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Abstract This article considers the problem of output feedback stabilization for a class of stochastic high‐order nonlinear time‐delay systems with unknown output function. For stochastic high‐order nonlinear time‐delay systems, based on the Lyapunov stability theorem, by combining the addition of one power integrator and homogeneous domination method, the maximal open sector Δ of output function is given. As long as output function belongs to any closed sector included in Δ, an output feedback controller can be developed to guarantee the closed‐loop system globally asymptotically stable in probability.

To explore the moisture variation law of high oleic peanuts during hot air drying, hot air drying characteristics of various high oleic peanuts under different hot air temperatures (35, 40, 45, 50 ℃) and hot air velocities (0.5, 0.8, 1.1 m/s) were studied in this paper, and their drying processes were analyzed by Weibull distribution function. The results showed that the drying process of high oleic peanuts mainly reduced the rate of drying. Increasing hot air temperature and hot air velocity led to a higher effective moisture diffusion coefficient for high oleic peanuts. In turn, accelerates drying rate and shortens drying time. Among all the peanuts, 'Shengyou 3' peanut had the fastest water diffusion rate and lowest activation energy, and the Weibull distribution function provided the most suitable fit for 'Shengyou 3'. The scale parameter α decreased as hot air temperature and hot air velocity increase. Hot air temperature had a highly significant effect on α (P

Abstract Single cell chromatin accessibility profiling and transcriptome sequencing are the most widely used technologies for single-cell genomics. Here, we present Microwell-seq3, a high-throughput and facile platform for high-sensitivity single-nucleus chromatin accessibility or full-length transcriptome profiling. The method combines a preindexing strategy and a penetrable chip-in-a-tube for single nucleus loading and DNA amplification and therefore does not require specialized equipment. We used Microwell-seq3 to profile chromatin accessibility in more than 200,000 single nuclei and the full-length transcriptome in ~50,000 nuclei from multiple adult mouse tissues. Compared with the existing polyadenylated transcript capture methods, integrative analysis of cell type-specific regulatory elements and total RNA expression uncovered comprehensive cell type heterogeneity in the brain. Gene regulatory networks based on chromatin accessibility profiling provided an improved cell type communication model. Finally, we demonstrated that Microwell-seq3 can identify malignant cells and their specific regulons in spontaneous lung tumors of aged mice. We envision a broad application of Microwell-seq3 in many areas of research.

This paper studies the global asymptotic stabilization problem of strict-feedforward nonlinear systems with state and input delays. We will first transform the considered system into an equivalent system by constructing the novel parameter-dependent state feedback controller and introducing the appropriate coordinate transformation. After that, the global asymptotic stability of the closed system is proved by giving the proper Lyapunov-Krasovskii functional and using the stability criterion of time-delay system.

BackgroundSingle atrium is very rare congenital cardiac anomaly in adults. The prognosis of patients with single atrium is very poor, with 50% of patients dying owing to cardiopulmonary complications in childhood. Herein, we focused on anesthesia management for noncardiac surgery in patients with single atrium.Case presentationA 58-year-old male with a history of bilateral varicocele underwent laparotomy for high-position ligation of the spermatic vein. The patient also had a history of single atrium, atrial fibrillation, chronic heart failure, pulmonary hypertension (PH), and complete right bundle branch block (CRBBB). Given the significant complications associated with general anesthesia in patients with PH, we preferred to use low-dose epidural anesthesia for this patient. Transthoracic echocardiography was used to assess cardiac function before and during surgery and guide perioperative fluid therapy. To limit the stress response, we used a regional nerve block for reducing postoperative pain. Furthermore, we used norepinephrine to appropriately increase the systemic vascular resistance in response to the reduction of systemic vascular resistance caused by epidural anesthesia.ConclusionLow-dose epidural anesthesia can be safely used in patients with single atrium and PH. The use of perioperative transthoracic echocardiography is helpful in guiding fluid therapy and effectively assessing the cardiac structure and function of patients. Prophylactic administration of norepinephrine before epidural injection may make it easier to maintain the patient’s BP.

Due to the swift progress of the economy and society and the rapid escalation of urbanization rates, the sustainable examination of individual water or land resources is no longer adequate to satisfy the rational allocation demands of urban development concerning the water and soil resource framework. To enhance the efficiency of utilizing water and land resources comprehensively and the rationality of the joint allocation of these resources, this paper presents a comprehensive analysis of the eco-economic system of water and land resources, encompassing six key aspects: system emergy flow, water resources subsystem, land resources subsystem, economic subsystem, ecological subsystem, and social subsystem. By considering three types of land use (construction land, agricultural land, and unused land), we constructed a sustainable evaluation index system for the eco-economic system of water and land resources based on the emergy theory. We employ the emergy theory analysis method to provide a comprehensive assessment of the sustainable development status and development trend of the Luoyang City from 2011 to 2020. The results show that Luoyang belongs to the consumer economy and the development of water and soil resources of the ecological economic system in Luoyang is in a critical state of unsustainable and mild sustainability from 2011 to 2020. HIGHLIGHTS This paper constructs the sustainability evaluation index system of water and soil resources of an eco-economic system.; This paper evaluates the sustainability of eco-economic system of water and soil resources by using emergy theory and analysis method.;

This study investigates the problem of finite-time output feedback stabilization in probability for a class of stochastic high-order nonlinear systems with unknown output function. By combining the homogeneous domination techniques, backstepping method and sign function, we obtain the output feedback controller that includes state controller and recursive reduced-order observer. Subsequently, we present an analytical method to deal with the unknown output function within the stochastic high-order nonlinear system such that the designed output feedback controller can make the closed-loop system globally finite-time stabilization in probability when the unknown output function belongs to the maximum open sector $\Omega $ . The numerical simulation results show that the proposed scheme is feasible.

Abstract Accurate prediction of urban floods is regarded as one of the critical means to prevent urban floods and reduce the losses caused by floods. In this study, a refined prediction and early warning method system for urban flood and waterlogging processes based on deep learning methods is proposed. The spatial autocorrelation of rain and ponding points is analyzed by Moran's I (a common used statistic for spatial autocorrelation). For each ponding point, the relationship model between the rainfall process and ponding process is constructed based on different deep learning methods, and the results are analyzed and verified by mean absolute error (MAE), root mean square error (RMSE), Nash efficiency coefficient (NSE) and correlation coefficient (CC). The results show that the gradient boosting decision tree algorithm has the highest accuracy and efficiency (with a 0.001 m RMSE of the predicted and measured ponding depth) for ponding process prediction and is regarded as the most suitable method for ponding process prediction. Finally, the real‐time prediction and early warning of urban floods and waterlogging processes driven by rainfall forecast data are realized, and the results are verified by the measured data. The research results can provide theoretical support for urban flood prevention and control.

