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Fish are often faced with selection pressure from human activities (e.g., fish angling). Therefore, morphological, physiological, personality, and life history characteristics have evolved directly in fish populations under this human-made selection. Here, we investigate the phenotypic basis of vulnerability to angling in juvenile Qingbo (Spinibarbus sinensis). The standard metabolic rate (SMR), maximum metabolic rate (MMR), and personality (i.e., exploration, activity and boldness) of juvenile S. sinensis were determined. An angling experiment was then conducted and the hormones (i.e., ghrelin) of the individuals were examined in a laboratory at 24.9 ± 0.1 °C. Our results showed that only frequency with which the fish touched the novel object in exploration was higher in the LVA (low vulnerability to angling) phenotype than the HVA (high vulnerability to angling) phenotype, but energy metabolism (SMR; MMR; AS, aerobic scope; FAS, factorial aerobic scope), hormone (ghrelin levels) and personality (exploration, activity and boldness) did not differ between the HVA and the LVA phenotype. Principal components analysis showed that exploration was associated with boldness while activity was not associated with boldness. The AS, exploration and boldness score were inhibitory factors for the HVA outcomes, but ghrelin, activity score and exploration score did not contribute to outcomes of the HVA. These results suggest that energy metabolism, hormone levels and personality are not predictors of vulnerability to angling in Qingbo under the laboratory condition, but individuals with higher tendency to explore the novel environment are more likely to be bolder.

In addition to defending against invasive microbes, T cells of the mammalian adaptive immune system also provide crucial protection against cancerous cells that spontaneously emerge from healthy host tissue. Cancer cells, in turn, co-opt many of the regulatory signaling pathways used by the body to prevent excessive T cell proliferation and activation. The tumor microenvironment (TMI) is frequently a highly immunosuppressive environment, and much research has been focused on identifying new targets that can enhance T cell antitumor immunity. Novel observations from my lab has found monoamine oxidase A (MAO-A) plays an important role in maintaining this immunosuppressive TMI. In Chapter 2, I observe that MAO-A functions as a “checkpoint” molecule that regulates CD8+ T cell antitumor immunity through modulating metabolization of serotonin, a neurotransmitter previously unassociated with the immune response. In Chapter 3, I observe that MAO-A also indirectly affect T cell antitumor immunity by promoting tumor associated macrophage polarization towards an immunosuppressive phenotype through signaling with oxidative stress. These two chapters provide exciting preclinical data and clinical correlation for repurposing clinical approved MAO-A inhibitors for cancer immunotherapy. Allogeneic hematopoietic stem cell transplantation is another approach to treating cancer, in particular hematological malignancies, and relies on donor T cell recognition of minor histocompatibility antigens to target residual cancer cells. However, its application is severely limited due to the risk of graft versus host disease (GvHD). Higher invariant natural killer T (iNKT) cell load following transplantation has been clinically associated with reduced GvHD without loss of the beneficial graft versus leukemia/lymphoma (GvL) effect. However, the accessibly of iNKT cells remains a major hurdle to their research and potential clinical application. In Chapter 4, I provide two protocols for generating large amounts of mouse and human iNKT cells in vivo through TCR engineering of hematopoietic stem cells (HSC-engineered iNKT) and a murine intermediary. In Chapter 5, a protocol to generate human HSC-engineered iNKT cells in vitro is introduced, and the resultant HSC-engineered iNKT are found capable of ameliorating xeno-GvHD without loss of GvL effect when added to the allograft, providing exciting preclinical data highlighting the possibly of using HSC-engineered iNKT cells as additives to the allograft to reduce GvHD risk and improve patient outcomes.

Despite an increasing number of environmental reports on plastic additives, gestational exposure to these chemicals has been poorly characterized. The present work aimed to characterize gestational exposure to a total of 50 broadly used plasticizers and antioxidants in women with full term (n = 155) and preterm deliveries (n = 75) and to explore the associations of prenatal exposure with the expressions of placental function related genes. A few of them exhibited significantly different concentrations between the preterm and full-term deliveries group, including 2,6-di-tert- butyl-4-(dimethylamino-methyl)phenol (AO4703), dibutyl fumarate (DBF), tributyl citrate (TBC), triethyl citrate (TEC) 2,4-di-tert-butyl-phenol (2,4DtBP), 2,4-(1,1,3,3-tetra-methylbutyl)phenol (4-tOP), 2,6-di-tert-butyl-4-hydroxytoluene (BHT), and their transformation products. Significant associations were determined between the concentrations of selected chemicals among the 14 substances with detection frequency greater than 60% and the mRNA expression levels of selected genes related to placental functions. The associations also exhibited chemical-specific patterns and significantly differed between preterm and full-term deliveries. Our work represents the first population-based study to assess potential links between gestational exposure to selected plasticizers and antioxidants and placental functions, calling for further efforts to elucidate the potential mechanisms and subsequent impacts on adverse pregnancy outcomes.

