SMARCA5 reprograms AKR1B1-mediated fructose metabolism to control leukemogenesis.

A significant variation in chromatin accessibility is an epigenetic feature of leukemia. The cause of this variation in leukemia, however, remains elusive. Here, we identify SMARCA5, a core ATPase of the imitation switch (ISWI) chromatin remodeling complex, as being responsible for aberrant chromatin accessibility in leukemia cells. We find that SMARCA5 is required to maintain aberrant chromatin accessibility for leukemogenesis and then promotes transcriptional activation of AKR1B1, an aldo/keto reductase, by recruiting transcription co-activator DDX5 and transcription factor SP1. Higher levels of AKR1B1 are associated with a poor prognosis in leukemia patients and promote leukemogenesis by reprogramming fructose metabolism. Moreover, pharmacological inhibition of AKR1B1 has been shown to have significant therapeutic effects in leukemia mice and leukemia patient cells. Thus, our findings link the aberrant chromatin state mediated by SMARCA5 to AKR1B1-mediated endogenous fructose metabolism reprogramming and shed light on the essential role of AKR1B1 in leukemogenesis, which may provide therapeutic strategies for leukemia.

Value of 2D speckle tracking technique combined with real-time 3-dimensional echocardiography in the evaluation of the right atrial function in patients with 3-branch coronary artery disease without myocardial infarction.

To evaluate the right atrial function in patients with 3-branch coronary artery disease (TBCAD) without myocardial infarction by 2D speckle tracking echocardiography (2D-STE) combined with real-time 3-dimensional echocardiography (RT-3DE). Fifty-six patients admitted to our hospital without myocardial infarction with TBCAD were selected. We divided them into 2 groups according to the coronary angiography results: 28 patients in group B (the rate of stenosis is 50% ~< 75%); 28 patients in group C (the rate of stenosis is ≥75%); in addition, 30 healthy volunteers were screened as group A. All subjects underwent RT-3DE to obtain the right atrial volume (RAVmax, RAVmin, and RAVp), and then we calculated the right atrial passive and active ejection fraction (RAPEF, RAAEF), and maximum volume index (RAVImax). In addition, to measure the strain rates (RASRs, RASRe, RASRa) of the right atrium during systole, early diastole, and late diastole, 2D-STE was applied. Correlations between the 2D-STE parameters and the results of N-terminal pro-brain natriuretic peptide (NT-proBNP) and Gensini scores were analyzed by Pearson linear analysis. Compared with group A, RAPEF and RASRe were reduced, while RAAEF and RASRa were elevated in group B (P < .05). RAPEF, RASRs, RASRe, and RASRa were decreased compared with groups A and B, while RAVmax, RAVmin, RAVp, RAVImax, and RAAEF were increased in group C (P < .05). There was a significant correlation between 2D-STE parameters and the results of NT-proBNP and Gensini scores (P < .05). The storage, conduit, and pump functions of the right atrium are reduced in patients with 3-branch coronary artery disease without myocardial infarction; 2D-STE combined with RT-3DE is valuable in the evaluation of the right atrium in patients with coronary artery disease.

Anchoring Single-Atomic Metal Sites in Metalloporphyrin-Based Covalent Organic Frameworks for Enhanced Photocatalytic Hydrogen Evolution.

A photoactive covalent organic framework (COF) was built from metalloporphyrin and bipyridine monomers and single-atomic Pt sites were subsequently installed. Integrating photosensitizing metalloporphyrin and substrate-activating Pt(bpy) moieties in a single solid facilitates multielectron transfer and accelerates photocatalytic hydrogen evolution with a maximum production rate of 80.4 mmol h-1 gPt-1 and turnover frequency (TOF) of 15.7 h-1 observed. This work demonstrates that incorporation of single-atomic metal sites with photoactive COFs greatly enhances photocatalytic activity and provides an effective strategy for the design and construction of novel photocatalysts.

Hydrogen-bonded organic frameworks in solution enables continuous and high-crystalline membranes.

