The ATF4-RPS19BP1 axis modulates ribosome biogenesis to promote erythropoiesis.

Hematopoietic differentiation is controlled by intrinsic regulators and the extrinsic hematopoietic niche. Activating transcription factor 4 (ATF4) plays a crucial role in the function of fetal and adult hematopoietic stem cell maintenance; however, the precise function of ATF4 in the bone marrow niche and the mechanism by which ATF4 regulates adult hematopoiesis remain largely unknown. Here, we employ four cell-type-specific mouse Cre lines to achieve conditional knockout of Atf4 in Cdh5+ endothelial cells, Prx1+ bone marrow stromal cells, Osx+ osteo-progenitor cells, and Mx1+ hematopoietic cells, and uncover the role of Atf4 in niche cells and hematopoiesis. Intriguingly, depletion of Atf4 in niche cells does not affect hematopoiesis; however, Atf4-deficient hematopoietic cells exhibit erythroid differentiation defects, leading to hypoplastic anemia. Mechanistically, ATF4 mediates direct regulation of Rps19bp1 transcription, which is, in turn, involved in 40S ribosomal subunit assembly to coordinate ribosome biogenesis and promote erythropoiesis. Finally, we demonstrate that under conditions of 5-fluorouracil-induced stress, Atf4 depletion impedes the recovery of hematopoietic lineages, which requires efficient ribosome biogenesis. Taken together, our findings highlight the indispensable role of the ATF4-RPS19BP1 axis in the regulation of erythropoiesis.

Interkingdom ecological networks between plants and fungi drive soil multifunctionality across arid inland river basin.

Despite the known collective contribution of above- (plants) and below-ground (soil fungi) biodiversity on multiple soil functions, how the associations among plant and fungal communities regulate soil multifunctionality (SMF) differentially remains unknown. Here, plant communities were investigated at 81 plots across a typical arid inland river basin, within which associated soil fungal communities and seven soil functions (nutrients storage and biological activity) were measured in surface (0-15 cm) and subsurface soil (15-30 cm). We evaluated the relative importance of species richness and biotic associations (reflected by network complexity) on SMF. Our results demonstrated that plant species richness and plant-fungus network complexity promoted SMF in surface and subsurface soil. SMF in two soil layers was mainly determined by plant-fungus network complexity, mean groundwater depth and soil variables, among which plant-fungus network complexity played a crucial role. Plant-fungus network complexity had stronger effects on SMF in surface soil than in subsurface soil. We present evidence that plant-fungus network complexity surpassed plant-fungal species richness in determining SMF in surface and subsurface soil. Moreover, plant-fungal species richness could not directly affect SMF. Greater plant-fungal species richness indirectly promoted SMF since they ensured greater plant-fungal associations. Collectively, we concluded that interkingdom networks between plants and fungi drive SMF even in different soil layers. Our findings enhanced our knowledge of the underlying mechanisms that above- and below-ground associations promote SMF in arid inland river basins. Future study should place more emphasis on the associations among plant and microbial communities in protecting soil functions under global changes.

Convenient method to improve efficiency of lymph node examination after gastrectomy with D2 lymphadenectomy for gastric cancer.

BACKGROUND: The D2 procedure has been accepted as the standard treatment for advanced gastric cancer (GC) in East Asia. Determination of the number of lymph nodes (LNs) after gastrectomy may influence the pathological stage assessment of lymph node metastasis, significantly influencing prognostic evaluations and formulation of chemotherapy regimens. METHODS: Between January 2020 and January 2022, the medical files of 312 patients with clinical stage T0-4aN0-3M0 gastric cancer were reviewed retrospectively, and the patients were assigned to the normal group (lymph nodes were examined roughly), manual group (lymph nodes were manually examined meticulously), and device group (lymph nodes were examined by device). The clinical and pathologic characteristics, number of lymph nodes harvested, and the time required for lymph node examination was compared. RESULTS: A total of 312 gastric cancer patients (mean age 65.8 ± 10.3 years, 85 females and 227 males) underwent gastrectomy with curative intent at our department. Sex, age, body mass index (BMI), tumor size, clinical TNM stage, and pathologic TNM stage in the three groups showed no statistically significant differences (P > 0.05). The mean number of harvested lymph nodes in the normal, manual, and device group was 24.2, 36.6 and 35.2, respectively, which showed significant differences (P < 0.0001). The mean number of positive lymph nodes in the normal, manual, and device group was 3.5, 3.9 and 3.9, respectively (P = 0.99). The mean time consumption in device group was 15 min while the time consumption in manual group was 52.3 min, which showed a significant difference (P < 0.0001). CONCLUSION: This improved lymph node examination method offers a simple approach that is worth promoting, and it can improve the number of harvested lymph nodes efficiently.

