Aging and comprehensive molecular profiling in acute myeloid leukemia.

Acute myeloid leukemia (AML) is an aging-related and heterogeneous hematopoietic malignancy. In this study, a total of 1,474 newly diagnosed AML patients with RNA sequencing data were enrolled, and targeted or whole exome sequencing data were obtained in 94% cases. The correlation of aging-related factors including age and clonal hematopoiesis (CH), gender, and genomic/transcriptomic profiles (gene fusions, genetic mutations, and gene expression networks or pathways) was systematically analyzed. Overall, AML patients aged 60 y and older showed an apparently dismal prognosis. Alongside age, the frequency of gene fusions defined in the World Health Organization classification decreased, while the positive rate of gene mutations, especially CH-related ones, increased. Additionally, the number of genetic mutations was higher in gene fusion-negative (GF-) patients than those with GF. Based on the status of CH- and myelodysplastic syndromes (MDS)-related mutations, three mutant subgroups were identified among the GF- AML cohort, namely, CH-AML, CH-MDS-AML, and other GF- AML. Notably, CH-MDS-AML demonstrated a predominance of elderly and male cases, cytopenia, and significantly adverse clinical outcomes. Besides, gene expression networks including HOXA/B, platelet factors, and inflammatory responses were most striking features associated with aging and poor prognosis in AML. Our work has thus unraveled the intricate regulatory circuitry of interactions among different age, gender, and molecular groups of AML.

Transcriptome-based molecular subtypes and differentiation hierarchies improve the classification framework of acute myeloid leukemia.

The current classification of acute myeloid leukemia (AML) relies largely on genomic alterations. Robust identification of clinically and biologically relevant molecular subtypes from nongenomic high-throughput sequencing data remains challenging. We established the largest multicenter AML cohort (n = 655) in China, with all patients subjected to RNA sequencing (RNA-Seq) and 619 (94.5%) to targeted or whole-exome sequencing (TES/WES). Based on an enhanced consensus clustering, eight stable gene expression subgroups (G1-G8) with unique clinical and biological significance were identified, including two unreported (G5 and G8) and three redefined ones (G4, G6, and G7). Apart from four well-known low-risk subgroups including PML::RARA (G1), CBFB::MYH11 (G2), RUNX1::RUNX1T1 (G3), biallelic CEBPA mutations or -like (G4), four meta-subgroups with poor outcomes were recognized. The G5 (myelodysplasia-related/-like) subgroup enriched clinical, cytogenetic and genetic features mimicking secondary AML, and hotspot mutations of IKZF1 (p.N159S) (n = 7). In contrast, most NPM1 mutations and KMT2A and NUP98 fusions clustered into G6-G8, showing high expression of HOXA/B genes and diverse differentiation stages, from hematopoietic stem/progenitor cell down to monocyte, namely HOX-primitive (G7), HOX-mixed (G8), and HOX-committed (G6). Through constructing prediction models, the eight gene expression subgroups could be reproduced in the Cancer Genome Atlas (TCGA) and Beat AML cohorts. Each subgroup was associated with distinct prognosis and drug sensitivities, supporting the clinical applicability of this transcriptome-based classification of AML. These molecular subgroups illuminate the complex molecular network of AML, which may promote systematic studies of disease pathogenesis and foster the screening of targeted agents based on omics.

Independent modulation of individual genomic component transcription and a cis-acting element related to high transcriptional activity in a multipartite DNA virus.

