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Shihuiyao Rb–Nb–Ta-rich granites from the Late Jurassic period are newly discovered rare-metal-bearing granites found in the southern Great Xing’an Range, NE China. Further research of these granites may contribute to better understanding the petrogenesis of rare-metal granites and their associated mineralization mechanisms. The granites are high-silica (SiO2 = 73.66–77.08 wt%), alkali-rich (K2O + Na2O = 8.18–9.49 wt%) and weakly to mildly peraluminous with A/CNK values (molar ratios of Al2O3/(CaO + Na2O + K2O)) ranging from 1.06 to 1.16. High differentiation indexes (DI = 95–97) and low P2O5 contents demonstrate that Shihuiyao rocks are low-P and peraluminous rare-metal granites. Mineral chemistry and whole-rock geochemistry can be used to obtain the following lithological sequence: zinnwaldite granite, muscovite–zinnwaldite granite, amazonite-bearing granite and amazonite pegmatite. The effect of the rare-earth element tetrad; low K/Rb (18.98–32.82), Nb/Ta (2.41–4.64) and Zr/Hf (5.99–8.80) ratios; and the occurrence of snowball-textured quartz suggest that extreme magmatic fractionation might be the key factor that causes Rb–Nb–Ta enrichment.

This study presents new zircon LA-ICP-MS U–Pb ages, zircon Hf isotopes, and whole-rock geochemical compositions for Late Palaeozoic–Early Mesozoic intrusive rocks from the Erguna Massif, Northeast ...

Objective: Rapid restoration of corneal epithelium integrity after injury is particularly important for preserving corneal transparency and vision. Mesenchymal stem cells (MSCs) can be taken into account as the promising regenerative therapeutics for improvement of wound healing processes based on the variety of the effective components. The extracellular vesicles form MSCs, especially exosomes, has been considered as important paracrine mediators though transferring microRNAs into recipient cell. This study investigated the mechanism of human umbilical cord MSC-derived exosomes (HUMSC-exosomes) on corneal epithelial wound healing.Methods: Exosomes extracted from HUMSCs were identified by transmission electron microscopy, nanoparticle tracking analysis, and Western blot. Corneal fluorescein staining and histological staining were evaluated in a corneal mechanical wound model. Changes in HCECs proliferation after HUMSC-exosomes or miR-21 mimics treatment were evaluated by CCK-8 and EdU assays, while migration was assessed by in vitro scratch wound assay. Full-length transcriptome sequencing was performed to identify the differentially expressed genes associated with HUMSC-exosomes treatment, followed by validation via real-time PCR and Western blot.Results: The exosomes derived from HUMSCs can significantly promote corneal epithelial cells proliferation, migration in vitro and corneal epithelial wound healing in vivo. Similar effects were obtained after miR-21 transfection, while the beneficial effects of HUMSC-exosomes were partially negated by miR-21 knockdown. Results also show that the benefits are associated with decreased PTEN level and activated the PI3K/Akt signaling pathway in HCECs.Conclusion: HUMSC-exosomes could enhance the recovery of corneal epithelial wounds though restraining PTEN by transferring miR-21, and may represent a promising novel therapeutic agent for corneal wound repair.

Ag nanoparticles (AgNPs) are considered an emerging contaminant in recent years, and their harmful effects on plants pose new concerns, especially in coexistence with soil microorganisms. Arbuscular mycorrhizal fungi (AMF), as mutualistic fungi with most terrestrial plants, may contribute to alleviating nanotoxicity in plants. Herein, AgNP toxicity of different concentrations (1, 5, 10, 50, 100 mg/kg) on reed (Phragmites australis (Cav.) Trin. ex Steudel) as influenced by mycorrhizal inoculation with Funneliformis mosseae was investigated. The results revealed that concentration is the main factor influencing the AgNP phytotoxicity; AgNP dose had biphasic effects on AMF colonization, plant biomass, and antioxidant enzyme activities. Thereinto, different antioxidant enzymes had different tolerances to AgNP stress, and the turning point of their activities was respectively the following: POD-5 mg/kgSOD-10 mg/kgCAT-50 mg/kg. The growth configuration (root:shoot ratio) of Phragmites australis increased firstly and then decreased to cope with the increasing AgNP concentration. Additionally, the Ag accumulation and translocation of AgNP-exposed plants were relatively lower than that of equivalent Ag

