MicroRNA networks in FLT3-ITD acute myeloid leukemia.

MiR-126 and miR-155 are key microRNAs (miRNAs) that regulate, respectively, hematopoietic cell quiescence and proliferation. Herein we showed that in acute myeloid leukemia (AML), the biogenesis of these two miRNAs is interconnected through a network of regulatory loops driven by the FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD). In fact, FLT3-ITD induces the expression of miR-155 through a noncanonical mechanism of miRNA biogenesis that implicates cytoplasmic Drosha ribonuclease III (DROSHA). In turn, miR-155 down-regulates SH2-containing inositol phosphatase 1 (SHIP1), thereby increasing phosphor-protein kinase B (AKT) that in turn serine-phosphorylates, stabilizes, and activates Sprouty related EVH1 domain containing 1 (SPRED1). Activated SPRED1 inhibits the RAN/XPO5 complex and blocks the nucleus-to-cytoplasm transport of pre-miR-126, which cannot then complete the last steps of biogenesis. The net result is aberrantly low levels of mature miR-126 that allow quiescent leukemia blasts to be recruited into the cell cycle and proliferate. Thus, miR-126 down-regulation in proliferating AML blasts is downstream of FLT3-ITD­dependent miR-155 expression that initiates a complex circuit of concatenated regulatory feedback (i.e., miR-126/SPRED1, miR-155/human dead-box protein 3 [DDX3X]) and feed-forward (i.e., miR-155/SHIP1/AKT/miR-126) regulatory loops that eventually converge into an output signal for leukemic growth.

A phase 1 trial of 8-chloro-adenosine in relapsed/refractory acute myeloid leukemia: An evaluation of safety and pharmacokinetics.

BACKGROUND: This study evaluated the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of 8-chloro-adenosine (8-Cl-Ado) in patients with relapsed/refractory acute myeloid leukemia (AML). METHODS: 8-Cl-Ado was administered daily for 5 days; the starting dose was 100 mg/m2 , the highest dose tested was 800 mg/m2 . The end points were toxicity, disease response, and PK/PD measurements. RESULTS: The predominant nonhematologic toxicity was cardiac with grade ≥3 toxicity. Plasma PK in all patients suggested heterogeneity among patients, yet, some dose-dependency for the accumulation of 8-Cl-Ado. Two 8-Cl-Ado metabolites accumulated at similar levels to 8-Cl-Ado. Cellular PK in eight patients indicated accumulation of 8-Cl-ATP, which was associated with AML blast cytoreduction in peripheral blood. The authors determined the RP2D of 8-Cl-Ado to be 400 mg/m2 . CONCLUSIONS: Given the cardiac adverse events observed, patients require monitoring for arrhythmias and QT interval during infusion. Although peripheral blood cytoreduction was observed, responses were transient, suggesting combination strategies will be required.

The mouse retinal pigment epithelium mounts an innate immune defense response following retinal detachment.

The retinal pigment epithelium (RPE) maintains photoreceptor viability and function, completes the visual cycle, and forms the outer blood-retinal barrier (oBRB). Loss of RPE function gives rise to several monogenic retinal dystrophies and contributes to age-related macular degeneration. Retinal detachment (RD) causes separation of the neurosensory retina from the underlying RPE, disrupting the functional and metabolic relationships between these layers. Although the retinal response to RD is highly studied, little is known about how the RPE responds to loss of this interaction. RNA sequencing (RNA-Seq) was used to compare normal and detached RPE in the C57BL6/J mouse. The naïve mouse RPE transcriptome was compared to previously published RPE signature gene lists and from the union of these 14 genes (Bmp4, Crim1, Degs1, Gja1, Itgav, Mfap3l, Pdpn, Ptgds, Rbp1, Rnf13, Rpe65, Slc4a2, Sulf1 and Ttr) representing a core signature gene set applicable across rodent and human RPE was derived. Gene ontology enrichment analysis (GOEA) of the mouse RPE transcriptome identified expected RPE features and functions, such as pigmentation, phagocytosis, lysosomal and proteasomal degradation of proteins, and barrier function. Differentially expressed genes (DEG) at 1 and 7 days post retinal detachment (dprd) were defined as mRNA with a significant (padj≤0.05) fold change (FC) of 0.67 ≥ FC ≥ 1.5 in detached versus naïve RPE. The RPE transcriptome exhibited dramatic changes at 1 dprd, with 2297 DEG identified. The KEGG pathways and biological process GO groups related to innate immune responses were significantly enriched. Lipocalin 2 (Lcn2) and several chemokines were upregulated, while numerous genes related to RPE functions, such as pigment synthesis, visual cycle, phagocytosis, and tight junctions were downregulated at 1 dprd. The response was largely transient, with only 18 significant DEG identified at 7 dprd, including upregulation of complement gene C4b. Validation studies confirmed RNA-Seq results. Thus, the RPE quickly downregulates cell-specific functions and mounts an innate immune defense response following RD. Our data demonstrate that the RPE contributes to the inflammatory response to RD and may play a role in attraction of immune cells to the subretinal space.

