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Abstract Background Tryptophan is an essential amino acid involved in critical cellular processes in vertebrates, serving as a precursor for serotonin and kynurenine, which are key neuromodulators to influence neural and immune functions. Systematic and quantitative measurement of tryptophan is vital to understanding these processes. Results Here, we utilized a robust and highly responsive green ratiometric indicator for tryptophan (GRIT) to quantitatively measure tryptophan dynamics in bacteria, mitochondria of mammalian cell cultures, human serum, and intact zebrafish. At the cellular scale, these quantitative analyses uncovered differences in tryptophan dynamics across cell types and organelles. At the whole-organism scale, we revealed that inflammation-induced tryptophan concentration increases in zebrafish brain led to elevated serotonin and kynurenine levels, prolonged sleep duration, suggesting a novel metabolic connection between immune response and behavior. Moreover, GRIT’s application in detecting reduced serum tryptophan levels in patients with inflammation symptoms suggests its potential as a high-throughput diagnostic tool. Conclusions In summary, this study introduces GRIT as a powerful method for studying tryptophan metabolism and its broader physiological implications, paving the way for new insights into the metabolic regulation of health and disease across multiple biological scales.

rs2736098 is a synonymous polymorphism in TERT (telomerase reverse transcriptase), an enzyme involved in tumor onset of multiple tissues, and should play no roles in carcinogenesis. However, a search in cancer somatic mutation database indicated that the mutation frequency at rs2736098 is much higher than the average one for TERT. Moreover, there are significant H3K4me1 and H3K27Ac signals, two universal histone modifications for active enhancers, surrounding rs2736098. Therefore, we hypothesized that rs2736098 might be within an enhancer region, regulate TERT expression and influence cancer risk. Through luciferase assay, it was verified that the enhancer activity of rs2736098C allele is significantly higher than that of T in multiple tissues. Transfection of plasmids containing TERT coding region with two different alleles indicated that rs2736098C allele can induce a significantly higher TERT expression than T. By chromatin immunoprecipitation, it was observed that the fragment spanning rs2736098 can interact with USF1 (upstream transcription factor 1). The two alleles of rs2736098 present evidently different binding affinity with nuclear proteins. Database and literature search indicated that rs2736098 is significantly associated with carcinogenesis in multiple tissues and count of multiple cell types. All these facts indicated that rs2736098 is also an oncogenic polymorphism and plays important role in cell proliferation.

This study analyzes the feed-in tariff strategy of steel enterprises in the context of the steel industry’s electricity market, which is composed of waste heat and pressure (WHP) power generation and traditional thermal power generation. A Stackelberg game model was developed to compare three pricing strategies (i.e., fixed price, fixed premium, and variable premium) for the feed-in tariff of WHP power generation technology among steel enterprises, traditional fossil fuel power generators, and local governments. Three pricing strategies for WHP generation feed-in tariffs are compared, and numerical simulations are run to examine the effects of market size, WHP generation cost coefficients, and steel firm environmental costs on optimal regulated prices, optimal steel firm profits, and optimal total social welfare, respectively. The following findings are obtained. (1) For optimal price regulation, increasing the market size and the coefficient of WHP generation cost has little effect on the optimal price regulation under the fixed price policy. The only way to increase the price of the fixed price policy is to increase the environmental cost of steel enterprises. Moreover, increasing the market size and the coefficient of WHP generation cost will reduce the price of fixed premia. Additionally, increasing the market size and the coefficient of WHP generation cost will reduce the price of fixed premia. Increases in market size and WHP generation costs will raise the price of variable premium insurance, whereas increases in enterprise environmental costs will lower and maintain the price of variable premium policy. (2) For optimal steel enterprise profit, increasing the market size and the cost coefficient of WHP generation will increase the profit of steel enterprises under the fixed premium policy. However, it will have little effect on the profit of the fixed price and variable premium policies. Moreover, increasing the environmental cost of enterprises will reduce the profit of the fixed premium policy, but it will have little effect on the profit of the fixed price and variable premium policy. (3) For optimal total social welfare, increasing the market size and environmental cost of steel enterprises can increase total social welfare under the fixed price policy. Moreover, increasing the coefficient of WHP generation cost has little effect on the fixed price policy welfare; increasing both the market size and the coefficient of WHP generation cost has little effect on the fixed premium policy welfare. Additionally, increasing the environmental cost of enterprises can increase the fixed premium policy welfare, and increasing the market size can increase the total variable premium policy welfare. Meanwhile, increasing the coefficient of WHP generation cost and the environmental cost of steel enterprises can reduce the variable premium policy welfare and finally level off. (4) Depending on the decision maker’s preferences, various optimal decisions can be made. Higher subsidies imply higher optimal regulation prices, which are accompanied by market riskiness, thus influencing the rate of market development of waste heat and waste pressure power feed-in tariffs. In optimal rule prices, low riskiness and low subsidies are fixed price strategies, high riskiness and moderate subsidies are fixed premium strategies, and high riskiness and high subsidies are variable premium strategies. In optimal steel firm profit, low riskiness and low subsidy, high riskiness and high subsidy, and low riskiness and high subsidy are fixed price, fixed premium, and variable premium strategies, respectively. In optimal total social welfare, moderate riskiness and moderate subsidy, low riskiness and low subsidy, and high riskiness and high subsidy are fixed price, fixed premium, and variable premium strategies, respectively.