Abstract Tumor heterogeneity and its drivers impair tumor progression and cancer therapy. Single‐cell RNA sequencing is used to investigate the heterogeneity of tumor ecosystems. However, most methods of scRNA‐seq amplify the termini of polyadenylated transcripts, making it challenging to perform total RNA analysis and somatic mutation analysis.Therefore, a high‐throughput and high‐sensitivity method called snHH‐seq is developed, which combines random primers and a preindex strategy in the droplet microfluidic platform. This innovative method allows for the detection of total RNA in single nuclei from clinically frozen samples. A robust pipeline to facilitate the analysis of full‐length RNA‐seq data is also established. snHH‐seq is applied to more than 730 000 single nuclei from 32 patients with various tumor types. The pan‐cancer study enables it to comprehensively profile data on the tumor transcriptome, including expression levels, mutations, splicing patterns, clone dynamics, etc. New malignant cell subclusters and exploring their specific function across cancers are identified. Furthermore, the malignant status of epithelial cells is investigated among different cancer types with respect to mutation and splicing patterns. The ability to detect full‐length RNA at the single‐nucleus level provides a powerful tool for studying complex biological systems and has broad implications for understanding tumor pathology.

A series of GdY2SbO7:Bi3+, Eu3+ phosphors were prepared using the conventional solid-state reaction. In this study, the photoluminescence properties and temperature sensitivity of the samples were investigated. When Bi3+ and Eu3+ were codoped into GdY2SbO7, the intensity of Bi3+ decreased with increasing Eu3+ concentration, indicating a potential energy transfer from Bi3+ to Eu3+. To examine the temperature sensitivity of the sample, its emission spectrum was investigated in the range of 300–500 K. Based on different temperature dependences of Bi3+ and Eu3+, the relative sensitivity (Sr) and absolute sensitivity (Sa) of the samples were calculated using the fluorescence intensity ratio (FIR) and thermochromic methods. In FIR modes, Sr based on IEu3+/IBi3+ reached 1.26 % K−1 at 500 K, while Sr on double excitation method reached 1.36 % K−1 at 340 K. In addition, according to the thermochromic properties of GdY2SbO7:Bi3+, Eu3+ phosphor, the temperature-sensing ability of the sample was investigated, and Sr reached a maximum value of 0.5996 % K−1 at 300 K.

High levels of tumor necrosis factor receptor type II (TNFR2) are preferentially expressed by immunosuppressive CD4+Foxp3+ regulatory T cells (Tregs), especially those present in the tumor microenvironment, as initially reported by us. There is compelling evidence that targeting TNFR2 markedly enhances antitumor immune responses. Furthermore, a broad spectrum of human cancers also expresses TNFR2, while its expression by normal tissue is very limited. We thus hypothesized that TNFR2 may be harnessed for tumor-targeted delivery of chemotherapeutic agents. In this study, we performed a proof-of-concept study by constructing a TNFR2-targeted PEGylated poly(dl-lactic-co-glycolic acid) (PLGA-PEG) nanodrug delivery system [designated as TNFR2-PLGA-ADR (Adriamycin)]. The results of in vitro study showed that this TNFR2-targeted delivery system had the properties in cellular binding and cytotoxicity toward mouse colon cancer cells. Further, upon intravenous injection, TNFR2-PLGA-ADR could efficiently accumulate in MC38 and CT26 mouse colon tumor tissues and preferentially bind with tumor-infiltrating Tregs. Compared with ADR and ISO-PLGA-ADR, the in vivo antitumor effect of TNFR2-PLGA-ADR was markedly enhanced, which was associated with a decrease of TNFR2+ Tregs and an increase of IFNγ+CD8+ cytotoxic T lymphocytes in the tumor tissue. Therefore, our results clearly show that targeting TNFR2 is a promising strategy for designing tumor-specific chemoimmunotherapeutic agent delivery system.

TNFR2 agonists have been investigated as potential therapies for inflammatory diseases due to their ability to activate and expand immunosuppressive CD4+Foxp3+ Treg cells and myeloid-derived suppressor cells (MDSCs). Despite TNFR2 being predominantly expressed in Treg cells at high levels, activated effector T cells also exhibit a certain degree of TNFR2 expression. Consequently, the role of TNFR2 signaling in coordinating immune or inflammatory responses under different pathological conditions is complex. In this review article, we analyze possible factors that may determine the therapeutic outcomes of TNFR2 agonism, including the levels of TNFR2 expression on different cell types, the biological properties of TNFR2 agonists, and disease status. Based on recent progress in the understanding of TNFR2 biology and the study of TNFR2 agonistic agents, we discuss the future direction of developing TNFR2 agonists as a therapeutic agents.

Hepatocytes are very difficult to expand in vitro. Here the authors discover that IL6 promotes long-term expansion (>30 passages) of primary mouse hepatocytes in vitro by converting the cells into hepatic progenitor cells, which maintain full capacity of differentiation into hepatocytes.

Background & Aims: Hepatocyte transplantation has emerged as a possible treatment option for end-stage liver disease. However, an important obstacle to therapeutic success is the low level of engraftment and proliferation of transplanted hepatocytes, which do not survive long enough to exert therapeutic effects. Thus, we aimed to explore the mechanisms of hepatocyte proliferation in vivo and find a way to promote the growth of transplanted hepatocytes. Methods: Hepatocyte transplantation was performed in Fah-/- mice to explore the mechanisms of hepatocyte proliferation in vivo. Guided by in vivo regeneration mechanisms, we identified compounds that promote hepatocyte proliferation in vitro. The in vivo effects of these compounds on transplanted hepatocytes were then evaluated. Results: The transplanted mature hepatocytes were found to dedifferentiate into hepatic progenitor cells (HPCs), which proliferate and then convert back to a mature state at the completion of liver repopulation. The combination of two small molecules Y-27632 (Y, ROCK inhibitor) and CHIR99021 (C, Wnt agonist) could convert mouse primary hepatocytes into HPCs, which could be passaged for more than 30 passages in vitro. Moreover, YC could stimulate the proliferation of transplanted hepatocytes in Fah-/- livers by promoting their conversion into HPCs. Netarsudil (N) and LY2090314 (L), two clinically used drugs which target the same pathways as YC, could also promote hepatocyte proliferation in vitro and in vivo, by facilitating HPC conversion. Conclusions: Our work suggests drugs promoting hepatocyte dedifferentiation may facilitate the growth of transplanted hepatocytes in vivo and may facilitate the application of hepatocyte therapy. Impact and implications: Hepatocyte transplantation may be a treatment option for patients with end-stage liver disease. However, one important obstacle to hepatocyte therapy is the low level of engraftment and proliferation of the transplanted hepatocytes. Herein, we show that small molecule compounds which promote hepatocyte proliferation in vitro by facilitating dedifferentiation, could promote the growth of transplanted hepatocytes in vivo and may facilitate the application of hepatocyte therapy.

