Effects of fissure length and angle on the fracture modes of 3D printed teeth model: Insights from DIC-based fracture tests and meshless numerical simulations.

To investigate the influences of teeth fissure properties on their failure modes, 3D Printing technology is used to prepare the teeth models. The strain distributions of the teeth model surfaces at each moment of the loading processes are obtained by the DIC technique. And the progressive failure processes as well as the stress distributions of the teeth models are simulated by the improved Smoothed Particle Hydrodynamics (SPH) Method. Experimental results show that under the action of the steel ball, the teeth models mainly produce two types of cracks: The tensile cracks along the pre-existing fissures and the shear cracks along both sides of the teeth model. The existence of prefabricated fissures greatly reduces the peak strength of the teeth models. Compared with the circumstances containing no pre-existing fissures, the peak strength of d = 1 cm, d = 2 cm and d = 3 cm decreases by 22.33%, 31.79% and 18.94%, respectively, and the peak strength of θ = 30°, θ = 45°, θ = 60° decreases by 10.78%, 44.01% and 34.3%, respectively. Numerical results show that the initiations of tensile cracks are induced by the high tensile stress concentrations at the pre-existing fissure tips, while the shear cracks are caused by the high tensile stress concentrations in the low tensile stress concentration areas after the initiation of tensile cracks. The research results can provide some references for the understandings of teeth failure mechanisms as well as the applications of SPH method into teeth crack propagation simulations.

Global Model Selection for Semi-Supervised Support Vector Machine via Solution Paths.

Semi-supervised support vector machine (S 3 VM) is important because it can use plentiful unlabeled data to improve the generalization accuracy of traditional SVMs. In order to achieve good performance, it is necessary for S 3 VM to take some effective measures to select hyperparameters. However, model selection for semi-supervised models is still a key open problem. Existing methods for semi-supervised models to search for the optimal parameter values are usually computationally demanding, especially those ones with grid search. To address this challenging problem, in this article, we first propose solution paths of S 3 VM (SPS 3 VM), which can track the solutions of the nonconvex S 3 VM with respect to the hyperparameters. Specifically, we apply incremental and decremental learning methods to update the solution and let it satisfy the Karush-Kuhn-Tucker (KKT) conditions. Based on the SPS 3 VM and the piecewise linearity of model function, we can find the model with the minimum cross-validation (CV) error for the entire range of candidate hyperparameters by computing the error path of S 3 VM. Our SPS 3 VM is the first solution path algorithm for nonconvex optimization problem of semi-supervised learning models. We also provide the finite convergence analysis and computational complexity of SPS 3 VM. Experimental results on a variety of benchmark datasets not only verify that our SPS 3 VM can globally search the hyperparameters (regularization and ramp loss parameters) but also show a huge reduction of computational time while retaining similar or slightly better generalization performance compared with the grid search approach.

Mettl3-dependent m6A modification is essential for effector differentiation and memory formation of CD8+ T cells.

Efficient immune responses rely on the proper differentiation of CD8+ T cells into effector and memory cells. Here, we show a critical requirement of N6-Methyladenosine (m6A) methyltransferase Mettl3 during CD8+ T cell responses upon acute viral infection. Conditional deletion of Mettl3 in CD8+ T cells impairs effector expansion and terminal differentiation in an m6A-dependent manner, subsequently affecting memory formation and the secondary response of CD8+ T cells. Our combined RNA-seq and m6A-miCLIP-seq analyses reveal that Mettl3 deficiency broadly impacts the expression of cell cycle and transcriptional regulators. Remarkably, Mettl3 binds to the Tbx21 transcript and stabilizes it, promoting effector differentiation of CD8+ T cells. Moreover, ectopic expression of T-bet partially restores the defects in CD8+ T cell differentiation in the absence of Mettl3. Thus, our study highlights the role of Mettl3 in regulating multiple target genes in an m6A-dependent manner and underscores the importance of m6A modification during CD8+ T cell response.

Clinical features and neurobiochemical mechanisms of olfactory dysfunction in patients with Parkinson disease.