Abstract The combination of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) has been demonstrated to have comparable effectiveness or better to ATRA and chemotherapy (CHT) in non-high-risk acute promyelocytic leukemia (APL). However, the efficacy of ATRA-ATO compared to ATRA-ATO plus CHT in high-risk APL remains unknown. Here we performed a randomized multi-center non-inferiority phase III study to compare the efficacy of ATRA-ATO and ATRA-ATO plus CHT in newly diagnosed all-risk APL to address this question. Patients were assigned to receive ATRA-ATO for induction, consolidation, and maintenance or ATRA-ATO plus CHT for induction followed by three cycles of consolidation therapy, and maintenance therapy with ATRA-ATO. In the non-CHT group, hydroxyurea was used to control leukocytosis. A total of 128 patients were treated. The complete remission rate was 97% in both groups. The 2-year disease-free, event-free survival rates in the non-CHT group and CHT group in all-risk patients were 98% vs 97%, and 95% vs 92%, respectively (P = 0.62 and P = 0.39, respectively). And they were 94% vs 87%, and 85% vs 78% in the high-risk patients (P = 0.52 and P = 0.44, respectively). This study demonstrated that ATRA-ATO had the same efficacy as the ATRA-ATO plus CHT in the treatment of patients with all-risk APL.

In this paper, 25 sampling points of overlying deposits in Tonglushan mining area, Daye City, Hubei Province, China were tested for heavy metal content to explore pollution characteristics, pollution sources and ecological risks of heavy metals in sediments. A geo-accumulation index method was used to evaluate the degree of heavy metal pollution in the sediment. The mean sediment quality guideline quotient was used for evaluating the ecological risk level of heavy metal in the sediment. And a method of correlation analysis, clustering analysis, and principal component analysis was used for preliminary analysis on the source of heavy metal in the sediment. It was indicated that there was extremely heavy metal pollution in the sediment, among which Cd was extremely polluted, Cu strongly contaminated, Zn, As, and Hg moderately contaminated, and Pb, Cr, and Ni were slightly contaminated. It was also indicated by the mean sediment quality guideline-quotient result that there was a high ecological risk of heavy metals in the sediment, and 64% of the sample sites had extremely high hidden biotoxic effects. For distribution, the contamination of branches was worse than that of the main channel of Daye Dagang, and the deposition of each heavy metal was mainly influenced by the distance from this sample site to the sewage draining exit of a tailings pond. The source analysis showed that the heavy metals in the sediment come from pollution discharging of mining and beneficiation companies, tailings ponds, smelting companies, and transport vehicles. In the study area, due to the influence of heavy metal discharging from these sources, the ecotoxicity of heavy metals in the sediment was extremely high, and Cd was the most toxic pollutant. The research figured out the key restoration area and elements for ecological restoration in the sediment of the Tonglüshan mining area, which could be referenced by monitoring and governance of heavy metal pollution in the sediment of the polymetallic mining area.©2022 China Geology Editorial Office.

In the area of “carbon peaking and carbon neutralization,” changing energy structure from primary energy to new energy is an extremely important issue. Due to the intermittent and fluctuating characteristics of new energy, energy storage technology has proven a viable solution to this issue thus has attracted extensive attention. As a key to energy storage technology, the problem of the low thermal conductivity of phase change materials (PCMs) requires immediate attention. Erythritol is a high enthalpy phase change material commonly used in low-to-medium temperature processes. Its thermal conductivity of only 0.7 W·m–1·K–1 seriously hinders its energy utilization efficiency in practical application. In this paper, erythritol is the main research focus, and single-walled carbon nanotubes (CNTs) of ultra-high thermal conductivity are used as thermal conductivity reinforcements. The effects of length, mass fraction, and the distribution of CNTs on the thermal conductivity of erythritol/CNT composite PCMs were studied by means of molecular dynamics simulation. When the axial lengths of the CNTs were less than their phonon mean free paths, the thermal conductivity of the composite PCMs increased with increasing CNT axial length and mass fraction, although clear anisotropy was exhibited. Due to the introduction of erythritol–CNTs interfacial thermal resistance, the radial thermal conductivity of the composite materials was lower than that of pure erythritol. When CNTs were randomly distributed in erythritol, the anisotropy of thermal conductivity was significantly improved, as was thermal conductivity in all directions. Comparing the phonon vibration densities of the states of erythritol and CNT before and after recombination, it was found that, due to the interaction between the two, the phonon vibration of CNT was suppressed, and the phonon heat transport in erythritol was excited, thus improving thermal conductivity.

An oxygen blast furnace (OBF) has the advantages of high productivity, high coal injection, low fuel ratio, high gas calorific value, and low carbon emissions; the OBF process is one of the most likely low-carbon ironmaking processes to achieve large-scale application. This paper first introduced the development history of an OBF. The early research work mainly focused on solving the problem of “upper cooling and lower overheating” caused by oxygen instead of air blasting and summarized the OBF process and its main characteristics proposed by researchers in various countries. Then, the progress made by the researchers of the University of Science and Technology Beijing in the research and development of the OBF process was systematically summarized. The studies include the process design of an OBF, the reduction and soft melting of iron-bearing furnace charge, pulverized coal combustion under the conditions of oxygen blast and circulating gas injection, the physical and chemical behavior of recirculating gas during the heating process, as well as the numerical simulation of the raceway and the whole furnace, which gives a theoretical foundation for the engineering implementation of the OBF. Finally, the carbon flow and carbon saving potential of the OBF were analyzed. It is proposed that a hydrogen rich carbon circulating oxygen blast furnace will be an important development in the direction of low-carbon ironmaking.

