Provincial-scale assessment of vulnerability and resilience to drought in China.

Frequent droughts have caused severe disaster losses in China. Such events can be minimized by enhancing the country's resilience and reducing its vulnerability, where this can ensure socioeconomic stability and sustainable development. Evaluating the vulnerability and resilience to drought is thus crucial for effectively managing the risk of disasters and promoting sustainable socioeconomic development. In this study, we constructed a comprehensive framework to assess the spatiotemporal characteristics of China's vulnerability and resilience to drought at the provincial scale from an input-output perspective by using the Super-efficiency Data Envelopment Analysis (DEA) model and the Super-efficiency Slacks-Based Measure DEA (SBM-DEA) model. This study focused on drought drivers, the disaster-forming environment, drought bearers, disaster intensity, and recovery. The results showed that the vulnerability to drought of 42 % of China's provinces decreased from 2010 to 2022, that of only 29 % of the provinces increased, while the status of a majority of provinces improved in general. The center of gravity of the vulnerability to drought moved toward the southwest over time and a spatial clustering of vulnerability was observed, with High-High clusters moving from the north to the south. Moreover, the resilience to drought declined in 36 % of provinces and increased in only 20 %, reflecting poor resilience overall. The center of gravity of China's overall resilience to drought moved northward, with a relatively stable spatial pattern and prominent clusters of Low-Low resilience indicating a pressing need for improvement. Areas with high vulnerability and low resilience were concentrated in inland western and eastern regions, and this highlights the importance of drought prevention and mitigation in provinces like Xinjiang, Inner Mongolia, Jiangxi, and Fujian. The findings here provide valuable insights for mitigating the risk of drought and promoting sustainable socioeconomic development.

Fungal Plasma Membrane H+-ATPase: Structure, Mechanism, and Drug Discovery.

The fungal plasma membrane H+-ATPase (Pma1) pumps protons out of the cell to maintain the transmembrane electrochemical gradient and membrane potential. As an essential P-type ATPase uniquely found in fungi and plants, Pma1 is an attractive antifungal drug target. Two recent Cryo-EM studies on Pma1 have revealed its hexameric architecture, autoinhibitory and activation mechanisms, and proton transport mechanism. These structures provide new perspectives for the development of antifungal drugs targeting Pma1. In this article, we review the history of Pma1 structure determination, the latest structural insights into Pma1, and drug discoveries targeting Pma1.

A rapid interactive chitosan-based medium with antioxidant and pro-vascularization properties for infected burn wound healing.

Large-pore hydrogels are better suited to meet the management needs of nutrient transportation and gas exchange between infected burn wounds and normal tissues. However, better construction strategies are required to balance the pore size and mechanical strength of hydrogels to construct a faster substance/gas interaction medium between tissues. Herein, we developed spongy large pore size hydrogel (CS-TA@Lys) with good mechanical properties using a simple ice crystal-assisted method based on chitosan (CS), incorporating tannic acid (TA) and ε-polylysine (Lys). A large-pore and mechanically robust hydrogel medium was constructed based on hydrogen bonding between CS molecules. On this basis, a pro-restorative functional platform with antioxidation and pro-vascularization was constructed using TA and Lys. In vitro experiments displayed that the CS-TA@Lys hydrogel possessed favorable mechanical properties and fast interaction performances. In addition, the CS-TA@Lys hydrogel possessed the capacity to remove intra/extracellular reactive oxygen species (ROS) and possessed antimicrobial and pro-angiogenic properties. In vivo experiments displayed that the CS-TA@Lys hydrogel inhibited wound inflammation and promoted wound vascularization. In addition, the CS-TA@Lys hydrogel showed the potential for rapid hemostasis. This study provides a potential functional wound dressing with rapid interaction properties for skin wound repair.

Whitening of brown adipose tissue inhibits osteogenic differentiation via secretion of S100A8/A9.

