BAG5 regulates HSPA8-mediated protein folding required for sperm head-tail coupling apparatus assembly.

Teratozoospermia is a significant cause of male infertility, but the pathogenic mechanism of acephalic spermatozoa syndrome (ASS), one of the most severe teratozoospermia, remains elusive. We previously reported Spermatogenesis Associated 6 (SPATA6) as the component of the sperm head-tail coupling apparatus (HTCA) required for normal assembly of the sperm head-tail conjunction, but the underlying molecular mechanism has not been explored. Here, we find that the co-chaperone protein BAG5, expressed in step 9-16 spermatids, is essential for sperm HTCA assembly. BAG5-deficient male mice show abnormal assembly of HTCA, leading to ASS and male infertility, phenocopying SPATA6-deficient mice. In vivo and in vitro experiments demonstrate that SPATA6, cargo transport-related myosin proteins (MYO5A and MYL6) and dynein proteins (DYNLT1, DCTN1, and DNAL1) are misfolded upon BAG5 depletion. Mechanistically, we find that BAG5 forms a complex with HSPA8 and promotes the folding of SPATA6 by enhancing HSPA8's affinity for substrate proteins. Collectively, our findings reveal a novel protein-regulated network in sperm formation in which BAG5 governs the assembly of the HTCA by activating the protein-folding function of HSPA8.

Tyrosine phosphorylation of IRF3 by BLK facilitates its sufficient activation and innate antiviral response.

Viral infection triggers the activation of transcription factor IRF3, and its activity is precisely regulated for robust antiviral immune response and effective pathogen clearance. However, how full activation of IRF3 is achieved has not been well defined. Herein, we identified BLK as a key kinase that positively modulates IRF3-dependent signaling cascades and executes a pre-eminent antiviral effect. BLK deficiency attenuates RNA or DNA virus-induced ISRE activation, interferon production and the cellular antiviral response in human and murine cells, whereas overexpression of BLK has the opposite effects. BLK-deficient mice exhibit lower serum cytokine levels and higher lethality after VSV infection. Moreover, BLK deficiency impairs the secretion of downstream antiviral cytokines and promotes Senecavirus A (SVA) proliferation, thereby supporting SVA-induced oncolysis in an in vivo xenograft tumor model. Mechanistically, viral infection triggers BLK autophosphorylation at tyrosine 309. Subsequently, activated BLK directly binds and phosphorylates IRF3 at tyrosine 107, which further promotes TBK1-induced IRF3 S386 and S396 phosphorylation, facilitating sufficient IRF3 activation and downstream antiviral response. Collectively, our findings suggest that targeting BLK enhances viral clearance via specifically regulating IRF3 phosphorylation by a previously undefined mechanism.

Symbiosis between Dendrobium catenatum protocorms and Serendipita indica involves the plant hypoxia response pathway.

Mycorrhizae are ubiquitous symbioses established between fungi and plant roots. Orchids, in particular, require compatible mycorrhizal fungi for seed germination and protocorm development. Unlike arbuscular mycorrhizal fungi, which have wide host ranges, orchid mycorrhizal fungi are often highly specific to their host orchids. However, the molecular mechanism of orchid mycorrhizal symbiosis is largely unknown compared to that of arbuscular mycorrhizal and rhizobial symbiosis. Here, we report that an endophytic Sebacinales fungus, Serendipita indica, promotes seed germination and the development of protocorms into plantlets in several epiphytic Epidendroideae orchid species (6 species in 2 genera), including Dendrobium catenatum, a critically endangered orchid with high medicinal value. Although plant-pathogen interaction and high meristematic activity can induce the hypoxic response in plants, it has been unclear whether interactions with beneficial fungi, especially mycorrhizal ones, also involve the hypoxic response. By studying the symbiotic relationship between D. catenatum and S. indica, we determined that hypoxia-responsive genes, such as those encoding alcohol dehydrogenase (ADH), are highly induced in symbiotic D. catenatum protocorms. In situ hybridization assay indicated that the ADH gene is predominantly expressed in the basal mycorrhizal region of symbiotic protocorms. Additionally, the ADH inhibitors puerarin and 4-methylpyrazole both decreased S. indica colonization in D. catenatum protocorms. Thus, our study reveals that S. indica is widely compatible with orchids and that ADH and its related hypoxia-responsive pathway are involved in establishing successful symbiotic relationships in germinating orchids.