Abstract Background Functional MRI (fMRI) parameters analysis has been proven to be a promising tool of predicting therapeutic response to induction chemotherapy (IC) in nasopharyngeal carcinoma (NPC). The study was designed to identify and compare the value of fMRI parameters in predicting early response to IC in patients with NPC. Methods This prospective study enrolled fifty-six consecutively NPC patients treated with IC from January 2021 to May 2021. Conventional diffusion weighted imaging (DWI), diffusion kurtosis imaging (DKI), intravoxel incoherent motion (IVIM) and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) protocols were performed before and after IC. Parameters maps (ADC, MD, MK, Dslow, Dfast, PF, Ktrans, Ve and Kep) of the primary tumor were calculated by the Functool post-processing software. The participants were classified as responding group (RG) and non-responding group (NRG) according to Response Evaluation Criteria in Solid Tumors 1.1. The fMRI parameters were compared before and after IC and between RG with NRG. Logistic regression analysis and ROC were performed to further identify and compare the efficacy of the parameters. Results After IC, the mean values of ADC(p

Background: Esophageal Squamous Cell Cancer (ESCC) is an aggressive disease associated with a poor prognosis. As a newly defined form of regulated cell death, ferroptosis plays a crucial role in cancer development and treatment and might be a promising therapeutic target. However, the expression patterns of ferroptosis-related genes (FRGs) in ESCC remain to be systematically analyzed.Methods: First, we retrieved the transcriptional profile of ESCC from TCGA and GEO datasets (GSE47404, GSE23400, and GSE53625) and performed unsupervised clustering to identify different ferroptosis patterns. Then, we used the ssGSEA algorithm to estimate the immune cell infiltration of these patterns and explored the differences in immune cell abundance. Common genes among patterns were finally identified as signature genes of ferroptosis patterns.Results: Herein, we depicted the multi-omics landscape of FRGs through integrated bioinformatics analysis and identified three ESCC subtypes with distinct immune characteristics: clusters A-C. Cluster C was abundant in CD8+ T cells and other immune cell infiltration, while cluster A was immune-barren. By comparing the differently expressed genes between clusters of diverse datasets, we defined a gene signature for each cluster and successfully validated it in the TCGA-ESCC dataset.Conclusion: We provided a comprehensive insight into the expression pattern of ferroptosis genes and their interaction with immune cell infiltration. Additionally, we established a gene signature to define the ferroptosis patterns, which might be used to predict the response to immunotherapy.

Type traits (TTs) can contribute to breeding animals with good economic traits such as production, longevity, fertility, and profitability. Dairy buffaloes are the second largest source of milk supply in the world, and their TTs should be taken into consideration in future dairy buffalo breeding programmes. However, the relationship between TTs and milk production traits in buffalo remains largely unknown. The study aimed to establish an early selection method for buffaloes with desirable milk performance by TTs. Using 1 908 records from 678 buffaloes, the relationship between TTs and milk production traits was analysed and the optimal growth curves of TTs related to milk production traits were constructed. We examined the correlations between 45 TTs (33 body structural, 12 udder and teat morphological traits) and three milk production traits (milk yield (MY), milk fat percentage (MF), and milk protein percentage (MP)). The results showed that the highest correlation was found between MY and udder circumference (r = 0.438), teat length (r = −0.380) or heart girth (r = −0.341). The teat distance and teat circumference exhibited a significant negative correlation with MF and MP. Rump length was the only trait that had a significant positive correlation with milk production traits, suggesting that milk performance could be comprehensively improved by including rump length in the selection procedure. Notably, we found that high milk production traits was obtained from the buffaloes with short teats (104 cm), long rump (>39 cm), and small distance between teats. Moreover, an early selection method for buffaloes with excellent milk performance was developed based on the non-linear models. Brody model exhibited the best fitting effect for heart girth and rump length, while the Logistic model displayed the best fitting effect for teat length. Our findings provide theoretical basis for the early selection of buffaloes with desirable milk performance.

Abstract Breast cancer is the most common malignant tumor in women. A previous genome-wide association study reports that rs72755295, a SNP locating at intron of EXO1 (exonuclease 1), is associated with breast cancer. Due to the complete linkage disequilibrium between rs72755295 and rs4149909, a nonsynonymous mutation for EXO1, rs4149909 is supposed to be the causal SNP. Since EXO1 is overexpressed in breast carcinoma samples, we hypothesized that the genetic variations in this locus might confer breast cancer risk by regulating EXO1 expression. To substantiate this, a functional genomics study was performed. The dual luciferase assay indicated that G of rs72755295 presents significantly higher relative enhancer activity than A, thus verifying that this SNP can influence gene expression in breast cell. Through chromosome conformation capture it was disclosed that the enhancer containing rs72755295 can interact with the EXO1 promoter. RNA-seq analysis indicated that EXO1 expression is dependent on the rs72755295 genotype. By chromatin immunoprecipitation, the transcription factor PAX6 (paired box 6) was recognized to bind the region spanning rs72755295. In electrophoretic mobility shift assay, G of rs72755295 displays obviously higher binding affinity with nuclear protein than A. Our results indicated that rs72755295 is a cis-regulatory variation for EXO1 and might confer breast cancer risk besides rs4149909.

Quantitative assessment of the impact of groundwater depletion on phreatophytes in (hyper-) arid regions is key to sustainable groundwater management. However, a parsimonious model for predicting the response of phreatophytes to a decrease of the water table is lacking. A variable saturated flow model, HYDRUS-1D, was used to numerically assess the influences of depth to the water table (DWT) and mean annual precipitation (MAP) on transpiration of groundwater-dependent vegetation in (hyper-) arid regions of northwest China. An exponential relationship is found for the normalized transpiration (a ratio of transpiration at a certain DWT to transpiration at 1 m depth, Ta*) with increasing DWT, while a positive linear relationship is identified between Ta* and annual precipitation. Sensitivity analysis shows that the model is insensitive to parameters, such as saturated soil hydraulic conductivity and water stress parameters, indicated by an insignificant variation (less than 20% in most cases) under ± 50% changes of these parameters. Based on these two relationships, a universal model has been developed to predict the response of phreatophyte transpiration to groundwater drawdown for (hyper-) arid regions using MAP only. The estimated Ta* from the model is reasonable by comparing with published measured values.© 2021 China Geology Editorial Office.

