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Background Maternal Toxoplasma gondii (T. gondii) infection during pregnancy has been associated with various mental illnesses in the offspring. Ginsenoside Rh2 (GRh2) is a major bioactive compound obtained from ginseng that has an anti-T. gondii effect and attenuates microglial activation through toll-like receptor 4 (TLR4)/nuclear factor-kappa B (NF-κB) signaling pathway. GRh2 also alleviated tumor-associated or lipopolysaccharide-induced depression. However, the effects and potential mechanisms of GRh2 on depression-like behavior in mouse offspring caused by maternal T. gondii infection during pregnancy have not been investigated. Methods We examined GRh2 effects on the depression-like behavior in mouse offspring, caused by maternal T. gondii infection during pregnancy, by measuring depression-like behaviors and assaying parameters at the neuronal and molecular level. Results We showed that GRh2 significantly improved behavioral measures: sucrose consumption, forced swim time and tail suspended immobility time of their offspring. These corresponded with increased tissue concentrations of 5-hydroxytryptamine and dopamine, and attenuated indoleamine 2,3-dioxygenase or enhanced tyrosine hydroxylase expression in the prefrontal cortex. GRh2 ameliorated neuronal damage in the prefrontal cortex. Molecular docking results revealed that GRh2 binds strongly to both TLR4 and high mobility group box 1 (HMGB1). Conclusion This study demonstrated that GRh2 ameliorated the depression-like behavior in mouse offspring of maternal T. gondii infection during pregnancy by attenuating the excessive activation of microglia and neuroinflammation through the HMGB1/TLR4/NF-κB signaling pathway. It suggests that GRh2 could be considered a potential therapy in preventing and treating psychiatric disorders in the offspring mice of mothers with prenatal exposure to T. gondii infection., Graphical abstract Image 1

The functionality of DNA biomacromolecules has been widely excavated, as therapeutic drugs, carriers, and functionalized modification derivatives. In this study, we developed a series of DNA tetrahedron nanocages (Td), via synchronous conjugating different numbers of i-(X) and therapeutic siRNA on four vertexes of tetrahedral DNA nanocage (aX-Td@bsiRNA, a+b = 4). This i-motif-conjugated Td exhibited good endosomal escape behaviours in A549 tumor cells, and the escape efficiency was affected by the number of i-motif. Furthermore, the downregulating mRNA and protein expression level of epidermal growth factor receptor (EGFR) caused by this siRNA embedded Td were verified in A549 cells. The tumor growth inhibition efficiency of the 2X-Td@2siRNA treated group in tumor-bearing mice was significantly higher than that of non-i-motif-conjugated Td@2siRNA (3.14-fold) and free siRNA (3.63-fold). These results demonstrate a general strategy for endowing DNA nanostructures with endosomal escape behaviours to achieve effective in vivo gene delivery and therapy., Graphical abstract siRNA-loaded DNA tetrahedron nanocages escape from the endosomal degradation and successfully interfere in gene and protein expression level of EGFR in tumor cells.Image 1

Ling Yu,1,* Yang Chen,2,* Xiang Xu,2 Qiwei Dong,2,3 Wenbo Xiu,2 Qinyuan Chen,2 Jinxia Wang,2 Chong He,2,3 Jian Ye,1 Fang Lu2,3 1Department of Ophthalmology, Daping Hospital, Army Medical Center, Army Medical University, Chongqing, People’s Republic of China; 2Clinical Immunology Translational Medicine Key Laboratory of Sichuan Province, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, People’s Republic of China; 3Medico-Engineering Cooperation on Applied Medicine Research Center, University of Electronic Science and Technology of China, Chengdu, People’s Republic of China*These authors contributed equally to this workCorrespondence: Fang LuClinical Immunology Translational Medicine Key Laboratory of Sichuan Province, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, 32 The First Ring Road West 2, Chengdu, Sichuan, 610072, People’s Republic of ChinaTel/Fax +86-028-87394201Email lufangfang@126.comJian YeDepartment of Ophthalmology, Daping Hospital, Army Medical Center, Army Medical University, No. 10, Changjiang Branch, Daping, Yuzhong District, Chongqing, 400042, People’s Republic of ChinaTel/Fax +86-023-68811229Email yejian1979@163.comBackground: Glaucoma is a group of retinal neurodegenerative diseases causing irreversible visual impairment. The pathogenesis of this disease is complicated. Studies have shown that the immune system is involved in the neurodegenerative process of glaucoma. There are continuous evidences that autoantibodies play a crucial role in the pathogenesis of glaucoma. However, focuses on B cells, the antibody-producing cells in glaucoma are surprisingly limited.Methods: Fresh peripheral blood samples were collected from 44 glaucoma patients (38 with primary angle-closure glaucoma (PACG) and 6 with (primary open-angle glaucoma POAG)) and 36 age-matched healthy donors (HD). Density gradient centrifugation was performed to obtain peripheral blood mononuclear cells (PBMC). Flow cytometry was performed to determine B cell phenotypes. The severity of glaucoma was determined based on the mean deviation (MD) of visual field.Results: In this study, we demonstrated that total B cells was significantly increased in glaucoma patients compared to HD. Next, we checked changes of different B cell subsets in glaucoma. Glaucoma patients were found to have a significant increase in the frequencies of antibody-secreting cells (ASC)/plasmablasts, naïve, and CD19+ CD27− IgD− double negative (DN) subpopulations, but a decrease in the CD27+ IgD+ unswitched memory compartment. Notably, we found that the increment of CD27− IgD− DN B cells was significantly magnified according to the clinical severity.Conclusion: We demonstrate, for the first time, that peripheral B cell subsets are altered and unveil the correlation of a newly identified pro-inflammatory CD27− IgD− DN subset with clinical features of glaucoma, suggesting that these B cell subsets could serve as potential biomarkers to monitor the disease progression of glaucoma patients.Keywords: glaucoma, B cells, CD27− IgD− double negative B cells, retinal neurodegeneration

Xiang Xu,1,* Qiwei Dong,1,* Qingling Zhong,2 Wenbo Xiu,1,2 Qinyuan Chen,1,2 Jinxia Wang,1 Zhou Zhou1,2 1Clinical Immunology Translational Medicine Key Laboratory of Sichuan Province, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, People’s Republic of China; 2Department of Gastroenterology and Hepatology, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, People’s Republic of China*These authors contributed equally to this workCorrespondence: Zhou ZhouClinical Immunology Translational Medicine Key Laboratory of Sichuan Province, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, People’s Republic of ChinaTel +86-028-87394201Fax +86-028-87394201Email doublezhou2006@126.comBackground: Irritable bowel syndrome (IBS) is characterized with abdominal pain, bloating, and changes in bowel habits, and dealing with IBS is still a clinical challenge. The pathogenesis of IBS has been reported to be linked to low-grade mucosal inflammation, and macrophages contribute to the pathological process of this disease. Kurarinone (KAR), a flavanoid derived from Sophora flavescens, has been found medically effective in many inflammatory conditions and cancers. KAR was previously reported to inhibit LPS-induced expression of inflammatory cytokines in macrophages, whether and how KAR regulates the functions of macrophage in IBS remains to be elusive.Methods: We established a TNBS-induced IBS mouse model, in which KAR was administrated, and mucosal cytokine expression was measured by qRT-PCR. Additionally, mouse macrophages were generated in vitro and their responses to LPS were evaluated by flow cytometry and qRT-PCR. AhR+/+ or AhR−/- macrophages were transferred into DTx-treated CD11b-DTR transgenic mice to investigate the role of AhR in IBS. We collected colonic biopsies and peripheral blood samples from 64 patients with IBS, and analyzed AhR expression by qRT-PCR.Results: We found KAR effectively alleviated visceral hypersensitivity and maintained intestinal barrier functions in mice with IBS. KAR inhibited LPS-induced macrophage activation and expression of pro-inflammatory genes, while increased anti-inflammatory gene expression including IL-10 in an AhR-dependent manner. Using macrophage-depleted mice, we found that chimera mice with AhR−/- macrophages were more susceptible to TNBS-induced IBS and the therapeutic effect of KAR on IBS was significantly impaired in mice with AhR−/- macrophages. Additionally, we found AhR expression in macrophages of IBS patients was associated with the disease severity.Conclusion: Our findings provide new evidences that KAR regulates IBS development via macrophage-intrinsic AhR. KAR might show promise as an immunomodulatory therapeutic agent in treating IBS.Keywords: aryl hydrocarbon receptor, irritable bowel syndrome, macrophage, kurarinone, flavonoid

Five new species of mimetid spiders from China are described: Mimetus subulatus n. sp., M. clavatus n. sp., M. dentatus n. sp., M. niveosignatus n. sp. and M. uncatus n. sp. The phylogenetic placement of these new species is inferred based on a cladistic analysis of an expanded version of the morphological dataset of Benavides and Hormiga (2020). The new species form a clade that can be distinguished from other Mimetus species by the presence of a subtegular apophysis between paracymbium and subtegulum, pilose cuticular projections on the membranous part of the conductor in the male palp and by a bicameral structure of the spermathecae in females. The new species are part of a clade that includes Mimetus syllepsicus Hentz, 1832, the type species of the genus. The genus Mimetus as currently circumscribed is not monophyletic, as the clade that includes all the Mimetus species also includes the genera Australomimetus Heimer, 1986 and Anansi Benavides and Hormiga, 2017, corroborating the results of Benavides and Hormiga (2020).

