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Acute myeloid leukemia (AML) with retinoic acid receptor gamma ( RARG ) fusions, which exhibits clinical features resembling acute promyelocytic leukemia (APL), has been identified as a new subtype with poor clinical outcomes. The underlying mechanism of RARG -fusion leukemia remains poorly understood, and needs to be explored urgently to instruct developing effective therapeutic strategies. Here, using the most prevalent RARG fusion, CPSF6-RARG ( CR ), as a representative, we reveal that the CR fusion, enhances the expansion of myeloid progenitors, impairs their maturation and synergizes with RAS mutations to drive more aggressive myeloid malignancies. Mechanistically, CR fusion interacts with histone deacetylase 3 (HDAC3) to suppress expression of genes associated with myeloid differentiation including the myeloid transcription factor PU.1. Disrupting CR-HDAC3 interaction, restores PU.1 expression and myeloid differentiation. Furthermore, HDAC inhibitors effectively suppress C R -driven leukemia in vitro and in vivo. Hence, our data reveals the molecular bases of oncogenic CR fusion and provides a potential therapeutic approach against AML with CR fusion. Acute myeloid leukemia (AML) with retinoic acid receptor-gamma (RARG) fusions have similarities to acute promyelocytic leukemia (APL) and poor prognosis. Here, the authors show that the CPSF6-RARG (CR) fusion interacts with histone deacetylase 3 (HDAC3) to promote myeloid transformation and HDAC inhibitors reduce CR-associated leukemia in preclinical murine models.

This study recommends a non-grinding measurement method of leaf pH which can reduce the destructive interference to the measured fresh-leaf pH values. To verify the accuracy of this method, we measured leaf pH with the non-grinding and grinding method and further assessed the dilution effect on leaf pH in the grinding process. Compared with the non-grinding method, the grinding method significantly increased the measured pH value; leaf pH increased with decreasing leaf–water ratio in the procedure of the grinding method, but gradually stabilized. The grinding effects of severe physical damage and thereafter oxidization of leaf samples, and the dilution effects according to the Debye–Hückel limiting law and acid-base ionization theory, may both contribute to the increased leaf pH measured with the grinding method. Thus, leaf pH measured with the non-grinding method was expected to be much closer to those of leaf sap in vivo and be more suitable to indicating the dynamic variation or instant response of leaf pH to the environmental changes. Finally, considering that non-significant difference had been proved in the measured leaf pH between dried, frozen, refrigerated, and fresh ground samples, a conversion equation was provided to facilitate mutual conversion of the results with non-grinding fresh samples (y) against those with grinding dried samples (as representative) (x): y = 1.097x − 0.722.

The incidence of lipid metabolism disorder and obesity that is caused by high-calorie diets is increasing year by year, which has become an urgent global health problem. This study was performed to explore the intervention effects of polysaccharides that were extracted from Auricularia auricula-judae resources in the Qinba Mountain area on nutritional obesity in C57BL/6J mice that was induced by high fat and high fructose diets (HFFD) and to investigate their underlying molecular mechanisms. The results showed that dietary supplementation of Auricularia auricula-judae polysaccharides (AAP) significantly improved mice’s insulin resistance state, altered serum lipid metabolites, and slowed down body weight gain that was induced by HFFD. In addition, AAP supplementation decreased inflammatory factor levels and alleviated liver histomorphology changes. Furthermore, AAP down-regulated liver adipogenic-related gene expressions, suppressed cholesterol synthesis-related gene levels, up-regulated fatty acid β-oxidation-related gene expressions, and promoted cholesterol efflux-related gene expressions, thus improving mice hepatic lipid metabolism homeostasis. Moreover, the intervention effects were closely related to mitochondrial function. These results provide a scientific basis for the further development and utilization of Auricularia auricula-judae resources in the Qinba Mountain area.