A diastereoselective three-component reaction for the assembly of succinimide and isatin hybrid molecules with potent anticancer activities.

A Rh2(OAc)4 catalyzed three-component reaction of vinyl diazosuccinimides with alcohols and isatins has been reported, which provides a practical assess to the direct assembly of succinimide and isatin hybrid molecules in good-to-high yields with excellent stereoselectivity. The antiproliferation activity of these synthesized succinimide and isatin hybrid products has been tested via the CCK8 assay in different cancer cell lines, and compounds 4g (SJSA-1, IC50 = 3.82 µM) and 4r (HCT-116, IC50 = 9.02 µM) exhibit higher anticancer potency than other tested compounds.

ZnBr2-Mediated oxidative spiro-bromocyclization of propiolamide for the synthesis of 3-bromo-1-azaspiro[4.5]deca-3,6,9-triene-2,8-dione.

ZnBr2-Mediated oxidative spiro-bromocyclization of N-arylpropiolamide has been described herein for the synthesis of 3-bromo-1-azaspiro[4.5]deca-3,6,9-triene-2,8-dione with high efficiency. One equivalent of water was introduced into the final product. The reaction efficiently proceeded at room temperature, and an excellent tolerance of functional groups was demonstrated. Under standard conditions, 3-bromo-1-oxaspiro[4.5]deca-3,6,9-triene-2,8-dione and 3-bromo-1-azaspiro[4.5]deca-3,6,9-trien-8-one were synthesized.

Baicalin attenuates bleomycin-induced pulmonary fibrosis via adenosine A2a receptor related TGF-ß1-induced ERK1/2 signaling pathway.

BACKGROUND: Baicalin has been reported to have anti-fibrosis effect; however, its mechanism still remains to be elucidated. Adenosine A2a receptor (A2aR) is a novel inflammation regulator, and transforming growth factor-ß1 (TGF-ß1)-induced extracellular signal regulated kinase1/2 (ERK1/2) signaling pathway plays an important role in idiopathic pulmonary fibrosis (IPF). This study was to explore the relationship of A2aR and TGF-ß1-induced ERK1/2 in bleomycin (BLM)-induced pulmonary fibrosis in mice, and to investigate whether A2aR mediate the anti-fibrosis effect of Baicalin on BLM-induced pulmonary fibrosis. METHODS: The A2aR-/- and A2aR+/+ mice were respectively divided into three groups: control group, model group, baicalin group. Pulmonary fibrosis was induced in mice of model groups by intratracheal instillation of bleomycin, and baicalin was administered in mice of baicalin groups daily for 28 days. Histopathological and ultrastructural changes of lung tissues were evaluated. Lung coefficient and the levels of hydroxyproline (HYP) in lung tissues were measured at the same time. The levels of serum TGF-ß1 were measured by ELISA. The expression of TGF-ß1, ERK1/2, p-ERK1/2 and A2aR were detected by western blot and immunohistochemical staining techniques. RESULTS: Severe lung fibrosis was observed in the bleomycin-treated mice on day 28. The histopathological findings and collagen content of lung tissues were much severer/higher in A2aR-/- mice than in A2aR+/+ mice. We also showed that TGF-ß1 and p-ERK1/2 were upregulated in bleomycin-treated mice and expressed higher in A2aR-/- mice compared to A2aR+/+ mice. Besides, bleomycin-treated A2aR+/+ mice had increased A2aR level in lungs. However, long-term treatment with baicalin in A2aR-/- and A2aR+/+ mice significantly ameliorated the histopathological changes in lungs. Moreover, Increased TGF-ß1 and p-ERK1/2 expressions in bleomycin-treated A2aR-/- and A2aR+/+ mice were obviously diminished by baicalin. The baicalin-treated A2aR-/- mice had severer lung fibrosis and higher expressions of TGF-ß1 and p-ERK1/2 than A2aR+/+ mice. Baicalin has also upregulated the expression of A2aR in A2aR+/+ mice. CONCLUSIONS: Genetic inactivation of A2aR exacerbated the pathological processes of bleomycin-induced pulmonary fibrosis. Together, baicalin could inhibit BLM-induced pulmonary fibrosis by upregulating A2aR, suggesting A2aR as a therapeutic target of baicalin for the treatment of pulmonary fibrosis.

