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.

Comprehensive Similarity Algorithm and Molecular Dynamics Simulation-Assisted Terahertz Spectroscopy for Intelligent Matching Identification of Quorum Signal Molecules (N-Acyl-Homoserine Lactones).

To investigate the mechanism of aquatic pathogens in quorum sensing (QS) and decode the signal transmission of aquatic Gram-negative pathogens, this paper proposes a novel method for the intelligent matching identification of eight quorum signaling molecules (N-acyl-homoserine lactones, AHLs) with similar molecular structures, using terahertz (THz) spectroscopy combined with molecular dynamics simulation and spectral similarity calculation. The THz fingerprint absorption spectral peaks of the eight AHLs were identified, attributed, and resolved using the density functional theory (DFT) for molecular dynamics simulation. To reduce the computational complexity of matching recognition, spectra with high peak matching values with the target were preliminarily selected, based on the peak position features of AHL samples. A comprehensive similarity calculation (CSC) method using a weighted improved Jaccard similarity algorithm (IJS) and discrete Fréchet distance algorithm (DFD) is proposed to calculate the similarity between the selected spectra and the targets, as well as to return the matching result with the highest accuracy. The results show that all AHL molecular types can be correctly identified, and the average quantization accuracy of CSC is 98.48%. This study provides a theoretical and data-supported foundation for the identification of AHLs, based on THz spectroscopy, and offers a new method for the high-throughput and automatic identification of AHLs.

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.

Gas phase fabrication of morphology-controlled ITO nanoparticles and their assembled conductive films.

ITO nanoparticles were generated in the gas phase with a magnetron plasma gas aggregation cluster source. Their morphologies were modified by modulating the discharging power of magnetron sputtering. The shape of the nanoparticles changed from rough spheroid formed with a higher discharging power to multi-branch formed with a lower discharging power. With a discharging power of 25 W, the ITO nanoparticles were enriched with tripod and tetrapod-shaped nanoparticles. The formation mechanism of multi-branch nanoparticles was attributed to the oriented attachment of the initially nucleated smaller nanocrystallites. Transparent conductive ITO nanoparticle films were fabricated by depositing the preformed nanoparticles with controlled thickness. The electron conduction in the film was dominated by electron tunnelling and/or hopping in the percolative channels comprised of closely spaced ITO nanoparticle assemblies and could be tuned from highly resistive nonmetal-like to highly conductive metal-like by changing the deposition thickness. The film also displayed a SPR band in the near-IR region. The conductivity of the multi-branch ITO nanoparticle film was significantly superior to that of the spheroidal nanoparticle film. For a 46 nm thick multi-branch ITO nanoparticle film, a surprisingly low specific resistance of 3.09 × 10-4 Ω cm, which is comparable to the top-class conductivity of bulk ITO films, was obtained after annealing at a mild temperature of 250 °C, with a transmittance larger than 85%.

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.

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.

A Comparison of CT Manifestations Between Coronavirus Disease 2019 (COVID-19) and Other Types of Viral Pneumonia.

BACKGROUND: Though imaging manifestations of COVID-19 and other types of viral pneumonia are similar, their clinical treatment methods differ. Accurate, non-invasive diagnostic methods using CT imaging can help develop an optimal therapeutic regimen for both conditions. OBJECTIVE: To compare the initial CT imaging features in COVID-19 with those in other types of viral pneumonia. METHODS: Clinical and imaging data of 51 patients with COVID-19 and 69 with other types of viral pneumonia were retrospectively studied. All significant imaging features (Youden index >0.3) were included for constituting the combined criteria for COVID-19 diagnosis, composed of two or more imaging features with a parallel model. McNemar's chi-square test or Fisher's exact test was used to compare the validity indices (sensitivity and specificity) among various criteria. RESULTS: Ground glass opacities (GGO) dominated density, peripheral distribution, unilateral lung, clear margin of lesion, rounded morphology, long axis parallel to the pleura, vascular thickening, and crazy-paving pattern were more common in COVID-19 (p <0.05). Consolidation-dominated density, both central and peripheral distributions, bilateral lung, indistinct margin of lesion, tree-inbud pattern, mediastinal or hilar lymphadenectasis, pleural effusion, and pleural thickening were more common in other types of viral pneumonia (p < 0.05). GGO-dominated density or long axis parallel to the pleura (with the highest sensitivity), and GGO-dominated density or long axis parallel to the pleura or vascular thickening (with the highest specificity) are well combined criteria of COVID-19. CONCLUSION: The initial CT imaging features are helpful for the differential diagnosis of COVID-19 and other types of viral pneumonia.