BackgroundSoil fauna is an important driver of carbon (C) and nitrogen (N) release from decomposing litter in forest ecosystems. However, its role in C and N cycling concerning climate and litter traits remains less known. In a 4-year field experiment, we evaluated the effects of soil fauna on litter C and N release across an elevation gradient (453, 945, 3023, and 3582 m) and litter traits (coniferous vs. broadleaf) in southwestern China.ResultsOur results showed that N was retained by –0.4% to 31.5%, but C was immediately released during the early stage (156–516 days) of decomposition for most litter species. Soil fauna significantly increased the peak N content and N retention across litter species, but reduced the C/N ratio for certain species (i.e., Juniperus saltuaria, Betula albosinensis, Quercus acutissima, and Pinus massoniana litter), leading to more C and N being released from decomposing litter across the elevation gradient. Contributions of soil fauna to C and N release were 3.87–9.90% and 1.10–8.71%, respectively, across litter species after 4 years of decomposition. Soil environment and initial litter quality factors caused by elevation directly affected litter C and N release. Changes in soil fauna resulting from elevation and fauna exclusion factors had a direct or indirect impact on C and N release during litter decomposition.ConclusionsOur findings suggest that soil fauna promote C and N release from decomposing litter in different magnitudes, mainly controlled by environmental conditions (i.e., temperature and moisture), litter quality (i.e., lignin and cellulose content, and lignin/cellulose), and its diversity across the elevation gradient.

CD19 chimeric antigen receptor (CAR) T-cell therapy has shown great success against B-cell acute lymphoblastic leukemia (B-ALL). Tandem and sequential CD19/CD22 dual-target CAR T-cell therapies have been developed to reduce the possibility of CD19-negative relapse; however, the superior strategy is still uncertain. This study screened 219 patients with relapsed/refractory B-ALL who were enrolled in clinical trials of either CD19 (NCT03919240) or CD19/CD22 CAR T-cell therapy (NCT03614858). The complete remission (CR) rates in the single CD19, tandem CD19/CD22, and sequential CD19/CD22 groups were 83.0% (122/147), 98.0% (50/51), and 95.2% (20/21), respectively (single CD19 vs. tandem CD19/CD22, P = 0.006). Patients with high-risk factors achieved a higher rate of CR in the tandem CD19/CD22 group than in the single CD19 group (100.0% vs. 82.4%, P = 0.017). Tandem CD19/CD22 CAR T-cell therapy was one of the significant favorable factors in the multivariate analysis of the CR rate. The incidence of adverse events was similar among the three groups. Multivariable analysis in CR patients showed that a low frequency of relapse, a low tumor burden, minimal residual disease-negative CR and bridging to transplantation were independently associated with better leukemia-free survival. Our findings suggested that tandem CD19/CD22 CAR T-cell therapy obtains a better response than CD19 CAR T-cell therapy and a similar response to sequential CD19/CD22 CAR T-cell therapy.

Resistance to tyrosine kinase inhibitor (TKI) is a tough problem in the treatment of chronic myeloid leukemia in blastic phase (CML-BP), which was often associated with acquired mutations in the kinase domain and not eliminating the leukemic stem cells. The efficacy of TKI or combination with chemotherapy in CML-BP remains unsatisfactory. Chimeric antigen receptor T (CAR-T) cell immunotherapy may overcome TKI and chemotherapy resistance. However, lack of ideal targetable antigens is a major obstacle for treating patients with myeloid malignancies. CD38 is known to be expressed on most (acute myeloid leukemia) AML cells, and its lack of expression on hematopoietic stem cells renders it as a potential therapeutic target for myeloid CML-BP. We develop a CD38-directed CAR-T cell therapy for AML, and two patients with myeloid CML-BP were enrolled (NCT04351022). Two patients, harboring E255K and T315I mutation in the ABL kinase domain, respectively, were resistant to multiple TKIs (imatinib, dasatinib, nilotinib, and ponatinib) and intensive chemotherapy. The blasts in the bone marrow of two patients exhibited high expression of CD38. After tumor reduction chemotherapy and lymphodepletion chemotherapy, 1 × 10 7 CAR-T-38 cells per kilogram of body weight were administered. They achieved minimal residual disease–negative and BCR::ABL1 -negative complete remission and experienced grade II cytokine release syndrome manifesting as fever. Our data highlighted that CAR-T-38 cell therapy may overcome TKI and chemotherapy resistance in patients with myeloid CML-BP.

