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Epiboly, the coordinated spreading of the enveloping layer (EVL), the yolk syncytial layer (YSL) and the deep cells (DCs) toward the vegetal pole, is required for gastrulation. Interference with the EVL leads to early developmental failure. However, the genetic factors underlying EVL differentiation are so far unknown. By in-depth analyzing of single-cell sequencing data from 4 h post fertilization zebrafish embryos, we identified 105 genes (FDR

Long non-coding RNAs (lncRNAs) are a novel class of non-coding RNA (ncRNA), that have been studied extensively in the field of tumor research in recent years. In the case of tumor-associated lncRNAs, lncRNA cytoskeleton regulator RNA (CYTOR) displays extensive functions in tumorigenesis, including invasion, metastasis, malignant proliferation, glycolysis, and inflammatory response. Moreover, the dysregulation of CYTOR is closely related to clinicopathological characteristics, such as tumor stage, lymph node metastasis and infiltration, and poor prognosis of tumor patients. In this review, we provide a novel strategy to summarize the biological functions and clinical value of CYTOR in tumors through an overview of the literature combined with gene set enrichment analysis. A deeper understanding of the role of CYTOR in tumorigenesis may provide new diagnostic, prognostic and therapeutic markers for human tumors.

China has the largest area of kiwifruit production in the world. Pathogens associated with root diseases of kiwi trees have not been investigated extensively. In this research, three Phytophthora species, Phytophthora cactorum, Phytophthora cinnamomi, and Phytophthora lateralis, which are pathogenic to kiwi trees in the main planting areas of China, were studied. The population densities of these species in 128 soil samples from 32 kiwi orchards in 2017 and 2018 were measured using multiplex real-time quantitative PCR based on the ras-related protein gene Ypt1. P. cactorum was the most widely distributed of the three species in orchards of the Zhouzhi and Meixian prefectures. We used redundancy analysis to examine soil factors in the kiwi orchards to understand their effects on the population densities of the Phytophthora species. The redundancy analysis indicated that soil temperature and pH were significantly correlated with the abundance of P. cactorum and P. cinnamomi. In addition, two loop-mediated isothermal amplification detection systems for P. cactorum were developed based on the tigA gene. The color-change detection system proved to be accurate, sensitive, and faster than quantitative PCR. The results of this study, along with the loop-mediated isothermal amplification detection systems, will be of great use in the control of Phytophthora diseases for the production of kiwifruits in China.

Isomers sometimes play a fundamental role in the formation of coordination architectures. In this article, bifunctional 5-(n-pyridyl)tetrazole-2-isopropanoic acid (n = 2, 3) has been designed and prepared. Then, reactions of Ca(NO3)2·4H2O with isomeric 5-(n-pyridyl)tetrazole-2-isopropanoic acid (denoted as Hn-pytzipa, n = 2, 3) afforded mononuclear [Ca(2-pytzipa)2(H2O)4] (1) and one-dimensional [Ca(3-pytzipa)2(H2O)2]n (2), respectively. In 1, 2-pytzipa is a bidentate ligand which chelates one Ca(II) via the nitrogen atoms of the pyridine and tetrazole rings while in 2, 3-pytzipa bridges adjacent Ca(II) centers in a μ 1,1,3-COO mode. PEG-5000 (poly(ethyleneglycol-5000)) coated [Ca(2-pytzipa)2(H2O)4] (1) and [Ca(3-pytzipa)2(H2O)2]n (2) nanoparticles (NPs) show toxicity towards Hela cells, but the ligands are non-toxic in nature and 2 is superior to 1. Furthermore, cell migration across a 2D artificial gap indicates that both NPs can inhibit the migration of Hela cells.

The current study aimed to dissect the impacts and mechanisms of hydroxycamptothecin on breast cancer. Collect conditioned medium from MSCs cells to apply it into the co-culture system of breast cancer cells, which were pre-treated with hydroxycamptothecin. The cell counting kit was employed to measure the proliferation potential of cells, while the phosphorylation degrees of AKT/MAPKrelated proteins were examined via Western blotting. Then the cellular migration was test by transwell. Finally, the transcriptional and translational levels of IL-6 and RANTES in cells were detected by real-time PCR and enzyme-linked immunosorbent assay. HC could remarkably influence the interplay between MSC and breast malignant cells, reduce the MSC-activated migrative behavior of breast malignant cells and impede the capability of MSC to maintain the migration of cancer cells. RANTES and IL-6 exerted a synergistic induction in the migrative feature of breast cancer cells. HC could retard the migrating activities of breast cancer cells via diminishing the RANTES and IL-6 levels. Hydroxycamptothecin could impede the proliferative and migrative activities of MSC, of which the impediment was accompanied by an inhibitory impact on the secretory production of two growth factors IL-6 and RANTES from MSC, thereby enhancing the migration of breast malignant cells.

Bromodomain containing protein 4 (BRD4), as an epigenetic reader, can specifically bind to the acetyl lysine residues of histones and has emerged as an attractive therapeutic target for various diseases, including cancer, cardiac remodeling and heart failure. Herein, we described the discovery of hit 5 bearing 4-phenylquinazoline skeleton through a high-throughput virtual screen using 2,003,400 compound library (enamine). Then, structure–activity relationship (SAR) study was performed and 47 new 4-phenylquinazoline derivatives toward BRD4 were further designed, synthesized and evaluated, using HTRF assay set up in our lab. Eventually, we identified compound C-34, which possessed better pharmacokinetic and physicochemical properties as well as lower cytotoxicity against NRCF and NRCM cells, compared to the positive control JQ1. Using computer-based molecular docking and cellular thermal shift assay, we further verified that C-34 could target BRD4 at molecular and cellular levels. Furthermore, treatment with C-34 effectively alleviated fibroblast activation in vitro and cardiac fibrosis in vivo, which was correlated with the decreased expression of BRD4 downstream target c-MYC as well as the depressed TGF-β1/Smad2/3 signaling pathway. Taken together, our findings indicate that novel BRD4 inhibitor C-34 tethering a 4-phenylquinazoline scaffold can serve as a lead compound for further development to treat fibrotic cardiovascular disease., Graphical abstract In current work, we performed high-throughput virtual screen and structure-based optimization targeting BRD4, leading to 47 new 4-phenylquinazoline derivatives with potent inhibitory activity toward BRD4. The representative compound C-34 shows favorable pharmacokinetic and physicochemical properties as well as low toxicity in vivo. Also, C-34 effectively reduced pathological cardiac fibrosis.Image 1

Swine acute diarrhea syndrome coronavirus (SADS-CoV) is a newly discovered enteric coronavirus. We have previously shown that the caspase-dependent FASL-mediated and mitochondrion-mediated apoptotic pathways play a central role in SADS-CoV-induced apoptosis, which facilitates viral replication. However, the roles of intracellular signaling pathways in SADS-CoV-mediated cell apoptosis and the relative advantages that such pathways confer on the host or virus remain largely unknown. In this study, we show that SADS-CoV induces the activation of ERK during infection, irrespective of viral biosynthesis. The knockdown or chemical inhibition of ERK1/2 significantly suppressed viral protein expression and viral progeny production. The inhibition of ERK activation also circumvented SADS-CoV-induced apoptosis. Taken together, these data suggest that ERK activation is important for SADS-CoV replication, and contributes to the virus-mediated changes in host cells. Our findings demonstrate the takeover of a particular host signaling mechanism by SADS-CoV and identify a potential approach to inhibiting viral spread.

