Anisotropic Damage Mechanism of Coal Seam Water Injection with Multiphase Coupling.

After coal seam water injection, coal mechanical properties will change with brittleness weakening and plasticity enhancement. Aiming at the problem of coal damage caused by the coal seam water injection process, based on nonlinear pore elasticity theory and continuum damage theory, a nonlinear pore elastic damage model considering anisotropic characteristics is proposed to calculate and analyze the gas-liquid-solid multiphase coupling effect with the fully coupled finite element method during the coal seam water injection process. The research results indicate that the wetting radius of calculated results by the model agrees well with the in situ test results, and the relative errors are less than 10%. Water saturation and induced damage of the coal body in the parallel bedding direction are greater than that in the vertical bedding direction during the coal seam water injection process, which exhibits significant anisotropic characteristics. With the increasing water injection time, the induced damage of the coal body also increases near the water injection hole. Considering the inherent permeability arising with damage, it has a significant impact on both water saturation and induced damage, which also indicates that there is a strong interaction between water saturation and induced damage. The theoretical model reveals the coal damage mechanism of gas-liquid-solid multiphase coupling after coal seam water injection and provides a theoretical prediction of coal containing water characteristics in engineering practice.

Desorption Characteristics of CH4-C2H6 Mixed Gas in Heavy Hydrocarbon-Rich Coal Seams.

The gas desorption characteristics of coal are closely related to the gas content of the coal seam. The gas in heavy hydrocarbon-rich coal seams contains CH4 and C2H6 heavy hydrocarbons. However, most current research on the gas desorption characteristics of coal seams focuses on CH4 analysis, ignoring the influence of the C2H6 heavy hydrocarbon gas. To accurately determine the gas content of a heavy hydrocarbon-rich coal seam, methods based on CH4 analysis are inadequate and the desorption characteristics of CH4-C2H6 mixed gas must be clarified. This work experimentally and theoretically studies the desorption characteristics of single-component gas and CH4-C2H6 mixed gas from coal samples. The results show that increasing the adsorption-equilibrium pressure was found to increase the desorption quantity and desorption speed of single-component gas and increase the desorption quantity, desorption ratio, and diffusion coefficient of mixed gas. Under the same adsorption-equilibrium pressure, the desorption quantity and rate of single-component CH4 gas exceeded those of C2H6. The quantity and speed of mixed gas desorption increased with rising CH4 concentration and decreased with rising C2H6 concentration. The change in the mixed gas concentration during desorption reflects the distribution characteristics of light hydrocarbon components on the outer surface and heavy hydrocarbon components on the inner surface of coal. From the desorption characteristics of mixed gas, desorption models of mixed gas were obtained at different concentrations, laying a theoretical foundation for accurate determinations of gas contents in heavy hydrocarbon-rich coal seams.

Enhancing m6A modification of lncRNA through METTL3 and RBM15 to promote malignant progression in bladder cancer.