Hydrogen-Bonded organic frameworks (HOFs) are a type of emerging porous materials. At present, little research has been conducted on their solution state. This work demonstrates that HOFs fragment into small particles while maintaining their original assemblies upon dispersing in solvents, as confirmed by Cryo-electron microscopy coupled with 3D electron diffraction technology. 1D and 2D-Nuclear Magnetic Resonance (NMR) and zeta potential analyses indicate the HOF-based colloid solution and the isolated molecular solution have significant differences in intermolecular interactions and aggregation behavior. Such unique solution processibility allows for fabricating diverse continuous HOF membranes with high crystallinity and porosity through solution-casting approach on various substrates. Among them, HOF-BTB@AAO membranes show high C3H6 permeance (1.979 × 10-7 mol·s-1·m-2·Pa-1) and excellent separation performance toward C3H6 and C3H8 (SF = 14). This continuous membrane presents a green, low-cost, and efficient separation technology with potential applications in petroleum cracking and purification.

ROBO1 deficiency impairs HSPC homeostasis and erythropoiesis via CDC42 and predicts poor prognosis in MDS.

Myelodysplastic syndrome (MDS) is a group of clonal hematopoietic neoplasms originating from hematopoietic stem progenitor cells (HSPCs). We previously identified frequent roundabout guidance receptor 1 (ROBO1) mutations in patients with MDS, while the exact role of ROBO1 in hematopoiesis remains poorly delineated. Here, we report that ROBO1 deficiency confers MDS-like disease with anemia and multilineage dysplasia in mice and predicts poor prognosis in patients with MDS. More specifically, Robo1 deficiency impairs HSPC homeostasis and disrupts HSPC pool, especially the reduction of megakaryocyte erythroid progenitors, which causes a blockage in the early stages of erythropoiesis in mice. Mechanistically, transcriptional profiling indicates that Cdc42, a member of the Rho-guanosine triphosphatase family, acts as a downstream target gene for Robo1 in HSPCs. Overexpression of Cdc42 partially restores the self-renewal and erythropoiesis of HSPCs in Robo1-deficient mice. Collectively, our result implicates the essential role of ROBO1 in maintaining HSPC homeostasis and erythropoiesis via CDC42.

The non-cell-autonomous function of ID1 promotes AML progression via ANGPTL7 from the microenvironment.

The bone marrow microenvironment (BMM) can regulate leukemia stem cells (LSCs) via secreted factors. Increasing evidence suggests that dissecting the mechanisms by which the BMM maintains LSCs may lead to the development of effective therapies for the eradication of leukemia. Inhibitor of DNA binding 1 (ID1), a key transcriptional regulator in LSCs, previously identified by us, controls cytokine production in the BMM, but the role of ID1 in acute myeloid leukemia (AML) BMM remains obscure. Here, we report that ID1 is highly expressed in the BMM of patients with AML, especially in BM mesenchymal stem cells, and that the high expression of ID1 in the AML BMM is induced by BMP6, secreted from AML cells. Knocking out ID1 in mesenchymal cells significantly suppresses the proliferation of cocultured AML cells. Loss of Id1 in the BMM results in impaired AML progression in AML mouse models. Mechanistically, we found that Id1 deficiency significantly reduces SP1 protein levels in mesenchymal cells cocultured with AML cells. Using ID1-interactome analysis, we found that ID1 interacts with RNF4, an E3 ubiquitin ligase, and causes a decrease in SP1 ubiquitination. Disrupting the ID1-RNF4 interaction via truncation in mesenchymal cells significantly reduces SP1 protein levels and delays AML cell proliferation. We identify that the target of Sp1, Angptl7, is the primary differentially expression protein factor in Id1-deficient BM supernatant fluid to regulate AML progression in mice. Our study highlights the critical role of ID1 in the AML BMM and aids the development of therapeutic strategies for AML.

Genome-Wide Effects on Gene Expression Between Parental and Filial Generations of Trisomy 11 and 12 of Rice.

Aneuploid refers to the gene dosage imbalance due to copy number alterations. Aneuploidy is generally harmful to the growth, development and reproduction of organisms according to the numerous research. However, it has rarely been reported on whether aneuploid have a relevant pattern of genome expression between the parental and its offspring generations. In this study, mRNA sequencing analysis was performed on rice (Oryza sativa L.) primary trisomes 11 and 12, same primary trisomes and normal individuals in their filial generation. We systematically summarized the changes in gene expression patterns that occur on cis genes and on trans genes between parental and filial generations. In T11 and T12, the ratio of cis-gene expression showed intermediate type in parents and dosage compensation in filial generations, which maybe due to more genes being downregulated. The trans genes were also affected by aneuploidy and manifested as cis-related. The strains with normal chromosomes in filial generations, there are still aneuploid-sensitive genes differentially expressed in their genomes, indicating that the effect of aneuploidy is far-reaching and could not be easily eliminated. Meanwhile, among these differentially expressed genes, genes with low-expression level were more likely to be upregulated, while genes with medium- and high-expression level were easy to be downregulated. For the different types of rice aneuploid, upregulated genes were mainly associated with genomic imbalance while downregulated genes were mainly influenced by the specific added chromosome. In conclusion, our results provide new insights into the genetic characterization and evolution of biological aneuploidy genomes.

