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The continuous variation of the seasonal influenza viruses, particularly A(H1N1)pdm09, persistently threatens human life and health around the world. In local areas of southwest china, the large time-scale genomic research on A(H1N1)pdm09 is still insufficient. Here, we sequenced 45 whole-genome sequences of influenza A(H1N1)pdm09 viruses in Lincang, China, from 2014 to 2018, by next-generation sequencing technology to characterize molecular mechanisms of their origin and evolution. Our phylogenetic analyses suggest that the A(H1N1)pdm09 strains circulating in Lincang belong to clade 6B and the subclade 6B.1A predominates in 2018. Further, the strains in 2018 possess elevated evolutionary rate as compared to strains in other years. Several newly emerged mutations for HA (hemagglutinin) in 2018 are revealed (i.e., S183P and R221K). Intriguingly, the substitution R221K falls into the RBS (receptor binding site) of HA protein, which could affect antigenic properties of influenza A(H1N1)pdm09 viruses, and another substitution S183P near to RBS with a high covering frequency (11/14 strains) in 2018 is exactly located at the epitope B. Notably, the NA (neuraminidase) protein harbors a new mutation I23T, potentially involved in N-glycosylation. Based on the background with a higher evolutionary rate in 2018 strains, we deeply evaluate the potential vaccine efficacy against Lincang strains and discover a substantive decline of the vaccine efficacy in 2018. Our analyses reaffirm that the real-time molecular surveillance and timely updated vaccine strains for prevention and control of influenza A(H1N1)pdm09 are crucial in the future., Competing Interests: The authors have declared that no competing interests exist.

Glutathione peroxidases (GPxs) belong to a family of enzymes that is important in organisms; these enzymes promote hydrogen peroxide metabolism and protect cell membrane structure and function from oxidative damage. Based on the establishment and development of the theory of the pathological roles of free radicals, the role of GPxs has gradually attracted researchers' attention, and the involvement of GPxs in the occurrence and development of malignant tumors has been shown. On the other hand, the incidence of breast cancer in increasing, and breast cancer has become the leading cause of cancer-related death in females worldwide; breast cancer is thought to be related to the increased production of reactive oxygen species, indicating the involvement of GPxs in these processes. Therefore, this article focused on the molecular mechanism and function of GPxs in the occurrence and development of breast cancer to understand their role in breast cancer and to provide a new theoretical basis for the treatment of breast cancer.

An efficient energy harvesting mechanism is likely critical for animals in their natural environment. Intestinal microbiota enriched by a high-fat diet aid in lipid accumulation, a strategy likely evolved for energy harvest in mammals. However, whether this strategy is conserved among vertebrate organisms remains unclear. A bacterial strain (S1), enriched on soybean oil rich medium, was isolated from the gut of Nile tilapia and demonstrated to be a member of the Citrobacter genus. Although a high-fat diet increased the number of Citrobacter spp., these bacteria were not abundant in the intestine by high-throughput sequencing. Addition of bacterium S1 to a high-fat diet modulated intestinal microbial composition and increased high-fat diet-induced lipid accumulation in mesenteric adipose tissue, accompanied by (i) increased triglyceride absorption efficiency and triglyceride reesterification and (ii) increased intestinal permeability. Collectively, our results provide evidence that specific intestinal bacteria aid the host in harvesting more energy from a high-fat diet in fish. Furthermore, the results from the present study also suggest that nondominant bacteria in the gut may play an important role in regulating host metabolism. IMPORTANCE This study shows that the ability of gut microbiota members to enhance host energy harvest from a high-fat diet is a conserved feature of host-microbe interactions in fish, as in mammals. It also underscores that gut microbiota members are able to significantly impact host biology even when at low abundance., (Copyright © 2020 Zhang et al.)

Potassium (K) is essential for plant growth and development. Here, we show that the KUP/HAK/KT K + transporter KUP9 controls primary root growth in Arabidopsis thaliana. Under low-K + conditions, kup9 mutants displayed a short-root phenotype that resulted from reduced numbers of root cells. KUP9 was highly expressed in roots and specifically expressed in quiescent center (QC) cells in root tips. The QC acts to maintain root meristem activity, and low-K + conditions induced QC cell division in kup9 mutants, resulting in impaired root meristem activity. The short-root phenotype and enhanced QC cell division in kup9 mutants could be rescued by exogenous auxin treatment or by specifically increasing auxin levels in QC cells, suggesting that KUP9 affects auxin homeostasis in QC cells. Further studies showed that KUP9 mainly localized to the endoplasmic reticulum (ER), where it mediated K + and auxin efflux from the ER lumen to the cytoplasm in QC cells under low-K + conditions. These results demonstrate that KUP9 maintains Arabidopsis root meristem activity and root growth by regulating K + and auxin homeostasis in response to low-K + stress., (© 2020 The Authors.)

Milk fat is secreted from the mammary gland in the form of milk fat globules (MFG). Although milk fat depression has been studied since the beginning of the last century, the extent to which this phenomenon alters MFG synthesis is not fully understood. The aim of this study was to evaluate the effect of conjugated linoleic acid (CLA) on the size and distribution of MFG during milk fat depression in dairy cows. Twelve Holstein cows in mid lactation (145 ± 31 d in milk, 583 ± 34.6 kg of body weight, and 27.2 ± 2.4 kg of milk/d) were randomly assigned to a control diet or control plus Ca-protected CLA at 15 g/kg of dry matter for a 6-d period. The average diameter and particle size distribution of MFG were measured using a Mastersizer 3000 laser particle size analyzer (Malvern Instruments Ltd., Malvern, UK). Feeding CLA did not affect dry matter intake (16.2 ± 0.4 kg/d), milk production (28.4 ± 0.4 kg/d), milk protein, or lactose, but it decreased milk fat content (3.46 vs. 2.52%). In addition, surface area-related mean diameter of fat globules in cows fed CLA was lower compared with controls (3.02 vs. 3.45 μm). The percentage of large fat globules decreased and that of small fat globules increased in response to CLA. Overall, the data suggest that the milk fat depression induced by CLA is accompanied by a decrease in average diameter of MFG., (Copyright © 2020 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.)

An amendment to this paper has been published and can be accessed via the original article.

Although most commonly benign, neurofibromas (NFs) can have devastating functional and cosmetic effects in addition to the possibility of malignant transformation. In orbitofacial neurofibromatosis type 1, NFs may cause progressive, disfiguring tumors of the lid, brow, temple, face and orbit. The purpose of this study was to identify biological differences between orbitofacial NFs and those occurring at other anatomic sites. We used Illumina Methylation EPIC BeadChip to study DNA methylation differences between orbitofacial NFs (N = 20) and NFs at other sites (N = 4). Global methylation differences were detected between the two groups and the top differentially methylated genes were part of the HOX (Homebox) family of transcription factors (HOXC8, HOXC4, HOXC6, HOXA6 and HOXD4), which were hypomethylated in orbitofacial NFs compared to the non-orbital NFs. Conversely, LTF (lactoferrin) was relatively hypermethylated in orbitofacial NF compared to non-orbitofacial NF. HOXC8 protein levels were higher in orbitofacial plexiform NFs (p = 0.04). We found no significant differences in the expression of HOXC4, HOXA6, or HOXD4 between the two groups. HOXC8 mRNA levels were also higher in orbitofacial NFs and HOXC8 overexpression in a non-neoplastic human Schwann cell line resulted in increased growth. In summary, we identified gene methylation and expression differences between orbitofacial NF and NFs occurring at other locations. Further investigation may be warranted, given that the HOX family of genes play an important role during development, are dysregulated in a variety of cancers, and may provide novel insights into therapeutic approaches.