Neuro death through autophagy via the acetylation of FoxO1 by SIRT2 in the hippocampus of mice in a autism spectrum disorder mice model.

Autism Spectrum Disorder (ASD) is a series of complex neurodevelopmental disorders, which can affect children's social, behavioral and communication abilities. A member of the Sirtuins family of NAD + dependent deacetylases called SIRT2 could regulate the inflammation progress during stress, but the relevant mechanism has not been clearly defined. In the present study, the ASD model of wild type and SIRT2 knock out mice was established to evaluate the impact on the homeostasis of neurons in the hippocampus using western blotting, immunofluorescence and Nissl staining. The results showed that the amplification of neuronal richness was significantly decreased and neuroinflammation increased in the hippocampus following ASD due to autophagy, caused by enhancing the acetylation of FoxO1 using SIRT2 gene deletion and indicating this should be the target for ASD or other psychological stress treatment.

Cold stress causes liver damage by inducing ferroptosis through the p38 MAPK/Drp1 pathway.

Acute extreme cold exposure impairs human health and even causes hypothermia which threatens human life. Liver, as a hub in metabolism and thermogenesis, is vital for cold acclimatization. Although accumulating evidence has suggested that cold exposure can cause liver damage, the underlying mechanisms remain poorly understood. This study investigated the role and underlying mechanisms of ferroptosis in cold stress-induced liver damage. To evaluate the role of ferroptosis in cold stress-induced liver damage, rats were pretreated with ferroptosis inhibitor liproxstatin-1 (Lip-1) before exposed to -10 °C for 8 h. Core body temperature was recorded. The levels of ferroptosis-related indicators were examined with the corresponding assay kits or by western blotting. Hepatic pathological changes were analyzed by hematoxylin-eosin staining and ultrastructural observation. Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were measured to assess liver function. Rats were also pretreated with p38 mitogen-activated protein kinase (MAPK) inhibitor SB203580 or Dynamin-related protein 1 (Drp1) inhibitor Mdivi-1 to determine the underlying mechanisms. We found that Lip-1 inhibited ferroptosis, attenuated hepatic pathological damages and blocked the increased ALT and AST levels in cold-exposed rats. Moreover, Mdivi-1 inhibited mitochondrial fission and suppressed ferroptosis. Furthermore, SB203580 and Mdivi-1 administration alleviated cold stress-induced liver injury. Our results suggested that cold stress caused liver damage partially by inducing ferroptosis through the p38 MAPK/Drp1 pathway. These findings might provide an effective preventive and therapeutic target for cold stress-induced liver injury.

Exposure to metals and the disruption of sex hormones in 6-19 years old children: An exploration of mixture effects.

BACKGROUND: Individual metals have been linked to sex hormones disruption, but the associations of metals mixture are rarely examined among children. METHODS: A total of 1060 participants of 6-19-year-old who participated in the National Health and Nutrition Examination Survey (2013-2016) were included. Eighteen metals were quantified in the whole blood and urine. Sex hormones were measured in serum, including total testosterone (TT), estradiol (E2), and sex hormone binding globulin (SHBG). In addition, free androgen index (FAI) and the ratio of TT to E2 were calculated. Bayesian kernel machine regression and latent class analysis were performed to assess the associations of metals mixture and exposure patterns of metals at varied levels with sex hormones while adjusting for selected covariates. All analyses were conducted by sex-age and sex-puberty groups to explore the potential sex-dimorphic effects. RESULTS: Exposure to metals mixture was associated with elevated levels of FAI and E2 among 12-19 years old girls. Moreover, the exposure pattern of metals that was characterized by high levels of blood and urinary cadmium, blood manganese, and urinary cobalt was associated with elevated E2 and reduced TT/E2 levels among girls of 12-19 years old. However, the associations of metals mixture with sex hormones were overall nonsignificant among boys. Nevertheless, metals exposure pattern that was characterized by high levels of blood lead, urinary barium, strontium, and lead but comparatively low levels of the other metals was consistently associated with reduced levels of FAI and E2 but elevated levels of TT/E2 and SHBG among boys of 12-19 years old. CONCLUSION: Metals mixture and exposure patterns that were dominated by high levels of certain metals were associated with sex hormones imbalance among 12-19 years old children in a sex-dimorphic pattern, with the identified individual metals that drove the associations of metals mixture varied by sex.