Histone deacetylase OsHDA706 increases salt tolerance via H4K5/K8 deacetylation of OsPP2C49 in rice.

High salt is a major environmental factor that threatens plant growth and development. Increasing evidence indicates that histone acetylation is involved in plant responses to various abiotic stress; however, the underlying epigenetic regulatory mechanisms remain poorly understood. In this study, we revealed that the histone deacetylase OsHDA706 epigenetically regulates the expression of salt stress response genes in rice (Oryza sativa L.). OsHDA706 localizes to the nucleus and cytoplasm and OsHDA706 expression is significantly induced under salt stress. Moreover, oshda706 mutants showed a higher sensitivity to salt stress than the wild-type. In vivo and in vitro enzymatic activity assays demonstrated that OsHDA706 specifically regulates the deacetylation of lysines 5 and 8 on histone H4 (H4K5 and H4K8). By combining chromatin immunoprecipitation and mRNA sequencing, we identified the clade A protein phosphatase 2 C gene, OsPP2C49, which is involved in the salt response as a direct target of H4K5 and H4K8 acetylation. We found that the expression of OsPP2C49 is induced in the oshda706 mutant under salt stress. Furthermore, the knockout of OsPP2C49 enhances plant tolerance to salt stress, while its overexpression has the opposite effect. Taken together, our results indicate that OsHDA706, a histone H4 deacetylase, participates in the salt stress response by regulating the expression of OsPP2C49 via H4K5 and H4K8 deacetylation.

Inhibition of USP1 reverses the chemotherapy resistance through destabilization of MAX in the relapsed/refractory B-cell lymphoma.

The patients with relapsed and refractory diffuse large B-cell lymphoma (DLBCL) have poor prognosis, and a novel and effective therapeutic strategy for these patients is urgently needed. Although ubiquitin-specific protease 1 (USP1) plays a key role in cancer, the carcinogenic effect of USP1 in B-cell lymphoma remains elusive. Here we found that USP1 is highly expressed in DLBCL patients, and high expression of USP1 predicts poor prognosis. Knocking down USP1 or a specific inhibitor of USP1, pimozide, induced cell growth inhibition, cell cycle arrest and autophagy in DLBCL cells. Targeting USP1 by shRNA or pimozide significantly reduced tumor burden of a mouse model established with engraftment of rituximab/chemotherapy resistant DLBCL cells. Pimozide significantly retarded the growth of lymphoma in a DLBCL patient-derived xenograft (PDX) model. USP1 directly interacted with MAX, a MYC binding protein, and maintained the stability of MAX through deubiquitination, which promoted the transcription of MYC target genes. Moreover, pimozide showed a synergetic effect with etoposide, a chemotherapy drug, in cell and mouse models of rituximab/chemotherapy resistant DLBCL. Our study highlights the critical role of USP1 in the rituximab/chemotherapy resistance of DLBCL through deubiquitylating MAX, and provides a novel therapeutic strategy for rituximab/chemotherapy resistant DLBCL.

Shear wave elastography to evaluate carotid artery elasticity in long-term drinkers with varying degrees of alcoholic fatty liver disease.