The mechanism by which brown adipose tissue (BAT) regulates bone metabolism is unclear. Here, we reveal that BAT secretes S100A8/A9, a previously unidentified BAT adipokine (batokine), to impair bone formation. Brown adipocytes-specific knockout of Rheb (RhebBAD KO), the upstream activator of mTOR, causes BAT malfunction to inhibit osteogenesis. Rheb depletion induces NF-κB dependent S100A8/A9 secretion from brown adipocytes, but not from macrophages. In wild-type mice, age-related Rheb downregulation in BAT is associated with enhanced S100A8/A9 secretion. Either batokines from RhebBAD KO mice, or recombinant S100A8/A9, inhibits osteoblast differentiation of mesenchymal stem cells in vitro by targeting toll-like receptor 4 on their surfaces. Conversely, S100A8/A9 neutralization not only rescues the osteogenesis repressed in the RhebBAD KO mice, but also alleviates age-related osteoporosis in wild-type mice. Collectively, our data revealed an unexpected BAT-bone crosstalk driven by Rheb-S100A8/A9, uncovering S100A8/A9 as a promising target for the treatment, and potentially, prevention of osteoporosis.

Structure of a fungal 1,3-ß-glucan synthase.

1,3-ß-Glucan serves as the primary component of the fungal cell wall and is produced by 1,3-ß-glucan synthase located in the plasma membrane. This synthase is a molecular target for antifungal drugs such as echinocandins and the triterpenoid ibrexafungerp. In this study, we present the cryo-electron microscopy structure of Saccharomyces cerevisiae 1,3-ß-glucan synthase (Fks1) at 2.47-Å resolution. The structure reveals a central catalytic region adopting a cellulose synthase fold with a cytosolic conserved GT-A-type glycosyltransferase domain and a closed transmembrane channel responsible for glucan transportation. Two extracellular disulfide bonds are found to be crucial for Fks1 enzymatic activity. Through structural comparative analysis with cellulose synthases and structure-guided mutagenesis studies, we gain previously unknown insights into the molecular mechanisms of fungal 1,3-ß-glucan synthase.

The Regulation of Exosome Generation and Function in Physiological and Pathological Processes.

Exosomes, a type of extracellular vesicle with a diameter of approximately 100 nm that is secreted by all cells, regulate the phenotype and function of recipient cells by carrying molecules such as proteins, nucleic acids, and lipids and are important mediators of intercellular communication. Exosomes are involved in various physiological and pathological processes such as immunomodulation, angiogenesis, tumorigenesis, metastasis, and chemoresistance. Due to their excellent properties, exosomes have shown their potential application in the clinical diagnosis and treatment of disease. The functions of exosomes depend on their biogenesis, uptake, and composition. Thus, a deeper understanding of these processes and regulatory mechanisms can help to find new targets for disease diagnosis and therapy. Therefore, this review summarizes and integrates the recent advances in the regulatory mechanisms of the entire biological process of exosomes, starting from the formation of early-sorting endosomes (ESCs) by plasma membrane invagination to the release of exosomes by fusion of multivesicular bodies (MVBs) with the plasma membrane, as well as the regulatory process of the interactions between exosomes and recipient cells. We also describe and discuss the regulatory mechanisms of exosome production in tumor cells and the potential of exosomes used in cancer diagnosis and therapy.

Structure and activation mechanism of the hexameric plasma membrane H+-ATPase.

The S. cerevisiae plasma membrane H+-ATPase, Pma1, is a P3A-type ATPase and the primary protein component of the membrane compartment of Pma1 (MCP). Like other plasma membrane H+-ATPases, Pma1 assembles and functions as a hexamer, a property unique to this subfamily among the larger family of P-type ATPases. It has been unclear how Pma1 organizes the yeast membrane into MCP microdomains, or why it is that Pma1 needs to assemble into a hexamer to establish the membrane electrochemical proton gradient. Here we report a high-resolution cryo-EM study of native Pma1 hexamers embedded in endogenous lipids. Remarkably, we found that the Pma1 hexamer encircles a liquid-crystalline membrane domain composed of 57 ordered lipid molecules. The Pma1-encircled lipid patch structure likely serves as the building block of the MCP. At pH 7.4, the carboxyl-terminal regulatory α-helix binds to the phosphorylation domains of two neighboring Pma1 subunits, locking the hexamer in the autoinhibited state. The regulatory helix becomes disordered at lower pH, leading to activation of the Pma1 hexamer. The activation process is accompanied by a 6.7 Å downward shift and a 40° rotation of transmembrane helices 1 and 2 that line the proton translocation path. The conformational changes have enabled us to propose a detailed mechanism for ATP-hydrolysis-driven proton pumping across the plasma membrane. Our structures will facilitate the development of antifungal drugs that target this essential protein.

Identification of a Novel Epithelial-Mesenchymal Transition Gene Signature Predicting Survival in Patients With HNSCC.