Wolbachia are maternally inherited endosymbiotic bacteria. These intracellular bacteria are common in arthropods and could manipulate host reproduction in diverse ways, such as feminization, parthenogenesis, male killing and cytoplasmic incompatibility. In spiders, infection by Wolbachia has been found in a total of 99 species belonging to 62 genera and 17 families. Furthermore, recent studies analyzed the phylogeny of Wolbachia in Hylyphantes graminicola, 2 cave spiders and Agelenopsis species using multilocus sequence typing (MLST) approach. However, the diversity of Wolbachia strains determined by MLST in spiders from China is still largely unknown. In this study, we collected 1153 spider individuals from Mangshan in China and screened for Wolbachia in 975 individuals representing 68 spider species belonging to 45 genera of 16 families. We analyzed the phylogenetic relationship between Wolbachia and their host spiders by MLST approach. We found novel infections of Wolbachia in 1 family, 9 genera and 20 species of spiders. We found 13 new Wolbachia strains and suggest that group A is more common than group B in Wolbachia that infect spiders. Our results revealed three recombination events of the concatenated multilocus sequences in Wolbachia that infect spiders. Furthermore, our results demonstrated the phylogenetic incongruence between Wolbachia and spiders, suggesting the horizontal transmission of Wolbachia in spiders. We suggest that recombination and horizontal transmission may play an important role in the diversity and evolution of Wolbachia in spiders.

Interleukin-26 (IL-26), a recently identified cytokine of the IL-20 subfamily, plays an important role in the regulation of host defense and inflammatory diseases. However, whether the role of IL-26 in the progression of hepatocellular carcinoma (HCC) occurs via autophagy remains unclear. Here, we investigated the IL-26 levels in the blood and tissues of subjects, its possible cellular source and its relationship with the prognosis of HCC patients. We also explored the mechanisms by which different pathophysiological levels of IL-26 affect the outcomes of patients; these studies were conducted only in vitro due to the lack of IL-26 gene expression in rodents. We found that IL-26 was highly expressed in HCC patients and was mainly derived from tumor-associated macrophages. Furthermore, we found that high expression of IL-26 was associated with good prognosis due to its inhibition of HCC cell migration and invasion abilities. This function of IL-26 was driven by JAK-STAT3-dependent autophagy. These findings suggest that the levels of IL-26 may be a useful prognostic marker for HCC patients and may offer insights into the clinical application of IL-26 in the future.

Based on the data of cores, thin sections, well logs, and test experiments, the characteristics and main controlling factors of lamellation fractures in continental shales of the third and fourth members of the Paleogene Qianjiang Formation in the Qianjiang Depression, Jianghan Basin, are studied. Lamellation fractures mainly develop along laminas in shales. They have various morphological characteristics such as straightness, bending, discontinuity, bifurcation, pinching out, and merging. Lamellation fractures with high density show poor horizontal continuity and connectivity characteristics. The average linear density of the lamellation fractures is mainly between 20 m-1 and 110 m-1, and the aperture is usually less than 160 μm. The density of lamellation fractures is related to their apertures. The smaller the apertures of lamellation fractures are, the higher the density is. The development degree of lamellation fractures is mainly controlled by mineral composition, type, thickness, density of lamination, contents of organic matter and pyrite, lithofacies, structural position, etc. Lamellation fractures develop well, especially under the conditions of medium dolomite content, large lamination density, small lamination thickness, and high total organic carbon (TOC) and pyrite contents. The influences of lithofacies on the lamellation fractures are complex. The lamellation fractures are most developed in carbonaceous layered limestone dolomite and carbonaceous layered dolomite mudstone, followed by stromatolite dolomite filled with carbonaceous pyroxene. The fractures in the massive argillaceous dolomites and carbonaceous massive mudstones are poorly developed. No fractures can be found in the carbonaceous dolomitic, argillaceous glauberites or salt rocks with high glauberite content. Structure is also an important factor controlling lamination fractures. Tectonic uplifts are beneficial to the expansion and extension of lamellation fractures, which increases fracture density. Therefore, when other influence factors are similar, lamellation fractures develop better in the high part of the structure than in the low part.

Neutrophil extracellular DNA traps (NETs) are newly discovered forms of activated neutrophils. Increasing researches have shown that NETs play important roles in cancer progression. Our previous study has proved that tumour‐infiltrating NETs could predict postsurgical survival in patients with pancreatic ductal adenocarcinoma (PDAC). However, the roles of NETs on the progression of pancreatic cancer are unknown. Here, we investigated the effects of NETs on pancreatic cancer cells. Results showed that both PDAC patients’ and normal individuals’ neutrophils‐derived NETs could promote migration and invasion of pancreatic cancer cells with epithelial‐mesenchymal transition. Further, study confirmed that EGFR/ERK pathway played an important role in this progression. The addition of neutralizing antibodies for IL‐1β could effectively block the activation of EGFR/ERK companied with reduction of EMT, migration and invasion. Taken together, NETs facilitated EMT, migration and invasion via IL‐1β/EGFR/ERK pathway in pancreatic cancer cells. Our study suggests that NETs may provide promising therapeutic targets for pancreatic cancer.

Variants in the melanocortin-1 receptor (MC1R) gene, encoding a trimeric G-protein-coupled receptor and activated by α-melanocyte-stimulating hormone (α-MSH), are frequently associated with red or blonde hair, fair skin, freckling, and skin sensitivity to ultraviolet (UV) light. Several red hair color variants of MC1R are also associated with increased melanoma risk. MC1R variants affect melanoma risk independent of phenotype. Here, we demonstrated that MC1R is a critical factor in chromosome stability and centromere integrity in melanocytes. α-MSH/MC1R stimulation prevents melanocytes from UV radiation-induced damage of chromosome stability and centromere integrity. Mechanistic studies indicated that α-MSH/MC1R-controlled chromosome stability and centromeric integrity are mediated by microphthalmia-associated transcription factor (Mitf), a transcript factor needed for the α-MSH/MC1R signaling and a regulator in melanocyte development, viability, and pigment production. Mitf directly interacts with centromere proteins A in melanocytes. Given the connection among MC1R variants, red hair/fair skin phenotype, and melanoma development, these studies will help answer a question with clinical relevance “why red-haired individuals are so prone to developing melanoma”, and will lead to the identification of novel preventive and therapeutic strategies for melanomas, especially those with redheads.

Presbycusis is the cumulative effect of aging on hearing. Recent studies have shown that common mitochondrial gene deletions are closely related to deafness caused by degenerative changes in the auditory system, and some of these nuclear factors are proposed to participate in the regulation of mitochondrial function. However, the detailed mechanisms involved in age-related degeneration of the auditory systems have not yet been fully elucidated. In this study, we found that FOXG1 plays an important role in the auditory degeneration process through regulation of macroautophagy/autophagy. Inhibition of FOXG1 decreased the autophagy activity and led to the accumulation of reactive oxygen species and subsequent apoptosis of cochlear hair cells. Recent clinical studies have found that aspirin plays important roles in the prevention and treatment of various diseases by regulating autophagy and mitochondria function. In this study, we found that aspirin increased the expression of FOXG1, which further activated autophagy and reduced the production of reactive oxygen species and inhibited apoptosis, and thus promoted the survival of mimetic aging HCs and HC-like OC-1 cells. This study demonstrates the regulatory function of the FOXG1 transcription factor through the autophagy pathway during hair cell degeneration in presbycusis, and it provides a new molecular approach for the treatment of age-related hearing loss. Abbreviations: AHL: age-related hearing loss; baf: bafilomycin A1; CD: common deletion; D-gal: D-galactose; GO: glucose oxidase; HC: hair cells; mtDNA: mitochondrial DNA; RAP: rapamycin; ROS: reactive oxygen species; TMRE: tetramethylrhodamine, ethyl ester

Four new species are described from Jinggang Mountain National Nature Reserve, Jiangxi Province of southern China: Draconarius lingdangsp. nov. (♂♀), D. substrophadatussp. nov. (♀), Orumcekia cipingensissp. nov. (♀) and Tonsilla shuikouensissp. nov. (♀). Additionally, Coelotes septus Wang, Yin, Peng & Xie, 1990 is redescribed and its male is described for the first time.