Disruption of dNTP homeostasis by ribonucleotide reductase hyperactivation overcomes AML differentiation blockade.

Differentiation blockade is a hallmark of acute myeloid leukemia (AML). A strategy to overcome such a blockade is a promising approach against the disease. The lack of understanding of the underlying mechanisms hampers development of such strategies. Dysregulated ribonucleotide reductase (RNR) is considered a druggable target in proliferative cancers susceptible to deoxynucleoside triphosphate (dNTP) depletion. Herein, we report an unanticipated discovery that hyperactivating RNR enables differentiation and decreases leukemia cell growth. We integrate pharmacogenomics and metabolomics analyses to identify that pharmacologically (eg, nelarabine) or genetically upregulating RNR subunit M2 (RRM2) creates a dNTP pool imbalance and overcomes differentiation arrest. Moreover, R-loop-mediated DNA replication stress signaling is responsible for RRM2 activation by nelarabine treatment. Further aggravating dNTP imbalance by depleting the dNTP hydrolase SAM domain and HD domain-containing protein 1 (SAMHD1) enhances ablation of leukemia stem cells by RRM2 hyperactivation. Mechanistically, excessive activation of extracellular signal-regulated kinase (ERK) signaling downstream of the imbalance contributes to cellular outcomes of RNR hyperactivation. A CRISPR screen identifies a synthetic lethal interaction between loss of DUSP6, an ERK-negative regulator, and nelarabine treatment. These data demonstrate that dNTP homeostasis governs leukemia maintenance, and a combination of DUSP inhibition and nelarabine represents a therapeutic strategy.

P T-symmetry breaking in dual-core phosphate-glass photonic crystal fibers.

We investigate the properties of a soft glass dual-core photonic crystal fiber for application in multicore waveguiding with balanced gain and loss. Its base material is a phosphate glass in a P2O5-Al2O3-Yb2O3-BaO-ZnO-MgO-Na2O oxide system. The separated gain and loss cores are realized with two cores with ytterbium and copper doping of the base phosphate glass. The ytterbium-doped core supports a laser (gain) activity under excitation with a pump at 1000 nm wavelength, while the CuO-doped is responsible for strong attenuation at the same wavelength. We establish conditions for an exact balance between gain and loss and investigate pulse propagation by solving a system of coupled generalized nonlinear Schrödinger equations. We predict two states of light under excitation with hyperbolic secant pulses centered at 1000 nm: 1) linear oscillation of the pulse energy between gain and loss core (P T-symmetry state), with strong power attenuation; 2) retention of the pulse in the excited gain core (broken P T-symmetry), with very modest attenuation. The optimal pulse energy levels were identified to be 100 pJ (first state) and 430 pJ (second state).

Analysis of high-contrast all-optical dual-wavelength switching in asymmetric dual-core fibers.

We systematically present experimental and theoretical results for the dual-wavelength switching of 1560 nm, 75 fs signal pulses (SPs) driven by 1030 nm, and 270 fs control pulses (CPs) in a dual-core fiber (DCF). We demonstrate a switching contrast of 31.9 dB, corresponding to a propagation distance of 14 mm, achieved by launching temporally synchronized SP-CP pairs into the fast core of the DCF with moderate inter-core asymmetry. Our analysis employs a system of three coupled propagation equations to identify the compensation of the asymmetry by nonlinearity as the physical mechanism behind the efficient switching performance.