Screening of sustainable supply chain performance evaluation indicators based on the ill-conditioned index cycle method.

The establishment of an evaluation indicator system that can accurately assess the sustainability of a supply chain while further enhancing its performance is vital and relevant. Based on the connotation of sustainable supply chains and triple bottom line theory, indicators are initially proposed from economic, environmental, and social dimensions. To increase the explanatory power of the indicator system and decrease information redundancy, the coefficient of variation is applied to identify the indicators with weak interpretation intensity, the ill-conditioned index cycle method is utilized to filter out indicators with redundant information, and data on 100 Chinese listed companies from 2019 to 2021 are used as samples. A performance evaluation indicator system of sustainable supply chains with 16 indicators is ultimately established. The information interpretation strength index and cumulative information contribution rate verify the rationality of the final indicator system. The outcome demonstrates that this screening method can strengthen the representativeness of the indicator system and rapidly reduce redundancy, leading to the better discrimination of the evaluation results. The findings of this study provide an indicator system and a methodological reference for both companies and policymakers and can aid in the transformation of supply chains toward sustainability.

Nitrogen enrichment delays the drought threshold responses of leaf photosynthesis in alpine grassland plants.

Extreme drought is found to cause a threshold response in photosynthesis in ecosystem level. However, the mechanisms behind this phenomenon are not well understood, highlighting the importance of revealing the drought thresholds for multiple leaf-level photosynthetic processes. Thus, we conducted a long-term experiment involving precipitation reduction and nitrogen (N) addition. Moreover, an extreme drought event occurred within the experimental period. We found the presence of drought thresholds for multiple leaf-level photosynthetic processes, with the leaf light-saturated carbon assimilation rate (Asat) displaying the highest threshold (10.76 v/v%) and the maximum rate of carboxylation by Rubisco (Vcmax) showing the lowest threshold (5.38 v/v%). Beyond the drought thresholds, the sensitivities of leaf-level photosynthetic processes to soil water content could be greater. Moreover, N addition lowered the drought thresholds of Asat and stomatal conductance (gs), but had no effect on that of Vcmax. Among species, plants with higher leaf K concentration traits had a lower drought threshold of Asat. Overall, this study highlights that leaf photosynthesis may be suppressed abruptly as soil water content surpasses the drought threshold. However, N enrichment helps to improve the resistance via delaying drought threshold response. These new findings have important implications for understanding the nonlinearity of ecosystem productivity response and early warning management in the scenario of combined extreme drought events and continuous N deposition.

Different microbial functional traits drive bulk and rhizosphere soil phosphorus mobilization in an alpine meadow after nitrogen input.