This study aimed to investigate clinical features, influencing factors and neurobiochemical mechanisms of olfactory dysfunction (OD) in Parkinson disease (PD). Total 39 patients were divided into the PD with OD (PD-OD) and PD with no OD (PD-nOD) groups according to overall olfactory function, including threshold, discrimination and identification, assessed by Sniffin' Sticks test. Motor function and non-motor symptoms were rated by multiple scales. Dopamine, acetylcholine, norepinephrine and 5-hydroxytryptamine levels in cerebrospinal fluid (CSF) were measured. We found that the PD-OD group showed significantly lower score of Montreal Cognitive Assessment Scale, higher scores of rapid eye movement sleep behavior disorder (RBD) Screening Questionnaire and Epworth Sleepiness Scale than the PD-nOD group (p < 0.05). RBD Screening Questionnaire score was independently associated with the scores of overall olfactory function and discrimination (p < 0.05). Dopamine and acetylcholine levels in CSF from the PD-OD group was significantly lower than that from the PD-nOD group (p < 0.05). Dopamine and acetylcholine levels in CSF were significantly and positively correlated with the scores of overall olfactory function, threshold, discrimination and identification in PD patients (p < 0.05). RBD Screening Questionnaire score was significantly and negatively correlated with acetylcholine level in CSF in PD patients with poor olfactory detection (p < 0.05). This investigation reveals that PD-OD is associated with cognitive impairment, probable RBD and excessive daytime sleepiness. PD-OD is correlated with the decreased levels of dopamine and acetylcholine in CSF. RBD is an independent influencing factor of overall olfactory function and discrimination, and the decreased acetylcholine level in CSF may be the common neurobiochemical basis of RBD and OD in PD patients.

Requirements for human natural killer cells.

'Requirements for Human Natural Killer Cells' is the latest set of guidelines on human NK cells in China, jointly drafted and agreed upon by experts from the Standards Committee of Chinese Society for Cell Biology. This standard specifies requirements for the human natural killer (NK) cells, including the technical requirements, test methods, test regulations, instructions for use, labeling requirements, packaging requirements, storage and transportation requirements, and waste disposal requirements of NK cells. This standard is applicable for the quality control of NK cells, derived from human tissues, or differentiated/transdifferentiated from stem cells. It was originally released by the Chinese Society for Cell Biology on 30 August, 2022. We hope that the publication of these guidelines will promote institutional establishment, acceptance, and execution of proper protocols and accelerate the international standardization of human NK cells for applications.

Whole genome sequence-based characterization of virulence and antimicrobial resistance gene profiles of Staphylococcus aureus isolated from food poisoning incidents in eastern China.

Staphylococcus aureus is an opportunistic foodborne pathogen occasionally isolated from diarrhea patients. In recent years, increasing studies have reported the detection of S. aureus in food poisoning incidents due to food contamination in the North and South of China. However, the epidemiology and genetic characteristics of S. aureus from food poisoning incidents in Eastern China remain unknown. The present study examined the genetic characteristics, antimicrobial resistance, and virulent factors of multidrug-resistant S. aureus isolated from 22 food poisoning incidents reported by the hospitals and health centers in Eastern China from 2011 to 2021. A total of 117 resistant and enterotoxigenic S. aureus isolates were collected and sequenced, among which 20 isolates were identified as methicillin resistant. Genetic analysis revealed 19 distinct CC/ST types, with CC6, CC22, CC59, CC88, and CC398 being the most frequent variants in methicillin-resistant S. aureus (MRSA). A considerable shift in CC types from CC1 to CC398 between 2011 and 2021 was observed in this study, indicating that CC398 may be the main epidemic strain circulating in the current food poisoning incidents. Additionally, genes for enterotoxins were detected in 55 isolates, with a prevalence of 27.8% (27/97) for methicillin-sensitive variants and 35.0% (7/20) for MRSA. The scn gene was detected in 59.0% of the isolates, demonstrating diverse contaminations of S. aureus among livestock-to-human transmission. Of the 117 isolates, only ten isolates displayed multi-drug resistance (MDR) to penicillin, tetracycline, and macrolides. None of the 117 foodborne S. aureus isolates tested positive for vanA in this study. Together, the present study provided phylogenetic characteristics of S. aureus from food poisoning incidents that emerged in Eastern China from 2011 to 2021. Our results suggested that these diarrhea episodes were hypotonic and merely transient low-MDR infections, however, further research for continued surveillance given the detection of virulence and antimicrobial resistance determinants is required to elucidate the genomic characteristics of pathogenic S. aureus in food poisoning incidents in the context of public health.

Numerical Simulation Analysis of Fracture Propagation in Rock Based on Smooth Particle Hydrodynamics.