Background and aims Nonalcoholic steatohepatitis (NASH) is a complicated disease characterized by hepatocyte steatosis, inflammation infiltration, and liver fibrosis. Accumulating evidence suggests that the innate immunity plays a key role in NASH progression. Here, we aimed to reveal the role of melanoma-differentiation-associated gene 5 (MDA5, also known as Ifih1), a conventional innate immune regulator upon viral infection, in the progression of NASH and investigate its underlying mechanism. Approach and results We first examined the expression of MDA5 and found that MDA5 was markedly downregulated in the livers with NASH in human individuals and mice models. MDA5 overexpression significantly inhibited the free fatty acid (FFA) induced lipid accumulation and inflammation in hepatocyte in vitro, while MDA5 knockdown promotes hepatocyte lipotoxicity. Using hepatocyte-specific Mda5 gene knockout and transgenic mice, we found that diet induced hepatic steatosis, inflammation and liver fibrosis were markedly exacerbated by Mda5 deficiency but suppressed by Mda5 overexpression. Mechanistically, we found that the activation of ASK1-MAPK pathway was significantly inhibited by MDA5 but enhanced by MDA5 deletion. We further validated that MDA5 directly interacted with ASK1 and suppressed its N-terminal dimerization. Importantly, blockage of ASK1 with adenovirus expressing dominant negative ASK1 (dnASK1) obviously reversed the lipid accumulation and ASK1 pathway activation when Mda5 knockout. Conclusions These data indicate that MDA5 is an essential suppressor in NASH, the findings support MDA5 as a novel regulator of ASK1 and a promising therapeutic target for NASH.

This paper aimed to study the clinical characteristics of patients with pulmonary embolism (PE) with syncope (PE + S) based on the three-dimensional (3D) reconstruction algorithm in computed tomography (CT) pulmonary angiography (CTPA). In this study, 857 patients with acute PE (APE) who were treated in hospital were selected as the research objects and divided into syncope group (group S) and nonsyncope group (group NS). The 3D reconstruction marching cubes (3DR-MC) algorithm was compared with the traditional MC (T-MC) algorithm and the mesh simplification MC (MMS-MC) algorithm, and the results proved that the running time of the 3DR-MC algorithm on the platform was shorter than that of the other two algorithms. The incidence of syncope in group S in women was higher than that in group NS (51.7% vs. 38.2%). The incidence of syncope classified as high risk in group S was higher than that in group NS, and the mortality rate of pulmonary embolism patients with syncope was higher, and the difference was statistically significant (χ2 = 113.332, P < 0.05 ). The incidence of syncope in group S was higher than that in group NS (χ2 = 4.074, P < 0.05 ). In short, hypertension was an independent risk factor for syncope. PE + S patients could be diagnosed and treated as early as possible based on the clinical characteristics, so as to reduce the adverse consequences of misdiagnosis.

We investigated whether the WNT/β-catenin signalling pathway is involved in paediatric Kashin–Beck disease (KBD) and T-2-toxin-induced cartilage injury in rats to better understand the mechanism of KBD. One hundred twenty-two children were selected and assigned to the case (31), internal control (41), and external control (50) groups. The serum β-catenin and bone morphogenetic protein 2（BMP2）levels in each group were measured and compared. Thirty-six rats were randomly assigned to three groups, which received no intervention, T-2 toxin, or solvent. After 18 weeks, the expression of LDL receptor related proteins 5 (LRP5), β-catenin, BMP2, BAX, BCL2, APAF1, and caspase 9 was measured and compared. The serum BMP2 levels were significantly elevated in the children with KBD and in the rats treated with T-2 toxin. In the T-2 toxin group, LRP5 and β-catenin expression was reduced, whereas BAX, APAF1, and caspase 9 expression was increased. In conclusion, the WNT/β-catenin signalling pathway is suppressed in KBD, which induces chondrocyte apoptosis, leading to cartilage injury. Therefore, BMP2 may play a role in the pathogenesis of KBD.

The phenotypic consequence of a genetic mutation depends on many factors including the expression level of a gene. However, a comprehensive quantification of this expression effect is still lacking, as is a further general mechanistic understanding of the effect. Here, we measured the fitness effect of almost all (>97.5%) single-nucleotide mutations in GFP, an exogenous gene with no physiological function, and URA3, a conditionally essential gene. Both genes were driven by two promoters whose expression levels differed by around tenfold. The resulting fitness landscapes revealed that the fitness effects of at least 42% of all single-nucleotide mutations within the genes were expression dependent. Although only a small fraction of variation in fitness effects among different mutations can be explained by biophysical properties of the protein and messenger RNA of the gene, our analyses revealed that the avoidance of stochastic molecular errors generally underlies the expression dependency of mutational effects and suggested protein misfolding as the most important type of molecular error among those examined. Our results therefore directly explained the slower evolution of highly expressed genes and highlighted cytotoxicity due to stochastic molecular errors as a non-negligible component for understanding the phenotypic consequence of mutations. Measuring fitness effects of mutations in the same gene expressed at two levels, the authors show expression dependency of fitness effects in at least 42% of all single-nucleotide mutations, probably driven by avoidance of stochastic molecular errors.

Objective Helicobacter pyloriinfection is mostly a family-based infectious disease. To facilitate its prevention and management, a national consensus meeting was held to review current evidence and propose strategies for population-wide and family-basedH. pyloriinfection control and management to reduce the related disease burden. Methods Fifty-seven experts from 41 major universities and institutions in 20 provinces/regions of mainland China were invited to review evidence and modify statements using Delphi process and grading of recommendations assessment, development and evaluation system. The consensus level was defined as ≥80% for agreement on the proposed statements. Results Experts discussed and modified the original 23 statements on family-basedH. pyloriinfection transmission, control and management, and reached consensus on 16 statements. The final report consists of three parts: (1)H. pyloriinfection and transmission among family members, (2) prevention and management ofH. pyloriinfection in children and elderly people within households, and (3) strategies for prevention and management ofH. pyloriinfection for family members. In addition to the ‘test-and-treat’ and ‘screen-and-treat’ strategies, this consensus also introduced a novel third ‘family-basedH. pyloriinfection control and management’ strategy to prevent its intrafamilial transmission and development of related diseases. Conclusion H. pyloriis transmissible from person to person, and among family members. A family-basedH. pyloriprevention and eradication strategy would be a suitable approach to prevent its intra-familial transmission and related diseases. The notion and practice would be beneficial not only for Chinese residents but also valuable as a reference for other highly infected areas.

Myo9a is an actin-based molecular motor with a RhoGAP domain in its C-terminal tail. It plays a role in a variety of biological processes, such as in regulating the immune response, neuron development, and cancer progression, and its deregulation can lead to the development of disease conditions. Myo9a acts mainly via its RhoGAP domain. In the current study, we used a pET32a vector with an N-terminal Trx-His6 tag to express Myo9a-RhoGAP in a soluble form. High-purity Myo9a-RhoGAP protein was obtained after two rounds of Ni2+ affinity and size-exclusion chromatography. We mixed Myo9a-RhoGAP and RhoA in equimolar ratios in the presence of 5 mM MgCl2 and 20 mM NaF to achieve a stable RhoA GTP hydrolysis transition state complex. Analytical gel filtration and SDS-PAGE were used to verify complex formation. ITC and GAP assays suggested that Myo9a-RhoGAP could bind to RhoA and accelerate RhoA GTP hydrolysis in vitro. We purified the soluble Myo9a-RhoGAP protein with GAP activity and achieved the Myo9a-RhoGAP/RhoA·GDP/MgF3− complex assembly in vitro for the first time. The data may provide novel insights into Myo9a structure and function.

