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Background: Serum uric acid (UA) has been reported to be associated with ischemic stroke and inflammation. However, whether or not UA is related to the recurrence of ischemic stroke, and whether inflammation plays a role in the relationship between them remain inconclusive., Objective: We sought to explore the relationship between UA and the recurrence of ischemic stroke and to define the role of neutrophil-to-lymphocyte ratio (NLR) in the aforementioned relationship., Methods: A total of 8,995 patients were included in this study. Basic information and blood samples were collected, and whether or not each participant experienced ischemic stroke recurrence within 3 years was documented. Patients were stratified into three groups according to their UA level, as follows: ≤ 266, 267-339, and ≥ 340 μmol/L. COX regression and restricted cubic spline regression models were used to evaluate the clinical correlation between UA and ischemic stroke recurrence, mediation analysis and interaction and joint analysis were used to evaluate the role of NLR in the association of UA and ischemic stroke recurrence, and sensitivity and subgroup analyses were performed to test the robustness of the data., Results: Ischemic stroke recurrence was related to male sex, older age, higher UA level, higher NLR, hypertension, diabetes, and cardiovascular disease. Following adjustment for potential confounders, a high level of UA (≥ 340 μmol/L) increased the risk of recurrence by 92.6% in patients with previous ischemic stroke. We also found that NLR affects the association between UA and the recurrence of ischemic stroke in older adults, suggesting that patients with high NLR and high UA levels are at greater risk for ischemic stroke recurrence., Conclusion: UA level is non-linearly associated with recurrence, and NLR has an additive interaction between UA and ischemic stroke recurrence., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Zhu, Zhao, Zhang, Wang, Pan, Cheng, Zhao and Wang.)

The spotted hyena (Crocuta crocuta) is a large and unique terrestrial carnivore. It is a particularly fascinating species due to its distinct phenotypic traits, especially its complex social structure and scavenging lifestyle, with associated high dietary exposure to microbial pathogens. However, the underlying molecular mechanisms related to these phenotypes remain elusive. Here, we sequenced and assembled a high-quality long-read genome of the spotted hyena, with a contig N50 length of ∼13.75 Mb. Based on comparative genomics, immunoglobulin family members (e.g., IGKV4-1) showed significant adaptive duplications in the spotted hyena and striped hyena. Furthermore, immune-related genes (e.g., CD8A, LAG3, and TLR3) experienced species-specific positive selection in the spotted hyena lineage. These results suggest that immune tolerance between the spotted hyena and closely related striped hyena has undergone adaptive divergence to cope with prolonged dietary exposure to microbial pathogens from scavenging. Furthermore, we provided the potential genetic insights underlying social complexity, hinting at social behavior and cognition. Specifically, the RECNE-associated genes (e.g., UGP2 and ACTR2) in the spotted hyena genome are involved in regulation of social communication. Taken together, our genomic analyses provide molecular insights into the scavenging lifestyle and societal complexity of spotted hyenas., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.)

The MYB-CC family is a subtype within the MYB superfamily. This family contains an MYB domain and a predicted coiled-coil (CC) domain. Several MYB-CC transcription factors are involved in the plant's adaptability to low phosphate (Pi) stress. We identified 30, 34, and 55 MYB-CC genes in Brassica rapa , Brassica oleracea , and Brassica napus , respectively. The MYB-CC genes were divided into nine groups based on phylogenetic analysis. The analysis of the chromosome distribution and gene structure revealed that most MYB-CC genes retained the same relative position on the chromosomes and had similar gene structures during allotetraploidy. Evolutionary analysis showed that the ancestral whole-genome triplication (WGT) and the recent allopolyploidy are critical for the expansion of the MYB-CC gene family. The expression patterns of MYB-CC genes were found to be diverse in different tissues of the three Brassica species. Furthermore, the gene expression analysis under low Pi stress revealed that MYB-CC genes may be related to low Pi stress responses. These results may increase our understanding of MYB-CC gene family diversification and provide the basis for further analysis of the specific functions of MYB-CC genes in Brassica species., Competing Interests: The authors declare that they have no competing interests., (© 2022 Gu et al.)

Spinal cord impairment involving motor neuron degeneration and demyelination can cause lifelong disabilities, but effective clinical interventions for restoring neurological functions have yet to be developed. In early spinal cord development, neural progenitors of the motor neuron (pMN) domain, defined by the expression of oligodendrocyte transcription factor 2 (OLIG2), in the ventral spinal cord first generate motor neurons and then switch the fate to produce myelin-forming oligodendrocytes. Given their differentiation potential, pMN progenitors could be a valuable cell source for cell therapy in relevant neurological conditions such as spinal cord injury. However, fast generation and expansion of pMN progenitors in vitro while conserving their differentiation potential has so far been technically challenging. In this study, based on chemical screening, we have developed a new recipe for efficient induction of pMN progenitors from human embryonic stem cells. More importantly, these OLIG2+ pMN progenitors can be stably maintained for multiple passages without losing their ability to produce spinal motor neurons and oligodendrocytes rapidly. Our results suggest that these self-renewing pMN progenitors could potentially be useful as a renewable source of cell transplants for spinal cord injury and demyelinating disorders., (© The Author(s) (2021). Published by Oxford University Press on behalf of Journal of Molecular Cell Biology, CEMCS, CAS.)

Five new oleanane-type triterpenoid saponins ( 1-5 ), together with 24 known saponins ( 6-29 ) were isolated from the fruit of Acanthopanax senticosus . Their structures were determined by extensive spectroscopic analysis, including 1D, 2D nuclear magnetic resonance (NMR), and high-resolution electrospray ionization mass spectrometry (HR-ESI-MS), in combination with chemical methods (acid hydrolysis). The neuroinflammation model was established by lipopolysaccharide (LPS)-induced BV2 microglia, and the neuroprotective effects of all compounds ( 1-29 ) were evaluated., Competing Interests: Author M-LZ is employed by China Resources Double-Crane Pharmaceutical Co., Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Liu, Jiang, Zhang, Pan, Guan, Li, Yang and Kuang.)

Background: Exercise prescription of cardiac rehabilitation (CR) is vital in patients with cardiovascular diseases (CVDs) and those carrying high risk for CVDs. However, the relation between the implementation rate of exercise prescription and cardiovascular events (CVEs) is unclear., Design and Methods: In this retrospective study, using the administration data from the Rehabilitation Center in a hospital, patients aged ≥18 years with CVDs were consecutively enrolled from November 2018 to May 2021. Patients were divided into the high execution group (HEG) and low execution group (LEG) depending on whether they completed more than half the time of the exercise prescriptions. Baseline characteristics, ultrasonic cardiogram, cardiopulmonary exercise test, follow-up data, and CVEs were collected., Results: The mean age of the 197 CR patients was 61.8 ± 13.7 years and the mean follow-up duration was 10.9 ± 4.2 months. Among them, 15 patients suffered CVEs: 4 in the HEG and 11 in the LEG. The incidence of CVEs showed significant differences between HEG and LEG (chi-square test). Free-event survival analysis using Kaplan-Meier survival plots showed that patients in LEG had poor survival. Cox proportional hazards regression analysis revealed that the prescription implementation rate was an independent predictor of CVEs., Conclusions: Our study suggested a significant effect of exercise prescription execution rate on the occurrence of CVEs. Further, the HEG of exercise prescription was associated with lower CVDs., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Zhu, Li, Li, Yang, Yang, Zhao, Yan, Li, Luo, Zhang and Su.)

Aim : To evaluate the protective effects of Platycladi Cacumen Carbonisata-derived nanoparticles (PCC-NPs) against 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced ulcerative colitis (UC) in rats. Methods : This study developed and characterized novel PCC-NPs synthesized by a green and simple pyrolysis process using Platycladi Cacumen (PC) as the sole precursor. The UC model prepared with rectal instillation of TNBS was used to evaluate the potential efficacy of PCC-NPs, and the underlying mechanisms were preliminarily explored from the perspective of anti-inflammatory and antioxidative stress for the first time. Results : PCC-NPs exhibited low cytotoxicity, good dispersibility and copious surface functional groups. Nanoparticles with diameters ranging from 40-60 nm mainly manifested a therapeutic effect by downregulating tumour necrosis factor- α (TNF- α ), interleukin-6 (IL-6) and upregulating interleukin-10 (IL-10). In addition, PCC-NPs relieved colon injury by inhibiting myeloperoxidase (MPO) activity, limiting the release of malondialdehyde (MDA) and increasing the activity of superoxide dismutase (SOD). Conclusion : Green synthetic PCC-NPs is a potential candidate as a complementary drug for intestinal inflammation of inflammatory bowel disease, and its regulatory mechanisms may be to balance the levels of pro-/anti-inflammatory cytokines and improve resistance to oxidative stress.

