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Objective: Improved understanding of metabolic obesity phenotypes holds great promise for personalized strategies to combat obesity and its co-morbidities. Such investigation is however lacking in Tibetans with unique living environments and lifestyle in the highlands. Effects of altitude on heterogeneous metabolic obesity phenotypes remain unexplored., Methods: We defined metabolic obesity phenotypes i.e., metabolically healthy/unhealthy and obesity/normal weight in Tibetans (n = 1204) living at 2800 m in the suburb or over 4000 m in pastoral areas. 129 lipoprotein parameters and 25 low-molecular-weight metabolites were quantified and their associations with each phenotype were assessed using logistic regression models adjusting for potential confounders. The metabolic BMI (mBMI) was generated using a machine learning strategy and its relationship with prevalence of obesity co-morbidities and dietary exposures were investigated., Results: Ultrahigh altitude positively associated with the metabolically healthy and non-obese phenotype and had a tendency towards a negative association with metabolically unhealthy phenotype. Phenotype-specific associations were found for 107 metabolites (e.g., lipoprotein subclasses, N-acetyl-glycoproteins, amino acids, fatty acids and lactate, p < 0.05), among which 55 were manipulated by altitude. The mBMI showed consistent yet more pronounced associations with cardiometabolic outcomes than BMI. The ORs for diabetes, prediabetes and hypertriglyceridemia were reduced in individuals residing at ultrahigh altitude compared to those residing at high altitude. The mBMI mediated the negative association between pastoral diet and prevalence of prediabetes, hypertension and hypertriglyceridemia, respectively., Conclusions: We found metabolite markers representing distinct obesity phenotypes associated with obesity co-morbidities and the modification effect of altitude, deciphering mechanisms underlying protective effect of ultrahigh altitude and the pastoral diet on metabolic health., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Patients with metastatic colorectal cancer often have poor outcomes, primarily due to hepatic metastasis. Colorectal cancer (CRC) cells have the ability to secrete cytokines and other molecules that can remodel the tumor microenvironment, facilitating the spread of cancer to the liver. Kupffer cells (KCs), which are macrophages in the liver, can be polarized to M2 type, thereby promoting the expression of adhesion molecules that aid in tumor metastasis. Our research has shown that huachanshu (with bufalin as the main active monomer) can effectively inhibit CRC metastasis. However, the underlying mechanism still needs to be thoroughly investigated. We have observed that highly metastatic CRC cells have a greater ability to induce M2-type polarization of Kupffer cells, leading to enhanced metastasis. Interestingly, we have found that inhibiting the expression of IL-6, which is highly expressed in the serum, can reverse this phenomenon. Notably, bufalin has been shown to attenuate the M2-type polarization of Kupffer cells induced by highly metastatic Colorectal cancer (mCRC) cells and down-regulate IL-6 expression, ultimately inhibiting tumor metastasis. In this project, our aim is to study how high mCRC cells induce M2-type polarization and how bufalin, via the SRC-3/IL-6 pathway, can inhibit CRC metastasis. This research will provide a theoretical foundation for understanding the anti-CRC effect of bufalin., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction: The escalation of urbanization correlates with rising rates of inflammatory bowel disease (IBD), necessitating research into new etiological factors. This study aims to elucidate the gut microbiota profiles in IBD patients and compare them with healthy controls in a western city of China., Methods: We conducted a multicenter case-control study from the end of 2020, using 16S rRNA gene sequencing ( n = 36) and metagenomic sequencing ( n = 12) to analyze the gut microbiota of newly diagnosed IBD patients, including those with Crohn's disease (CD) and ulcerative colitis (UC)., Results: Our results demonstrated a significant enrichment of the phylum Proteobacteria, particularly the genus Escherichia-Shigella , in CD patients. Conversely, the genus Enterococcus was markedly increased in UC patients. The core gut microbiota, such as the Christensenellaceae R-7 group, Fusicatenibacter , and Holdemanella , were primarily identified in healthy subjects. Additionally, significant interactions between the microbiome and virulence factors were observed., Discussion: The findings suggest that oxidative stress may play a pivotal role in the pathology of IBD. This study contributes to the growing dialogue about the impact of gut microbiota on the development of IBD and its variations across different geographies, highlighting potential avenues for further research., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Wang, Wang, Yang, Feng, Tian, Chen, Huang, Liu and Wang.)

China introduced civil and administrative public interest litigation (PIL) through a series of pilot projects and legislative revisions in recent years. Now a procuratorate has the standing to bring civil PIL cases against polluters and administrative PIL cases against administrative agencies in its jurisdictions while a qualified non-governmental organization (NGO) has no geographic limits and may bring civil PIL cases against polluters anywhere in mainland China. Previous literature focused on the use of PIL for redressing environmental damages in individual cases. This paper studies the function of PIL beyond individual cases with game theory. This paper uses data collected through autoethnography, interviews, databases of judgements, statistics, and previous literature. This paper finds that local procuratorates and NGOs brought a large number of environmental PIL cases and changed the behavior patterns of local governments and their environmental protection agencies as well as that of polluters. Before the introduction of PIL rules, governmental officers of local governments and their environmental protection agencies were more discretionary and selective in environmental law enforcement and were more cooperative with polluters. After the law introduced PIL rules, they are now less discretionary in environmental law enforcement, less cooperative with polluters, and more likely to strictly enforce the environmental law. This paper models the interaction between local governments and polluters before the introduction of environmental PIL as an infinitely repeated game and reveals the ensuing cooperation. This infinitely repeated game was broken by new players introduced by the PIL, i.e., the procuratorate, NGOs, and the court, which changed the behavior patterns of the local government and its environmental protection agencies as well as that of polluters. This paper concludes that the function of PIL beyond individual cases lies in that it breaks the chain of infinitely repeated game between the local government and polluters and thus changes their behavior patterns., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Mingqing You reports financial support was provided by the National Social Science Fund of China (Project No. 20WFXA001). Mingqing You reports financial supports was provided by the Fundamental Research Funds for the Central Universities administered by 10.13039/100007839Zhongnan University of Economics and Law (Project No.: 2722023DK018). Mingqing You reports financial support was provided by an Open Fund of the Hubei Research Center of Cultural Economy (Grant No. HBCIR202311). If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Maternal metal (loid)s exposure has been related to birth outcomes but the results are still inconclusive. Most previous studies have discussed the single metal (loid)s, neglecting the scene of co-exposure. We examined the associations of both single metal (loid)s and metal mixtures with birth outcomes in a birth cohort from the Tibetan Plateau, including body weight, body length, head circumference, small for gestational age (SGA), and Ponderal index (PI). In our analysis of 1069 women, we measured 29 metal (loid)s in urine samples in the third trimester. The associations of single metal (loid)s with categorical or continuous birth outcomes were evaluated using a generalized linear mixed-effects model or linear mixed-effects model, respectively. The least absolute shrinkage and selection operator, Bayesian kernel machine, and Quantile g-computation regression were used to explore the joint association. We also evaluated the interactive effects of ethnicity and altitude on the effect of metal (loid)s on birth outcomes. Copper (Cu) concentration in maternal urine was positively associated with SGA, birth weight, birth length, and head circumference in the single pollutant models. For instance, Cu was associated with an increased risk of SGA [OR (95% CI) = 1.56 (1.23, 1.97); P < 0.001]. We didn't find significant joint association of metal mixtures with birth outcomes except a positive association between the mixture of Cu, Magnesium (Mg), and Iron (Fe) with the risk of SGA when the exposure level was above its 80th percentile, and Cu dominated the adverse association in a non-linear manner. Living altitude modified the associations of Cu with SGA and the positive association was only found in participants living at high altitude. In conclusion, maternal urinary metal (loid)s, especially Cu, was the dominant harmful metal (loid)s when associated with SGA on the Tibetan Plateau., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Ltd.)

