Search

Leukocyte immunoglobulin-like receptor B (LILRB), a family of immune checkpoint receptors, contributes to acute myeloid leukemia (AML) development, but the specific mechanisms triggered by activation or inhibition of these immune checkpoints in cancer is largely unknown. Here we demonstrate that the intracellular domain of LILRB3 is constitutively associated with the adaptor protein TRAF2. Activated LILRB3 in AML cells leads to recruitment of cFLIP and subsequent NF-κB upregulation, resulting in enhanced leukemic cell survival and inhibition of T-cell-mediated anti-tumor activity. Hyperactivation of NF-κB induces a negative regulatory feedback loop mediated by A20, which disrupts the interaction of LILRB3 and TRAF2; consequently the SHP-1/2-mediated inhibitory activity of LILRB3 becomes dominant. Finally, we show that blockade of LILRB3 signaling with antagonizing antibodies hampers AML progression. LILRB3 thus exerts context-dependent activating and inhibitory functions, and targeting LILRB3 may become a potential therapeutic strategy for AML treatment., (© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Introduction: Although the traditional bilateral surgical approach to treat hiatal hernia (HH) with gastroesophageal reflux disease (GERD) can provide local protection of the vagus nerve, the integrity of the entire vagus nerve cannot be evaluated. Therefore, we developed and described the total left-side surgical approach (TLSA), which theoretically reduces injury to the vagus nerve, and described the detailed surgical procedure., Methods: Initially, we performed a cadaver study to explore the characteristics of the vagus nerve. Then, we prospectively evaluated the TLSA in 5 patients with HH and GERD between June 2020 and September 2020. Demographic characteristics, surgical parameters, perioperative outcomes, and follow-up findings were analyzed., Results: The TLSA was successfully used in five patients (40-64 years old), and no major complications were noted. The median total operative time was 114 min, median blood loss was 50 mL, and median postoperative hospital stay was 3.8 days. Gastrointestinal function recovered within 4 days of surgery in all the patients. The 6-month follow-up gastroscopy examination showed well-established gastroesophageal flap valves. Compared with the baseline results, the 6-month follow-up results showed lower values for the total GerdQ score (12.4 vs. 6.2) and the total esophageal acid exposure time (3.48% vs. 0.38%). Based on the European Organization for Research and Treatment of Cancer quality of life questionnaire-stomach module 52 results, the incidence of dysphagia and flatulence decreased over time after the TLSA., Conclusions: The TLSA provides a clear and broad surgical field, less trauma, and rapid recovery; moreover, it is technically simple. Although our results suggest that the TLSA provides safety and short-term efficacy and is feasible for patients with HH and GERD, long-term results from a larger clinical trial are needed to validate these findings. Trial registration ChiCTR2000034028, registration date is June 21, 2020. The study was registered prospectively., (© 2021. The Author(s).)

Pathogenic bacteria evolve multiple strategies to hijack host cells for intracellular survival and persistent infections. Previous studies have revealed the intricate interactions between bacteria and host cells at genetic, biochemical and even single molecular levels. Mechanical interactions and mechanotransduction exert a crucial impact on the behaviors and functions of pathogenic bacteria and host cells, owing to the ubiquitous mechanical microenvironments like extracellular matrix (ECM) stiffness. Nevertheless, it remains unclear whether and how ECM stiffness modulates bacterial infections and the sequential outcome of antibacterial therapy. Here we show that bacteria tend to adhere to and invade epithelial cells located on the regions with relatively high traction forces. ECM stiffness regulates spatial distributions of bacteria during the invasion through arrangements of F-actin cytoskeletons in host cells. Depolymerization of cytoskeletons in the host cells induced by bacterial infection decreases intracellular accumulation of antibiotics, thus preventing the eradication of invaded bacterial pathogens. These findings not only reveal the key regulatory role of ECM stiffness, but suggest that the coordination of cytoskeletons may provide alternative approaches to improve antibiotic therapy against multidrug resistant bacteria in clinic., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