Many metabolic diseases in fish are often associated with lowered mitochondrial fatty acid β-oxidation (FAO). However, the physiological role of mitochondrial FAO in lipid metabolism has not been verified in many carnivorous fish species, for example in largemouth bass (Micropterus salmonids). In the present study, a specific mitochondrial FAO inhibitor, mildronate (MD), was used to investigate the effects of impaired mitochondrial FAO on growth performance, health status, and lipid metabolism of largemouth bass. The results showed that the dietary MD treatment significantly suppressed growth performance and caused heavy lipid accumulation, especially neutral lipid, in the liver. The MD-treated fish exhibited lower monounsaturated fatty acid and higher long-chain polyunsaturated fatty acids in the muscle. The MD treatment downregulated the gene expressions in lipolysis and lipogenesis, as well as the expressions of the genes and some key proteins in FAO without enhancing peroxisomal FAO. Additionally, the MD-treated fish had lower serum aspartate aminotransferase activity and lower pro-inflammation- and apoptosis-related genes in the liver. Taken together, MD treatment markedly induced lipid accumulation via depressing lipid catabolism. Our findings reveal the pivotal roles of mitochondrial FAO in maintaining health and lipid homeostasis in largemouth bass and could be hopeful in understanding metabolic diseases in farmed carnivorous fish., (© 2021. The Author(s), under exclusive licence to Springer Nature B.V.)

Introduction: Fluoride can induce the proliferation and activation of osteoblasts, resulting in skeletal fluorosis progression; however, the specific mechanism is unclear., Methods: Cell proliferation was examined using the MTT assay. Flow cytometry was performed to detect the cell cycle distribution. Alkaline phosphatase (ALP) was calculated to evaluate bone formation and turnover. Gene methylation was examined using the MSP assay. mRNA and protein expression levels were assessed using qRT-PCR and Western blot assays., Results: Low-concentration NaF treatment promoted the cell cycle progression of osteoblasts to S-phase, thus accelerating cell proliferation and activation in a concentration-dependent manner. In addition, the methylation of the MGMT and MLH1 genes was increased, and their mRNA expression was reduced. Furthermore, the DNA methyltransferase inhibitor 5-AZA-dC suppressed cell viability, cell number in S-phase, ALP activity and osteogenesis-related protein levels in osteoblasts treated with low doses of NaF. Meanwhile, 5-AZA-dC suppressed the increase in MGMT and MLH1 gene methylation in osteoblasts treated with low doses of NaF, leading to enhanced expression of MGMT and MLH1 mRNA., Conclusion: NaF treatment led to methylation of the DNA repair genes MGMT and MLH1 in osteoblasts, resulting in cell proliferation and activation and causing the development of skeletal fluorosis., Competing Interests: The authors declare that they have no conflict of interest., (© 2022 The Japanese Society for Regenerative Medicine. Production and hosting by Elsevier B.V.)

Central nervous system tumors are classified as diseases of special clinical significance with high disability and high mortality. In addition to cerebrovascular diseases and craniocerebral injuries, tumors are the most common diseases of the central nervous system. Hydrogen sulfide, the third endogenous gas signaling molecule discovered in humans besides nitric oxide and carbon monoxide, plays an important role in the pathophysiology of human diseases. It is reported that hydrogen sulfide not only exerts a wide range of biological effects, but also develops a certain relationship with tumor development and neovascularization. A variety of studies have shown that hydrogen sulfide acts as a vasodilator and angiogenetic factor to facilitate growth, proliferation, migration and invasion of cancer cells. In this review, the pathological mechanisms and the effect of hydrogen sulfide on the central nervous system tumors are introduced., Competing Interests: None

Immune checkpoint inhibitors target checkpoint proteins with the goal of reinvigorating the host immune system and thus restoring antitumor response. With the dramatic increase in the use of checkpoint inhibitors for cancer treatment, surgical pathologists have assumed a major role in predicting the therapeutic efficacy (score based on programmed cell death ligand 1 immunohistochemistry and mismatch repair protein loss) as well as diagnosing the complications associated with these medications. Immune-related adverse events (irAEs) manifest as histologic changes seen in both the upper and lower gastrointestinal tract, and when viewed in isolation, may be morphologically indistinguishable from a wide range of diseases including infections, celiac disease, and inflammatory bowel disease, among others. Evaluation of biopsies from both the upper and lower gastrointestinal tract can aid in the distinction of gastrointestinal irAEs from their mimics. In the liver, the histologic changes of hepatic irAEs overlap with de novo diseases associated with hepatitic and cholangitic patterns of injury. The diagnosis of irAEs requires communication and collaboration from the pathologist, oncologist, and gastroenterologist. This review provides a background framework and illustrates the histologic features and differential diagnosis of gastrointestinal and hepatic irAEs., Competing Interests: Conflicts of Interest and Source of Funding: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article, (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

This study was designed to explore the alleviating effect and mechanism of Glycyrrhizae Radix et Rhizoma against Psora-leae Fructus-induced liver injury based on network pharmacology and cell experiments. The active components of Glycyrrhizae Radix et Rhizoma and Psoraleae Fructus were first retrieved from the Encyclopedia of Traditional Chinese Medicine(ETCM), Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform(TCMSP), Comparative Toxicogenomics Database(CTD), and literature and further screened by SwissADME. The obtained 25 potential toxic components of Psoraleae Fructus and 29 flavonoids in Glycyrrhizae Radix et Rhizoma were input into the SwissTargetPrediction for target predication. A total of 818 targets related to liver injury were screened out based on GeneCards and MalaCards, and 91 common targets of Psoraleae Fructus, Glycyrrhizae Radix et Rhizoma, and liver injury were obtained from Venny. STRING was applied for constructing the PPI network, and Metascape for analyzing the biological processes and signaling pathways that common targets participated in. Cytoscape was used to construct the component-target-disease network and component-target-pathway network for Glycyrrhizae Radix et Rhizoma against Psoraleae Fructus-induced liver injury. The predicted core targets were proto-oncogene tyrosine-protein kinase(SRC), phosphatidylinositol 4,5-bisphosphate 3-kinase subunit alpha(PIK3 CA), RAC-alpha serine/threonine-protein kinase(AKT1), etc, with PI3 K-AKT signaling pathway, MAPK signaling pathway, apoptosis, Toll-like receptor signaling pathway, and NF-κB signaling pathway mainly involved. Following the scree-ning of the main toxic and pharmacodynamic components, the pharmacodynamic effects were investigated by cell experiments. The results showed that licochalcone A was mainly responsible for alleviating coryfolin-induced liver injury, licochalcone B for coryfolin-and psoralidin-induced liver injury, and echinatin for corylifolinin-and bakuchiol-induced liver injury. The preliminary revealing of the alleviating effect of Glycyrrhizae Radix et Rhizoma on Psoraleae Fructus-induced liver injury and the prediction of related mechanisms will provide reference for further mechanism research and reasonable clinical compatibility.