Taraxacum kok-saghyz Rodin (TKS) has abundant natural rubber in its root and the molecular weight of its natural rubber is higher than that in Hevea brasiliensis. Thus, TKS is an excellent alternative for the commercial production of natural rubber. The content and molecular weight of natural rubber are two qualitative indicators. Efficient determination for both indicators is still a challenge. In this study, we developed a method to simultaneously determine the content and molecular weight of natural rubber in TKS with pyrolysis－gas chromatography-mass spectrometry. The content of natural rubber was quantified by internal standard method. We optimized the pyrolysis temperature and chromatographic method during content determination. The limits of detection and quantification were 0.47 and 1.56 μg, respectively. In addition, the arachidonic acid methyl ester, an unsaturated fatty acid proposed from the α-end group of natural rubber, was quantified to obtain the number of natural rubber polymers. Based on the content and the polymer number, we also quantified the molecular weight of natural rubber. Thus, the content and molecular weight of natural rubber were simultaneously determined in TKS. Our study provides a new perspective for the high throughput analysis of natural rubber., (© 2023 Wiley-VCH GmbH.)

Maintaining a healthy status is crucial for the successful captive breeding of endangered alpine musk deer (Moschus chrysogaster, AMD), and captive breeding programs are beneficial to the ex-situ conservation and wild population recovery of this species. Meanwhile, the gut microbiota is essential for host health, survival, and environmental adaptation. However, changes in feeding environment and food can affect the composition and function of gut microbiota in musk deer, ultimately impacting their health and adaptation. Therefore, regulating the health status of wild and captive AMD through a non-invasive method that targets gut microbiota is a promising approach. Here, 16S rRNA gene sequencing was employed to reveal the composition and functional variations between wild (N = 23) and captive (N = 25) AMD populations. The results indicated that the gut microbiota of wild AMD exhibited significantly higher alpha diversity (P < 0.001) and greater abundance of the phylum Firmicutes, as well as several dominant genera, including UCG-005, Christensenellaceae R7 group, Monoglobus, Ruminococcus, and Roseburia (P < 0.05), compared to captive AMD. These findings suggest that the wild AMD may possess more effective nutrient absorption and utilization, a more stable intestinal microecology, and better adaption to the complex natural environment. The captive individuals displayed higher metabolic functions with an increased abundance of the phylum Bacteroidetes and certain dominant genera, including Bacteroides, Rikenellaceae RC9 gut group, NK4A214 group, and Alistipes (P < 0.05), which contributed to the metabolic activities of various nutrients. Furthermore, captive AMD showed a higher level of 11 potential opportunistic pathogens and a greater enrichment of disease-related functions compared to wild AMD, indicating that wild musk deer have a lower risk of intestinal diseases and more stable intestinal structure in comparison to captive populations. These findings can serve as a valuable theoretical foundation for promoting the healthy breeding of musk deer and as a guide for evaluating the health of wild-released and reintroduced musk deer in the future. KEY POINTS: • Wild and captive AMD exhibit contrasting gut microbial diversity and certain functions. • With higher diversity, certain bacteria aid wild AMD's adaptation to complex habitats. • Higher potential pathogens and functions increase disease risk in captive AMD., (© 2023. The Author(s).)

Fruit size and shape are controlled by genes expressed during the early developmental stages of fruit. Although the function of ASYMMETRIC LEAVES 2 (AS2) in promoting leaf adaxial cell fates has been well characterized in Arabidopsis thaliana, the molecular mechanisms conferring freshy fruit development as a spatial-temporal expression gene in tomato pericarp remain unclear. In the present study, we verified the transcription of SlAS2 and SlAS2L, two homologs of AS2, in the pericarp during early fruit development. Disruption of SlAS2 or SlAS2L caused a significant decrease in pericarp thickness as a result of a reduction in the number of pericarp cell layers and cell area, leading to smaller tomato fruit size, which revealed their critical roles in tomato fruit development. In addition, leaves and stamens exhibited severe morphological defects in slas2 and slas2l single mutants, as well as in the double mutants. These results demonstrated the redundant and pleiotropic functions of SlAS2 and SlAS2L in tomato fruit development. Yeast two-hybrid and split-luciferase complementation assays showed that both SlAS2 and SlAS2L physically interact with SlAS1. Molecular analyses further indicated that SlAS2 and SlAS2L regulate various downstream genes in leaf and fruit development, and that some genes participating in the regulation of cell division and cell differentiation in the tomato pericarp are affected by these genes. Our findings demonstrate that SlAS2 and SlAS2L are vital transcription factors required for tomato fruit development., (© 2023 Society for Experimental Biology and John Wiley & Sons Ltd.)

Little is known about the longitudinal association between dietary patterns (DPs) and metabolic disorders in people living at high altitude areas, such as Tibetans. We constructed the first open cohort, with 1832 Tibetans, and collected data in 2018 and in 2022. The metabolic syndrome (MetS) prevalence was 30.1% (32.3% in men and 28.3% in women). Three different DPs were identified: modern DP (pulses, poultry, offal, and processed meat), urban DP (vegetables, refined grain, beef/mutton, and eggs), and pastoral DP (Tibetan cheese, tsamba, butter/milk tea, and desserts). Participants within the third tertile of the urban DP had a 3.42-fold (95% CI 1.65-7.10) higher risk of MetS than those with the first tertile. Modern DP was positively associated with elevated blood pressure (BP) and elevated triglycerides (TAG), while it was inversely associated with low HDL-C. The urban DP was associated with a higher risk of low HDL-C, but a lower risk of impaired fasting blood glucose (FBG). The pastoral DP was a risk factor for impaired FBG, but protective for central obesity and elevated BP. Associations of modern DP with elevated BP, and pastoral DP with low HDL-C, were modified by altitude. In conclusion, among Tibetan adults, DPs were associated with MetS and its components, and the associations were modified by altitude among Tibetans.

At present, recurrence and metastasis are still important factors that lead to a poor prognosis among colorectal cancer (CRC) patients. Cancer-associated fibroblasts (CAFs) can promote tumorigenesis and development. Bufalin is the main active monomer of the clinical drug cinobufacini, which exhibits antitumor activity in various cancers. But few research have investigated the effect of bufalin in inhibiting metastasis from the perspective of the tumor microenvironment. We first isolated CAFs from freshly resected colorectal cancer patient specimens and observed the effect of CAFs on CRC cell invasion through a series of experiments. We explored the effect of bufalin on the physiological activity of CRC mediated by CAFs through experiments. In our study, we found that CAFs could promote CRC cell activity through the STAT3 pathway. Bufalin reversed CAF-mediated CRC invasion and metastasis by inhibiting the STAT3 pathway. Overexpression of STAT3 attenuated the inhibitory function of bufalin on invasion and metastasis. Taken together, bufalin can reverse CAF-mediated colorectal cancer metastasis based on inhibiting the STAT3 signaling pathway., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: The diagnosis of Parkinson's disease (PD) is complex and there are no biomarkers for early identification. Many studies have reported altered gut microbiota in patients with PD compared with healthy individuals. However, results from previous studies vary across countries., Aims: The aim of this study was to identify gut microbiota biomarkers that could be used as a marker for the diagnosis of PD., Methods: Firstly, the differential gut microbiota was obtained by meta-analysis, and then the results of meta-analysis were validated through metagenomic cohort. Finally, the ROC curve was drawn based on the metagenomic validation results., Results: The meta-analysis showed a lower relative abundance of Prevotellaceae ( p < 0.00001) and Lachnospiraceae ( p = 0.002), and a higher of Ruminococcaceae ( p < 0.00001), Christensenellaceae ( p = 0.03), Bifidobacteriaceae ( p < 0.00001), and Verrucomicrobiaceae ( p = 0.02) in patients with PD. Only Bifidobacteriaceae was also at high levels in the validation cohort of the metagenome. Meanwhile, three species from the Bifidobacteriaceae , including Scardovia&#95;inopinata ( p = 0.022), Bifidobacterium&#95;dentium ( p = 0.005), and Scardovia&#95;wiggsiae ( p = 0.024) were also high. The ROC curve showed that the three species (71.2%) from Bifidobacteriaceae had good predictive efficiency for PD., Conclusion: Elevated Bifidobacteriaceae may be associated with PD. Elevated three species from the Bifidobacteriaceae , including Scardovia&#95;inopinata , Bifidobacterium&#95;dentium and Scardovia&#95;wiggsiae may provide new potential biomarkers for the diagnosis of PD., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Zuo, Wang, Zhao, Tang, Wang, Zhang, Sang, Tian and Wang.)

