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Abstract The mechanisms underlying the transformation of chronic myeloid leukemia (CML) from chronic phase (CP) to blast crisis (BC) are not fully elucidated. Here, we show lower levels of miR-142 in CD34+CD38− blasts from BC CML patients than in those from CP CML patients, suggesting that miR-142 deficit is implicated in BC evolution. Thus, we create miR-142 knockout CML (i.e., miR-142 −/− BCR-ABL) mice, which develop BC and die sooner than miR-142 wt CML (i.e., miR-142 +/+ BCR-ABL) mice, which instead remain in CP CML. Leukemic stem cells (LSCs) from miR-142 −/− BCR-ABL mice recapitulate the BC phenotype in congenic recipients, supporting LSC transformation by miR-142 deficit. State-transition and mutual information analyses of “bulk” and single cell RNA-seq data, metabolomic profiling and functional metabolic assays identify enhanced fatty acid β-oxidation, oxidative phosphorylation and mitochondrial fusion in LSCs as key steps in miR-142-driven BC evolution. A synthetic CpG-miR-142 mimic oligodeoxynucleotide rescues the BC phenotype in miR-142 −/− BCR-ABL mice and patient-derived xenografts.

Abstract Chitin is one of the most abundant natural biopolymers and serves as a critical structural component of extracellular matrices, including fungal cell walls and insect exoskeletons. As a linear polymer of β-(1,4)-linked N-acetylglucosamine, chitin is synthesized by chitin synthases, which are recognized as targets for antifungal and anti-insect drugs. In this study, we determine seven different cryo-electron microscopy structures of a Saccharomyces cerevisiae chitin synthase in the absence and presence of glycosyl donor, acceptor, product, or peptidyl nucleoside inhibitors. Combined with functional analyses, these structures show how the donor and acceptor substrates bind in the active site, how substrate hydrolysis drives self-priming, how a chitin-conducting transmembrane channel opens, and how peptidyl nucleoside inhibitors inhibit chitin synthase. Our work provides a structural basis for understanding the function and inhibition of chitin synthase.

BackgroundDuring acute myeloid leukemia (AML) growth, the bone marrow (BM) niche acquires significant vascular changes that can be offset by therapeutic blast cytoreduction. The molecular mechanisms of this vascular plasticity remain to be fully elucidated. Herein, we report on the changes that occur in the vascular compartment of the FLT3-ITD+ AML BM niche pre and post treatment and their impact on leukemic stem cells (LSCs).MethodsBM vasculature was evaluated in FLT3-ITD+ AML models (MllPTD/WT/Flt3ITD/ITD mouse and patient-derived xenograft) by 3D confocal imaging of long bones, calvarium vascular permeability assays, and flow cytometry analysis. Cytokine levels were measured by Luminex assay and miR-126 levels evaluated by Q-RT-PCR and miRNA staining. Wild-type (wt) and MllPTD/WT/Flt3ITD/ITD mice with endothelial cell (EC) miR-126 knockout or overexpression served as controls. The impact of treatment-induced BM vascular changes on LSC activity was evaluated by secondary transplantation of BM cells after administration of tyrosine kinase inhibitors (TKIs) to MllPTD/WT/Flt3ITD/ITD mice with/without either EC miR-126 KO or co-treatment with tumor necrosis factor alpha (TNFα) or anti-miR-126 miRisten.ResultsIn the normal BM niche, CD31+Sca-1high ECs lining arterioles have miR-126 levels higher than CD31+Sca-1low ECs lining sinusoids. We noted that during FLT3-ITD+ AML growth, the BM niche lost arterioles and gained sinusoids. These changes were mediated by TNFα, a cytokine produced by AML blasts, which induced EC miR-126 downregulation and caused depletion of CD31+Sca-1high ECs and gain in CD31+Sca-1low ECs. Loss of miR-126high ECs led to a decreased EC miR-126 supply to LSCs, which then entered the cell cycle and promoted leukemia growth. Accordingly, antileukemic treatment with TKI decreased the BM blast-produced TNFα and increased miR-126high ECs and the EC miR-126 supply to LSCs. High miR-126 levels safeguarded LSCs, as shown by more severe disease in secondary transplanted mice. Conversely, EC miR-126 deprivation via genetic or pharmacological EC miR-126 knock-down prevented treatment-induced BM miR-126high EC expansion and in turn LSC protection.ConclusionsTreatment-induced CD31+Sca-1high EC re-vascularization of the leukemic BM niche may represent a LSC extrinsic mechanism of treatment resistance that can be overcome with therapeutic EC miR-126 deprivation.