Despite tremendous progress made in the diagnosis and managements, head and neck squamous cell carcinoma (HNSC) remains a global medical dilemma with dismal clinical prognosis and high mortality. Gene NT5E encodes the ecto-5’-nucleotidase (CD73), which facilitates the formation of immunosuppressive tumor microenvironment (TME) permissive for tumor progression in various malignancies. Nevertheless, the cell subsets NT5E expressed on and the potential function of NT5E in the TME of HNSC remain virgin lands in HNSC. In this study, we comprehensively performed integrated prognostic analysis and elucidated that NT5E was an independent prognostic indicator for HNSC, for which a high NT5E level predicted poor overall survival (OS), disease-specific survival (DSS) and progression-free interval (PFI) in HNSC patients (p

Abstract Lipid-based nanocarriers have been extensively investigated for drug delivery due to their advantages including biodegradability, biocompatibility, nontoxicity, and nonimmunogenicity. However, the shortcomings of traditional lipid-based nanocarriers such as insufficient targeting, capture by the reticuloendothelial system, and fast elimination limit the efficiency of drug delivery and therapeutic efficacy. Therefore, a series of multifunctional lipid-based nanocarriers have been developed to enhance the accumulation of drugs in the lesion site, aiming for improved diagnosis and treatment of various diseases. In this review, we summarized the advances and applications of lipid-based nanocarriers from traditional to novel functional lipid preparations, including liposomes, stimuli-responsive lipid-based nanocarriers, ionizable lipid nanoparticles, lipid hybrid nanocarriers, as well as biomembrane-camouflaged nanoparticles, and further discussed the challenges and prospects of this system. This exploration may give a complete idea viewing the lipid-based nanocarriers as a promising choice for drug delivery system, and fuel the advancement of pharmaceutical products by materials innovation and nanotechnology.

PurposeThe aim of this study was to identify the efficacy of diffusion kurtosis imaging (DKI) in tracking and monitoring the dynamic change of parotid glands (PGs), submandibular glands (SMGs), sublingual glands (SLGs), and acute xerostomia in nasopharyngeal carcinoma (NPC) patients treated with induction chemotherapy (IC) plus concurrent chemoradiotherapy (CCRT).MethodsThe prospective study recruited 42 participants treated with IC+CCRT. All patients underwent DKI scanning six times: before IC, before RT, in the middle of the RT course, immediately after RT, and 1 and 3 months post-RT. Mean diffusion coefficient (MD) and mean kurtosis (MK) of PG, SMG, SLG, saliva flow rate measured under resting (uSFR) and stimulated condition (sSFR), and xerostomia questionnaire (XQ) scores were recorded.ResultsAt each time point, sSFR was significantly higher than uSFR (p < 0.05 for all). MD of the salivary glands and XQ scores increased over time while MK, uSFR, and sSFR decreased. After IC, the significant differences were detected in MD and MK of bilateral SMG and MK of the left SLG (p < 0.05 for all), but not in MD and MK of PG, uSFR, sSFR, and XQ scores. After RT, sSFR at 1m-RT decreased significantly (p = 0.03) while no significant differences were detected in uSFR and XQ scores. Moderate-strong correlations were detected in ΔMD-PG-R%, ΔMK-PG-R%, ΔMD-PG-L%, ΔMK-PG-L%, ΔMD-SMG-R%, ΔMK-SMG-R%, ΔMD-SMG-L%, ΔMK-SMG-L%, and ΔMD-SLG-R%, with correlation coefficients (p < 0.05 for all) ranging from 0.401 to 0.714. ΔuSFR% was correlated with ΔMD-SMG% (p = 0.01, r = −0.39), ΔMD-SLG% (p < 0.001, r = −0.532), and ΔMK-SMG% (p < 0.001, r = −0.493). ΔsSFR% correlated with ΔMD-PG% (p = 0.001, r = −0.509), ΔMD-SMG% (p = 0.015, r = −0.221), and ΔMK-PG% (p < 0.001, r = 0.524). ΔXQ% was only correlated with ΔMK-PG% (p = 0.004, r = 0.433).ConclusionDKI is a promising tool for tracking and monitoring the acute damage of PG, SMG, and SLG induced by IC+CCRT in NPC patients.

ABSTRACT Background: Enriched environment (EE) is a simple and effective intervention to improve cognitive function in post-stroke cognitive impairment (PSCI), partly due to the rebalancing of the cholinergic signaling pathway in the hippocampus. α7-nicotinic acetylcholine receptor (α7-nAChR) is a cholinergic receptor whose activation inhibits inflammation and promotes the recovery of neurological function in PSCI patients. However, it is still unclear whether EE can regulate α7-nAChR and activate the cholinergic anti-inflammatory pathway (CAP) in PSCI. Objective: To investigate the effects of EE on cognitive impairment, and the role of α7-nAChR in PSCI. Methods: A PSCI rat model was induced by middle cerebral artery occlusion and reperfusion (MCAO/R) and were reared in standard environment (SE) or EE for 28d, control group with sham surgery. Cognitive function was determined by Morris water maze test. The long-term potentiation (LTP) was assessed by Electrophysiology. Histopathological methods were used to determine infarct volume, α7-nAChR expression and the cytokines and cholinergic proteins expression. Results: Compared with SE group, rats in EE group had better cognitive function, higher expression of α7-nAChR positive neurons in hippocampal CA1 region. In addition, EE attenuated unfavorable changes induced by MCAO/R in cytokines and cholinergic proteins, and also enhanced LTP promoted by nicotine and attenuated by α-BGT; but showed no significantly difference in infarct volume. Conclusions: EE markedly improves cognitive impairment and enhances neuroplasticity in PSCI rats, which may be closely related to enhancement of α7-nAChR expression.