Phytoremediation is a promising and sustainable technology to remediate the risk of heavy metals (HMs) contaminated soils, however, this way is limited to some factors contributing to slow plant growth and low remediation efficiency. As soil beneficial microbe, arbuscular mycorrhizal fungi (AMF) assisted phytoremediation is an environment-friendly and high-efficiency bioremediation technology. However, AMF-symbiotic formation and their functional expression responsible for HMs-polluted remediation are significantly influenced by edaphic fauna. Earthworms as common soil fauna, may have various effects on formation of AMF symbiosis, and exhibit synergy with AMF for the combined remediation of HMs-contaminated soils. For now, AMF-assisted phytoremediation incorporating earthworm coexistence is scarcely reported. Therefore, the main focus of this review is to discuss the AMF effects under earthworm coexistence. Effects of AMF-symbiotic formation influenced by earthworms are fully reviewed. Moreover, underlying mechanisms and synergy of the two in HMs remediation, soil improvement, and plant growth were comprehensively elucidated. Phenomenon of "functional synergism" between earthworms and AMF may be a significant mechanism for HMs phytoremediation. Finally, this review analyses shortcomings and prescriptions in the practical application of the technology and provides new insights into AMF- earthworms synergistic remediation of HMs-contaminated soils.

The application of engineered nanomaterials (ENMs) is increasing in all walks of life, inevitably resulting in a high risk of ENMs entering the natural environment. Recent studies have demonstrated that phytoaccumulation of ENMs in the environment may be detrimental to plants to varying degrees. However, plants primarily assimilate ENMs through the roots, which are inevitably affected by rhizomicroorganisms. In this review, we focus on a group of common rhizomicroorganisms-arbuscular mycorrhizal fungi (AMF). These fungi contribute to ENMs immobilization and inhibition of phytoaccumulation, improvement of host plant growth and activation of systematic protection in response to excess ENMs stress. In present review, we summarize the biological responses of plants to ENMs and the modulatory mechanisms of AMF on the immobilization of ENMs in substrate-plant interfaces, and indirectly regulatory mechanisms of AMF on the deleterious effects of ENMs on host plants. In addition, the information of feedback of ENMs on mycorrhizal symbiosis and the prospects of future research on the fate and mechanism of phyto-toxicity of ENMs mediated by AMF in the environment are also addressed. In view of above, synergistic reaction of plants and AMF may prove to be a cost-effective and eco-friendly technology to bio-control potential ENMs contamination on a sustainable basis.

BackgroundRapid restoration of corneal epithelium integrity after injury is particularly important for preserving corneal transparency and vision. Mesenchymal stem cells (MSCs) can be taken into account as the promising regenerative therapeutics for improvement of wound healing processes based on the variety of the effective components. The extracellular vesicles form MSCs, especially exosomes, has been considered as important paracrine mediators though transferring microRNAs into recipient cell. This study investigated the mechanism of human umbilical cord MSC-derived exosomes (HUMSC-exosomes) on corneal epithelial wound healing.MethodsExosomes extracted from HUMSCs were identified by transmission electron microscopy, nanoparticle tracking analysis, and Western blot. Corneal fluorescein staining and histological staining were evaluated in a corneal mechanical wound model. Changes in HCECs proliferation after HUMSC-exosomes or miR-21 mimic treatment were evaluated by CCK-8 and EdU assays, while migration was assessed by in vitro scratch wound assay. Full-length transcriptome sequencing was performed to identify the differentially expressed genes associated with HUMSC-exosomes treatment, followed by validation via real-time PCR and Western blot.ResultsThe exosomes derived from HUMSCs can significantly promote corneal epithelial cells proliferation, migration in vitro and accelerate corneal epithelial wound healing in vivo. Similar effects were obtained after miR-21 transfection, while the beneficial effects of HUMSC-exosomes were partially negated by miR-21 knockdown. Results also show that the benefits are associated with decreased PTEN level and activated the PI3K/Akt signaling pathway in HCECs.Conclusions HUMSC-exosomes could accelerate the recovery of corneal epithelial wounds though restraining PTEN by transferring miR-21, and may represent a promising novel therapeutic agent for corneal wound repair.