A new species of Fomitiporia, F. tasmanica, is described from Tasmania (Australia) based on morphological examination and phylogenetic analysis of the nuc rDNA region encompassing the internal transcribed spacers 1 and 2, along with the 5.8S rDNA and nuc 28S rDNA D1-D2 domains. The new species is characterized by perennial, resupinate basidiocarps, very small pores (10–12 per mm), a dimitic hyphal system, presence of hymenial setae and cystidioles, and subglobose basidiospores measuring 5.5–6.6 × 5–6 µm.

Objective:. Acne inversa is a multifactorial chronic debilitating disease. Genetic factors are involved in 40% of patients, especially the nicastrin (NCSTN) gene. However, the role of the mutated NCSTN gene in the pathogenesis of acne inversa remains unclear. Retinoic acid is recommends to treat moderate to severe acne inversa, therefor we conduct this in vitro research to study the association between NCSTN gene mutation and the retinoic acid signaling pathway in human immortalized skin keratinocyte (HaCaT) cells. Methods:. HaCaT cells were infected with a lentivirus-mediated short hairpin RNA (shRNA) expression plasmid specifically targeting the NCSTN gene. Real-time polymerase chain reaction (PCR) and Western blotting were used to detect the interference efficiency of NCSTN. RNA sequencing was used to detect differential genes in the NSCTN-deficient HaCaT cells. Based on bioinformatics analysis and clinical treatment data, the retinoic acid signal pathway was selected for screening. Quantitative PCR was used to verify the changes in the expressions of retinoic acid signaling pathway-related receptors and molecules in the HaCaT cell line after NCSTN silencing. The Student t test and one-way analysis of variance were used to evaluate intergroup differences. Results:. Sequencing showed that the NCSTN-shRNA lentiviral recombinant expression plasmid was successfully constructed. After lentivirus infection of HaCaT cells, real-time PCR results showed significantly reduced NCSTN mRNA expression in the interference group compared with the negative control group, and the interference efficiency was 75.0%. Western blotting showed that the inhibition rate of NCSTN protein expression in the shRNA group was 71.7%. RNA sequencing revealed significant differential expression of some genes, and changes in signaling pathways. Compared with the control group, the group with the silenced NCSTN showed significantly decreased expression of retinoic acid receptors (RARα: F=23.482, RARβ: F=603.241, RXRα: F=69.689, and RARRES1: F=167.482, and all P

Di-(2-ethylhexyl) phthalate (DEHP) is a male reproductive toxicant. This research is aimed at investigating the effect of pubertal DEHP exposure on testicular endoplasmic reticulum (ER) stress and germ cell apoptosis. Five-week-old male mice were orally administered with DEHP (0, 0.5, 50, or 500 mg/kg/day) for 35 days. Testis weight and sperm count were reduced in mice exposed to 500 mg/kg/day DEHP. The number of seminiferous tubules in stages VII-VIII, mature seminiferous tubules, was reduced and the number of seminiferous tubules in stages IX-XII, immature seminiferous tubules, was elevated in mice treated with 500 mg/kg/day DEHP. Numerous apoptotic germ cells were observed in mouse seminiferous tubules exposed to 50 and 500 mg/kg/day DEHP. Moreover, cleaved caspase-3 was elevated in mouse testes exposed to 500 mg/kg/day DEHP. In addition, Bcl-2 was reduced and Bax/Bcl-2 was elevated in mouse testes exposed to 500 mg/kg/day DEHP. Additional experiment showed that GRP78, an ER molecular chaperone, was downregulated in mouse testes exposed to 500 mg/kg/day DEHP. Testicular p-IRE-1α, p-JNK, and CHOP, three markers of ER stress, were upregulated in mice exposed to 500 mg/kg/day DEHP. These results suggest that pubertal exposure to high doses of DEHP induces germ cell apoptosis partially through initiating ER stress in testes.

Chronic inflammation-induced metastases have long been regarded as one of the significant obstacles in treating cancer. Tumor necrosis factor-α (TNF-α), a main inflammation mediator within tumor microenvironment, affects tumor development by inducing multiple chemokines to establish a complex network. Recent reports have revealed that CXCL10/CXCR3 axis affects cancer cells invasiveness and metastases, and Epithelial-mesenchymal transition (EMT) is the main reason for frequent proliferation and distant organ metastases of colon cancer (CC) cells, However, it is unclear whether TNF-α- mediated chronic inflammation can synergically enhance EMT-mediated CC metastasis through promoting chemokine expression. According to this study, TNF-α activated the PI3K/Akt and p38 MAPK parallel signal transduction pathways, then stimulate downstream NF-κB pathway p65 into the nucleus to activate CXCL10 transcription. CXCL10 enhanced the metastases of CC-cells by triggering small GTPases such as RhoA and cdc42. Furthermore, overexpression of CXCL10 significantly enhanced tumorigenicity and mobility of CC cells in vivo. We further clarified that CXCL10 activated the PI3K/Akt pathway through CXCR3, resulting in suppression of GSK-3β phosphorylation and leading to upregulation of Snail expression, thereby regulating EMT in CC cells. These outcomes lay the foundation for finding new targets to inhibit CC metastases.

Graphical abstract, Highlights • The hierarchical levels of TAD boundaries were tissue- and cell type-specific. • The TAD nesting level of genes in tumors is different from that in normal tissue. • Hierarchical TAD level of genes is related to abnormal transcription and prognosis in cancers., Recent studies have shown that the three-dimensional (3D) structure of chromatin is associated with cancer progression. However, the roles of the 3D genome structure and its dynamics in cancer remains largely unknown. In this study, we investigated hierarchical topologically associating domain (TAD) structures in cancers and defined a “TAD hierarchical score (TH score)” for genes, which allowed us to assess the TAD nesting level of all genes in a simplified way. We demonstrated that the TAD nesting levels of genes in a tumor differ from those in normal tissue. Furthermore, the hierarchical TAD level dynamics were related to transcriptional changes in cancer, and some of the genes in which the hierarchical level was altered were significantly related to the prognosis of cancer patients. Overall, the results of this study suggest that the folding dynamics of TADs are closely related to transcriptional abnormalities in cancers, emphasizing that the function of hierarchical chromatin organization goes beyond simple chromatin packaging efficiency.

Background As the largest group of mammalian species, which are also widely distributed all over the world, rodents are the natural reservoirs for many diverse zoonotic viruses. A comprehensive understanding of the core virome of diverse rodents should therefore assist in efforts to reduce the risk of future emergence or re-emergence of rodent-borne zoonotic pathogens. Results This study aimed to describe the viral range that could be detected in the lungs of rodents from Mainland Southeast Asia. Lung samples were collected from 3284 rodents and insectivores of the orders Rodentia, Scandentia, and Eulipotyphla in eighteen provinces of Thailand, Lao PDR, and Cambodia throughout 2006–2018. Meta-transcriptomic analysis was used to outline the unique spectral characteristics of the mammalian viruses within these lungs and the ecological and genetic imprints of the novel viruses. Many mammalian- or arthropod-related viruses from distinct evolutionary lineages were reported for the first time in these species, and viruses related to known pathogens were characterized for their genomic and evolutionary characteristics, host species, and locations. Conclusions These results expand our understanding of the core viromes of rodents and insectivores from Mainland Southeast Asia and suggest that a high diversity of viruses remains to be found in rodent species of this area. These findings, combined with our previous virome data from China, increase our knowledge of the viral community in wildlife and arthropod vectors in emerging disease hotspots of East and Southeast Asia.