Head and neck squamous cell cancer (HNSCC) is one of the most common types of cancer worldwide. There have been many reports suggesting that biomarkers explored via database mining plays a critical role in predicting HNSCC prognosis. However, a single biomarker for prognostic analysis is not adequate. Additionally, there is growing evidence indicating that gene signature could be a better choice for HNSCC prognosis. We performed a comprehensive analysis of mRNA expression profiles using clinical information of HNSCC patients from The Cancer Genome Atlas (TCGA). Gene Set Enrichment Analysis (GSEA) was performed, and we found that a set of genes involved in epithelial mesenchymal transition (EMT) contributed to HNSCC. Cox proportional regression model was used to identify a four-gene (WIPF1, PPIB, BASP1, PLOD2) signature that were significantly associated with overall survival (OS), and all the four genes were significantly upregulated in tumor tissues. We successfully classified the patients with HNSCC into high-risk and low-risk groups, where in high-risk indicated poorer patient prognosis, indicating that this gene signature might be a novel potential biomarker for the prognosis of HNSCC. The prognostic ability of the gene signature was further validated in an independent cohort from the Gene Expression Omnibus (GEO) database. In conclusion, we identified a four-EMT-based gene signature which provides the potentiality to serve as novel independent biomarkers for predicting survival in HNSCC patients, as well as a new possibility for individualized treatment of HNSCC.

Iron oxides decorated graphene oxide/chitosan composite beads for enhanced Cr(VI) removal from aqueous solution.

This study is the first to evaluate the effects of Iron oxides (FeOx) species and their decoration on graphene oxide/chitosan (GO/CS) composites for Cr(VI) removal and the possibility of Fe secondary pollution. Results show that Fe(III) is a better decoration material than Fe(II) and decoration through immersion-evaporation shows a higher adsorption capacity of Cr(VI) (Qe) than co-precipitation. Fe2O3-GO/CS as the only eco-friendly composite for enhanced Cr(VI) removal is further used for batch adsorption experiments, characterization, kinetics, isotherms, and thermodynamic studies. It is found that Cr(VI) removal mainly includes electrostatic attraction between Cr(VI) oxyanions and surface -NH3+ and -OH2+, and the adsorbed Cr(VI) partially reduces to Cr(III). Qe increases with the increasing initial Cr(VI) concentration, contact time, and temperature, while decreases with the increasing pH and mass and volume ratio (m/v). The coexisting ions (Cl-, NO3-, SO42-, PO43-, As, Fe, and Pb) can cause an obvious decrease of Qe. The removal efficiency (Re) and Qe are 94.3% and 83.8 mg/g, respectively under the optimal conditions. After five times of regeneration, Re is still as high as 84% and Qe drops about 2.6%. Cr(VI) adsorption is spontaneous and endothermic, which is best fitted with the Sips model, and the fitted maximum Qe is 131.33 mg/g.

A quantitative proteomics analysis for small molecule Stemazole's effect on human neural stem cells.

BACKGROUND: Stemazole is a novel small molecule that has been suggested to have the ability to protect multiple stem cells. The proliferation-promoting activity and promising neuroprotective effects of stemazole make it a prospective drug for neurodegenerative disease treatment. METHODS: Since previous studies have shown that it protective effect in extreme conditions, to understand more aspects of stemazole, in this study, a systematic tandem mass tags (TMT)-labelled proteomics approach was used to address the whole proteome expression profile with or without stemazole in normal conditions instead of extreme conditions. Bioinformatics analyses, including Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment and protein-protein interaction (PPI) network analyses, were employed. RESULTS: The effect of stemazole on the expression profiles of neural stem cells was obtained. A total of 408 proteins with changes at the abundance level of two groups were identified: 178 proteins increase in abundance and 240 proteins decrease in abundance, respectively. Low abundance of some mitochondrial respiratory chain enzyme, overproduction of reactive oxygen species (ROS) and reduction of mitochondrial membrane potential may indicate stemazole has cytotoxicity. CONCLUSIONS: It is the first proteomics research about stemazole, and the possible cytotoxicity of stemazole has been reported for the first time. The information about proteins that were affected by stemazole and more characteristics of stemazole will help obtain a complete picture of this small molecule drug. These findings provide a scientific basis for further stemazole treatment research.

[Adsorption of As(â ¢) in Water by Iron-loaded Graphene Oxide-Chitosan].