Background Acute lymphoblastic leukemia (ALL) is an aggressive hematopoietic malignancy that is most commonly observed in children. Alantolactone (ALT) has been reported to exhibit anti-tumor activity in different types of cancer. The aim of the present study was to investigate the anti-tumor activity and molecular mechanism of ALT in ALL. Methods ALL cell lines were treated with 1, 5 and 10 μM ALT, and cell viability was assessed using an MTT assay and RNA sequencing. Flow cytometry, JC-1 staining and immunofluorescence staining assays were used to measure cell apoptosis and autophagy. Additionally, western blot analysis was used to detect expression of apoptosis and autophagy related proteins. Finally, the effects of ALT on tumor growth were assessed in a BV173 xenograft nude mouse model. Results ALT inhibited the proliferation of ALL cells in a dose-dependent manner. Additionally, it was demonstrated that ALT inhibited cell proliferation, colony formation, autophagy, induced apoptosis and reduced tumor growth in vivo through upregulating the expression of adaptor related protein complex 2 subunit mu 1 (AP2M1). Moreover, the autophagy activator rapamycin, attenuated the pro-apoptotic effects of ALT on BV173 and NALM6 cell lines. Overexpression of AP2M1 decreased the expression of Beclin1 and the LC3-II/LC3-1 ratio, and increased p62 expression. Knockdown of Beclin1 increased the levels of bax, cleaved caspase 3 and cytochrome C, and decreased bcl-2 expression. Conclusions The present study demonstrated that ALT exerts anti-tumor activity through inducing apoptosis and inhibiting autophagy by upregulating AP2M1 in ALL, highlighting a potential therapeutic strategy for treatment of ALL.

Cytokine cascades exist in many autoimmune disorders which amplify and sustain the autoimmune process and lead to chronic inflammatory injury to the host tissues. Increasing evidence indicates that chondrocytes can interact with T cells, which may be a crucial event in inflammatory arthritis. To address the reciprocal influences of cartilage-reactive T cells and chondrocytes, we constructed cartilage-reactive T cells by developing a type II collagen-specific chimeric antigen receptor (CII-CAR). An in vitro co-culture model of CII-CAR-T cells and fresh cartilage was developed, in which CII-CAR-T displayed specific proliferative capacity and cytokine release against fresh cartilage samples, and chondrocytes could respond to CII-CAR-T cells by secreting IL-6. The proposed model will help us to explore the possible cytokine cascades between cartilage-reactive T cells and cartilage.