Urban areas with parks tend to have the best outdoor thermal comfort in regions with high urban heat island effects during summer. This study analyzed the synergistic cooling effects of 94 urban parks and the adjacent built-up areas in six districts of Xi’an City using four cooling indicators: park cooling intensity (PCI), park cooling area (PCA), park cooling effect (PCE), and park cooling gradient (PCG). The results showed that 84 out of 94 parks exhibited significant cooling effects, with an average PCI of 1.98 °C, PCA of 51.7 ha, PCE of 6.6, and PCG of 8.2 °C/km. Correlation analyses indicated that the intrinsic park attributes, external buffer zone building height, and building density were the main factors affecting the cooling effect. The park landscape configuration, building height, and density significantly influenced the PCI and PCG, while the park shape and size were crucial for the PCA (positive) and PCE (negative). The optimal park areas for improving the thermal environment were identified as 26 ha (cooling area focus, building density 32%). This study provides theoretical guidance for planning urban parks and the surrounding areas based on cooling effects, offering insights for future climate resilience planning.

In this article, we advance a model for the traction power supply of a medium-capacity railway system along the major Pham Van Dong (PVD) arterial route situated in the northeastern sector of Ho Chi Minh City (HCMC), Vietnam. This study simulates an in-depth analysis of the carrying capacity and feasibility of traction power supply for this scenario based on a safe moving-block system utilizing Communications-based Train Control (CBTC). The research results show that the 750 V DC traction system uses a rigid overhead conductor rail system (ROCS) with distances between traction power stations of up to 6 km with double feeding. The system provides a service frequency of 36 trains per hour per direction, and has a transport capacity of up to 47,520 passengers per hour per direction. The implementation of this solution, as proposed, has the potential to improve traffic flow, reduce congestion, reduce environmental pollution, and provide a complete and modern urban railway network for HCMC. The system could also be implemented in other similar global scenarios. Additionally, this investigation also demonstrates the feasibility of applying the new ROCS to medium-capacity railway systems (MCSs), which have garnered increasing attention in recent years owing to their discernible advantages over extant systems. The outcomes of this study underscore the pragmatic nature of the proposed solution, which orients sustainable and integrated development in the realm of urban rail transport.

We report here on a novel pro-leukemogenic role of FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) that interferes with microRNAs (miRNAs) biogenesis in acute myeloid leukemia (AML) blasts. We showed that FLT3-ITD interferes with the canonical biogenesis of intron-hosted miRNAs such as miR-126, by phosphorylating SPRED1 protein and inhibiting the "gatekeeper" Exportin 5 (XPO5)/RAN-GTP complex that regulates the nucleus-to-cytoplasm transport of pre-miRNAs for completion of maturation into mature miRNAs. Of note, despite the blockage of "canonical" miRNA biogenesis, miR-155 remains upregulated in FLT3-ITD+ AML blasts, suggesting activation of alternative mechanisms of miRNA biogenesis that circumvent the XPO5/RAN-GTP blockage. MiR-155, a BIC-155 long noncoding (lnc) RNA-hosted oncogenic miRNA, has previously been implicated in FLT3-ITD+ AML blast hyperproliferation. We showed that FLT3-ITD upregulates miR-155 by inhibiting DDX3X, a protein implicated in the splicing of lncRNAs, via p-AKT. Inhibition of DDX3X increases unspliced BIC-155 that is then shuttled by NXF1 from the nucleus to the cytoplasm, where it is processed into mature miR-155 by cytoplasmic DROSHA, thereby bypassing the XPO5/RAN-GTP blockage via "non-canonical" mechanisms of miRNA biogenesis.

