919; p<0.005). The diagnostic sensitivity and specificity were 87.1% and 100%, respectively. CONCLUSION: The RT-LAMP assay, paired with a straightforward and disposable lateral immunochromatographic strip, achieves visual detection of dual targets for SARS-CoV-2 immediatly. Moreover, the entire procedure abstains from nucleic acids extraction. The samples are lysed at room temperature and subsequently proceed directly to the RT-LAMP reaction, which can be executed within 30 minutes at a constant temperature of 60-65°C. Then, the RT-LAMP amplification products are visualized using colloidal gold test strips. TRIAL REGISTRATION: This study was registered at the Chinese Clinical Trial Registry (Registration number: ChiCTR2200060495, Date of registration 2022-06-03).

NLRP3 regulates CIITA/MHC II axis and interferon-γ-inducible chemokines in Malassezia globosa-infected keratinocytes.

CIITA, a member of NOD-like receptor (NLR) family, is the major MHC II trans-activator and mediator of Th1 immunity, but its function and interaction with NLRP3 have been little studied. We found activation of NLRP3 inflammasome, increased expression of CIITA, CBP, pSTAT1, STAT1, MHC II, IFN-γ and IFN-γ-inducible chemokines (CCL1 and CXCL8), and colocalisation of NLRP3 with CIITA in Malassezia folliculitis lesions, Malassezia globosa-infected HaCaT cells and mouse skin. CoIP with anti-CIITA or anti-NLRP3 antibody pulled down NLRP3 or both CIITA and ASC. NLRP3 silencing or knockout caused CIITA downexpression and their colocalisation disappearance in HaCaT cells and mouse skin of Nlrp3-/- mice, while CIITA knockdown had no effect on NLRP3, ASC, IL-1ß and IL-18 expression. NLRP3 inflammasome inhibitors and knockdown significantly suppressed IFN-γ, CCL1, CXCL8 and CXCL10 levels in M. globosa-infected HaCaT cells. CCL1 and CXCL8 expression was elevated in Malassezia folliculitis lesions and reduced in Nlrp3-/- mice. These results demonstrate that M. globosa can activate NLRP3 inflammasome, CIITA/MHC II signalling and IFN-γ-inducible chemokines in human keratinocytes and mouse skin. NLRP3 may regulate CIITA by their binding and trigger Th1 immunity by secreting CCL1 and CXCL8/IL-8, contributing to the pathogenesis of Malassezia-associated skin diseases.

GATA3 mediates doxorubicin resistance by inhibiting CYB5R2-catalyzed iron reduction in breast cancer cells.

AIMS: Neoadjuvant chemotherapy (NAC) is the primary preoperative therapy for breast cancer. The luminal subtype of breast cancer shows less NAC response than the basal subtype, with an inefficient NAC treatment effect. Understanding of the molecular and cellular mechanisms responsible for this chemoresistance is an important issue when determining optimal treatment. METHODS: Doxorubicin-induced apoptosis and ferroptosis was investigated using cytotoxicity, western blotting, and flow cytometry assays. The role of GATA3 in modulating doxorubicin-induced cell death was investigated both in vitro and in vivo. RNA-seq, qPCR, ChIP, and luciferase assay and association analyses were performed to investigate the regulation of CYB5R2 by GATA3. The function of GATA3 and CYB5R2 in regulating doxorubicin-induced ferroptosis was evaluated with iron, ROS, and lipid peroxidation detection assays. Immunohistochemistry was performed for results validation. RESULTS: Doxorubicin-induced basal breast cancer cell death is dependent on iron-mediated ferroptosis. Overexpression of the luminal signature transcriptional factor GATA3 mediates doxorubicin resistance. GATA3 promotes cell viability by decreasing ferroptosis-related gene CYB5R2 expression and by maintaining iron homeostasis. Analyzing data from the public and our cohorts demonstrates that GATA3 and CYB5R2 are associated with NAC response. CONCLUSIONS: GATA3 promotes doxorubicin resistance by inhibiting CYB5R2-mediated iron metabolism and ferroptosis. Therefore, patients with breast cancer who display high GATA3 expression do not benefit from doxorubicin-based NAC regimens.

Analytic and heuristic process for prudent antimicrobial use in animals: What are triggers and how do they work?