Synthesis of geopolymer using municipal solid waste incineration fly ash and steel slag: Hydration properties and immobilization of heavy metals.

In this study, a novel method for the disposal of municipal solid waste incineration fly ash (MSWIFA) was proposed. By applying geopolymer technology, steel slag (SS) and MSWIFA were used together as precursors to synthesize a cementitious material with sufficient strength that is useable in construction. The effects of the dosages of SS and alkaline activator on the properties of the geopolymer were investigated. Compressive testing was used to characterize the mechanical properties of the geopolymer. X-ray diffraction (XRD), thermogravimetric analysis (TGA), Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM) and energy dispersive spectroscopy (EDS) were used for microscopic analysis. Leaching tests were performed to assess the immobilization effect of the geopolymer on heavy metals. The results showed that the compressive strength of the geopolymer reached 23.03 MPa at 56 d with 20% SS and 11% Na2O admixture. Highly polymerized hydration products, such as C-(A)-S-H gels and N-A-S-H gels, contributed to the compact microstructure, which provided mechanical strength and limited the migration and leaching of heavy metals in the geopolymer matrix. In terms of the results, this work is significant for the development of MSWIFA management.

Selective depletion of hepatic stellate cells-specific LOXL1 alleviates liver fibrosis.

The role of LOXL1 in fibrosis via mediating ECM crosslinking and stabilization is well established; however, the role of hepatic stellate cells (HSCs)-specific LOXL1 in the development of fibrosis remains unknown. We generated HSCs-specific Loxl1-depleted mice (Loxl1Gfap-cre mice) to investigate the HSCs-specific contribution of LOXL1 in the pathogenesis of fibrosis. Loxl1fl/fl mice were used as the control. Furthermore, we used RNA sequencing to explore the underlying changes in the transcriptome. Results of the sirius red staining, type I collagen immunolabeling, and hydroxyproline content analysis, coupled with the reduced expression of profibrogenic genes revealed that Loxl1Gfap-cre mice with CCl4 -induced fibrosis exhibited decreased hepatic fibrosis. In addition, Loxl1Gfap-cre mice exhibited reduced macrophage tissue infiltration by CD68-positive cells and decreased expression of inflammatory genes compared with the controls. RNA sequencing identified integrin α8 (ITGA8) as a key modulator of LOXL1-mediated liver fibrosis. Functional analyses showed that siRNA silencing of Itga8 in cultured fibroblasts led to a decline in the LOXL1 expression and inhibition of fibroblast activation. Mechanistic analyses indicated that LOXL1 activated the FAK/PI3K/AKT/HIF1a signaling pathway, and the addition of inhibitors of FAK or PI3K reversed these results via downregulation of LOXL1. Furthermore, HIF1a directly interacted with LOXL1 and upregulated its expression, indicating that LOXL1 can positively self-regulate by forming a positive feedback loop with the FAK/PI3K/AKT/HIF1a pathway. We demonstrated that HSCs-specific Loxl1 deficiency prevented fibrosis, inflammation and that ITGA8/FAK/PI3K/AKT/HIF1a was essential for the function and expression of LOXL1. Knowledge of this approach can provide novel mechanisms and targets to treat fibrosis in the future.

Visible-Light-Enabled Ph3P/LiI-Promoted Tandem Radical Trifluoromethylation/Cyclization/Iodination of 1,6-Enynes with Togni's Reagent.