Telomeres are specific nucleoprotein structures that are located at the ends of linear eukaryotic chromosomes and play crucial roles in genomic stability. Telomere DNA consists of simple repeats of a short G-rich sequence: TTAGGG in mammals and TTTAGGG in most plants. In recent years, the mammalian telomeric G-rich repeats have been shown to form G-quadruplex (G4) structures, which are crucial for modulating telomere functions. Surprisingly, even though plant telomeres are essential for plant growth, development, and environmental adaptions, only few reports exist on plant telomeric G4 DNA (pTG4). Here, using bulk and single-molecule assays, including CD spectroscopy, and single-molecule FRET approaches, we comprehensively characterized the structure and dynamics of a typical plant telomeric sequence, d[GGG(TTTAGGG) 3 ]. We found that this sequence can fold into mixed G4s in potassium, including parallel and antiparallel structures. We also directly detected intermediate dynamic transitions, including G-hairpin, parallel G-triplex, and antiparallel G-triplex structures. Moreover, we observed that pTG4 is unfolded by the AtRecQ2 helicase but not by AtRecQ3. The results of our work shed light on our understanding about the existence, topological structures, stability, intermediates, unwinding, and functions of pTG4., (© 2020 Wu et al.)

Aim: The aim of this study is to explain the effects of miRNA-186 in renal injury induced by sepsis., Methods: The Wistar rats were divided into 3 groups: the Sham group, Sepsis model group and the miRNA-186 group based on the model group; there were 9 rats in every group. The rat sepsis model was reproduced by cecal ligation and puncture (CLP). The rats of the miRNA-186 group were injected miRNA-186 from caudal vein. The rats of the difference group were killed after operation 24 h. The kidneys of the difference groups were taken for histopathological and cell apoptosis analysis by H&E and TUNEL assay. The relative protein expressions were measured by WB assay. miRNA-186 target to Phosphatase and tensin homologous protein (PTEN)., Results: Compared with the Sham group, the kidney histopathological and cell apoptosis rates of the model group were significantly damaged (P<0.05, respectively), however, the kidney histopathological and cell apoptosis rate of miRNA-186 group were significantly improved compared with the model group (P<0.05, respectively). The relative protein expressions were significantly different among 3 groups (P<0.05, respectively). The PTEN was the target of the miRNA-186., Conclusion: miRNA-186 over-expression has effects that improve renal injury induced by sepsis via PTEN pathway., Competing Interests: Conflict of interest Conflict of interest statement: Authors state no conflict of interest, (© 2020 Min Li et al., published by De Gruyter.)

The maintenance of genomic stability is crucial for species survival, and its failure is closely associated with tumorigenesis. The Fanconi anemia (FA) pathway, involving 22 identified genes, plays a central role in repairing DNA interstrand cross-links. Importantly, a germline defect in any of these genes can cause Fanconi's anemia, a heterogeneous genetic disorder, characterized by congenital growth abnormalities, bone marrow failure, and predisposition to cancer. On the other hand, the breast cancer susceptibility genes, BRCA1 and BRCA2 , also known as FANCS and FANCD1 , respectively, are involved in the FA pathway; hence, researchers have studied the association between the FA pathway and cancer predisposition. Here, we mainly focused on and systematically reviewed the clinical and mechanistic implications of the predisposition of individuals with abnormalities in the FA pathway to cancer, especially breast cancer., (Copyright © 2020 Fang, Wu, Zhang, Liu and Zhang.)

Oxygen deprivation (hypoxia) is a common challenge in water environment, which causes lack of energy and oxidative damage in organisms. Many studies have indicated a number of physiological and metabolic changes under hypoxia, but the effects of dietary nutrients on hypoxia tolerance have not been well evaluated. In the present 7-week feeding trial, we fed zebrafish with low-protein diet (LP), high-protein diet (HP), low-fat diet (LF), high-fat diet (HF), low-carbohydrate diet (LC), and high-carbohydrate diet (HC), respectively. Afterward, the resistance to acute hypoxia challenge, growth, body composition, activities of metabolic enzymes, and expressions of energy homeostasis-related genes and six hifαs genes were measured. The results indicated that only the HC diet could significantly improve the resistance to hypoxia challenge. Moreover, the HC diet feeding caused higher glycogen deposition in the liver and muscle, and these glycogens were significantly reduced after 6-h acute hypoxia challenge. Meanwhile, the lactate content in the liver and blood was increased in the HC groups. At hypoxia status, the relative mRNA expressions of the genes related to glycolysis, ATP production, insulin signaling pathway, and hif-3a (hif1al) were all significantly increased in the muscle of the HC diet-fed fish. This study revealed that high-carbohydrate diet could improve the resistance to hypoxia by activating glycolysis and hif/insulin signaling pathway in zebrafish, mainly in the muscle, to efficiently supply energy. Therefore, our results highlight the importance of dietary carbohydrate in resisting hypoxia in fish.

Two new types of cyclic pyridinium ylides were designed and further used in reactions with azoalkenes to access structurally diverse spirocyclic compounds. A range of spiropyrazoline oxindoles could be smoothly obtained in up to 99% yield via a [4 + 1] annulation process with oxindole 3-pyridinium ylides as C1 synthons. Similarly, a series of spiropyrazoline indanones could be prepared with indanone 2-pyridinium ylides as C1 synthons. This work represents the first example of cyclic pyridinium ylides as C1 synthons for the efficient construction of spirocyclic compounds.

In December 2019, novel coronavirus pneumonia epidemic occurred in Wuhan, Hubei Province, and spread rapidly across the country. In the early stages of the epidemic, China adopted the containment strategy and implemented a series of core measures around this strategic point, including social mobilization, strengthening case isolation and close contacts tracking management, blocking epidemic areas and traffic control to reduce personnel movements and increase social distance, environmental measures and personal protection, with a view to controlling the epidemic as soon as possible in limited areas such as Wuhan. This article summarizes the background, key points and core measures in the country and provinces. It sent prospects for future prevention and control strategies.

Introduction: The aim of this study was to compare the efficacy of vildagliptin as add-on therapy to short-term continuous subcutaneous insulin infusion (CSII) with CSII monotherapy in hospitalized patients with type 2 diabetes mellitus (T2DM)., Methods: A total of 200 hospitalized patients with inadequately controlled T2DM were randomized into groups, with one group receiving CSII monotherapy (CSII group, n =100) and the other group receiving CSII plus vildagliptin as add-on (CSII + Vig group, n = 100). Of these, 191 completed the 7-day trial (CSII group, n = 99; CSII + Vig group, n = 92) and included in the analysis. The glycemic control and variability of the patients were measured using all-day capillary blood glucose (BG) monitoring. Weight and fasting C-peptide levels were evaluated before and after the interventions., Results: Mean BG concentrations during the whole treatment period were lower and the time to reach target BG was reduced in the CSII + Vig group compared with the CSII group (9.89 ± 3.37 vs. 9.46 ± 3.23 mmol/L, P < 0.01; 129 ± 4 vs. 94 ± 5 h, P < 0.01, respectively). Similarly, the indicators of glycemic variability, namely the standard deviation of BG and the largest amplitude of glycemic excursion, were significantly decreased in the CSII + Vig group compared with the CSII group (2.68 ± 1.05 vs. 2.39 ± 1.00 mmol/L, P < 0.01; 7.19 ± 2.86 vs. 6.23 ± 2.73 mmol/L, P < 0.01, respectively)., Conclusions: Short-term CSII with vildagliptin as add-on therapy may be an optimized treatment for hospitalized patients with T2DM compared with short-term CSII monotherapy.