Earthworms and arbuscular mycorrhizal fungi (AMF) act synergistically in the rhizosphere and may increase host plant tolerance to Cd. However, mechanisms by which earthworm-AMF-plant partnerships counteract Cd phytotoxicity are unknown. Thus, we evaluated individual and interactive effects of these soil organisms on photosynthesis, antioxidant capacity, and essential nutrient uptake by Solanum nigrum, as well as on soil quality following Cd exposure (0–120 mg kg−1). Decreases in biomass and photosynthetic activity, as well as nutrient imbalances were observed in Cd-stressed plants; however, the addition of AMF and earthworms reversed these effects. Cd exposure increased superoxide dismutase (SOD), peroxidase (POD), and catalase (CAT) activities, whereas inoculation with Rhizophagus intraradices decreased those. Soil enzymatic activity decreased by 15–60% with increasing Cd concentrations. However, Cd-mediated toxicity was partially reversed by soil organisms. Earthworms and AMF ameliorated soil quality based on soil enzyme activity. At 120 mg kg−1 Cd, the urease, catalase, and acid phosphatase activities were 1.6-, 1.4-, and 1.2-fold higher, respectively, in soils co-incubated with earthworms and AMF than in uninoculated soil. Cd inhibited shoot Fe and Ca phytoaccumulation, whereas AMF and earthworms normalized the status of essential elements in plants. Cd detoxification by earthworm-AMF-S. nigrum symbiosis was manifested by increases in plant biomass accumulation (22–117%), chlorophyll content (17–63%), antioxidant levels (SOD 10–18%, POD 9–25%, total polyphenols 17–22%, flavonoids 15–29%, and glutathione 7–61%). It also ameliorated the photosynthetic capacity, and macro- and micronutrient statuses of plants; markedly reduced the levels of malondialdehyde (20–27%), superoxide anion (29–36%), and hydrogen peroxide (19–30%); and upregulated the transcription level of FeSOD. Thus, the combined action of earthworms and AMF feasibly enhances metal tolerance of hyperaccumulating plants and improves the quality of polluted soil.

Background: Acute lymphoblastic leukemia (ALL) is an aggressive hematopoietic malignancy and most commonly seen in children. Alantolactone (ATL) has been reported to have anti-tumor activities in different types of cancer. This study aimed to evaluate the anti-tumor activity and molecular mechanisms of ATL in ALL. Methods: The ALL cells were treated with 1, 5 and 10μM of of ALT, and then subjected to MTT assay and RNA sequencing. Flow cytometry, JC-1 staining and immunofluorescence staining assay were employed to measure cell apoptosis and autophagy. Meanwhile, western blot analysis was used to detect apoptosis and autophagy-related proteins. Finally, the effect of ALT on tumor growth was measured in BV173 xenograft nude mouse model. Results: In this study, we demonstrated that ALT could inhibit the proliferation of ALL cells by inducing apoptosis and inhibiting autophagy. Administration of rapamycin activated autophagy while reversing the effect of ALT on apoptosis. Mechanically, ALT could induce apoptosis and inhibit autophagy by promoting AM2P1 expression. Further, AM2P1 was figured to inhibit beclin1 phosphorylation so that the apartment between beclin1 and bcl-2 was alleviated to participate in the regulation of autophagy and apoptosis in ALL cell. Conclusions: This study disclosed that Alantolactone can inhibit cell autophagy and promote apoptosis through targeting AP2M1 in acute lymphotic leukemia, indicating a potential therapeutic strategy for ALLtreatment.

Cancer metastasis arises from magical pathological cell migration. An accurate and rapid evaluation of cell migration can reduce the number of animals used in experiments to develop a new drug to restrain the metastasis. In this work, high-strength double network hydrogels were synthesized to develop the three-dimensional (3D) scaffolds, which were applied to screen drug of anticancer in vitro. Compression strength was examined for Poly(2-acrylamido-2-methyl-1-propanesulfonic acid)/ Polyacrylamide (PAMPS/PAAm) double network hydrogel, Polyethylene glycol-Poly(2-acrylamido-2-methyl-1-propanesulfonic acid)/ Polyacrylamide (PEG-PAMPS/PAAm) double network hydrogel and Poly(vinyl alcohol)-Poly(2-acrylamido-2-methyl-1-propanesulfonic acid)/ Polyacrylamide (PVA-PAMPS/PAAm) double network hydrogel in more than 90% deformation rate. The results showed that PEG-PAMPS/PAAm hydrogel and PVA-PAMPS/PAAm hydrogel could provide high mechanical property to afford the scaffold durability and simulate cell metastasis under a simulated blood pressure. Used as the in vitro scaffold, the PEG-PAMPS/PAAm hydrogel and PVA-PAMPS/PAAm hydrogel were co-cultured with the two cancer cell, NB4 cell and A549 cell, which is the acute promyelocytic leukemia cell line and the human lung cancer cell, respectively. The results showed that the hydrogels had no intrinsic cytotoxicity to the two cells. Furthermore, under adriamycin treatment, the NB4 cell migration in two-dimensional (2D) polycarbonate membranes and PEG-PAMPS/PAAm hydrogel scaffold was investigated. The results indicated that the PEG-PAMPS/PAAm hydrogel had inter-connective porous structures and hole walls with deformability, could provide more practical channels to decrease the damage of the amoeboid migrated cells. This paper provides a 3D scaffold for studying cell migration and thus finds a rapid in vitro evaluation of a new drug to restrain the cancer cell metastasis.