The mechanical properties of fractured rock have always been a focal point in the rock mechanics field. Based on previous research, this paper proposes improvements to the SPH method and applies it to the study of crack propagation in fractured rocks. By conducting uniaxial compression tests and simulating crack propagation on various specimens with different crack shapes, the characteristics of crack propagation were obtained. The comparison between the simulated results in this study and existing experimental and numerical simulation results confirms the validity of the SPH method employed in this paper. The present study utilizes the proposed methodology to analyze the influence of the crack angle, width, and orientation on crack propagation. The SPH method employed in this study effectively demonstrates the expansion process of fractured rock under uniaxial compression, providing valuable insights for the engineering applications of SPH.

Mettl3-m6A-Creb1 forms an intrinsic regulatory axis in maintaining iNKT cell pool and functional differentiation.

N6-methyladenosine (m6A) methyltransferase Mettl3 is involved in conventional T cell immunity; however, its role in innate immune cells remains largely unknown. Here, we show that Mettl3 intrinsically regulates invariant natural killer T (iNKT) cell development and function in an m6A-dependent manner. Conditional ablation of Mettl3 in CD4+CD8+ double-positive (DP) thymocytes impairs iNKT cell proliferation, differentiation, and cytokine secretion, which synergistically causes defects in B16F10 melanoma resistance. Transcriptomic and epi-transcriptomic analyses reveal that Mettl3 deficiency disturbs the expression of iNKT cell-related genes with altered m6A modification. Strikingly, Mettl3 modulates the stability of the Creb1 transcript, which in turn controls the protein and phosphorylation levels of Creb1. Furthermore, conditional targeting of Creb1 in DP thymocytes results in similar phenotypes of iNKT cells lacking Mettl3. Importantly, ectopic expression of Creb1 largely rectifies such developmental defects in Mettl3-deficient iNKT cells. These findings reveal that the Mettl3-m6A-Creb1 axis plays critical roles in regulating iNKT cells at the post-transcriptional layer.

Shear Damage Simulations of Rock Masses Containing Fissure-Holes Using an Improved SPH Method.

Fissures and holes widely exist in rock mechanics engineering, and, at present, their failure mechanisms under complex compress and shear stress states have not been well recognized. In our work, a fracture mark, ξ, is introduced, and the kernel function of the smoothed-particle hydrodynamics (SPH) is then re-written, thus realizing the fracture modelling of the rock media. Then, the numerical models containing the fissures and holes are established, and their progressive failure processes under the compress and shear stress states are simulated, with the results showing that: (1) the improved SPH method can reflect the dynamic crack propagation processes of the rock masses, and the numerical results are in good agreement with the previous experimental results. Meanwhile, the improved SPH method can get rid of the traditional mesh re-division problems, which can be well-applied to rock failure modeling; (2) the hole shapes, fissure angles, fissure lengths, fissure numbers, and confining pressure all have great impacts on the final failure modes and peak strengths of the model; and (3) in practical engineering, the rock masses are in the 3D stress state, therefore, developing a high performance 3D SPH program and applying it to engineering in practice will be of great significance.

Molecular Characteristics of Methicillin-Resistant and Susceptible Staphylococcus aureus from Pediatric Patients in Eastern China.

Staphylococcus aureus is an opportunistic pathogen that causes invasive infections in humans. In recent years, increasing studies have focused on the prevalence of S. aureus infections in adults; however, the epidemiology and molecular characteristics of S. aureus from Chinese pediatric patients remain unknown. The present study examined the population structure, antimicrobial resistance, and virulent factors of methicillin-resistant and -susceptible S. aureus isolated from Chinese pediatric patients from one medical center in eastern China. A total of 81 cases were screened with positive S. aureus infections among 864 pediatric patients between 2016 and 2022 in eastern China. Molecular analysis showed that ST22 (28.4%) and ST59 (13.6%) were the most typical strains, and associations between different clonal complex (CC) types/serotype types (ST) and the age of pediatric patients were observed in this study. CC398 was the predominant type in neonates under 1 month of age, while CC22 was mainly found in term-infant (under 1 year of age) and toddlers (over 1 year of age). Additionally, 17 S. aureus isolates were resistant to at least three antimicrobials and majority of them belonged to CC59. The blaZ gene was found in 59 isolates and mecA gene was present in 26 strains identified as methicillin-resistant. Numerous virulent factors were detected in S. aureus isolated from present pediatric patients. Remarkably, lukF-PV and lukS-PV were dominantly carried by CC22, tsst-1 genes were detected in CC188, CC7, and CC15, while exfoliative toxin genes were found only in CC121. Only 41.98% of the S. aureus isolates possessed scn gene, indicating that the sources of infections in pediatric patients may include both human-to-human transmissions as well as environmental and nosocomial infections. Together, the present study provided a phylogenetic and genotypic comparison of S. aureus from Chinese pediatric patients in Suzhou city. Our results suggested that the colonization of multi-drug resistant isolates of S. aureus may raise concern among pediatric patients, at least from the present medical center in eastern China.