Nonribosomal peptide synthetases (NRPSs) are modular enzymes that use a thiotemplate mechanism to assemble the peptide backbones of structurally diverse and biologically active natural products in bacteria and fungi. Unlike these canonical multi-modular NRPSs, single-module NRPS-like enzymes, which lack the key condensation (C) domain, are rare in bacteria, and have been largely unexplored to date. Here, we report the discovery of a gene cluster (gup) encoding a NRPS-like megasynthetase through genome mining. Heterologous expression of the gup cluster led to the production of two unprecedented alkaloids, guanipiperazines A and B. The NRPS-like enzyme activates two l-tyrosine molecules, reduces them to the corresponding amino aldehydes, and forms an unstable imine product. The subsequent enzymatic reduction affords piperazine, which can be morphed by a P450 monooxygenase into a highly strained compound through C–O bond formation. Further intermolecular oxidative coupling forming the C–C or C–O bond is catalyzed by another P450 enzyme. This work reveals the huge potential of NRPS-like biosynthetic gene clusters in the discovery of novel natural products., Genome mining of a NRPS-like gene cluster led to the identification of two novel alkaloids with antimicrobial activity. This work reveals the huge potential of NRPS-like biosynthetic gene clusters in the discovery of novel natural products.

The complete mitochondrial genome sequence of Atypus karschi has a circular genome of 14,149 bp, comprised of 13 protein-coding genes, two rRNA genes, 22 tRNA genes, and a control region. The nucleotide composition is 35.82% of T, 35.13% of A, 17.19% of G, and 9.16% of C. Most genes are encoded on the heavy strand except seven tRNA genes (Leu, Phe, His, Pro, Leu, Ile, Gln), four protein-coding genes (nad5, nad4, nad4l, nad1), and 16S-rRNA on the light strand. Most protein-coding genes start with TTG, ATT or ATA initiation codon except cox1, cox1’s start codon cannot be determined, and three types of inferred termination codons are TAA, TAG, and an incomplete stop codon. There are four intergenic spacers and 25 gene overlaps. The phylogenetic analysis shows that A. karschi has closer genetic relationship with Cyriopagopus schmidti (von Wirth, 1991) and Phyxioschema suthepium (Raven & Schwendinger, 1898) with high bootstrap support.

Fenvalerate, a synthetic pyrethroid insecticide, is an environmental endocrine disruptor and neurodevelopmental toxicant. An early report found that pubertal exposure to high-dose fenvalerate impaired cognitive and behavioral development. Here, we aimed to further investigate the effect of pubertal exposure to low-dose fenvalerate on cognitive and behavioral development. Mice were orally administered with fenvalerate (0.2, 1.0 and 5.0 mg/kg) daily from postnatal day (PND) 28 to PND56. Learning and memory were assessed by Morris water maze. Anxiety-related activities were detected by open-field and elevated plus-maze. Increased anxiety activities were observed only in females exposed to fenvalerate. Spatial learning and memory were damaged only in females exposed to fenvalerate. Histopathology observed numerous scattered shrinking neurons and nuclear pyknosis in hippocampal CA1 region. Neuronal density was reduced in hippocampal CA1 region of fenvalerate-exposed mice. Mechanistically, hippocampal thyroid hormone receptor (TR)β1 was down-regulated in a dose-dependent manner in females. In addition, TRα1 was declined only in females exposed to 5.0 mg/kg fenvalerate. Taken together, these suggests that pubertal exposure to low-dose fenvalerate impairs cognitive and behavioral development in a gender-dependent manner. Hippocampal TR signaling may be, at least partially, involved in fenvalerate-induced impairment of cognitive and behavioral development.

The rice planthoppers, Nilaparvata lugens and Sogatella furcifera, are important sap-sucking pests of rice in Asia. The mesoionic insecticide triflumezopyrim was previously shown to be highly effective in controlling both N. lugens and S. furcifera. In this study, electropenetrography (EPG) was used to evaluate the effect of three triflumezopyrim concentrations (LC10, LC50 and LC90) on the feeding behavior of N. lugens and S. furcifera. EPG signals of planthoppes indicated that there were six different waveforms NP, N1, N2, N3, N4, and N5, which corresponded to non-penetration, stylet penetration into epidermis, salivation, extracellular movement of stylet, sap ingestion in phloem, and water ingestion in xylem during feeding. Compared to untreated controls, triflumezopyrim at LC50 and LC90 prolonged the duration of the non-penetration period by 105.3 to 333.7%. The probing frequencies of N. lugens exposed to triflumezopyrim at LC10 and LC50 were significantly increased; however, the probing frequencies of S. furcifera showed a significant decrease when exposed to triflumezopyrim at all concentrations. Triflumezopyrim exposure prolonged the duration of salivation and shortened the duration of extracellular movement. The duration of phloem sap ingestion decreased from 37.2 to 77.7% in the LC50 and LC90 treatments, respectively. Differences in feeding behavior in response to triflumezopyrim and pymetrozine were minimal. In summary, the results show that the LC50 and LC90 concentrations of triflumezopyrim inhibit the feeding activities of N. lugens and S. furcifera mainly by prolonging the duration of non-penetration and by shortening the duration of phloem sap ingestion, which may foster more efficient use of triflumezopyrim in Asia.

Background Ginsenoside Rh2 (GRh2) is a characterized component in red ginseng widely used in Korea and China. GRh2 exhibits a wide range of pharmacological activities, such as anti-inflammatory, antioxidant, and anticancer properties. However, its effects on Toxoplasma gondii (T. gondii) infection have not been clarified yet. Methods The effect of GRh2 against T. gondii was assessed under in vitro and in vivo experiments. The BV2 cells were infected with tachyzoites of T. gondii RH strain, and the effects of GRh2 were evaluated by MTT assay, morphological observations, immunofluorescence staining, a trypan blue exclusion assay, reverse transcription PCR, and Western blot analyses. The in vivo experiment was conducted with BALB/c mice inoculated with lethal amounts of tachyzoites with or without GRh2 treatment. Results and conclusion The GRh2 treatment significantly inhibited the proliferation of T. gondii under in vitro and in vivo studies. Furthermore, GRh2 blocked the activation of microglia and specifically decreased the release of inflammatory mediators in response to T. gondii infection through TLR4/NF-κB signaling pathway. In mice, GRh2 conferred modest protection from a lethal dose of T. gondii. After the treatment, the proliferation of tachyzoites in the peritoneal cavity of infected mice markedly decreased. Moreover, GRh2 also significantly decreased the T. gondii burden in mouse brain tissues. These findings indicate that GRh2 exhibits an anti–T. gondii effect and inhibits the microglial activation through TLR4/NF-κB signaling pathway, providing the basic pharmacological basis for the development of new drugs to treat toxoplasmic encephalitis.

Chemoresistance is a major obstacle to prolonging pancreatic ductal adenocarcinoma (PDAC) patient survival. TET1 is identified as the most important epigenetic modification enzyme that facilitates chemoresistance in cancers. However, the chemoresistance mechanism of TET1 in PDAC is unknown. This study aimed to determine the role of TET1 in the chemoresistance of PDAC. TET1-associated chemoresistance in PDAC was investigated in vitro and in vivo. The clinical significance of TET1 was analyzed in 228 PDAC patients by tissue microarray profiling. We identified that TET1 downregulation is caused by its promoter hypermethylation and correlates with poor survival in PDAC patients. In vitro and in vivo functional studies performed by silencing or overexpressing TET1 suggested that TET1 is able to suppress epithelial-mesenchymal transition (EMT) and sensitize PDAC cells to 5FU and gemcitabine. Then RNA-seq, whole genome bisulfite sequencing (WGBS) and ChIP-seq were used to explore the TET1-associated pathway, and showed that TET1 promotes the transcription of CHL1 by binding and demethylating the CHL1 promoter, which consequently inhibits the Hedgehog pathway. Additionally, inhibiting Hedgehog signaling by CHL1 overexpression or the Hedgehog pathway inhibitor, GDC-0449, reversed the chemoresistance induced by TET1 silencing. Regarding clinical significance, we found that high TET1 and high CHL1 expression predicted a better prognosis in resectable PDAC patients. In summary, we demonstrated that TET1 reverses chemoresistance in PDAC by downregulating the CHL1-associated Hedgehog signaling pathway. PDAC patients with a high expression levels of TET1 and CHL1 have a better prognosis.