BACKGROUND: The genome of Banana bunchy top virus (BBTV) consists of at least six circular, single-stranded DNA components of ~ 1 kb in length. Some BBTV isolates may also carry satellite DNA molecules that are not essential for BBTV infection. The relation between multipartite DNA virus replication and their transcriptional levels and the underlying mechanism remain unclear. RESULTS: To understand the coordinated replication and transcription of the multiple genomic components, the absolute amounts of each BBTV DNA component were measured by real-time PCR (qPCR), and their transcriptional levels were determined by RNAseq and reverse transcription-qPCR (qRT-PCR). Significant differences were found in the absolute amounts of individual BBTV genomic components. Transcriptional levels of each BBTV genomic component obtained from the RNAseq data matched closely to those obtained from qRT-PCR, but did not correspond to the absolute amount of each DNA component. The ratio of transcript over DNA copies ranged from 46.21 to 1059.44%, which was possibly regulated by the promoter region in the intergenic region of each component. To further determine this speculation, the promoter region of the DNA-S, -M or -N was constructed to the upstream of green fluorescent protein (GFP) gene for transient expression by agrobacterium-mediated transformation method. The qRT-PCR showed the highest transcriptional activity was promoted by DNA-N promoter, about 386.58% activity comparing with CaMV 35S promoter. Confocal microscopy observation showed that the intensity of green fluorescence was corresponding to that of qRT-PCR. CONCLUSIONS: Our data clearly showed that BBTV was able to control the transcriptional level of each DNA component independently by through the promoter sequences in the intergenic region. Moreover, a cis-acting element from DNA-N component had a high transcriptional activity.

Geographical and Genetic Divergence Among Papaya ringspot virus Populations Within Hainan Province, China.

Papaya ringspot virus (PRSV) severely affects the global papaya industry. Transgenic papaya has been proven to have effective resistance to PRSV isolates from Hawaii, Thailand, Taiwan, and other countries. However, those transgenic cultivars failed to show resistance to Hainan Island isolates. Some 76 PRSV samples, representative of all traditional papaya planting areas across five cities (Wen Chang, n = 13; Cheng Mai, n = 14; Chang Jiang, n = 11; Le Dong, n = 25; and San Ya, n = 13) within Hainan Province, were investigated. Results revealed three genetic diversity groups (Hainan I, II, and III) that correlated with geographical distribution. Frequent mutations among PRSV isolates from Hainan were also observed. The high genetic divergence in PRSV isolates from Hainan is likely to be the cause of the failure of genetically modified papaya that targets sequence-specific virus.

Proteomics of methyl jasmonate induced defense response in maize leaves against Asian corn borer.

BACKGROUND: Jasmonic acid (JA) and methyl jasmonate (MeJA) regulate plant development, resistance to stress, and insect attack by inducing specific gene expression. However, little is known about the mechanism of plant defense against herbivore attack at a protein level. Using a high-resolution 2-D gel, we identified 62 MeJA-responsive proteins and measured protein expression level changes. RESULTS: Among these 62 proteins, 43 proteins levels were increased while 11 proteins were decreased. We also found eight proteins uniquely expressed in response to MeJA treatment. Data are available via ProteomeXchange with identifier PXD001793. The proteins identified in this study have important biological functions including photosynthesis and energy related proteins (38.4%), protein folding, degradation and regulated proteins (15.0%), stress and defense regulated proteins (11.7%), and redox-responsive proteins (8.3%). The expression levels of four important genes were determined by qRT-PCR analysis. The expression levels of these proteins did not correlate well with their translation levels. To test the defense functions of the differentially expressed proteins, expression vectors of four protein coding genes were constructed to express in-fusion proteins in E. coli. The expressed proteins were used to feed Ostrinia furnacalis, the Asian corn borer (ACB). Our results demonstrated that the recombinant proteins of pathogenesis-related protein 1 (PR1) and thioredoxin M-type, chloroplastic precursor (TRXM) showed the significant inhibition on the development of larvae and pupae. CONCLUSIONS: We found MeJA could not only induce plant defense mechanisms to insects, it also enhanced toxic protein production that potentially can be used for bio-control of ACB.

Numerical study on the forward and inverse problems of the mobile pump truck frame.