ABSTRACT: Regional aridity is increasing under global climate change, and therefore the sustainable use of water resources has drawn attention from scientists and the public. Land-use changes can have a significant impact on groundwater recharge in arid regions, and quantitative assessment of the impact is key to sustainable groundwater resources management. In this study, the changes of groundwater recharge after the conversion of natural lands to croplands were investigated and compared in inland and arid region, i.e., the northern slope of the Tianshan Mountain. Stable isotopes suggest that soil water in topsoil (< 2 m) has experienced stronger evaporation under natural lands than croplands, and then moves downward as a piston flow. Recharge was estimated by the tracer-based mass balance method, i.e., chloride and sulfate. Recharge rates under natural conditions estimated by the chloride mass balance (CMB) method were estimated to be 0.07 mm/a in deserts and 0.4 mm/a in oases. In contrast, the estimated groundwater recharge ranged from 61.2 mm/a to 44.8 mm/a in croplands, indicating that groundwater recharge would increase significantly after land changes from natural lands to irrigated croplands in arid regions. Recharge estimated by the sulfate mass balance method is consistent with that from the CMB method, indicating that sulfate is also a good tracer capable of estimating groundwater recharge.

Glucocorticoid (GC)-induced avascular osteonecrosis of femoral head (AOFH) is a devastating complication, and no cures are currently available for it. Previous studies have demonstrated that implantation of bone marrow mesenchymal stem cells (BMMSCs) may prevent the progression of pre-collapse AOFH. Based on previous observations, we hypothesized that GCs induce AOFH via the COX-2 (cyclooxygenase-2)–PGE-2 (prostaglandin E2)–HIF-1α (hypoxia-inducible factor-1α) axis, and that modification of BMMSCs may improve the efficacy of their implantation. BMMSCs isolated from wild-type (WT) mice were treated with dexamethasone (Dex) and the results showed that Dex repressed the expression of COX-2. Femoral head samples harvested from both WT and COX-2 knock-out (COX-2 −/− ) mice were subjected to micro–computed tomography and histological examinations. Compared with their WT littermates, COX-2 −/− mice had larger trabecular separations, diminished microvasculature, and reduced HIF-1α expression in their femoral heads. In vitro angiogenesis assays with tube formation and fetal metatarsal sprouting demonstrated that Dex repressed angiogenesis and PGE-2 antagonized its effects. An AOFH model was successfully established in C57BL/6J mice. In vitro experiment showed that BMMSCs infected with Lentivirus encoding HIF-1α (Lenti-HIF-1α) resulted in a robust increase in the production of HIF-1α protein. Implantation of BMMSCs overexpressing HIF-1α into femoral heads of AOFH mice significantly reduced osteonecrotic areas and enhanced bone repair, thus largely preserving the structural integrity of femoral heads. Our studies provide strong rationales for early intervention with core decompression and implantation of modified BMMSCs for GC-induced AOFH, which may spare patients from expensive and difficult surgical procedures.

Convection heat transfer (CHT) in porous media founds broad significance in the applications of solar collectors, geothermal systems, and biological sciences. In this work, the natural CHT in a porous medium embedded with a rectangular thermal source at the bottom is numerically solved via the lattice Boltzmann method (LBM). The generalized Brinkman-Forchheimer-extended-Darcy model is applied to describe the momentum equation. The numerical solutions obtained by the LBM are verified against the experimental data for the correctness validation of the presented lattice Boltzmann model. Effects of the Darcy number (Da), medium porosity (ε), size of the thermal source, and the aspect ratio of the thermal source on the temperature- and flow-field in the porous medium are systematically investigated. Results show that the increase of Da remarkably enhances the heat exchange and changes the heat transfer mode from conduction to convection. The existence of the thermal source sidewall has a suppression effect on the heat exchange along the top wall of the thermal source, and this suppression effect is pronounced when the CHT is weak.

Virtual reality (VR) is an artificial environment which is experienced through sensory stimuli provided by a computer. The capability of VR to simulate reality could greatly increase access to psychological therapies. The model of early intervention training and partial intelligent feedback was established to analyze the effect of cognitive training based on VA on children with autism spectrum disorder (ASD). The Autism Behavior Checklist (ABC), Childhood Autism Rating Scale (CARS) and Clancy Autism Behavior Scale (CABS) were used to assist the severity of symptoms and treatment effectiveness of cognitive training based on VA on children with ASD. The results showed that the cognitive training based on VA was very attractive to children with ASD; cognitive training based on VA significantly improved the typical symptoms (the social communication disorder, speech retardation, narrow interest and rigid behavior) of children with ASD and perfected the Autism Behavior Checklist (ABC), Childhood Autism Rating Scale (CARS) and Autism Behavior Scale (CABS) during 4 weeks after treatment. The data suggested that cognitive training based on VA might be a good method to treat children with ASD.

The Asian citrus psyllid Diaphorina citri (Hemiptera: Liviidae) is a major citrus pest spread around the world. It is also a vector of the bacterium ‘Candidatus Liberibacter asiaticus’, considered the cause of the fatal citrus disease huanglongbing (HLB). Insect ryanodine receptors (RyRs) are the primary target sites of diamide insecticides. In this study, full-length RyR cDNA from D. citri (named DcRyR) was isolated and identified. The 15,393 bp long open reading frame of DcRyR encoded a 5130 amino acid protein with a calculated molecular weight of 580,830 kDa. This protein had a high sequence identity (76–79%) with other insect homologs and a low sequence identity (43–46%) with mammals. An MIR domain, two RIH domains, three SPRY domains, four RyR repeat domains, an RIH-associated domain at the N-terminus, two consensus calcium-binding EF-hands, and six transmembrane domains were among the characteristics that DcRyR shared with insect and vertebrate RyRs. In expression analysis, the DcRyR gene displayed transcript abundance in all tissues and developmental stages as well as gene-differential and stage-specific patterns. In addition, diagnostic PCR experiments revealed that DcRyR had three potential alternative splice variants and that splicing events might have contributed to the various functions of DcRyR. However, diamide resistance-related amino acid residue mutations I4790M/K and G4946E were not found in DcRyR. These results can serve as the basis for further investigation into the target-based diamide pesticide resistance of D. citri.