Sapindus saponins are potential biosurfactants that can widely be used to replace many chemical cleaning products. This study aimed to investigate the water extraction of saponins from the pericarps of Sapindus mukorossi and enhance the sensory properties of the extract by yeast fermentation. Extraction conditions including temperature, solid-to-liquid ratio, extraction time, and number of extraction times were studied. A yield of 21.4% was obtained by 2 h of extraction at 80 °C with a solid-to-liquid of 1/6 (w/v) and two times. Fermentation was used to purify the Sapindus extract, inoculum amount and fermentation time were optimized. The fermentation by S. cerevisiae (2%) within 4 days significantly improved the color and smell of aqueous extract, turbidity decreased by 75.6%, total sugar content decreased by nearly 50% and saponins content slightly decreased. These results could contribute to the development of industrial–scale production of Sapindus saponins.

Conducting research on nutritional status and dietary intake of pulmonary tuberculosis patients is essential for developing interventions in clinical nutrition practice and treatment during hospitalization, which can improve the quality of patients life. This cross-sectional descriptive study aimed to determine nutritional status and some related factors (such as geography, occupation, educational level, economic classification, etc.) of 221 patients with pulmonary tuberculosis who were examined and treated at the Respiratory Tuberculosis Department, National Lung Hospital in July 2019–May 2020. The results showed that the risk of undernutrition: According to BMI (Body Mass Index): 45.8% of patients were malnourished, 44.2% normal and 10.0% overweight/obese. According to MUAC (Mid-Upper Arm Circumference): 60.2% of patients were malnourished, 39.8% of patients were normal. According to SGA (Subjective Global Assessment): 57.9% of patients were at risk of undernutrition, of which 40.7% were at moderate risk of undernutrition and 17.2% risk of severe undernutrition. Classification of nutritional status according to serum albumin index: 50% of patients were malnourished, the rate of undernutrition of mild, moderate and severe levels was 28.9%, 17.9% and 3.2%, respectively. Most patients eat with others and eat less than four meals a day. The average dietary energy of patients with pulmonary tuberculosis in was 1242.6 ± 46.5 Kcal and 1084 ± 57.9 Kcal, respectively. 85.52% of patients did not eat enough food, 4.07% had enough, 10.41% consumed excess energy. The ratio of energy-generating substances in the diet (Carbohydrate:Protein:Lipid) was on average 54:18:28 for males and 55:16:32 for females. Most of the study population had diets that did not meet the experimental study in terms of micronutrient content. Specifically, more than 90% do not meet the requirements for magnesium, calcium, zinc, and vitamin D. The water-soluble and fat-soluble vitamins respond poorly, only about 30–40%. Selenium is the mineral with the best response rate, above 70%. Our findings revealed that the majority of the study subjects had poor nutritional status, as evidenced by diets lacking in essential micronutrients.

This article discusses the outcomes of a study conducted to explore new power supply sources for subway trains. The power supply system for traction is an integral and inseparable component of subway rail infrastructure, encompassing both its management and operation. As a result, the specific choice of a power supply type has a lasting impact, either positive or negative, on the overall performance of a subway system. Consequently, researching power supply for traction presents a considerably more intricate challenge when compared to other railway transportation systems. In this study, the results obtained shed light on the pros and cons of utilizing the 25,000 V / 50 Hz system in comparison with the 1,500 V DC system, with a particular focus on traffic capacity and the efficiency of supplying traction power.