The gene polymorphisms of ABCB1, EPHX1, and SCN1A were found to influence carbamazepine (CBZ) metabolism and resistance in epilepsy patients, but the relevance remains controversial. To reveal the relationships among the gene polymorphisms of ABCB1, EPHX1, SCN1A and the metabolism and resistance of CBZ, the databases of PubMed, EMBASE, Cochrane Library, Chinese National Knowledge Infrastructure, Chinese Science and Technique Journals, China Biology medicine disc and Wan Fang were retrieved for suitable studies up to April 2021. 18 studies containing 3293 epilepsy patients were included. The result revealed the gene polymorphism of ABCB1 c.3435C > T is significantly associated with altered concentration-dose ratios of CBZ (CDR CBZ ) (CC vs. CT, OR = 0.25 (95% CI: 0.08-0.42), P = 0.004), and EPHX c.416A > G gene polymorphism may also significantly adjusted the concentration-dose ratios of carbamazepine-10, 11-trans dihydrodiol (CDR CBZD ) (AA vs. GG, OR = 0.48 (95% CI: 0.01-0.96), P = 0.045; AG vs. GG, OR = 0.68 (95% CI: 0.16-1.20), P = 0.010, respectively) and the ratio of CBZD:carbamazepine-10,11-epoxide (CBZE) (CDR CBZD :CDR CBZE ) (AG vs GG, OR = 0.83 (95% CI: 0.31-1.36), P = 0.002). Furthermore, ABCB1 c.3435C > T polymorphism was also observed to be significantly influenced CBZ resistance (CC vs TT, OR = 1.78 (95% CI: 1.17-2.72), P = 0.008; CT vs TT, OR = 1.60 (95% CI: 1.12-2.30), P = 0.01; CC + CT vs TT, OR = 1.61 (95% CI: 1.15-2.26), P = 0.006, respectively). Therefore, CBZ metabolism and resistance in patients with epilepsy may be adjusted by the gene polymorphisms of ABCB1 c.3435C > T and EPHX1 c.416A > G which provides the further scientific basis for clinical individualized therapy of epilepsy. However, larger sample size studies are still needed to provide further conclusive evidence., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Objectives: To investigate the inhibitory effect of cholecystokinin octapeptide (CCK-8) binding to cholecystokinin 2 receptor (CCK2R) on methamphetamine (METH)-induced neuronal apoptosis, and to explore the signal transduction mechanism of β-arrestin 2 in CCK-8 inhibiting METH-induced neuronal apoptosis., Methods: SH-SY5Y cell line was cultured, and HEK293-CCK1R and HEK293-CCK2R cell line were constructed by lentivirus transfection. Small interfering RNA (siRNA) was used to knockdown the expression of β-arrestin 2. Annexin Ⅴ-FITC/PI staining and flow cytometry were used to detect the apoptotic rate of cells, and Western blotting was used to detect the expression of apoptosis-related proteins., Results: The apoptosis of SH-SY5Y cells was induced by 1 mmol/L and 2 mmol/L METH treatment, the number of nuclear fragmentation and pyknotic cells was significantly increased, and the expression of apoptosis-related proteins Bax and cleaved caspase-3 were increased. CCK-8 pre-treatment at the dose of 0.1 mmol/L and 1 mmol/L significantly reversed METH-induced apoptosis in SH-SY5Y cells, and inhibited cell nuclear fragmentation, pyknosis and the changes of apoptosis-related proteins induced by METH. In lentivirus transfected HEK293-CCK1R and HEK293-CCK2R cells, the results revealed that CCK-8 had no significant effect on METH-induced changes of apoptosis-related proteins in HEK293-CCK1R cells, but it could inhibit the expression level of apoptosis-related proteins in HEK293-CCK2R cells induced by METH. The inhibitory effect of CCK-8 on METH-induced apoptosis was blocked by the knockdown of β-arrestin 2 expression in SH-SY5Y cells., Conclusions: CCK-8 can bind to CCK2R and exert an inhibitory effect on METH-induced apoptosis by activating the β-arrestin 2 signal.

In multi-label classification, the strategy of label-specific features has been shown to be effective to learn from multi-label examples by accounting for the distinct discriminative properties of each class label. However, most existing approaches exploit the semantic relations among labels as immutable prior knowledge, which may not be appropriate to constrain the learning process of label-specific features. In this paper, we propose to learn label semantics and label-specific features in a collaborative way. Accordingly, a deep neural network (DNN) based approach named CLIF, i.e. Collaborative Learning of label semantIcs and deep label-specific Features for multi-label classification, is proposed. By integrating a graph autoencoder for encoding semantic relations in the label space and a tailored feature-disentangling module for extracting label-specific features, CLIF is able to employ the learned label semantics to guide mining label-specific features and propagate label-specific discriminative properties to the learning process of the label semantics. In such a way, the learning of label semantics and label-specific features interact and facilitate with each other so that label semantics can provide more accurate guidance to label-specific feature learning. Comprehensive experiments on 14 benchmark data sets show that our approach outperforms other well-established multi-label classification algorithms.

Aims: Coronavirus disease 2019 (COVID-19) has been recognised as a predominantly respiratory tract infection, but some patients manifest severe systemic symptoms/coagulation abnormalities. The aim of this study was to evaluate the impact of severe COVID-19 infection on the gastrointestinal tract., Methods and Results: We examined clinicopathological findings in 28 resected ischaemic bowels from 22 patients with severe COVID-19. Most patients required intubation preoperatively and presented with acute decompensation shortly before surgery. D-dimer levels were markedly elevated in all measured cases (mean, 5394 ng/ml). Histologically, 25 cases (19 patients) showed evidence of acute ischaemia with necrosis. In this group, the most characteristic finding was the presence of small vessel fibrin thrombi (24 of 25 cases, 96%), which were numerous in 64% of cases. Patients with COVID-19 were significantly more likely than a control cohort of 35 non-COVID-19-associated acute ischaemic bowels to show isolated small intestine involvement (32% versus 6%, P < 0.001), small vessel fibrin thrombi (100% versus 43%, P < 0.001), submucosal vessels with fibrinous degeneration and perivascular neutrophils (90% versus 54%, P < 0.001), fibrin strands within submucosal vessels (58% versus 20%, P = 0.007), and histological evidence of pneumatosis (74% versus 34%, P = 0.010). Three cases in this cohort had histopathological findings normally seen in the setting of chronic ischaemia, notably prominent fibroblastic proliferation affecting the outer layer of the muscularis propria., Conclusions: Herein, we describe the histopathological findings in COVID-19-associated ischaemic bowels and postulate a relationship with the hypercoagulable state seen in patients with severe COVID-19 infection. Additional experience with these cases may further elucidate specific features or mechanisms of COVID-19-associated ischaemic enterocolitis., (© 2021 John Wiley & Sons Ltd.)

Background: Intimal hyperplasia is a major complication of restenosis after angioplasty. The abnormal proliferation and oxidative stress of vascular smooth muscle cells (VSMCs) are the basic pathological feature of neointimal hyperplasia. 17β-Estradiol can inhibit VSMCs proliferation and inflammation. However, it is still unclear whether and how 17β-Estradiol affects intimal hyperplasia. Methods: The neointima hyperplasia was observed by hematoxylin/eosin staining. The expression of PCNA, cyclin D1, NOX1, NOX4 and p47 phox in neointima hyperplasia tissues and VSMCs was determined by qRT-PCR and Western blotting. MTS assay, cell counting and EdU staining were performed to detect cells proliferation. The oxidative stress was assessed by ROS staining. Results: 17β-Estradiol suppressed carotid artery ligation-induced intimal hyperplasia, which is accompanied by an increase of BHLHE40 level. Furthermore, loss- and gain-of-function experiments revealed that BHLHE40 knockdown promotes, whereas BHLHE40 overexpression inhibits TNF-α-induced VSMC proliferation and oxidative stress. 17β-Estradiol inhibited TNF-α-induced VSMC proliferation and oxidative stress by promoting BHLHE40 expression, thereby suppressing MAPK signaling pathways. In addition, enforcing the expression of BHLHE40 leads to amelioration of intimal hyperplasia. Conclusions: Our study demonstrates that 17β-Estradiol inhibits proliferation and oxidative stress in vivo and in vitro by promotion of BHLHE40 expression., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Feng, Zheng, Yu, Zhang, Ma, Hao, Wen and Zhang.)

The inner cell mass of the pre-implantation blastocyst consists of the epiblast and hypoblast from which embryonic stem cells (ESCs) and extra-embryonic endoderm (XEN) stem cells, respectively, can be derived. Importantly, each stem cell type retains the defining properties and lineage restriction of its in vivo tissue origin. We have developed a novel approach for deriving porcine XEN (pXEN) cells via culturing the blastocysts with a chemical cocktail culture system. The pXEN cells were positive for XEN markers, including Gata4, Gata6, Sox17, and Sall4, but not for pluripotent markers Oct4, Sox2, and Nanog. The pXEN cells also retained the ability to undergo visceral endoderm (VE) and parietal endoderm (PE) differentiation in vitro. The maintenance of pXEN required FGF/MEK+TGFβ signaling pathways. The pXEN cells showed a stable phenotype through more than 50 passages in culture and could be established repeatedly from blastocysts or converted from the naïve-like ESCs established in our lab. These cells provide a new tool for exploring the pathways of porcine embryo development and differentiation and providing further reference to the establishment of porcine ESCs with potency of germline chimerism and gamete development.