We recently demonstrated that leukocyte Ig-like receptor 4 (LILRB4) expressed by monocytic acute myeloid leukemia (AML) cells mediates T-cell inhibition and leukemia cell infiltration via its intracellular domain. The cytoplasmic domain of LILRB4 contains three immunoreceptor tyrosine-based inhibitory motifs (ITIMs); the tyrosines at positions 360, 412, and 442 are phosphorylation sites. Here, we analyzed how the ITIMs of LILRB4 in AML cells mediate its function. Our in vitro and in vivo data show that Y 412 and Y 442 , but not Y 360 , of LILRB4 are required for T-cell inhibition, and all three ITIMs are needed for leukemia cell infiltration. We constructed chimeric proteins containing the extracellular domain of LILRB4 and the intracellular domain of LILRB1 and vice versa. The intracellular domain of LILRB4, but not that of LILRB1, mediates T-cell suppression and AML cell migration. Our studies thus defined the unique signaling roles of LILRB4 ITIMs in AML cells.

Genetic interactions have been reported to underlie phenotypes in a variety of systems, but the extent to which they contribute to complex disease in humans remains unclear. In principle, genome-wide association studies (GWAS) provide a platform for detecting genetic interactions, but existing methods for identifying them from GWAS data tend to focus on testing individual locus pairs, which undermines statistical power. Importantly, a global genetic network mapped for a model eukaryotic organism revealed that genetic interactions often connect genes between compensatory functional modules in a highly coherent manner. Taking advantage of this expected structure, we developed a computational approach called BridGE that identifies pathways connected by genetic interactions from GWAS data. Applying BridGE broadly, we discover significant interactions in Parkinson's disease, schizophrenia, hypertension, prostate cancer, breast cancer, and type 2 diabetes. Our novel approach provides a general framework for mapping complex genetic networks underlying human disease from genome-wide genotype data.

To explore the feasibility of using herbal medicine waste (HMW) as solid fuel, HMW was torrefied under different temperatures and atmospheres. The physicochemical properties and combustion behaviors of the torrefied HMW were investigated. Temperature was found to be the most influential factor affecting the torrefaction. Torrefaction improved the hydrophobicity of HMW and decreased the equilibrated moisture uptake from 24.48(0.083) % to 15.22(0.054) %. The HMW samples torrefied under different conditions are easy to ignite. The comprehensive combustibility index (S) of the torrefied HMW increased by 3-5 folds compared to that of the raw sample. In general, the HMW torrefied under lower temperatures and under CO 2 and O 2 have better flammability. The present results revealed that the torrefied HMW exhibited good combustion characteristics and can thus be used for solid fuel production, such as fuels for co-combustion or raw materials for pelletization., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Immune checkpoint blockade therapy has been successful in treating some types of cancer but has not shown clinical benefits for treating leukaemia 1 . This result suggests that leukaemia uses unique mechanisms to evade this therapy. Certain immune inhibitory receptors that are expressed by normal immune cells are also present on leukaemia cells. Whether these receptors can initiate immune-related primary signalling in tumour cells remains unknown. Here we use mouse models and human cells to show that LILRB4, an immunoreceptor tyrosine-based inhibition motif-containing receptor and a marker of monocytic leukaemia, supports tumour cell infiltration into tissues and suppresses T cell activity via a signalling pathway that involves APOE, LILRB4, SHP-2, uPAR and ARG1 in acute myeloid leukaemia (AML) cells. Deletion of LILRB4 or the use of antibodies to block LILRB4 signalling impeded AML development. Thus, LILRB4 orchestrates tumour invasion pathways in monocytic leukaemia cells by creating an immunosuppressive microenvironment. LILRB4 represents a compelling target for the treatment of monocytic AML.

Leukemia-initiating cells (LICs) are responsible for the initiation, development, and relapse of leukemia. The identification of novel therapeutic LIC targets is critical to curing leukemia. In this report, we reveal that junctional adhesion molecule 3 (JAM3) is highly enriched in both mouse and human LICs. Leukemogenesis is almost completely abrogated upon Jam3 deletion during serial transplantations in an MLL-AF9-induced murine acute myeloid leukemia model. In contrast, Jam3 deletion does not affect the functions of mouse hematopoietic stem cells. Moreover, knockdown of JAM3 leads to a dramatic decrease in the proliferation of both human leukemia cell lines and primary LICs. JAM3 directly associates with LRP5 to activate the downstream PDK1/AKT pathway, followed by the downregulation of GSK3β and activation of β-catenin/CCND1 signaling, to maintain the self-renewal ability and cell cycle entry of LICs. Thus, JAM3 may serve as a functional LIC marker and play an important role in the maintenance of LIC stemness through unexpected LRP5/PDK1/AKT/GSK3β/β-catenin/CCND1 signaling pathways but not via its canonical role in cell junctions and migration. JAM3 may be an ideal therapeutic target for the eradication of LICs without influencing normal hematopoiesis.