Aiming at the requirements of strong mobility and high flexibility of rescue and relief mobile pump trucks, this paper designs a new type of mobile pump truck frame based on existing mobile vehicle frame models. The materials used for the frame are 40Cr and Q235, and the finite element method is utilized to carry out static mechanical analysis and dynamic characteristic analysis. Simultaneously utilizing topology optimization and multi-objective genetic algorithm to optimize the design of the frame structure. The results show that the optimized pump truck frame can meet the strength design requirements of four typical working conditions: full load bending, full load torsion, emergency turning and emergency braking, while avoiding resonance phenomena caused by road surface and diesel engine vibration. Compared with the original frame model, the weight of the optimized frame is reduced by 87.88 kg, with a weight reduction rate of 10.89%, realizing the lightweight design requirements.

Numerical investigation of flow characteristics in the front and rear chambers of centrifugal pump and pump as turbine.

To investigate the flow characteristics in front chamber and rear chamber in pump mode and pump as turbine mode, a 3D computational model of a centrifugal pump was established, including the front and rear chamber. Based on Realizable k-ε turbulence model, numerical calculations of incompressible flow were carried out for internal viscous flow in two operating modes. Further analysis was conducted on the flow stability and hydraulic losses under two modes using energy gradient theory and entropy production theory. The numerical simulation results are within reasonable error compared to the experimental results in pump operation mode, which ensures the reliability of the numerical calculation method. The results indicate that the volumetric efficiency in both two modes is on an upward trend with increasing flow, but the volumetric efficiency of the pump mode is more significantly affected by changes in flow; the distribution patterns of dimensionless circumferential velocity and dimensionless radial velocity in the front and rear chambers under two operating modes are similar, but the distribution pattern of dimensionless radial velocity in the front chamber in turbine mode is significantly different from other operating conditions; flow instability is most likely to occur at the outlet of impeller, and the energy loss in clearance of wear-rings is greater than that in the pump chamber.

A theoretical model for predicting the startup performance of pumps as turbines.

Using the unsteady Bernoulli equation for the piping system and the angular momentum equation for the rotor, derives here a theoretical model to predict the startup performance of a pump as turbine (PAT). This model is effective for predicting the instantaneous evolution characteristics of the main performance parameters of PAT during startup, and these changings are initially faster and then slowly as a whole. The effect of the rotor moment of inertia and the final stabilized rotational speed of PAT on evolution characteristics of parameters is opposite. The rotational speed, head, hydraulic power, and conversion efficiency show a upward rising trend with the startup time, whereas the flow rate and hydraulic head loss display a downward trend.

Hydraulic loss experiment of straight-through Tesla valve in forward and reverse directions.

Tesla valves are widely used in the field of fluid control. To study the hydraulic performance of straight-through Tesla valves in forward and reverse flow, 16 straight-through Tesla valves with diverse blade parameters were designed in this paper, and hydraulic loss tests were carried out in forward and reverse flow under different working conditions. The results show that the hydraulic loss increases with the increasing working flow rate in forward and reverse flow; at the identical flow rate, the reverse loss is higher than the forward loss. Both the hydraulic loss through the valve and the unidirectional conductivity of the valve increase with increasing blade length, pitch, and number of blades, but too long of a length results in weakened unidirectional conductivity. The hydraulic loss increases with the increase of blade angle, and the unidirectional conductivity decreases with the increase of blade angle. When the blades are arranged in perfect symmetry, the hydraulic loss through the valve is maximum, and the valve has the best unidirectional conductivity.

Study on the integrated self-priming process of a vehicle-mounted self-priming pump.