Osteoarthritis (OA) is a chronic, debilitating joint disease characterized by progressive destruction of articular cartilage. For a long time, OA has been considered as a degenerative disease, while recent observations indicate the mechanisms responsible for the pathogenesis of OA are multifaceted. Aging is a key factor in its development. Current treatments are palliative and no disease modifying anti-osteoarthritis drugs (DMOADs) are available. In addition to articular cartilage degradation, cellular senescence, synovial inflammation, and epigenetic alterations may all have a role in its formation. Accumulating data demonstrate a clear relationship between the senescence of articular chondrocytes and OA formation and progression. Inhibition of cell senescence may help identify new agents with the properties of DMOADs. Several anti-cellular senescence strategies have been proposed and these include sirtuin-activating compounds (STACs), senolytics, and senomorphics drugs. These agents may selectively remove senescent cells or ameliorate their harmful effects. The results from preclinical experiments and clinical trials are inspiring. However, more studies are warranted to confirm their efficacy, safety profiles and adverse effects of these agents.

Osteoporosis (OP) is a chronic bone disease characterized by aberrant microstructure and macrostructure of bone, leading to reduced bone mass and increased risk of fragile fractures. Anti-resorptive drugs, especially, bisphosphonates, are currently the treatment of choice in most developing countries. However, they do have limitations and adverse effects, which, to some extent, helped the development of anabolic drugs such as teriparatide and romosozumab. In patients with high or very high risk for fracture, sequential or combined therapies may be considered with the initial drugs being anabolic agents. Great endeavors have been made to find next generation drugs with maximal efficacy and minimal toxicity, and improved understanding of the role of different signaling pathways and their crosstalk in the pathogenesis of OP may help achieve this goal. Our review focused on recent progress with regards to the drug development by modification of Wnt pathway, while other pathways/molecules were also discussed briefly. In addition, new observations made in recent years in bone biology were summarized and discussed for the treatment of OP.

Background. Diabetic nephropathy (DN) is an important cause of end-stage renal disease and is recognized as a public health problem worldwide. However, there have been no nationwide surveys of DN prevalence in China. This study is aimed at estimating the pooled prevalence of DN among patients with type 2 diabetes in China. Methods. Published studies on the prevalence of DN among patients with type 2 diabetes published from January 1980 to October 2019 were systematically reviewed using PubMed, Embase, Google Scholar, Chinese Wanfang databases, and Chinese National Knowledge Infrastructure. The pooled prevalence of DN was estimated with the random effects model using R software. Prevalence estimates were also stratified by study design, methodological approach, and study population characteristics. Results. Thirty studies with a total of 79,364 participants were included in our study. The overall pooled prevalence of DN was 21.8% [95% confidence interval (CI): 18.5-25.4%]. Subgroup analysis found that the prevalence of DN varied significantly according to different DM and DN diagnostic criteria (P

Oxytropis falcata Bunge is a plant used in traditional Tibetan medicine, with reported anti-inflammatory and antioxidants effects and alleviation of myocardial ischemia reperfusion injury (MIRI). However, the underlying mechanism against MIRI and the phytochemical composition of O. falcata are vague. One fraction named OFF1 with anti-MIRI activity was obtained from O. falcata, and the chemical constituents were identified by ultra-high-performance liquid chromatography coupled with tandem mass spectrometry (UHPLC–MS). The potential targets and signaling pathways involved in the action of O. falcata against MIRI were predicted by network pharmacology analysis, and its molecular mechanism on MIRI was determined by in vitro assays. The results revealed that flavonoids are the dominant constituents of OFF1. A total of 92 flavonoids reported in O. falcata targeted 213 potential MIRI-associated factors, including tumor necrosis factor (TNF), prostaglandin-endoperoxide synthase 2 (PTGS2), and the NF-κB signaling pathway. The in vitro assay on H9c2 cardiomyocytes subjected to hypoxia/reoxygenation injury confirmed that the flavonoids in OFF1 reduced myocardial marker levels, apoptotic rate, and the inflammatory response triggered by oxidative stress. Moreover, OFF1 attenuated MIRI by downregulating the ROS-mediated JNK/p38MAPK/NF-κB pathway. Collectively, these findings provide novel insights into the molecular mechanism of O. falcata in alleviating MIRI, being a potential therapeutic candidate.

Abstract Seasonal H3N2 influenza viruses are recognized as major epidemic viruses, exhibiting complex seasonal patterns in regions with temperate climates. To investigate the influence of viral evolution and mutations on the seasonality of influenza, we performed a genome-wide analysis of samples collected from 62 influenza A/H3N2-infected patients in Shanghai during 2016–2017. Phylogenetic analysis of all eight segments of the influenza A virus revealed that there were two epidemic influenza virus strains circulating in the 2016–2017 winter season (2016–2017win) and 2017 summer season (2017sum). Replication of the two epidemic viral strains at different temperatures (33, 35, 37, and 39 °C) was measured, and the correlation of the mutations in the two epidemic viral strains with temperature sensitivity and viral replication was analyzed. Analysis of the replication kinetics showed that replication of the 2016–2017win strains was significantly restricted at 39 °C compared with that of the 2017sum strains. A polymerase activity assay and mutational analysis demonstrated that the PA I668V mutation of the 2016–2017win viruses suppressed polymerase activity in vitro at high temperatures. Taken together, these data suggest that the I668V mutation in the PA subunit of the 2016–2017win strains may confer temperature sensitivity and attenuate viral replication and polymerase activity; meanwhile, the 2017sum strains maintained virulence at high temperatures. These findings highlight the importance of certain mutations in viral adaptation and persistence in subsequent seasons.