With the development of aquaculture industry, high-carbohydrate diet is used to stimulate protein-sparing effect and reduce feed cost. However, fish utilize carbohydrates poorly in general, and instead, high level of carbohydrates in the diet influence the growth condition of fish. How to alleviate the side effects of high carbohydrate diet on fish health has attracted more and more attentions. In the present study, Nile tilapia (Oreochromis niloticus) were fed with 25% and 45% of carbohydrate diet for eight weeks. Higher body weight but lower resistance to pathogen was found in 45% carbohydrate diet group. Higher expression level of inflammation cytokines, increased expression of total NF-κB protein and phosphorylated NF-κB protein (p-NF-κB) were detected in higher carbohydrate group. Concentration of short-chain fatty acids (SCFAs) was measured and the results indicated that high-carbohydrate diet decreased acetate content in the intestine. In order to detect the relationship between the decreased concentration of acetate and lower resistance to pathogen in high-carbohydrate group, 45% of carbohydrate diets (HC) supplemented with different concentrations of sodium acetate (HC + LA, 100 mmol/L; HC + MA, 200 mmol/L; HC + HA, 400 mmol/L) were used to raise Nile Tilapia for eight weeks. The results indicated that addition of 200 mmol/L sodium acetate (HC + MA) reduced the mortality when fish were challenged with Aeromonas hydrophila. Furthermore, we also found that addition of 200 mmol/L sodium acetate mainly inhibited p38 mitogen-activated protein kinase (p38MAPK) and NF-κB phosphorylation to decrease the expression level of inflammation cytokines (IL-8, IL-12, TNF-α and IL-1β) in the intestine. The present study indicated that certain concentration of sodium acetate could alleviate high-carbohydrate induced intestinal inflammation mainly by suppressing MAPK activation and NF-κB phosphorylation., Competing Interests: Declaration of competing interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that may be construed as a potential conflict of interest., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

A Gram-stain-positive, aerobic, non-motile and coccoid-shaped bacterium, designated XNB-1 T , was isolated from farmland soil in Taian, Shandong province, China. Strain XNB-1 T contained iso-C 15 : 0 and iso-C 16 : 0 as the predominant fatty acids. The diagnostic diamino acid of the peptidoglycan was ornithine, and the interpeptide bridge was l-Orn←Gly (1, 2) ←d-Glu. The polar lipid profile of strain XNB-1 T consisted of diphosphatidylglycerol, phosphatidylglycerol, an unidentified phosphoglycolipid and three unidentified phospholipids. The predominant menaquinone of strain XNB-1 T was MK-8(H 4 ) and the DNA G+C content was 70.1 mol%. Phylogenetic analysis based on 16S rRNA gene sequences showed that strain XNB-1 T belonged to the genus Ornithinicoccus , and shared the highest similarity with Ornithinicoccus hortensis HKI 0125 T (96.0 %), followed by Ornithinicoccus halotolerans EGI 80423 T (95.5 %). Genome-based analysis of average nucleotide identity of strain XNB-1 T with O. hortensis HKI 0125 T and O. halotolerans EGI 80423 T yielded values of 73.1 and 73.3 %, respectively, while the digital DNA-DNA hybridization values were 19.5 and 19.9 %, respectively. On the basis of phenotypic, chemotaxonomic and phylogenetic data, strain XNB-1 T is considered to represent a novel species of the genus Ornithinicoccus , for which the name Ornithinicoccus soli sp. nov. is proposed. The type strain is XNB-1 T (=CCTCC AB 2019099 T =KCTC 49259 T ).

For sexual reproduction, oocytes are mammalian female germ cells that provide the majority of maternal genetic material for early stage embryo production and development. Early stage embryos begin the process of multicellular organism formation through cell differentiation. Studies on mammalian female germ cells (oocytes) not only reveal its unique physiological characteristics, but also help understand the mechanism involved in cell differentiation of other cell types. However, because it is difficult to culture in vitro, our understanding of the function of oocytes and early stage embryos remains very limited. Gene editing or manipulation is one of the most commonly used method, which is also useful in the field of gametes study. In this review, we summarized the principles, advantages and disadvantages of techniques, which include conditional knockout, RNA interference, Morpholino, Trim-Away and antibody-mediated inhibition of protein function, currently used for gene manipulation in oocytes and early stage embryos. We also discuss the issues the investigators need to consider. Finally, we highlight the future directions for gene manipulation or editing in female germ cells and early stage embryos.

The present study sought to examine the therapeutic effect of a novel antidiabetic monomer combination (AMC) in treating type 2 diabetes mellitus (T2DM); while also elucidating the potential functional mechanism. Male C57BL/6J mice were fed a high-fat diet (HFD) for 12 weeks to establish T2DM. The AMC group showed significant reduction in weight, fasting blood glucose (FBG), serum total cholesterol (TC) and low density lipoprotein cholesterol (LDL-C), and experienced reduced insulin resistance based on oral glucose tolerance testing (OGTT) and hyperinsulinemic-euglycemic clamp testing ("gold standard" for determining in vivo insulin sensitivity). Further, AMC restored the altered intestinal flora by increasing the abundance of the beneficial bacteria Akkermansia , and decreasing the number of harmful bacteria, including Bacteroides , Odoribacter , Prevotella 9 , Alistipes , and Parabacteroides . Components of the host-microbial metabolome were also significantly changed in the AMC group compared to the HFD group, including hydroxyphenyllactic acid, palmitoleic acid, dodecanoic acid, linoleic acid, and erucic acid. Furthermore, AMC was found to inhibit inflammation and suppress signaling pathways related to insulin resistance. Lastly, spearman correlation analysis revealed relationships between altered microbial community and co-metabolite levels, co-metabolites and inflammatory cytokines. Hence, the potential mechanism responsible for AMC-mediated alleviation of insulin resistance was suggested to be involved in modulation of bacteria-cometabolism-inflammation responses., (Copyright © 2020 Han, Zhao, Zhang, Li, Gao, Zheng, Wang, Wu, Zheng, Jiang, Ding, Yang, Jia and Tong.)

Ascomycete fungi Cordyceps are widely used in traditional Chinese medicine, and numerous investigations have been carried out to uncover their biological activities. However, primary researches on the physiological effects of Cordyceps were committed using crude extracts. At present, there are only a few compounds which were comprehensively characterized from Cordyceps, partial owing to the low production. In order to scientifically take advantage of Cordyceps, we used the strategy of genome mining to discover bioactive compounds from Cordyceps militaris. We found the putative biosynthetic gene cluster of the acyl-CoA:cholesterol acyltransferase inhibitor beauveriolides in the genome of C. militaris, and produced the compounds by heterologous expression in Aspergillus nidulans. Production of beauveriolide I and III also was detected in both ferment mycelia and fruiting bodies of C. militaris. The possible biosynthetic pathway was proposed. Our studies unveil the active compounds of C. militaris against atherosclerosis and Alzheimer's disease and provide the enzyme resources for the biosynthesis of new cyclodepsipeptide molecules., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Zinc finger E-box binding homeobox 1 (ZEB1, also termed TCF8 and δEF1) is a crucial member of the zinc finger-homeodomain transcription factor family, originally identified as a binding protein of the lens-specific δ1-crystalline enhancer and is a pivotal transcription factor in the epithelial-mesenchymal transition (EMT) process. ZEB1 also plays a vital role in embryonic development and cancer progression, including breast cancer progression. Increasing evidence suggests that ZEB1 stimulates tumor cells with mesenchymal traits and promotes multidrug resistance, proliferation, and metastasis, indicating the importance of ZEB1-induced EMT in cancer development. ZEB1 expression is regulated by multiple signaling pathways and components, including TGF-β, β-catenin, miRNA and other factors. Here, we summarize the recent discoveries of the functions and mechanisms of ZEB1 to understand the role of ZEB1 in EMT regulation in breast cancer.

A Gram-stain-positive, strictly aerobic, non-motile, non-spore-forming and rod-shaped bacterium, designated as strain G-1 T , was isolated from farmland soil sampled in in Fuyang, Anhui Province, PR China. Phylogenetic analysis based on 16S rRNA gene sequences showed that strain G-1 T was closely related to Cumulibacter manganitolerans 2-36 T (97.7 % similarity). Strain G-1 T contained iso-C 16 : 0 , C 17 : 1 ω6 c , iso-C 15 : 0 and iso-C 14 : 0 as the predominant fatty acids. The polar lipids of strain G-1 T were diphosphatidylglycerol, phosphatidylethanolamine, an unidentified phospholipid, an unidentified lipid and two unidentified glycolipids. The predominant respiratory quinone of strain G-1 T was MK-9(H 4 ). The cell wall contained meso -diaminopimelic acid as the diagnostic diamino acid. The G+C content of the genomic DNA based on genome calculations was 64.2 mol%. Average nucleotide identity and the digital DNA-DNA hybridization values for the draft genomes between strain G-1 T and strain 2-36 T were 75.7 and 20.2 %, respectively. On the basis of phenotypic and phylogenetic data, strain G-1 T is considered to represent a novel species of the genus Cumulibacter , for which the name Cumulibacter soli sp. nov. is proposed. The type strain is G-1 T (=CCTCC AB2019021 T =KCTC 49258 T ).