Probiotic administration is a potential strategy against enteric pathogen infection in either clinical treatment or animal nutrition industry, but the administration duration of probiotics varied and the underlying mechanisms remain unclear. A strain (YC) affiliated to Pediococcus pentosaceus , a commonly used probiotic, was isolated from fish gut and the potential role of YC against Aeromonas hydrophila was detected in zebrafish. We found that 3- or 4-week YC administration (YC3W or YC4W) increased the resistance against A. hydrophila while 1- or 2-week treatment (YC1W or YC2W) did not. To determine the possible reason, intestinal microbiota analysis and RNAseq were conducted. The results showed that compared with CON and YC1W, YC4W significantly increased the abundance of short-chain fatty acids (SCFAs) producing bacteria and elevated the gene expression of nlrp3 . Higher butyrate content and enhanced expression of IL1β were subsequently found in YC4W. To identify the causal relationship between butyrate and the higher pathogen resistance, different concentrations of sodium butyrate (SB) were supplemented. The results suggested that 10 mmol/kg SB addition mirrored the protective effect of YC4W by increasing the production of IL-1β. Furthermore, the increased IL-1β raised the percentage of intestinal neutrophils, which endued the zebrafish with A. hydrophila resistance. In vivo knockdown of intestinal il1b eliminated the anti-infection effect. Collectively, our data suggested that the molecular mechanism of probiotics determined the administration duration, which is vital for the efficiency of probiotics. Promoting host inflammation by probiotic pretreatment is one potential way for probiotics to provide their protective effects against pathogens., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Shan, Li, Liu, Xu, Qiao, Du and Zhang.)

In the electronics industry environment, rapid recognition of objects to be grasped from digital images is essential for visual guidance of intelligent robots. However, electronic components have a small size, are difficult to distinguish, and are in motion on a conveyor belt, making target detection more difficult. For this reason, the YOLOv4-tiny method is used to detect electronic components and is improved. Then, different network structures are built for the adaptive integration of middle- and high-level features to address the phenomenon in which the original algorithm integrates all feature information indiscriminately. The method is deployed on an electronic component dataset for validation. Experimental results show that the accuracy of the original algorithm is improved from 93.74 to 98.6%. Compared with other current mainstream algorithms, such as Faster RCNN, SSD, RefineDet, EfficientDet, and YOLOv4, the method can maintain high detection accuracy at the fastest speed. The method can provide a technical reference for the development of manufacturing robots in the electronics industry., (© 2021. The Author(s).)

Background: The etiology and pathogenesis of cough are complex. As a Chinese patent medicine that has been on the market, ErtongKe (ETK) granules have a good effect in treating acute and chronic cough in children. The purpose of this research was to determine the bioactive components and possible action mechanisms of ETK in the treatment of cough using an integrated network pharmacology method., Methods: The Traditional Chinese Medicine Systems Pharmacology (TCMSP) and Swiss target prediction databases were used to screen the potential components and associated targets of ETK. The Genecards database was then used to gather targets interacting with cough. An analysis of the signaling pathways associated with ETK for cough treatment was carried out using the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and Gene Ontology (GO) enrichment analysis methods. Cytoscape 3.8.1 was used to design the protein-protein interaction (PPI) and compound-target-pathway networks. Finally, the important genes and active components of ETK were confirmed using Auto Dock vina and Discovery studio software., Results: Total 242 active components of ETK were screened, 1,173 potential targets related to the ingredients and 4,400 targets related to cough were collected separately. Moreover, 600 candidate targets and 39 signaling pathways were determined. We also screened out the following core components, including tuberostemonone, quercetin, kaempferol, praeruptorin E, stigmasterol, oroxylin A, and other potentially active ingredients. At the same time, 8 core targets, including JUN, PIK3CA, PIK3R1, MAPK14, EGFR, SRC, AKT1, and MAPK1, and 20 key pathways, including the cAMP signaling pathway, calcium signaling pathway, and PI3K-Akt signaling pathway among others, were also selected. All the 8 core targets were verified by molecular docking., Conclusions: This research established that ETK exerts anti-cough activity by modulating several targets and pathways through multiple components. Additionally, the pooled results shed light on ETK compounds being investigated as potential antitussives.

Intracellular transport is the basis for the transfer of matter, energy, and information in cells and is critical to many cellular functions. Within the nonequilibrium environment of living cells, the transport behaviours are far from the traditional motion in liquid but are more complex and active. With the advantage of high spatial and temporal resolution, the single-particle tracking (SPT) method is widely utilized and has achieved great advances in revealing intracellular transport dynamics. This review describes intracellular transport from a physical perspective and classifies it into two modes: diffusive motion and directed motion. The biological functions and physical mechanisms for these two transport modes are introduced. Next, we review the principle of SPT and its advances in two aspects of intracellular transport. Finally, we discuss the prospect of near infrared SPT in exploring the in vivo intracellular transport dynamics., Competing Interests: Ming-Li Zhang, Hui-Ying Ti, Peng-Ye Wang and Hui Li declare that they have no conflict of interest., (© The Author(s) 2021.)

Partial multi-label learning (PML) deals with the problem where each training example is associated with an overcomplete set of candidate labels, among which only some candidate labels are valid. The task of PML naturally arises in learning scenarios with inaccurate supervision, and the goal is to induce a multi-label predictor which can assign a set of proper labels for unseen instance. The PML training procedure is prone to be misled by false positive labels concealed in the candidate label set, which serves as the major modeling difficulty for partial multi-label learning. In this paper, a novel two-stage PML approach is proposed which works by eliciting credible labels from the candidate label set for model induction. In the first stage, the labeling confidence of candidate label for each PML training example is estimated via iterative label propagation. In the second stage, by utilizing credible labels with high labeling confidence, multi-label predictor is induced via pairwise label ranking coupled with virtual label splitting or maximum a posteriori (MAP) reasoning. Experimental studies show that the proposed approach can achieve highly competitive generalization performance by excluding most false positive labels from the training procedure via credible label elicitation.

Disease burden prior to hematopoietic cell transplantation (HCT) is difficult to assess in myelodysplastic syndrome (MDS), particularly in patients without excess blasts. We assessed whether morphologic dysplasia at the time of transplant can be a metric of disease burden that is associated with post-transplant outcomes in MDS patients. We identified 84 MDS patients undergoing allogeneic HCT at our institution between 2010 and 2017 who received a bone marrow evaluation immediately prior to HCT. Dysplasia was independently determined by two hematopathologists blinded to existing pathology reports. Erythroid nuclear dysplasia, but not megakaryocytic or myeloid, was associated with post-HCT outcomes. Presence compared to absence of erythroid nuclear dysplasia was associated with lower 2-year progression-free survival (PFS; 34 % vs 62 %, p = 0.0495) and 2-year overall survival (OS; 34 % vs 62 %, p = 0.042). In a multivariate analysis including age, IPSS-R at the time of transplant, pre-HCT therapy, and donor type as covariates, erythroid nuclear dysplasia remained associated with lower PFS (HR 2.6, p = 0.036) and OS (HR 2.7, p = 0.028). Dysplasia assessment prior to transplant may serve as an estimate of disease burden in MDS and identify high-risk patients who merit additional therapies pre- or post-transplant., (Copyright © 2021. Published by Elsevier Ltd.)

Objective To compare the efficacy and safety of cyclosporin A(CsA)and CsA combined with recombined human erythropoietin(rhEPO)in the treatment of patients with chronic aplastic anemia(CAA).Methods Data of 79 patients with CAA treated at Department of Hematology,PUMC Hospital between January 2016 and June 2018 were collected for retrospective analysis.Forty-five patients were treated with CsA+rhEPO,and the other 34 patients with CsA alone.All the enrolled patients were treated for at least 1.5-2.0 years and followed for at least 1.0 year.The efficacy,side effects,long-term outcomes were compared between the two groups,and factors that may influence the efficacy were analyzed.Results The patients treated with CsA+rhEPO included 14 males and 31 females,with a median age of 43(19,73)years old.The median treatment duration of CsA and rhEPO was 26(12,38)and 4(3,6)months,respectively,and the median followed-up time was 24(12,42)months.The patients treated with CsA alone included 16 males and 18 females,with a median age of 36(16,85)years old.The median CsA treatment duration was 24(12,40)months and the median follow-up time was 25(12,40)months.There was no statistical difference in baseline characteristics between the two groups(all P >0.05).After 6 months of treatment,CsA+rhEPO group had higher overall response(OR)rate(55.6% vs. 31.3%; χ 2 =4.456, P =0.040)and partial response(PR)rate(53.3% vs. 25.0%; χ 2 =6.181, P =0.019)than CsA group,and the complete response(CR)rate showed no statistical difference between the two groups(2.2% vs. 6.3%; χ 2 =0.810, P =0.567).The CR,PR,and OR rates showed no statistical difference between the two groups after 3 and 12 months of treatment and at the end of follow-up(all P >0.05).Similarly,the hemoglobin level at the sixth month of treatment with CsA+rhEPO was higher than that with CsA alone [(102.6±24.0)g/L vs. (90.3±29.1)g/L; t =2.017, P =0.047].However,it showed no significant difference between the two groups at other time points(all P >0.05).The side effects,including an increase in serum creatinine,slight increase in bilirubin,increase in aminotransferase,mild to moderate gingival hyperplasia,gastrointestinal reaction,and muscular fibrillation,had no significant differences between the two groups(all P >0.05),except that 11.1%(5/45)patients in the CsA+rhEPO group reported soreness at the injection site.The two groups showed similar rates of clonal revolution during the follow-up period and no death.No clinical factor was found for prediction of the efficacy of CsA+rhEPO. Conclusion CsA+rhEPO has higher OR rate and hemoglobin level than CsA alone at the sixth month of treatment,and it has similar side effects compared with CsA alone.