Flavonoids have a variety of biological activities that are beneficial to human health. However, owing to low bioavailability, most flavonoids exert beneficial effects in the intestine through metabolism by the flora into a variety of structurally different derivatives. Also, flavonoids can modulate the type and structure of intestinal microorganisms to improve human health. It has been reported that the development of depression is accompanied by changes in the type and number of intestinal microorganisms, and gut microbes can significantly improve depressive symptoms through the gut-brain axis. Therefore, the interaction between flavonoids and intestinal microbes to alleviate depression is discussed. © 2021 Society of Chemical Industry.

Neuroligin (NLG) protein is a nerve cell adhesion molecule and plays a key role in the precision apposition of presynaptic domains on inhibitory and excitatory synapses. Existing studies mainly focused on the function of NLG3 against the excitatory channel. However, the interaction between insect NLG3 and ionotropic GABA receptor, which is the main inhibitory channel, remains unclear. In this study, the Nlg3 of common cutworm (CCW), Spodoptera litura Fabricius, one important agricultural Lepidopteron, is selected to explore its function in the inhibitory channel.The SlNlg3 was obtained and the SlNLG3 contains the characteristic features including transmembrane domain, PDZ-binding motif and type-B carboxylesterases signature 2 motif. The SlNlg3 messenger RNA (mRNA) was most abundant in midgut, and exhibited multiple expression patterns in different developmental stages and tissues or body parts. Compared with the single injection of SlRDL1, the median effective concentration value of GABA in activating currents was smaller in Xenopus laevis oocytes co-injected with SlRDL1 and SlNlg3. In addition, SlNlg3 could enhance the GABA-induced current of homomeric SlRDL1 channel from -391.86 ± 15.41 to -2152.51 ± 30.09 nA. DsSlNlg3 depressed the expression level of SlNlg3 mRNA more than 64.29% at 6 h. After exposure to median lethal dose of fluralaner, the mortality of CCW injected with dsSlNlg3 was significantly decreased by 13.34% and 30.00% at 24 and 48 h, respectively, compared to injection of dsEGFP.NLG3 should have physiological function on ionotropic GABA receptor in vitro, which provided a favorable foundation for further research on the physiological function of Nlg gene in Lepidopteron. © 2021 Society of Chemical Industry.

Non-obstructive azoospermia (NOA) represents one of the most serious forms of male infertility caused by spermatogenic failure. Despite multiple genes found to be associated with human NOA, the genetic basis of this idiopathic disease remains largely unknown. FBXO43 is a direct inhibitor of the anaphase-promoting complex/cyclosome (APC/C) E3 ligase and crucially important in mouse spermatogenesis. In this study, for the first time, we identified a homozygous nonsense mutation in FBXO43 c.1747C > T:p.Gln583X in two NOA brothers from a Chinese consanguineous family via whole-exome sequencing. FBXO43 was absent from testicular tissue of the proband, and FBXO43-immunostaining signals were invisible in the affected seminiferous tubules. Furthermore, in humans, FBXO43 defects cause meiotic arrest within early diplotene of prophase I. The results here demonstrate the pathogenicity of this loss-of-function mutation and confirmed that spermatocytes were unable to complete meiotic divisions without FBXO43 in humans. In mouse testicular protein extracts, three subunits of the APC/C, including ANAPC2, ANAPC8 and ANAPC10, were validated to interact directly with FBXO43, whereas no interactions were detected for FBXO43 and SKP1. This study furthers our understanding of the genetic basis of human NOA and provides insights into FBXO43 and male infertility.

Rubia plants are one of the most important plant resources possessing significant commercial and medicinal values. Plant endophytes could benefit their host plants in different ways. Rubiaceae-type cyclopeptides (RAs), mainly isolated from Rubia plants, have attracted considerable attentions for their distinctive bicyclic structures and significant antitumor activities, but their contents in plants are low. The aim of this study is to investigate the diversity of endophytic fungi in Rubia plants and their potential for production of RAs. In this work, 143 endophytic fungi isolates were obtained from two Rubia plants. Phylogenetic analysis was performed based on the ITS rDNA sequences, and the isolates were classified into 29 genera. Among them, four endophytic fungal strains were found to produce anti-tumour RAs by LC-MS/MS analysis. This work successfully provides valuable knowledges of endophytic fungi microbiome in Rubia plants for agricultural and industrial applications, and exploits a new environmental-friendly resource of RAs.

Furin is one of the nine-member proprotein convertase family. Furin cleaves proteins with polybasic residues, which includes many viral glycoproteins such as SARS-Cov-2 spike protein. The cleavage is required for the activation of the proteins. Currently, the mechanisms that regulate Furin activity remain largely unknown. Here we demonstrated that Furin is a novel heparin/heparan sulfate binding protein by the use of biochemical and genetic assays. The KD is 9.78 nM based on the biolayer interferometry assay. Moreover, we found that sulfation degree, site-specific sulfation (N-sulfation and 3-O-sulfation), and iduronic acid are the major structural determinants for the binding. Furthermore, we found that heparin inhibits the enzymatic activity of Furin when pre-mixes heparin with either Furin or Furin substrate. We also found that the Furin binds with cells of different origin and the binding with the cells of lung origin is the strongest one. These data could advance our understanding of the working mechanism of Furin and will benefit the Furin based drug discovery such as inhibitors targeting the interaction between heparan sulfate and Furin for inhibition of viral infection. Supplementary information The online version contains supplementary material available at 10.1007/s10719-021-10018-8.

Background Xylanase, an important accessory enzyme that acts in synergy with cellulase, is widely used to degrade lignocellulosic biomass. Thermostable enzymes with good catalytic activity at lower temperatures have great potential for future applications in the feed and fuel industries, which have distinct demands; however, the potential of the enzymes is yet to be researched. Results In this study, a structure-based semi-rational design strategy was applied to enhance the low-temperature catalytic performance of Bispora sp. MEY-1 XYL10C_∆N wild-type (WT). Screening and comparisons were performed for the WT and mutant strains. Compared to the WT, the mutant M53S/F54L/N207G exhibited higher specific activity (2.9-fold; 2090 vs. 710 U/mg) and catalytic efficiency (2.8-fold; 1530 vs. 550 mL/s mg) at 40 °C, and also showed higher thermostability (the melting temperature and temperature of 50% activity loss after 30 min treatment increased by 7.7 °C and 3.5 °C, respectively). Compared with the cellulase-only treatment, combined treatment with M53S/F54L/N207G and cellulase increased the reducing sugar contents from corn stalk, wheat bran, and corn cob by 1.6-, 1.2-, and 1.4-folds, with 1.9, 1.2, and 1.6 as the highest degrees of synergy, respectively. Conclusions This study provides useful insights into the underlying mechanism and methods of xylanase modification for industrial utilization. We identified loop2 as a key functional area affecting the low-temperature catalytic efficiency of GH10 xylanase. The thermostable mutant M53S/F54L/N207G was selected for the highest low-temperature catalytic efficiency and reducing sugar yield in synergy with cellulase in the degradation of different types of lignocellulosic biomass. Graphic Abstract Supplementary Information The online version contains supplementary material available at 10.1186/s13068-021-02044-3., Highlights Key sites were proved to promote low-temperature catalytic efficiency of xylanase.Thermostable mutant with improved catalytic efficiency at 40 °C was obtained.Synergistic hydrolysis was dramatically improved between the mutant and cellulase.Agricultural wastes were converted into fermentable sugars by enzymolysis. Supplementary Information The online version contains supplementary material available at 10.1186/s13068-021-02044-3.