Intestinal lipases are fat-digesting enzymes, which play vital roles in lipid absorption in the intestine. To study the regulation of intestinal lipase activity in systemic lipid metabolism in fish, especially in the metabolic diseases caused by high-fat diet (HFD) feeding, we inhibited intestinal lipases in Nile tilapia to investigate the physiological consequences. In the present study, Nile tilapia were firstly fed with HFD (12% fat) for 6 weeks to establish a fatty fish model. Afterwards, Orlistat as a potent intestinal lipase inhibitor was added into the HFD for the following 5-week feeding trial, with two dietary doses (Orlistat16 group, 16 mg/kg body weight; Orlistat32 group, 32 mg/kg body weight). After the trial, both doses of Orlistat treatment significantly reduced intestinal lipase activity, fat absorption, hepatic lipid accumulation, and gene expression of lipogenesis, whereas increased gene expression of lipid catabolism. Moreover, intestinal lipase inhibition increased immune enzyme activities, antioxidant capacity, and gene expression of anti-inflammatory cytokines, whereas lowered gene expression of pro-inflammatory cytokines. Besides, Orlistat could also improve the structure of the intestine and increase expression of intestinal tight-coupling protein. Taken together, intestinal lipase inhibition alleviated the adverse effects caused by HFD in Nile tilapia. Thus, intestinal lipases played key roles in absorbing dietary lipid and could be a promising target in regulating systemic lipid metabolism in fish.

Hypoxia is a common pathological process caused by insufficient oxygen. Long noncoding RNAs (lncRNAs) have been proven to participate in this pathology. Hypoxia is reported to significantly reduce the secretion of tissue inhibitor of metalloproteinase 2 (TIMP2) and TIMP2 induces pheochromocytoma-12 (PC12) cell cycle arrest. Thus, our study aimed to explore the mechanism by which lncRNA maternally expressed gene 3 (MEG3) was implicated in hypoxia-induced PC12 cell injury through TIMP2 promoter methylation. To elucidate the potential biological significance of MEG3 and the regulatory mechanism between MEG3 and TIMP2, a hypoxia-induced PC12 cell injury model was generated. The hypoxia-exposed cells were subjected to a series of overexpression plasmids and short hairpin RNAs, followed by the measurement of levels of MEG3, TIMP2, lactate dehydrogenase (LDH), malondialdehyde (MDA), superoxide dismutase (SOD), reactive oxygen species (ROS), Bcl-2-associated X protein, B-cell lymphoma-2, and caspase-3, as well as the changes in MMP, cell proliferation, apoptosis, and cell cycle progression. On the basis of the findings, MEG3 was upregulated in hypoxia-injured PC12 cells. MEG3 recruited methylation proteins DNMT3a, DNMT3b, and MBD1 and accelerated TIMP2 promoter methylation, which in turn inhibited its expression. Moreover, PC12 cells following MEG3 silencing and TIMP2 overexpression exhibited significantly decreased levels of LDH, MDA, and ROS along with cell apoptosis, yet increased SOD and MMP levels, as well as cell cycle entry to the S phase and cell proliferation. In conclusion, MEG3 silencing suppresses hypoxia-induced PC12 cell injury by inhibiting TIMP2 promoter methylation. This study may provide novel therapeutic targets for hypoxia-induced injury., (© 2019 Wiley Periodicals, Inc.)

Purpose: To identify potential metabolic biomarkers for distinguishing malignant and benign thyroid nodules in children and adolescents using a metabolomics approach., Methods: A total of 96 consecutive patients (median age 14.29 ± 2.31 years, range 9-18 years) who underwent thyroidectomy and 40 healthy controls were enrolled. Patients were assigned to the papillary thyroid carcinoma and benign thyroid adenoma groups according to postoperative pathologic biopsy. Plasma samples were preoperatively collected, and multivariate analysis was performed to identify differential metabolites., Results: Papillary thyroid carcinoma could be distinguished not only from healthy serum but also from benign thyroid adenoma according to the metabolic profiles. A total of 17 metabolites were identified. Compared with those from benign thyroid adenoma patients and healthy controls, the metabolites from papillary thyroid carcinoma patients, including leucine, lactate, alanine, glycine, acetate, lysine and choline, were increased, while glucose was decreased., Conclusion: The metabolomics method based on proton nuclear magnetic resonance has great potential for identifying papillary thyroid carcinoma in children and adolescents. Lactate and glycine may be used as potential serum markers for the diagnosis of papillary thyroid carcinoma.

Background: Oral squamous cell carcinoma (OSCC) is a solid tumor, which originates from squamous epithelium, with about 400,000 new-cases/year worldwidely. Presently, chemoradiotherapy is the most important adjuvant treatment for OSCC, mostly in advanced tumors. However, clinical resistance to chemotherapy still leads to poor prognosis of OSCC patients. Via high-throughput analysis of gene expression database of OSCC, we investigated the molecular mechanisms underlying cisplatin resistance in OSCC, analyzing the differentially expressed genes (DEGs) and their regulatory relationship, to clarify the molecular basis of OSCC chemotherapy resistance and provide a theoretical foundation for the treatment of patients with OSCC and individualized therapeutic targets accurately., Methods: Datasets related to "OSCC" and "cisplatin resistance" (GSE111585 and GSE115119) were downloaded from the GEO database and analyzed by GEO2R. Venn diagram was used to obtain drug-resistance-related DEGs. Functional enrichment analysis and Kyoto encyclopedia of genes and genomes (KEGG) pathway analysis were performed on DEGs using The Database for Annotation, Visualization and Integrated Discovery (DAVID) software. Protein-protein interaction (PPI) network was constructed by STRING (search tool for recurring instances of neighbouring genes) database. Potential target genes of miRNA were predicted via miRDB, and cBioportal was used to analyze the function and survival of the potential functional genes., Results: Forty-eight upregulated DEGs and 49 downregulated DEGs were obtained from the datasets, with cutoff as p < 0.01 and |log FC| > 1. The DEGs in OSCC mainly enriched in cell proliferation regulation, and chemokine activity. In PPI network with hub score > 300, the hub genes were identified as NOTCH1 , JUN , CTNNB1 , CEBPA , and ETS1 . Among miRNA-mRNA targeting regulatory network, hsa-mir-200c-3p, hsa-mir-200b-3p, hsa-mir-429, and hsa-mir-139-5p were found to simultaneously regulate multiple hub genes. Survival analysis showed that patients with high CTNNB 1 or low CEBPA expression had poor outcome., Conclusions: In the OSCC cisplatin-resistant cell lines, NOTCH1 , JUN , CTNNB1 , CEBPA , and ETS1 were found as the hub genes involved in regulating the cisplatin resistance of OSCC. Members of the miR-200 family may reverse drug resistance of OSCC cells by regulating the hub genes, which can act as potential targets for the treatment of OSCC patients with cisplatin resistance., (Copyright © 2020 Wu, Chen, Li, Shen, Ye, Zhang, Chen and Liu.)