We report the visible-light-induced Ph3P/LiI-promoted intermolecular cascade trifluoromethyl radical addition/5-exo-dig cyclization/iodination of 1,6-enynes with Togni's reagent using LiI as the iodine source without the need of the transition metal, oxidant, and base. This reaction promises to be a useful method for the preparation of trifluoromethyl-substituted and vinyl C-I bond-containing pyrrolidines and benzofuran products with good regioselectivity and functional-group tolerance under ambient conditions.

Dendritic organic molecular gel coating with molecular shape selectivity and its application in selective separation by liquid chromatography.

Dendritic organic molecular gels are a promising class of three-dimensional network compounds. Here, we have synthesized a new type of dendritic organic molecular gel stationary phase (SiO2-G3) by using benzyl alcohol as raw material and dimethyl 5-hydroxyisophthalate as growth unit to synthesize a third-generation organic molecular gel G3, which grafted onto the silica surface by cyanogen chloride (CC). The developed stationary phase not only exhibits high molecular shape selectivity but also has a RPLC/HILIC/IEC mixed-mode characteristic for HPLC due to the ordered structure, the multiple strong π-π stacking interactions and the introduction of a hydrophilic triazine fraction during the grafting process. Compared with a commercial C18 column, the developed column exhibited flexible selectivity, enhanced separation performance and excellent separation of monosubstituted benzene, polycyclic aromatic hydrocarbons (PAHs), positional isomers, nucleosides and nucleobases, benzoic acid and aniline compounds. In addition, the new column provided baseline separation of polycyclic aromatic hydrocarbon contaminants in Yellow River water, verifying its potential for application in the analysis of real samples.

High prevalence and low awareness of hyperuricemia in hypertensive patients among adults aged 50-79 years in Southwest China.

INTRODUCTION: This study was aimed to assess the prevalence of hyperuricemia and its associated risk factors among hypertensive patients in Southwest China. METHODS: From September 2013 to March 2014, a multistage, stratified sampling was conducted on 3505 hypertensive people aged 50-79 years who lived in urban communities within Chengdu and Chongqing, using a questionnaire and performing physical and biochemical measurements. RESULTS: In the study population, approximately 18.2% of all hypertensive participants had hyperuricemia (638/3505), with a prevalence rate of 21.5% in men and 16.2% in women (p < 0.05). Multivariate logistic regression analysis showed that aging, without spouse, current drinking, preferring hotpot, hypertriglyceridemia, BMI ≥ 25 kg/ m2, and central obesity were all positively correlated with hyperuricemia, whereas female gender was negatively correlated with hyperuricemia. The prevalence of hyperuricemia among hypertensive patients in urban adults aged 50-79 years in southwestern China was high, while levels of awareness were extremely low. DISCUSSION: Improved hyperuricemia health knowledge should be delivered to improve public awareness of the disease and it may need aggressive strategies aiming at the prevention and treatment of hyperuricemia. It is may necessary to encourage people to check blood uric acid levels when they first time to be diagnosed with hypertension, especially in the elderly.

Genetic diversity analysis of grapevine rupestris stem pitting-associated virus from grapevine by colony PCR-SSCP and -RFLP.

We have developed methods for detecting the genetic diversity of grapevine rupestris stem pitting-associated virus (GRSPaV) based on restriction fragment length polymorphism (RFLP) and single stranded conformational polymorphism (SSCP) in the 905 nt 3' sequence. The amplicons were cloned from six grapevine cultivars, and colony polymerase chain reaction (colony PCR) using recombination bacteria was subsequently analyzed by RFLP and SSCP. Four haplotypes of SSCP and six haplotypes of Sac I RFLPs were defined. The two methods had a 40% discrepancy rate in showing the degree of diversity. All clones were sequenced and were used to construct a phylogenetic tree with seven previously reported GRSPaV sequences. In the tree, all the newly acquired sequences were divided into three clusters, I, II, and III, which corresponded to haplotypes I, II, and III of SSCP, respectively. Haplotype IV of SSCP was grouped into cluster II. A recombination analysis showed that haplotype IV has undergone a recombination event. Together, these results indicate that the SSCP assay is useful for the rapid identification of genetic diversity of GRSPaV. This is the first report of an analysis of the large fragment of GRSPaV by colony PCR-SSCP. Keywords: grapevine; grapevine rupestris stem pitting-associated virus (GRSPaV); RFLP; SSCP; genetic diversity analysis.