Tuberculous meningitis (TBM) is an incurable disease with high mortality. It is an extrapulmonary tuberculosis caused by mycobacterium tuberculosis which penetrated the blood-brain barrier and infected the meninges. Mycobacterium tuberculosis lurking in the body mainly reside in macrophages. Anti-tuberculous drugs usually can not target the blood-brain barrier and macrophages, the drug concentration in the lesion is low, which cannot effectively kill mycobacterium tuberculosis, making TBM difficult to treat. Targeted drug delivery systems can target drugs to specific nidus. In the study, we constructed a drug delivery system, which was a cell penetrate peptide B6 and phosphatidylserine (PS) modified polyethylene glycol (PEG) nanomaterial to target the blood-brain barrier and to target macrophages. This nanomaterial was a combined anti-tuberculosis drug delivery system encapsulating antituberculosis drugs rifampicin and pyrazinamide, designed to target macrophages in the brain and kill mycobacterium tuberculosis lurking in the macrophages. We have physically characterized the drug delivery system, and verified the bactericidal ability at cellular and animal level. Results have shown that the targeted drug delivery system had a remarkable efficacy to treat TBM in mice.

Melanoma causes the highest mortality rate among all skin cancers. However, the underlying molecular mechanisms leading to metastasis and poor prognosis in melanoma have not been fully elucidated. In this study, the differentially expressed genes (DEGs) related to metastasis in melanoma were screened out. The results of gene annotation was combined with The Cancer Genome Atlas (TCGA) database. The microRNA (miRNA) network that regulates key genes and their correlation with BRAFV600E was preliminarily analyzed. Cell and molecular biology experiments were conducted to verify the results of bioinformatics analysis. Results showed that the PI3K-Akt signaling pathway contained the key genes CDK2, CDK4, KIT, and Von Willebrand factor. Survival analysis showed that high expression of the four key genes significantly reduced the survival rate of patients with melanoma. Correlation analysis showed that BRAFV600E may regulate the expression of the four key genes, and a total of 240 miRNAs may regulate this expression. Experiments showed that the inactivation of key genes inhibits the proliferation, migration, and invasion of melanoma. In conclusion, the PI3K-Akt signaling pathway and the four key genes promoted the proliferation, migration, and invasion of melanoma, and related to poor prognosis of patients with melanoma.

Rubichaetoglobin A (1), a new cytochalasan alkaloid, together with nine closely related known ones (2-10), were isolated from the ethyl acetate extracts of the endophytic fungus Chaetomium tectifimeti S104 harbored in the root of Rubia podantha Diels. Their structures were elucidated based on comprehensive spectroscopic analysis. All isolated compounds were tested for cytotoxic, antibacterial, and nitric oxide inhibitory activities. The results showed that 2, 4, and 5 possessed moderate cytotoxicity against MDA-MB-231 cells with the IC50 values of 19.14, 11.43, and 10.27 μM, respectively.

Vasculopathy is an important complication of type 2 diabetes mellitus (T2DM) and the leading cause of morbidity and mortality in type 2 diabetes mellitus (T2DM), which is closely related to oxidative stress and inflammation. Haptoglobin (Hp), an acute-phase protein, binds to hemoglobin (Hb) and prevents haeme-iron oxidative damage. To investigate the distribution of the frequencies of Hp genotypes and to analyse the association between Hp gene polymorphisms and vascular complications in diabetes patients. The study included 171 patients with T2DM without vascular complications and 797 patients with T2DM with vascular complications. The clinical characteristics of the studied population were recorded. Hp genotyping was performed using polymerase chain reaction–sequence specific primers (PCR-SSP). Our results showed that the frequencies of Hp genotypes in all 968 T2DM patients were as follows: Hp1-1, 4.98%; Hp2-1, 38.07%; and Hp2-2, 56.95%. Although there was no significant difference in the Hp allele or genotype frequencies among individuals with vascular complications in the T2DM groups and controls regardless of gender, we found that the distribution of the Hp2-2 genotype and allele frequency was higher in males with diabetic retinopathy than in the control group (p

Avian pathogenic E. coli (APEC) caused avian colibacillosis is mostly common in poultry industry worldwide. APEC virulence factors lead to pathogenesis and the quorum sensing (QS) system is actively involved in the regulation of these virulence factors. Signaling molecules in QS are known as autoinducers (AIs). In QS-1, E. coli encodes a single LuxR homolog, i.e., SdiA, but does not express the LuxI homolog, an acyl-homoserine lactone (AHL) synthase of producing AI-1. Avian pathogenic E. coli (APEC) regulates its virulence genes expression in response to exogenous AHLs, but regulatory mechanisms of AHL and QS-1 are still unknown. This study targeted the APEC CE129 isolate as the reference strain, and the Yersinia enterocolitica yenI gene was expressed into APEC CE129. CE129/pyenI was conferred the ability to produce AHL signal. The CE129 SdiA mutant strain with an in-frame sdiA (AHL receptor) gene deletion was constructed by a λRed recombination system, which lost the ability to sense AHL. The goal of this study was to explore the function of QS-1 upon virulence and elucidate the regulatory effect of QS-1/AHL signals in the APEC strain. Adherence and invasion assays revealed that QS-1 affected APEC adherence and survival ability. APEC biofilm formation was also suppressed under C6HSL. Interestingly, APEC exhibited different phenotypes of acid tolerance and flagella expression when compared to enterotoxigenic E. coli or enterohemorrhagic E. coli (ETEC and EHEC, respectively). These findings enhance our understanding of the QS mechanism.

Aberrant lipid metabolism has recently been recognized as a new hallmark of malignancy, but the characteristics of fatty acid metabolism in breast cancer stem cells (BCSC) and potential interventions targeting this pathway remain to be addressed. Here, by using the in vitro BCSC models, mammosphere-derived MCF-7 cells and HMLE-Twist-ER cells, we found that the cells with stem cell-like properties exhibited a very distinct profile of fatty acid metabolism compared with that of their parental cancer cells, characterized by increased lipogenesis, especially the activity of stearoyl-CoA desaturase 1 (SCD1) responsible for the production of monounsaturated fatty acids, and augmented synthesis and utilization of the omega-6 arachidonic acid (AA). Suppression of SCD1 activity by either enzyme inhibitors or small interfering RNA (siRNA) knockdown strikingly limited self-renewal and growth of the BCSC, suggesting a key role for SCD1 in BCSC proliferation. Furthermore, elevated levels of SCD1 and other lipogenic enzymes were observed in human breast cancer tissues relative to the noncancer tissues from the same patients and correlated with the pathological grades. Interestingly, treatment of BCSC with omega-3 fatty acids, eicosapentaenoic acid and docosahexaenoic acid, effectively downregulated the expression of the lipogenic enzymes and markedly suppressed BCSC self-renewal and growth. Dietary supplementation of nude mice bearing BCSC-derived tumors with omega-3 fatty acids also significantly reduced their tumor load. These findings have demonstrated that increased lipogenesis is critical for self-renewal and growth of BCSC, and that omega-3 fatty acids are effective in targeting this pathway to exert their anticancer effect.