Enhanced nitrogen (N) input is expected to influence the soil phosphorus (P) cycling through biotic and abiotic factors. Among these factors, soil microorganisms play a vital role in regulating soil P availability. However, the divergent contribution of functional microorganisms to soil P availability in the rhizosphere and bulk soil under N addition remains unclear. We conducted an N addition experiment with four N input rates (0, 5, 10, and 15 g N m-2 year-1) in an alpine meadow over three years. Metagenomics was employed to investigate the functional microbial traits in the rhizosphere and bulk soil. We showed that N addition had positive effects on microbial functional traits related to P-cycling in the bulk and rhizosphere soil. Specifically, high N addition significantly increased the abundance of most microbial genes in the bulk soil but only enhanced the abundance of five genes in the rhizosphere soil. The soil compartment, rather than the N addition treatment, was the dominant factor explaining the changes in the diversity and network of functional microorganisms. Furthermore, the abundance of functional microbial genes had a profound effect on soil available P, particularly in bulk soil P availability driven by the ppa and ppx genes, as well as rhizosphere soil P availability driven by the ugpE gene. Our results highlight that N addition stimulates the microbial potential for soil P mobilization in alpine meadows. Distinct microbial genes play vital roles in soil P availability in bulk and rhizosphere soil respectively. This indicates the necessity for models to further our knowledge of P mobilization processes from the bulk soil to the rhizosphere soil, allowing for more precise predictions of the effects of N enrichment on soil P cycling.

Soil properties and fungal community jointly explain N2O emissions following N and P enrichment in an alpine meadow.

Nutrient enrichment, such as nitrogen (N) and phosphorus (P), typically affects nitrous oxide (N2O) emissions in terrestrial ecosystems, predominantly via microbial nitrification and denitrification processes in the soil. However, the specific impact of soil property and microbial community alterations under N and P enrichment on grassland N2O emissions remains unclear. To address this, a field experiment was conducted in an alpine meadow of the northeastern Qinghai-Tibetan Plateau. This study aimed to unravel the mechanisms underlying N and P enrichment effects on N2O emissions by monitoring N2O fluxes, along with analyzing associated microbial communities and soil physicochemical properties. We observed that N enrichment individually or in combination with P enrichment, escalated N2O emissions. P enrichment dampened the stimulatory effect of N enrichment on N2O emissions, indicative of an antagonistic effect. Structural equation modeling (SEM) revealed that N enrichment enhanced N2O emissions through alterations in fungal community composition and key soil physicochemical properties such as pH, ammonium nitrogen (NH4+-N), available phosphorus (AP), microbial biomass carbon (MBC), and microbial biomass nitrogen (MBN)). Notably, our findings demonstrated that N2O emissions were significantly more influenced by fungal activities, particularly genera like Fusarium, rather than bacterial processes in response to N enrichment. Overall, the study highlights that N enrichment intensifies the role of fungal attributes and soil properties in driving N2O emissions. In contrast, P enrichment exhibited a non-significant effect on N2O emissions, which highlights the critical role of the fungal community in N2O emissions responses to nutrient enrichments in alpine grassland ecosystems.

Modular Divergent Synthesis of Functionalized Indoles via TFA-Promoted Amino-Claisen Rearrangement at Room Temperature.

A conceptually novel approach for the modular and divergent synthesis of highly functionalized indoles via trifluoroacetic acid-promoted amino-Claisen rearrangement is reported. This metal-free protocol could be performed at room temperature with wide functional group tolerance. The substitution type of the resultant indoles could be easily adjusted by the variation of the starting propargyl amines. The resultant products could be easily transformed into different value-added indole derivatives with simple experimental operations.

Differential Outcomes of Infection by Wild-Type SARS-CoV-2 and the B.1.617.2 and B.1.1.529 Variants of Concern in K18-hACE2 Transgenic Mice.