Sanjiangyuan National Park (SNP), the first national park in China, is one of the most important biodiversity conservation areas in the Sanjiangyuan National Nature Reserve (SNNR) and even the world. The threatened ungulates play an irreplaceable role in maintaining the ecosystem diversity and stability in SNNR. Here, based on 1434 occurrence records of six ungulates, the maximum entropy model, with two different strategies, was utilized to determine the priority reserves. The results indicated that the priority reserves in SNNR was mainly located in and around SNP, which were mainly distributed in the middle east, middle west, and southwest of SNNR. Six ungulates shared preference for altitude ranging 4000-5000 m, the average annual temperature below -3.0°C, and average annual precipitation ranging 200-400 mm on meadow, steppe, and unused land. The proportion of high and medium suitable areas for ungulates in SNP was higher than that in SNNR. As the SNP is not contiguously spaced in space, and some core wildlife habitats are not included, it is suggested to optimize the functional areas and adjust the boundary range on the basis of the pilot scope of SNP, so as to enhance the integrity and connectivity of each functional area., Competing Interests: The authors declare that they have no competing interests., (© 2022 The Authors. Ecology and Evolution published by John Wiley & Sons Ltd.)

This paper focuses on the impedance control for robotic manipulators with time-varying output constraints. High-order control barrier functions (HoCBFs) are firstly proposed for a nonlinear system with high relative-degree time-varying constraints. Then, the HoCBFs are introduced to impedance control for robotic manipulators, where the HoCBFs are employed to avoid the violation of time-varying output constraints in Cartesian space by quadratic program (QP), and the impedance control is designed to achieve compliance for human-robot interaction (HRI). In this way, the desired trajectory within the safety-critical region can be tracked without violating the output constraints due to the controller generated from QP, and the safe HRI can also be achieved because of the usage of impedance control method. Finally, simulation tests are conducted to verify the proposed control design methods., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 ISA. Published by Elsevier Ltd. All rights reserved.)

Objective: The aim of this study was to compare the radiographic features of patients with progressive and nonprogressive coronavirus disease 2019 (COVID-19) pneumonia., Methods: PubMed, Embase, and Cochrane Library databases were searched from January 1, 2020, to February 28, 2022, by using the keywords: "COVID-19", "novel Coronavirus", "2019-novel coronavirus", "CT", "radiology" and "imaging". We summarized the computed tomography manifestations of progressive and nonprogressive COVID-19 pneumonia. The meta-analysis was performed using the Stata statistical software version 16.0., Results: A total of 10 studies with 1092 patients were included in this analysis. The findings of this meta-analysis indicated that the dominating computed tomography characteristics of progressive patients were a crazy-paving pattern (odds ratio [OR] = 2.10) and patchy shadowing (OR = 1.64). The dominating lesions distribution of progressive patients were bilateral (OR = 11.62), central mixed subpleural (OR = 1.37), and central (OR = 1.36). The other dominating lesions of progressive patients were pleura thickening (OR = 2.13), lymphadenopathy (OR = 1.74), vascular enlargement (OR = 1.39), air bronchogram (OR = 1.29), and pleural effusion (OR = 1.29). Two patterns of lesions showed significant links with the progression of disease: nodule (P = .001) and crazy-paving pattern (P = .023). Four lesions distribution showed significant links with the progression of disease: bilateral (P = .004), right upper lobe (P = .003), right middle lobe (P = .001), and left upper lobe (P = .018)., Conclusion: Nodules, crazy-paving pattern, and/or new lesions in bilateral, upper and middle lobe of right lung, and lower lobe of left lung may indicate disease deterioration. Clinicians should formulate or modify treatment strategies in time according to these specific conditions., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

Objective: To explore how AADAC functions in the malignant progression of ovarian cancer, and the effect of AADAC on drug therapeutic activity against ovarian cancer cells., Methods: AADAC level in tumor and normal samples from TCGA-OV dataset and its survival significance were analyzed by bioinformatics methods. Signaling pathway enrichment analysis for the high- and low-AADAC patients was achieved by using GSEA software. AADAC expression in the cell lines with different treatments was evaluated via qRT-PCR. Cell proliferative ability was assessed via MTT assay Cell migratory and invasive abilities were evaluated via transwell assay. Angiogenesis assay was performed to examine the angiogenetic ability., Results: AADAC was upregulated in ovarian cancer tissues, and patients with high expression of AADAC had favorable survival conditions compared to the low AADAC expression ones. Overexpression of AADAC inhibited the malignant progression of ovarian cancer cells. Both cisplatin and imatinib suppressed cancer cell malignant progression, while overexpressed AADAC synergistically enhanced such inhibition., Conclusions: The study demonstrated that AADAC could somehow suppress the malignant progression of ovarian cancer, especially at the cellular level. In addition, synergic tumor-inhibitory effects between AADAC and the anti-cancer drugs were identified. All the above results proposed a novel idea and candidate biomarker for ovarian cancer therapy., (©The Author(s) 2022. Open Access. This article is licensed under a Creative Commons CC-BY International License.)

Blood flesh is a key fruit trait in peaches ( Prunus persica ) and can be attributed to the accumulation of anthocyanins. The roles of long non-coding RNAs (lncRNAs) have been highlighted by multiple studies in regulating fruit ripening, anthocyanin accumulation, and abiotic stress responses in many flowering plants. Such regulatory functions of lncRNAs in Prunus persica, nonetheless, have not been reported. In this research, we sequenced and analyzed the complete transcriptome of C3-20 (a blood-fleshed peach) fruit at four developmental stages. Analyses of the correlated genes and differentially expressed lncRNA target genes helped to forecast lncRNAs' possible functions. The RNA-seq data were generated using high-throughput sequencing. In total, 17,456 putative lncRNAs, including 4,800 intergenic lncRNAs, 2,199 antisense lncRNAs, and 10,439 intronic lncRNAs were discovered, of which 4,871 differentially expressed lncRNAs (DE-lncRNAs) were annotated in the fruit developmental processes. The target genes of these DE-lncRNAs and their regulatory relationship identifying 21,795 cis-regulated and 18,271 trans-regulated targets of the DE-lncRNAs were in a similar way predicted by us. The enriched GO terms for the target genes included anthocyanin biosynthesis. Flavonoid biosynthesis and plant hormone signal transduction were also included in the enriched KEGG pathways. Co-expression network construction demonstrated that the highly expressed genes might co-regulate multiple other genes associated with auxin signal transduction and take effect in equal pathways. We discovered that lncRNAs, including LNC&#95;000987, LNC&#95;000693, LNC&#95;001323, LNC&#95;003610, LNC&#95;001263, and LNC&#95;003380, correlated with fruit that ripened and could take part in ethylene biosynthesis and metabolism and the ABA signaling pathway. Several essential transcription factors, such as ERFs, WRKY70, NAC56 , and NAC72 , may in a similar way regulate fruit ripening. Three DE-lncRNAs, XLOC&#95;011933, XLOC&#95;001865, and XLOC&#95;042291, are involved in UV-B-induced anthocyanin biosynthesis and positively regulating UVR8 and COP10, were identified and characterized. Our discovery and characterization of XLOC&#95;011933, XLOC&#95;001865, and XLOC&#95;042291 provide a more precise understanding and preliminarily establishes a theoretical framework for UV-B-induced flesh anthocyanin biosynthesis. This phenomenon might encourage more in-depth investigations to study the molecular mechanisms underlying peach flesh coloring., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Zhang, Zhang, Wang, Ye, Liu, Song, Du, Cao, Song, Xiao, Liu, Zhang, Song, Yang, Meng and Wu.)