TLE3 and TLE4-coordinated colonic macrophage-CD4+ T cell crosstalk maintains intestinal immune homeostasis.

Colonic macrophages are critical for maintenance of cluster of differentiation 4 T helper (CD4+ T) cell homeostasis in the intestinal lamina propria. However, the mechanisms by which this process is regulated at the transcriptional level remain unknown. In this study, we found that the transcriptional corepressors transducin-like enhancer of split (TLE)3 and TLE4, but not TLE1 or TLE2, in colonic macrophages controlled homeostasis of CD4+ T-cell pool in the colonic lamina propria. Mice lacking TLE3 or TLE4 in myeloid cells exhibited markedly increased numbers of regulatory T (Treg) and T helper (TH) 17 cells under homeostatic conditions, rendering them more resistant to experimental colitis. Mechanistically, TLE3 and TLE4 negatively regulated matrix metalloproteinase (Mmp)9 transcription in colonic macrophages. Tle3 or Tle4 deficiency in colonic macrophages resulted in upregulated MMP9 production and thus enhanced latent transforming growth factor-beta (TGF-ß) activation, which subsequently led to Treg and TH17 cell expansion. These results advanced our knowledge regarding the intricate crosstalk between the intestinal innate and adaptive immune compartments.

An improved Smoothed Particle Hydrodynamics (SPH) method for modelling the cracking processes of teeth and its applications.

The present work aims to propose a meshless method to establish the tooth meso-structures and model the tooth fracturing processes as well as investigate the influencing factors that affect the dental mechanical properties. To this end, the traditional kernel function in the SPH method has been improved by introducing a fracture mark ξ to realize the progressive failure processes of teeth; The "Particle Searching Method" has been proposed, which can realize the establishments of microstructures of teeth such as enamel, dentine, pulp, PDL and alvedar bones. The Weibull function is introduced to represent the heterogeneity of teeth, which can realize the random distribution characteristics of dental mechanical parameters. The simulation results of homogeneous and heterogeneous teeth show that the failure mode changes from tensile splitting (homogeneous) to shear failure (heterogeneous). Meanwhile, the fracture networks become more complex, and the failure stress decreases sharply. The cuspal angles also have a great impact on the teeth fracture characteristics. The failure modes changes from tensile splitting of the enamel tip to the cracking from the contact points between the enamel and the rigid ball; Different fssural morphologies have little influences on the teeth failure characteristics. The research results can provide some references for the applications of SPH method into biomechanical simulations such as teeth failure. Meanwhile, it can also provide some guidance for the understandings of the internal mechanisms of teeth fracture processes, the diagnosis and treatments of clinical diseased teeth as well as the design of bionic teeth materials.

METTL3 preferentially enhances non-m6A translation of epigenetic factors and promotes tumourigenesis.

METTL3 encodes the predominant catalytic enzyme to promote m6A methylation in nucleus. Recently, accumulating evidence has shown the expression of METTL3 in cytoplasm, but its function is not fully understood. Here we demonstrated an m6A-independent mechanism for METTL3 to promote tumour progression. In gastric cancer, METTL3 could not only facilitate cancer progression via m6A modification, but also bind to numerous non-m6A-modified mRNAs, suggesting an unexpected role of METTL3. Mechanistically, cytoplasm-anchored METTL3 interacted with PABPC1 to stabilize its association with cap-binding complex eIF4F, which preferentially promoted the translation of epigenetic factors without m6A modification. Clinical investigation showed that cytoplasmic distributed METTL3 was highly correlated with gastric cancer progression, and this finding could be expanded to prostate cancer. Therefore, the cytoplasmic METTL3 enhances the translation of epigenetic mRNAs, thus serving as an oncogenic driver in cancer progression, and METTL3 subcellular distribution can assist diagnosis and predict prognosis for patients with cancer.

An Oomycete-Specific Leucine-Rich Repeat-Containing Protein Is Involved in Zoospore Flagellum Development in Phytophthora sojae.