BACKGROUND: SARS-CoV-2 is a respiratory virus with neurological complications including the loss of smell and taste, headache, and confusion that can persist for months or longer. Severe neuronal cell damage has also been reported in some cases. The objective of this study was to compare the infectivity of the wild-type virus, Delta (B.1.617.2) and Omicron (B.1.1.529) variants in transgenic mice that express the human angiotensin-converting enzyme 2 (hACE2) receptor under the control of the keratin 18 promoter (K18) and characterize the progression of infection and inflammatory response in the lungs, brain, medulla oblongata, and olfactory bulbs of these animals. We hypothesized that wild type, Delta and Omicron differentially infect K18-hACE2 mice, thereby inducing distinct cellular responses. METHODS: K18-hACE2 female mice were intranasally infected with wild-type, Delta, or Omicron variants and euthanized either at 3 days post-infection (dpi) or at the humane endpoint. None of the animals infected with the Omicron variant reached the humane endpoint and were euthanized at day 8 dpi. Virological and immunological analyses were performed in the lungs, brains, medulla oblongata and olfactory bulbs isolated from infected mice. RESULTS: At 3 dpi, mice infected with wild type and Delta displayed significantly higher levels of viral RNA in the lungs than mice infected with Omicron, while in the brain, Delta and Omicron resulted in higher levels of viral RNA than with the wild type. Viral RNA was also detected in the medulla oblongata of mice infected by all these virus strains. At this time point, the mice infected with wild type and Delta displayed a marked upregulation of many inflammatory markers in the lungs. On the other hand, the upregulation of inflammatory markers was observed only in the brains of mice infected with Delta and Omicron. At the humane endpoint, we observed a significant increase in the levels of viral RNA in the lungs and brains of mice infected with wild type and Delta, which was accompanied by the elevated expression of many inflammatory markers. In contrast, mice which survived infection with the Omicron variant showed high levels of viral RNA and the upregulation of cytokine and chemokine expression only in the lungs at 8 dpi, suggesting that infection and inflammatory response by this variant is attenuated in the brain. Reduced RNA levels and the downregulation of inflammatory markers was also observed in the medulla oblongata and olfactory bulbs of mice infected with Omicron at 8 dpi as compared with mice infected with wild-type and Delta at the humane end point. Collectively, these data demonstrate that wild-type, Delta, and Omicron SARS-CoV-2 induce distinct levels of infection and inflammatory responses in K18-hACE2 mice. Notably, sustained brain infection accompanied by the upregulation of inflammatory markers is a critical outcome in mice infected with wild type and Delta but not Omicron.

Shifting biomass allocation and light limitation co-regulate the temporal stability of an alpine meadow under eutrophication.

Eutrophication generally promotes but destabilizes grassland productivity. Under eutrophication, plants tend to decrease biomass allocation to roots but increase aboveground allocation and light limitation, likely affecting community stability. However, it remains unclear to understand how shifting plant biomass allocation and light limitation regulate grassland stability in response to eutrophication. Here, using a 5-yr multiple nutrient addition experiment in an alpine meadow, we explored the role of changes in plant biomass allocation and light limitation on its community stability under eutrophication as well as traditionally established mechanisms (i.e., plant Shannon diversity, species asynchrony and grass subcommunity stability). Our results showed that nitrogen (N) addition, rather than phosphorus (P) or potassium (K) addition, significantly reduced the temporal stability of the alpine meadow. In accordance with previous studies, we found that N addition decreased plant Shannon diversity, species asynchrony and grass subcommunity stability, further destabilizing meadow community productivity. In addition, we also found the decrease in biomass allocation to belowground by N addition, further weakening its community stability. Moreover, this shifts in plant biomass allocation from below- to aboveground, intensifying plant light limitation. Further, the light limitation reduced plant species asynchrony, which finally weakened its community stability. Overall, in addition to traditionally established mechanisms, this study highlights the role of plant biomass allocation shifting from belowground to aboveground in determining grassland community stability. These "unseen" mechanisms might improve our understanding of grassland stability in the context of ongoing eutrophication.

Depth-dependent drivers of soil aggregate carbon across Tibetan alpine grasslands.