Fault tolerance is one of the important ways to measure the reliability of multiprocessor interconnection networks.g-restricted edge connectivity and g-restricted connectivity can ensure every remaining component is disconnected ,the number of neighbors of vertex is no less than g,which can measure the fault tolerance and reliability of multiprocessor and multichannel system more accurately.Balanced hypercubes is a variant of the hypercube,which has some specific topological properties,it can better meet the needs of the multiprocessor system and many new networks.The {1,2}-restricted edge connectivity and the {1,2}-restricted connectivity of balanced hypercubes were proposed,which could enrich the evaluation system of network fault tolerance and reliability in balanced hypercubes topology and it laid a good foundation for the fault diagnosis algorithm of balances hypercube.

Abstract Background Using propensity score matching method (PSM) to evaluate the feasibility and clinical outcomes of simultaneous modulated accelerated radiation therapy (SMART) using helical tomotherapy (HT) in patients with nasopharyngeal carcinoma (NPC). Methods Between August 2007 and January 2016, 381 newly diagnosed NPC patients using HT were enrolled in pre-PSM cohort, including 161 cases in a prospective phase II study (P67.5 study, with a prescription dose of 67.5Gy in 30 fractions to the primary tumour and positive lymph nodes) and 220 cases in a retrospective study (P70 study, with a prescription dose of 70Gy in 33 fractions to the primary tumour and positive lymph nodes). Acute and late toxicities were assessed according to the established RTOG/EORTC criteria and Common Terminology Criteria for Adverse Events (CTCAE) V 3.0. Survival rate were assessed with Kaplan-Meier method, log-rank test and Cox regression. Results After matching, 148 sub-pairs of 296 patients were generated in post-PSM cohort. The incidence of grade 3–4 leukopenia, thrombocytopenia and anemia in the P67.5 group was significantly higher than in the P70 study, but no significant different was found in other acute toxicities or late toxicities between the two groups. The median follow-up was 33 months in the P67.5 and P70 group, ranging 12–54 months and 6–58 months, respectively. No significant differences in 3-year local-regional recurrence free survival (LRRFS), distant metastasis-free survival (DMFS), disease free survival (DFS) and overall survival (OS) were observed between the 2 groups. Univariate analysis showed that age, T stage, clinical stage were the main factors effecting survival. Cox proportional hazards model showed that 67.5Gy/30F pattern seemed superior in 3-year OS (HR = 0.476, 95% CI: 0.236-0.957). Conclusions Through increasing fraction dose and shortening treatment time, the P67.5 study achieved excellent short-term outcomes and potential clinical benefits, with acceptable acute and late toxicities. Trial registration The trial was registered at Chinese Clinical Trial Registry on 5 July 2014 with a registration code of ChiCTRONC-14,004,895.

The recent success of derivation of mammalian haploid embryonic stem cells (haESCs) has provided a powerful tool for large-scale functional analysis of the mammalian genome. However, haESCs rapidly become diploidized after differentiation, posing challenges for genetic analysis. Here, we show that the spontaneous diploidization of haESCs happens in metaphase due to mitotic slippage. Diploidization can be suppressed by small-molecule-mediated inhibition of CDK1 and ROCK. Through ROCK inhibition, we can generate haploid somatic cells of all three germ layers from haESCs, including terminally differentiated neurons. Using piggyBac transposon-based insertional mutagenesis, we generated a haploid neural cell library harboring genome-wide mutations for genetic screening. As a proof of concept, we screened for Mn2+-mediated toxicity and identified the Park2 gene. Our findings expand the applications of mouse haploid cell technology to somatic cell types and may also shed light on the mechanisms of ploidy maintenance.

Coexistence of the hepatitis B surface antigen (HBsAg) and hepatitis B surface antibody (anti-HBs) is an uncommon phenomenon, and the underlying mechanisms remain largely unknown. Amino-acid (aa) substitution from glycine to arginine at aa 145 (G145R), in the major hydrophilic region, has been reported in patients with HBsAg and anti-HBs coexistence. However, there is limited knowledge about the clinical features and viral quasispecies characteristics associated with G145R mutant hepatitis B virus (HBV) infection. We herein describe the dynamic changes in the serological and virological markers in a case of hepatitis B with coexisting HBsAg and anti-HBs, caused by a G145R immune escape mutant (genotype C). Entecavir was administered during the 4th week after admission. Alanine aminotransferase peaked in the 16th week, while both the HBsAg and HBeAg declined rapidly. HBsAg clearance and hepatitis B e antigen (HBeAg)/hepatitis B e antibody (anti-HBe) seroconversion were achieved in the 36th week, and then entecavir was withdrawn. A follow-up of 96 weeks showed that HBV DNA remained undetectable and that anti-HBs was maintained above 100 mIU/mL. The quasispecies characteristics of the G145R mutant HBV were investigated via ultra-deep sequencing. The complexity and genetic distance of the S and RT regions were much higher in the 8th week than at baseline or in the 4th week. Moreover, the frequencies of mutations (L173P, Q181R and A184V) in cytotoxic T lymphocyte epitopes increased before entecavir treatment. These findings extend understanding of the evolution of HBV under host immune pressure and of the clinical outcomes of affected patients.Emerging Microbes & Infections (2017) 6, e15; doi:10.1038/emi.2017.2; published online 22 March 2017