Objectives: Peripheral blood flow cytometry (PBFC) is useful for evaluating circulating hematologic malignancies (HM) but has limited diagnostic value for screening. We used machine learning to evaluate whether clinical history and CBC/differential parameters could improve PBFC utilization., Methods: PBFC cases with concurrent/recent CBC/differential were split into training (n = 626) and test (n = 159) cohorts. We classified PBFC results with abnormal blast/lymphoid populations as positive and used two models to predict results., Results: Positive PBFC results were seen in 58% and 21% of training cases with and without prior HM (P < .001). % neutrophils, absolute lymphocyte count, and % blasts/other cells differed significantly between positive and negative PBFC groups (areas under the curve [AUC] > 0.7). Among test cases, a decision tree model achieved 98% sensitivity and 65% specificity (AUC = 0.906). A logistic regression model achieved 100% sensitivity and 54% specificity (AUC = 0.919)., Conclusions: We outline machine learning-based triaging strategies to decrease unnecessary utilization of PBFC by 35% to 40%., (© American Society for Clinical Pathology, 2019. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The dysfunction of long non-coding RNAs (lncRNAs), without protein-coding potential, has been implicated in drug resistance against treatment in various human diseases, especially in malignant tumors. As the most common-diagnosed female malignancy worldwide, breast cancer is also the second-leading cause of cancer-related mortality in women. Despite the improvement in neo-adjuvant therapy, endocrine therapy, molecular-targeted treatment, and chemotherapy, drug resistance to various treatment regimens is still quite prevalent. This article focused on the lncRNAs and their functions in drug resistance against breast cancer therapeutic agents, in order to develop new precise treatment strategies for patients with breast cancers. The discovery of lncRNA opened new doors to the molecular mechanisms of the biological processes, and has provided new pathways to regulate biochemical events. Thus, lncRNAs may be developed as a biomarker for the detection and/or prevention of breast cancer. Additionally, lncRNA-based approaches may provide an additional treatment modality in personalized medicine alone or in combination with existing tumor-directed interventions to improve patient outcomes. In conclusion, lncRNAs molecules may represent the "next generation" therapy option for breast cancer patients.

Background: Ovarian cancer (OC) is one of the most malignant gynecological cancers. Platelets play a profound role in cancer growth and metastasis. Platelet distribution width (PDW) is an indicator of platelet activation and is altered in malignancies. However, the prognostic value of PDW in OC remains unclear. This present study aimed to investigate the predictive significance of PDW in OC., Methods: 221 OC patients, between January 2013 and December 2013, were included in this study. The correlations between PDW and clinicopathological features were analyzed. Kaplan-Meier method and Cox regression were used to evaluate the prognostic impact of PDW., Results: Of the 221 patients, increased PDW levels were observed in 163 (73.6%) patients. Kaplan-Meier analysis revealed that higher PDW levels were associated with poor progression-free survival and overall survival (both p< 0.001). Cox-regression analysis confirmed the independent predictive value of PDW on overall survival (HR = 2.820, 95% CI = 1.776-4.476, p< 0.001)., Conclusion: Higher PDW levels predict poor prognosis in patients with OC. Elevated PDW may be a novel target for therapy.

Aims: Immune checkpoint inhibitors (ICIs) improve survival across a range of malignancies but are also associated with a spectrum of gastrointestinal (GI) immune-related adverse events (GI-irAEs). The aims of this study were to explore the diagnostic value of gastric and duodenal biopsies and to address considerations in the differential diagnosis., Methods and Results: We identified 39 patients who were treated with ICIs and had a subsequent upper GI biopsy. We recorded clinical data and endoscopic findings, and reviewed their gastric, duodenal and colonic biopsies. Twenty-one (54%) patients were treated with an anti-programmed cell death protein 1 (PD-1)/anti-programmed cell death ligand 1 antibody alone, and 17 (44%) patients were treated with a combination of anti-cytotoxic T-lymphocyte-associated protein-4 and anti-PD-1 antibodies. Thirty-two (82%) patients presented with diarrhoea. Gastric alterations included periglandular inflammation and granulomas, and duodenal changes included villous blunting, intraepithelial lymphocytosis, granulomas, and neutrophilic activity. We recognised four patterns of colonic injury: (i) acute self-limiting colitis; (ii) lymphocytic colitis; (iii) collagenous colitis; and (iv) apoptosis-only. Twenty-nine (74%) and 10 (26%) patients were diagnosed clinically as positive and negative for GI-irAEs, respectively. Gastric periglandular inflammation (P = 0.004) and an increased number of colonic lamina propria mononuclear cells (P = 0.04) correlated with the clinical diagnosis of a GI-irAE. Histological alterations associated with ICI injury were more often identified in upper GI biopsies (71%) than in colonic biopsies (65%)., Conclusions: The morphological spectrum of ICI-related GI disease is broad, and mimics a range of infectious and inflammatory diseases. Gastric periglandular inflammation represents one of the more characteristic histological features of GI-irAEs. The study underscores the importance of a comprehensive review of upper and lower GI biopsies for the diagnosis of GI-irAEs., (© 2019 John Wiley & Sons Ltd.)

Objective: To explore the mechanism of miR-223-3p regulating the occurrence and development of liver cancer cells by targeting FAT1 gene. Methods: Bioinformatics analysis was used to analyze the differentially expressed genes in liver cancer tissue chips. Forty-eight cases of liver cancer tissues and corresponding adjacent tissues were selected, and qRT-PCR was used to detect the expression of miR-223-3p and FAT1mRNA in tissues. Wound healing assay was used to detect the migration ability of liver cancer cells. Transwell assay was used to detect cells invasion ability. Dual-luciferase assay was used to detect the targeting relationship between miR-223-3p and FAT1. Western blot was used to detect the protein expression of EMT-related markers, E-cadherin and Vimentin. Results: FAT1 was highly expressed in liver cancer tissues and cells, while miR-223-3p was lowly expressed. Silencing FAT1 could inhibite the proliferation, migration, invasion and EMT of liver cancer cells. miR-223-3p targeted down-regulated the expression of FAT1, and inhibited the proliferation, migration, invasion and EMT of liver cancer cells by targeting FAT1. Conclusion: miR-223-3p regulates the occurrence and development of liver cancer cells by targeted down-regulating the expression of FAT1.

Environmental estrogenic compounds are important pollutants, which are widely distributed in natural water bodies. They produce various adverse effects on fish, but their concentration-dependent toxicities in fish metabolism and health are not fully understood. This study investigated the effects of 17β-estradiol (E2) and bisphenol A (BPA) at low and high concentrations on lipid deposition, inflammation and antioxidant response in male zebrafish. We measured fish growth parameters, gonad development, lipid contents and the activities of inflammatory and antioxidant enzymes, as well as their mRNA expressions. All E2 and BPA concentrations used increased body weight, damaged gonad structure and induced feminization in male zebrafish. The exposure of zebrafish to E2 and BPA promoted lipid accumulation by increasing total fat, liver triglycerides and free fatty acid contents, and also upregulated lipogenic genes expression, although they decreased total cholesterol content. Notably, zebrafish exposed to low concentrations of E2 (200 ng/L) and BPA (100 μg/L) had higher lipid synthesis and deposition compared to high concentrations (2000 ng/L and 2000 μg/L, respectively). However, the high concentrations of E2 and BPA increased inflammation and antioxidant response. Furthermore, BPA caused greater damage to fish gonad development and more severe lipid peroxidation compared to E2. Overall, the results suggest that the toxic effects of E2 and BPA on zebrafish are concentration-dependent such that, the relative low concentrations used induced lipid deposition, whereas the high ones caused adverse effects on inflammation and antioxidant response., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Elucidating the closest living relatives of extant primates is essential for fully understanding important biological processes related to the genomic and phenotypic evolution of primates, especially of humans. However, the phylogenetic placement of these primate relatives remains controversial, with three primary hypotheses currently espoused based on morphological and molecular evidence. In the present study, we used two algorithms to analyze differently partitioned genomic datasets consisting of 45.4 Mb of conserved non-coding elements and 393 kb of concatenated coding sequences to test these hypotheses. We assessed different genomic histories and compared with other molecular studies found solid support for colugos being the closest living relatives of primates. Our phylogeny showed Cercopithecinae to have low levels of nucleotide divergence, especially for Papionini, and gibbons to have a high rate of divergence. The MCMCtree comprehensively updated divergence dates of early evolution of Primatomorpha and Primates.