Arbuscular mycorrhizal fungi (AMF) and earthworms independently enhance plant growth, heavy metal (HM) tolerance, and HM uptake, thus they are potential key factors in phytoremediation. However, few studies have investigated their interactions in HM phytoextraction by hyperaccumulators. This study highlights the independent and interactive effects of earthworms and AMF on Solanum nigrum. Plants inoculated with either AMF or earthworms exhibited ameliorated growth via enhancement of productivity, metal tolerance, and phosphorus (P) acquisition. Co-inoculation with both had more pronounced effects on plant biomass and P acquisition in shoots, but not in roots, and in Cd-polluted soils it significantly promoted (P0.05) shoot biomass (20.7-134.6 %) and P content (20.4-112.0 %). AMF and earthworms increased Cd accumulation in plant tissues, but only AMF affected Cd partitioning between shoots and roots. Although AMF decreased root-to-shoot translocation of Cd at high Cd levels, this was counterbalanced by earthworms. Both AMF and its combination with earthworms enhanced Cd phytoavailability by altering Cd chemical fractions and decreasing pH. Co-inoculation increased Cd removal amounts up to 149.3 % in 120 mg kg

RNA-Seq is emerging as an increasingly important tool in biological research, and it provides the most direct evidence of the relationship between the physiological state and molecular changes in cells. A large amount of RNA-Seq data across diverse experimental conditions have been generated and deposited in public databases. However, most developed approaches for coexpression analyses focus on the coexpression pattern mining of the transcriptome, thereby ignoring the magnitude of gene differences in one pattern. Furthermore, the functional relationships of genes in one pattern, and notably among patterns, were not always recognized. In this study, we developed an integrated strategy to identify differential coexpression patterns of genes and probed the functional mechanisms of the modules. Two real datasets were used to validate the method and allow comparisons with other methods. One of the datasets was selected to illustrate the flow of a typical analysis. In summary, we present an approach to robustly detect coexpression patterns in transcriptomes and to stratify patterns according to their relative differences. Furthermore, a global relationship between patterns and biological functions was constructed. In addition, a freely accessible web toolkit “coexpression pattern mining and GO functional analysis” (COGO) was developed.

Background/Aim: Dysregulated Hedgehog (Hh) signaling has been implicated in several human malignancies. Hh signaling inhibitors are predicted to have a minimal effect when the Smoothened receptor is mutated. Implications that Gli proteins are molecular targets of arsenic trioxide (ATO) action prompted us to investigate the expression of Hh signaling in acute promyelocytic leukemia (APL) and the influence of ATO on the Hh signaling pathway in APL. Methods: Quantitative real-time reverse transcription polymerase chain reaction and Western blot were employed to analyze the expression of Hh pathway components and the influence of ATO on the Hh signaling pathway in APL. Results: The expression of Hh pathway components was significantly upregulated in APL. In newly diagnosed APL patients, Gli2 expression was significantly positively correlated with Gli1 (R = 0.57, p < 0.001) and Smo (R = 0.56, p < 0.001) and the expression of Hh pathway components was significantly higher in the high WBC group (p < 0.05). ATO can significantly downregulate the expression of Hh pathway components in vitro and in vivo (p < 0.05). Conclusion: The Hh pathway is aberrantly activated in APL and associated with a bad prognostic factor. ATO can effectively inhibit the expression of the Hh pathway. The obtained data give the first clinical evidence for the application of ATO in tumors exhibiting an aberrantly activated Hh pathway.