Immune checkpoint inhibitors (ICIs) by targeting PD-1/PD-L1 or CTLA-4 have markedly improved the outcome of cancer patients. However, most solid tumor patients can’t benefit from such therapy. Identification of novel biomarkers to predict the responses of ICIs is crucial to enhance their therapeutic efficacy. TNFR2 is highly expressed by the maximally immunosuppressive subset of CD4+Foxp3+ regulatory T cells (Tregs), especially those present in tumor microenvironment (TME). Since Tregs represent a major cellular mechanism in tumor immune evasion, TNFR2 may be a useful biomarker to predict the responses to ICIs therapy. This notion is supported by our analysis of the computational tumor immune dysfunction and exclusion (TIDE) framework from published single-cell RNA-seq data of pan-cancer databases. The results show that, as expected, TNFR2 is highly expressed by tumor-infiltrating Tregs. Interestingly, TNFR2 is also expressed by the exhausted CD8 T cells in breast cancer (BRCA), hepatocellular carcinoma (HCC), lung squamous cell carcinoma (LUSC), and melanoma (MELA). Importantly, high expression of TNFR2 is associated with poor responses to the treatment with ICIs in BRCA, HCC, LUSC, and MELA. In conclusion, the expression of TNFR2 in TME may be a reliable biomarker for the precision of ICIs treatment of cancer patients, and this idea merits further research.

The role of Hippo pathway in ferroptosisThe Hippo pathway is mainly composed of mammalian serine/threonine (Ste20)like kinases 1/2 (MST1/2), large tumor suppressor 1/2 (LATS1/2), and transcriptional coactivator Yes-associated protein (YAP), and is closely related to cell growth, survival, proliferation, and migration; tissue and organ size control; and tumorigenesis and development. Ferroptosis is a regulated form of cell death characterized by the accumulation of iron-dependent reactive oxygen species (ROS) and the depletion of plasma membrane polyunsaturated fatty acids (PUFAs), which is caused by the imbalance of oxidation and the antioxidant system. This article elaborates the role of Hippo pathway in ferroptosis, providing ideas for the regulation of cell fate and the treatment of tumors.

While the coupling between various energy systems is deepening as integrated energy develops quickly, security risks in the information network system will be introduced into the physical system, and the interaction between the systems causes the security risks to increase. It is essential to maintain the multi-energy coupling integrated energy system’s safe and reliable operation. Therefore, this paper first constructs the cyber physics system (CPS) model based on the electricity-gas integrated energy system (EGIES), the fault propagation mechanism of the system caused by the cyber attack is analyzed, and the cyber attack scenario simulation method based on the N-n predicted fault set is proposed. Secondly, based on the optimal load shedding model and the reliability assessment index, the reliability assessment method of the electricity-gas integrated system under cyber attack is proposed. Then, on the basis of system reliability assessment, a multi-time scale reliability improvement strategy based on branch power and pipeline flow optimization of EGIES under cyber attack is proposed. Finally, the simulation results of the IEEE57-NGS20 electricity-gas integrated system verified the effectiveness of the proposed method. The proposed optimization strategy reduces the out-of-limit range of power transmission lines and natural gas pipelines, reduces the probability of cascading failure in the system under information attacks, and improves the resistance and energy supply reliability of the system against cyber attacks.

Peritrich ciliates are a species-rich group of sessile unicellular eukaryotes, which can be found in various aquatic habitats from all over the world. It is well accepted that there are still many ciliates to be uncovered. During a survey on ciliate biodiversity in the coastal waters of China, three solitary peritrich species were identified as members of the genus Pseudovorticella Foissner & Schiffmann, 1975, including two new species and a rare one. Pseudovorticella zhejiangensis sp. n. differs from its congeners mainly by having a conical-shaped zooid, conspicuous pellicular blisters, one ventral and one dorsal contractile vacuoles, and an infundibular polykinety 3 with three rows of nearly equal length but different beginning positions. Pseudovorticella dalianensis sp. n. can be defined mainly by an obovoid-shaped zooid, one ventral contractile vacuole, and a three-rowed infundibular polykinety 3 with the middle row being the longest. The rare species, Pseudovorticella verrucosa (Dons, 1915) Sun et al., 2009, was redescribed. The small subunit (SSU) rDNA sequences of these three species were sequenced for the first time, the phylogeny of Pseudovorticella species was analyzed, and the results verified the non-monophyly of this genus. This study demonstrates that the morphologic and gene barcoding data are the optimum combination to disclose the biodiversity of ciliates.

Background Tumor necrosis factor receptor type 2 (TNFR2) is primarily expressed by CD4+FoxP3+ regulatory T cells (Tregs), especially those present in tumor microenvironment. There is compelling evidence that TNFR2 plays a crucial role in the activation, expansion, and phenotypic stability of Tregs and promotes tumor immune evasion. Understanding of epigenetic regulation of TNFR2 expression in Tregs may help device a novel strategy in cancer immunotherapy.Methods MiR-125b-5p-overexpressing or knockdown murine CD4 T cells and Tregs were constructed, and the effect of miR-125b-5p on Tregs proliferation, suppressive function and TNFR2 expression were examined. In vivo antitumor efficacy of Ago-125b-5p (miR-125b-5p agomir) was evaluated in MC38 tumor bearing mice, and tumor-infiltrating Tregs and CD8+ cytotoxic T lymphocytes (CTLs) were analyzed. RNA-seq analysis was applied to reveal the genes and signaling pathways regulated by miR-125b-5p in Tregs.Results In this study, we found that TNFR2 was a direct target of miR-125b-5p. Overexpression of miR-125b-5p decreased the proportion of Tregs and their expression of TNFR2 and consequently inhibited its proliferation and suppressive function by regulating the metabolism-related signaling pathways. Moreover, in colon cancer bearing mice, the administration of Ago-125b-5p markedly inhibited the tumor growth, which was associated with reduction of Tregs and increase of IFNγ+CD8+ T cells in tumor environment. Furthermore, in human colon adenocarcinoma patients, we verified that miR-125b-5p expression was downregulated, and low levels of miR-125b-5p were associated with poor prognosis. Interestingly, the expression of miR-125b-5p and TNFR2 were negatively correlated.Conclusions Our study for the first time found that the expression of TNFR2 by Tregs was regulated by miR-125b-5p. Our results showed that miR-125b-5p had the capacity to inhibit the expression of TNFR2 and immunosuppressive activity of Tregs and consequently enhanced the antitumor efficacy. This property of miR-125b-5p may be therapeutically harnessed in the treatment of human cancers.