Purpose To develop a pulsed CEST magnetization-transfer method for rapidly acquiring relayed nuclear Overhauser enhancement (rNOE)-weighted images with magnetic transfer contrast (MTC) suppression at clinical field strength (3 T). Methods Using a pulsed CEST magnetization-transfer method with low saturation powers (B1 ) and long mixing time (tmix ) to suppress contributions due to strong MTC from solid-like macromolecules, a low B1 also minimized direct water saturation. These MTC contributions were further reduced by subtracting the Z-spectral signals at two or three offsets by assuming that the residual MTC is a linear function between -3.5 ppm and -12.5 ppm. Results Phantom studies of a lactic acid (Lac) solution mixed with cross-linked bovine serum albumin show that strong MTC interference has a significant impact on the optimum B1 for detecting rNOEs, due to lactate binding. The MTC could be effectively suppressed using a pulse train with a B1 of 0.8 μT, a pulse duration (tp ) of 40 ms, a tmix of 60 ms, and a pulse number (N) of 30, while rNOE signal was well maintained. As a proof of concept, we applied the method in mouse brain with injected hydrogel and a cell-hydrogel phantom. Results showed that rNOE-weighted images could provide good contrast between brain/cell and hydrogel. Conclusion The developed pulsed CEST magnetization-transfer method can achieve MTC suppression while preserving most of the rNOE signal at 3 T, which indicates the potential for translation of this technique to clinical applications related to mobile proteins/lipids change.

In this study, we applied on-resonance variable delay multiple pulse (onVDMP) MRI to study D-glucose uptake in a mouse model of Alzheimer’s disease (AD) tauopathy and demonstrated its feasibility in discriminating AD mice from wild-type mice. The D-glucose uptake in the cortex of AD mice (1.70 ± 1.33%) was significantly reduced compared to that of wild-type mice (5.42 ± 0.70%, p = 0.0051). Also, a slower D-glucose uptake rate was found in the cerebrospinal fluid (CSF) of AD mice (0.08 ± 0.01 min−1) compared to their wild-type counterpart (0.56 ± 0.1 min−1, p

Inactivating mutations in the liver kinase B1 (LKB1) tumor suppressor gene underlie Peutz-Jeghers syndrome (PJS) and occur frequently in various human cancers. We previously showed that LKB1 regulates centrosome duplication via PLK1. Here, we report that LKB1 further helps to maintain genomic stability through negative regulation of survivin, a member of the chromosomal passenger complex (CPC) that mediates CPC targeting to the centromere. We found that loss of LKB1 led to accumulation of misaligned and lagging chromosomes at metaphase and anaphase and increased the appearance of multi- and micro-nucleated cells. Ectopic LKB1 expression reduced these features and improved mitotic fidelity in LKB1-deficient cells. Through pharmacological and genetic manipulations, we showed that LKB1-mediated repression of survivin is independent of AMPK, but requires p53. Consistent with the key influence of LKB1 on survivin expression, immunohistochemical analysis indicated that survivin is highly expressed in intestinal polyps from a PJS patient. Lastly, we reaffirm a potential therapeutic avenue to treat LKB1-mutated tumors by demonstrating the increased sensitivity to survivin inhibitors of LKB1-deficient cells.

The holotypes of four species of Alopecosa Sundevall, 1833 described from China, A. disca Tang, Yin & Yang, 1997 (♀); A. orbisaca Peng, Yin, Zhang & Kim, 1997 (♀); A. wenxianensis Tang, Yin & Yang, 1997 (♂), and A. xilinensis Peng, Yin, Zhang & Kim, 1997 (♀), are reexamined. Detailed descriptions, illustrations, remarks, and a distribution map of the three valid species are given. Alopecosa xilinensissyn. nov. is found to be junior synonym of Alopecosa licenti (Schenkel, 1953).

DEHP is a wildly used plasticizer. Maternal DEHP exposure induced fetal growth restriction (FGR) and behavioral abnormalities in adolescence and adulthood mouse. The effect of low birth weight induced by DEHP on behaviors after growing up is not certain. In this study, the ICR pregnant mice were exposed to 200 mg/kg DEHP during gestation 6–12 days or 13–17 days, which can create FGR model. The F1 offspring were performed three ethological experiments at puberty (6 weeks postpartum) and adult period (8 weeks postpartum). The open field test was performed to detect the locomotor activity and anxiety, the elevated plus maze to test anxiety-like behavior, and the Morris water maze assay to measure the spatial learning and memory capability of male and female offspring. The results showed that spatial memory ability was dramatically impaired for male rather than female offspring in gestation 13–17 days’ group. Other behaviors had no statistically different between groups. These findings suggest that prenatal DEHP exposure disturbed mouse offspring spatial memory ability in a phase- and gender-dependent manner.

ObjectiveThis study retrospectively characterized the immune infiltrating profile in nonfunctional pancreatic neuroendocrine tumors (NF-PanNETs).MethodsTumor tissues from the 109-patient Fudan cohort and a 73-patient external validation set were evaluated by immunohistochemistry for 9 immune cell types: tumor-infiltrating neutrophils (TINs), tumor-associated macrophages (TAMs), CD11c+ dendritic cells, anti-NCR1+ natural killer (NK) cells, CD4+ and CD8+ T cells, CD45RO+ memory T cells, FOXP3+ regulatory T cells (Tregs), and CD20+ B cells.ResultsTINs were primarily distributed in the intratumoral area, dendritic cells and NK cells were scattered evenly in intratumoral and stromal areas, and Tregs were rarely detected. The remaining 5 cell types were primarily present in peritumoral stroma. Total TINs (P < .001) and TAMs (P = .002) increased as NF-PanNET grade rose. Kaplan-Meier analyses showed that high intratumoral TINs, total TAMs, and stromal CD4+ T-cell infiltration correlated with shorter recurrence-free survival (RFS, P = .010, P = .027, and P = .035, respectively) and overall survival (OS, P = .017, P = .029, and P = .045, respectively). Additionally, high intratumoral CD8+ T cell infiltration correlated with prolonged RFS (P = .039). Multivariate Cox regression demonstrated that intratumoral TINs, World Health Organization (WHO) classification, and eighth edition of the American Joint Committee on Cancer tumor-node-metastasis staging system (AJCC8th TNM) were independent factors for RFS (P = .043, P = .023, and P = .029, respectively), whereas intratumoral TINs and WHO classification were independent factors for OS (P = .010 and P = .007, respectively). Furthermore, the combination of TINs, WHO classification, and AJCC8th TNM remarkably improved prognostic accuracy for RFS. These results have been verified in the external validation set.ConclusionIntratumoral TINs are an independent and unfavorable predictor of postoperative NF-PanNETs. A combination of TINs, WHO classification, and AJCC8th TNM could improve prognostic accuracy for RFS.

Non-small cell lung cancer (NSCLC) is the leading cause of cancer-associated mortality worldwide. yrdC N6-threonylcarbamoltransferase domain containing protein (YRDC) has been demonstrated to be involved in the formation of threonylcarbamoyladenosine in transfer ribonucleic acid. However, the molecular mechanisms underlying NSCLC progression remain largely unclear. The present study revealed that YRDC was upregulated in NSCLC samples compared with adjacent non-cancerous tissues by analyzing datasets obtained from the Gene Expression Omnibus and The Cancer Genome Atlas. Higher expression of YRDC was associated with overall survival time and disease-free survival time in patients with NSCLC, particularly in lung adenocarcinoma. Furthermore, knockdown of YRDC in NSCLS cell lines significantly suppressed cell growth and cell colony formation in vitro. Additionally, the results demonstrated that silencing of YRDC induced apoptosis of A549 cells. Then, the protein-protein interaction networks associated with yrdC N6-threonylcarbamoltransferase domain containing protein (YRDC) in NSCLC were subsequently constructed to investigate the potential molecular mechanism underlying the role of YRDC in NSCLC. The results revealed that YRDC was involved in the regulation of spliceosomes, ribosomes, the p53 signaling pathway, proteasomes, the cell cycle and DNA replication. The present study demonstrated that YRDC may serve as a novel biomarker for the prognosis prediction and treatment of NSCLC.