In order to explore the self-priming characteristics of the self-priming pump at the mobile pump truck, this paper established a complete three-dimensional circulatory piping system including the self-priming pump, tank, valves, inlet pipe and outlet pipe. The UDF(User Defined Functions) was used to realize the acceleration-constant speed operation process of the impeller, thus reflecting the actual changing state of the rotational speed. Based on the VOF(Volume Of Fluid) multiphase flow model and the Realizable k-ε turbulence model, a coupled numerical calculation of unsteady incompressible viscous flow was conducted for its self-priming process. The results show that the self-priming process of the pump can be roughly divided into four stages: the rapid suction stage, the shock exhaust stage, the rapid exhaust period and the pump residual gas discharge stage. The proportion of each stage in the total self-priming time showed an increasing trend. During the rapid suction stage, the water level in the vertical section of the inlet pipe showed a slow and then fast-rising pattern. During the shock exhaust stage, the average gas-phase volume fraction in the volute is lower than that of the impeller, and the gas content at the volute outlet is lower than that of the impeller inlet. The region at the inlet and outer edge of the impeller consistently experience significant energy losses.

Risk of cardiovascular death in patients with hepatocellular carcinoma based on the Fine-Gray model.

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most common types of cancers worldwide, ranking fifth among men and seventh among women, resulting in more than 7 million deaths annually. With the development of medical technology, the 5-year survival rate of HCC patients can be increased to 70%. However, HCC patients are often at increased risk of cardiovascular disease (CVD) death due to exposure to potentially cardiotoxic treatments compared with non-HCC patients. Moreover, CVD and cancer have become major disease burdens worldwide. Thus, further research is needed to lessen the risk of CVD death in HCC patient survivors. AIM: To determine the independent risk factors for CVD death in HCC patients and predict cardiovascular mortality (CVM) in HCC patients. METHODS: This study was conducted on the basis of the Surveillance, Epidemiology, and End Results database and included HCC patients with a diagnosis period from 2010 to 2015. The independent risk factors were identified using the Fine-Gray model. A nomograph was constructed to predict the CVM in HCC patients. The nomograph performance was measured using Harrell's concordance index (C-index), calibration curve, receiver operating characteristic (ROC) curve, and area under the ROC curve (AUC) value. Moreover, the net benefit was estimated via decision curve analysis (DCA). RESULTS: The study included 21545 HCC patients, of whom 619 died of CVD. Age (< 60) [1.981 (1.573-2.496), P < 0.001], marital status (married) [unmarried: 1.370 (1.076-1.745), P = 0.011], alpha fetoprotein (normal) [0.778 (0.640-0.946), P = 0.012], tumor size (≤ 2 cm) [(2, 5] cm: 1.420 (1.060-1.903), P = 0.019; > 5 cm: 2.090 (1.543-2.830), P < 0.001], surgery (no) [0.376 (0.297-0.476), P < 0.001], and chemotherapy(none/unknown) [0.578 (0.472-0.709), P < 0.001] were independent risk factors for CVD death in HCC patients. The discrimination and calibration of the nomograph were better. The C-index values for the training and validation sets were 0.736 and 0.665, respectively. The AUC values of the ROC curves at 2, 4, and 6 years were 0.702, 0.725, 0.740 in the training set and 0.697, 0.710, 0.744 in the validation set, respectively. The calibration curves showed that the predicted probabilities of the CVM prediction model in the training set vs the validation set were largely consistent with the actual probabilities. DCA demonstrated that the prediction model has a high net benefit. CONCLUSION: Risk factors for CVD death in HCC patients were investigated for the first time. The nomograph served as an important reference tool for relevant clinical management decisions.

A sterol analog inhibits hedgehog pathway by blocking cholesterylation of smoothened.

The hedgehog (Hh) signaling pathway has long been a hotspot for anti-cancer drug development due to its important role in cell proliferation and tumorigenesis. However, most clinically available Hh pathway inhibitors target the seven-transmembrane region (7TM) of smoothened (SMO), and the acquired drug resistance is an urgent problem in SMO inhibitory therapy. Here, we identify a sterol analog Q29 and show that it can inhibit the Hh pathway through binding to the cysteine-rich domain (CRD) of SMO and blocking its cholesterylation. Q29 suppresses Hh signaling-dependent cell proliferation and arrests Hh-dependent medulloblastoma growth. Q29 exhibits an additive inhibitory effect on medulloblastoma with vismodegib, a clinically used SMO-7TM inhibitor for treating basal cell carcinoma (BCC). Importantly, Q29 overcomes resistance caused by SMO mutants against SMO-7TM inhibitors and inhibits the activity of SMO oncogenic variants. Our work demonstrates that the SMO-CRD inhibitor can be a new way to treat Hh pathway-driven cancers.