The over and misuse of antimicrobials in animal agriculture causes a prevailing crisis for humans, animals, and the environment. From the One Health approach perspective, the formation process of adopting prudent antimicrobial use (AMU), once established, can be used to mitigate this crisis. The study aimed to determine the analytic-based and heuristic-based process that evoked prudent AMU among animal farmers by synthesis of stimulus-organism-response framework and dual-system theory and to explore gender differences on risk-benefit trade-offs. A structural equation model was employed to test the proposed hypotheses with field survey data from 1100 small-scale farmers. The results reveal that for the analytic-based process, social influence, antimicrobial-related threats, and self-efficacy are all salient stimuli having indirect effects on intention via the two organisms of perceived risks and perceived benefits. For heuristic-based process, farmers' altruistic value orientations are positively associated with intention. An interesting fact is that threat awareness has two opposite effects on intention, namely, the suppression effect and the enhancement effect. Moreover, the negative effect of perceived risks on intention is greater among female farmers, compared to male counterparts. These findings provide valuable insights for the forming of theory-based intervention strategies to perfect China's national action plan.

Examining the Effect of Entrepreneurial Leadership on Nursing Team Creativity in New Hospitals: A Structural Equation Model.

METHODS: This cross-sectional study sampled 833 nurses from 2 new hospitals in Guizhou Province, China. They completed a questionnaire on entrepreneurial leadership, nursing team creativity, innovation climate, creative self-efficacy, team psychological safety, and knowledge sharing. Data were analyzed using structural equation modeling. RESULTS: Entrepreneurial leadership positively influenced nursing team creativity. Innovation climate, creative self-efficacy, team psychological safety, and knowledge sharing mediated the relationship between entrepreneurial leadership and nursing team creativity in new hospitals. CONCLUSIONS: This study confirmed the significant role of innovation climate, creative self-efficacy, team psychological safety, and knowledge sharing in mediating the relationship between entrepreneurial leadership and nursing team creativity through empirical analysis.

Anomalous Nernst Effect Induced Terahertz Emission in a Single Ferromagnetic Film.

Despite its important role in understanding ultrafast spin dynamics and revealing novel spin/orbit effects, the mechanism of the terahertz (THz) emission from a single ferromagnetic nanofilm upon a femtosecond laser pump still remains elusive. Recent experiments have shown exotic symmetry, which is not expected from the routinely adopted mechanism of ultrafast demagnetization. Here, by developing a bidirectional pump-THz emission spectroscopy and associated symmetry analysis method, we set a benchmark for the experimental distinction of the THz emission induced by various mechanisms. Our results unambiguously unveil a new mechanism─anomalous Nernst effect (ANE) induced THz emission due to the ultrafast temperature gradient created by a femtosecond laser. Quantitative analysis shows that the THz emission exhibits interesting thickness dependence where different mechanisms dominate at different thickness ranges. Our work not only clarifies the origin of the ferromagnetic-based THz emission but also offers a fertile platform for investigating the ultrafast optomagnetism and THz spintronics.

An automated method for assessing condyle head changes in patients with skeletal class II malocclusion based on Cone-beam CT images.

OBJECTIVES: Currently, there is no reliable automated measurement method to study the changes in the condylar process after orthognathic surgery. Therefore, this study proposes an automated method to measure condylar changes in patients with skeletal class II malocclusion following surgical-orthodontic treatment. METHODS: Cone-beam CT (CBCT) scans from 48 patients were segmented using the nnU-Net network for automated maxillary and mandibular delineation. Regions unaffected by orthognathic surgery were selectively cropped. Automated registration yielded condylar displacement and volume calculations, each repeated three times for precision. Logistic regression and linear regression were used to analyse the correlation between condylar position changes at different time points. RESULTS: The Dice score for the automated segmentation of the condyle was 0.971. The intraclass correlation coefficients (ICCs) for all repeated measurements ranged from 0.93 to 1.00. The results of the automated measurement showed that 83.33% of patients exhibited condylar resorption occurring six months or more after surgery. Logistic regression and linear regression indicated a positive correlation between counterclockwise rotation in the pitch plane and condylar resorption (P < .01). And a positive correlation between the rotational angles in both three planes and changes in the condylar volume at six months after surgery (P ≤ .04). CONCLUSIONS: This study's automated method for measuring condylar changes shows excellent repeatability. Skeletal class II malocclusion patients may experience condylar resorption after bimaxillary orthognathic surgery, and this is correlated with counterclockwise rotation in the sagittal plane. ADVANCES IN KNOWLEDGE: This study proposes an innovative multi-step registration method based on CBCT, and establishes an automated approach for quantitatively measuring condyle changes post-orthognathic surgery. This method opens up new possibilities for studying condylar morphology.