Based on the principle of self-assembly, graphene oxide, chitosan, and FeCl3·6H2O were mixed to prepare graphene oxide-chitosan coated iron-composite particles (Fe@ GOCS). Batch static experiments were carried out to investigate the kinetic and thermodynamic characteristics of As(Ⅲ) adsorption, and to identify the adsorption mechanism. Results showed that the iron on the GOCS was mainly in the form of α-FeO(OH). The As(Ⅲ) adsorption capacity increased with decreasing pH, and the highest adsorption capacity occurred at pH 3. After approximately 45 h, As(Ⅲ) adsorption reached equilibrium under the conditions of pH 3 and a temperature of 298.15, 308.15, and 318.15 K. The maximum adsorption capacity was 289.4 mg·g-1 for an optimal dosage of adsorbents of 1.0 g·L-1. After five times of repeated adsorption-desorption, the adsorption capacity increased slightly. The thermodynamic parameters showed that ΔGθ<0, ΔSθ > 0, and ΔHθ>0, thus indicating that As(Ⅲ) adsorption on Fe@GOCS was a spontaneous, endothermic, and entropy-increasing reaction, and that a higher temperature was more favorable for As(Ⅲ) adsorption. The pseudo-second-order model provided a good fit of the As(Ⅲ) adsorption kinetics for Fe@GOCS. Compared to the Langmuir isotherm, As(Ⅲ) adsorption experimental data fitted better to the Freundlich and Sips models. In combination with the characterization results, it was found that ion exchange and surface complexation were the main mechanisms of As(Ⅲ) removal from aqueous solution using Fe@GOCS.

Study on the relationship between PM2.5 concentration and intensive land use in Hebei Province based on a spatial regression model.

Based on 0.01°×0.01° grid data of PM2.5 annual concentration and statistical yearbook data for 11 cities in Hebei Province from 2000 to 2015, the temporal and spatial distribution characteristics of PM2.5 in the study area are analysed, the level of intensive land use in the area is evaluated, and decoupling theory and spatial regression are used to discuss the relationship between PM2.5 concentration and intensive land use and the influence of intensive land use variables on PM2.5 in Hebei Province. The results show that 1. In terms of time, the concentration of PM2.5 in Hebei Province showed an overall upward trend from 2000 to 2015, with the highest in winter and the lowest in summer. The daily variations show double peaks at 8:00-10:00 and 21:00-0:00 and a single valley at 16:00-18:00. 2. In terms of space, the concentration of PM2.5 in Hebei Province is high in the southeast and low in the northwest, and the pollution spillover initially decreases and then increases. 3. In the past 16 years, the level of intensive land use in Hebei Province has increased annually, but blind expansion still exists. 4. Decoupling theory and the spatial lag model show that land use intensity, land input level and land use structure are positively correlated with PM2.5 concentration, land output benefit is negatively correlated with PM2.5 concentration, and PM2.5 concentration and land intensive use level have not yet been decoupled; thus, the relationship is not harmonious. This research can provide a scientific basis for reducing air pollution and promoting the development of urban land resources for intensive and sustainable development.

Highly efficient removal of As(III) from aqueous solutions using goethite/graphene oxide/chitosan nanocomposite.

A goethite/graphene oxide/chitosan (α-FeO(OH)/GO/CS) nanocomposite adsorbent was prepared and firstly used to remove As(III) from aqueous solution. The composite was characterized by FTIR, XPS, XRD, and EDS techniques. Batch experiments were conducted to investigate the effects of several factors (initial concentration, pH, m/v, contact time, co-existing ions, and temperature) on As(III) adsorption and to evaluate adsorption kinetic, equilibrium isotherm, and thermodynamics. Results showed that As(III) adsorption increased with the increasing initial concentration, contact time, and temperature, but decreased with the increasing m/v and co-existing ions concentrations of SO42-, PO43- and Fe3+. As(III) adsorption remained high at a wide pH range of 3-10. The adsorption was well fitted to a pseudo-second-order kinetic model and was endothermic and spontaneous. The best fit of As(III) adsorption with the Freundlich and Sips models indicated that it was monolayer adsorption, and the maximum adsorption capacity was 289.42 mg/g. As(III) removal was related to -NHCO-, CO, OH, and FeO groups, but the complexation between As(III) ions and hydroxyl iron oxide was the major contributor. After the fifth desorption, the removal efficiency was still as high as 79.6%, indicating excellent reusability. Thus, this composite had great potential for removing As(III) from aqueous solutions.