High-directivity far-field radiation of quantum dot-based single-photon emitter coupled to polymeric circular waveguide resonant grating.

Solid-state single-photon emitters (SPEs) commonly encounter the limitation of quasi-omnidirectional radiation patterns, which poses challenges in utilizing their emission with conventional optical instruments. In this study, we demonstrate the tailoring of the far-field radiation patterns of SPEs based on colloidal quantum dots (QDs), both theoretically and experimentally, by employing a polymer-based dielectric antenna. We introduce a simple and cost-effective technique, namely low one-photon absorption direct laser writing, to achieve precise coupling of a QD into an all-polymer circular waveguide resonance grating. By optimizing the geometry parameters of the structure using 3D finite-difference time-domain simulations, resonance at the emission wavelength of QDs is achieved in the direction perpendicular to the substrate, resulting in photon streams with remarkably high directivity on both sides of the grating. Theoretical calculations predict beam divergence values below 2°, while experimental measurements using back focal plane imaging yield divergence angles of approximately 8°. Our study contributes to the evaluation of concentric circular grating structures employing low refractive index polymer materials, thereby expanding the possibilities for their application.

Optimization of the Zhou Tian Formula extraction technology based on AHP-CRITIC method and analysis of transfer efficiency of key components based on HPLC fingerprinting.

INTRODUCTION: Zhou Tian Formula (ZTF) is an antidepressant traditional Chinese medicine utilized widely in clinical settings for the treatment of patients with depression. However, shortcomings persist in its extraction technology and quality control. OBJECTIVE: This study aimed to propose a methodology for ZTF extraction technology based on the analytic hierarchy process (AHP)-criteria importance through intercriteria correlation (CRITIC) method and to establish a quality control framework for the efficient transfer of index components. METHOD: Firstly, we analyzed the chemical components of ZTF and determined the optimal extraction technology. Secondly, we calculated the transfer efficiency of the index components during the conversion of water decoction to extract powder and subsequently to granules. Thirdly, we established HPLC fingerprints for 15 batches of ZTF water decoction, extract powder, and granules. We employed SIMCA software to analyze the chemicals responsible for variations in quality among different batches of ZTF granules. RESULTS: We determined the optimal extraction process. The average transfer efficiency of ferulic acid, puerarin, mirificin, isoferulic acid, and calycosin during the conversion of water decoction to extract powder and subsequently to granules exceeded 41%. The HPLC fingerprints of ZTF exhibited a similarity exceeding 0.890. Variable importance in projection values indicated that calycosin, ferulic acid, and puerarin were the primary contributors to quality variations. CONCLUSIONS: The AHP-CRITIC method, coupled with an orthogonal array design, could be used for exploring extraction technology. In addition, the rules governing the transfer of index components from water decoction to extract powder, and subsequently to granules, could be applied for the evaluation and quality assessment of ZTF.

Construction of a rapid electrochemical biosensor consisting of a nanozyme/aptamer conjugate for waterborne microcystin detection.

Microcystin-LR (MC-LR) is a hepatotoxin generated by the excessive proliferation of cyanobacteria, which is a threat to humans and wildlife. Therefore, rapid detection of MC-LR is an important challenge. This study describes a rapid electrochemical biosensor comprising nanozymes and aptamers. Alternating current electrothermal flow (ACEF) significantly reduced the MC-LR detection period to 10 min. We also used MnO2/MC-LR aptamer conjugates to improve the sensitivity to MC-LR detection. Here, MnO2 amplified the electrochemical signal and the aptamer showed high selectivity for MC-LR. Under the optimal conditions, the limit of detection (LOD) and selectivity in freshwater were detected using cyclic voltammetry and differential pulse voltammetry. As a result, an LOD of 3.36 pg mL-1 was observed in the linear concentration range of 10 pg mL-1 to 1 µg mL-1. This study quickly and sensitively detected MC-LR in a situation where it causes serious damage worldwide. In addition, the ACEF technology introduction is the first example of MC-LR detection, suggesting a wide range of possibilities for MC-LR biosensors.

Comparison of the radioprotective effects of the liposomal forms of five natural radioprotectants in alleviating the adverse effects of ionising irradiation on human lymphocytes and skin cells in radiotherapy.