Objective: Bladder cancer is one of the most prominent malignancies affecting the urinary tract, characterized by a poor prognosis. Our previous research has underscored the pivotal role of m6A methylation in the progression of bladder cancer. Nevertheless, the precise relationship between N6-methyladenosine (m6A) regulation of long non-coding RNA (lncRNA) and bladder cancer remains elusive. Methods: This study harnessed sequencing data and clinical records from 408 bladder cancer patients in the TCGA database. Employing R software, we conducted bioinformatics analysis to establish an m6A-lncRNA co-expression network. Analyzing the differences between high and low-risk groups, particularly at the immunological level, and subsequently investigating the primary regulatory factors of these lncRNA, validating the findings through experiments, and exploring their specific cellular functions. Results: We identified 50 m6A-related lncRNA with prognostic significance through univariate Cox regression analysis. In parallel, we employed a LASSO-Cox regression model to pinpoint 11 lncRNA and calculate risk scores for bladder cancer patients. Based on the median risk score, patients were categorized into low-risk and high-risk groups. The high-risk cohort exhibited notably lower survival rates than their low-risk counterparts. Further analysis pointed to RBM15 and METTL3 as potential master regulators of these m6A-lncRNA. Experimental findings also shed light on the upregulated expression of METTlL3 and RBM15 in bladder cancer, where they contributed to the malignant progression of tumors. The experimental findings demonstrated a significant upregulation of METTL3 and RBM15 in bladder cancer specimens, implicating their contributory role in the oncogenic progression. Knockdown of METTL3 and RBM15 resulted in a marked attenuation of tumor cell proliferation, invasion, and migration, which was concomitant with a downregulation in the cellular m6A methylation status. Moreover, these results revealed that RBM15 and METTL3 function in a synergistic capacity, positing their involvement in cancer promotion via the upregulation of m6A modifications in long non-coding RNAs. Additionally, this study successfully developed an N-methyl-N-nitrosourea (MNU)-induced rat model of in situ bladder carcinoma, confirming the elevated expression of RBM15 and METTL3, which paralleled the overexpression of m6A-related- lncRNAs observed in bladder cancer cell lines. This congruence underscores the potential utility of these molecular markers in in vivo models that mirror human malignancies. Conclusion: This study not only offers novel molecular targets,but also enriches the research on m6A modification in bladder cancer, thereby facilitating its clinical translation.

Mechanism and endoscopic-treatment-induced evolution of biliary non-anastomotic stricture after liver transplantation revealed by single-cell RNA sequencing.

BACKGROUND: Biliary complications, especially non-anastomotic stricture (NAS), are the main complications after liver transplantation. Insufficient sampling and no recognized animal models obstruct the investigation. Thus, the mechanisms and alterations that occur during endoscopic treatment (ET) of NAS remain unclear. METHODS: Samples were obtained with endoscopic forceps from the hilar bile ducts of NAS patients receiving continuous biliary stent implantation after diagnosis. Retrospective analysis of multiple studies indicated that the duration of ET for NAS was approximately 1-2 years. Thus, we divided the patients into short-term treatment (STT) and long-term treatment (LTT) groups based on durations of less or more than 1 year. Samples were subjected to single-cell RNA sequencing. Transcriptomic differences between STT and normal groups were defined as the NAS mechanism. Similarly, alterations from STT to LTT groups were regarded as endoscopic-treatment-induced evolution. RESULTS: In NAS, inflammation and immune-related pathways were upregulated in different cell types, with nonimmune cells showing hypoxia pathway upregulation and immune cells showing ATP metabolism pathway upregulation, indicating heterogeneity. We confirmed a reduction in bile acid metabolism-related SPP1+ epithelial cells in NAS. Increases in proinflammatory and profibrotic fibroblast subclusters indicated fibrotic progression in NAS. Furthermore, immune disorders in NAS were exacerbated by an increase in plasma cells and dysfunction of NK and NKT cells. ET downregulated multicellular immune and inflammatory responses and restored epithelial and endothelial cell proportions. CONCLUSIONS: This study reveals the pathophysiological and genetic mechanisms and evolution of NAS induced by ET, thereby providing preventive and therapeutic insights into NAS. HIGHLIGHTS: For the first time, single-cell transcriptome sequencing was performed on the bile ducts of patients with biliary complications. scRNA-seq analysis revealed distinct changes in the proportion and phenotype of multiple cell types during Nonanastomotic stricture (NAS) and endoscopic treatment. A reduction in bile acid metabolism-related SPP1+ epithelial cells and VEGFA+ endothelial cells, along with explosive infiltration of plasma cells and dysfunction of T and NK cells in NAS patients. SPP1+ macrophages and BST2+ T cells might serve as a surrogate marker for predicting endoscopic treatment.

Corrigendum: Untreated depression and anxiety in patients with common skin diseases: a cross-sectional study in China.

[This corrects the article DOI: 10.3389/fpsyg.2023.1150998.].