[Pseudo-targeted metabolomics for differential components of Rhei Radix et Rhizoma from three plant species].

Rhei Radix et Rhizoma is common traditional Chinese medicine with multiple original plants. The content and proportion of the active components in Rhei Radix et Rhizoma from different plant species were compared to accurately evaluate the medicine qua-lity and provide a theoretical basis for precise use of this medicine in clinical practice. In this study, fresh Rhei Radix et Rhizoma samples were collected from the four-year-old plants of Rheum palmatum, R. tanguticum, and R. officinale. The relative content of 220 anthraquinones, anthrones, and tannins in the samples were determined by pseudo-targeted metabolomics, and the differential components were screened by multivariate statistical methods. The principal component analysis classified the samples into three clusters according to the original plants. The orthogonal partial least squares-discriminant analysis(OPLS-DA) screened out 117 differential components, including 8 free anthraquinones, 18 anthraquinone glycosides, 80 anthrones, and 11 tannins. Twenty-eight components had the highest content in R. tanguticum, mainly including sennosides, anthraquinone glycosides, and procyanidins. Thirty-five components showed the highest content in R. officinale, mainly including free anthraquinones and catechines. Fifty-four components showed the highest content in R. palmatum, mainly including dianthrones, while the structures of most of them cannot be determined temporarily. The content distribution of differential components in the three original plants indicates that R. tanguticum has the strongest effect of purging, while R. officinale has the strongest effect of clearing heat and purging fire, and both have stronger effects of resolvong stasis and dredging meridians than R. palmatum.

[Identification and expression analysis of whole gene family of Isatis indigotica 4-coumarate: CoA ligase].

The 4-coumarate: CoA ligase(4CL) is a key enzyme in the upstream pathway of phenylpropanoids such as flavonoids, soluble phenolic esters, lignans, and lignins in plants. In this study, 13 4CL family members of Arabidopsis thaliana were used as reference sequences to identify the 4CL gene family candidate members of Isatis indigotica from the reported I. indigotica genome. Further bioinformatics analysis and analysis of the expression pattern of 4CL genes and the accumulation pattern of flavonoids were carried out. Thirteen 4CL genes were obtained, named Ii4CL1-Ii4CL13, which were distributed on chromosomes 1, 2, 3, 4, and 6. The analysis of the gene structure and conserved structural domains revealed the intron number of I. indigotica 4CL genes was between 1 and 12 and the protein structural domains were highly conserved. Cis-acting element analysis showed that there were multiple response elements in the promoter sequence of I. indigotica 4CL gene family, and jasmonic acid had the largest number of reaction elements. The collinearity analysis showed that there was a close relationship between the 4CL gene family members of I. indigotica and A. thaliana. As revealed by qPCR results, the expression analysis of the 4CL gene family showed that 10 4CL genes had higher expression levels in the aboveground part of I. indigotica. The content assay of flavonoids in different parts of I. indigotica showed that flavonoids were mainly accumulated in the aboveground part of plants. This study provides a basis for further investigating the roles of the 4CL gene family involved in the biosynthesis of flavonoids in I. indigotica.

Two-Orders-of-Magnitude Enhancement of Photoinitiation Activity via a Simple Surface Engineering of Metal Nanoclusters.

Development of high-performance photoinitiator is the key to enhance the printing speed, structure resolution and product quality in 3D laser printing. Here, to improve the printing efficiency of 3D laser nanoprinting, we investigate the underlying photochemistry of gold and silver nanocluster initiators under multiphoton laser excitation. Experimental results and DFT calculations reveal the high cleavage probability of the surface S-C bonds in gold and silver nanoclusters which generate multiple radicals. Based on this understanding, we design several alkyl-thiolated gold nanoclusters and achieve a more than two-orders-of-magnitude enhancement of photoinitiation activity, as well as a significant improvement in printing resolution and fabrication window. Overall, this work for the first time unveils the detailed radical formation pathways of gold and silver nanoclusters under multiphoton activation and substantially improves their photoinitiation sensitivity via surface engineering, which pushes the limit of the printing efficiency of 3D laser lithography.

Anomalous Structural Transformation of Cu(I) Clusters into Multifunctional CuAg Nanoclusters.