Luteirhabdus pelagi gen. nov., sp. nov., a novel member of the family Flavobacteriaceae, isolated from the West Pacific Ocean.

A Gram-stain-negative, aerobic, and yellow-pigmented bacterium, designated A3-108T, was isolated from seawater of the West Pacific Ocean. Cells were non-motile and rod-shaped, with carotenoid-type pigments. Strain A3-108T grew at pH 6.0-8.5 (optimum 6.5) and 15-40 °C (optimum 28 °C), in the presence of 0.5-10% (w/v) NaCl (optimum 1.0%). It possessed the ability to produce H2S. Based on the 16S rRNA gene analysis, strain A3-108T exhibited highest similarity with Aureisphaera salina A6D-50T (90.6%). Phylogenetic analysis shown that strain A3-108T affiliated with members of the family Flavobacteriaceae and represented an independent lineage. The principal fatty acids were iso-C15:0, iso-C17:0 3-OH, iso-C15:1 G, and summed feature 3 (C16:1ω7c and/or C16:1ω6c). The sole isoprenoid quinone was MK-6. The major polar lipids were phosphatidylethanolamine, one unidentified aminophospholipid, one unidentified aminolipid and one unidentified lipid. The ANIb, in silico DDH and AAI values among the genomes of strain A3-108T and three reference strains were 67.3-71.1%, 18.7-22.1%, and 58.8-71.4%, respectively. The G + C content was 41.0%. Distinctness of the phylogenetic position as well as differentiating chemotaxonomic and other phenotypic traits revealed that strain A3-108T represented a novel genus and species of the family Flavobacteriaceae, for which the name Luteirhabdus pelagi gen. nov., sp. nov. is proposed (type strain, A3-108T = CGMCC 1.18821T = KCTC 82563T).

Euzebya pacifica sp. nov., a novel member of the class Nitriliruptoria.

A Gram-stain-positive, aerobic, chemo-organotrophic, rod-shaped, non-spore-forming strain, which produced convex, circular, pink-pigmented colonies, designated as DY32-46T, was isolated from seawater collected from the Pacific Ocean. DY32-46T was found to grow at 20-40 °C (optimum, 30-35 °C), pH 6.0-8.0 (optimum, pH 6.5) and with 0-5 % (w/v) NaCl (optimum, 1-2 %). The results of chemotaxonomic analysis indicated that the respiratory quinone of DY32-46T was MK-9(H4), and major fatty acids (>10 %) were C17 : 1 ω8c, summed feature 3 (C16 : 1 ω7c and/or C16 : 1 ω6c), C16 : 0 and C15 : 1 ω6c. The polar lipids included diphosphatidylglycerol, phosphatidylglycerol, one unidentified aminophospholipid, three unidentified glycolipids, three unidentified phospholipids, one unidentified phosphoglycolipid and five unidentified lipids. The DNA G+C content of DY32-46T was 70.6 mol%. The results of phylogenetic analysis based on 16S rRNA gene sequences and genomic data indicated that DY32-46T should be assigned to the genus Euzebya. ANI and in silico DNA-DNA hybridization values between strain DY32-46T and type strains of Euzebya species were 73.1-87.2 % and 20.2-32.4 %, respectively. Different phenotypic properties, together with genetic distinctiveness, demonstrated that strain DY32-46T was clearly distinct from recognized species of the genus Euzebya. Therefore, DY32-46T represents a novel species within the genus Euzebya, for which the name Euzebya pacifica sp. nov is proposed. The type strain is DY32-46T (=MCCC 1K03476T=KCTC 49091T).

Lipid/PAA-coated mesoporous silica nanoparticles for dual-pH-responsive codelivery of arsenic trioxide/paclitaxel against breast cancer cells.