Our aim is to assess the optimal cutoff value of fasting plasma glucose (FPG) in Chinese women at 24-28 weeks' gestation by performing oral glucose tolerance test (OGTT) to improve diagnostic rate of gestational diabetes mellitus (GDM). Data were derived from the Medical Birth Registry of Xiamen. A FPG cutoff value of 5.1 mmol/L confirmed the diagnosis of GDM in 4,794 (6.10%) pregnant women. However, a FPG cutoff value of 4.5 mmol/L should rule out the diagnosis of GDM in 35,932 (45.73%) pregnant women. If we use this cutoff value, the diagnosis of GDM to about 27.3% of pregnant women will be missed. Additionally, a 75-g OGTT was performed in pregnant women with FPG values between 4.5 and 5.1 mmol/L, avoiding the performance of formal 75-g OGTT in about 50.37% pregnant women. Meanwhile, according to maternal age and pre-pregnancy BMI categories, with FPG values between 4.5 mmol/L and 5.1 mmol/L, which had high sensitivity, to improve the diagnostic rate of GDM in all groups. Further researches are needed to present stronger evidences for the screening value of FPG in establishing the diagnosis of GDM in pregnant women.

Stressed oligodendrocytes (OLGs) activate microglia to produce an inflammatory response, and the impairment of mitochondria further aggravates OLG damage, which is the earliest pathological change in multiple sclerosis (MS), an inflammatory demyelinating disease of the central nervous system. Matrine (MAT), a tetracyclic quinolizine alkaloid derived from the herb radix sophorae flavescentis, has been shown to effectively ameliorate clinical signs of experimental autoimmune encephalomyelitis (EAE), an animal model of MS. However, the mechanisms underlying the effect of MAT treatment need to be further studied. In the present study, we show that MAT effectively suppressed ongoing EAE, and significantly reduced the expression of caspase-3 and alpha B-crystallin in OLGs, therefore lessen OLG apoptosis, microglial activation and inflammatory factors secretion. MAT treatment also reduced the content of cytochrome c and malondialdehyde, an oxidative stress marker, in the central nervous system. In contrast, the levels of autophagy-related proteins Beclin1, microtubule-associated protein l light chain 3 and glutathione peroxidase was upregulated, hence enhancing mitochondrial autophagy and alleviating the imbalance of the oxidation/antioxidation system caused by mitochondrial damage. Our research indicates that MAT is effective in treating EAE, at least in part, by protecting OLGs through inhibiting their apoptosis and enhancing mitochondrial autophagy., (Copyright © 2019. Published by Elsevier Inc.)

Osteosarcoma is a serious malignancy in pediatric patients, which comprises 2.4% of fatal cancer in children and achieves 20% of all primary bone cancers. In the present study, we employed three human osteosarcoma cell lines MG‑63, HOS and U2OS for susceptibility to cytolytic activity of freshly isolated healthy donor NK cells. Cells were lysed by NK cells in a dose dependent manner. MG‑63 cells exhibited less susceptibility to NK cells than HOS and U2OS cells at all cell ratios. The specific mechanism underlying the effects of NK cells on osteosarcoma cells was determined by antibody blockage experiments. The results revealed that granzyme B was the key factor in the NK cell‑induced cytotoxicity of human osteosarcoma cells. To the best of our knowledge, the present study is the first to investigate the expression of PD‑L1 in MG‑63, HOS and U2OS cells. The relative expression of the PD‑L1 gene and protein in MG‑63 cell was greater than HOS and U2OS cells. The specific lysis of human osteosarcoma cells induced by NK cells was enhanced when PD‑L1/PD‑1 was blocked by the PD‑L1 antibody. The present study proposed that the PD‑L1/PD‑1 axis serves an important role in NK cell‑induced cytotoxicity in osteosarcoma via granzyme B secretion. Our findings may contribute to the development of precise treatments for osteosarcoma based on the expression profile of PD‑L1 in patients with this disease.

Peroxisome proliferator-activated receptor α (PPARα) plays critical physiological roles in energy metabolism, antioxidation and immunity of mammals, however, these functions have not been fully understood in fish. In the present study, Nile tilapia (Oreochromis niloticus) were fed with fenofibrate, an agonist of PPARα, for six weeks, and subsequently challenged with Aeromonas hydrophila. The results showed that PPARα was efficiently activated by fenofibrate through increasing mRNA and protein expressions and protein dephosphorylation. PPARα activation increased significantly mitochondrial fatty acid β-oxidation efficiency, the copy number of mitochondrial DNA and expression of monoamine oxidase (MAO), a marker gene of mitochondria. Meanwhile, PPARα activation also increased significantly the expression of NADH dehydrogenase [ubiquinone] 1α subcomplex subunit 9 (NDUFA9, complex I) and mitochondrial cytochrome c oxidase 1 (MTCO1, complex IV). The fenofibrate-fed fish had higher survival rate when exposed to A. hydrophila. Moreover, the fenofibrate-fed fish also had higher activities of immune and antioxidative enzymes, and gene expressions of anti-inflammatory cytokines, while had lower expressions of pro-inflammatory cytokine genes. Taken together, PPARα activation improved the ability of Nile tilapia to resist A. hydrophila, mainly through enhancing mitochondrial fatty acids β-oxidation, immune and antioxidant capacities, as well as inhibiting inflammation. This is the first study showing the regulatory effects of PPARα activation on immune functions through increasing mitochondria-mediated energy supply in fish., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Autophagy is a conserved cellular degradation process through which intracellular components are degraded by the lysosome, but its roles in fish metabolism have not been studied in depth. Therefore, the present study aimed to investigate whether autophagy plays a key role in maintaining metabolic homeostasis in fish. In an 8-week feeding trial, Nile tilapia were fed either a control diet with medium fat and medium carbohydrate (Control), or a control diet supplemented with a classic autophagy inhibitor (chloroquine, CQ). CQ supplementation significantly inhibited autophagy and impaired fish growth and protein synthesis, and the glycolysis was stimulated, accompanied by fat accumulation, high oxidative stress and inflammation. Physiological status and gene expressions suggested that impaired autophagy might be at least one cause of the metabolic diseases which has been commonly seen in aquaculture. These results indicate that inhibition of autophagy could significantly affect the metabolism of lipid, carbohydrate and protein in fish; hence, autophagy could play important roles in maintaining homeostasis of nutrient metabolism in cultured fish., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Lysosomes generally maintain the weak acidic microenvironment, to ensure highly efficient activity and functions of hydrolytic enzymes and proteins. Aberrations of the lysosomal pH may result in cellular functional changes and influence human physiology, possibly causing serious diseases. Small-molecular fluorescent probes based imaging techniques capable of providing information on target locations are considerably appreciated. Herein, by reducing the size of the typical lysosome targetable group 4-(2-aminoethyl) morpholine, we rationally designed a rhodamine analogue probe Ly-HN2AM with N-Aminomorpholine as the ring-closed switch and the lysosome targetable moiety for visualizing lysosomal pH changes. With the benefit of constructing multi-pentacyclic intramolecular hydrogen bond when binding with the H + , Ly-HN2AM gives a highly sensitive response towards pH values ranging from 4.79 to 6.07, with a remarkable higher pK a 5.35 over the typical 4-(2-aminoethyl) morpholine modified probes. The new probe was successfully applied to visualize pH value changes in lysosome-associated physiological and pathological processes with excellent photostability and low cytotoxicity, indicating the potential applications of lysosome specific bioimaging., (Copyright © 2019 Elsevier B.V. All rights reserved.)

l-Carnitine is essential for mitochondrial β-oxidation and has been used as a lipid-lowering feed additive in humans and farmed animals. d-Carnitine is an optical isomer of l-carnitine and dl-carnitine has been widely used in animal feeds. However, the functional differences between l- and d-carnitine are difficult to study because of the endogenous l-carnitine background. In the present study, we developed a low-carnitine Nile tilapia model by treating fish with a carnitine synthesis inhibitor, and used this model to investigate the functional differences between l- and d-carnitine in nutrient metabolism in fish. l- or d-carnitine (0·4 g/kg diet) was fed to the low-carnitine tilapia for 6 weeks. l-Carnitine feeding increased the acyl-carnitine concentration from 3522 to 10 822 ng/g and alleviated the lipid deposition from 15·89 to 11·97 % in the liver of low-carnitine tilapia. However, as compared with l-carnitine group, d-carnitine feeding reduced the acyl-carnitine concentration from 10 822 to 5482 ng/g, and increased lipid deposition from 11·97 to 20·21 % and the mRNA expression of the genes involved in β-oxidation and detoxification in the liver. d-Carnitine feeding also induced hepatic inflammation, oxidative stress and apoptosis. A metabolomic investigation further showed that d-carnitine feeding increased glycolysis, protein metabolism and activity of the tricarboxylic acid cycle and oxidative phosphorylation. Thus, l-carnitine can be physiologically utilised in fish, whereas d-carnitine is metabolised as a xenobiotic and induces lipotoxicity. d-Carnitine-fed fish demonstrates increases in peroxisomal β-oxidation, glycolysis and amino acid degradation to maintain energy homeostasis. Therefore, d-carnitine is not recommended for use in farmed animals.