Elucidating the effects underlying soil organic carbon (SOC) variation is imperative for ascertaining the potential drivers of mitigating climate change. However, the drivers of variations in various SOC fractions (e.g., macroaggregate C, microaggregate C, and silt and clay C) at different soil depths remain poorly understood. Here, we investigated the effects and relative contributions of climatic, plant, edaphic, and microbial factors on soil aggregate C between the topsoil (0-10 cm) and subsoil (20-30 cm) across alpine grasslands on the Tibetan Plateau. Results showed that the C content of macroaggregates, microaggregates, and silt and clay fractions in the topsoil was 128.6 %, 49.6 %, and 242.4 % higher than that in the subsoil, respectively. Overall, plant properties were the most determinants controlling soil macroaggregate, microaggregate, and silt + clay associated C for both two soil depths, accounting for 32.2 %, 37.4 %, and 38.8 % of the variation, respectively, followed by edaphic, microbial, and climatic factors. The aggregate C of both soil depths was significantly related with the climatic, plant, edaphic, and microbial factors, but the relative importance of these determinants was soil-depth dependent. Specifically, the effects of plant root biomass and microbial (e.g., microbial biomass carbon and fungal diversity index) factors on each aggregate C weakened with soil depth, but the importance of edaphic factors (e.g., clay content, pH, and bulk density) strengthened with soil depth, except for the weakened effect of bulk density on the microaggregate C. And the effects of climatic factor (e.g., mean annual precipitation) on macroaggregate and microaggregate C increased with soil depth. Our results highlight differential drivers and their impacts on soil aggregate C between the topsoil and subsoil, which benefits biogeochemical models for more accurately forecasting soil C dynamics and its feedbacks to environmental changes.

Kinetically Controllable Construction of Nine-Membered Carbocycles via Pd-Catalyzed Decarboxylative Cycloaddition.

A kinetically controllable strategy toward the construction of otherwise challenging nine-membered carbocycles is reported. This Pd-catalyzed decarboxylative procedure utilizes vinyl methylene cyclic carbonates as the C5-dipole and allylidenemalononitriles as C4-building blocks. The protocol features user-friendly operations with controllable regioselectivity and generates CO2 as the sole byproduct. The formation of synthetically valuable and thermodynamically favored seven-membered carbocycles was also investigated.

The complete mitochondrial genome of Melanostoma mellinum (Linnaeus, 1758) (Diptera: Syrphidae) and phylogenetic analysis.

In this study, the complete mitochondrial genome (mitogenome) of Melanostoma mellinum (Linnaeus, 1758) was sequenced using the-next generation sequencing technology. The assembled mitogenome of M. mellinum has a total length of 16,055bp and contains 13 protein-coding genes (PCGs), 22 transfer RNA genes (tRNAs), and 2 ribosomal RNA genes (rRNAs). The results of phylogenetic reconstruction based on the combined mitochondrial gene dataset indicated that M. mellinum belongs to Melanostoma genus with a close relationship to Melanostoma orientale, but the monophyly of the tribe Bacchini is not well supported.

The complete mitochondrial genome of Eristalinus viridis (Coquillett, 1898) (Diptera: Syrphidae) and its phylogenetic implications.

The complete mitochondrial genome of Eristalinus viridis (Coquillett, 1898) was obtained for the first time using Next Generation Sequencing (NGS). The mitogenome assembly of E. viridis is 15,640 bp in length and its annotation confirms the presence of 13 protein-coding genes (PCGs), 22 transfer RNA genes (tRNAs), two ribosomal RNA genes (rRNAs), and one putative control region. The results of the phylogenetic analyses using Maximum Likelihood and Bayesian inference recover a highly supported sister relationship between E. viridis and Mallota bellus.

Plant Evolution History Overwhelms Current Environment Gradients in Affecting Leaf Chlorophyll Across the Tibetan Plateau.