Nanomedicine has attracted increasing attention and emerged as a safer and more effective modality in cancer treatment than conventional chemotherapy. In particular, the distinction of tumor microenvironment and normal tissues is often used in stimulus-responsive drug delivery systems for controlled release of therapeutic agents at target sites. In this study, we developed mesoporous silica nanoparticles (MSNs) coated with polyacrylic acid (PAA), and pH-sensitive lipid (PSL) for synergistic delivery and dual-pH-responsive sequential release of arsenic trioxide (ATO) and paclitaxel (PTX) (PL-PMSN-PTX/ATO). Tumor-targeting peptide F56 was used to modify MSNs, which conferred a target-specific delivery to cancer and endothelial cells under neoangiogenesis. PAA- and PSL-coated nanoparticles were characterized by TGA, TEM, FT-IR, and DLS. The drug-loaded nanoparticles displayed a dual-pH-responsive (pHe = 6.5, pHendo = 5.0) and sequential drug release profile. PTX within PSL was preferentially released at pH = 6.5, whereas ATO was mainly released at pH = 5.0. Drug-free carriers showed low cytotoxicity toward MCF-7 cells, but ATO and PTX co-delivered nanoparticles displayed a significant synergistic effect against MCF-7 cells, showing greater cell-cycle arrest in treated cells and more activation of apoptosis-related proteins than free drugs. Furthermore, the extracellular release of PTX caused an expansion of the interstitial space, allowing deeper penetration of the nanoparticles into the tumor mass through a tumor priming effect. As a result, FPL-PMSN-PTX/ATO exhibited improved in vivo circulation time, tumor-targeted delivery, and overall therapeutic efficacy.

Phase shift approach for engineering desired radiation force: Acoustic pulling force example.

Phase shifts from scattering are used to analyze and engineer acoustic radiation forces. With the aid of phase shifts, analytical results for acoustic radiation forces can be simplified into compact and physically meaningful expressions, which can be used to develop a simplified procedure for the engineering of the radiation force. The desired radiation force can be fulfilled by a specific set of phase shifts up to a certain order, and then the required phase shifts can be fulfilled by engineering object and beam parameters. As an example, the phase shift approach is used to engineer the inner-to-outer radius ratio and the outer radius of a spherical shell to show how to use the phase shift method for the design of acoustic radiation forces. The example here is a force that is desired to pull particles against the propagation of a Bessel beam. A small paraxial parameter to pull a spherical shell is satisfied by in-phase scattering of monopole, dipole, quadrupole, octupole, and beyond. The example presented here is relatively simple yet reveals the advantages of the phase shift approach. The phase shift method can provide a simplified route for the design of acoustic tweezers using either traveling beams or standing waves.

The Harvest of a Lateral Segment of Costal Cartilage for Treating Nasal Deformities.

BACKGROUND: Although costal cartilage has many uses and is a reliable source of cartilage for rhinoplasty procedures, donor-site complications may arise with conventional harvesting techniques. The present report reports a novel technique of harvesting costal cartilage using a specially designed scalpel and studies the use of the harvested cartilage in the reconstruction of secondary nasal deformities in patients with cleft lips. METHODS: Ten patients (7 females and 3 males) with nasal deformities secondary to cleft lip underwent rhinoplasty using this new technique at the Department of Oral and Maxillofacial Surgery, Second Hospital of Hebei Medical University, China, between May 2011 and December 2013. Clinical outcomes were evaluated with a follow-up period of 6 to 30 months. RESULTS: The new technique successfully corrected primary nasal deformities, including flat nasal tip, short columella, flaring alae, and asymmetrical nostrils. Surgeons and patients assessed the outcome to be either good or satisfactory. Patients experienced transient discomfort at the wound site but there were no major complications (such as wound infection, dehiscence, exposure, graft extrusion, and pulmonary involvement). CONCLUSIONS: The novel technique can harvest a lateral segment of costal cartilage for use in the reconstruction of nasal deformities secondary to cleft lip in a one-stage procedure, with minimal donor-site morbidity.

Transitions between the Terrestrial and Epiphytic Habit Drove the Evolution of Seed-Aerodynamic Traits in Orchids.