We report an anomalous structural transformation of a Cu(I) cluster into two different types of copper-silver (CuAg) alloy nanoclusters. Different from previous reports, we demonstrate that under specifically designed reaction conditions, the Ag-doping could induce a substantial growth of the starting Cu15 and a Ag13Cu20 nanocluster was obtained via the unexpected insertion of an Ag13 kernel inside the Cu(I)-S shell. Ag13Cu20 demonstrates high activity to initiate the photopolymerization of previously hard-to-print inorganic polymers in 3D laser microprinting. Interestingly, a slight modification of the reaction condition leads to the formation of another Ag18-xCuxS (8≤x) nanocluster templated by a central S2- anion, which possesses a unique electronic structure compared to conventional template-free CuAg nanoclusters. Overall, this work unveils the intriguing doping chemistry of Cu clusters, as well as their capability to create different types of alloy nanoclusters with previously unobtainable structures and multifunctionality.

CrMP-Sol database: classification, bioinformatic analyses and comparison of cancer-related membrane proteins and their water-soluble variant designs.

Membrane proteins are critical mediators for tumor progression and present enormous therapeutic potentials. Although gene profiling can identify their cancer-specific signatures, systematic correlations between protein functions and tumor-related mechanisms are still unclear. We present here the CrMP-Sol database ( https://bio-gateway.aigene.org.cn/g/CrMP ), which aims to breach the gap between the two. Machine learning was used to extract key functional descriptions for protein visualization in the 3D-space, where spatial distributions provide function-based predictive connections between proteins and cancer types. CrMP-Sol also presents QTY-enabled water-soluble designs to facilitate native membrane protein studies despite natural hydrophobicity. Five examples with varying transmembrane helices in different categories were used to demonstrate the feasibility. Native and redesigned proteins exhibited highly similar characteristics, predicted structures and binding pockets, and slightly different docking poses against known ligands, although task-specific designs are still required for proteins more susceptible to internal hydrogen bond formations. The database can accelerate therapeutic developments and biotechnological applications of cancer-related membrane proteins.

A Droplet Method for Synthesis of Multiclass Ultrathin Metal Halides.

2D metal halides have attracted increasing research attention in recent years; however, it is still challenging to synthesize them via liquid-phase methods. Here it is demonstrated that a droplet method is simple and efficient for the synthesis of multiclass 2D metal halides, including trivalent (BiI3 , SbI3 ), divalent (SnI2 , GeI2 ), and monovalent (CuI) ones. In particular, 2D SbI3 is first experimentally achieved, of which the thinnest thickness is ≈6 nm. The nucleation and growth of these metal halide nanosheets are mainly determined by the supersaturation of precursor solutions that are dynamically varying during the solution evaporation. After solution drying, the nanosheets can fall on the surface of many different substrates, which further enables the feasible fabrication of related heterostructures and devices. With SbI3 /WSe2 being a good demonstration, the photoluminescence intensity and photo responsivity of WSe2 is obviously enhanced after interfacing with SbI3 . The work opens a new pathway for 2D metal halides toward widespread investigation and applications.

Prediction of biochemical nonresolution in patients with chronic drug-induced liver injury: A large multicenter study.

BACKGROUND AND AIMS: To clarify high-risk factors and develop a nomogram model to predict biochemical resolution or biochemical nonresolution (BNR) in patients with chronic DILI. APPROACH AND RESULTS: Retrospectively, 3655 of 5326 patients with chronic DILI were enrolled from nine participating hospitals, of whom 2866 underwent liver biopsy. All of these patients were followed up for over 1 year and their clinical characteristics were retrieved from electronic medical records. The endpoint was BNR, defined as alanine aminotransferase or aspartate aminotransferase >1.5× upper limit of normal or alkaline phosphatase >1.1× ULN, at 12 months from chronic DILI diagnosis. The noninvasive high-risk factors for BNR identified by multivariable logistic regression were used to establish a nomogram, which was validated in an independent external cohort. Finally, 19.3% (707 of 3655) patients presented with BNR. Histologically, with the increase in liver inflammation grades and fibrosis stages, the proportion of BNR significantly increased. The risk of BNR was increased by 21.3-fold in patients with significant inflammation compared to none or mild inflammation (p < 0.001). Biochemically, aspartate aminotransferase and total bilirubin, platelets, prothrombin time, sex, and age were associated with BNR and incorporated to construct a nomogram model (BNR-6) with a concordance index of 0.824 (95% CI, 0.798-0.849), which was highly consistent with liver histology. These results were successfully validated both in the internal cohort and external cohort. CONCLUSIONS: Significant liver inflammation is a robust predictor associated with biochemical nonresolution. The established BNR-6 model provides an easy-to-use approach to assess the outcome of chronic DILI.