Cobalt-free manganese-based lithium-rich layered oxides (LLOs) have garnered research attention as prospective lithium-ion cathode materials owing to their large specific capacity and low price. However, their large-scale application is hindered by their low Coulombic efficiency, poor cycling performance, voltage attenuation, and structural phase transition. To address these issues, the LLO structure is modified via Ti doping at the manganese site herein. Ti-doped Li1.2Mn0.6−xTixNi0.2O2 (x = 0, 0.03, 0.05, 0.10, and 0.15) is prepared using the high-temperature solid-state method. The Ti-doped Li1.2Mn0.6Ni0.2O2 is calculated via first principles. The results show that Ti4+ doping improves the cycle stability and rate performance of Li1.2Mn0.6Ni0.2O2. Electrochemical test results show that the sample exhibits enhanced electrochemical performance when the Ti doping amount is 0.05. The discharge specific capacity at 0.1C is 210.4 mAh·g−1, which reaches 191.1 mAh·g−1 after 100 cycles, with a capacity retention rate of 90.7%. This study proves the feasibility of using cheap cobalt-free LLOs as cathode materials for LIBs and provides a novel system for exploiting low-cost and high-performance cathode materials.

Relapse is a major limitation of chimeric antigen receptor (CAR) T-cell therapy. Here, we speculated that decitabine (DAC) in combination with fludarabine and cyclophosphamide (FC) as a lymphodepletion regimen may improve the efficacy of CD19/CD22 CAR T-cell therapy. Fourteen of 26 patients with relapsed/refractory B cell acute lymphoblastic leukemia (r/r B-ALL) without remission before lymphodepletion treatment were treated with DAC (total dose 100 mg/m 2 in 3 days) followed by the FC regimen (DAC group), while twelve patients received the FC regimen (CON group). On Day 28 after CAR T-cells infusion, no significant differences in complete remission (CR) and minimal residual disease negative CR rates were found between both groups. However, there were significant differences in overall survival (OS) and leukemia-free survival (LFS) between two groups: 3-year OS, 92.3% (DAC) versus 41.7% (CON), P = 0.005 and 3-year LFS, 92.9% (DAC) versus 27.3% (CON), P < 0.001. There was no significant difference in the incidence of cytokine release syndrome between both groups. Median time to platelet and neutrophil counts recovery was similar in both groups. All adverse events were reversible and manageable. In conclusion, DAC in combination with the FC lymphodepletion regimen may be a new treatment option that can improve the efficacy of CAR T-cell therapy in r/r B-ALL.

Soil organic carbon (SOC) is critical for carbon cycling and sequestration in forest ecosystems. However, how stand age affects SOC components and stability still remains poorly understood. Here, soil samples (0–20 cm) were collected from Cryptomeria japonica var. sinensis (L. f.) D. Don plantations of seven stand ages (6, 12, 23, 27, 32, 46, 52 a) in the rainy area of western China. SOC fractions, including soil particulate organic carbon (POC), easily oxidizable carbon (EOC), labile organic carbon (LOC), recalcitrant organic carbon (ROC), and light fraction organic carbon (LFOC), were determined to explore the nature of carbon components and stability across a chronosequence of C. japonica plantation. Soil carbon fractions first increased and then trended to be stable with an increase in stand age. SOC concentrations were the largest in mature forests (27 or 32 a), but the concentrations of other carbon components often peaked in early over-mature forests (46 a). The concentrations of all carbon fractions were the lowest in the young forests (6 a). The ratios of ROC/SOC increased and LOC/SOC decreased with increasing stand age. Almost all carbon fractions were positively correlated with soil bulk density and negatively correlated with soil moisture. The allometric exponent of ROC or HFOC and soil physicochemical properties was higher as compared to LOC and LFOC. The results noted in this study indicate that SOC components often accumulate fast over the first 20 years of afforestation and SOC stability increases with increasing stand age for C. japonica plantation in this specific region.

Nitrogen deposition has a considerable impact on biogeochemical cycling in terrestrial ecosystems. However, how litter production and element return respond to N addition remains poorly understood in nitrogen-rich subtropical regions. In this study, a 4-year nitrogen addition experiment explored its effects on foliar litter production and carbon, nitrogen and phosphorus in a subtropical Michelia wilsonii forest. A clear seasonal pattern in foliar litterfall was observed, regardless of nitrogen treatments, with a peak in spring and a smaller one in autumn. Foliar litter increased with increasing nitrogen but did not affect litter carbon concentrations and often decreased nitrogen and phosphorous concentrations. The effect of nitrogen addition was dependent on time (month/year). Carbon, nitrogen and phosphorous return showed similar bimodal seasonal patterns. Nitrogen addition increased carbon and nitrogen return but did not affect phosphorous. Our results suggest that the addition of nitrogen stimulates carbon and nutrient return via litterfall.