Aims: Leaf chlorophyll (Chl) is a fundamental component and good proxy for plant photosynthesis. However, we know little about the large-scale patterns of leaf Chl and the relative roles of current environment changes vs. plant evolution in driving leaf Chl variations. Locations: The east to west grassland transect of the Tibetan Plateau. Methods: We performed a grassland transect over 1,600 km across the Tibetan Plateau, measuring leaf Chl among 677 site-species. Results: Leaf Chl showed a significantly spatial pattern across the grasslands in the Tibetan Plateau, decreasing with latitude but increasing with longitude. Along with environmental gradient, leaf Chl decreased with photosynthetically active radiation (PAR), but increased with water availability and soil nitrogen availability. Furthermore, leaf Chl also showed significant differences among functional groups (C4 > C3 species; legumes < non-legume species), but no difference between annual and perennial species. However, we surprisingly found that plant evolution played a dominant role in shaping leaf Chl variations when comparing the sum and individual effects of all the environmental factors above. Moreover, we revealed that leaf Chl non-linearly decreased with plant evolutionary divergence time. This well-matches the non-linearly increasing trend in PAR or decreasing trend in temperature during the geological time-scale uplift of the Tibetan Plateau. Main Conclusion: This study highlights the dominant role of plant evolution in determining leaf Chl variations across the Tibetan Plateau. Given the fundamental role of Chl for photosynthesis, these results provide new insights into reconsidering photosynthesis capacity in alpine plants and the carbon cycle in an evolutionary view.

MiRNA-124-3p.1 sensitizes hepatocellular carcinoma cells to sorafenib by regulating FOXO3a by targeting AKT2 and SIRT1.

As a multikinase inhibitor, sorafenib is commonly used to treat patients with advanced hepatocellular carcinoma (HCC), however, acquired resistance to sorafenib is a major obstacle to the effectiveness of this treatment. Thus, in this study, we investigated the mechanisms underlying sorafenib resistance as well as approaches devised to increase the sensitivity of HCC to sorafenib. We demonstrated that miR-124-3p.1 downregulation is associated with early recurrence in HCC patients who underwent curative surgery and sorafenib resistance in HCC cell lines. Regarding the mechanism of this phenomenon, we identified FOXO3a, an important cellular stress transcriptional factor, as the key factor in the function of miR-124-3p.1 in HCC. We showed that miR-124-3p.1 binds directly to AKT2 and SIRT1 to reduce the levels of these proteins. Furthermore, we showed that AKT2 and SIRT1 phosphorylate and deacetylate FOXO3a. We also found that miR-124-3p.1 maintains the dephosphorylation and acetylation of FOXO3a, leading to the nuclear location of FOXO3a and enhanced sorafenib-induced apoptosis. Moreover, the combination of miR-124-3p.1 mimics and sorafenib significantly enhanced the curative efficacy of sorafenib in a nude mouse HCC xenograft model. Collectively, our data reveal that miR-124-3p.1 represents a predictive indicator of early recurrence and sorafenib sensitivity in HCC. Furthermore, we demonstrate that miR-124-3p.1 enhances the curative efficacy of sorafenib through dual effects on FOXO3a. Thus, the miR-124-3p.1-FOXO3a axis is implicated as a potential target for the diagnosis and treatment of HCC.

WDR82-binding long noncoding RNA lncEry controls mouse erythroid differentiation and maturation.

Hematopoietic differentiation is controlled by both genetic and epigenetic regulators. Long noncoding RNAs (lncRNAs) have been demonstrated to be important for normal hematopoiesis, but their function in erythropoiesis needs to be further explored. We profiled the transcriptomes of 16 murine hematopoietic cell populations by deep RNA sequencing and identified a novel lncRNA, Gm15915, that was highly expressed in erythroid-related progenitors and erythrocytes. For this reason, we named it lncEry. We also identified a novel lncEry isoform, which was the principal transcript that has not been reported before. lncEry depletion impaired erythropoiesis, indicating the important role of the lncRNA in regulating erythroid differentiation and maturation. Mechanistically, we found that lncEry interacted with WD repeat-containing protein 82 (WDR82) to promote the transcription of Klf1 and globin genes and thus control the early and late stages of erythropoiesis, respectively. These findings identified lncEry as an important player in the transcriptional regulation of erythropoiesis.