OBJECTIVE: To evaluate carotid artery elasticity in long-term drinkers with varying degrees of alcoholic fatty liver disease (AFLD) by shear wave elastography (SWE). METHODS: Of the 92 drinkers with alcohol drinking for greater than or equal to 5 years, were fell into three groups depending on the liver ultrasound results: group B (without AFLD), group C (with mild AFLD), and group D (moderate-to-severe AFLD). Another 32 healthy adults were selected as the control group (group A). All participants had no significant carotid plaque. Gray scale ultrasound and color doppler ultrasound were used to obtain the left common carotid peak systolic velocity (PSV), carotid diastolic internal diameter (Dd ), carotid intima-media thickness (IMT), carotid systolic internal diameter (Ds ) and the stiffness coefficient (ß). Mean values of mean elastic modulus (MEmean ), minimum elastic modulus (MEmin ), and maximum elastic modulus (MEmax ) of the anterior wall of the left common carotid artery at end-diastole were measured by SWE. RESULTS: Dd , Ds , and PSV among the four groups showed no differences. (all P > 0.05). Compared with groups A and B, MEmin , MEmax , and MEmean were significantly higher in group C (all P < 0.05), while IMT and ß were not statistically different (all P > 0.05). MEmean , MEmin , MEmax , IMT, and ß were significantly higher in group D compared with the other three groups (all P < 0.05). No significant differences were observed in IMT, ß, MEmean , MEmax , and MEmin between groups A and B (all P > 0.05). CONCLUSIONS: Shear wave elastography can provide a quantitative evaluation for the carotid artery elasticity in long-term drinkers with varying degrees of AFLD.

Targeting UHRF1-SAP30-MXD4 axis for leukemia initiating cell eradication in myeloid leukemia.

Aberrant self-renewal of leukemia initiation cells (LICs) drives aggressive acute myeloid leukemia (AML). Here, we report that UHRF1, an epigenetic regulator that recruits DNMT1 to methylate DNA, is highly expressed in AML and predicts poor prognosis. UHRF1 is required for myeloid leukemogenesis by maintaining self-renewal of LICs. Mechanistically, UHRF1 directly interacts with Sin3A-associated protein 30 (SAP30) through two critical amino acids, G572 and F573 in its SRA domain, to repress gene expression. Depletion of UHRF1 or SAP30 derepresses an important target gene, MXD4, which encodes a MYC antagonist, and leads to suppression of leukemogenesis. Further knockdown of MXD4 can rescue the leukemogenesis by activating the MYC pathway. Lastly, we identified a UHRF1 inhibitor, UF146, and demonstrated its significant therapeutic efficacy in the myeloid leukemia PDX model. Taken together, our study reveals the mechanisms for altered epigenetic programs in AML and provides a promising targeted therapeutic strategy against AML.

Evaluate the elasticity of carotid artery in the type 2 diabetes mellitus patients with nonalcoholic fatty liver disease by two-dimensional strain imaging.

To evaluate carotid elasticity by using two-dimensional strain imaging (2DSI) in type 2 diabetes mellitus (T2DM) patients with nonalcoholic fatty liver disease (NAFLD). 98 patients with T2DM diagnosed in our hospital were selected. All the patients were without carotid plaque, which were proved by carotid ultrasonography. According to the fatty liver classification standard, patients were divided into three groups. There were 35 cases without NAFLD in group A, 33 cases with mild NAFLD in group B and 30 cases with moderate to severe NAFLD in group C. By using two-dimensional and M-mode ultrasound to measure the left carotid intima-media thickness (IMT), common carotid arterial systolic diameter (Ds) and diastolic diameter (Dd). The systolic peak velocity was measured by spectral Doppler ultrasound. The systolic global peak circumferential strain (CS), early and late systolic global circumferential strain rate (CSr) were measured by 2DSI. The stiffness parameters ß1 and ß2 were calculated by M-mode ultrasound and 2DSI separately. Among three groups, the Ds, Dd and systolic peak velocity showed no significant difference (all P > .05). In group C, IMT and ß1 were obviously increased than those of groups A and B (all P < .05). Compared groups A and B, there were no significant difference in IMT and ß1 (all P > .05). ß2 was higher in groups B and C than those in group A, CS, CSr were lower in groups B and C than those in group A (both P > .05). The carotid elasticity of T2DM patients with NAFLD can be evaluated by 2DSI.

Thyroid follicular renal cell carcinoma excluding thyroid metastases: A case report.