This study aims to evaluate the radioprotective effects of liposomes encapsulating curcumin (Lip-CUR), silibinin (Lip-SIL), α-tocopherol (Lip-TOC), quercetin (Lip-QUE) and resveratrol (Lip-RES) in alleviating the adverse effects of ionising irradiation on human lymphoctyes and skin cells in radiotherapy. Liposomes encapsulating the above natural radioprotectants (Lip-NRPs) were prepared by the film hydration method combined with sonication. Their radioprotective effects for the cells against X-irradiation was evaluated using trypan-blue assay and γ-H2AX assay. All prepared Lip-NRPs had a mean diameter less than 240 nm, polydispersity index less than 0.32, and zeta potential more than -23 mV. Among them, the radioprotective effect of Lip-RES was lowest, while that of Lip-QUE was highest. Lip-SIL also exhibited a high radioprotective effect despite its low DPPH-radical scavenging activity (12.9%). The radioprotective effects of Lip-NRPs do not solely depend on the free radical scavenging activity of NRPs but also on their ability to activate cellular mechanisms.

Effects of dietary rambutan (Nephelium lappaceum L.) peel powder on growth performance, immune response and immune-related gene expressions of striped catfish (Pangasianodon hypophthalmus) raised in biofloc system.

This study aimed to evaluate the effects of rambutan peel powder (RP) on growth, skin mucosal and serum immunities, and immune-related gene expression of striped catfish (Pangasianodon hypophthalmus) reared in a biofloc system. Three hundred fingerlings (17.14 ± 0.12 g fish-1) were randomly selected and assigned to five treatments corresponding to five diets: 0 g kg-1 (control - RP0); 10 g kg-1 (RP10); 20 g kg-1 (RP20); 40 g kg-1 (RP40), and 80 g kg-1 (RP80) for 8 weeks. At weeks 4 and 8 post-feeding, growth, skin mucus, and serum immunity parameters were determined, whereas immune-related gene expressions were performed at the end of the feeding trial. Based on the results, skin mucus lysozyme (SML) and skin mucus peroxidase (SMP) were significantly higher in fish fed the RP diets compared to the control diet (P < 0.05). The highest SML and SMP levels were observed in fish fed RP40 diet, followed by RP20, RP80, RP10, and RP0. Fish-fed RP diets had higher serum lysozyme and serum peroxidase activities, with the highest value found in the RP40 diet (P < 0.05), followed by RP20, RP80, and RP10. Similarly, immune-related gene expressions (IFN2a, IFN2b, and MHCII) in the liver were significantly up-regulated in fish fed RP40. Up-regulation (P < 0.05) of IL-1, IFN2a, IFN2b, and MHCII genes was also observed in fish intestines, with the highest values observed in fish fed RP40 diet, followed by RP10, RP20, RP80, and RP0. Fish-fed diet RP diets also showed enhanced growth and FCR compared to the control, with the highest values observed in fish fed diet RP40. However, no significant differences in survival rates were found among diets. In conclusion, dietary inclusion of RP at 40 g kg-1 resulted in better growth performance, immune response, and immune related gene expressions of striped catfish (Pangasianodon hypophthalmus).

Modulatory effects of longan seed powder on growth performance, immune response, and immune-antioxidant related gene expression in Nile tilapia (Oreochromis niloticus) raised under biofloc system.

This study evaluates the effects of longan seed powder (LS) on the growth performance, immunological response, and immune-antioxidant related gene expression of Nile tilapia (Oreochromis niloticus). Three hundred fish (13.82 ± 0.06 g) were divided into five experiments and fed 5 diets, including the basal diet (control without LS) and basal diet containing 10 (LS10), 20 (LS20), 40 (LS40), and 80 (LS80) g kg-1 LS for eight weeks. A completely randomized design (CRD) with three replications was utilised. The growth performance and immune response were measured at weeks 4 and 8 post feeding, while the gene expressions were determined at the end of the feeding trial. The results revealed that administration of LS could significantly (P < 0.05) improve specific growth rate (SGR), weight gain (WG), and feed conversion ratio (FCR) in Nile tilapia as compared to the control group. However, no significant differences (P > 0.05) were observed in survival rates among treatments. LS-supplemented diets showed enhanced serum peroxidase activity (SPA), serum lysozyme activity (SLA), skin mucus lysozyme activity (MLA), and skin mucus peroxidase activity (MPA) at weeks 4 and 8 post-feeding, with the highest values observed in the LS20 diet (P < 0.05). Additionally, LS-supplemented diets significantly up-regulated (P < 0.05) immune and antioxidant related gene expressions (IL1, IL8, LBP, GSTa, GPX, and GSR) in the liver and intestine, with highest values observed in the LS20 treatment. The present results confirmed the beneficial effects of LS as a functional feed additive and immunostimulant for Nile Tilapia culture in a biofloc system.