A gradual increase in population and urbanization has increased the demand for global resources, which ultimately burdens the depletion of resources and challenges environmental sustainability worldwide. In recent decades, nature sustainability has been the biggest challenge encountered by humankind. In addition, the changing lifestyle and consumption patterns have enormously played a key role. However, the consumption pattern from the employee’s perspective suffers from the lack of research. Therefore, grounded on the theory of planned behavior (TPB), this research explores the antecedents and consequences of employees’ buying intentions in the world’s emerging market (China). Data were collected using a web-based link shared via WeChat and Q.Q.; resultants into 451 valid responses and partial least square structural equation modeling (PLS-SEM) using SmartPLS 4 have been administered for the analysis. Besides the insignificant effect of descriptive norms on buying intention and environmental concerns on purchasing behavior, other factors significantly impact purchase intention and actual buying behavior. This research witnesses a significant mediating role of buying intention. This research suggests that practitioners (i.e., marketers, government, policymakers, and environmental focus companies) develop strategies for public advertisement and launch a general message and campaigns both in urban and rural areas to prevent environmental sustainability and increases awareness related to organic consumption.

Identifying the spatial distribution characteristics and influencing factors (SDC-IF) of the social value of water resources (SVWR) within a basin is an effective means to realize the dynamic regulation of water resources. In this paper, the concept of the SVWR was based on energy flow in the water resources social subsystem. Spatial econometric methods were initially introduced into the study of the SVWR to establish an emergy-spatial autocorrelation-spatial regression (ESSR) model to explore the above problem. The study area, the Yellow River Basin (YRB), was used to verify model applicability, in which the analysis highlighted three key findings: 1) The Moran’s I of the SVWR exceeded 0, indicating the SVWR had spatial correlation in the YRB. 2) The SVWR in provinces (regions) and cities were 30.76–32.87 and 24.88–30.67 yuan/m3, respectively, and its spatial distribution in the YRB was non-uniform, highlighting inequity in current water allocation. 3) The greatest spatial influencing factors of the SVWR in provinces (regions) were agriculture and forestry water inputs, whereas it was domestic water consumption in cities. The factors with the least influence were the employees of agriculture-forestry-stockbreeding-fishery; these should be considered in future water resources management. The findings show that the dynamic equilibrium regulation of water resources in the basin can be realized by adjusting the SDC-IF of SVWR, contributing to the fair distribution of water resources. In addition, the model may provide technical references for similar studies in other watersheds, contributing to the sustainable development of global water resources.

Under the influence of global climate change and urbanization processes, the number of available water resources (AWRs) in basins has become significantly more uncertain, which has restricted the sustainable development of basins. Therefore, it is important for us to understand the relationship between land use (LU) patterns and climate change on AWRs in a basin for sustainable development. To this end, the vector autoregressive (VAR) method was adopted to construct a quantitative model for AWRs in the basin in this study. Taking the Yiluo River Basin (YRB) as an example, the dynamic relationship between the five elements of agricultural land (AD), woodland (WD), grassland (GD), construction land (CD), and annual precipitation (PREP) and AWRs in the basin was studied. The results show the following: (1) The constructed VAR model was stable, indicating that the use of the proposed VAR model to characterize the degree of the effect of LU pattern and PREP on AWRs in the YRB was reasonable and effective. (2) AWRs in the YRB showed a downward trend, and their responses to the change in LU and PREP were delayed. The changes in the AWRs in the YRB tended to occur the year after changes to the LU pattern and PREP occurred. (3) In the long run, the degree of the contribution of each influencing factor to changes to AWRs was 23.76% (AD), 6.09% (PREP), 4.56% (CD), 4.40% (WD), and 4.34% (GD), which meant that the impact of the LU pattern was more than 90%. This study provides new ideas for similar research, water resource allocation, and LU planning in other river basins from a macroscopic perspective.

Background: The kidney is a highly complex organ that performs diverse functions that are essential for health. Kidney disease occurs when the kidneys are damaged and fail to function properly. Single-cell analysis is a powerful technology that provides unprecedented insights into normal and abnormal kidney cell types and will transform our understanding of the mechanism underlying common kidney diseases. Summary: Our understanding of kidney disease pathogenesis is limited by the incomplete molecular characterization of cell types responsible for kidney functions. Application of single-cell technologies for the study of the kidney has revealed cellular heterogeneity, gene expression signatures, and molecular dynamics during the onset and development of kidney diseases. Single-cell analyses of kidney organoids and allograft tissues offer new insights into kidney organogenesis, disease mechanisms, and therapeutic outcomes. Collectively, a better understanding of kidney cell heterogeneity and the molecular dynamics of kidney diseases will improve diagnostic accuracy and facilitate the identification of novel treatment strategies in nephrology. Key Message: In this review article, we summarize recent single-cell studies on kidney diseases and discuss the impact of single-cell technology on both basic and clinical nephrology research.

Abstract Background Although vascular endothelial growth factor A (VEGF-A) is known to play a key role in causing retinal edema, whether and how VEGF-A induces intracellular edema in the retina still remains unclear. Methods Sprague-Dawley rats were rendered diabetic with intraperitoneal injection of streptozotocin. Intravitreal injection of ranibizumab was performed 8 weeks after diabetes onset. rMC-1 cells (rat Müller cell line) were treated with glyoxal for 24 h with or without ranibizumab. The expression levels of inwardly rectifying K+ channel 4.1 (Kir4.1), aquaporin 4 (AQP4), Dystrophin 71 (Dp71), VEGF-A, glutamine synthetase (GS) and sodium-potassium-ATPase (Na+-K+-ATPase) were examined using Western blot. VEGF-A in the supernatant of the cell culture was detected with ELISA. The intracellular potassium and sodium levels were detected with specific indicators. Results Compared with normal control, protein expressions of Kir4.1 and AQP4 were down-regulated significantly in diabetic rat retinas, which were prevented by ranibizumab. The above changes were recapitulated in vitro. Similarly, the intracellular potassium level in glyoxal-treated rMC-1 cells was increased, while the intracellular sodium level and Na+-K+-ATPase protein level remained unchanged, compared with control. However, ranibizumab treatment decreased intracellular sodium, but not potassium. Conclusion Ranibizumab protected Müller cells from diabetic intracellular edema through the up-regulation of Kir4.1 and AQP4 by directly binding VEGF-A. It also caused a reduction in intracellular osmotic pressure.