[Salicylic acid derivatives as simplified and novel GK small molecule activators].

Glucokinase (GK) is a new target for the treatment of type II diabetes mellitus (T2DM). In order to find a structure-simplified small molecule GK activator, 19 salicylic acid derivatives were designed and synthesized based on new lead compound (1). Experimental results showed that the potency of compound 8h is superior to control RO-28-0450 in GK activation.

Optimization design and analysis of mobile pump truck frame using response surface methodology.

In order to realize the lightweight design of mobile pump truck, this paper takes the frame of a certain type of mobile pump truck as the research object. The response surface method is used to carry out lightweight design of the longitudinal beam structure of the frame, and the finite element method is used to establish the finite element model to compare and analyze the optimized and original designs. The results show that the height, width and thickness of the optimized longitudinal beam section are reduced by 10mm, 11mm, and 0.8mm respectively, and the weight of the whole frame is reduced by 35.8kg. Before and after optimization, the displacement and stress changes of the frame are small in four motion situations, which meet the lightweight requirements of optimization design.

Numerical calculation of forward and reverse flow in Tesla valves with different longitudinal width-to-narrow ratios.

To study the effect of the width-to-narrow ratio on the forward and reverse flow characteristics of the Tesla valve, five different models of the Tesla valve with different width-to-narrow ratios are established in this paper. The numerical calculations of forward and reverse flow under different working conditions are carried out by the CFD method in the laminar flow regime, and the reliability of the numerical calculation method is verified by comparing it with the experimental results. The results show that: in forward flow, the main flow-through channel is not related to the width-to-narrow ratio, the flow rate of the straight channel increases with the increase of the width-to-narrow ratio, and the static pressure in the diversion section is in the shape of "∞"; while in reverse flow, the main flow-through channel is weakly related to the width-to-narrow ratio, the flow rate of the arc channel is not increased with the increase of the width-to-narrow ratio, and the static pressure in the diversion section is in the shape of "bench". As the width-to-narrow ratio decreases, the pressure drop during forward and reverse flow becomes more significant.

The acceleration effect of pump as turbine system during starting period.

In order to reveal the influence of starting acceleration on starting process of a pump as turbine system, this paper carries out a numerical calculation of the three-dimensional viscous unsteady flow of pump as turbine circulating piping system under three starting acceleration conditions, and obtains the external and internal flow characteristics of each overflow component during the starting process, and also analyzes the energy loss of each component in the piping system in depth with the help of entropy production method and Q criterion method. The results show that during system start-up, the flow rate and outlet static pressure curves of the pump as turbine are hysteresis relative to the rotational speed, the head curve is similar to a linear rise during slow and medium speed start-up, while it shows a parabolic rise during rapid start-up, the entropy production and vorticity in the impeller domain of the pump as turbine are mainly distributed between the blades, and the distribution decreases during start-up. In addition, the pump similarity law does not apply to the performance prediction during the transient start of the pump as turbine.

Optimal design of impeller for self-priming pump based on orthogonal method.

In order to improve the efficiency of the self-priming pump in the outdoor emergency rescue mobile pump truck, this paper took the key energy conversion component-impeller as the target and used the orthogonal experimental design method to optimize its hydraulic performance. Firstly the numerical calculations were compared with the experimental results to confirm the reliability of the calculation method. Then, L9 (34) orthogonal design was applied to investigate the influence of the impeller diameter, the blade outlet width, the blade wrap angle and the number of blades on the hydraulic performance of the self-priming pump. Through range analysis, the order of influence of each influencing factor on the head and efficiency of the self-priming pump was determined, and finally obtained the optimal parameter combination scheme. The results show that the optimized self-priming pump exceeds the head of the prototype pump at all flow conditions, and the efficiency curve at high flow conditions is significantly improved and has a wide high efficiency zone.