Modulation of growth, immune response, and immune-antioxidant related gene expression of Nile tilapia (Oreochromis niloticus) reared under biofloc system using mango peel powder.

This study aimed to investigate the effects of mango peel powder (MGPP) on growth, innate immunity, and immune-antioxidant related gene expression of Nile tilapia reared under biofloc system. Three hundred Nile tilapia (average weight 14.78 ± 0.05 g) were distributed into 15 fiber tanks (300 L per tank) assigned to five treatments in triplication. Fish were fed basal diet containing different levels MGPP as follows: 0 (MGPP0: control), 6.25 (MGPP 6.25), 12.5 (MGPP 12.25), 25 (MGPP 25), and 50 (MGPP 50) g kg-1 diet for 8 weeks. Specific growth rate (SGR), weight gain (WG), final weight (FW), feed conversion ratio (FCR), skin mucus of lysozyme (SMLA), and peroxidase activities (SMPA), serum of lysozyme (SL) and peroxidase (SP) were measured every for weeks; while immune-antioxidant-related gene expressions were determined after 8 weeks post-feeding. The results indicated that MGPP 25 diet resulted in higher SGR, WG, FW, and FCR but no significant differences among treatments were noticed. In terms of immune responses, lysozyme and peroxidase activities in mucus and serum were significantly higher in MGPP 12.5 and MGPP 25 diets against the control. Similarly, significant up-regulation of IL-1 and IL-8 gene expressions was observed in fish fed MGPP 25 against the control. However, no significant differences in LBP, GSTa, GPX, and GSR among treatments were observed. Overall, dietary inclusion of MGPP 25 significantly enhanced immune response and immune related gene expressions but not growth performance and antioxidant gene expressions. The results implied that MGPP can be potentially used as an immunostimulants in Nile tilapia culture.

Influence of black rice (Oryza sativa L.) bran derived anthocyanin-extract on growth rate, immunological response, and immune-antioxidant gene expression in Nile tilapia (Oreochromis niloticus) cultivated in a biofloc system.

This study investigated the effects of dietary supplementation with anthocyanin extracted from black rice bran (AR) on the growth rate, immunological response, and expression of immune and antioxidant genes in Nile tilapia raised in an indoor biofloc system. A total of 300 Nile tilapia fingerlings (15.14 ± 0.032 g) were maintained in 150 L tanks and acclimatized for two weeks. Five experimental AR diets (0, 1, 2, 4, and 8 g kg-1) with various anthocyanin doses were used to feed the fish. We observed that the growth and feed utilization of fish fed with different dietary AR levels increased significantly after eight weeks (p < 0.05). In addition, the serum immunity of fish fed AR diets was much greater than that of those fed non-AR diets (p < 0.05). However, there were little or no difference in between fish fed AR enriched diets and the control AR-free diet (p > 0.05). After eight weeks, fish fed AR-supplemented diets had significantly higher mRNA transcript levels in immune (interleukin [IL]-1, IL-8, and liposaccharide-binding protein [LBP]) and antioxidant (glutathione transferase-alpha [GST-α] and glutathione reductase [GSR]) genes compared to control fish fed the AR-free diet, with the greatest enhancement of mRNA transcript levels (in the case of IL-8 by up to about 5.8-fold) in the 4 g kg-1 AR diet. These findings suggest that dietary inclusion of AR extract from black rice bran at 4-8 g kg-1 could function as a herbal immunostimulant to enhance growth performance, feed consumption, and immunity in Nile tilapia.