Guanine (G) quadruplexes (G4s) can be formed by G-rich sequences when stabilized by the binding of cations (typically K + or Na + ) and play an essential role in replication, recombination, transcription, and telomere maintenance. Understanding of the G4 folding process is crucial for determining their cellular functions. However, G4-K + interactions and folding pathways are still not well understood. By using human telomeric G4 (hTG4) as an example, two binding states corresponding to two K + cations binding to hTG4 were distinguished clearly and fitted precisely. The basic binding parameters during G4-K + interactions were measured and calculated by taking advantage of microscale thermophoresis (MST), which monitors the changes in charge and size at the same time. The G-hairpin and G-triplex have been suggested as intermediates during G4 folding and unfolding. We further analyzed the equilibrium dissociation constants of 10 possible folding intermediates using MST; thus, the energetically favorable folding/unfolding pathways were proposed. The results might not only shed new light on G4-K + interactions and G4 folding pathways but also provide an example for experimentally studying DNA-ion interactions.

Cold stress is a major threat to fish in both nature and aquaculture, and can induce oxidative stress in various fish. While the exact role of oxidative stress in cold-caused mortality is still unknown. The purpose of the present study was to evaluate the effects of oxidative stress on cold tolerance in fish and verify whether changing oxidative status could affect cold tolerance. We firstly demonstrated that acute cold exposure induced high oxidative stress in zebrafish liver, which may lead to mortality. Then we performed in vivo and in vitro experiments to determine the effects of the altered oxidative status on cold tolerance in zebrafish and zebrafish liver cell line (ZFL), respectively. In the in vivo study, the zebrafish which were fed with α-lipoic acid or reduced glutathione had lower cold-caused oxidative stress and tissues damage, and showed higher cold tolerance. In the experiment using zebrafish cells, increasing oxidative stress by H 2 O 2 decreased the cellular cold tolerance, and the cold tolerance was partly recovered when oxidative stress was reduced by the addition of Vitamin C (VC). Taken together, we conclude that the reduction of oxidative stress increases cold tolerance in fish., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Antibiotics and high fat diets are commonly used independently in global aquaculture production for fish health management and to spare the use of costly protein as energy sources, respectively, causing relatively similar metabolic effects and stresses. However, it is unknown whether dietary high fat worsens or attenuates the adverse effects caused by antibiotics in fish. We determined the ability of high fat diet to influence the adverse effects of oxytetracycline on Nile tilapia, Oreochromis niloticus. Thirty Nile tilapia weighing 8.45 ± 0.15 g were fed on medium fat (MF; 70 g/kg) and high fat (HF; 120 g/kg) diets and the same fat levels supplemented with 2.00 g/kg diet of OTC (80 mg/kg body weight/day) hereafter, MFO and HFO for 65 days. The general growth performance, feed efficiency and intestinal health of fish were evaluated. The Nile tilapia fed on HFO diet had significantly lower growth rate, body protein content and feed efficiency compared to those fed on MFO diet. Dietary HFO affected the intestine histomorphology, which decreased dramatically the tight junction proteins of Nile tilapia and induced microbiota dysbiosis compared to MFO diet. The Nile tilapia fed on HFO diet had increased oxidative stress, which stimulated drug detoxification response, caused endoplasmic reticulum stress and apoptosis compared to those fed on MFO diet. The new findings from our study demonstrate that, the adverse effects of antibiotics in fish are different at medium and high fat contents. Feeding fish with high fat diets with antibiotics worsen the adverse effects. This enlightens our understanding on the risks of antibiotics misuse and also suggests that antibiotics should be more strictly limited in aquaculture, in which high fat diets are currently widely used in fish production worldwide., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Lipophagy degrades lipid droplets (LDs) through the lysosomal degradative pathway, thus plays important roles in regulating lipid metabolism in mammals. However, information on the existence and functions of lipophagy in fish lipid metabolism is still limited. In the present study, we confirmed the existence of lipophagy by observing the structures of LDs sequestered in autophagic vacuoles in the zebrafish liver cell line (ZFL) via electronic microscopy. Moreover, starved cells increased the mRNA expression of the microtubule-associated protein 1A/1B light chain 3 beta ( LC3 ), which is a marker protein for autophagy and protein conversion from LC3-I to LC3-II. Inhibiting autophagy with chloroquine increased significantly the LDs content and decreased fatty acid β-oxidation and esterification activities in the ZFL cells cultured in the fed state. Furthermore, inhibiting autophagy function downregulated the mRNA expression of the genes and their proteins related to lipid metabolism. Altogether, the present study verified the existence of lipophagy and its essential regulatory roles in lipid metabolism in fish cells.

Emerging evidence revealed that thyroglobulin (TG) contributes to the development of autoimmune disease, and the relationship between TG and autoimmune thyroid disease (AITD) is still controversial. The aim of this study was to quantify the association between rs2076740, rs853326, rs180223, and rs2069550 TG polymorphisms and risk of AITD using a meta-analysis approach. We identified all studies that assessed the association between TG polymorphisms and AITD from PubMed, Embase, and Web of Science databases. A total of 3013 cases and 1812 controls from ten case-control studies were included. There was no significant associations found between rs2069550, rs180223, and rs853326 polymorphisms and AITD risk. The association between the rs2076740 polymorphism and AITD risk was significant in the codominant model (P = 0.005), suggesting the CC rs2076740 genotype might be a protective factor for AITD. Sensitivity analysis by removing one or two study changed the results in dominant rs2076740 and rs853326 and rs2069550 allele models (P = 0.016, 0.024, 0.027). Latitude and ethnicity significantly affected the association between rs2076740 and rs2069550 polymorphisms and AITD, indicating their protective effects in allele or dominant model (P = 0.012, 0.012, 0.012, 0.009, 0.009). The association between rs2076740, rs2069550, and rs853326 polymorphisms and AITD risk is significantly affected by study characteristics.