A leucine-rich repeat (LRR) is a widespread structural motif of 20 to 30 amino acids with characteristic repetitive sequences rich in leucine. LRR-containing proteins are critical for ligand recognition and binding, participating in plant development and defense. Like plants, oomycetes also harbor genes encoding LRR-containing proteins, but their functions remain largely unknown. We identified a zoospore-upregulated gene from Phytophthora sojae with LRRs and an extra structural maintenance of chromosomes-like domain. We generated knockout and complemented knockout strains of this LRR protein and found that its deletion resulted in a pronounced reduction in zoospore mobility and chemotaxis, cyst germination, and virulence. Interestingly, micro-examination of zoospores under a scanning electron microscope revealed irregularly shaped zoospores without flagella in these deletion mutants. In addition, the reintroduction of this LRR protein into the knockout mutant reversed all the deficiencies. Our data demonstrate a critical role for the Phytophthora LRR protein in modulating zoospore development, which impairs migration to the host soybean and affects the spread of Phytophthora pathogens.

Endothelial Dysfunction Induced by Extracellular Neutrophil Traps Plays Important Role in the Occurrence and Treatment of Extracellular Neutrophil Traps-Related Disease.

Many articles have demonstrated that extracellular neutrophil traps (NETs) are often described as part of the antibacterial function. However, since the components of NETs are non-specific, excessive NETs usually cause inflammation and tissue damage. Endothelial dysfunction (ED) caused by NETs is the major focus of tissue damage, which is highly related to many inflammatory diseases. Therefore, this review summarizes the latest advances in the primary and secondary mechanisms between NETs and ED regarding inflammation as a mediator. Moreover, the detailed molecular mechanisms with emphasis on the disadvantages from NETs are elaborated: NETs can use its own enzymes, release particles as damage-associated molecular patterns (DAMPs) and activate the complement system to interact with endothelial cells (ECs), drive ECs damage and eventually aggravate inflammation. In view of the role of NETs-induced ED in different diseases, we also discussed possible molecular mechanisms and the treatments of NETs-related diseases.

Heterochronic parabiosis induces stem cell revitalization and systemic rejuvenation across aged tissues.

The young circulatory milieu capable of delaying aging in individual tissues is of interest as rejuvenation strategies, but how it achieves cellular- and systemic-level effects has remained unclear. Here, we constructed a single-cell transcriptomic atlas across aged tissues/organs and their rejuvenation in heterochronic parabiosis (HP), a classical model to study systemic aging. In general, HP rejuvenated adult stem cells and their niches across tissues. In particular, we identified hematopoietic stem and progenitor cells (HSPCs) as one of the most responsive cell types to young blood exposure, from which a continuum of cell state changes across the hematopoietic and immune system emanated, through the restoration of a youthful transcriptional regulatory program and cytokine-mediated cell-cell communications in HSPCs. Moreover, the reintroduction of the identified rejuvenating factors alleviated age-associated lymphopoiesis decline. Overall, we provide comprehensive frameworks to explore aging and rejuvenating trajectories at single-cell resolution and revealed cellular and molecular programs that instruct systemic revitalization by blood-borne factors.

Experimental and Numerical Study on the Failure Characteristics of Brittle Solids with a Circular Hole and Internal Cracks.

A stress analysis of a circular hole is one of the classical problems in mechanics. Internal cracks are inherent properties of materials, and they are mostly three-dimensional in form. However, studies on hole problems with three-dimensional internal cracks are still lacking. In this paper, internal cracks were generated in brittle materials containing circular holes based on 3D internal laser-engraved crack technology. Then, uniaxial compression tests were performed. The experimental results were compared with the existing literature, and theoretical and numerical simulation studies were carried out. The results show that: (1) The main crack shapes are the primary cracks and remote cracks. (2) The dynamic fracture characteristics existed in the formation of primary cracks and the surface of remote cracks. The tips of primary cracks were arc-shaped, and the surfaces of the remote cracks were curved. Remote cracks were tangential to the orifice where type III spear-like characteristics appeared. (3) The stress birefringence technology can be combined with 3D internal laser-engraved crack technology for internal crack stress information monitoring, the moire around the orifice was "flamboyant", and the moire at the tip of the prefabricated crack was "petallike". (4) The existence of internal cracks reduced the cracking and breaking load of the specimen, and compared with the intact orifice specimen, the upper primary crack, the lower primary crack, the remote crack and the failure load were reduced by 41.2%, 31.7%, 15.9%, and 32.3%, respectively. (5) The results of qualitative stress analysis of the orifice specimen were consistent with the initiation law of primary cracks and remote cracks. The K distribution based on M integral and the numerical simulation of crack propagation process based on the maximum tensile stress criterion were consistent with the law of primary crack growth. Compared with the current mainstream method of transparent rock research, 3D internal laser-engraved crack technology has certain advantages in terms of brittleness, crack authenticity, stress field visualization, and fracture characteristics, and the result will provide experimental and theoretical references for research on three-dimensional problems and internal cracks in fracture mechanics.