Diet and host genetics influence the composition of intestinal microbiota, yet few studies have compared the function of intestinal microbiota in the diet- or genotype-induced lipid deposition, which limits our understanding of the role of intestinal bacteria in metabolic disorders. The lipid accumulation in wild-type zebrafish fed with control (CON) or high-fat (HF) diet and two gene-knockout zebrafish lines ( cpt1b -/- or pparab -/- ) fed with control diet was measured after a 4-week feeding experiment. The intestinal microbiota composition of these groups was investigated using 16S ribosomal RNA (rRNA) gene sequencing (DNA-based) and 16S rRNA sequencing (RNA-based). The HF diet or deficiency of two genes induced more weight gain and higher triglyceride content in the liver compared with their control group. 16S rRNA gene sequencing (DNA-based) indicated the decreased abundance of Proteobacteria in the HF group compared with CON, but there was no significant difference in bacterial α diversity among treatments. 16S rRNA sequencing (RNA-based) confirmed the decreased abundance of Proteobacteria and the bacterial α diversity in the HF group compared with CON. Deficiency of cpt1b or pparab showed less change in microbiota composition compared with their wild-type group. Intestinal microbiota of each group was transferred to germ-free zebrafish, and the quantification of Nile red staining indicated that the intestinal microbiota of the HF group induced more lipid accumulation compared with CON, whereas intestinal microbiota of cpt1b -/- and pparab -/- zebrafish did not. The results showed that RNA-based bacterial sequencing revealed more bacterial alteration than DNA-based bacterial sequencing. HF diet had a more dominant role in shaping gut microbiota composition to induce lipid accumulation compared with the gene-knockout of cpt1b or pparab in zebrafish, and the transplant of intestinal microbiota from HF-fed fish induced more lipid deposition in germ-free zebrafish. Together, these data suggested that a high-fat diet exerted a more dominant role over the deletion of cpt1b or pparab on the intestinal bacterial composition, which corresponded to lipid accumulation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Qiao, Tan, Li, Lv, Chen, Du and Zhang.)

Phenotypic switch of vascular smooth muscle cells (VSMCs) is important in vascular remodeling which causes hyperplasia and restenosis after intimal injury. Platelets are activated at injured intima and secrete platelet-derived microvesicles (PMVs). Herein, we demonstrated the role of PMVs in VSMC phenotypic switch and the potential underlying mechanisms. In vivo , platelets were locally adhered and activated at intimal injury site, while Lamtor1 was promoted and VSMCs were dedifferentiated. PMVs, collected from collagen-activated platelets in vitro which mimicked collagen exposure during intimal injury, promoted VSMC dedifferentiation, induced Lamtor1 expression, and activated mTORC1 signaling, reflected by the phosphorylation of two downstream targets, i.e., S6K and 4E-BP1. Knockdown of Lamtor1 with small interfering RNA attenuated these processes induced by PMVs. Based on the previously published proteomic data, Ingenuity Pathway Analysis revealed that Src may participate in regulating effects of PMVs. Src inhibitor significantly reversed the effects of PMVs on VSMC dedifferentiation, Lamtor1 expression and mTORC1 activation. Furthermore, in SMC-specific Lamtor1 knockout mice, intimal hyperplasia was markedly attenuated after intimal injury compared with the wild type. Our data suggested that PMVs secreted by activated platelets promoted VSMC dedifferentiation via Src/Lamtor1/mTORC1 signaling pathway. Lamtor1 may be a potential therapeutic target for intimal hyperplasia after injury., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Liu, Bao, Fan, Li, Yao, Han, Zhang, Jiang and Qi.)

High level of carbohydrate in aquafeed could achieve cost-sparing effect, but it may cause adverse effects on flesh quality of aquatic products. An eight-week trial was conducted to investigate whether oligosaccharides-supplementation, including Galacto-oligosaccharides (GOS) and xylo-oligosaccharide (XOS), could systematically improve the growth performance, texture characteristics and nutrition composition of Nile tilapia fed with high-carbohydrate diet. The results indicated that GOS-supplementation improved the amino acid composition, while XOS-supplementation showed beneficial effects on growth performance. High-carbohydrate diet had adverse effects on fillet texture, while oligosaccharide-supplementation regulated the expression of muscle development-related genes to help restoring muscle texture properties. Furthermore, either high-carbohydrate or addition of oligosaccharides could change the intestinal microbiota composition and their metabolites. Further correlation analysis suggested that intestinal microbiota may account for the improvement in fish growth condition and texture characteristics. Application of oligosaccharides may be an innovative strategy for flesh quality modulation in aquaculture., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2021 The Author(s).)

Neutral lipases-mediated lipolysis and acid lipases-moderated lipophagy are two main processes for degradation of lipid droplets (LDs). However, the individual and interactive roles of these metabolic pathways are not well known across vertebrates. This study explored the roles of lipolysis and lipophagy from the aspect of neutral and acid lipases in zebrafish. We established zebrafish strains deficient in either adipose triglyceride lipase (atgl -/- ; AKO fish) or lysosomal acid lipase (lal -/- ; LKO fish) respectively, and then inhibited lipolysis in the LKO fish and lipophagy in the AKO fish by feeding diets supplemented with the corresponding inhibitors Atglistatin and 3-Methyladenine, respectively. Both the AKO and LKO fish showed reduced growth, swimming activity, and oxygen consumption. The AKO fish did not show phenotypes in adipose tissue, but mainly accumulated triacylglycerol (TAG) in liver, also, they had large LDs in the hepatocytes, and did not stimulate lipophagy as a compensation response but maintained basal lipophagy. The LKO fish reduced total lipid accumulation in the body but had high cholesterol content in liver; also, they accumulated small LDs in the hepatocytes, and showed increased lipolysis, especially Atgl expression, as a compensatory mechanism. Simultaneous inhibition of lipolysis and lipophagy in zebrafish resulted in severe liver damage, with the potential to trigger mitophagy. Overall, our study illustrates that lipolysis and lipophagy perform individual and interactive roles in maintaining homeostasis of TAG and cholesterol metabolism. Furthermore, the interactive roles of lipolysis and lipophagy may be essential in regulating the functions and form of mitochondria., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Objective: To investigate the clinical efficacy and safety of compound wild chrysanthemum eye masks for mild and moderate dry eye. Methods: In this double-masked, multicenter, placebo-controlled, randomized trial, middle-aged and elderly patients with mild and moderate dry eye were enrolled from six hospitals (Xiamen Eye Center of Xiamen University, China-Japan Friendship Hospital, Peking Union Medical College Hospital, Wangjing Hospital of China Academy of Chinese Medical Sciences, Affiliated Eye Hospital of Shandong University of Traditional Chinese Medicine and Hebei Eye Hospital). The patients were assigned to the compound wild chrysanthemum eye mask group and the eye mask simulator group based on the random number table. Subjective symptoms of dry eye, visual acuity, break-up time (BUT), Schirmer Ⅰ test, and corneal fluorescent staining were evaluated in all patients before treatment and at 1 and 2 weeks after treatment. All adverse reactions during the treatment and follow-up were recorded. Results: A total of 120 patients were enrolled. Among them, 112 subjects were included for statistical analyses after the exclusion of 8 subjects who were lost for follow-up or had an adverse event, with an age of (54.26±7.44) years. All the indicators were equally comparable between the two groups. Before treatment and at 1 and 2 weeks after treatment, the median (lower quartile, upper quartile) of total score of questionnaires in the eye mask group was 14.50 (10.00, 19.00), 9.00 (5.00, 14.00) and 7.00 (4.00, 10.00), respectively, and that in the control group was 14.00 (9.00, 22.50), 12.00 (6.00, 20.00) and 10.00 (3.50, 17.00), respectively. The score decreased significantly in both groups after 1 week ( t =9.1604, S =398.00; P< 0.01) and 2 weeks ( S =681.00, 575.50; P <0.05) of treatment. The total score of questionnaires in the eye mask group was significantly lower than that in the control group ( Z =3.27, 2.81; P< 0.05) after treatment. After 1 week of treatment, the average BUT of the eye mask group was (5.71±2.31) s, which was significantly longer than that before treatment (5.06±2.00) s ( S =208.50, P< 0.05). But there was no significant difference in the control group ( S =150.00, P >0.05). After 2 weeks of treatment, there was statistically significant difference in BUT between the two groups ( S =407.00, t =3.07; P <0.01). After 1 week of the treatment, the amount of tear secretion in the eye mask group [(6.88±4.78) mm] was significantly larger than that before treatment ( S =196.50, P <0.05), while the control group [(6.80±5.85) mm] showed no significant difference ( S =55.00, P <0.05). After 2 weeks of the treatment, the amount increased significantly to (7.43±4.86) mm and (7.29±4.56) mm, respectively, in both groups ( t =-3.29, -2.26; P <0.05). The difference in the average BUT, Schirmer Ⅰ test result and corneal fluorescent staining between both groups was not statistically significant at each time point. Five mild adverse events occurred, including 2 adverse events (2 times, 3.51%) in the eye mask group and 3 adverse events (4 times, 5.36%) in the control group. Conclusions: Compound wild chrysanthemum eye masks can effectively improve the symptoms and physical signs of mild and moderate dry eye and can be used as an auxiliary treatment. (Chin J Ophthalmol, 2021, 57: 601-607) .