Genome-wide association analysis is a powerful tool to identify genomic loci underlying complex traits. However, the application in natural populations comes with challenges, especially power loss due to population stratification. Here, we introduce a bivariate analysis approach to a GWAS dataset ofArabidopsis thaliana. We demonstrate the efficiency of double-phenotype analysisto uncover hidden genetic loci masked by population structure via a series of simulations. In real data analysis, acommon allele, strongly confounded with population structure, is discovered to be associated with late flowering and slow maturation of the plant. The discovered genetic effect on flowering time is further replicated in independent datasets. Using Mendelian randomization analysis based on summary statistics from our GWAS and expression QTL scans, we predicted and replicated a candidate geneAT1G11560that potentially causes this association. Further analysis indicates that this locusis co-selected with flowering-time-related genes. The discovered pleiotropic genotypephenotype map provides new insights into understanding the genetic correlation of complex traits.

Protein adsorption preferentially occurs and significantly affects the physicochemical reactions once the biodegradable magnesium alloys as bone replacements have been implanted. To date, interactions mechanisms between Mg implants and proteins remain unclear at a molecular level. Thereby, a combination of molecular dynamic (MD) simulations and experimental exploration is used to investigate the adsorption behavior and conformational change of bovine serum albumin (BSA), a representative protein of blood plasma, upon the surface of micro-arc oxidation (MAO) coated Mg alloy AZ31. The influences of absorbed proteins on the cytocompatibility of MAO coating are evaluated by virtue of cytotoxicity assay. Results indicate that the negatively charged O atoms (BSA) exhibit strong interaction with Mg2+ ions of Mg(OH)2, revealing that BSA molecules are ionically adsorbed on the AZ31 surface. Interestingly, MD simulation reveals that MAO coating demonstrates superior ability to capture BSA molecules during the process of adsorption owing to strong electric attraction between the negatively charged O atoms in BSA molecules with Mg atoms of MgO in MAO coating. Moreover, the α-helix part of absorbed BSA molecules on AZ31 substrate and MAO coating markedly decreases with an increase in β-sheet, β-turn and unordered contents, which is attributed to the reduction in the number of hydrogen bonds in BSA molecules. Furthermore, the adsorbed BSA molecules improve the cytocompatibility of MAO coating since the positively charged -NH3+ group and β-sheet content of absorbed BSA molecules mediate the cell adhesion by interacting with the negatively charged cell membrane.

With the population increasing, fish communities, as important components in the river system, were inescapably impacted by human activities. To investigate these impacts, we characterized the fish community's composition by environmental DNA metabarcoding in the urban and suburban sites along Xiang River in central China. The results showed that 32 species were identified, and most species were from Cypriniform. The analysis indicated no significant differences in fish communities among the three urban areas. However, significant differences were observed between the bank solidified and non-solidified areas, which indicated that the channelization significantly influenced the biodiversity and abundances. An alien species, Clarias gariepinus, was discovered in all examined sites, and it was negatively associated with ten native species. Furthermore, human populations and acidification were also negatively related to diversity. Our findings clearly showed that the consequences of anthropogenic activities shaped ichthyofauna and caused biodiversity loss in the urban river.

In this study, the effects of crude Fuzhuan brick tea polysaccharide (CFBTPS) and purified fraction (FBTPS-3) on colitis induced by dextran sulfate sodium (DSS) in mice were investigated. Both CFBTPS and FBTPS-3 exhibited intestinal anti-inflammatory activities, including restoring body weight, colon length and solid fecal weight, and decreasing disease activity index score in mice. Moreover, the expression of lipocalin-2 in colitis could be significantly reduced. The inflammatory cytokines (IL-6, IL-1, IFN- and TNF-) and lipopolysaccharide in serum and the expression of inflammation-related mRNA in colon tissue were decreased. Both CFBTPS and FBTPS-3 could increase tight junction proteins (Occludin, Claudin-1 and ZO-1), promoting intestinal barrier function. For gut microbiota, DSS treatment resulted in abnormal proliferation of Bifidobacteria, while FBTPS-3 could restore this disorder to a certain extent. In addition, FBPTS-3 promoted the growth of probiotics such as Bacteroides, Parasutterella and Collinsella. Both CFBTPS and FBTPS-3 could attenuate colitis, what's more, FBTPS-3 showed better anti-inflammatory effect than CFBTPS.

The diversity of Asian horned toads is considered highly underestimated and to contain a large number of undescribed cryptic species. In this work, we describe three new species of Boulenophrys from south China, namely, Boulenophrys yaoshanensis sp. nov. from central Guangxi, Boulenophrys yingdeensis sp. nov. from northern Guangdong, and Boulenophrys yunkaiensis sp. nov. from western Guangdong. These three new species can be distinguished from all recognized congeners by a combination of morphological characteristics and significant genetic divergences. These descriptions increase the number of recognized species of Boulenophrys to 61. In addition, an updated checklist of the Asian horned toads of the subfamily Megophryinae is provided in this study.