KGE-UNIT: toward the unification of molecular interactions prediction based on knowledge graph and multi-task learning on drug discovery.

The prediction of molecular interactions is vital for drug discovery. Existing methods often focus on individual prediction tasks and overlook the relationships between them. Additionally, certain tasks encounter limitations due to insufficient data availability, resulting in limited performance. To overcome these limitations, we propose KGE-UNIT, a unified framework that combines knowledge graph embedding (KGE) and multi-task learning, for simultaneous prediction of drug-target interactions (DTIs) and drug-drug interactions (DDIs) and enhancing the performance of each task, even when data availability is limited. Via KGE, we extract heterogeneous features from the drug knowledge graph to enhance the structural features of drug and protein nodes, thereby improving the quality of features. Additionally, employing multi-task learning, we introduce an innovative predictor that comprises the task-aware Convolutional Neural Network-based (CNN-based) encoder and the task-aware attention decoder which can fuse better multimodal features, capture the contextual interactions of molecular tasks and enhance task awareness, leading to improved performance. Experiments on two imbalanced datasets for DTIs and DDIs demonstrate the superiority of KGE-UNIT, achieving high area under the receiver operating characteristics curves (AUROCs) (0.942, 0.987) and area under the precision-recall curve ( AUPRs) (0.930, 0.980) for DTIs and high AUROCs (0.975, 0.989) and AUPRs (0.966, 0.988) for DDIs. Notably, on the LUO dataset where the data were more limited, KGE-UNIT exhibited a more pronounced improvement, with increases of 4.32$\%$ in AUROC and 3.56$\%$ in AUPR for DTIs and 6.56$\%$ in AUROC and 8.17$\%$ in AUPR for DDIs. The scalability of KGE-UNIT is demonstrated through its extension to protein-protein interactions prediction, ablation studies and case studies further validate its effectiveness.

Unnatural amino acid substitutions to improve in vivo stability and tumor uptake of 68Ga-labeled GRPR-targeted TacBOMB2 derivatives for cancer imaging with positron emission tomography.

BACKGROUND: Overexpressed in various solid tumors, gastrin-releasing peptide receptor (GRPR) is a promising cancer imaging marker and therapeutic target. Although antagonists are preferable for the development of GRPR-targeted radiopharmaceuticals due to potentially fewer side effects, internalization of agonists may lead to longer tumor retention and better treatment efficacy. In this study, we systematically investigated unnatural amino acid substitutions to improve in vivo stability and tumor uptake of a previously reported GRPR-targeted agonist tracer, [68Ga]Ga-TacBOMB2 (68Ga-DOTA-Pip-D-Phe6-Gln7-Trp8-Ala9-Val10-Gly11-His12-Leu13-Thz14-NH2). RESULTS: Unnatural amino acid substitutions were conducted for Gln7, Trp8, Ala9, Val10, Gly11 and His12, either alone or in combination. Out of 25 unnatural amino acid substitutions, tert-Leu10 (Tle10) and NMe-His12 substitutions were identified to be preferable modifications especially in combination. Compared with the previously reported [68Ga]Ga-TacBOMB2, the Tle10 and NMe-His12 derived [68Ga]Ga-LW01110 showed retained agonist characteristics and improved GRPR binding affinity (Ki = 7.62 vs 1.39 nM), in vivo stability (12.7 vs 89.0% intact tracer in mouse plasma at 15 min post-injection) and tumor uptake (5.95 vs 16.6 %ID/g at 1 h post-injection). CONCLUSIONS: Unnatural amino acid substitution is an effective strategy to improve in vivo stability and tumor uptake of peptide-based radiopharmaceuticals. With excellent tumor uptake and tumor-to-background contrast, [68Ga]Ga-LW01110 is promising for detecting GRPR-expressing cancer lesions with PET. Since agonists can lead to internalization upon binding to receptors and foreseeable long tumor retention, our optimized GRPR-targeted sequence, [Tle10,NMe-His12,Thz14]Bombesin(7-14), is a promising template for use for the design of GRPR-targeted radiotherapeutic agents.