A certain level of disagreement between the chemical analysis of androstenone and skatole and the human perception of boar taint has been found in many studies. Here we analyze whether the fatty acid composition can explain such inconsistency between sensory evaluation and chemical analysis of boar taint compounds. Therefore, back fat samples (n=143) were selected according to their sensory evaluation by a 10-person sensory panel, and the chemical analysis (stable isotope dilution analysis with headspace solid-phase microextraction and gas chromatography-mass spectrometry) of androstenone and skatole. Subsequently a quantification of fatty acids using gas chromatography-flame ionization detection was conducted. The correlation analyses revealed that several fatty acids are significantly correlated with androstenone, skatole, and the sensory rating. However, multivariate analyses (principal component analysis) revealed no explanation of the fatty acid composition with respect to the (dis-)agreement between sensory and chemical analysis., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Certain secretory proteins are known to be critical for maintaining the stemness of stem cells through autocrine signaling. However, the processes underlying the biogenesis, maturation, and secretion of these proteins remain largely unknown. Here we demonstrate that many secretory proteins produced by hematopoietic stem cells (HSCs) undergo exosomal maturation and release that is controlled by vacuolar protein sorting protein 33b (VPS33B). Deletion of VPS33B in either mouse or human HSCs resulted in impaired exosome maturation and secretion as well as loss of stemness. Additionally, VPS33B deficiency led to a dramatic delay in leukemogenesis. Exosomes purified from either conditioned medium or human plasma could partially rescue the defects of HSCs and leukemia-initiating cells (LICs). VPS33B co-existed in exosomes with GDI2, VPS16B, FLOT1, and other known exosome markers. Mechanistically, VPS33B interacted with the GDI2/RAB11A/RAB27A pathway to regulate the trafficking of secretory proteins as exosomes. These findings reveal an essential role for VPS33B in exosome pathways in HSCs and LICs. Moreover, they shed light on the understanding of vesicle trafficking in other stem cells and on the development of improved strategies for cancer treatment., Competing Interests: The authors have declared that no conflict of interest exists.

Sulfate-rich wastewater is an indirect threat to the environment especially at low pH. Sulfate reducing bacteria (SRB) could use sulfate as the terminal electron acceptor for the degradation of organic compounds and hydrogen transferring SO(4)(2-) to H2S. However their acute sensitivity to acidity leads to a greatest limitation of SRB applied in such wastewater treatment. With the addition of iron shavings SRB could adapt to such an acidic environment, and 57.97, 55.05 and 14.35% of SO(4)(2-) was reduced at pH 5, pH 4 and pH 3, respectively. Nevertheless it would be inhibited in too acidic an environment. The behavior of SRB after inoculation in acidic synthetic wastewater with and without iron shavings is presented, and some glutinous substances were generated in the experiments at pH 4 with SRB culture and iron shavings.

Objective: To study the absorption kinetics of dehydrocavidine in rats' stomachs and intestines., Method: The absorption kinetics was investigated by the in situ perfusion in rats and the concentrations of drug perfusion solutions were determined by HPLC., Result: The hourly absorption percentages of dehydrocavidine in stomach, small intestine were 8.88%, 2.08%, respectively. Although the absorption rate constants of dehydrocavidine in duodenum and jejunum are more than that in ileum and colon, there is no significance difference between them. The absorption rate constants kept at the same level when the concentrations of drug perfusion solution are at middle and high level. The increase of the pH of perfusion solution didnt significantly affect the absorption rate constants of the drug., Conclusion: Dehydrocavidine was absorbed poorly at stomach and all segments of intestine in rats, but the absorptions in stomach are better than intestine. Dehydrocavidine was absorbed mainly via passive transport mechanism between middle and high concentration levels.