BACKGROUND The 13C-urea breath test (13C-UBT) is a kind of safe, noninvasive, and reliable measure for Helicobacter pylori (H. pylori) infection diagnosis in patients with complete stomach. Nevertheless, the test has not indicated fully precision in people who have had a gastrectomy. So, we made the use of a systematic review of plentiful published resources and research and meta-analysis. There are prominent research achievements regarding of utilizing 13C-UBT for H. pylori infection patients diagnosis with the residual stomach. METHOD We searched publications available on Cochrane, PubMed, and Embase databases, and on the web of science. The last search was performed in May 2021. The basis model for this meta-analysis was fixed-effect through Metadisc Beta 1.4 software (Universidad Complutense, Madrid, Spain). When measuring the precision of 13C-urea breath test, we utilized the ratio analysis such as Ratio of diagnostic odds ratio (DOR) and its corresponding 95% confidence interval (95%CI). RESULTS Ten associated researches were analyzed with a total of 1065 patients. In general, the sensitivity of included studies ranged from 0.40 to 1.00 (I2 = 81.2%), whereas the specificity ranged from 0.59 to 1.00 (I2 = 90.1%). The pooled sensitivity, specificity were 0.83 (95% CI, 0.79-0.86; P

Mucins are the major proteins that distributed on the intestinal mucosa layer and protect the intestine from pathogens infection. The composition of intestinal mucin O-glycans can affect the health of the gastrointestinal tract in pigs. Porcine intestinal mucosa is widely used as the main raw material of heparin extraction. The heparin extraction residues rich in mucins were usually wasted. The structure of mucin derived O-glycans in porcine intestinal mucosa are currently unknown. In this study, we isolated the mucins from the heparin extraction residues and profiled the O-glycans. After heparin extraction, mucin was digested with trypsin, and separated by strong anion exchange chromatography. The mucin derived O-glycans were release by alkaline β elimination, and analyzed by ultra high performance liquid chromatography-porous graphitized carbon-Fourier transform mass spectrometry (UPLC-PGC-FTMS/MS). Thirty five kinds of O-glycans were identified, most of which were Core 3-derived glycans. In particular, the O-glycans containing sialic acid Neu5Ac accounted for 71.93% of the total O-glycans, which were different from that of other species, including mouse intestine, fish intestine, and porcine colon. The high content sialylated mucin may explain its effect in biological processes. Furthermore, the immunological activity results indicated that the porcine intestinal mucin could promote phagocytosis and proliferation without any cytotoxic effects, which may aid in the development of immunomodulators.

Aneurysmal subarachnoid hemorrhage (aSAH) is a life-threatening medical condition with a high mortality and disability rate. aSAH has an unclear pathogenesis, and limited treatment options are available. Here, we aimed to identify critical genes involved in aSAH pathogenesis using peripheral blood gene expression data of 43 patients with aSAH due to ruptured intracranial aneurysms and 18 controls with headache, downloaded from Gene Expression Omnibus. These data were used to construct a co-expression network using weighted gene co-expression network analysis (WGCNA). The biological functions of the hub genes were explored, and critical genes were selected by combining with differentially expressed genes analysis. Fourteen modules were identified by WGCNA. Among those modules, red, blue, brown and cyan modules were closely associated with aSAH. Moreover, 364 hub genes in the significant modules were found to play important roles in aSAH. Biological function analysis suggested that protein biosynthesis-related processes and inflammatory responses-related processes were involved in the pathology of aSAH pathology. Combined with differentially expressed genes analysis and validation in 35 clinical samples, seven gene (CD27, ANXA3, ACSL1, PGLYRP1, ALPL, ARG1, and TPST1) were identified as potential biomarkers for aSAH, and three genes (ANXA3, ALPL, and ARG1) were changed with disease development, that may provide new insights into potential molecular mechanisms for aSAH.

Aberrant expression of the zinc finger protein (ZIC) family has been extensively reported to contribute to progression and metastasis in multiple human cancers. However, the functional roles and underlying mechanisms of ZIC2 in non-small cell lung cancer (NSCLC) are largely unknown. In this study, ZIC2 expression was evaluated using qRT-PCR, western blot, and immunohistochemistry, respectively. Animal experiments in vivo and functional assays in vitro were performed to investigate the role of ZIC2 in NSCLC. Luciferase assays and chromatin immunoprecipitation (ChIP) were carried out to explore the underlying target involved in the roles of ZIC2 in NSCLC. Here, we reported that ZIC2 was upregulated in NSCLC tissues, and high expression of ZIC2 predicted worse overall and progression-free survival of NSCLC patients. Silencing ZIC2 repressed tumorigenesis and reduced the anoikis resistance of NSCLC cells. Mechanical investigation further revealed that silencing ZIC2 transcriptionally inhibited Src expression and inactivated steroid receptor coactivator/focal adhesion kinase signaling, which further attenuated the anoikis resistance of NSCLC cells. Importantly, our results showed that the number of circulating tumor cells (CTCs) was positively correlated with ZIC2 expression in NSCLC patients. Collectively, our findings unravel a novel mechanism implicating ZIC2 in NSCLC, which will facilitate the development of anti-tumor strategies in NSCLC., Graphical abstract, We pinpointed the oncogenic role of ZIC2 in NSCLC. Silencing ZIC2 abrogates tumorigenesis and anoikis resistance of non-small cell lung carcinoma cells (NSCLCs) by transcriptionally inhibiting Src/FAK signaling. Summarily, ZIC2 may hold the potential biomarker for early diagnosis and anti-tumor strategy in NSCLC.

Objectives The hospital environment has been implicated in the enrichment and exchange of pathogens and antibiotic resistance, but its potential in shaping the symbiotic microbial community of hospital staff is unclear. This study was designed to evaluate the alteration of the gut microbiome in medical workers compared to non-medical controls. Methods A prospective cross-sectional cohort study was conducted in the intensive care unit (ICU) and other departments of a centre in north-eastern China. Faecal samples of 175 healthy medical workers—short-term (1–3 months) workers (n = 80) and long-term (>1 year) workers (n = 95)—and 80 healthy non-medical controls were analysed using 16S rRNA amplicon sequencing. The hospital environmental samples (n = 9) were also analysed. Results The gut microbiomes of medical workers exhibited marked deviations in diversity and alteration in microbial composition and function. Short-term workers showed significantly higher abundances of taxa such as Lactobacillus, Butyrivibrio, Clostridiaceae, Clostridium, Ruminococcus, Dialister, Bifidobacterium, Odoribacter, and Desulfovibrio and lower abundances of Bacteroides and Blautia than the controls. Long-term workers showed higher abundances of taxa such as Dialister, Veillonella, Clostridiaceae, Clostridium, Bilophila, Desulfovibrio, Pseudomonas, and Akkermansia and lower abundances of Bacteroides and Coprococcus than the controls. The medical workers' department (ICU versus non-ICU) and position (resident doctor versus nursing staff) also impacted their gut microbiome. Compared with the non-ICU workers, workers in the ICU showed a significant increase in the abundances of Dialister, Enterobacteriaceae, Phascolarctobacterium, Pseudomonas, Veillonella, and Streptococcus and a marked depletion of Faecalibacterium, Blautia, and Coprococcus. In contrast with the nursing staff, the resident doctors showed a significant increase in Erysipelotrichaceae and Clostridium and a decrease in Bacteroides, Blautia, and Ruminococcus in the gut microbiome. Moreover, we found that the microbiota of hospital environments potentially correlated with the workers' gut microbiota. Conclusions Our findings demonstrated structural changes in the gut microbial community of medical workers.