Exploration of commercial cyclen-based chelators for mercury-197 m/g incorporation into theranostic radiopharmaceuticals.

A comprehensive investigation of the Hg2+ coordination chemistry and 197m/gHg radiolabeling capabilities of cyclen-based commercial chelators, namely, DOTA and DOTAM (aka TCMC), along with their bifunctional counterparts, p-SCN-Bn-DOTA and p-SCN-Bn-TCMC, was conducted to assess the suitability of these frameworks as bifunctional chelators for the 197m/gHg2+ theranostic pair. Radiolabeling studies revealed that TCMC and DOTA exhibited low radiochemical yields (0%-6%), even when subjected to harsh conditions (80°C) and high ligand concentrations (10-4 M). In contrast, p-SCN-Bn-TCMC and p-SCN-Bn-DOTA demonstrated significantly higher 197m/gHg radiochemical yields (100% ± 0.0% and 70.9% ± 1.1%, respectively) under the same conditions. The [197 m/gHg]Hg-p-SCN-Bn-TCMC complex was kinetically inert when challenged against human serum and glutathione. To understand the differences in labeling between the commercial chelators and their bifunctional counterparts, non-radioactive natHg2+ complexes were assessed using NMR spectroscopy and DFT calculations. The NMR spectra of Hg-TCMC and Hg-p-SCN-Bn-TCMC suggested binding of the Hg2+ ion through the cyclen backbone framework. DFT studies indicated that binding of the Hg2+ ion within the backbone forms a thermodynamically stable product. However, competition can form between isothiocyanate binding and binding through the macrocycle, which was experimentally observed. The isothiocyanate bound coordination product was dominant at the radiochemical scale as, in comparison, the macrocycle bound product was seen at the NMR scale, agreeing with the DFT result. Furthermore, a bioconjugate of TCMC (TCMC-PSMA) targeting prostate-specific membrane antigen was synthesized and radiolabeled, resulting in an apparent molar activity of 0.089 MBq/nmol. However, the complex demonstrated significant degradation over 24 h when exposed to human serum and glutathione. Subsequently, cell binding assays were conducted, revealing a Ki value ranging from 19.0 to 19.6 nM. This research provides crucial insight into the effectiveness of current commercial chelators in the context of 197m/gHg2+ radiolabeling. It underscores the necessity for the development of specific and customized chelators to these unique "soft" radiometals to advance 197m/gHg2+ radiopharmaceuticals.

Spatial stratified heterogeneity analysis of field scale permafrost in Northeast China based on optimal parameters-based geographical detector.

Affected by global warming, the permafrost in Northeast China (NEC) has been continuously degrading in recent years. Many researchers have focused on the spatial and temporal distribution characteristics of permafrost in NEC, however, few studies have delved into the field scale. In this study, based on the Optimal Parameters-based Geographical Detector (OPGD) model and Receiver Operating Characteristic (ROC) test, the spatial stratified heterogeneity of permafrost distribution and the indicating performance of environmental variables on permafrost in NEC at the field scale were analyzed. Permafrost spatial distribution data were obtained from the Engineering Geological Investigation Reports (EGIR) of six highways located in NEC and a total of 19 environmental variables related to heat transfer, vegetation, soil, topography, moisture, and ecology were selected. The H-factors (variables with the highest contribution in factor detector results and interaction detector results): slope position (γ), surface frost number (SFN), elevation (DEM), topographic diversity (TD), and annual snow cover days (ASCD) were found to be the major contributors to the distribution of permafrost at the field scale. Among them, γ has the highest contribution and is a special explanatory variable for permafrost. In most cases, interaction can improve the impact of variables, especially the interaction between H-factors. The risk of permafrost decreases with the increase of TD, RN, and SBD, and increases with the increase of SFN. The performance of SFN to indicate permafrost distribution was found to be the best among all variables (AUC = 0.7063). There is spatial heterogeneity in the distribution of permafrost on highways in different spatial locations. This study summarized the numerical and spatial location between permafrost and different environmental variables at the field scale, and many results were found to be informative for environmental studies and engineering construction in NEC.