A high-carbohydrate diet could achieve a protein-sparing effect, but it may cause negative impacts on the growth condition of fish due to their poor utilisation ability of carbohydrate. How to reduce the adverse effects caused by a high-carbohydrate diet is important for the development of aquaculture. In the present study, we aimed to identify whether inulin could attenuate the metabolic syndrome caused by a high-carbohydrate diet in fish. Nile tilapia (Oreochromis niloticus) (1·19 (sd 0·01) g) were supplied with 35 % carbohydrate (CON), 45 % carbohydrate (HC) and 45 % carbohydrate + 5 g/kg inulin (HCI) diets for 10 weeks. The results showed that addition of inulin improved the survival rate when fish were challenged with Aeromonas hydrophila, indicating that inulin had an immunostimulatory effect. Compared with the HC group, the HCI group had lower lipid accumulation in liver and the gene expression analyses indicated that addition of inulin down-regulated genes related to lipogenesis and up-regulated genes relevant to β-oxidation significantly (P < 0·05). Higher liver glycogen and glucose tolerance were found in the HCI group compared with the HC group (P < 0·05). These results indicated that inulin could alleviate the metabolic syndrome induced by a high-carbohydrate diet. Furthermore, addition of inulin to a high-carbohydrate diet changed the intestinal bacterial composition and significantly increased the concentration of acetic acid and propionic acid in fish gut which have the potential to increase pathogen resistance and regulate metabolic characteristics in fish. Collectively, our results demonstrated a possible causal role for the gut microbiome in metabolic improvements induced by inulin in fish.

Background: As a highly contagious disease, coronavirus disease 2019 (COVID-19) is wreaking havoc around the world due to continuous spread among close contacts mainly via droplets, aerosols, contaminated hands or surfaces. Therefore, centralized isolation of close contacts and suspected patients is an important measure to prevent the transmission of COVID-19. At present, the quarantine duration in most countries is 14 d due to the fact that the incubation period of severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) is usually identified as 1-14 d with median estimate of 4-7.5 d. Since COVID-19 patients in the incubation period are also contagious, cases with an incubation period of more than 14 d need to be evaluated., Case Summary: A 70-year-old male patient was admitted to the Department of Respiratory Medicine of The First Affiliated Hospital of Harbin Medical University on April 5 due to a cough with sputum and shortness of breath. On April 10, the patient was transferred to the Fever Clinic for further treatment due to close contact to one confirmed COVID-19 patient in the same room. During the period from April 10 to May 6, nucleic acid and antibodies to SARS-CoV-2 were tested 7 and 4 times, respectively, all of which were negative. On May 7, the patient developed fever with a maximum temperature of 39℃, and his respiratory difficulties had deteriorated. The results of nucleic acid and antibody detection of SARS-CoV-2 were positive. On May 8, the nucleic acid and antibody detection of SARS-CoV-2 by Heilongjiang Provincial Center for Disease Control were also positive, and the patient was diagnosed with COVID-19 and reported to the Chinese Center for Disease Control and Prevention., Conclusion: This case highlights the importance of the SARS-CoV-2 incubation period. Further epidemiological investigations and clinical observations are urgently needed to identify the optimal incubation period of SARS-CoV-2 and formulate rational and evidence-based quarantine policies for COVID-19 accordingly., Competing Interests: Conflict-of-interest statement: All authors declare that they have no conflicts of interest., (©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.)

Additional sex combs-like 1 (ASXL1) interacts with BRCA1-associated protein 1 (BAP1) deubiquitinase to oppose the polycomb repressive complex 1 (PRC1)-mediated histone H2A ubiquitylation. Germline BAP1 mutations are found in a spectrum of human malignancies, while ASXL1 mutations recurrently occur in myeloid neoplasm and are associated with poor prognosis. Nearly all ASXL1 mutations are heterozygous frameshift or nonsense mutations in the middle or to a less extent the C-terminal region, resulting in the production of C-terminally truncated mutant ASXL1 proteins. How ASXL1 regulates specific target genes and how the C-terminal truncation of ASXL1 promotes leukemogenesis are unclear. Here, we report that ASXL1 interacts with forkhead transcription factors FOXK1 and FOXK2 to regulate a subset of FOXK1/K2 target genes. We show that the C-terminally truncated mutant ASXL1 proteins are expressed at much higher levels than the wild-type protein in ASXL1 heterozygous leukemia cells, and lose the ability to interact with FOXK1/K2. Specific deletion of the mutant allele eliminates the expression of C-terminally truncated ASXL1 and increases the association of wild-type ASXL1 with BAP1, thereby restoring the expression of BAP1-ASXL1-FOXK1/K2 target genes, particularly those involved in glucose metabolism, oxygen sensing, and JAK-STAT3 signaling pathways. In addition to FOXK1/K2, we also identify other DNA-binding transcription regulators including transcription factors (TFs) which interact with wild-type ASXL1, but not C-terminally truncated mutant. Our results suggest that ASXL1 mutations result in neomorphic alleles that contribute to leukemogenesis at least in part through dominantly inhibiting the wild-type ASXL1 from interacting with BAP1 and thereby impairing the function of ASXL1-BAP1-TF in regulating target genes and leukemia cell growth.

Low winter temperatures in temperate climates can limit the success of non-native species. The Asian longhorned beetle, Anoplophora glabripennis, is an invasive wood-boring pest of hardwood trees in North America and Europe. Native A. glabripennis populations are spread across several climate zones in China and the Korean Peninsula and are likely to encounter low temperatures in at least some of this range. Understanding the lethal limits of the overwintering life stages of A. glabripennis is essential for accurately modeling the risk that invasive populations pose to non-native environments. In this study, we provide the first systematic characterization of the cold tolerance strategy and lower lethal limits of A. glabripennis eggs, larvae, and pupae. In diapausing larvae, the most common overwintering stage in this species, we measure hemolymph glycerol and osmolality and identify the effects of prolonged low temperature exposure. In developing pupae, we identify sublethal effects caused by low temperature exposure before freezing. Eggs and larvae were the most cold-tolerant life stages; eggs were freeze-avoidant with an average supercooling point of -25.8 °C and larvae were freeze tolerant with an LT 90 of -25 °C. Hemolymph osmolality of freeze-tolerant larvae, on average, increased to 811 mOsm during chilling. This increase was primarily driven by a concurrent, average increase of 232 mM hemolymph glycerol. Pupae died upon exposure to freezing temperatures, but accumulate strong sublethal effects prior to freezing, indicating that they are chill susceptible. Taken together, these data will be useful to inform species distribution modeling in A. glabripennis., (Crown Copyright © 2021. Published by Elsevier Inc. All rights reserved.)