BACKGROUND Gastric glomus tumor (GGT) is rare submucosal mesenchymal tumor that lacks specific clinical manifestations and is usually treated mainly by traditional surgical resection. This paper presents a case of a GGT, exhibited both intraluminally and extraluminally growth that was removed by laparoscopy-gastroscopy cooperative surgery. CASE SUMMARY A 52-year-old male presented with epigastric discomfort accompanied by a sense of fullness for 3 mo. Upper gastrointestinal endoscopy identified a submucosal lump located in the gastric antrum. Endoscopic ultrasonography identified a 2.4 cm × 1.8 cm lump located in the gastric antrum. It originated from the muscularis propria and exhibited both intraluminally and extraluminally growth, with hypoechoicity on the periphery, hyperechoicity in the middle, and unclear boundaries. Computed tomography showed nodular thickening of 3.0 cm × 2.2 cm in the gastric wall of the gastric antrum, and after enhancement, the lesion exhibited obvious enhancement We suspected that it was a gastrointestinal stromal tumor (glomus tumor and schwannoma were not excluded) and planned to perform laparoscopy-gastroscopy cooperative surgery. Immunohistochemical staining after the operation revealed that spinal muscular atrophy (+), h-caldesmon (+), cluster of differentiation 34 (CD34) (+), 2% Ki-67-positive rate, CD56, melanoma antigen, CD117, discovered on GIST-1, leukocyte common antigen, caudal type homeobox 2, cytokeratin, and S-100 were all negative. The tumor was finally diagnosed as a GGT. CONCLUSION GGTs are rare submucosal tumors of the stomach and should be considered in the differential diagnosis of gastric submucosal tumors. Laparoscopy-gastroscopy cooperative surgery is less invasive and more precise and could be an effective method for the treatment of GGTs.

To examine and understand mechanisms of hydrological functions and water transport of Larix gmelinii ecosystems, we quantified water consumption (ET), including soil evaporation (E) and vegetation transpiration (T), and the role of environmental factors. Stable isotope technology was utilized to make high-frequency in situ observations on the oxygen isotope composition (δ18O) of water vapor from six vertical heights (0.1–40 m above ground) in the cold-temperate Larix gmelinii forests in Northeast China. The dynamics of δ18O and its responses to environmental factors were detected during the water consumption process. One-way analysis of variance, independent-samples t test, and path analysis were used in data analysis. The oxygen isotope composition of water vapor decreased with increasing vertical height. Contribution of T to ET varied between 79 and 96%. Values of δ18O in water vapor produced by E (δ18OE) corresponded most closely to water content at 10-cm soil depth (SWC10), while those produced by T (δ18OT) were associated with different environmental factors: air temperature (Ta) for the shrub-based stand, relative humidity (RH) for the herb-based stand, and temperature at 5-cm soil depth (Ts5) for the moss-based stand. Solar radiation (SR) was the dominant factor controlling the δ18O of water vapor produced by ET (δ18OET). Transpiration is the primary means of ecosystem water loss in Larix gmelinii forests. Overall, water loss from T of shrub-based Larix gmelinii stand is greater than those of herb-based and moss-based stands. Meteorological and soil factors mutually affect ecosystem water loss to atmosphere.

Combination therapy has attracted extensive interest in alleviating the shortcomings of monotherapy and enhancing the treatment efficacy. In this work, hollow mesoporous silica nanoparticles (HMSNs) play the role of nanocarriers in the delivery of Cu(II)-doped polydopamine (PDA), termed as HMSNs@PDA-Cu, for synergistic therapy. PDA acts as a traditional photothermal agent to realize photothermal treatment (PTT). Chemodynamic therapy (CDT) is realized by the reaction of Cu(II) with intracellular glutathione (GSH), and subsequently, the generated Cu(I) reacts with H2O2 to produce toxic hydroxyl radical (•OH) through a Fenton-like reaction. The photothermal performance of PDA is improved after its coordination with Cu(II). On the other hand, PDA exhibits superoxide dismutase (SOD)-mimicking activity. PDA converts O2•- to H2O2 and improves the production of H2O2, which promotes the therapeutic effect of CDT. Moreover, the high temperature caused by PTT further enhances the yield of •OH for CDT. This nanotheranostic platform perfectly applied to the tumor depletion of mice, presenting great potential for cancer metastasis therapy in vitro and in vivo.

Zygophyllum xanthoxylum, a succulent xerophyte, possesses excellent salt tolerance which is closely associated with vacuolar Na+ compartmentation via ZxNHX1. RNA interference (RNAi)-mediated ZxNHX1 silencing impaired the characteristics of Na+ accumulation and thus inhibited normal growth of Z. xanthoxylum. To explore the molecular mechanisms underlying the changed phenotype, here we compared the different expression of salt-responsive genes between ZxNHX1-RNAi line and wild type at transcriptome level. The result showed that vast genes were differently expressed in leaves or roots between ZxNHX1-RNAi line and wild type under control condition or salt treatment. Among them, 142 unigenes were differently expressed in both roots and leaves under 50 mM NaCl for 6 h and 24 h between ZxNHX1-RNAi line and WT. These differentially expressed genes (DEGs) were related to transmembrane transportation based on Gene Ontology (GO) annotations. In terms of ion transport, 49 DEGs were identified, in which some genes associated with Na+ and K+ homeostasis were down-regulated; meanwhile, silencing of ZxNHX1 triggered the differential expression of several genes involved in the transport of important nutrient elements including N, P, Ca, and Mg. Besides, silencing of ZxNHX1 affected the expression level of 18 and 26 genes related to photosynthesis and ROS scavenging, respectively. This study provided strong evidences to indicate the dominant role of ZxNHX1 in maintaining the characteristics of salt accumulation and regulating the salt tolerance of Z. xanthoxylum.

Seed germination is the process by which an organism grows from a seed. It requires suitable conditions and environmental factors. Maize is one of the most important crops worldwide. Germination influences both final maize yield and quality. Seed germination is regulated by a complex gene network. It is also influenced by endogenous (phytohormones and nutrients) and exogenous (temperature and water) inputs, involving molecular networks only partly identified to date. This review describes current understanding of the influence of temperature, water, phytohormones, and nutrients in regulating maize seed germination, and indicates knowledge gaps that should be addressed.

Clonostachys rosea is a necrotrophic mycoparasitic fungus with excellent biological control ability against numerous fungal plant pathogens. Here, we performed genomic sequencing of C. rosea strain CanS41 using Oxford Nanopore sequencing technology. We generated a high-quality genome assembly (>99.99% accuracy), which comprised 26 contigs containing 60.68 Mb sequences with a GC content of 48.55% and a repeat content of 8.38%. The N50 contig length is 3.02 Mb. In total, 20,818 protein-coding genes were identified and functionally annotated. Genes encoding secreted proteins and carbohydrate-active enzymes as well as secondary metabolic gene clusters were also identified and analyzed. In summary, the high-quality genome assembly and gene annotation provided here will allow further exploration of biological functions and enhance biological control ability of C. rosea.

Roots can effectively consolidate and support the soil and are affected by external forces. To identify the survival strategies and soil reinforcement capability of roots against damaging forces, we investigated Hippophae rhamnoides taproots with a diameter of 1-4 mm in a coal mining subsidence area. To simulate root damage from erosion, an HG100 digital push&pull tester and self-developed experimental installation were used in situ. Relative growth rate, activity, tensile force, and strength of taproots were inhibited by damage. Significant differences occurred in these indicators depending on drawing damage type and level. Inhibition effects from persistent drawing damage on growth and tensile properties were markedly greater than those from instantaneous drawing. Inhibition effects of severe damage were markedly greater than those of mild damage. The number of living roots declined more after persistent drawing or severe injury than after instantaneous or mild damage. The taproots showed self-healing ability, and the inhibitory effect of drawing damage gradually weakened with the time of self-repair, ensuring H. rhamnoides taproots could continue to play a role in soil reinforcement. The self-healing ability of roots should be considered in vegetation restoration of erosion-prone areas to ensure that the roots' ability to resist erosion is accurately estimated. Novelty statementResearch on the soil reinforcement ability of damaged plant roots is very limited at present. This study provides a new perspective for soil reinforcement: roots can be destroyed by erosional forces while providing support for soil, the self-healing ability of plants determines whether they can provide effective support for soil in the erosive environment.