Apart from mitigating endoplasmic reticulum (ER) stress, vast studies have demonstrated the crucial role of inositol-requiring transmembrane kinase and endonuclease 1α (IRE1α) - spliced X-box binding protein 1 (XBP1s) signaling pathway in inflammatory response in mammals. In addition, palmitic acid (PA)-induced inflammation has been verified in large yellow croaker (Larimichthys crocea). However, whether the IRE1α-XBP1s signaling pathway is involved in inflammatory response caused by PA remains poorly studied in fish. The present study was aimed at elucidating the role of the IRE1α-XBP1s signaling pathway in inflammatory response induced by PA in primary hepatocytes from large yellow croaker. In the present study, the full-length cDNA of ire1α and xbp1s were cloned and comprised 3793 bp and 1789 bp with an open reading frame of 3279 bp and 1170 bp, encoding 1093 and 390 amino acids, respectively. IRE1α protein possessed a protein kinase and endoribonuclease domain and XBP1s protein possessed a basic-leucine zipper domain. The IRE1α protein and XBP1s protein located to the ER membrane and nucleus respectively. The ire1α and xbp1s were widely transcribed in various tissues with the higher level in intestine, liver, adipose and head kidney. The ER stress-inducing agent tunicamycin (Tm) and PA treatment significantly activated the IRE1α-XBP1s signaling pathway and increased the pro-inflammatory genes expression including tumor necrosis factor α (tnfα), interleukin 6 (il-6) and interleukin 1β (il-1β) (P

Aim Patients with acute-on-chronic liver failure (ACLF) have a high risk of developing infections while hospitalized. Nosocomial bloodstream infection (BSI) is not uncommon, particular in patients who receive invasive operation, which may have negative impact on prognosis. In this study, we aim to investigate the characteristics and short-term outcome of nosocomial BSI in patients with ACLF. Methods Sixty-three patients with ACLF and nosocomial BSI from January 2014 to December 2015 were retrospectively studied. Clinical characteristics and distribution of bacteria at the time of BSI onset and short-term mortality were collected. Results The most common etiology of ACLF was hepatitis B virus infection. Eighty-one percent of ACLF patients had other types of infections at BSI onset. Gram-negative bacteria (77.8%) were the main pathogens, among which Escherichia coli was responsible for 46.9%. Staphylococcus epidermidis was the main Gram-positive bacteria. The most prevalent multidrug resistance (MDR) bacteria was extended-spectrum β-lactamase (ESBL)-producing E. coli. The overall 28-day mortality rate was 42.9%. Multivariate analysis found that model for end-stage liver disease (MELD) score and number of organ failures were predictors of 28-day mortality. The area under the receiver operating characteristic of the numbers of organ failures to predict 28-day mortality was higher than MELD score (0.833 vs. 0.784, 0.4099), but without significant difference. Conclusion Gram-negative bacteria were the most prevalent pathogens and ESBL-producing bacteria were responsible for most of the MDR bacteria in patients with ACLF and nosocomial BSI. Higher MELD score and multiorgan failure were associated with worse outcomes.

Glioblastoma (GBM) continues to show a poor prognosis despite advances in diagnostic and therapeutic approaches. The discovery of reliable prognostic indicators may significantly improve treatment outcome of GBM. In this study, we aimed to explore the function of verbascoside (VB) in GBM and its effects on GBM cell biological processes via let‐7g‐5p and HMGA2. Differentially expressed GBM‐related microRNAs (miRNAs) were initially screened. Different concentrations of VB were applied to U87 and U251 GBM cells, and 50 µmol/L of VB was selected for subsequent experiments. Cells were transfected with let‐7g‐5p inhibitor or mimic, and overexpression of HMGA2 or siRNA against HMGA2 was induced, followed by treatment with VB. The regulatory relationships between VB, let‐7g‐5p, HMGA2 and Wnt/β‐catenin signalling pathway were determined. The results showed that HMGA2 was a direct target gene of let‐7g‐5p. VB treatment or let‐7g‐5p overexpression inhibited HMGA2 expression and the activation of Wnt/β‐catenin signalling pathway, which further inhibited cell viability, invasion, migration, tumour growth and promoted GBM cell apoptosis and autophagy. On the contrary, HMGA2 overexpression promoted cell viability, invasion, migration, tumour growth while inhibiting GBM cell apoptosis and autophagy. We demonstrated that VB inhibits cell viability and promotes cell autophagy in GBM cells by up‐regulating let‐7g‐5p and down‐regulating HMGA2 via Wnt/β‐catenin signalling blockade.

Objectives The knowledge that agmatine is found in the human body has existed for several years; however, its role in sepsis has not yet been studied. In the present study, we investigate the role of agmatine in the progression and treatment of sepsis. Design Clinical/laboratory investigations. Setting Medical centers/University-based research laboratory. Subjects Elective ICU patients with severe sepsis and healthy volunteers; C57BL/6 mice weighing 18-22 g. Interventions Serum agmatine level and its associations with inflammatory markers were assessed in patients with sepsis. Agmatine was administered intraperitoneally to mice before a lipopolysaccharide challenge. Human peripheral blood mononuclear cells and murine macrophages were pretreated with agmatine followed by lipopolysaccharide stimulation. Measurements and main results Serum agmatine levels were significantly decreased in patients with sepsis and lipopolysaccharide-induced mice, and correlated with Acute Physiology and Chronic Health Evaluation II score, procalcitonin, tumor necrosis factor-α, and interleukin-6 levels. In a therapeutic experiment, exogenous agmatine attenuated the cytokine production of peripheral blood mononuclear cells from patients with sepsis and healthy controls. Agmatine also exerted a significant beneficial effect in the inflammatory response and organ damage and reduced the death rate in lipopolysaccharide-induced mice. Imidazoline I2 receptor agonist 2-benzofuran-2-yl blocked the pharmacological action of agmatine; whereas, other imidazoline receptor ligands did not. Furthermore, agmatine significantly impaired the inflammatory response by inactivating nuclear factor-κB, but not protein 38 mitogen-activated protein kinase, c-Jun N-terminal kinase, extracellular signal-regulated kinase, and inducible nitric oxide synthase signaling in macrophages. Activation of imidazoline I2 receptor or knockdown of ribosomal S6 kinase 2 counteracted the effects of agmatine on phosphorylation and degradation of inhibitor of nuclear factor-κBα. Conclusions Endogenous agmatine metabolism correlated with the progression of sepsis. Supplemental exogenous agmatine could ameliorate the lipopolysaccharide-induced systemic inflammatory responses and multiple organ injuries through the imidazoline I2 receptor-ribosomal S6 kinase 2-nuclear factor-κB pathway. Agmatine could be used as both a clinical biomarker and a promising pharmaconutrient in patients with severe sepsis.

Low vitamin D status is associated with progression in patients with renal cell carcinoma (RCC). The present study found that vimentin, a mesenchymal marker, was accordingly upregulated, and E‐cadherin, an epithelial marker, was downregulated in RCC patients with low vitamin D status. Thus, we investigated the effects of calcitriol or vitamin D3, an active form of vitamin D, on epithelial‐mesenchymal transition (EMT) in RCC cells. RCC cells were treated by two models. In model 1, three RCC cell lines, ACHN, 786‐O and CAKI‐2, were incubated with either LPS (2.0 μg/mL) or transforming growth factor (TGF)‐β1 (10 ng/mL) in the presence or absence of calcitriol (200 nmol/L). In model 2, two RCC cell lines, ACHN and CAKI‐2, were incubated with calcitriol (200 nmol/L) only. Calcitriol inhibited migration and invasion not only in TGF‐β1‐stimulated but also in TGF‐β1‐unstimulated RCC cells. Moreover, calcitriol suppressed E‐cadherin downregulation and vimentin upregulation not only in TGF‐β1‐stimulated but also in TGF‐β1‐unstimulated ACHN and CAKI‐2 cells. Calcitriol attenuated LPS‐induced upregulation of MMP‐2, MMP‐7, MMP‐9, MMP‐26 and urokinase‐type plasminogen activator (u‐PA) in ACHN cells. In addition, calcitriol blocked TGF‐β1‐induced nuclear translocation of ZEB1, Snail and Twist1 in ACHN and CAKI‐2 cells. Mechanistically, calcitriol suppressed EMT through different signaling pathways: (i) calcitriol suppressed Smad2/3 phosphorylation by reinforcing physical interaction between vitamin D receptor (VDR) and Smad3 in TGF‐β1‐stimulated RCC cells; (ii) calcitriol inhibited signal transducer and activator of transcription (STAT)3 activation in LPS‐stimulated RCC cells; (iii) calcitriol inhibited β‐catenin/TCF‐4 activation by promoting integration of VDR with β‐catenin in TGF‐β1‐unstimulated RCC cells. Taken together, calcitriol inhibits migration and invasion of RCC cells partially by suppressing Smad2/3‐, STAT3‐ and β‐catenin‐mediated EMT., Calcitriol suppressed EMT through two different signaling pathways: (i) calcitriol suppressed Smad2/3 phosphorylation by reinforcing physical interaction between vitamin D receptor (VDR) and Smad3 in TGF‐β1‐stimulated RCC cells; (ii) calcitriol inhibited β‐catenin/TCF‐4 activation by promoting integration of VDR with β‐catenin in TGF‐β1‐unstimulated RCC cells. Taken together, calcitriol inhibits migration and invasion of RCC cells by suppressing Smad2/3‐ and β‐catenin‐mediated EMT.