Background: Murine model of coronary arterial inflammation has been widely accepted as an animal model of and used in Kawasaki disease (KD). This study sought to evaluate the developmental changes of coronary arteries and cardiac function in a murine model of KD with a high-frequency ultrasound system and to provide evidence for the preparation of the model of KD. Methods: Lactobacillus casei cell wall extract was prepared and injected into C57BL/6 mice intraperitoneally (i.p.) to induce KD. A total of 120 mice were grouped into three groups. The intravenous immunoglobulin (IVIG) treatment group was i.p. injected with IVIG (2 g/kg), while the KD model and normal control groups were i.p. injected with 0.5 ml of phosphate buffered solution on day 5. All high-resolution echocardiography detection of mouse heart was performed by the same senior technician. Animal echocardiography was performed by measuring the coronary artery dimensions and cardiac function on days 0, 7, 14, 28, and 56 (high-resolution small animal ultrasound [Vevo770 pattern; VisualSonic, Canada] with broadband probe [RMVTM707B; frequency, 30 mHz; depth of focus, 1.2 cm]) which were measured and analyzed with Vevo770 software. Results: Pathological studies revealed focal inflammatory infiltrate asymmetrically distributed around the coronary artery trunk in the KD model group. Echocardiographic study including coronary dimension and cardiac function measurements was successfully performed in all subjects. The KD model and IVIG treatment groups showed left coronary artery dilation on days 7, 14, 28, and 56. The diameter of left coronary artery in the KD model group (0.53 ± 0.09 mm; 0.36 ± 0.07 mm; 0.34 ± 0.05 mm; 0.34 ± 0.04 mm) was significantly larger than those of IVIG treatment group (0.22 ± 0.02 mm; 0.28 ± 0.03 mm; 0.26 ± 0.03 mm; 0.27 ± 0.05 mm; 0.26 ± 0.03 mm; all P < 0.01) and the normal control group (0.21 ± 0.02 mm; 0.22 ± 0.03 mm; 0.22 ± 0.02 mm; 0.23 ± 0.02 mm; 0.27 ± 0.04 mm; all P< 0.01) on days 7, 14, 28, and 56. No significant differences were observed in the measurements of cardiac function among the groups on days 0, 7, 14, 28, and 56 (all P > 0.05). Conclusions: Echocardiography could identify the consecutive changes of coronary artery in KD mice. Echocardiography is more convenient and direct in evaluating the coronary abnormalities in this animal model.

Fluidic oscillators (FOs) can be used as an efficient fluidic vibration tool to solve high friction problems in extended-reach wells. However, the complex mechanism of FOs makes the design challenging, and the dynamic erosion behavior inside FOs is still unclear. In this paper, new FOs are proposed and the working characteristics under the influence of periodic particle-laden jets are investigated. Firstly, the results reveal the working mechanism of new FOs, showing that the generation of pressure pulses is closely connected with periodic jet switching and the development of vortices. Secondly, the important performance parameters, i.e., pressure pulse and oscillation frequency, are extensively studied through numerical simulation and experimental verification. It is found that the performance can be optimized by adjusting the tool structure according to different engineering requirements. Finally, the oscillating solidliquid two-phase flow inside FO is studied. It is demonstrated that the accumulation of particles leads to a significant reduction in performance. The results also reveal five locations that are susceptible to erosion and the erosion behavior of these locations are studied. It has been shown that the periodic jet causes fluctuations in the amount of erosion at the outlet and splitter. This research can provide valuable references for the design and optimization of vibration friction-reduction tools. [ABSTRACT FROM AUTHOR]

Abstract Background Previously, we have demonstrated that spleen-derived dendritic cells (DCs) modified with atorvastatin suppressed immune responses of experimental autoimmune myasthenia gravis (EAMG). However, the effects of exosomes derived from atorvastatin-modified bone marrow DCs (BMDCs) (statin-Dex) on EAMG are still unknown. Methods Immunophenotypical characterization of exosomes from atorvastatin- and dimethylsulfoxide (DMSO)-modified BMDCs was performed by electron microscopy, flow cytometry, and western blotting. In order to investigate whether statin-DCs-derived exosomes (Dex) could induce immune tolerance in EAMG, we administrated statin-Dex, control-Dex, or phosphate-buffered saline (PBS) into EAMG rats via tail vein injection. The tracking of injected Dex and the effect of statin-Dex injection on endogenous DCs were performed by immunofluorescence and flow cytometry, respectively. The number of Foxp3+ cells in thymuses was examined using immunocytochemistry. Treg cells, cytokine secretion, lymphocyte proliferation, cell viability and apoptosis, and the levels of autoantibody were also carried out to evaluate the effect of statin-Dex on EAMG rats. To further investigate the involvement of FasL/Fas in statin-Dex-induced apoptosis, the underlying mechanisms were studied by FasL neutralization assays. Results Our data showed that the systemic injection of statin-Dex suppressed the clinical symptoms of EAMG rats. These statin-Dex had immune regulation functions in immune organs, such as the spleen, thymus, and popliteal and inguinal lymph nodes. Furthermore, statin-Dex exerted their immunomodulatory effects in vivo by decreasing the expression of CD80, CD86, and MHC class II on endogenous DCs. Importantly, the therapeutic effects of statin-Dex on EAMG rats were associated with up-regulated levels of indoleamine 2,3-dioxygenase (IDO)/Treg and partly dependent on FasL/Fas pathway, which finally resulted in decreased synthesis of anti-R97–116 IgG, IgG2a, and IgG2b antibodies. Conclusions Our data suggest that atorvastatin-induced immature BMDCs are able to secrete tolerogenic Dex, which are involved in the suppression of immune responses in EAMG rats. Importantly, our study provides a novel cell-free approach for the treatment of autoimmune diseases.

N6-methyladenosine (m6A) RNA methylation is the most abundant modification on mRNAs and plays important roles in various biological processes. The formation of m6A is catalyzed by a methyltransferase complex including methyltransferase-like 3 (METTL3) as a key factor. However, the in vivo functions of METTL3 and m6A modification in mammalian development remain unclear. Here, we show that specific inactivation of Mettl3 in mouse nervous system causes severe developmental defects in the brain. Mettl3 conditional knockout (cKO) mice manifest cerebellar hypoplasia caused by drastically enhanced apoptosis of newborn cerebellar granule cells (CGCs) in the external granular layer (EGL). METTL3 depletion-induced loss of m6A modification causes extended RNA half-lives and aberrant splicing events, consequently leading to dysregulation of transcriptome-wide gene expression and premature CGC death. Our findings reveal a critical role of METTL3-mediated m6A in regulating the development of mammalian cerebellum.