Orchids are globally distributed, a feature often attributed to their tiny dustlike seeds. They were ancestrally terrestrial but in the Eocene expanded into tree canopies, with some lineages later returning to the ground, providing an evolutionarily replicated system. Because seeds are released closer to the ground in terrestrial species than in epiphytic ones, seed traits in terrestrials may have been under selective pressure to increase seed dispersal efficiency. In this study, we test the expectations that seed airspace-a trait known to increase seed flotation time in the air-is (i) larger in terrestrial lineages and (ii) has increased following secondary returns to a terrestrial habit. We quantified and scored 20 seed traits in 121 species and carried out phylogenetically informed analyses. Results strongly support both expectations, suggesting that aerodynamic traits even in dust seeds are under selection to increase dispersal ability, following shifts in average release heights correlated with changes in habit.

Irradiated and CCl4 -treated bone marrow-derived liver macrophages exhibit different gene expression patterns and phenotypes.

Myeloid cells infiltrate into the liver and differentiate into macrophages in different liver injury mouse models. However, the heterogeneity of bone marrow (BM)-derived LMs populations remains to be understood. To investigate this and understand the impact of the macrophage niche on the properties of recruited BM-derived macrophages, we used a non-myeloablation BM transplantation model to label and trace BM-derived LMs. Subsequently, we quantified the number of embryonic-derived liver-resident macrophages, BM-derived LMs and total LMs in CCl4 and irradiated acute liver injury mouse models, respectively. Finally, we compared the cell fate, gene expression patterns, chemokine signals, and surface markers of irradiated and CCl4 -treated BM-derived LMs. We observed that, as compared to CCl4, radiation generated a macrophage niche by depleting embryonic-derived liver-resident macrophages and induced the recruitment of BM-derived LMs that further settled in the liver. Irradiated and CCl4 -treated BM-derived LMs are different with respect to their cell fates, gene expression patterns, and chemokine expression and recruitment. They also have different surface markers shortly after differentiating from their progenitors. Our findings suggest that irradiated and CCl4 -treated LM populations derived from the bone marrow display different patterns of gene expression and phenotypes; these differences may be due to the availability of macrophage niche.

LncRNA MAGI2-AS3 inhibits the self-renewal of leukaemic stem cells by promoting TET2-dependent DNA demethylation of the LRIG1 promoter in acute myeloid leukaemia.

The presence or absence of cytogenetic mutations is proposed to be responsible for the pathogenesis of acute myeloid leukaemia (AML). However, the current classification system is inadequate to elucidate the molecular heterogeneity of the disease, and therapy failures frequently occur. Leukaemia stem cells (LSCs) initiate and maintain the clonal hierarchy of AML and exhibit properties of self-renewal remaining recalcitrant to conventional chemotherapy. In this study, we identified a novel long non-coding RNA (lncRNA) MAGI2 antisense RNA 3 (MAGI2-AS3) in AML and investigated its functional role in regulating LSCs self-renewal. LSCs were identified by immunoprofiling of CD34+ CD123+ in AML patients' marrow. MAGI2-AS3 exhibited a poor expression level in LSCs than the normal human haematopoietic stem cells. Lentivirus-mediated upregulation of MAGI2-AS3 or leucine-rich repeats and Ig-like domains 1 (LRIG1) impaired LSCs self-renewal. MAGI2-AS3-overexpressed LSCs acquired the ability of self-renewal following lentivirus-mediated knockdown of LRIG1. Methylation-dependent inhibition of LRIG1 was evident in LSCs. MAGI2-AS3 was found to induce occupancy of TET2 at the LRIG1 promoter. Lentivirus-mediated downregulation of TET2 could impair MAGI2-AS3-mediated elevation of LRIG1 and neutralize the inhibitory effect of MAGI2-AS3 on LSCs self-renewal. In vivo analysis indicated an elevated overall survival of NOD/SCID mice injected with LSCs in the presence of MAGI2-AS3. Altogether, the key findings support the potential of lncRNA MAGI2-AS3 to serve as a novel candidate for the improvement of AML treatment.