Objectives: Long noncoding RNAs (lncRNAs) play substantial roles in cerebral ischemia. Growth arrest-specific 5 (GAS5) was reported to be involved in stroke. In the present study, we aimed to inves...

The 3-hydroxyanthranilic acid (3-HAA), a derivative of kynurenine, was reported to suppress tumor growth. However, the function of 3-HAA largely remains unclear. Here, we report that 3-hydroxyanthranilic acid (3-HAA) is lower in tumor cells, while adding exogenous 3-HAA induces apoptosis in hepatocellular carcinoma by binding YY1. This 3-HAA binding of YY1 leads to phosphorylation of YY1 at the Thr 398 by PKCζ, concomitantly enhances YY1 chromatin binding activity to increase expression of target genes. These findings demonstrate that 3-HAA is a ligand of YY1, suggesting it is a promising therapeutic candidate for HCC. Supplementary Information The online version contains supplementary material available at 10.1186/s13045-021-01165-4.

The AMP-activated protein kinase (AMPK) is a central regulator of energy homeostasis. Although much has been learned on how low energy status and glucose starvation activate AMPK, how AMPK activity is properly controlled in vivo is still poorly understood. Here we report that UHRF1, an epigenetic regulator highly expressed in proliferating and cancer cells, interacts with AMPK and serves to suppress AMPK activity under both basal and stressed conditions. As a nuclear protein, UHRF1 promotes AMPK nuclear retention and strongly suppresses nuclear AMPK activity toward substrates H2B and EZH2. Importantly, we demonstrate that UHRF1 also robustly inhibits AMPK activity in the cytoplasm compartment, most likely as a consequence of AMPK nucleocytoplasmic shuttling. Mechanistically, we found that UHRF1 has no obvious effect on AMPK activation by upstream kinases LKB1 and CAMKK2 but inhibits AMPK activity by acting as a bridging factor targeting phosphatase PP2A to dephosphorylate AMPK. Hepatic overexpression of UHRF1 showed profound effects on glucose and lipid metabolism in wild-type mice but not in those with the liver-specific knockout of AMPKα1/α2, whereas knockdown of UHRF1 in adipose tissue led to AMPK activation and reduced sizes of adipocytes and lipogenic activity, highlighting the physiological significance of this regulation in glucose and lipid metabolism. Thus, our study identifies UHRF1 as a novel AMPK gate-keeper with critical roles in cellular metabolism.

In the past decade, natural deep eutectic solvents (NADESs) as green and sustainable extraction solvents with great potential for the efficient extraction of bioactive compounds from the plants are emerging. In this study, a microwave-assisted technology is used to prepare natural deep eutectic solvents. And natural deep eutectic solvents as pretreatment solvents coupled with microwave-assisted hydrodistillation (MAHD) for isolating essential oil (EO) derived from turmeric (Curcuma longa L.) is investigated. To improve the essential oil yield of turmeric (Curcuma longa L.) as a target, various factors affecting extraction efficiency including the type and amount of natural deep eutectic solvents, pretreatment time, pretreatment temperature and hydrodistillation (HD) time are discussed and optimized through central composite design (CCD) of the response surface methodology (RSM). The optimal conditions are as follows: natural deep eutectic solvent composed of choline chloride and oxalic acid (molar ratio with 1:1) as a pretreatment solvent, an amount of 60 g, a pretreatment time of 5 min, a pretreatment temperature of 84 oC, a hydrodistillation time of 76 min. Under the optimum conditions, the highest essential oil yield of 0.85% is achieved. Additionally, the essential oil is analyzed by using gas chromatography-mass spectrometry (GC-MS), with a total of 49 compounds being identified. Through combining natural deep eutectic solvents with a microwave-assisted hydrodistillation technique, this work provides an eco-friendly extraction way of isolating essential oil, which boosts development in the monitoring other spice quality field.

A Gram-stain-negative, coccus-shaped, obligately anaerobic, non-motile and non-spore-forming bacterium, designated strain JN500902T, was isolated from the mud in a fermentation cellar used continuously over 30 years for Chinese strong-flavour baijiu production. Colonies were white, circular, convex and smooth-edged. Growth was observed at 20–40 °C (optimum, 37 °C), at pH 5.0–10 (optimum, pH 7.5), with 0–2 % (w/v) NaCl and with 0–4 % (v/v) ethanol. The Biolog assay demonstrated positive reactions of strain JN500902T in the metabolism of l-fucose and pyruvate. The predominant cellular fatty acids (>10 %) consisted of C16 : 0 and C14 : 0. The major end metabolites of strain JN500902T were acetic acid and ethanol when incubated anaerobically in liquid reinforced clostridial medium. Acetate was the major organic acid end product. The complete genome size of strain JN500902T was 3 420 321 bp with 3327 identified genes. The G+C content was 43.5 mol%. Phylogenetic analysis based on 16S rRNA gene sequences affiliated strain JN500902T with the family Lachnospiraceae , having low sequence similarity (92.8 %) to the nearest type strain, Syntrophococcus sucromutans DSM 3224T and forming a clearly distinct branch. Core genome phylogenetic analysis of the isolate and 134 strains belonging to the family Lachnospiraceae also revealed that strain JN500902T was well-separated from other genera of this family as a monophyletic clade. The average nucleotide identity and amino acid identity values between strain JN500902T and 134 Lachnospiraceae strains were less than 74 and 65 %, respectively. Considering its polyphasic characteristics, strain JN500902T represents a novel genus and species within the family Lachnospiraceae , for which the name Novisyntrophococcus fermenticellae gen. nov., sp. nov. is proposed. The type strain is JN500902T (=CICC 24502T=JCM 33939T).

Aphrocallistes vastus lectin (AVL) is a C-type marine lectin produced by sponges. Our previous study demonstrated that genes encoding AVL enhanced the cytotoxic effect of oncolytic vaccinia virus (oncoVV) in a variety of cancer cells. In this study, the inhibitory effect of oncoVV-AVL on Hela S3 cervical cancer cells, a cell line with spheroidizing ability, was explored. The results showed that oncoVV-AVL could inhibit Hela S3 cells growth both in vivo and in vitro. Further investigation revealed that AVL increased the virus replication, promote the expression of OASL protein and stimulated the activation of Raf in Hela S3 cells. This study may provide insight into a novel way for the utilization of lection AVL.

A novel magnetic hydrochar synthesized from Fenton sludge (FS) and sewage sludge (SS) was employed in the anaerobic decolorization of acid orange 7 (AO7). The stable presence of Fe3O4 in magnetic hydrochar was confirmed by physicochemical characterization. The degradation efficiency of AO7 in the anaerobic system with the addition of hydrochar prepared in an optimal proportion (SS:FS=1:3, named as HC-1:3) could reach 98.55%, which was 1.91 times higher than the control system. Particularly, superior electrical conductivity, electron transport system activity and azo reductase activity of the sludge in anaerobic system with HC-1:3 were achieved. The redox of Fe(Ⅲ)/Fe(Ⅱ) in anaerobic system was realized by dissimilatory iron-reducing bacteria enriched with HC-1:3. According to the six-cycle batch experiments and 120-day continuous-flow UASB experiments, the addition of HC-1:3 into the anaerobic system facilitated the diversity of microbiological community and increased the ecological stability of anaerobic system. The possible electron transfer mechanism involving in the magnetic hydrochar-based anaerobic system for AO7 removal was speculated preliminarily. The as-prepared magnetic hydrochar not only showed a promising future in anaerobic system for recalcitrant contaminants degradation, but also provided a new approach for the resource utilization of FS and SS.