BACKGROUND: Few prospective studies have investigated the relationship between IgE variability and risk for asthma exacerbations (AEs). OBJECTIVE: To explore the relationship between IgE variability and AEs. METHODS: Recruited patients with stable asthma underwent two serum total IgE tests within a month (at screening [baseline IgE] and at 1 month) to obtain the coefficient of variation (CV) of base 10 log-transformed IgE. Patients with IgE CV were divided into IgE CV-high and IgE CV-low cohorts based on the CV median and were observed within 12 months, during which the association between IgE variability and AEs was explored using a negative binomial regression model. RESULTS: The IgE CV levels obtained from 340 patients classified patients into two groups (n = 170 for the IgE CV-high and IgE CV-low groups, respectively) based on the serum total IgE CV median of 2.12% (quartiles 1 and 3: 0.98% and 3.91%, respectively). The IgE CV-high patients exhibited worse asthma control and lung function and more marked airway inflammation, and received more intensive medication use compared with IgE CV-low patients. The IgE CV-high patients exhibited increased rates of moderate-to-severe (adjusted rate ratio = 2.88; 95% confidence interval, 1.65-5.03; P < .001) and severe (adjusted rate ratio = 2.16; 95% confidence interval, 1.08-4.32; P = .029) AEs during the follow-up year compared with IgE CV-low patients. Furthermore, sputum IL-6 partially mediated the associations between IgE CV with moderate-to-severe and severe AEs. CONCLUSIONS: Variability in total serum IgE levels is an easily obtained and practical measure for predicting AEs. Future studies are needed to investigate whether IgE variability can be used to guide precision medicine in asthma.

As the largest tissue in the body, skeletal muscle not only plays key roles in movement and glucose uptake and utilization but also mediates insulin sensitivity in the body by myokines. Insulin resistance in the skeletal muscle is a major feature of type 2 diabetes (T2D). A weakened response to insulin could lead to muscle mass loss and dysfunction. Increasing evidence in skeletal muscle cells, rodents, nonhuman primates, and humans has shown that restriction of caloric or protein intake positively mediates insulin sensitivity. Restriction of essential or nonessential amino acids was reported to facilitate glucose utilization and regulate protein turnover in skeletal muscle under certain conditions. Furthermore, some minerals, such as zinc, chromium, vitamins, and some natural phytochemicals such as curcumin, resveratrol, berberine, astragalus polysaccharide, emodin, and genistein, have been shown recently to protect skeletal muscle cells, mice, or humans with or without diabetes from insulin resistance. In this review, we discuss the roles of nutritional interventions in the regulation of skeletal muscle insulin sensitivity. A comprehensive understanding of the nutritional regulation of insulin signaling would contribute to the development of tools and treatment programs for improving skeletal muscle health and for preventing T2D.

Objectives Tuberculosis (TB), an infectious disease caused by Mycobacterium tuberculosis (MTB), has similar clinical, radiological, and histopathological characteristics to sarcoidosis (SA). Accurately distinguishing SA from TB remains a clinical challenge. Methods A total of 44 TB patients and 47 SA patients who were clinically diagnosed using chest radiography, pathological examination, routine smear microscopy, and microbial culture were enrolled in this study. The MTB genome was captured and sequenced directly from tissue specimens obtained upon operation or biopsy, and the feasibility of next-generation sequencing (NGS) for the MTB genome in the differential diagnosis of TB from SA was evaluated. Results Using a depth >10× and coverage >15% of the sequencing data, TB patients were identified via the NGS approach directly using operation or biopsy specimens without clinical pretreatment. The sensitivity, specificity, and concordance of the NGS method were 81.8% (36/44), 95.7% (45/47), and 89.0% (81/91), respectively (kappa = 0.78, 95% confidence interval 0.65–0.91; P Conclusions This study established an improved NGS strategy for rapidly distinguishing patients with TB from those with SA and has potential clinical benefits.

Summary Mutations in HPRT1, a gene encoding a rate-limiting enzyme for purine salvage, cause Lesch-Nyhan disease which is characterized by self-injury and motor impairments. We leveraged stem cell and genetic engineering technologies to model the disease in isogenic and patient-derived forebrain and midbrain cell types. Dopaminergic progenitor cells deficient in HPRT showed decreased intensity of all developmental cell-fate markers measured. Metabolic analyses revealed significant loss of all purine derivatives, except hypoxanthine, and impaired glycolysis and oxidative phosphorylation. real-time glucose tracing demonstrated increased shunting to the pentose phosphate pathway for de novo purine synthesis at the expense of ATP production. Purine depletion in dopaminergic progenitor cells resulted in loss of RHEB, impairing mTORC1 activation. These data demonstrate dopaminergic-specific effects of purine salvage deficiency and unexpectedly reveal that dopaminergic progenitor cells are programmed to a high-energy state prior to higher energy demands of terminally differentiated cells., Graphical abstract, Highlights • HPRT1 KO reduces cell-fate marker expression in NPCs and neurons • NPCs have a programmed high-energy state compared with cortical NPCs • HPRT1 KO NPCs prioritize de novo purine synthesis over energy production • HPRT1 KO NPCs have reduced levels of RHEB and mTORC1 activation, Ernst and colleagues show neuronal cell-type-specific effects of cell-fate markers and oxidative phosphorylation capacity from HPRT-deficient cells, providing mechanistic insight into the neurological features of Lesch-Nyhan disease.

Acquired resistance to glucocorticoids (GCs) is an obstacle to the effective treatment of leukemia, but the molecular mechanisms of steroid insensitivity have not been fully elucidated. In this study, we established an acquired GC-resistant leukemia cell model and found a long noncoding RNA, HOTAIRM1, was overexpressed in the resistant cells by transcriptional profiling, and was higher expressed in patients with poor prognosis. The whole-genome-binding sites of HOTAIRM1 were determined by ChIRP-seq (chromatin isolation by RNA purification combined with sequencing) analysis. Further study determined that HOTAIRM1 bound to the transcriptional inhibitory region of ARHGAP18 and repressed the expression of ARHGAP18, which led to the increase of RHOA/ROCK1 signaling pathway and promoted GC resistance through antiapoptosis of leukemia cells. The inhibition of ROCK1 in GC-resistant cells could restore GCs responsiveness. In addition, HOTAIRM1 could also act as a protein sequester to prevent transcription factor AML1(acute myeloid leukemia 1) from binding to the regulatory region of ARHGAP18 by interacting with AML1. At last, we also proved AML1 could directly activate the expression of HOTAIRM1 through binding to the promoter of HOTAIRM1, which enriched the knowledge on the regulation of lncRNAs. This study revealed epigenetic causes of glucocorticoid resistance from the perspective of lncRNA, and laid a foundation for the optimization of glucocorticoid-based leukemia treatment strategy in clinic.

Background and aims The apolipoprotein A-I mimetic peptide D-4F, among its anti-atherosclerotic effects, improves vasodilation through mechanisms not fully elucidated yet. Methods Low-density lipoprotein (LDL) receptor null (LDLr−/−) mice were fed Western diet with or without D-4F. We then measured atherosclerotic lesion formation, endothelial nitric oxide synthase (eNOS) phosphorylation and its association with heat shock protein 90 (HSP90), nitric oxide (NO) and superoxide anion (O2•-) production, and tetrahydrobiopterin (BH4) and GTP-cyclohydrolase 1 (GCH-1) concentration in the aorta. Human umbilical vein endothelial cells (HUVECs) and aortas were treated with oxidized LDL (oxLDL) with or without D-4F; subsequently, BH4 and GCH-1 concentration, NO and O2•- production, eNOS association with HSP90, and endothelium-dependent vasodilation were measured. Results Unexpectedly, eNOS phosphorylation, eNOS-HSP90 association, and O2•- production were increased, whereas BH4 and GCH-1 concentration and NO production were reduced in atherosclerosis. D-4F significantly inhibited atherosclerosis, eNOS phosphorylation, eNOS-HSP90 association, and O2•- generation but increased NO production and BH4 and GCH-1 concentration. OxLDL reduced NO production and BH4 and GCH-1 concentration but enhanced O2•- generation and eNOS association with HSP90, and impaired endothelium-dependent vasodilation. D-4F inhibited the overall effects of oxLDL. Conclusions Hypercholesterolemia enhanced uncoupled eNOS activity by decreasing GCH-1 concentration, thereby reducing BH4 levels. D-4F reduced uncoupled eNOS activity by increasing BH4 levels through GCH-1 expression and decreasing eNOS phosphorylation and eNOS-HSP90 association. Our findings elucidate a novel mechanism by which hypercholesterolemia induces atherosclerosis and D-4F inhibits it, providing a potential therapeutic approach.