The zinc finger protein CG12744 regulates intestinal stem cells in aged Drosophila through the EGFR and BMP pathways.

AIM: Aging is a process characterized by a time-dependent decline in the functionality of adult stem cells and is closely associated with age-related diseases. However, understanding how aging promotes disease and its underlying causes is critical for combating aging. MAIN METHODS: The offspring of UAS-Gal4 and CG12744RNAiDrosophila were cultured for 33 days to evaluate the role of CG12744 in the aging intestine. Immunofluorescence was performed to detect specific cell type markers for assessing proliferation and differentiation. qRT-PCR was used to observe the changes in signaling regulating intestinal homeostasis in the aging intestine after CG12744 knockdown. 16S rRNA-seq analysis was also conducted to elucidate the role of gut microbes in CG12744-mediated intestinal dysfunction. KEY FINDINGS: The mRNA levels of CG12744 were significantly increased in the aged midguts. Knockdown of CG12744 in progenitor cells further exacerbates the age-related intestinal hyperplasia and dysfunction. In particular, upon depletion of CG12744 in progenitors, enteroblasts (EBs) exhibited an increased propensity to differentiate along the enteroendocrine cell (EE) lineage. In contrast, the overexpression of CG12744 in progenitor cells restrained age-related gut hyperplasia in Drosophila. Moreover, CG12744 prevented age-related intestinal stem cell (ISC) overproliferation and differentiation by modulating the EGFR, JNK, and BMP pathways. In addition, the inhibition of CG12744 resulted in a significant increase in the gut microbial composition in aging flies. SIGNIFICANCE: This study established a role for the CG12744 in regulating the proliferation and differentiation of adult stem cells, thereby identifying a potential therapeutic target for diseases caused by age-related dysfunction stem cell dysfunction.

An orally active entry inhibitor of influenza A viruses protects mice and synergizes with oseltamivir and baloxavir marboxil.

Seasonal or pandemic illness caused by influenza A viruses (IAVs) is a major public health concern due to the high morbidity and notable mortality. Although there are several approved drugs targeting different mechanisms, the emergence of drug resistance calls for new drug candidates that can be used alone or in combinations. Small-molecule IAV entry inhibitor, ING-1466, binds to hemagglutinin (HA) and blocks HA-mediated viral infection. Here, we show that this inhibitor demonstrates preventive and therapeutic effects in a mouse model of IAV with substantial improvement in the survival rate. When administered orally it elicits a therapeutic effect in mice, even after the well-established infection. Moreover, the combination of ING-1466 with oseltamivir phosphate or baloxavir marboxil enhances the therapeutic effect in a synergistic manner. Overall, ING-1466 has excellent oral bioavailability and in vitro absorption, distribution, metabolism, excretion, and toxicity profile, suggesting that it can be developed for monotherapy or combination therapy for the treatment of IAV infections.

Elevated expression of WSB2 degrades p53 and activates the IGFBP3-AKT-mTOR-dependent pathway to drive hepatocellular carcinoma.