In high-altitude environments, the prevalence of high-altitude polycythemia (HAPC) ranges between 5 and 18 percent. However, there is currently no effective treatment for this condition. Therefore, disease prevention has emerged as a critical strategy against this disease. Here, we looked into the microarray profiles of GSE135109 and GSE29977, linked to either short- or long-term exposure to the Qinghai Tibet Plateau (QTP). The results revealed inhibition in the adaptive immune response during 30 days of exposure to QTP. Following a gene set enrichment analysis (GSEA) discovered that genes associated with HAPC were enriched in Cluster1, which showed a dramatic upregulation on the third day after arriving at the QTP. We then used GeneLogit to construct a logistic prediction model, which allowed us to identify 50 genes that classify HAPC patients. In these genes, LRRC18 and HCAR3 were also significantly altered following early QTP exposure, suggesting that they may serve as hub genes for HAPC development. The in-depth study of a combination of the datasets of transcriptomic changes during exposure to a high altitude and whether diseases occur after long-term exposure in Hans can give us some inspiration about genes associated with HAPC development during adaption to high altitudes.

We report electrically pumped continuous-wave (CW) InAs/GaAs quantum dot lasers directly grown on planar exact silicon (001) with asymmetric waveguide structures. Surface hydrogen-annealing for the GaAs/ Si (001) templates and low-temperature growth for GaInP upper cladding layers were combined in the growth of the laser structure to achieve a high slope efficiency. For the broad-stripe edge-emitting lasers with 2-mm cavity length and 20-µm stripe width made from the above laser structure, a threshold current density of 203.5 A/cm 2 and a single-facet slope efficiency of 0.158 W/A are achieved at ∼1.31 µm band under CW conditions. The extrapolated mean-time-to-failure reaches up to 21000 hours at room temperature, which is deduced from the data measured from C-mount packaged devices. Importantly, these results can provide a practical strategy to realize 1.3 µm wavelength band distributed feedback lasers directly on planar exact Si (001) templates with thin buffer layers.

The volatile compound 6-methyl-5-hepten-2-one (MHO) is an important chemical intermediate and flavor component derived from carotenoid during fruit metabolism, which is important factor impacting consumer-liking. Fruit has complex matrix and is difficult to be purified during MHO analysis. A rapid liquid-liquid extraction-gas chromatography-mass spectrometry (LLE-GC-MS) method was developed for effective determination of MHO in fruit in this study. The calibration curves for MHO showed high linearity in the range of 100-2000 ng/ml with internal standard method. The limit of detection (LOD), limit of quantification (LOQ) were both <100 ng/ml. Real samples of tomato cultivar fruit were analyzed and RSD of biological replicates varied in the range of 2.01% to 12.59%. MHO showed varied content in different tomato fruit tissues of the selected cultivars, in addition to the variation between cultivars. Furthermore, the possible fragmentation patterns were proposed for the main characteristic ions of MHO and internal standard, based on isolation of the fragment ions after the precursor ion underwent splitting at the electron impact ion source. Compared with reported solid-phase microextraction (SPME)-GC-MS method, the validated method was more rapid, precise, accurate and low cost for MHO quantitation., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Carbon dots (CDots), a class of environmentally friendly carbon-based luminescent nanomaterial, have been applied in a wide variety of fields, including bioimaging and light-emitting diodes (LEDs). Prior to these applications, however, CDots usually require modifications because some of its limitations (e.g., the aggregation-induced luminescence quenching) make it difficult to apply in solid state. In order to realize CDots-based multiple applications simultaneously, this paper examines how CDots with a strong greenish-yellow fluorescence in both dispersed and aggregated states are prepared by microwave-assisted heating salicylic acid and thiourea. Based on control testing and the analysis of density functional theory calculations, S element from thiourea is doped into CDots and proves to be critical in governing the photoluminescence (PL) emission color. Featured with excellent biocompatibility and photostability, the dispersed CDots with photoluminescence quantum yields (32%) are able to function as a biological imaging reagent in vitro and in vivo without any side effect. Furthermore, the aggregated CDots also exhibit high photoluminescence quantum yields (26%) and remarkable resistance to organic solvent. These advantages will ensure that S-doped CDots can be applied as a color conversion layer so that white LEDs with different Commission International de L'Eclariage coordinates and tunable color temperature can be fabricated., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objective: The aim of the present study is to investigate whether parenting stress mediate the relationship between social support and quality of life in parents of children with Autistic Spectrum Disorder. In addition, we examined what other variables moderate the relationships in this mediation model., Methods: Using the two-stage meta-analytic structural equation modeling approach (MASEM), 44 correlation matrices were synthesized from 28 empirical studies ( N = 13,270) and fitted to the hypothesized mediation model., Results: There is a significant partial mediation effect of parenting stress on the relationship between social support and quality of life. Subgroup analysis through the first stage analysis suggested that social support measurements, parental role, and child's age moderated the relationship between social support and parenting stress, and that the focus of quality of life moderated the relationship between social support and quality of life. Subgroup analysis through the second stage analysis indicated that parenting stress had a significantly stronger predictive effect on quality of life in Western culture, while the predictive effect of social support on quality of life was significantly stronger in Eastern culture., Conclusion: Having more social support can reduce parents' stress and then improving their quality of life, which can help them cope more positively and effectively with their autistic children., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Wang, Wang, Chang and Wang.)

The endothelial-mesenchymal transition (EndMT) participates in the progression of diabetic retinopathy (DR), but cell-intrinsic factors modulating this process remain elusive. In this study, we explored the role of lysophosphatidic acid (LPA) - producing enzyme, acylglycerol kinase (AGK), in the EndMT of human retinal microvascular endothelial cells (HRECs) under high-glucose (HG) conditions. We found that AGK was significantly elevated in HG-treated cells. In addition, AGK knockdown reversed the HG-induced EndMT in HRECs, which was evidenced by the increased endothelial markers (CD31 and VE-cadherin) and decreased mesenchymal markers (FSP1 and α-SMA). Furthermore, downregulation of AGK inhibited the HG-induced activation of transforming growth factor β (TGF-β)/Notch pathways, whereas exogenous TGF-β1 (10 ng/mL) impeded the inhibitory effects of AGK knockdown on HG-induced EndMT in HRECs. Additionally, the silencing of AGK abolished the HG-induced upregulation of LPA and its receptor, LPA receptor 1 (LPAR1), and overexpression of LPAR1 further rescued the AGK knockdown-mediated inhibition of the EndMT process. In conclusion, we demonstrate that downregulation of AGK suppresses HG-induced EndMT in HRECs through regulating the LPAR1/TGF-β/Notch signaling pathway, indicating that AGK might be a potential therapeutic target for the treatment of DR.

Gut microbiota forms a unique microecosystem and performs various irreplaceable metabolic functions for ruminants. The gut microbiota is important for host health and provides new insight into endangered species conservation. Forest musk deer (FMD) and alpine musk deer (AMD) are typical small ruminants, globally endangered due to excessive hunting and habitat loss. Although nearly 60 years of captive musk deer breeding has reduced the hunting pressure in the wild, fatal gastrointestinal diseases restrict the growth of captive populations. In this study, 16S rRNA high-throughput sequencing revealed the differences in gut microbiota between FMD and AMD based on 166 fecal samples. The alpha diversity was higher in FMD than in AMD, probably helping FMD adapt to different and wider habitats. The ß-diversity was higher between adult FMD and AMD than juveniles and in winter than late spring. The phylum Firmicutes and the genera Christensenellaceae R7 group, Ruminococcus, Prevotellaceae UCG-004, and Monoglobus were significantly higher in abundance in FMD than in AMD. However, the phylum Bacteroidetes and genera Bacteroides, UCG-005, Rikenellaceae RC9 gut group, and Alistipes were significantly higher in AMD than FMD. The expression of metabolic functions was higher in AMD than in FMD, a beneficial pattern for AMD to maintain higher energy and substance metabolism. Captive AMD may be at higher risk of intestinal diseases than FMD, with higher relative abundances of most opportunistic pathogens and the expression of disease-related functions. These results provide valuable data for breeding healthy captive musk deer and assessing their adaptability in the wild. KEY POINTS: • Alpha diversity of gut microbiota was higher in FMD than that in AMD • Expression of metabolic and disease-related functions was higher in AMD than in FMD., (© 2022. The Author(s).)