In order to optimize the convective drying process parameters of peanuts and to provide a theoretical basis for the scientific use of energy in the drying process, this study took single-particle peanuts as the research object and analyzed the heat and mass transfer process during convective drying. In addition, a 3D two-component moisture heat transfer model for peanuts was constructed based on the mass balance and heat balance theorem. Moreover, the changes in the internal temperature and concentration fields of peanut pods during the whole drying process were investigated by simulations using COMSOL Multiphysics. The model was validated by thin-layer drying experiments, compared with the one-component model, and combined with low-field NMR technology to further analyze the internal moisture distribution state of peanut kernel drying process. The results show that both models can effectively simulate the peanut thin-layer drying process, and consistency is found between the experimental and simulated values, with the maximum errors of 10.25%, 9.10%, and 7.60% between the simulated moisture content and the experimental values for the two-component model, peanut shell, and peanut kernel models, respectively. Free water and part of the weakly bound water was the main water lost by peanuts during the drying process, the change in oil content was small, and the bound water content was basically unchanged. The results of the study provide a theoretical basis to accurately predict the moisture content within different components of peanuts and reveal the mechanism of moisture and heat migration during the drying process of peanut pods.

Introduction: Chronic kidney disease-mineral and bone disorder (CKD-MBD) is frequently observed in maintenance hemodialysis (MHD) patients, and is associated with fracture, muscle weakness, malnutrition, etc.; however, relationships of CKD-MBD markers and fatigue are not well established. Methods: This was a cross-sectional study included 244 MHD patients (89 elders) from July to September 2021 in The First Affiliated Hospital of Shandong First Medical University. CKD-MBD markers and other clinical data were collected from medical records. Fatigue in the past week was measure by Standardized Outcomes in Nephrology-Hemodialysis (SONG-HD) fatigue measure; fatigue at the end of hemodialysis was measure by numeric rating scale (NRS). Spearman correlation, linear regression and robust linear regression were. Results: In all MHD patients, Lg(25(OH)D(nmol/L) were negatively correlated with SONG-HD score (β=-1.503, 95%CI: -2.826--0.18, P=0.026) and NRS score (β=-1.532, P=0.04) in multiple regression models adjusting for sex, age and all CKD-MBD characters; but no correlations were found on univariate regression or in other multiple regression models. Interactions effects between age≥65years and Lg(25(OH)D(nmol/L)) in terms of fatigue scores were significant base on multiple linear regressions (SONG-HD score β=-3.613, P for interaction =0.006; NRS score β=-3.943, P for interaction=0.008). Compared with non-elderly patients, elderly patients were with higher ACCI scores(7(6, 8) VS 4(3, 5), P

BackgroundThe transcription factor Spi-1 proto-oncogene (SPI1, also known as PU.1) is a key regulator of signal communication in the immune system and is essential for the development of myeloid cells and lymphocytes. However, the potential role of SPI1 in gastric cancer (GC) and the correlations between SPI1 and immune infiltration remain unclear.MethodsIn the present study, multiple databases including ONCOMINE, TIMER, Kaplan–Meier Plotter, and The Cancer Genome Atlas were used to explore the expression levels and prognostic value of SPI1 in GC. cBioPortal was used to explore the possible reasons for the increased expression of SPI1 in GC. The correlations between SPI1 expression and tumor-infiltrating immune cells (TICs) were analyzed using CIBERSORT and TIMER. Gene set enrichment analysis was used to determine the biological function of SPI1 in the development of GC. In addition, a risk signature based on SPI1-related immunomodulators was constructed to accurately evaluate the prognosis of patients with GC. The upregulation of SPI1 expression in GC was further confirmed through immunohistochemistry, western blotting, and real-time quantitative PCR (RT-qPCR) assay.ResultsThe expression of SPI1 was increased significantly in GC according to multiple databases, and high expression of SPI1 was related to poor prognosis and progression of GC. The main factor influencing the high expression of SPI1 mRNA in GC may be diploidy, not DNA methylation. Moreover, immunohistochemistry, western blotting, and RT-qPCR assays also confirmed the upregulated expression of SPI1 in GC. CIBERSORT analysis revealed that SPI1 expression was correlated with seven types of TICs (naive B cells, resting memory CD4 T cells, activated memory CD4 T cells, activated natural killer cells, resting natural killer cells, M2 macrophages, and resting dendritic cells). Gene set enrichment analysis indicated that SPI1 might be related to immune activation in GC and participate in cell cycle regulation. In addition, based on SPI1-related immunomodulators, we developed multiple-gene risk prediction signatures and constructed a nomogram that can independently predict the clinical outcome of GC.ConclusionThe results of the present study suggest that SPI1 has a critical role in determining the prognosis of GC patients and may be a potential immunotherapeutic target.

Purposes and ObjectivesThe aim of this study was to predict the progression-free survival (PFS) in patients with small cell lung cancer (SCLC) by radiomic signature from the contrast-enhanced computed tomography (CT).MethodsA total of 186 cases with pathological confirmed small cell lung cancer were retrospectively assembled. First, 1,218 radiomic features were automatically extracted from tumor region of interests (ROIs) on the lung window and mediastinal window, respectively. Then, the prognostic and robust features were selected by machine learning methods, such as (1) univariate analysis based on a Cox proportional hazard (CPH) model, (2) redundancy removing using the variance inflation factor (VIF), and (3) multivariate importance analysis based on random survival forests (RSF). Finally, PFS predictive models were established based on RSF, and their performances were evaluated using the concordance index (C-index) and the cumulative/dynamic area under the curve (C/D AUC).ResultsIn total, 11 radiomic features (6 for mediastinal window and 5 for lung window) were finally selected, and the predictive model constructed from them achieved a C-index of 0.7531 and a mean C/D AUC of 0.8487 on the independent test set, better than the predictions by single clinical features (C-index = 0.6026, mean C/D AUC = 0.6312), and single radiomic features computed in lung window (C-index = 0.6951, mean C/D AUC = 0.7836) or mediastinal window (C-index = 0.7192, mean C/D AUC = 0.7964).ConclusionThe radiomic features computed from tumor ROIs on both lung window and mediastinal window can predict the PFS for patients with SCLC by a high accuracy, which could be used as a useful tool to support the personalized clinical decision for the diagnosis and patient management of patients with SCLC.

Abstract Background Acute myeloid leukemia (AML) is a fatal hematopoietic malignancy and has a prognosis that varies with its genetic complexity. However, there has been no appropriate integrative analysis on the hierarchy of different AML subtypes. Methods Using Microwell-seq, a high-throughput single-cell mRNA sequencing platform, we analyzed the cellular hierarchy of bone marrow samples from 40 patients and 3 healthy donors. We also used single-cell single-molecule real-time (SMRT) sequencing to investigate the clonal heterogeneity of AML cells. Results From the integrative analysis of 191727 AML cells, we established a single-cell AML landscape and identified an AML progenitor cell cluster with novel AML markers. Patients with ribosomal protein high progenitor cells had a low remission rate. We deduced two types of AML with diverse clinical outcomes. We traced mitochondrial mutations in the AML landscape by combining Microwell-seq with SMRT sequencing. We propose the existence of a phenotypic “cancer attractor” that might help to define a common phenotype for AML progenitor cells. Finally, we explored the potential drug targets by making comparisons between the AML landscape and the Human Cell Landscape. Conclusions We identified a key AML progenitor cell cluster. A high ribosomal protein gene level indicates the poor prognosis. We deduced two types of AML and explored the potential drug targets. Our results suggest the existence of a cancer attractor.