Excessive release of cytokines such as IL-1 β and other inflammatory mediators synthesized and secreted by macrophages is the fundamental link of uncontrolled inflammatory response in sepsis. 17 β -Estradiol (E2) plays anti-inflammatory and vascular protective effects by regulating leukocyte infiltration and the expression of chemokines or cytokines induced by injury. However, the role of E2 in the inflammatory response of macrophages in sepsis and its mechanism are still not fully understood. In the present study, we show that E2 alleviates vascular inflammation in sepsis mice induced by cecal ligation puncture (CLP). E2 significantly decreases RAW 264.7 cell inflammation response by downregulating the expression of NLRP3. Furthermore, we found that miR-29a-5p was significantly downregulated in LPS-treated macrophages. Treating RAW 264.7 cells with E2 markedly upregulated the miR-29a-5p expression level. More importantly, we demonstrated that miR-29a-5p repressed NLRP3 expression by directly targeting its 3'-UTR. Loss- and gain-of-function experiments revealed that transfection of the miR-29a-5p mimic abrogates LPS-induced macrophage inflammation. Moreover, depletion of miR-29a-5p by its inhibitor largely promotes LPS-induced macrophage inflammation. In summary, miR-29a-5p upregulation induced by E2 alleviated RAW 264.7 cell inflammation response by aggravating miR-29a-5p repression of NLRP3 expression. E2 exerts significant anti-inflammatory efficacy in macrophages by regulating the miR-29a-5p/NLRP3 axis. Targeting miR-29a-5p may be a novel therapeutic strategy to suppress sepsis-induced vascular inflammation., Competing Interests: The authors have no conflict of interest to disclose., (Copyright © 2021 Man-li Zhang et al.)

To investigate the community structure and diversity of endophytic fungi in the leaves of Artemisia argyi , leaf samples were collected from five A. argyi varieties grown in different cultivation areas in China, namely, Tangyin Beiai in Henan (BA), Qichun Qiai in Hubei (QA), Wanai in Nanyang in Henan (WA), Haiai in Ningbo in Zhejiang (HA), and Anguo Qiai in Anguo in Hebei (AQA), and analyzed using Illumina high-throughput sequencing technology. A total of 365,919 pairs of reads were obtained, and the number of operational taxonomic units for each sample was between 165 and 285. The alpha diversity of the QA and BA samples was higher, and a total of two phyla, eight classes, 12 orders, 15 families, and 16 genera were detected. At the genus level, significant differences were noted in the dominant genera among the samples, with three genera being shared in all the samples. The dominant genus in QA was Erythrobasidium , while that in AQA, HA, and BA was Sporobolomyces , and that in WA was Alternaria , reaching a proportion of 16.50%. These results showed that the fungal community structure and diversity in QA and BA were high. The endophytes are of great importance to the plants, especially for protection, phytohormone and other phytochemical production, and nutrition. Therefore, this study may be significant with the industrial perspective of Artemisia species., Competing Interests: Conflict of interest The authors do not report any financial or personal connections with other persons or organizations, which might negatively affect the contents of this publication and/or claim authorship rights to this publication., (© 2021 Qiu-Fang Wu et al.)

Fungi are a rich source of novel anticancer compounds. Bioassay-guided isolation has led to the isolation of four polyketide-amino acid hybrid compounds with trans -fused decalin system from the fungus Thermothelomyces thermophilus ATCC 42464 (= Myceliophthora thermophila ATCC 42464): myceliothermophins A, B, E and F ( 1 - 4 ). The structure of the new compound (myceliothermophin F, compound 4 ) was clearly determined by a combination of nuclear magnetic resonance (NMR) analysis and high-resolution electrospray ionisation mass spectroscopy (HRESIMS). The new compound exhibited promising cytotoxicity against some cell lines derived from colorectal carcinoma, hepatic carcinoma and gastric carcinoma, indicating that compounds with trans -fused decalin system would be promising in the course of developing novel anticancer drugs.

Epstein-Barr virus (EBV) T/NK-cell lymphoproliferative diseases are characterized by clonal expansion of EBV-infected T or NK cells, including chronic active EBV infection of T/NK-cell type (CAEBV + T/NK), EBV-associated hemophagocytic lymphohistiocytosis (EBV + HLH), extranodal NK/T-cell lymphoma of nasal type (ENKTL), and aggressive NK-cell leukemia (ANKL). However, the role of inherited genetic variants to EBV + T/NK-LPDs susceptibility is still unknown. A total of 171 nonimmunosuppressed patients with EBV + T/NK-LPDs and 104 healthy donors were retrospectively collected and a targeted sequencing study covering 15 genes associated with lymphocyte cytotoxicity was performed. The 94 gene variants, mostly located in UNC13D, LYST, ITK, and PRF1 genes were detected, and mutations covered 28/50 (56.00%) of CAEBV-T/NK, 31/51 (60.78%) of EBV + HLH, 13/28 (46.42%) of ENKTL, and 13/48 (27.09%) of ANKL. Most mutations represented monoallelic and missense. Three-year overall survival rate of patients with CAEBV-T/NK and EBV + HLH was significantly lower in patients with germline mutations than in those without germline mutations (P=0.0284, P=0.0137). Our study provided novel insights into understanding a spectrum of nonimmunosuppressed EBV + T/NK-LPDs with respect to genetic defects associated with lymphocyte cytotoxicity and reminded us that the gene sequencing may be an auxiliary test for diagnosis and risk stratification of EBV + T/NK-LPDs., (© 2021. The Author(s).)

Objective: The aim of the study was to perform a systematic literature search and conduct a meta-analysis of studies comparing clinical and functional outcomes of open reduction with internal fixation (ORIF) using a volar plate and closed reduction with casting for distal radius fracture in older adults (≥60 years of age)., Materials and Methods: A comprehensive electronic search was done for PubMed, Scopus, CENTRAL (Cochrane Central Register of Controlled Trials), and Google scholar databases. Only randomized controlled trials (RCTs) comparing the two treatment modalities for functional and clinical outcomes were eligible to be included., Results: A total of 5 RCTs were included. The pooled estimates suggested reduced DASH scores (WMD 5.62; 95% CI, -8.55, -2.69) and improved grip strength [Grip strength compared to the contralateral side (%): WMD 13.07; 95% CI, 6.11, 20.02] in subjects receiving ORIF with volar plating. There were no significant differences in the range of motion of the wrist joint, pain scores, and rates of complications between the two treatment modalities. The overall quality of the included studies was moderate., Conclusions: Our study indicates that older adults treated with volar plating for fracture of distal radius have better DASH scores and improved grip strengths. However, improved DASH scores may not be clinically relevant. Furthermore, there may be no difference in pain scores, ROM, and the rates of complications between the two treatment modalities. Further trials with large sample size are required to provide more robust evidence on this topic.

Background: The lack of understanding of molecular pathologies of the solitary functioning kidney makes improving and strengthening the continuity of care between pediatric and adult nephrological patients difficult. Copy number variations (CNVs) account for a molecular cause of solitary functioning kidney, but characterization of the pathogenic genes remains challenging., Methods: In our prospective cohort study, 99 fetuses clinically diagnosed with a solitary functioning kidney were enrolled and evaluated using chromosomal microarray analysis (CMA). The genetic drivers for the pathogenic CNVs were analyzed. We characterized QPRT localization in fetal kidneys using immunohistochemistry and its expression in adult kidneys using quantitative RT-PCR. Further, QPRT was knocked down using siRNA in human embryonic kidney (HEK293T) cells, and the cell cycle and proliferation were tested., Results: Besides one Triple X syndrome and one Down syndrome, we identified a total of 45 CNVs out of 34 subjects. Among the 14 pathogenic CNVs, CNV 16p11.2 reached the highest number of records with the phenotype of kidney anomalies in the Decipher database. Among the 26 genes within the 16p11.2 region, as a key enzyme for nicotinamide adenine dinucleotide (NAD+) biosynthesis, QPRT was distinctly localized in renal tubules but was barely observed in renal interstitial and glomeruli in fetal kidneys. The loss of QPRT prevented cells' efficient transition into S phase, affected cell-cycle progression, and abrogated proliferation of human embryonic kidney cells., Conclusion: Our data suggest that QPRT is a candidate gene associated with susceptibility for solitary functioning kidney. The CNVs discovered in our study exhibit great potential for future applications in genetic counseling and pregnancy management., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Zhou, Zheng, Han, Wang, Zhang, Shu, Zhang, Liu and Ding.)

Background: Schistosomiasis is very common in the southern part of the Yangtze River Basin in China. It is mainly manifested as appendicitis, ulcers, hematomas, and thickening of the intestinal tract. Schistosomiasis of the appendix is rare, mainly manifested as appendicitis, which is easy to be misdiagnosed., Case Presentation: Here we report a rare case of a Chinese female whose intestinal mass manifested as intestinal polyps and was eventually diagnosed pathologically as schistosomiasis infection (appendix schistosomiasis). So far, there are rare relevant cases reported., Conclusions: Intestinal schistosomiasis is easily misdiagnosed, and appendix schistosomiasis is rare. The final diagnosis requires pathology, especially surgical pathology.