Dysregulation of wild-type p53 turnover is a key cause of hepatocellular carcinoma (HCC), yet its mechanism remains poorly understood. Here, we report that WD repeat and SOCS box containing protein 2 (WSB2), an E3 ubiquitin ligase, is an independent adverse prognostic factor in HCC patients. WSB2 drives HCC tumorigenesis and lung metastasis in vitro and in vivo. Mechanistically, WSB2 is a new p53 destabilizer that promotes K48-linked p53 polyubiquitination at the Lys291 and Lys292 sites in HCC cells, leading to p53 proteasomal degradation. Degradation of p53 causes IGFBP3-dependent AKT/mTOR signaling activation. Furthermore, WSB2 was found to bind to the p53 tetramerization domain via its SOCS box domain. Targeting mTOR with everolimus, an oral drug, significantly blocked WSB2-triggered HCC tumorigenesis and metastasis in vivo. In clinical samples, high expression of WSB2 was associated with low wild-type p53 expression and high p-mTOR expression. These findings demonstrate that WSB2 is overexpressed and degrades wild-type p53 and then activates the IGFBP3-AKT/mTOR axis, leading to HCC tumorigenesis and lung metastasis, which indicates that targeting mTOR could be a new therapeutic strategy for HCC patients with high WSB2 expression and wild-type p53.

Repeatedly Programmable Liquid Crystal Dielectric Elastomer with Multimodal Actuation.

Dielectric elastomers (DEs) are actuatable under an electric field, whose large strain and fast response speed compare favorably with natural muscles. However, the actuation of DE-based devices is generally limited to a single mode and cannot be reconfigured after fabrication, which pales in comparison to biological counterparts given the ability to alter actuation modes according to external conditions. To address this, liquid crystal dielectric elastomers (LC-DEs) that can alter the dielectric actuation modes based on the thermally triggered shape-changing are prepared. Specifically, the two shapes through the LC phase transition possess different bending stiffness, which leads to distinct actuation modes after an electric field is applied. Moreover, the two shapes can be individually programmed/reprogrammed, that is, the one before the transition is regulated through force-directed solvent evaporation and the one after the transition is via bond exchange-enabled stress relaxation. As such, the multimodal dielectric actuation behaviors upon temperature change can be readily diversified. Meanwhile, the space charge mechanism endows LC-DEs with the significantly reduced driving e-field (8 V µm-1) and bidirectional actuation manners. It is believed this unique adaptivity in the actuation modes under a low electric field shall offer versatile designs for practical soft robots.

On the topological surface states of the intrinsic magnetic topological insulator Mn-Bi-Te family.

We review recent progress in the electronic structure study of intrinsic magnetic topological insulators (MnBi2Te4) · (Bi2Te3)n ([Formula: see text]) family. Specifically, we focus on the ubiquitously (nearly) gapless behavior of the topological Dirac surface state observed by photoemission spectroscopy, even though a large Dirac gap is expected because of surface ferromagnetic order. The dichotomy between experiment and theory concerning this gap behavior is perhaps the most critical and puzzling question in this frontier. We discuss various proposals accounting for the lack of magnetic effect on the topological Dirac surface state, which are mainly categorized into two pictures, magnetic reconfiguration and topological surface state redistribution. Band engineering towards opening a magnetic gap of topological surface states provides great opportunities to realize quantized topological transport and axion electrodynamics at higher temperatures.

Dynamic response of different types of gut microbiota to fructooligosaccharides and inulin.

Fructooligosaccharides (FOS) and inulin are beneficial for human health. However, their benefits differ in individuals who consume prebiotics. Several factors contribute to this variation, including host genetics and differences in the gut microbiota. Bifidobacterium and Bacteroides are strong carbohydrate-utilizing bacteria in the gut, and the level of the Bacteroides/Bifidobacterium (Ba/Bi) ratio in the gut is closely related to the body's ability to utilize prebiotics. However, how to select the type of prebiotics more beneficial for populations with specific Ba/Bi backgrounds and the underlying regulatory mechanisms remain unclear. Here, we explored the dynamics of the gut microbiota and metabolic functions during the in vitro fermentation of FOS and inulin in two different groups: Bacteroides/Bifidobacterium high (H) and Bacteroides/Bifidobacterium low (L). This study revealed that the baseline Ba/Bi ratio had a greater impact on the gut microbiota compared to prebiotic species. Noticeable differences were observed between the two groups after prebiotic intervention, with the H group being more likely to benefit from the prebiotic intervention. Compared to the L group, the H group exhibited significantly higher microbial α-diversity; the co-abundance response group 1 (CARG1) members Ruminococcus gnavus and Blautia involved in the synthesis of propionic and butyric acids increased significantly, the abundance of pathogenic bacteria such as Escherichia Shigella decreased significantly, and the ability to degrade carbohydrates and synthesize fatty acids was greater. Regression modeling showed that the key microbiota could predict the short-chain fatty acid (SCFA) levels, with FOS associated with the ecological roles of CARG2 and CARG7 and inulin associated with CARG4, which provides the basis for the use of prebiotics in nutritional applications and the stratification of populations based on pertinent microbiota profiles to explain the incongruent health effects in human intervention studies.