Consortship has been defined as a temporary association between an adult male and an estrous/receptive female. It has been considered as male mating strategies to improve male mating success and potential reproductive success. However, the female roles have been more or less neglected, and thus, less is known about female behavioral strategies during the consortship periods. In this study, during the two consecutive mating seasons, we collected behavioral data of free‐ranging Tibetan macaques (Macaca thibetana) habituated in Mt. Huangshan, China, to investigate female behaviors when she was consorted by an adult male. The results showed that (a) females were more likely to approach and exhibit sexual solicitation to their consorting males during the consorted period, and females also exhibited less approach to their nonconsorting males; (b) females exhibited strong responses (either departed distantly or formed affiliative relationships with their consorting male partner) when their consorting males mated with rival females or showed sexual motivation toward rival females; (c) female preferences were positively correlated to the duration of consortships and the frequencies of ejaculation copulations, independent of the social ranks of their consorting male partners. Our results suggested that female strategies played much more important roles in forming and maintaining consortship than previously assumed. It provides new insight into understanding female adaptive strategies to male strategies by forming consortships in multimale–multifemale primate species when males could not identify female's fertile phase accurately., The study is relevant in today's society and should be of interest to a wide readership. The contribution of the study and the wider implications of the results are clearly presented and discussed in the manuscript.

In 1993, the apple buprestid, Agrilus mali Matsumura (Coleoptera: Buprestidae) native to northeast Asia, invaded the Yili River valley, Xinjiang Uyghur Autonomous Region, China. It is now widespread across 95% of wild apple forests (Malus sieversii (Ledeb.) Roem) in the region. This invasive species poses a major threat to wild apple populations serving as the key germplasm refuge for the ancestor of domestic apples across 6 countries in Central Eurasia. We first described the symptoms and damage caused by A. mali to wild apple trees, and then assessed the abundance of A. mali and tree damage under four different management strategies in three consecutive years (2016–2018): release of commercial biocontrol agents, aerial spraying of insecticide, aerial spraying/pruning, and establishment of fenced areas aiming to preserve understory veg-etation and enhance natural pest control. The apple buprestid feeds on inner bark and preferentially damages the small branches (1–4 cm in diameter) located in the canopy 4–6 m above ground. The average fruit production declined from 90 kg to 10 kg per tree after the pest invasion. Pest abundance, as measured by counting damage scars, declined in sprayed areas. Fenced areas had higher pest abundance (damage). Fruit production in biological control and spraying/pruning areas increased slightly, while tree damage ranking declined over the years. Our results suggest that a combination of biological control and spraying/pruning may contribute to pest management of A. mali and resilience of wild apple forests in Central Eurasia.

Xin Zhang *, Feng-Shuang Yi *, Huan-Zhong Shi Department of Respiratory and Critical Care Medicine, Beijing Institute of Respiratory Medicine and Beijing Chao-Yang Hospital, Capital Medical University, Beijing, 100020, People’s Republic of China*These authors contributed equally to this workCorrespondence: Huan-Zhong Shi; Feng-Shuang YiDepartment of Respiratory and Critical Care Medicine, Beijing Institute of Respiratory Medicine and Beijing Chao-Yang Hospital, Capital Medical University, 8 Gongti Nanlu, Chao-Yang District, Beijing, 100020, People’s Republic of ChinaTel/Fax +86 10 85231890Email shihuanzhong@ccmu.edu.cn; yifengshuang@ccmu.edu.cnBackground: Malignant pleural effusion (MPE) is a frequent complication of advanced malignancies that leads to a poor quality of life and limits treatment options.Objective: The objective of this study was to identify biomarkers of survival in patients with MPE, which will greatly facilitate the clinical management of this complication.Methods: This retrospective study recruited patients who had been pathologically diagnosed with MPE, regardless of the type of primary cancer, at Beijing Chao-Yang Hospital over 158 months. Demographic, clinical, hematological, and pleural fluid data were collected and analyzed as potential predictors of survival, and a new predictive model was developed based on Cox and logistic regression analyses.Results: In our alternative prognostic model (n = 281), four routinely detected variables, namely, carcinoembryonic antigen (CEA) level, monocyte count, N-terminal pro B-type natriuretic peptide (NT-pro-BNP) level, and pleural effusion chloride level on admission, were identified as predictors (the CONCH prognostic score). Patients were divided into three prognosis subgroups based on risk stratification, with median survival periods of 17, 11, and 5 months, respectively. In comparison with the low-risk group, patients in the medium- and high-risk groups showed significantly poorer survival (medium-risk group: hazard ratio [HR], 1.586; 95% confidence interval [CI], 1.047– 2.402; P = 0.029; high-risk group: HR, 4.389; 95% CI, 2.432– 7.921; P < 0.001).Conclusion: Four routinely detected variables were used to develop the CONCH scoring system, which was confirmed to be an accurate prognostic score for patients with MPE. This system can guide the selection of interventions and management for MPE.Keywords: malignant pleural effusion, prognosis, CEA, monocyte, NT-pro-BNP

Background Local ischemia and defective osteogenesis are implicated in the progression of glucocorticoid (GC)-induced osteonecrosis of the femoral head (ONFH). Recent studies have revealed that exosomes released from adipose-derived stem cells (ASCs) play important roles in ONFH therapy. The present study aimed to investigate whether exosomes derived from miR-378-overexpressing ASCs (miR-378-ASCs-Exos) could promote angiogenesis and osteogenesis in GC-induced ONFH. Methods In vitro, we investigated the osteogenic potential of miR-378-ASCs-Exos on bone marrow stromal cells (BMSCs) by alkaline phosphatase staining and western blotting. The angiogenic effects of miR-378-ASCs-Exos on human umbilical vein endothelial cells (HUVECs) were examined by evaluating their proliferation, migration, and tube-forming analyses. We identified the underlying mechanisms of miR-378 in osteogenic and angiogenic regulation. In addition, an ONFH rat model was established to explore the effects of miR-378-ASCs-Exos through histological and immunohistochemical staining and micro-CT in vivo. Results Administration of miR-378-ASCs-Exos improved the osteogenic and angiogenic potentials of BMSCs and HUVECs. miR-378 negatively regulated the suppressor of fused (Sufu) and activated Sonic Hedgehog (Shh) signaling pathway, and recombinant Sufu protein reduced the effects triggered by miR-378-ASCs-Exos. In vivo experiments indicated that miR-378-ASCs-Exos markedly accelerated bone regeneration and angiogenesis, which inhibited the progression of ONFH. Conclusion Our study indicated that miR-378-ASCs-Exos enhances osteogenesis and angiogenesis by targeting Sufu to upregulate the Shh signaling pathway, thereby attenuating GC-induced ONFH development.