BACKGROUND: Thyroid follicular renal cell carcinoma is a special type of renal cell carcinoma newly recognized in recent years. It has attracted attention because of its unique histology, immunophenotype, and clinical characteristics. It has a very low incidence, and the number of case reports available for review is limited. Moreover, a thyroid mass with type of tumour is rare. CASE SUMMARY: We report a case of a renal mass with a bilateral thyroid mass that was accidentally discovered in a 60-year-old man during physical examination. B-mode ultrasound showed a hypoechoic mass in the middle and lower parenchyma of the right kidney, and computed tomography showed an iso-density shadow tumour in the right kidney. Contrast agents had a significant continuous enhancement effect on the tumour, and the enhancement was not uniform. After partial nephrectomy, pathological analysis was performed to rule out the possibility that the renal tumour was caused by thyroid tumour metastasis. Needle biopsy of the thyroid tumour confirmed that the renal cell carcinoma was not related to the thyroid tumour. The patient was alive at the last postoperative follow-up. CONCLUSION: This is the third published case in which thyroid tumour biopsy was performed to confirm that thyroid follicular renal cell carcinoma is not thyroid related.

The Retromer Subunit CfVps29 Is Involved in the Growth, Development, and Pathogenicity of Colletotrichum fructicola.

Camellia oleifera is an edible oil tree species native to China. Anthracnose is a common disease of Ca. oleifera, which reduces the production of the trees and brings huge economic losses. We have previously identified the fungus Colletotrichum fructicola as the major pathogen of anthracnose in Ca. oleifera. The retromer complex participates in the intracellular retrograde transport of the cargos from the endosome to the trans-Golgi network in the eukaryotes. Vacuolar protein sorting 29 is a subunit of the retromer complex. Targeted CfVPS29 gene deletion revealed that CfVps29 is involved in growth, conidiation, and the response to cell wall stress. We further found that the ΔCfvps29 mutant was minimally pathogenic to Ca. oleifera leaves, as a result of its defect in appressorium formation. This study illustrated the crucial functions of CfVps29 in the development, cell wall stress response, and pathogenicity of C. fructicola and, therefore, identified it as a potential fungicide target for the control of anthracnose.

Primary renal small cell carcinoma: A case report.

BACKGROUND: Small cell carcinoma (SCC) is a malignant tumour that is frequently accompanied by extensive metastasis. Primary renal SCC has typical characteristics related to SCC and is extremely rare, with no uniform treatment standard. Clinical treatment is mainly based on the literature. Here we report the diagnosis and treatment of an interesting case of primary renal SCC. CASE SUMMARY: We report a tortuous course of treatment for a 68-year-old man. Four years before diagnosis, the patient developed continuous gross haematuria, during which he underwent several ureteral biopsies, ureteral stricture relief, and urine exfoliated cell examinations; however, SCC was not confirmed. One month before radical resection of the renal pelvic carcinoma, the severe haematuria recurred. Computed tomography revealed transitional cell carcinoma in the right kidney and right upper ureter. A preoperative examination exluded the possibility of a pulmonary origin of the tumour, and primary renal SCC was diagnosed. The postoperative pathology findings were suggestive of SCC. The patient was treated with combined chemotherapy but died of tumour progression at 7 mo postoperative. CONCLUSION: Our patient's disease onset in the context of a succession of regular testing and the fact that it occurred so quickly with perirenal encroachment immediately after diagnosis reveals the cruel and unforgiving side of the disease. Furthermore, patients with poor comprehensive treatment results require new treatment regimens.

Retromer subunit, CfVps35 is required for growth development and pathogenicity of Colletotrichum fructicola.

BACKGROUND: Tea oil is widely used as edible oil in China, which extracted from the seeds of Camellia oleifera. In China, the national oil-tea camellia planting area reached 4.533 million hectares, the output of oil-tea camellia seed oil was 627 000 tons, and the total output value reached 18.3 billion dollars. Anthracnose is the common disease of Ca. oleifera, which affected the production and brought huge economic losses. Colletotrichum fructicola is the dominant pathogen causing anthracnose in Ca. oleifera. The retromer complex participates in the intracellular retrograde transport of cargos from the endosome to the trans-Golgi network in eukaryotes. Vacuolar protein sorting 35 is a core part of the retromer complex. This study aimed to investigate the role of CfVps35 in C. fructicola. RESULTS: The CfVPS35 gene was deleted, resulting in reduced mycelial growth, conidiation, and response to cell wall stresses. Further analysis revealed that CfVps35 was required for C. fructicola virulence on tea oil leaves. In addition, the ΔCfvps35 mutant was defective in glycogen metabolism and turgor during appressorium development. CONCLUSION: This study illustrated that the crucial functions of CfVps35 in growth, development, and pathogenicity.