The mixed hexa-transition metal (hexa-TM) sandwiched arsenotungstate derivative, [Cu I 3 (pz) 2 (phen) 3 ] 2 [Cu I (phen) 2 ][{Na(H 2 O) 2 }{(V IV 5 Cu II O 6 )(As III W 9 O 33 ) 2 }]·6H 2 O (1) (pz = pyrazine; phen = 1,10-phenanthroline), has been hydrothermally synthesized and structurally characterized. In compound 1, two {AsW 9 O 33 } clusters are connected by mixed hexa-TM ring unit {V VI 5 Cu II O 6 } to form a sandwich-type dimer, which are further bonded in "ABAB" mode by the {Na(H 2 O) 2 } linker resulting in pure inorganic chains. The unique "L-shaped" trinuclear complex {Cu 3 (phen) 3 (pz) 2 } is supported together via staggered π-π interactions to generate extending waveform two-dimensional supramolecular layers, which are further aggregated with their adjacent analogues by complexes {Cu(phen) 2 } via H-bonding interaction to yield an unprecedented three-dimensional (3D) metal-organic networks with one-dimensional (1D) cavities. The pure inorganic 1D sandwich chains are implanted in the cavities as guest units via supramolecular interactions to form a POMOF 3D framework. Compound 1, as the electrode of the supercapacitor, exhibits higher specific capacitances (825 F g -1 at a current density of 2.4 A g -1 ), better rate capability, more durable cyclic stability (91.4% of cycle efficiency after 3000 cycles), and improved conductivity and electroactivity compared to those of parent polyoxometalate (POM) Na 9 [AsW 9 O 33 ]·19H 2 O (2) and 6-Cu-substituted POM [Cu 6 (imi) 6 {As III W 9 O 30 Cl 3 } 2 ]·6H 2 O (3), which may be attributed to the introduction of V 4+ , the unique host-guest structure, and the rich π electron system. In addition, compound 1 exhibits dual-function electrocatalytic behavior in reducing inorganic salt IO 3 - and oxidizing the organic molecule dopamine.

Purpose: The purpose of this work was to establish a map model of the local recurrence location after pancreatic cancer resection and to generate a new delineation method of clinical target volume, with the aim to effectively improve the adjuvant radiotherapeutic gain ratio., Methods and Materials: The clinical and imaging data of 48 patients with resected pancreatic head cancer and pancreatic body cancer with local recurrences were collected. Local recurrences were all plotted with reference to the geometric centre of the local recurrent foci. Based on the coordinates of the local recurrences with respect to the celiac artery or the superior mesenteric artery, a three-dimensional local recurrence map model was established on the computed tomography image. The adjuvant radiation clinical target volumes encompassing 90% of all local failures and encompassing 90% of postoperative pancreatic head cancer local failures were created respectively. This new delineation method and RTOG 0848 protocol were applied in five simulated cases, then corresponding types of target volumes and plans were generated for comparison., Results: The clinical target volume encompassing 90% of all local failures was generated by expanding the combined celiac artery and superior mesenteric artery contour by 1.4cm superior, 1.9cm inferior, 2.6cm left-lateral, 3.1cm right-lateral, 1.9cm anterior and 1.6cm posterior. The corresponding expansions of clinical target volume encompassing 90% of postoperative pancreatic head cancer local failures were 1.4cm, 1.4cm, 2.1cm, 3.1cm, 1.6cm and 2.0cm. The volumes of "new" target PTV-90&#95;edited, PTV-90&#95;H&#95;edited, and the standard target PTV&#95;edited were 217.64±58.67 cm 3 , 207.78±50.94 cm 3 and 320.72±50.94 cm 3 in simulated cases. Comparison showed that the "new" target volumes were much smaller than the standard volumes per RTOG 0848 protocol, and the dose received by organs at risk was also lower in the "new" plans., Conclusions: A majority of postoperative local recurrences in patients with pancreatic head and body cancer are contained within a smaller region surrounding the celiac artery and superior mesenteric artery. The "new" volumes targeting high risk local failures may allow dose escalation and enhanced local control while minimizing radiation-related toxicity., (Copyright © 2019 Société française de radiothérapie oncologique (SFRO). Published by Elsevier Masson SAS. All rights reserved.)

Objective: To investigate the short-term therapeutic efficacy, survival time and side effects in newly diagnosed multiple myeloma patients treated with TCD regimen consisted of thalidomide, cyclophosphiamide and dexamethasone, and BCD reginen consisted of bortezomib, cyclophsphamide and dexamethasone., Methods: The clinical data of newly diagnosed MM patients admitted in our hospital from January 2011 to January 2018 were collected and analyzed retrospectively. According to chemotherapectic regimen, 106 patients were divided into 2 groups: 53 cases in one group were treated with TCD regimen (TCD group), and 53 cases in another group were treaded with BCD regimen (BCD group). The therapeutic efficacy, median PFS and OS time and incidence of side effects in 2 groups were compared, at the same time the relationship of the remission degree and the factors in different subgroups with the therapeutic efficacy was analyzed in 2 groups., Results: There was no significant difference in the ≥MR rate between 2 groups (P＞0.05). The ≥PR rate, ≥VGPR rate and CR rate of BCD group were significantly higher than TCD group (P＜0.05). The median PFS time of patients in BCD group were significantly longer than that in TCD group (P＜0.05). There was no significant difference in the median OS time of patients between 2 groups (P＜0.05). The median OS time of ≥MR patients in TCD group was significantly longer than that of ＜MR patients (P＜0.05). The median OS time of ≥PR patients in TCD group were significantly longer than that of ＜PR patients (P＜0.05). The median OS time of ≥VGPR patients in BCD group was significantly longer than that of ＜VGPR patients (P＜0.05). There was no significant difference in the median OS time of ≥PR and ＜PR patients in BCD group (P＞0.05). The ORR of ≥VGPR patients in BCD group was significantly higher than that in TCD group (P＜0.05). There was no significant difference in the incidence of infection, fatigue, gastrointestinal reactions and bone marrow suppression between 2 groups (P＜0.05). The incidence of numbness in distal extremities and herpes zoster in BCD group was significantly higher than that in TCD group (P＜0.05)., Conclusion: TCD and BCD in the treatment of patients with NDMM possess the same disease control effects; BCD regimen application can efficiently improve remission degree and prolong PFS time; but TCD regimen application have the advantages in reducing the side effects risk and improving treatment tolerance.

Major depressive disorder (MDD) is a recurrent, chronic mental illness. While music therapy has been established as an effective treatment for MDD patients, the effects of this therapy on brain function remain unclear. This research employed near-infrared spectroscopy (NIRS) to explore the effects of music therapy on brain activity in mild or moderate MDD patients and to illustrate the potential mechanism of music therapy. Methods: Fifteen MDD patients and fifteen healthy controls (HC) underwent neuropsychological evaluations and NIRS measurements. All participants were treated with continuous music therapy for 10 days. Subsequently, all individuals were evaluated with neuropsychological assessments and NIRS measurements again. Results: The verbal fluency task (VFT) performances of the participants yielded significantly higher scores after music therapy in terms of vegetables, four-footed animals and fruit blocks. After the music treatment, the NIRS data showed that the mean active oxy-Hb values of channels 21, 23, 19, and 41 were significantly increased in both the MDD and HC groups. The MDD group showed significant activation in the dorsolateral prefrontal cortex (DLPFC), orbitofrontal cortex (OFC) and ventromedial prefrontal cortex (VMPFC) after music therapy. The results indicate that music therapy could improve the brain function of MDD patients., (Copyright © 2019. Published by Elsevier B.V.)

We synthesized the scientific research carried out in Changbai Mountain from 1956 to 2018 by mapping knowledge domains and bibliometrics based on the literature from international database (WOS) and domestic databases (CNKI and CSCD). The results showed that natural science research in Changbai Mountain underwent three stages during 1956-2018, including embryo stage, growing stage, and rapid development stage. The natural research in Changbai Mountain could be divided into five fields, i.e., forest and ecological science, volcano and geology science, environmental change science, resource sciences and utilization, animal and microbial science, with a total of 20 main research directions. Since 2000, forest and ecological science, volcano and geological science, environmental change science dominated the natural science research in Changbai Mountain. The researches in recent 20 years mainly concentrated on the following seven disciplines: community ecology, forest management, soil ecology, ecosystem ecology, eco-climatology, forest responses to environmental change, and volcanic geology. International researches showed a trend of strong integration of different disciplines. We forecast that the natural science research in the Changbai Mountain would deepen its research in the next decade. Moreover, other fields such as old-growth forest and large-scale ecosystem carbon processes, forest-altitude-climate change, soil fauna and microorganisms, forest management and human activities, biodiversity, volcanic origin and eruption history, volcanic eruption dynamics and volcanic monitoring will emerge as the new research focus. Scale polarization, elements diversification, discipline crossing, and research deepening would be the future trend of natural science research in Changbai Mountain.