Selection for favorable inflorescence architecture to improve yield is one of the crucial targets in crop breeding. Different tomato varieties require distinct inflorescence-branching structures to enhance productivity. While a few important genes for tomato inflorescence-branching development have been identified, the regulatory mechanism underlying inflorescence branching is still unclear. Here, we confirmed that SISTER OF TM3 (STM3), a homolog of Arabidopsis SOC1, is a major positive regulatory factor of tomato inflorescence architecture by map-based cloning. High expression levels of STM3 underlie the highly inflorescence-branching phenotype in ST024. STM3 is expressed in both vegetative and reproductive meristematic tissues and in leaf primordia and leaves, indicative of its function in flowering time and inflorescence-branching development. Transcriptome analysis shows that several floral development-related genes are affected by STM3 mutation. Among them, FRUITFULL1 (FUL1) is downregulated in stm3cr mutants, and its promoter is bound by STM3 by ChIP-qPCR analysis. EMSA and dual-luciferase reporter assays further confirmed that STM3 could directly bind the promoter region to activate FUL1 expression. Mutation of FUL1 could partially restore inflorescence-branching phenotypes caused by high STM3 expression in ST024. Our findings provide insights into the molecular and genetic mechanisms underlying inflorescence development in tomato., (© 2021. The Author(s).)

Plant glandular trichomes are epidermal secretory structures that are important for plant resistance to pests. Although several regulatory genes have been characterized in trichome development, the molecular mechanisms conferring glandular trichome morphogenesis are unclear. We observed the differences in trichomes in cultivated tomato cv. 'Moneymaker' (MM) and the wild species Solanum pimpinellifolium PI365967 (PP), and used a recombinant inbred line (RIL) population to identify the genes that control trichome development in tomato. We found that the genomic variations in two genes, HAIR (H) and SPARSE HAIR (SH), contribute to the trichome differences between MM and PP. H and SH encode two paralogous C2H2 zinc-finger proteins that function redundantly in regulating trichome formation. Loss-of-function h/sh double mutants exhibited a significantly decreased number of Type I trichomes and complete loss of long stalk trichomes. Molecular and genetic analyses further indicate that H and SH act upstream of ZFP5. Overexpression of ZFP5 partially restored the trichome defects in NIL-h PP sh PP . Moreover, H and SH expression is induced by high temperatures, and their mutations inhibit the elongation of trichomes that reduce the plant repellent to whiteflies. Our findings confirm that H and SH are two vital transcription factors controlling initiation and elongation of Type I and III multicellular trichomes in tomato., Competing Interests: Conflict of interest The authors declare that they have no conflict of interest., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

In this study, based on high-throughput sequencing technology, the biodiversity and the community structure of microbiota in different GIT segments (the stomach, small intestine, cecum and rectum) of plateau zokors and Gansu zokors were studied and compared. A source tracking analysis for the microbial communities of different GIT segments was carried out using the fast expectation-maximization microbial source tracking (FEAST) method. We found that, for both species, the microbial community richness and diversity of the small intestine were almost the lowest while those of the cecum were the highest among the four segments of the GIT. Beta diversity analyses revealed that the bacterial community structures of different GIT segments were significantly different. As for the comparison between species, the bacterial community compositions of the whole GIT, as well as for each segment, were all significantly different. Source tracking conducted on both zokors indicated that the soil has little effect on the bacterial community of the GIT. A fairly high percentage of rectum source for the bacterial community of the stomach indicated that both zokors may engage in coprophagy.

Musk deer ( Moschus spp.) is a globally endangered species due to excessive hunting and habitat fragmentation. Captive breeding of musk deer can efficiently relieve the hunting pressure and contribute to the conservation of the wild population and musk supply. However, its effect on the gut microbiota of musk deer is unclear. Recent studies have indicated that gut microbiota is associated with host health and its environmental adaption, influenced by many factors. Herein, high-throughput sequencing of the 16S rRNA gene was used based on 262 fecal samples from forest musk deer ( M. berezovskii ) (FMD) and 90 samples from alpine musk deer ( M. chrysogaster ) (AMD). We sought to determine whether seasonal variation can affect the structure and function of gut microbiota in musk deer. The results demonstrated that FMD and AMD had higher α-diversity of gut microbiota in the cold season than in the warm season, suggesting that season change can affect gut microbiota diversity in musk deer. Principal coordinate analysis (PCoA) also revealed significant seasonal differences in the structure and function of gut microbiota in AMD and FMD. Particularly, phyla Firmicutes and Bacteroidetes significantly dominated the 352 fecal samples from captive FMD and AMD. The relative abundance of Firmicutes and the ratio of Firmicutes to Bacteroidetes were significantly decreased in summer than in spring and substantially increased in winter than in summer. In contrast, the relative abundance of Bacteroidetes showed opposite results. Furthermore, dominant bacterial genera and main metabolic functions of gut microbiota in musk deer showed significant seasonal differences. Overall, the abundance of main gut microbiota metabolic functions in FMD was significantly higher in the cold season. WGCNA analysis indicated that OTU6606, OTU5027, OTU7522, and OTU3787 were at the core of the network and significantly related with the seasonal variation. These results indicated that the structure and function in the gut microbiota of captive musk deer vary with seasons, which is beneficial to the environmental adaptation and the digestion and metabolism of food. This study provides valuable insights into the healthy captive breeding of musk deer and future reintroduction programs to recover wild populations., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Jiang, Gao, Qin, Song, Wang, Zhang, Liu, Wang and Zhang.)

M2-polarized macrophages are one of critical factors in tumour chemoresistance. An increasing number of studies have shown that M2 macrophage polarization can be promoted by chemoresistance. A large number of evidences indicate that Bufalin has significant antitumour effect, previous studies have found that Bufalin can reduce the polarization of M2 macrophages to play an anti-tumour effect in vivo, but the mechanism remains unclear. In our study, we found that Bufalin reduced the polarization of M2 macrophages induced by chemoresistant cells both in vivo and in vitro; however, Bufalin had no obvious direct effect on M2 macrophage polarization. Furthermore, we demonstrated that Bufalin targeted the SRC-3 protein to reduce MIF release in chemoresistant cells in order to regulate the polarization of M2 macrophages. More interestingly, we also found that Cinobufacini, Bufalin is its main active monomer, which its could regulate the polarization of M2 macrophages to enhance the anti-tumour effect of oxaliplatin in vivo and in the clinic. Overall, this study provides a theoretical basis for the clinical application of drugs containing Bufalin as the main active ingredient in combination with established chemotherapy for the treatment of colorectal cancer., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: The spleen is the largest secondary lymphoid organ and the main site where stress erythropoiesis occurs. It is known that hypoxia triggers the expansion of erythroid progenitors; however, its effects on splenic gene expression are still unclear. Here, we examined splenic global gene expression patterns by time-series RNA-seq after exposing mice to hypoxia for 0, 1, 3, 5, 7 and 13 days., Results: Morphological analysis showed that on the 3rd day there was a significant increase in the spleen index and in the proliferation of erythroid progenitors. RNA-sequencing analysis revealed that the overall expression of genes decreased with increased hypoxic exposure. Compared with the control group, 1380, 3430, 4396, 3026, and 1636 genes were differentially expressed on days 1, 3, 5, 7 and 13, respectively. Clustering analysis of the intersection of differentially expressed genes pointed to 739 genes, 628 of which were upregulated, and GO analysis revealed a significant enrichment for cell proliferation. Enriched GO terms of downregulated genes were associated with immune cell activation. Expression of Gata1, Tal1 and Klf1 was significantly altered during stress erythropoiesis. Furthermore, expression of genes involved in the immune response was inhibited, and NK cells decreased., Conclusions: The spleen of mice conquer hypoxia exposure in two ways. Stress erythropoiesis regulated by three transcription factors and genes in immune response were downregulated. These findings expand our knowledge of splenic transcriptional changes during hypoxia.