Background: Heart failure (HF) is a complex pathophysiological state in which the delivery of blood and nutrients to the tissues is inadequate. It is rarely curable and often associated with poor prognosis. The current study aimed to analyze the exomic and RNA-Seq data of patients with HF to identify the key altered pathways. Methods: Heart failure participants were recruited, and whole blood samples were collected. The samples were used for whole exome sequencing and RNA-Seq analysis. Gene expression and RNA-Seq results were verified by Gene chips and RT-PCRResults: We report a dysregulation of phosphorylation and immune signaling in patients with HF both by exomic and RNA-Seq data. We identified mutations in TITIN,OBSCURIN, NOD2, CDH2, MAP3K5, and SLC17A4 to be associated with HF by exomic analysis. And certain genes, S100A12, S100A8, S100A9, PFDN5, and TMCC2, were found upregulated in patients with HF by RNA-Seq. Conlcusion: Our results demonstrated the overall disruption of key phosphorylation and immune signaling pathways in patients with HF.

Background Knee osteoarthritis (KOA) is a common cause of disability among the elderly. We aimed to explore the effects of aldehyde dehydrogenase (ALDH) 2 on the progression of KOA and identifying the potential mechanisms. Methods First, ALDH2 expression in knee joint effusion of patients with KOA and the levels of oxidative stress-related markers were determined. After ALDH2 overexpression in monosodium iodoacetate (MIA)-treated SW1353 cells, cell viability was tested with CCK-8 assay. Subsequently, oxidative stress and inflammation-associated factors were measured. Meanwhile, cell apoptosis was assessed with TUNEL staining and expression of apoptosis-related proteins was detected by western blotting. To analyze the mechanism of ALDH2 in KOA, aquaporin 4 (AQP4) expression was determined using western blotting following ALDH2-upregulation. Subsequently, AQP4 was overexpressed to evaluate the changing of oxidative stress, inflammation and apoptosis in SW1353 cells exposed to MIA with ALDH2 overexpression. Results Results indicated that knee joint effusion with higher ALDH2 expression displayed lower oxidative stress. In addition, significantly upregulated ALDH2 expression was observed in MIA-treated SW1353 cells. ALDH2 overexpression oxidative stress, inflammation and apoptosis in SW1353 cells exposed to MIA. Moreover, MIA-triggered elevated expression of AQP4, which was reduced by ALDH2 overexpression. By contrast, AQP4-upregulation abrogated the inhibitory effects of ALDH2 on oxidative stress, inflammation and apoptosis in MIA-induced SW1353 cells. Conclusions ALDH2 inactivates the expression of AQP4, by which mechanism the MIA-induced oxidative stress, inflammation and apoptosis injuries were alleviated, which provides a novel insight for understanding the mechanism of KOA and a promising target for the treatment of this disease.

Radiotherapy is an important treatment for abdominal tumors. A critical side effect for this therapy is enteritis. In this review, we aim to summarize recent findings in radiation enteritis, in particular the role of gut microbiota dysbiosis in the development and therapy of the disease. Gut microbiota dysbiosis plays an important role in the occurrence of various diseases, such as radiation enteritis. Abdominal radiation results in changes in the composition of microbiota and reduces its diversity, which is mainly reflected in the decrease of Lactobacillus spp. and Bifidobacterium spp. and increase of Escherichia coli and Staphylococcus spp. Gut microbiota dysbiosis aggravates radiation enteritis, weakens intestinal epithelial barrier function, and promotes inflammatory factor expression. Pathogenic Escherichia coli induce the rearrangement and redistribution of claudin-1, occludin, and ZO-1 in tight junctions, a critical component in intestinal epithelial barrier. In view of the role that microbiome plays in radiation enteritis, we believe that intestinal flora could be a potential biomarker for the disease. Correction of microbiome by application of probiotics, fecal microbiota transplantation (FMT), and antibiotics could be an effective method for the prevention and treatment of radiation-induced enteritis.

Due to the poor prognosis for hepatocellular carcinoma (HCC) presently, a systemic analysis supported by the multi-omics data is extremely necessary to search for gene markers for the clinical prognostic prediction of HCC. The data on RNA-seq, single nucleotide polymorphism (SNP), and copy number variation (CNV), etc. were downloaded from TCGA, leading to a final of 367 samples, which were divided into training set and testing set randomly. In the training set, both prognosis-related genes and those with SNP or CNV were screened, which were incorporated for feature selection using the random forest method. The testing and GEO verification sets (N = 265) were used to verify the constructed gene-related prognosis model. qPCR was used to detect the expression of 5 genes in clinical specimens. After including genomic variant and prognosis-related genes, we got 78 candidate genes and 5 feature genes (CISH, LHPP, MGMT, PDRG1, and LCAT) eventually through random forest feature selection. The 5-gene signature is an independent prognostic risk factor for HCC patients. In addition, the signature shows good predicting performance and clinical practicality in train- ing set, testing set and external verification set. The results of qPCR based on clinical samples showed that the expression of PDRG1 was increased in colon cancer tissues and the expression of CISH, LHPP, MGMT and LCAT were decreased in colon cancer tissues. We identify the ability of 5-gene signature to serve as an innovative marker of survival prediction for patients with HCC.

Gut microbiota has been proved to be involved in the occurrence and development of many diseases, such as type 2 diabetes, obesity, coronary heart disease, etcetera. It provides a new idea for the pathogenesis of polycystic ovary syndrome (PCOS). Our study showed that the gut microbial community of PCOS with high low-density lipoprotein cholesterol (LDLC) has a noticeable imbalance. Gut microbiota of PCOS patients was significantly changed compared with CON, and these changes were closely related to LDLC. Gut microbiota may affect the metabolic level of PCOS patients through multiple metabolic pathways, and lipid metabolism disorder may further aggravate the imbalance of gut microbiota. Actinomycetaceae, Enterobacteriaceae and Streptococcaceae had high accuracy in the diagnosis of PCOS and the differentiation of subgroups, suggesting that they may play an important role in the diagnosis and treatment of PCOS in the future. Also, the model we built showed good specificity and sensitivity for distinguishing PCOS from CON (including L_CON and L_PCOS, H_CON and H_PCOS). In conclusion, this is the first report on the gut microbiota of PCOS with high LDLC, suggesting that in the drug development or treatment of PCOS patients, the difference of gut microbiota in PCOS patients with different LDLC levels should be fully considered.

Simple Summary The immunosuppressive microenvironment is closely related to the poor prognosis of patients with PDAC. Tfh cells play an anti-tumor function in various malignant solid tumors; however, the role of Tfh cells in PDAC has not been determined. In this study, we aimed to explore the function of Tfh cells in PDAC, and revealed a novel immunosuppressive mechanism mediated by Tfh cells. Tfh cells promoted the formation of an immunoactive tumor microenvironment by secreting CXCL13 and IL-21, and the high infiltration of Tfh cells correlated with better patient prognosis. However, the anti-tumor function of Tfh cells was inhibited by the PD-L1/PD-1 signaling pathway. Neoadjuvant chemotherapy could further reverse the function of Tfh cells. Our results provided new strategies to remodel the immunoactive tumor microenvironment of PDAC. Abstract Immunosuppression is an important factor for the poor prognosis of pancreatic ductal adenocarcinoma (PDAC). Follicular helper T cells (Tfh cells) play an anti-tumor role in various malignant solid tumors and predict better patient prognosis. In the present study, we aimed to determine the immunosuppressive mechanism associated with Tfh cells and explore a new strategy to improve the tumor microenvironment of PDAC. Flow cytometry was used to detect the infiltration and proportion of Tfh cells in tumor tissues and peripheral blood from patients with PDAC. The spatial correlations of Tfh cells with related immune cells were evaluated using immunofluorescence. The function of Tfh cells was examined using in vitro and in vivo model systems. The high infiltration of Tfh cells predicted better prognosis in patients with PDAC. Tfh cells recruited CD8+ T cells and B cells by secreting C-X-C motif chemokine ligand 13 (CXCL13), and promoted the maturation of B cells into antibody-producing plasma cells by secreting interleukin 21 (IL-21), thereby promoting the formation of an immunoactive tumor microenvironment. The function of Tfh cells was inhibited by the programmed cell death 1 ligand 1 (PD-L1)/programmed cell death 1 (PD-1) signaling pathway in PDAC, which could be reversed using neoadjuvant chemotherapy. Treatment with recombinant CXCL13, IL-21 and Tfh cells alleviated tumor growth and enhanced the infiltration of CD8+ T cells and B cells, as well as B cell maturation in a PDAC mouse model. Our results revealed the important role of Tfh cells in mediating anti-tumor cellular immunity and humoral immunity in PDAC via secreting CXCL13 and IL-21 and determined a novel mechanism of immunosuppression in PDAC.