Laccase-mimicking Mn-Cu hybrid nanoflowers for paper-based visual detection of phenolic neurotransmitters and rapid degradation of dyes.

BACKGROUND: Laccase-based biosensors are efficient for detecting phenolic compounds. However, the instability and high cost of laccases have hindered their practical utilization. RESULTS: In this study, we developed hierarchical manganese dioxide-copper phosphate hybrid nanoflowers (H-Mn-Cu NFs) as excellent laccase-mimicking nanozymes. To synthesize the H-Mn-Cu NFs, manganese dioxide nanoflowers (MnO2 NFs) were first synthesized by rapidly reducing potassium permanganate using citric acid. The MnO2 NFs were then functionalized with amine groups, followed by incubation with copper sulfate for three days at room temperature to drive the coordination interaction between the amine moieties and copper ions and to induce anisotropic growth of the petals composed of copper phosphate crystals, consequently yielding H-Mn-Cu NFs. Compared with those of free laccase, at the same mass concentration, H-Mn-Cu NFs exhibited lower Km (~ 85%) and considerably higher Vmax (~ 400%), as well as significantly enhanced stability in the ranges of pH, temperature, ionic strength, and incubation periods evaluated. H-Mn-Cu NFs also catalyzed the decolorization of diverse dyes considerably faster than the free laccase. Based on these advantageous features, a paper microfluidic device incorporating H-Mn-Cu NFs was constructed for the convenient visual detection of phenolic neurotransmitters, including dopamine and epinephrine. The device enabled rapid and sensitive quantification of target neurotransmitters using an image acquired using a smartphone. CONCLUSIONS: These results clearly show that H-Mn-Cu NFs could be potential candidates to replace natural laccases for a wide range of applications in biosensing, environmental protection, and biotechnology.

Emotional Speech Recognition Using Deep Neural Networks.

The expression of emotions in human communication plays a very important role in the information that needs to be conveyed to the partner. The forms of expression of human emotions are very rich. It could be body language, facial expressions, eye contact, laughter, and tone of voice. The languages of the world's peoples are different, but even without understanding a language in communication, people can almost understand part of the message that the other partner wants to convey with emotional expressions as mentioned. Among the forms of human emotional expression, the expression of emotions through voice is perhaps the most studied. This article presents our research on speech emotion recognition using deep neural networks such as CNN, CRNN, and GRU. We used the Interactive Emotional Dyadic Motion Capture (IEMOCAP) corpus for the study with four emotions: anger, happiness, sadness, and neutrality. The feature parameters used for recognition include the Mel spectral coefficients and other parameters related to the spectrum and the intensity of the speech signal. The data augmentation was used by changing the voice and adding white noise. The results show that the GRU model gave the highest average recognition accuracy of 97.47%. This result is superior to existing studies on speech emotion recognition with the IEMOCAP corpus.

Bioinformatics and Experimental Analyses Reveal Immune-Related LncRNA-mRNA Pair AC011483.1-CCR7 as a Biomarker and Therapeutic Target for Ischemic Cardiomyopathy.

Ischemic cardiomyopathy (ICM), which increases along with aging, is the leading cause of heart failure. Currently, immune response is believed to be critical in ICM whereas the roles of immune-related lncRNAs remain vague. In this study, we aimed to systematically analyze immune-related lncRNAs in the aging-related disease ICM. Here, we downloaded publicly available RNA-seq data from ischemic cardiomyopathy patients and non-failing controls (GSE116250). Weighted gene co-expression network analysis (WGCNA) was performed to identify key ICM-related modules. The immune-related lncRNAs of key modules were screened by co-expression analysis of immune-related mRNAs. Then, a competing endogenous RNA (ceRNA) network, including 5 lncRNAs and 13 mRNAs, was constructed using lncRNA-mRNA pairs which share regulatory miRNAs and have significant correlation. Among the lncRNA-mRNA pairs, one pair (AC011483.1-CCR7) was verified in another publicly available ICM dataset (GSE46224) and ischemic cell model. Further, the immune cell infiltration analysis of the GSE116250 dataset revealed that the proportions of monocytes and CD8+ T cells were negatively correlated with the expression of AC011483.1-CCR7, while plasma cells were positively correlated, indicating that AC011483.1-CCR7 may participate in the occurrence and development of ICM through immune cell infiltration. Together, our findings revealed that lncRNA-mRNA pair AC011483.1-CCR7 may be a novel biomarker and therapeutic target for ICM.