[Characteristics and Influencing Factors of Monothioarsenate Adsorption on Goethite].

The adsorption kinetic of monothioarsenate (MTA) on goethite was characterized in this study, and batch experiments were then designed to further explore the effects of arsenate, arsenite, humic acid (HA), nitrate, and phosphate on the adsorption of MTA on goethite, and to identify the adsorption mechanism. The results showed that:① When a single arsenic species was present in a solution, the adsorption equilibrium times of MTA, arsenate, and arsenite on goethite were 8, 2, and 4 h, respectively. The adsorption experimental data of these three arsenic species were well fitted to a pseudo-second-order kinetic model. The equilibrium adsorption capacities (qe) of MTA, arsenate, and arsenite on goethite were 2129.851, 3291.838, and 1788.767 mg·kg-1, respectively. When MTA coexisted with arsenate or arsenite in a solution, MTA adsorption on goethite continued to be well fitted to a pseudo-second-order kinetic model. The value of qe for MTA was significantly reduced to 1236.941 mg·kg-1 when MTA coexisted with arsenate, and to 1532.287 mg·kg-1 when MTA coexisted with arsenite, due to the fact that arsenate and arsenite competed for adsorption sites with MTA. ② With an increase in HA concentration (10-50 mg·L-1), the qe of MTA decreased gradually, due to the fact that a large number of functional groups in HA preempted the surface adsorption sites of goethite with MTA. ③ When phosphate was added into the MTA solution, the qe values of MTA, arsenate, and arsenite on goethite were reduced greatly, to 492.802, 815.782, and 303.714 mg·kg-1, respectively, which was caused by the competitive adsorption of P and As. When nitrate was added into the MTA solution, the number of electron receptors and Eh of the solution increased, leading to the qe values of MTA, arsenate, and arsenite on goethite increasing to 2211.030, 3444.023, and 1835.537 mg·kg-1, respectively.

Uncovering the Pharmacological Mechanism of Stemazole in the Treatment of Neurodegenerative Diseases Based on a Network Pharmacology Approach.

Stemazole exerts potent pharmacological effects against neurodegenerative diseases and protective effects in stem cells. However, on the basis of the current understanding, the molecular mechanisms underlying the effects of stemazole in the treatment of Alzheimer's disease and Parkinson's disease have not been fully elucidated. In this study, a network pharmacology-based strategy integrating target prediction, network construction, gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses, and molecular docking was adopted to predict the targets of stemazole relevant to the treatment of neurodegenerative diseases and to further explore the involved pharmacological mechanisms. The majority of the predicted targets were highly involved in the mitogen-activated protein kinase (MAPK) signaling pathway. RAC-alpha serine/threonine-protein kinase (AKT1), caspase-3 (CASP3), caspase-8 (CASP8), mitogen-activated protein kinase 8 (MAPK8), and mitogen-activated protein kinase 14 (MAPK14) are the core targets regulated by stemazole and play a central role in its anti-apoptosis effects. This work provides a scientific basis for further elucidating the mechanism underlying the effects of stemazole in the treatment of neurodegenerative diseases.

Pharmacokinetics and absolute oral bioavailability of stemazole by UPLC-MS/MS and its bio-distribution through tritium labeling.

The small molecule, stemazole, has significant therapeutic effects on neurodegenerative diseases, such as Alzheimer's disease (AD), due to its neuroprotective effects and remarkable survival-promoting activity in stem cells. However, pharmacokinetic properties of stemazole were unclear. In this study, a rapid and effective ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was developed to detect stemazole. The detector was operated in the positive-ion mode with an electrospray ionization (ESI) interface in multiple reaction monitoring (MRM) mode. Chromatographic separation was performed on an Acquity UPLC® BEH C18 column with gradient elution. Stemazole was extracted from plasma following a one-step protein precipitation method. The method was fully validated for its selectivity, specificity, and sensitivity. The calibration curve range of 5-1125 ng/mL showed good linearity for stemazole. Intra-day and inter-day precision rates were less than 10%, and accuracy ranged from 95.87% to 105.23%. The pharmacokinetic profiles were illustrated through the newly developed method for the first time. The absolute oral bioavailability of stemazole is 32.10%. Therefore, it is feasible as an oral medication, which greatly facilitates its broad application. The biological distribution of tritium-labeled stemazole in mice was studied, and the results showed that stemazole was absorbed rapidly and distributed widely, mainly in the liver and kidneys. A specific amount was also detected in the brain, which provides a prerequisite for the use of stemazole to treat neurodegenerative diseases. This work represents first description of the pharmacokinetics, bioavailability, and tissue distribution of stemazole and will lay the foundation for further investigation and drug development.