FAM135B (family with sequence similarity 135, member B) is related to the progression of esophageal squamous cell carcinoma (ESCC). However, the role played by the gene in radiosensitivity remains unknown. Herein, we examined the relationship between FAM135B and radiosensitivity. According to the results, FAM135B is highly expressed in ESCC cells, and ESCC cells with high levels of FAM135B are resistant to irradiation. Silencing FAM135B inhibits colony formation capability and cell cycle protein expression (pP53, CDK1), promotes cell cycle arrest at the G2/M phase following irradiation. Moreover, transcriptome sequencing analysis demonstrates that FAM135B regulates downstream PI3K/Akt/mTOR signaling pathway, and western blot verifies the result. One of the mechanisms of increasing radiosensitivity by silencing FAM135B expression in ESCC cells may be achieved by regulating the PI3K/Akt/mTOR signaling pathway. Silencing FAM135B shows synergy with PI3K/Akt/mTOR pathway inhibitor (rapamycin) in increasing radiosensitivity, regulating the expression of cell cycle protein and inducing apoptosis of ESCC cells. The results indicate that FAM135B could be a potential treatment target for ESCC in management of radiosensitivity., (Copyright © 2020. Published by Elsevier B.V.)

Wild-caught animals must cope with drastic lifestyle and dietary changes after being induced to captivity. How the gut microbiome structure of these animals will change in response receives increasing attention. The plateau zokor ( Eospalax baileyi ), a typic subterranean rodent endemic to the Qinghai-Tibet plateau, spends almost the whole life underground and is well adapted to the environmental pressures of both plateau and underground. However, how the gut microbiome of the plateau zokor will change in response to captivity has not been reported to date. This study compared the microbial community structure and functions of 22 plateau zokors before (the WS group) and after being kept in captivity for 15 days (the LS group, fed on carrots) using the 16S rRNA gene via high-throughput sequencing technology. The results showed that the LS group retained 973 of the 977 operational taxonomic units (OTUs) in the WS group, and no new OTUs were found in the LS group. The dominant bacterial phyla were Bacteroides and Firmicutes in both groups. In alpha diversity analysis, the Shannon, Sobs, and ACE indexes of the LS group were significantly lower than those of the WS group. A remarkable difference ( P  < 0.01) between groups was also detected in beta diversity analysis. The UPGMA clustering, NMDS, PCoA, and Anosim results all showed that the intergroup difference was significantly greater than the intragroup difference. And compared with the WS group, the intragroup difference of the gut microbiota in the LS group was much larger, which failed to support the assumption that similar diets should drive convergence of gut microbial communities. PICRUSt revealed that although some functional categories displayed significant differences between groups, the relative abundances of these categories were very close in both groups. Based on all the results, we conclude that as plateau zokors enter captivity for a short time, although the relative abundances of different gut microbiota categories shifted significantly, they can maintain almost all the OTUs and the functions of the gut microbiota in the wild. So, the use of wild-caught plateau zokors in gut microbial studies is acceptable if the time in captivity is short., Competing Interests: Declaration of conflicting interests:The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2021.)

Anthocyanin is derived from a flavylium cation structure, and it promotes health in humans and functions in plants as protection against environmental stress. The rapid analysis of anthocyanin structure and content is a critical challenge for improving fruit quality. In this study, the tomato cultivar Indigo Rose, which is a popular purple cultivated tomato used for breeding, was taken as an example for anthocyanin analysis. A rapid analysis method was developed to minimize anthocyanin loss from the fresh fruit. Four new anthocyanins were discovered in the tomato, and the structures of a total of 12 anthocyanins were determined. Among these, petunidin-3-(trans-p-coumaroyl)-rutinoside-5-glucoside and malvidin-3-(trans-p-coumaroyl)-rutinoside-5-glucoside were the main anthocyanins in Indigo Rose. The structural modifications of these anthocyanins were mainly glycosylation and acylation, and there were also hydroxylation and methylation. Our findings provide new insight into the biosynthesis pathway in tomato fruit., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Fruit firmness is a target trait in tomato breeding because it facilitates transportation and storage. However, it is also a complex trait and uncovering the molecular genetic mechanisms controlling fruit firmness has proven challenging. Here, we report the map-based cloning and functional characterization of qFIRM SKIN 1 (qFIS1), a major quantitative trait locus that partially determines the difference in compression resistance between cultivated and wild tomato accessions. FIS1 encodes a GA2-oxidase, and its mutation leads to increased bioactive gibberellin content, enhanced cutin and wax biosynthesis, and increased fruit firmness and shelf life. Importantly, FIS1 has no unfavorable effect on fruit weight or taste, making it an ideal target for breeders. Our study demonstrates that FIS1 mediates gibberellin catabolism and regulates fruit firmness, and it offers a potential strategy for tomato breeders to produce firmer fruit.

Graphene oxide (GO) and its composite membranes have exhibited great potential for application in water purification and desalination. This article reports that a novel graphene oxide membrane (GOM) of ~5 µm thickness was fabricated onto a nylon membrane by vacuum filtration and cross-linked by amino acids (L-alanine, L-phenylalanine, and serine). The GOM cross-linked by amino acids (GOM-A) exhibits excellent stability, high water flux, and high rejection to metal ions. The rejection coefficients to alkali and alkaline earth metal ions through GOM-A were over 94% and 96%, respectively. The rejection coefficients decreased with an increasing H + concentration. Metal ions (K + , Ca 2+ , and Fe 3+ ) can be inserted into GOM-A layers, which enlarges the interlayer spacing of GOM-A and neutralizes the electronegativity of the membrane, resulting in the decease in the rejection coefficients to metal ions. Meanwhile, GOM-A showed quite high antibacterial efficiency against E. coli. With the excellent performance as described above, GOM-A could be used to purify and desalt water.

Recent studies have shown that MDR could be induced by the high stemness of cancer cells. In a previous study, we found bufalin could reverse MDR and inhibit cancer cell stemness in colorectal cancer, but the relationship between them was unclear. Here we identified overexpressing CD133 increases levels of Akt/nuclear factor-κB signaling mediators and MDR1, while increasing cell chemoresistance. Furthermore, bufalin reverses colorectal cancer MDR by regulating cancer cell stemness through the CD133/nuclear factor-κB/MDR1 pathway in vitro and in vivo. Taken together, our results suggest that bufalin could be developed as a novel 2-pronged drug that targets CD133 and MDR1 to eradicate MDR cells and could ultimately be combined with conventional chemotherapeutic agents to improve treatment outcomes for patients with colorectal cancer., (© 2020 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Aims: Glioma is the most common type of malignant tumor of the nervous system, and aggressiveness and recurrence are major obstacles for treatment. This study is designed to explore the effects of amentoflavone (AF) on glioma, and to investigate the underlying mechanism of the anti-cancer activities of AF., Methods: Cell morphology was recorded under microscopy. Cell viability and cell death ratio were determined by CCK-8 assay and lactate dehydrogenase (LDH) release assay, respectively. Cell cycle progression was assessed by flow cytometry. The levels of iron, MDA (malondialdehyde), lipid ROS, and GSH (reduced glutathione) were assessed by ELISA kit. The cycle-related proteins, ferroptosis-related protein, autophagy-related protein, and the phosphorylation of AMPK, mTOR and p70S6K were analyzed by western blotting. The autophagic flux was observed by transfecting cells with mRFP-GFP-LC3 plasmids. The xenograft murine models were established to analyze the effects of amentoflavone in vivo. The immunohistochemistry assay was performed to analyze the expression of LC3B, Beclin1, ATG5, ATG7, and ferritin heavy chain (FTH)., Results: Our results showed that AF treatment led to reduction in cell viability and cell death. In addition, AF was found to block cell cycle progression in a dose-dependent manner in vitro. Following treatment with AF, the intracellular levels of iron, MDA, and lipid OS were increased, and the levels of GSH and the mitochondrial membrane potential were reduced. In addition, our results showed that AF promoted the autophagic by regulating autophagy-relevant proteins. Our results also showed that the autophagy-induction by AF was associated with regulation of AMPK/mTOR signaling. Mechanistically, the inhibition effects of AF on glioma cell were reversed by DFO, ferreostatin-1 as well as upregulation of FTH. Meanwhile, the FTH levels were increased by compound C and knockdown of ATG7. Moreover, both autophagy inhibitor Baf A1 and knockdown of ATG7 were able to compromising AF-induce ferroptosis and cell death. In vivo, the tumor growth was suppressed by AF in a dose-dependent manner. The level of MDA in the tumor tissue was increased while the level of GSH in tumor tissue was decreased by AF in a dose-dependent manner. Furthermore, the expression of LC3B, Beclin1, ATG5, ATG7 were increased, and the expression of FTH were decreased by AF in a dose-dependent manner in vivo. Conclusion These results demonstrate that AF triggered ferroptosis in autophagy-dependent manner. Our results suggest that AF has the potential to be considered as a novel treatment agent in glioma., Competing Interests: Declaration of competing interest None., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objective: To evaluate the effect of a decrease in blood pressure (BP) fulfilling the diagnostic criteria for orthostatic hypotension (OH) on performance in each domain of cognitive function in patients with type 2 diabetes mellitus using a cross-sectional and within-group design., Methods: Subjects were individuals without dementia and with type 2 diabetes mellitus, including 107 individuals without OH and 94 with OH (DMOH); 95 control participants were also included. BP was assessed in both the supine and standing positions. A detailed neuropsychological assessment was made in each posture for all subjects., Results: There were statistically significant differences between the patients without OH and the DMOH group with regard to some cognitive measures while supine. Standing posture exacerbated and broadened cognitive deficits in the DMOH group for all measures in the different domains of cognition including executive functioning, memory, visuospatial skills, information processing speed, and attention. When group-specific supine scores were used as baseline anchors, both the patients without OH and the DMOH group showed cognitive changes when transitioning from a supine to a standing, upright position, with the DMOH group exhibiting a wider range of neuropsychological deficits in memory, visuospatial skills, executive function, and sustained attention, as well as significant changes in information processing speed., Interpretation: These data demonstrate that type 2 diabetes mellitus patients with OH had transient, posture-mediated cognitive deficits in excess of those found in diabetes mellitus without OH. Understanding the effects of OH on cognition due to autonomic failure is important, particularly as clinical assessments and neuroimaging collect data only in the seated or supine positions. ANN NEUROL 2019;86:754-761., (© 2019 American Neurological Association.)