Flea distribution in northern region of Xinjiang Uygur Autonomous Region (XUAR) and fluctuations of the annual fleas index in Alataw Pass were investigated. During a 4-year (2015–2018) study, 5789 fleas were collected directly from 15 mammals at eight counties in northern XUAR of northwestern China. Nineteen flea species, belonging to sixteen genera and seven families, were further confirmed by four genetic markers (18S rDNA, 28S rDNA, COI and COII) after morphological observation. Pulex irritans and Paraceras crispum parasitizing Asian badgers (Meles leucurus) were recorded for the first time. In addition, the fluctuations of the annual fleas index in Alataw Pass were surveyed. Xenopsylla gerbilli minax, Xenopsylla conformis conformis and Nosopsyllus laeviceps laeviceps were highly detected in the warm season while Paradoxopsyllus repandus, Ctenophthalmus dolichus dolichus and Coptopsylla lamellifer ardua were only found in the cold season. These findings extend our knowledge of flea species, distribution and annual fluctuations especially in China-Kazakhstan border. Keywords: Flea distribution, XUAR, Fluctuations, The annual fleas index, Wild mammals

A study of pesticide residues was investigated in vegetable samples to highlight the trend of drugs obtained from the Jilin Province, China. Total of 230 samples obtained from four regions over the period 2016–2017 were screened for 18 pesticides that were analyzed using gas chromatography with electron capture (GC-ECD). The results showed that 45 samples (19.6%) were positive including 17 samples (7.39%) exceeded the national maximum residue limit (MRL). Pesticides positive samples were detected in 32 leafy vegetables, 14 of which exceeded the MRLs (6.07%). There are 12 samples detected in celery that its detection rate was 5.22%, five of which exceeded the MRLs at the same time. In contrast, no pesticide residues were detected in beans or cauliflower. In the four types of pesticides, organophosphorus pesticides had the highest detection rate, which was 12.6% (29 samples). On the other hand, detectable residues of organochlorine pesticides were found, but it did not exceed the standard. Regional variations in pesticide occurrence were observed: fifteen, seven, and ten samples were positive from Ji’an, Siping City, and Tonghua City, respectively, six samples from the last city exceeded MRLs. There were 30 samples tested for pesticides at the farmers’ market and its detection rate was 13.04%, while only 15 samples contain pesticides that the samples (6.5%) purchased in the supermarket. The results indicated that high levels of the occurrence of pesticide residues in vegetables was an important source of exposure to pesticides. Therefore, we should pay attention to the consumers and their impact of pesticide residues on food and human health should be considered.

In this paper, we propose to boost the cross-modal retrieval through mutually aligning images and captions on the aspects of both features and relationships. First, we propose a multi-feature based visual-semantic embedding (MVSE++) space to retrieve the candidates in another modality, which provides a more comprehensive representation of the visual content of objects and scene context in images. Thus, we have more potential to find a more accurate and detailed caption for the image. However, captioning concentrates the image contents by semantic description. The cross-modal neighboring relationships start from the visual and semantic sides are asymmetric. To retrieve a better cross-modal neighbor, we propose to re-rank the initially retrieved candidates according to the ${k}$ nearest reciprocal neighbors in MVSE++ space. The method is evaluated on the benchmark datasets of MSCOCO and Flickr30K with standard metrics. We achieve highe accuracy in caption retrieval and image retrieval at both R@1 and R@10.

Zebrafish have been found to be a premier model organism in biological and regeneration research. However, the comprehensive cell compositions and molecular dynamics during tissue regeneration in zebrafish remain poorly understood. Here, we utilized Microwell-seq to analyze more than 250,000 single cells covering major zebrafish cell types and constructed a systematic zebrafish cell landscape. We revealed single-cell compositions for 18 zebrafish tissue types covering both embryo and adult stages. Single-cell mapping of caudal fin regeneration revealed a unique characteristic of blastema population and key genetic regulation involved in zebrafish tissue repair. Overall, our single-cell datasets demonstrate the utility of zebrafish cell landscape resources in various fields of biological research.

The lack of awareness regarding the risks of e-cigarettes and the misleading business propaganda caused an increase in the popularity of e-cigarettes among young people. The effective communication of the risks associated with e-cigarettes is an important part of current work to control their usage, and the use of fear appeals is an effective method to achieve good control. Based on the Extended Parallel Process Model (EPPM) and Appraisal-Tendency Framework (ATF), this article presents a 2 × 2 control experiment to test the impact of fear appeals on the perception of risk, emotions, and behavioral motivation of young people aged 35 and less. A total of 333 valid samples of adolescents and young adults were included to investigate the different response paths to fear appeals among young people of different age, sex and smoking history. The results show that high-threat, high-efficacy fear appeals are able to: (1) significantly increase young people’s perception of the e-cigarette-associated threats, (2) trigger fear and anger amongst young people, and (3) stimulate their self-protection motivation. Fear appeals do not have an impact on young people’s perception of efficacy, regardless of their level of threat and efficacy. High fear appeals can also increase young people’s perception of threat, which in turn enhances their anger and protection motivation. Furthermore, while this type of fear appeal can enhance young women’s perception of efficacy, it cannot enhance the perception of e-cigarette risks in adolescents, young men and young smokers, regardless of their level of threat and efficacy. Young non-smokers have a higher perception of the risks involved in the use of e-cigarettes compared with young smokers.

The zoonotic rickettsial pathogen Anaplasma species have a broad geographical distribution and are important intracellular agents. Domestic animals and wild rodents may play an important role in the epidemiology of this disease. The aim of this study was to estimate the prevalence of infection with Anaplasma species among domestic animals and wild rodents in northern Xinjiang Uygur Autonomous Region (XUAR), Northwest China, during 2015-2016. In this study, DNA from Anaplasma ovis was detected by nested PCR in blood samples from 21/137 sheep (15.3%) in Ili Kazakh Autonomous Prefecture (Ili), 18/79 sheep (22.8%) in Bole Mongol Autonomous Prefecture (Bole) and 13/71 sheep (18.3%) in Shihezi City. In addition, detection of Anaplasma phagocytophilum DNA in spleen samples from great gerbils (Rhombomys opimus) in Urumqi (37/356, 10.4%) and Bole (21/134, 15.7%). Interestingly, co-infection A. ovis and A. phagocytophilum in blood of sheep (9/137, 6.7%) from Ili, northern XUAR. Based on 16S rRNA sequence, phylogenetic analyses showed that A. ovis were separated into one clade, while the A. phagocytophilum was separated into another clade. This analysis demonstrated that there are at least two different Anaplasma species widespread. The present investigation revealed high infection rates of A. phagocytophilum and A. ovis, which shed light on making effective measures to prevent and control Anaplasma species infection in animals in XUAR, Northwest China.