Mercury pollution risks of agricultural soils and crops in mercury mining areas in Guizhou Province, China: effects of large mercury slag piles.

The historical large mercury slag piles still contain high concentrations of mercury and their impact on the surrounding environment has rarely been reported. In this study, three different agricultural areas [the area with untreated piles (PUT), the area with treated piles (PT), and the background area with no piles (NP)] were selected to investigate mercury slag piles pollution in the Tongren mercury mining area. The mercury concentrations of agricultural soils ranged from 0.42 to 155.00 mg/kg, determined by atomic fluorescence spectrometry of 146 soil samples; and mercury concentrations in local crops (rice, maize, pepper, eggplant, tomato and bean) all exceeded the Chinese food safety limits. Soil and crop pollution trends in the three areas were consistent as PUT > PT > NP, indicating that mercury slag piles have exacerbated pollution. Mercury in the slag piles was adsorbed by multiple pathways of transport into soils with high organic matter, which made the ecological risk of agricultural soils appear extremely high. The total hazard quotients for residents from ingesting mercury in these crops were unacceptable in all areas, and children were more likely to be harmed than adults. Compared to the PT area, treatment of slag piles in the PUT area may decrease mercury concentrations in paddy fields and dry fields by 46.02% and 70.36%; further decreasing health risks for adults and children by 47.06% and 79.90%. This study provided a scientific basis for the necessity of treating large slag piles in mercury mining areas.

Fc gamma receptors promote antibody-induced LILRB4 internalization and immune regulation of monocytic AML.

The immune checkpoint leukocyte immunoglobulin-like receptor B4 (LILRB4) is found specifically on the cell surface of acute monocytic leukemia (monocytic AML), an aggressive and common subtype of AML. We have developed a humanized monoclonal IgG1 LILRB4-blocking antibody (h128-3), which improved immune regulation but reduced cell surface expression of LILRB4 in monocytic AML models by 40-60%. Interestingly, most of this effect was neutralized by mutation of the Fc region of the antibody (h128-3/N297A), which prevents interaction with Fc gamma receptors (FcγRs). This suggested that there is FcγR-dependent antigenic modulation underlying h128-3's effects, a mechanism known to alter the function of antibodies targeting B-cell malignancies. We disrupted the Fc-FcγR interaction pharmacologically and with stable CRISPR-Cas9-mediated genetic knockout of FcγRs in monocytic AML cell lines to investigate the role of FcγR-dependent antigenic modulation in the regulation of LILRB4 by h128-3. When FcγRI is inhibited or removed from the surface of monocytic AML cells, h128-3 cannot optimally perform its blocking function, resulting in activation of the LILRB4 inhibitory receptor and leading to a 15-25% decrease in T-cell-mediated cytotoxicity in vitro. In the absence of FcγRI, scaffolding by FcγRIIa allows h128-3 to maintain LILRB4-blocking function. Here we define a FcγR-dependent antigenic modulation mechanism underlying the function of an immunoreceptor blocking antibody for the first time in myeloid malignancy. This research will facilitate the development of safe, precision-targeted antibody therapeutics in myeloid malignancies with greater potency and efficacy.