Arsenic Trioxide and Venetoclax Synergize against AML Progenitors by ROS Induction and Inhibition of Nrf2 Activation.

Venetoclax (VEN) in combination with hypomethylating agents induces disease remission in patients with de novo AML, however, most patients eventually relapse. AML relapse is attributed to the persistence of drug-resistant leukemia stem cells (LSCs). LSCs need to maintain low intracellular levels of reactive oxygen species (ROS). Arsenic trioxide (ATO) induces apoptosis via upregulation of ROS-induced stress to DNA-repair mechanisms. Elevated ROS levels can trigger the Nrf2 antioxidant pathway to counteract the effects of high ROS levels. We hypothesized that ATO and VEN synergize in targeting LSCs through ROS induction by ATO and the known inhibitory effect of VEN on the Nrf2 antioxidant pathway. Using cell fractionation, immunoprecipitation, RNA-knockdown, and fluorescence assays we found that ATO activated nuclear translocation of Nrf2 and increased transcription of antioxidant enzymes, thereby attenuating the induction of ROS by ATO. VEN disrupted ATO-induced Nrf2 translocation and augmented ATO-induced ROS, thus enhancing apoptosis in LSCs. Using metabolic assays and electron microscopy, we found that the ATO+VEN combination decreased mitochondrial membrane potential, mitochondria size, fatty acid oxidation and oxidative phosphorylation, all of which enhanced apoptosis of LSCs derived from both VEN-sensitive and VEN-resistant AML primary cells. Our results indicate that ATO and VEN cooperate in inducing apoptosis of LSCs through potentiation of ROS induction, suggesting ATO+VEN is a promising regimen for treatment of VEN-sensitive and -resistant AML.

Multi-step-ahead water level forecasting for operating sluice gates in Hai Duong, Vietnam.

Recently, machine learning (ML) is being applied to various fields, including hydrology and hydraulics. The numerical models based on ML algorithms have been widely used for forecasting water levels or flowrate in different timescales. Especially in estuary areas where the hydrodynamic regime becomes complicated, the water level forecast information in this area plays an essential role in the operation of tidal sluices. This study proposes an efficient approach using an ML model, long short-term memory (LSTM), to predict short-term water levels in tidal sluice gates from 6 to 48 hours ahead. The An Tho culvert located in the Bac Hung Hai irrigation system, the most extensive irrigation system in Vietnam, was selected as a case study station. The high accuracy of predictive results reveals LSTM models' effectiveness in different forecasting scenarios. In the first scenario using just water level data at the prediction station, the Kling-Gupta efficiency (KGE) coefficient ranges from nearly 0.89 to 0.96. Meanwhile, in the second scenario, the combination of observed data of three gauge stations exhibited better performance with KGE coefficients ranging from just under 0.93 to 0.98 for eight forecasted cases. The findings of this study highlight the performance of LSTM models in providing high-accuracy short-period water level forecasts for areas near estuaries. These obtained results can play a vital role in the management and operation of tidal sluices in the Bac Hung Hai irrigation system, as well as a reference for the operation of other irrigation systems around the world.

Entropy Analysis of the Thermal Convection of Nanosuspension within a Chamber with a Heat-Conducting Solid Fin.

Heat transport augmentation in closed chambers can be achieved using nanofluids and extended heat transfer surfaces. This research is devoted to the computational analysis of natural convection energy transport and entropy emission within a closed region, with isothermal vertical borders and a heat-conducting solid fin placed on the hot border. Horizontal walls were assumed to be adiabatic. Control relations written using non-primitive variables with experimentally based correlations for nanofluid properties were computed by the finite difference technique. The impacts of the fin size, fin position, and nanoadditive concentration on energy transfer performance and entropy production were studied. It was found that location of the long fin near the bottom wall allowed for the intensification of convective heat transfer within the chamber. Moreover, this position was characterized by high entropy generation. Therefore, the minimization of the entropy generation can define the optimal location of the heat-conducting fin using the obtained results. An addition of nanoparticles reduced the heat transfer strength and minimized the entropy generation.