This study was designed to investigate clenbuterol, salbutamol, and ractopamine concentrations in fresh meat products. A total of 801 samples of ribs, loin, and internal organs of pigs, cattle, and lamb were collected from retail and wholesale markets in nine districts of Jilin Province, Northeast China. The three β-agonists were analyzed by LC-MS/MS. Results showed that 11.36% of the samples contained prohibited β-agonists. Detection rates of β-agonists decreased in the following order: Clenbuterol (6.37%) > Ractopamine (2.62%) > Salbutamol (2.37%). The β-agonists levels were higher for pork than for beef and lamb. The detection rate of meat products decreased in the following order: pork loin (28.72%) > pork ribs (24.72%) > pork internal organs (20.24%) > beef loin (6.67%) > beef internal organs (6.19%) > beef ribs (5.00%) > lamb internal organs (3.45%) > lamb ribs (3.41%) > lamb loin (3.26%). Only one β-agonists was detected per sample. On the surface of our research, the amount β-agonists of added to fresh meat products in Jilin Province of China is relatively safe.

In contrast to common meiotic gene conversion, mitotic gene conversion, because it is so rare, is often ignored as a process influencing allelic diversity. We show that if there is a large enough number of premeiotic cell divisions, as seen in many organisms without early germline sequestration, such as plants, this is an unsafe position. From examination of 1.1 million rice plants, we determined that the rate of mitotic gene conversion events, per mitosis, is 2 orders of magnitude lower than the meiotic rate. However, owing to the large number of mitoses between zygote and gamete and because of long mitotic tract lengths, meiotic and mitotic gene conversion can be of approximately equivalent importance in terms of numbers of markers converted from zygote to gamete. This holds even if we assume a low number of premeiotic cell divisions (approximately 40) as witnessed in Arabidopsis. A low mitotic rate associated with long tracts is also seen in yeast, suggesting generality of results. For species with many mitoses between each meiotic event, mitotic gene conversion should not be overlooked.

Abstract DNA methylation patterns are frequently deregulated in t(8;21) acute myeloid leukaemia (AML), but little is known of the mechanisms by which specific gene sets become aberrantly methylated. Here, we found that the promoter DNA methylation signature of t(8;21)+ AML blasts differs from that of t(8;21)− AMLs. This study demonstrated that a novel hypermethylated zinc finger‐containing protein, THAP10, is a target gene and can be epigenetically suppressed by AML1‐ETO at the transcriptional level in t(8;21) AML. Our findings also show that THAP10 is a bona fide target of miR‐383 that can be epigenetically activated by the AML1‐ETO recruiting co‐activator p300. In this study, we demonstrated that epigenetic suppression of THAP10 is the mechanistic link between AML1‐ETO fusion proteins and tyrosine kinase cascades. In addition, we showed that THAP10 is a nuclear protein that inhibits myeloid proliferation and promotes differentiation both in vitro and in vivo. Altogether, our results revealed an unexpected and important epigenetic mini‐circuit of AML1‐ETO/THAP10/miR‐383 in t(8;21) AML, in which epigenetic suppression of THAP10 predicts a poor clinical outcome and represents a novel therapeutic target.

Given the disposability of somatic tissue, selection can favor a higher mutation rate in the early segregating soma than in germline, as seen in some animals. Although in plants intra-organismic mutation rate heterogeneity is poorly resolved, the same selectionist logic can predict a lower rate in shoot than in root and in longer-lived terminal tissues (e.g., leaves) than in ontogenetically similar short-lived ones (e.g., petals), and that mutation rate heterogeneity should be deterministic with no significant differences between biological replicates. To address these expectations, we sequenced 754 genomes from various tissues of eight plant species. Consistent with a selectionist model, the rate of mutation accumulation per unit time in shoot apical meristem is lower than that in root apical tissues in perennials, in which a high proportion of mutations in shoots are themselves transmissible, but not in annuals, in which somatic mutations tend not to be transmissible. Similarly, the number of mutations accumulated in leaves is commonly lower than that within a petal of the same plant, and there is no more heterogeneity in accumulation rates between replicate branches than expected by chance. High mutation accumulation in runners of strawberry is, we argue, the exception that proves the rule, as mutation transmission patterns indicate that runner has a restricted germline. However, we also find that in vitro callus tissue has a higher mutation rate (per unit time) than the wild-grown comparator, suggesting nonadaptive mutational "fragility". As mutational fragility does not obviously explain why the shoot-root difference varies with plant longevity, we conclude that some mutation rate variation between tissues is consistent with selectionist theory but that a mechanistic null of mutational fragility should be considered.

Interleukin-6 (IL-6) is an important trigger for the expansion and recruitment of myeloid-derived suppressor cells (MDSCs), which are regarded to be major coordinators of the immunosuppressive tumor microenvironment. In this study, we constructed IL-6-knockdown breast cancer mice models to explore the molecular events involved in the IL-6-mediated effects on MDSC development. We defined a subset of early-stage MDSCs (e-MDSCs) with the phenotype of CD11b+Gr-1−F4/80−MHCII− in IL-6 high-expressing 4T1 mice mammary carcinoma models, which were the precursors of CD11b+Gr-1+ conventional MDSCs. Furthermore, sustained suppression of SOCS3 and aberrant hyperactivation of the JAK/STAT signaling pathway was exclusively detected in wide-type 4T1 tumor-bearing mice, which promoted the accumulation of e-MDSCs in situ and their immunosuppressive capability in vitro. After blocking the IL-6/STAT3 signaling pathway with the IL-6 receptor antibody or STAT3 antagonist JSI-124 in tumor-bearing mice, significant shrinkage of primary tumors and decrease in lung metastatic nodules were observed in vivo, accompanied by the dramatic decrease of e-MDSC recruitment and recovery of anti-tumor T cell immunity. Thus, SOCS3 suppression accelerated the IL-6-mediated growth and metastasis of mammary carcinoma via affecting myeloid differentiation in breast cancer. Moreover, the IL-6/STAT3 signaling pathway might be a promising candidate target in developing novel therapeutic strategies to eliminate e-MDSCs and improve breast cancer prognosis.