Effect of valve opening on starting performance of pump as turbine.

The study on transient characteristics of pump as turbines during atypical startup has not been deeply explored yet. In order to reveal the transient characteristics of a small centrifugal pump reversing as turbine during startup process in this paper, the transient hydraulic performance experiments are conducted for three steady rotational speed cases. Under the condition of each case, three, five and, three valve opening scenarios are completed to measure the performance. The dimensionless analysis are also employed so as to better reveal transient behavior of the pump as turbine during atypical startup. The results show that the rise rate of each performance parameter is different, wherein the shaft power and rotational speed have the fastest rising rate, followed by the flow rate, and the head rise is the slowest. It is clearly seen that the shock phenomenon in static pressure easily occurs at the outlet of pump as turbine. With the increase of valve opening, the dimensionless flow rate, head and, power coefficient all show the evolution trend of gradually increasing.

Modulation of gut microbiota alleviates cerebral ischemia/reperfusion injury in rats by inhibiting M1 polarization of microglia.

Gut microbiota affects the gut-brain axis; hence, the modulation of the microbiota has been proposed as a potential therapeutic strategy for cerebral ischemia/reperfusion injury (CIRI). However, the role and mechanism of the gut microbiota in regulating microglial polarization during CIRI remain poorly understood. Herein, using a middle cerebral artery occlusion and reperfusion (MCAO/R) rat model, we evaluated changes in the gut microbiota after CIRI and the potential effects of fecal microbiota transplant (FMT) on the brain. Rats underwent either MCAO/R or sham surgery, and then they received FMT (started 3 days later; continued for 10 days). 2,3,5-Triphenyltetrazolium chloride staining, neurological outcome scale, and Fluoro-Jade C staining showed that MCAO/R induced cerebral infarction, neurological deficits, and neuronal degeneration. In addition, immunohistochemistry or real-time PCR assay showed increased expression levels of M1-macrophage markers-TNF-α, IL-1ß, IL-6, and iNOS-in the rats following MCAO/R. Our finding suggests that microglial M1 polarization is involved in CIRI. 16 S ribosomal RNA gene sequencing data revealed an imbalance in the gut microbiota of MCAO/R animals. In contrast, FMT reversed this MCAO/R-induced imbalance in the gut microbiota and ameliorated nerve injury. In addition, FMT prevented the upregulation in the ERK and NF-κB pathways, which reversed the M2-to-M1 microglial shift 10 days after MCAO/R injury in rats. Our primary data showed that the modulation of the gut microbiota can attenuate CIRI in rats by inhibiting microglial M1 polarization through the ERK and NF-κB pathways. However, an understanding of the underlying mechanism requires further study.

Cloning and sequence analysis of two banana bunchy top virus genomes in Hainan.

The genome of Banana bunchy top virus (BBTV) consists of six segments of single-stranded DNA of approximately 1 kb in length. We identified and sequenced the complete genomes of two BBTV isolates, one with and one without satellite DNA, from Haikou, Hainan, China. The Haikou-2 isolate contains six genomic segments and an additional satellite DNA while the Haikou-4 isolate contains only six genomic segments. Typical of other babuviruses, each genomic segment encodes a single open reading frame and contains the highly conserved stem-loop and major common regions. Phylogenetic analysis of the two Haikou isolates together with existing sequence records in GenBank confirmed the grouping of BBTV into two large groups and further refined the geographical distribution of each group. To accommodate the changes in the BBTV geographical distribution, the two groups are proposed as the Southeast Asian group and the Pacific-Indian Oceans group. Both the Haikou-2 and Haikou-4 isolates belong to the newly proposed Southeast Asian group.