SRSF1 Deficiency Impairs the Late Thymocyte Maturation and the CD8 Single-Positive Lineage Fate Decision.

The underlying mechanisms of thymocyte development and lineage determination remain incompletely understood, and the emerging evidences demonstrated that RNA binding proteins (RBPs) are deeply involved in governing T cell fate in thymus. Serine/arginine-rich splicing factor 1 (SRSF1), as a classical splicing factor, is a pivotal RBP for gene expression in various biological processes. Our recent study demonstrated that SRSF1 plays essential roles in the development of late thymocytes by modulating the T cell regulatory gene networks post-transcriptionally, which are critical in response to type I interferon signaling for supporting thymocyte maturation. Here, we report SRSF1 also contributes to the determination of the CD8+ T cell fate. By specific ablation of SRSF1 in CD4+CD8+ double positive (DP) thymocytes, we found that SRSF1 deficiency impaired the maturation of late thymocytes and diminished the output of both CD4+ and CD8+ single positive T cells. Interestingly, the ratio of mature CD4+ to CD8+ cells was notably altered and more severe defects were exhibited in CD8+ lineage than those in CD4+ lineage, reflecting the specific function of SRSF1 in CD8+ T cell fate decision. Mechanistically, SRSF1-deficient cells downregulate their expression of Runx3, which is a crucial transcriptional regulator in sustaining CD8+ single positive (SP) thymocyte development and lineage choice. Moreover, forced expression of Runx3 partially rectified the defects in SRSF1-deficient CD8+ thymocyte maturation. Thus, our data uncovered the previous unknown role of SRSF1 in establishment of CD8+ cell identity.

Robust Unsupervised Domain Adaptation from A Corrupted Source.

Unsupervised Domain Adaptation (UDA) provides a promising solution for learning without supervision, which transfers knowledge from relevant source domains with accessible labeled training data. Existing UDA solutions hinge on clean training data with a short-tail distribution from the source domain, which can be fragile when the source domain data is corrupted either inherently or via adversarial attacks. In this work, we propose an effective framework to address the challenges of UDA from corrupted source domains in a principled manner. Specifically, we perform knowledge ensemble from multiple domain-invariant models that are learned on random partitions of training data. To further address the distribution shift from the source to the target domain, we refine each of the learned models via mutual information maximization, which adaptively obtains the predictive information of the target domain with high confidence. Extensive empirical studies demonstrate that the proposed approach is robust against various types of poisoned data attacks while achieving high asymptotic performance on the target domain.

Tcf1 Sustains the Expression of Multiple Regulators in Promoting Early Natural Killer Cell Development.

T cell factor 1 (Tcf1) is known as a critical mediator for natural killer (NK) cell development and terminal maturation. However, its essential targets and precise mechanisms involved in early NK progenitors (NKP) are not well clarified. To investigate the role of Tcf1 in NK cells at distinct developmental phases, we employed three kinds of genetic mouse models, namely, Tcf7fl/flVavCre/+, Tcf7fl/flCD122Cre/+ and Tcf7fl/flNcr1Cre/+ mice, respectively. Similar to Tcf1 germline knockout mice, we found notably diminished cell number and defective development in BM NK cells from all strains. In contrast, Tcf7fl/flNcr1Cre/+ mice exhibited modest defects in splenic NK cells compared with those in the other two strains. By analyzing the published ATAC-seq and ChIP-seq data, we found that Tcf1 directly targeted 110 NK cell-related genes which displayed differential accessibility in the absence of Tcf1. Along with this clue, we further confirmed that a series of essential regulators were expressed aberrantly in distinct BM NK subsets with conditional ablating Tcf1 at NKP stage. Eomes, Ets1, Gata3, Ikzf1, Ikzf2, Nfil3, Runx3, Sh2d1a, Slamf6, Tbx21, Tox, and Zeb2 were downregulated, whereas Spi1 and Gzmb were upregulated in distinct NK subsets due to Tcf1 deficiency. The dysregulation of these genes jointly caused severe defects in NK cells lacking Tcf1. Thus, our study identified essential targets of Tcf1 in NK cells, providing new insights into Tcf1-dependent regulatory programs in step-wise governing NK cell development.