Hypoxia is associated with poor prognosis and therapeutic resistance in cancer patients. Accumulating evidence has shown that microRNA (miRNA) plays an important role in the acquired drug resistance in colorectal carcinoma (CRC). However, the role of miRNA in hypoxia-induced CRC drug resistance remains to be elucidated. Here, we identified a hypoxia-triggered feedback loop that involves hypoxia-inducible transcription factor 1α (HIF-1α)-mediated repression of miR-338-5p and confers drug resistance in CRC. In this study, the unbiased miRNA array screening revealed that miR-338-5p is downregulated in both hypoxic CRC cell lines tested. Repression of miR-338-5p was required for hypoxia-induced CRC drug resistance. Furthermore, we identified interleukin-6 (IL-6), which mediates STAT3/Bcl2 activation under hypoxic conditions, as a direct miR-338-5p target. The resulting HIF-1α/miR-338-5p/IL-6 feedback loop was necessary for drug resistance in colon cancer cell lines. Using CRC patient samples, we found miR-338-5p has a negative correlation with HIF-1α and IL-6. Finally, in a xenograft model, overexpressing miR-338-5p in CRC cells and HIF-1α inhibitor PX-478 were able to enhance the sensitivity of CRC to oxaliplatin (OXA) via suppressing the HIF-1α/miR-338-5p/IL-6 feedback loop in vivo. Taken together, our results uncovered an HIF-1α/miR-338-5p/IL-6 feedback circuit that is critical in hypoxia-mediated drug resistance in CRC; targeting each member of this feedback loop could potentially reverse hypoxia-induced drug resistance in CRC., (Copyright © 2019 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.)

The mol-ecular structure of the title compound, C 23 H 34 N 2 O 4 , has C 2 symmetry. In the crystal, inter-locked dimers are formed through quadruple N-H⋯O hydrogen bonds between pyrrole N-H groups and carbonyl O atoms.

High quantities of anthocyanins in plants confer potential protective benefits against biotic and abiotic stressors. Studies have shown that the bZIP transcription factor HY5 plays a key role in controlling anthocyanin accumulation in response to light. However, in hy5 mutants, residual anthocyanins have been detected, indicating that other regulators exist to regulate anthocyanin biosynthesis in an HY5-independent manner. Here, we employed the CRISPR/Cas9 (clustered regularly interspersed short palindromic repeats/CRISPR-associated protein 9) system specifically to induce targeted mutagenesis of SlHY5 in the purple tomato cultivar 'Indigo Rose'. The T2 generation of tomato plants homozygous for the null allele of the SlHY5 frameshift mutated by a 1 bp insertion contained a lower anthocyanin content. Transcriptional analysis showed that most of the anthocyanin biosynthesis structural genes and several regulatory genes were down-regulated in the hy5 mutant lines. With transcriptome analyses of the various tissues from hy5 mutant lines, eight candidate transcription factors were identified that may regulate anthocyanin biosynthesis in an HY5-independent manner. These findings deepen our understanding of how light controls anthocyanin accumulation and facilitate the identification of the regulators of anthocyanin biosynthesis in an HY5-independent manner., (� The Author(s) 2018. Published by Oxford University Press on behalf of Japanese Society of Plant Physiologists. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Tetrabromobisphenol A (TBBPA) is the most widely used brominated flame retardant. Most studies regarding TBBPA have concentrated on its occurrence, distribution, toxicity and degradation in the environment. However, little is known about its ecological effects on soil microbial communities. In this study, we investigated the effect of TBBPA on soil microbial community. Overall, the data suggested that the growth and composition of soil microorganisms were correlated to the TBBPA concentration and exposure time. Phospholipid-derived fatty acid analysis (PLFAs) showed that significant microbial growth inhibitions were 46.1% and 46.9% in 40 mg/kg TBBPA-treated soils after 45-day incubation under aerobic and anaerobic conditions, respectively. Results of PLFAs and llumina sequencing indicated that TBBPA mainly inhibited Gram-positive bacteria, but not Gram-negative bacteria. The selective antibacterial activity of TBBPA toward Gram-positive bacteria was further confirmed in pure bacteria cultures. These data suggested that, in addition to their effect on microbial growth and composition, TBBPA may affect the microbial ecology. Additional research should be carried out to identify the ecological risk of TBBPA in soil., (Copyright © 2018. Published by Elsevier Inc.)

Oxidative stress can cause injury in retinal endothelial cells. Carboxymethyl cellulose modified with collagen peptide (CMCC) is of a distinct antioxidant capacity and potentially a good drug carrier. In this study, the protective effects of CMCC against H 2 O 2 -induced injury of primary retinal endothelial cells were investigated. In vitro, we demonstrated that CMCC significantly promoted viability of H 2 O 2 -treated cells, efficiently restrained cellular reactive oxygen species (ROS) production and cell apoptosis. Then, the CMCC was employed as both drug and anti-inflammatory drug carrier for treatment of retinal ischaemia/reperfusion (I/R) in rats. Animals were treated with CMCC or interleukin-10-loaded CMCC (IL-10@CMCC), respectively. In comparisons, the IL-10@CMCC treatment exhibited superior therapeutic effects, including better restoration of retinal structural thickness and less retinal apoptosis. Also, chemiluminescence demonstrated that transplantation of IL-10@CMCC markedly reduced the retinal oxidative stress level compared with CMCC alone and potently recovered the activities of typical antioxidant enzymes, SOD and CAT. Therefore, it could be concluded that CMCC provides a promising platform to enhance the drug-based therapy for I/R-related retinal injury., (© 2018 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.)