Sesarmops sinensis is a dominant omnivorous crab species, which plays an important ecological function in salt marsh ecosystems. To better understand its immune system and immune related genes under pathogen infection, the transcriptome was analyzed by comparing the data of S. sinensis hepatopancreas stimulated by PBS and PGN. A set of assembly and annotation identified 39,039 unigenes with an average length of 1105 bp, obtaining 1300 differentially expressed genes (DEGs) in all, which included 466 remarkably up-regulated unigenes and 834 remarkably down-regulated unigenes. In addition, based on mensurable real time-polymerase chain reaction and high-throughput sequencing, several immune responsive genes were found to be markedly up-regulated under PGN stimulation. In conclusion, in addition to enriching the existing transcriptome data of S. sinensis, this study also clarified the immune response of S. sinensis to PGN stimulation, which will help us to further understand the crustacean's immune system., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Hypoxia and high-fat diet (HFD) feeding are two factors commonly existing in aquaculture. However, their individual and combined effects on nutrient composition and flesh quality in fish have not been investigated. The present study evaluated the alterations of growth, nutrient composition and flesh quality in Nile tilapia (initially 7.0 ± 0.1 g and 5.6 ± 0.2 cm) fed with normal fat diet (5.95% fat) or HFD (11.8% fat) at two dissolved oxygen levels (1.1 ± 0.1 and 7.2 ± 0.1 mg/L) for 8 weeks. The results showed that hypoxia and HFD had similar effects in inducing lipid deposition, reducing flesh protein and amino acids content, pH values and water holding ability. Hypoxia had additional adverse effects in decreasing meat yield, flesh contents of n-3 PUFA and glycogen, increasing flesh fragmentation and causing liver damages. The combination of hypoxia and HFD significantly decreased feed intake, survival rate and muscle protein content, but didn't affect flesh quality-related parameters., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Objective: To describe the clinical manifestations, neuroimaging, cerebrospinal fluid(CSF) cytology and prognosis of Leptomeningeal metastases(LM). Methods: The clinical manifestations, imaging features and CSF cytology of LM patients admitted to Henan Provincial People's Hospital from May 1, 2015 to May 31, 2020 were retrospectively analyzed. The overall survival (OS) was evaluated by the time from the diagnosis of LM to death. Results: A total of 88 patients with LM were enrolled in the study, and the median age was 59 years (range:28-78 years). There were 42 males (47.7%) and 46 females (52.3%). According to the pathological classification, it was lung cancer in 58 cases (65.9%), gastric cancer in 13 cases (14.8%), breast cancer in 7 cases (8.0%), melanoma in 1 case, esophageal cancer in 1 case, gallbladder cancer in 1 case, renal cell carcinoma in 1 case, double source cancer in 2 cases, and unknown source in 4 cases. The median Karnofsky Performance Scale (KPS) score was 50. LM was the initial manifestation of cancer in 34 patients. All patients had LM-related clinical symptoms, including headache in 73 cases (83.0%), nausea and vomiting in 63 cases (71.6%), abnormal physical and mental behaviors in 37 cases (42.0%), seizure in 41 cases (46.6%). Cranial nerve involvement was observed in 23 patients (39.0%) and spinal nerve involvement in 20(33.9%). There were 61 patients (83.6%) who showed neuroimaging features of LM. Tumor cells or atypical cells were found in 90.8% of patients for the first time, and activated monocytes in 47 cases (54.7%). The median OS was 13.0 weeks (95% CI :2.9-23.1) with the 1-year survival rate of 19.1%. Univariate analysis of survival indicated that lung cancer, lower KPS score, tyrosine kinase inhibitors (TKIs) and whole brain radiotherapy were favorable predictors of survival ( P <0.05). Conclusions: The overall prognosis of LM is poor. Good physical condition, TKIs treatment and whole brain radiotherapy might improve clinical outcomes of LM patients.

Mg-Li based alloys have been widely used in various fields. However, the widespread use of Mg-Li based alloys were restricted by their poor properties. The addition of rare earth element in Mg-Li can significantly improve the properties of alloys. In the present work, different electrochemical methods were used to investigate the electrochemical behavior of Y(iii) on the W electrode in LiCl-KCl melts and LiCl-KCl-MgCl 2 melts. In LiCl-KCl melts, typical cyclic voltammetry was used to study the electrochemical mechanism and thermodynamic parameters for the reduction of Y(iii) to metallic Y. In LiCl-KCl-MgCl 2 melts, the formation mechanism of Mg-Y intermetallic compounds was investigated, and the results showed that only one kind of Mg-Y intermetallic compound was formed under our experimental conditions. Mg-Li-Y alloys were prepared via galvanostatic electrolysis, and XRD and SEM equipped with EDS analysis were used to analyze the samples. Because of the restrictions of EDS analysis, ICP-AES was used to analyze the Li content in Mg-Li-Y alloys. The microhardness and Young's modulus of the Mg-Li-Y alloys were then evaluated., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Objectives: This study aims to construct endogenous exosomes abundantly loaded with miR-1 and investigate the role of exosome-mediated microRNA-1 (miR-1) delivery on CAL-27 cell proliferation., Methods: Exosomes secreted by miR-1-overexpressing HEK293 cells (miR1-EXO) were purified via ultracentrifugation and subjected to transmission electron microscopy, nanoparticle analysis, Western blot analysis, and quantitative polymerase chain reaction (qPCR). CAL-27 cells were cocultured with exosomes secreted by HEK293 cells (CON-EXO) and miR1-EXO and equivalent phosphate buffer saline. The intracellular transport of exosomes was measured by using immunofluorescence, the expression of miR-1 and its target gene MET were investigated via qPCR, CAL-27 cell proliferation was measured through MTT assay, and cell cycle state was determined by applying flow cytometry., Results: Electron microscopy revealed that miR1-EXO and CON-EXO were spherical or cup-shaped with an average diameter of approximately 110 nm. The well-known exosome markers CD9, Tsg101, and Alix were enriched. The expression of miR-1 in miR1-EXO was higher than that in CON-EXO (285.80±14.33 vs 1.00±0.06, P< 0.000 1). After coculture with CAL-27 cells, miR1-EXO was internalized and unloaded miR-1 into CAL-27 cells. After coculture with miR1-EXO, the expression of miR-1 in CAL-27 cells was upregulated, whereas that of MET, the target gene of miR-1, was suppressed and the proliferation of CAL-27 cells was inhibited significantly. Normal oral keratinocyte cell proliferation was negligibly affected after coculture with miR1-EXO., Conclusions: Exosomes secreted from miR1-EXO cells could load abundant miR-1. Exosomal miR-1 delivered into CAL-27 cells by using miR1-EXO suppressed the expression of MET mRNA and inhibited cell proliferation.

Urinary cytology (UC) is one of the primary diagnostic modalities used for the screening and surveillance of urothelial carcinoma. Despite its widespread use, UC has suffered from a lack of standardized or reproducible criteria and wide interobserver variability, particularly of the designation of atypical urothelial cells. The Paris System for Reporting Urinary Cytology (TPS), published in 2016, aimed to provide a standardized approach for evaluating UC by creating diagnostic categories with specific cytomorphologic criteria. Recent studies have primarily investigated the application of TPS on lower urinary tract specimens and have mostly shown that TPS implementation has improved the performance of UC specimens. Only a few studies have reported the impact of TPS on upper urinary tract (UUT) cytology. Additionally, there is uncertainty as to which cytological features are most predictive of high-grade urothelial carcinoma (HGUC) in the UUT. This review summarizes the literature regarding the utility and performance of UUT cytology and highlights findings before and after the implementation of TPS., (© 2020 American Cancer Society.)

Hydrogen sulfide (H 2 S) is recognized to be a novel mediator after carbon monoxide and nitric oxide in the organism. It can be produced in various mammalian tissues and exert many physiological effects in many systems including the cardiovascular system. A great amount of recent studies have demonstrated that endogenous H 2 S and exogenous H 2 S-releasing compounds (such as NaHS, Na 2 S, and GYY4137) provide protection in many cardiovascular diseases, such as ischemia/reperfusion injury, heart failure, cardiac hypertrophy, and atherosclerosis. In recent years, many mechanisms have been proposed and verified the protective role exhibited by H 2 S against myocardial ischemia/reperfusion injury, and this review is to demonstrate the protective role of exogenous and endogenous H 2 S on myocardial ischemia/reperfusion injury.