Human pluripotent stem cells (hPSCs)/OP9 coculture system is a widely used hematopoietic differentiation approach. The limited understanding of this process leads to its low efficiency. Thus, we used single-cell qPCR to reveal the gene expression profiles of individual CD34+ cells from different stages of differentiation. According to the dynamic gene expression of hematopoietic transcription factors, we overexpressed specific hematopoietic transcription factors (Gata2, Lmo2, Etv2, ERG, and SCL) at an early stage of hematopoietic differentiation. After overexpression, we generated more CD34+ cells with normal expression level of CD43 and CD31, which are used to define various hematopoietic progenitors. Furthermore, these CD34+ cells possessed normal differentiation potency in colony-forming unit assays and normal gene expression profiles. In this study, we demonstrated that single-cell qPCR can provide guidance for optimization of hematopoietic differentiation and transient overexpression of selected hematopoietic transcription factors can enhance hematopoietic differentiation.

Interleukin-6 (IL-6) has been reported to stimulate myeloid-derived suppressor cells (MDSCs) in multiple cancers, but the molecular events involved in this process are not completely understood. We previously found that cancer-derived IL-6 induces T cell suppression of MDSCs in vitro via the activation of STAT3/IDO signaling pathway. In this study, we aimed to elucidate the underlying mechanisms. We found that in primary breast cancer tissues, cancer-derived IL-6 was positively correlated with infiltration of MDSCs in situ, which was accompanied by more aggressive tumor phenotypes and worse clinical outcomes. In vitro IL-6 stimulated the amplification of MDSCs and promoted their T cell suppression ability, which were fully inhibited by an IL-6-specific blocking antibody. Our results demonstrate that IL-6-dependent suppressor of cytokine signaling 3 (SOCS3) suppression in MDSCs induced phosphorylation of the JAK1, JAK2, TYK2, STAT1, and STAT3 proteins, which was correlated with T cell suppression of MDSCs in vitro. Therefore, dysfunction in the SOCS feedback loop promoted long-term activation of the JAK/STAT signaling pathway and predominantly contributed to IL-6-mediated effects on MDSCs. Furthermore, IL-6-induced inhibition of SOCS3 and activation of the JAK/STAT pathway was correlated with an elevated expression of IL-6 receptor α (CD126), in which the soluble CD126-mediated IL-6 trans-signaling pathway significantly regulated IL-6-mediated effects on MDSCs. Finally, IL-6-induced SOCS3 dysfunction and sustained activation of the JAK/STAT signaling pathway promoted the amplification and immunosuppressive function of breast cancer MDSCs in vitro and in vivo, and thus blocking the IL-6 signaling pathway is a promising therapeutic strategy for eliminating and inhibiting MDSCs to improve prognosis.

The specific degradation of type II collagen and aggrecan by matrix metalloproteinase (MMP)-9, -13 and ADAMTS-4 and -5 (aggrecanase-1 and -2) in the cartilage matrix is a critical step in pathology of osteoarthritis (OA). The aims of this study were: i) To investigate the relative contribution of ADAMTS-4 and ADAMTS-5 to cartilage degradation upon catabolic stimulation; ii) To investigate the effect of regulating the activities of key enzymes by mean of broad-spectrum inhibitors.Bovine full-depth cartilage explants stimulated with tumor necrosis factor alpha (TNF-α) and Oncostatin M (OSM) were cultured for 21 days with or without a number of inhibitors targeting different types of proteases. Monoclonal antibodies were raised against the active sites of ADAMTS-4, -5, MMP-9 and -13, and 4 ELISAs were developed and technically validated. In addition, the established AGNxI (ADAMTS-degraded aggrecan), AGNxII (MMP-degraded aggrecan), and CTX-II (MMP-derived type II collagen) were quantified in the explants-conditioned media.We found that: i) Active ADAMTS-4, MMP-9, -13 were released in the late stage of TNF-α/ OSM stimulation, whereas no significant active ADAMTS-5 was detected in either extracts or supernatants; ii) Active ADAMTS-4 was primarily responsible for E373-374A bond cleavage in aggrecan in this setting; and iii) The compensatory mechanism could be triggered following the blockage of the enzyme caused by inhibitors.ADAMTS-4 appeared to be the major protease for the generation of 374ARGS aggrecan fragment in the TNF-α/OSM stimulated bovine cartilage explants. This study addresses the need to determine the roles of ADAMTS-4 and ADAMTS-5 in human articular degradation in OA and hence identify the attractive target for slowing down human cartilage breakdown.

FHL1 is an important tumor-suppressor that is downregulated in multiple tumors by unknown mechanisms. We demonstrated that miR-410 specifically targets the 3'UTR of FHL1. Furthermore, using DNA bisulfite modification and sequencing experiments, we demonstrated that the FHL1 promoter is hypermethylated in cancer cells. FHL1 methylation is increased upon miR-410 expression, suggesting that the regulation of FHL1 by miR-410 occurs by a dual mechanism. Using chromatin immunoprecipitation assays, we observed that miR-410 overexpression results in the increased binding of DNMT3A at the FHL1 promoter, which could explain how miR-410 regulates FHL1 methylation. Importantly, in vitro and in vivo results suggest that miR-410 may have oncogenic properties. Furthermore, both miR-410 and DNMT3A are upregulated in clinical human liver and colorectal tumors cancers. Our results suggest that miR-410 may function as an oncomiR and are consistent with its key function in regulating FHL1 in certain digestive system cancers.

As one of the best known cancer testis antigens, PRAME is overexpressed exclusively in germ line tissues such as the testis as well as in a variety of solid and hematological malignant cells including acute myeloid leukemia. Therefore, PRAME has been recognized as a promising target for both active and adoptive anti-leukemia immunotherapy. However, in most patients with PRAME-expressing acute myeloid leukemia, PRAME antigen-specific CD8(+) CTL response are either undetectable or too weak to exert immune surveillance presumably due to the inadequate PRAME antigen expression and PRAME-specific antigen presentation by leukemia cells. In this study, we observed remarkably increased PRAME mRNA expression in human acute myeloid leukemia cell lines and primary acute myeloid leukemia cells after treatment with a novel subtype-selective histone deacetylase inhibitor chidamide in vitro. PRAME expression was further enhanced in acute myeloid leukemia cell lines after combined treatment with chidamide and DNA demethylating agent decitabine. Pre-treatment of an HLA-A0201(+) acute myeloid leukemia cell line THP-1 with chidamide and/or decitabine increased sensitivity to purified CTLs that recognize PRAME(100-108) or PRAME(300-309) peptide presented by HLA-A0201. Chidamide-induced epigenetic upregulation of CD86 also contributed to increased cytotoxicity of PRAME antigen-specific CTLs. Our data thus provide a new line of evidence that epigenetic upregulation of cancer testis antigens by a subtype-selective HDAC inhibitor or in combination with hypomethylating agent increases CTL cytotoxicity and may represent a new opportunity in future design of treatment strategy targeting specifically PRAME-expressing acute myeloid leukemia.