Epithelial ovarian cancer (EOC) is one of the most prevalent gynaecological cancers. Euxanthone, an active ingredient of the medicinal plant Polygala caudata, exhibits a selective cytotoxic effect in tumour cells. The present study was aimed to determine whether euxanthone could suppress ovarian tumour growth, and to study the relevant mechanism. Two EOC cell lines, SKOV3 and A2780, were used as the in vitro model and treated with euxanthone. Cell viability and apoptosis were assayed using Cell Counting Kit-8 (CCK-8) and Annexin-V FITC/PI staining, respectively. Commercially available kits were used to measure the glucose consumption, lactate production, and intracellular ATP levels. Western blots assay was conducted to examine the level of apoptotic markers. To examine the roles of HK2 and STAT3 in the anti-tumour effect of euxanthone, cells were transfected with vectors overexpressing HK2 or STAT3, and assayed as above. Finally, SKOV3 cells were injected to mice models to appreciate the anti-neoplastic effect of euxanthone in vivo. We found that euxanthone impaired the cell viability and induced apoptosis via the intrinsic pathway in a concentration-dependent fashion in both SKOV3 and A2780 cells. Euxanthone also caused inhibition of glycolysis. Apoptosis and glycolysis inhibition was mediated by the downregulation of HK2, which in turn was a result of STAT3 inactivation. In vivo experiments also supported that euxanthone could exert anti-cancer activities without general toxicity. In conclusion, euxanthone triggered mitochondrial apoptosis and inhibited glycolysis in EOC cells., Significance of the Study: Euxanthone triggered mitochondrial apoptosis and inhibited glycolysis in EOC cells. Our findings provide preliminary experimental data that support further studies on the potential therapeutic role of euxanthone in ovarian cancer., (© 2018 John Wiley & Sons, Ltd.)

Epigenetic modifications serve important roles in non-small cell lung cancer (NSCLC) tumorigenesis; however, the role of DNA methyltransferase 1 (DNMT1) in lung cancer progression remains unclear. In the present study, the expression of DNMT1 in the human NSCLC cell lines 95D (high invasive ability) and 95C (low invasive ability) was analyzed by western blotting. The results demonstrated that the expression of DNMT1 in 95D cells was significantly higher, compared with in 95C cells and small airway epithelial cells. To further define the role of DNMT1 in tumor migration and invasion in NSCLC cells, RNA interference was used to silence DNMT1 expression. Depletion of DNMT1 significantly inhibited 95D cell invasion and migration. In addition, treatment with DNMT1 small interfering RNA resulted in compact cell morphology and significantly increased epithelial marker E-cadherin expression whilst also decreasing the expression of certain mesenchymal markers, including vimentin and fibronectin. Suppression of DNMT1 increased cytoplasmic β-catenin levels while downregulating nuclear β-catenin and Snail, an important regulator of EMT. The results from the present study suggest that the inhibition of DNMT1 reverses the epithelial-mesenchymal transition partly via the inhibition of the Wnt/β-catenin signaling pathway, and therefore inhibits cell migration and invasion. These results indicate that targeting DNMT1 may inhibit tumor metastasis and that DNMT1 is a promising target for the novel treatment of lung cancer.

Graphene oxides (GO) are attracting much attention in the diagnosis and therapy of the subcutaneous tumor as a novel biomaterial, but its diagnosis to tissue dysfunction is yet to be found. Here, a novel application of GO for diagnosis of renal dysfunction via contrast-enhanced computed tomography (CT) is proposed. In order to serve as contrast-enhanced agent, Ag nanoparticles (AgNPs) are composited on the surface of GO to promote its X-ray absorption, and then simvastatin is coinjected for eliminating in vivo toxicity induced by AgNPs. It is found that GO/AgNPs can enhance the imaging of CT into the lung, liver, and kidney of mice for a long circulation time (≈24 h) and a safety profile in vivo in the presence of simvastatin. Interestingly, the lower dose of GO/AgNPs (≈0.5 mg per kg bw) shows an excellent performance for CT imaging of renal perfusion, and visually exhibits the right renal dysfunction in model mice. Hence, this work suggests that graphene nanoparticles will play a vital role for the future medical translational development including drug carrier, biosensing, and disease therapy., (© 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Typically in English, a "satellite-framed" language, manner is expressed in the verb and path is expressed in supporting words. Past studies using looking time techniques suggest that English-speaking 3-year-olds show language-specific action processing, but 2.5-year-olds preferentially attend to path regardless of native language. In Study 1, we test whether language-specific action component preferences will be reflected in children's imitation, as a more explicit measure. Children who spoke English saw an adult move an object along a series of platforms using one of two paths and manners. Then, the children were given the opportunity to move the object on a different test platform, which was designed to force them to choose to reproduce either the demonstrated path or the manner. The results showed that 3-year-olds, but not 2.5-year-olds, were more likely to imitate the manner versus the path. In Study 2, we extend the investigation to a less commonly studied language within this domain, Mandarin. Typically in Mandarin, an "equipollently framed" language, both manner and path are expressed within equally significant verbs. The results indicated that 3-year-olds did not show a consistent preference to imitate either the path or the manner. In contrast, 2.5-year-olds were more likely to imitate the path than the manner. This research highlights the potential for the imitation choice paradigm, as an explicit measure, to understand how language affects cognition, and suggests a new language-specific pattern in action interpretation.

The tyrosine phosphatase Shp2 is associated with tumorigenesis in small cell lung cancer (SCLC). However, the relationship between Shp2 and resistance to chemotherapy remains unclear. Here, we show that Shp2 plays an important role in inducing resistance to cisplatin-based chemotherapy via the SHP2-AKT-CA916798 pathway. In an SCLC cell line, overexpression of Shp2 induced cisplatin resistance and the increased expression of AKT, pAKT, pmTOR, and CA916798. Conversely, depletion of Shp2 in a cisplatin-resistant cell line via RNA interference increased cisplatin sensitivity and decreased AKT, pAKT, pmTOR, and CA916798 expression levels. Activation of AKT stimulated CA916798 expression and altered the level of Shp2. A mouse xenograft model verified the results obtained from the in vitro experiments. In addition, we collected and analyzed clinical SCLC specimens and found that Shp2 levels correlated with CA916798 expression in tumor tissues. Importantly, higher levels of Shp2 or CA916798 were associated with a poorer prognosis in SCLC patients who received chemotherapy. Together, our findings indicate that Shp2 induces cisplatin resistance in SCLC patients via the SHP2-AKT-CA916798 pathway. Therefore, Shp2 and CA916798 may be promising biomarkers for predicting resistance to chemotherapy and may function as targets for enhancing treatments.

Aim: Ceramic restoration experiences the non-linear wear process during the chewing simulation, which contains running-in, steady and severe wear stages. However since various levels of contact stress may be applied on the occlusal surface during chewing, the cycle-dependent wear behaviors of ceramic crowns may differ. The aim of this study was to investigate the effect of contact stress on the development of wear behavior, as tested in a chewing simulator., Materials and Methods: Thirty-six anatomical metal-ceramic crowns using Ceramco III as the veneering porcelain were randomly assigned to two groups based on the contact stress applied in the wear testing. Stainless steel balls served as antagonists. The specimens were dynamically loaded in a chewing simulator up to 2.4×10 6 loading cycles, with additional thermal cycling between 5 and 55℃. For each group, several checkpoints were employed to measure the substance loss of the crowns' occlusal surfaces and to evaluate the microstructure of the worn areas., Results: After 2.4×10 6 cycles, the ceramic restorations with lower contact stress demonstrated a long steady wear stage following the running-in, but without the severe wear stage. And a slowly microstructural degradation was observed that the subsurface defect could not be seen until final. With higher contact stress, however, the ceramic restorations experienced a faster transition from running-in to severe wear stage that the steady wear stage nearly disappeared. And an early formation of subsurface defects and the deterioration of microstructure were observed., Conclusions: Contact stress is a key factor affecting the wear development of ceramic restoration. The higher contact stress promotes the veneering porcelain to evolve into severe wear stage. In contrast, lower contact stress is prone to keep the veneering porcelain operating in steady wear stage, which delays the arrival of severe wear region., (Copyright © 2017 Elsevier Ltd. All rights reserved.)