Objective: To investigate the point mutations within the ABL kinase domain (KD) of Bcr-Abl fusion gene in Chinese patients with chronic myeloid leukemia who develop IM resistance and investigate the mutation. Method: We collect a total of 17 bone marrow samples obtained from 11 patients who showed hematology resistance(n=7) or cytogenetic refractoriness(n=4). A long semi-nest PCR method was used to amplify the ABL KD of the Bcr-Abl fusion gene. After two cycles of PCR reaction, we get a fragment including 863 bases, purified and sequenced it. Result: The ABL point mutation was detected in 45.45% of patients. The mutation rate of hematology resistance is 57.14% and the mutation rate of cytogenetic refractoriness is 25%. In total, we find three point mutation in all of our patients tested, ie, G250E(2), E255K(1) and T315I(2). In patients who develop hematology resistance, the earliest time to detect mutation is 4 months later after the therapy of IM and the longest time to detect mutation is 9 months later after the therapy of IM. In patients who develop cytogenetic refractoriness, the time to detect mutation is 12 months later after the therapy of IM .For the patients whose samples are available, no single mutation happens before IM thearpy. Conclusion: There is high frequency of point mutations clustered within the adenosine triphosphate-binding region of Bcr-Abl fusion gene in Chinese patients with chronic myeloid leukemia, and the mutation is related to IM therapy. It’s good for patients to switch to another therapeutic strategy when the mutations were detected earlier. Figure Figure

Targeted therapy with the Bcr-Abl tyrosine kinase inhibitor Imatinib Mesylate can induce high response rates in chronic myelogenous leukemia (CML) patients. However, evidences that discontinuation of imatinib mesylate inevitably exerts rapid loss of response and some patients with imatinib mesylate monotherapy virtually occur potential relapse suggest that the modification of treatment strategy is critical. We have previously demonstrated that the combination of trisenox (arsenic trioxide) with the tyrosine kinase inhibitor imatinib mesylate or genistein appears to induce markedly more cell apoptosis than imatinib mesylate alone through downregulating Bcl-XL and Bcr-Abl in Bcr-Abl gene transfected HL-60 cells. We here report the preliminary results of a pilot study comparing imatinib mesylate plus trisenox with imatinib mesylate alone for frontline treatment of CML patients. Up to date 56 patients were enrolled in this clinical trail. All patients (required to be 18 years or older with Bcr-Abl positive CML in chronic phase within three month of diagnosis) were divided into two groups, i.e., monotherapy group and combined therapy group. 42 patients entering monotherapy received imatinib mesylate 400mg daily and 14 patients entering combined therapy imatinib mesylate 400mg daily plus trisenox 10mg daily for one week and then twice a week. We compared treatment results of both groups including complete hematologic response(CHR), major/complete cytogenetic response(MCR/CCR),--defined as 1–35% Ph+ and 0% Ph+ metaphases respectively and major/complete molecular response(MMR/CMR),--defined as ≥ 3 log reduction and negative expression in Bcr-Abl transcript numbers assayed by RQ-PCR respectively. The median follow-up for patients in both groups lasted 36 months. In the combined therapy group, the median age of patients is 42 years old (range, 22–61), the CHR, MCR, CCR, MMR and CMR is 92.8%, 64.3%, 42.9%, 35.7% and 21.4%, respectively. While in the imatinib mesylate monotherapy group, the median age of patients is 46 years old (range, 23–65), the CHR, MCR, CCR, MMR and CMR is 85.7%, 59.5%, 40.5%, 33.3% and 19%, respectively. Although combination therapy of imatinib with trisenox is not significantly superior to imatinib mesylate monotherapy in efficacy, no resistance case happens in the combination therapy group, in the imatinib mesylate monotherapy group, imatinib resistance occurs in 4 patients. In addition, the safety and tolerability of a combination of imatinib mesylate and trisenox is good. This result indicates that the combination of imatinib and trisenox to treat chronic myeloid leukemia may be promising in avoiding the occur of imatinib resistance.