[Characteristics and Mechanism of Monothioarsenate Adsorption on Sand, Sediment, and Goethite].

Batch experiments were conducted to investigate the adsorption characteristics and mechanism of monothioarsenate (MTA) (>99%) on sand, soil sediment, and goethite under different pH and solid-liquid ratio conditions. Results showed the following. ① When MTA ranged from 0.14 to 23.59, 0.19 to 41.27, and 0.27 to 32.02 mg·L-1 in solutions, its maximum equilibrium adsorption capacity (Qm) in sand, soil sediment, and goethite was 21.54, 277.98, and 2607.42 mg·kg-1, respectively. After its adsorption reached equilibrium, a small amount of the MTA in the solutions transformed into arsenite and arsenate. ② As pH increased from 4 to 10, the equilibrium adsorption capacity (Qe) of MTA on sand decreased gradually, whereas Qe first decreased and then increased for soil sediment and goethite. As the solid-liquid ratio increased, the Qe of MTA in the three media gradually decreased. ③ X-ray powder diffraction (XRD), scanning electron microscope (SEM), and BET results further showed that the major factors controlling MTA adsorption on the three media included the low pore volume of sand, the high degree of crystallization of the soil sediment, and the large number of hydroxyl functional groups (-OH) on goethite.

Correction to: Efficient derivation of extended pluripotent stem cells from NOD-scid Il2rg-/- mice.

In the original publication Fig. 1D and supplementary material is incorrect. The correct figure and supplementary material is provided in this correction.

Efficient derivation of extended pluripotent stem cells from NOD-scid Il2rg-/- mice.

Recently we have established a new culture condition enabling the derivation of extended pluripotent stem (EPS) cells, which, compared to conventional pluripotent stem cells, possess superior developmental potential and germline competence. However, it remains unclear whether this condition permits derivation of EPS cells from mouse strains that are refractory or non-permissive to pluripotent cell establishment. Here, we show that EPS cells can be robustly generated from non-permissive NOD-scid Il2rg-/- mice through de novo derivation from blastocysts. Furthermore, these cells can also be efficiently generated by chemical reprogramming from embryonic NOD-scid Il2rg-/- fibroblasts. NOD-scid Il2rg-/- EPS cells can be expanded for more than 20 passages with genomic stability and can be genetically modified through gene targeting. Notably, these cells contribute to both embryonic and extraembryonic lineages in vivo. More importantly, they can produce chimeras and integrate into the E13.5 genital ridge. Our study demonstrates the feasibility of generating EPS cells from refractory mouse strains, which could potentially be a general strategy for deriving mouse pluripotent cells. The generation of NOD-scid Il2rg-/- EPS cell lines permits sophisticated genetic modification in NOD-scid Il2rg-/- mice, which may greatly advance the optimization of humanized mouse models for biomedical applications.

Rapid generation of gene-targeted EPS-derived mouse models through tetraploid complementation.

One major strategy to generate genetically modified mouse models is gene targeting in mouse embryonic stem (ES) cells, which is used to produce gene-targeted mice for wide applications in biomedicine. However, a major bottleneck in this approach is that the robustness of germline transmission of gene-targeted ES cells can be significantly reduced by their genetic and epigenetic instability after long-term culturing, which impairs the efficiency and robustness of mouse model generation. Recently, we have established a new type of pluripotent cells termed extended pluripotent stem (EPS) cells, which have superior developmental potency and robust germline competence compared to conventional mouse ES cells. In this study, we demonstrate that mouse EPS cells well maintain developmental potency and genetic stability after long-term passage. Based on gene targeting in mouse EPS cells, we established a new approach to directly and rapidly generate gene-targeted mouse models through tetraploid complementation, which could be accomplished in approximately 2 months. Importantly, using this approach, we successfully constructed mouse models in which the human interleukin 3 (IL3) or interleukin 6 (IL6) gene was knocked into its corresponding locus in the mouse genome. Our study demonstrates the feasibility of using mouse EPS cells to rapidly generate mouse models by gene targeting, which have great application potential in biomedical research.