Emission characteristics of fine particulate matter from ultra-low emission power plants.

As one of the highest energy consuming and polluting industries, the power generation industry is an important source of particulate matter emissions. Recently, implementation of ultra-low emission technology has changed the emission characteristic of fine particulate matter (PM2.5). In this study, PM2.5 emitted from four typical power plants in China was sampled using a dilution channel sampling system, and analyzed for elements, water-soluble ions and carbonaceous fractions. The results showed that PM2.5 concentrations emitted from the four power plants were 0.78 ±â€¯0.16, 0.63 ±â€¯0.09, 0.29 ±â€¯0.07 and 0.28 ±â€¯0.01 mg m-3, respectively. Emission factors were 0.004-0.005 g/kg coal, nearly 1-2 orders of magnitude lower than those reported in previous studies. The highest proportions of PM2.5 consisted of organic carbon (OC), SO42-, elemental carbon (EC), NH4+, Al and Cl-. Coefficients of divergence (CDs) were in the ranges 0.22-0.41 (for an individual plant), 0.43-0.69 (among different plants), and 0.60-0.99 (in previous studies). The results indicated that the source profiles of each tested power plant were relatively similar, but differed from those in previous studies. Enrichment factors showed elevated Se and Hg, in accordance with the source markers Se and As. Comparing source profiles with previous studies, the proportion of OC, EC and NH4+ were higher, while the proportion of Al in PM2.5 were relatively lower. The OC/EC ratio became concentrated at ∼5. Results from this study can be used for source apportionment and emission inventory calculations after implementation of ultra-low emission technologies.

Dust aerosol properties and radiative forcing observed in spring during 2001-2014 over urban Beijing, China.

The ground-based characteristics (optical and radiative properties) of dust aerosols measured during the springtime between 2001 and 2014 were investigated over urban Beijing, China. The seasonal averaged aerosol optical depth (AOD) during spring of 2001-2014 was about 0.78 at 440 nm. During dust days, higher AOD occurred associated with lower Ångström exponent (AE). The mean AE440-870 in the springtime was about 1.0, indicating dominance of fine particles over the region. The back-trajectory analysis revealed that the dust was transported from the deserts of Inner Mongolia and Mongolia arid regions to Beijing. The aerosol volume size distribution showed a bimodal distribution pattern, with its highest peak observed in coarse mode for all episodes (especially for dust days with increased volume concentration). The single scattering albedo (SSA) increased with wavelength on dust days, indicating the presence of more scattering particles. Furthermore, the complex parts (real and imaginary) of refractive index showed distinct characteristics with lower imaginary values (also scattering) on dust days. The shortwave (SW; 0.2-4.0 µm) and longwave (LW; 4-100 µm) aerosol radiative forcing (ARF) values were computed from the Santa Barbara DISORT Atmospheric Radiative Transfer (SBDART) model both at the top of atmosphere (TOA) and the bottom of atmosphere (BOA) during dust and non-dust (dust free) days, and the corresponding heating rates and forcing efficiencies were also estimated. The SW (LW) ARF, therefore, produced significant cooling (warming) effects at both the TOA and the BOA over Beijing.

Mixing of dust with pollution on the transport path of Asian dust--revealed from the aerosol over Yulin, the north edge of Loess Plateau.

Both PM(2.5) and TSP were monitored in the spring from 2006 to 2008 in an intensive ground monitoring network of five sites (Tazhong, Yulin, Duolun, Beijing, and Shanghai) along the pathway of Asian dust storm across China to investigate the mixing of dust with pollution on the pathway of the long-range transport of Asian dust. Mineral was found to be the most loading component of aerosols both in dust event days and non-dust days. The concentrations of those pollution elements, As, Cd, Pb, Zn, and S in aerosol were much higher than their mean abundances in the crust even in dust event days. The high concentration of SO(4)(2-) could be from both sources: one from the transformation of the local emitted SO(2) and the other from the sulfate that existed in primary dust, which was transported to Yulin. Na(+), Ca(2+), and Mg(2+) were mainly from the crustal source, while NO(3)(-) and NH(4)(+) were from the local pollution sources. The mixing of dust with pollution aerosol over Yulin in dust event day was found to be ubiquitous, and the mixing extent could be expressed by the ratio of NO(3)(-)/Al in dust aerosol. The ratio of Ca/Al was used as a tracer to study the dust source. The comparison of the ratios of Ca/Al together with back trajectory analysis indicated that the sources of the dust aerosol that invaded Yulin could be from the northwestern desert in China and Mongolia Gobi.