Metabolic regulation plays important roles in embryo development and uterine receptivity during early pregnancy, ultimately influencing pregnancy efficiency in mammals. The important roles of lipid metabolism during early pregnancy have not been fully understood. Here, we described the regulatory roles of phospholipid, sphingolipid, and cholesterol metabolism on early embryo development, implantation, and uterine receptivity through production of cannabinoids, prostaglandins, lysophosphatidic acid, sphingosine-1-phosphate, and steroid hormones. Moreover, the impacts of lipids and fatty acids on embryo development potential and the related epigenetic modifications are also discussed. This review aims to elucidate the modulations of lipid metabolism on uterine receptivity and embryo development, contributing to novel strategies to establish dietary balanced lipids and fatty acids for reducing early embryo loss.

Human immunodeficiency virus (HIV) is a retrovirus that progressively attacks the human immune system. It is known that the HIV viral protein Tat recruits the host elongation factor, positive transcription elongation factor b (P-TEFb), onto the nascent HIV viral transactivation response element (TAR) RNA to overcome the elongation pause for active transcription of the entire viral genome. Interestingly, there exists an amplifying feedback loop between Tat and TAR—a reduction in Tat increases the elongation pause, resulting in more TAR RNA fragments instead of the entire viral genome transcript, and the TAR fragments as a scaffold for PRC2 complex in turn promote Tat ubiquitination and degradation. In this study, the structural ensembles and binding dynamics of various interfaces in the Tat/TAR/P-TEFb complex are probed by all-atom accelerated sampling molecular dynamics simulations. The results show that a protein-binding inhibitor F07#13 targeting the Tat/P-TEFb interface initiates the above feedback loop and shuts down the active transcription. Another RNA binding inhibitor, JB181, targeting the Tat/TAR interface, can prevent TAR from pulling down the Tat from P-TEFb protein and further reducing Tat degradation. The detailed mechanism of the complex dynamics helps elucidate how Tat and TAR coordinate the regulation between HIV genome transcription versus possible HIV latency.

Objective The objective of this study was to evaluate the influence of ACE I/D gene polymorphisms on diabetic kidney disease (DKD) risk. Methods All eligible investigations were identified, the number of various genotype in the case and control group were reviewed. The pooled analysis was performed using Stata software. Results In overall subjects, 24,321 participants with 12,961 cases and 11,360 controls were included. the pooled analysis showed a significant link between D allele, DD or II genotype and DKD risk (D versus I: OR = 1.316, 95% CI: 1.213–1.427, P = 0.000; DD versus ID + II: OR = 1.414, 95% CI: 1.253–1.595, P = 0.000; II versus DD + ID: OR = 0.750, 95% CI: 0.647–0.869, P = 0.000). The subgroup pooled analysis showed that ACE I/D gene polymorphism was correlated with DKD both in Asian and in Chinese population. In addition, ACE I/D gene polymorphism was correlated with type 2 DKD (D versus I: OR = 1.361, 95% CI: 1.243–1.490, P = 0.000; DD versus ID + II: OR = 1.503, 95% CI: 1.310–1.726, P = 0.000; II versus DD + ID: OR = 0.738, 95% CI: 0.626 –0.870, P = 0.000). However, there was no obvious correlation in Caucasian subjects and type 1 diabetic patients. Conclusion ACE I/D polymorphisms were correlated with DKD in Asian and type 2 diabetic populations. ACE D allele/DD genotype might be a risk factor, while ACE II genotype might be a protective factor for DKD.

Spermatogenesis is a complex process in which spermatogonial stem cells differentiate and develop into mature spermatozoa. The transcriptional regulatory network involved in fish spermatogenesis remains poorly understood. Here, we demonstrate in Nile tilapia that the Sox transcription factor family member Sox30 is specifically expressed in the testes and mainly localizes to spermatocytes and spermatids. CRISPR/Cas9-mediated sox30 mutation results in abnormal spermiogenesis, reduction of sperm motility, and male subfertility. Comparative transcriptome analysis shows that sox30 mutation alters the expression of genes involved in spermatogenesis. Further chromatin immunoprecipitation followed by high-throughput sequencing (ChIP-seq), ChIP-PCR, and luciferase reporter assays revealed that Sox30 positively regulates the transcription of ift140 and ptprb, two genes involved in spermiogenesis, by directly binding to their promoters. Our data, taken together, indicate that Sox30 plays an essential role in Nile tilapia spermatogenesis by directly regulating the transcription of the spermiogenesis-related genes ift140 and ptprb.

The development and deployment of diverse resistance sources in new wheat cultivars underpin the durable control of stripe rust. In the present study, two loci for adult plant resistance (APR), QYrSM155.1 and QYrSM155.2, were identified in the Chinese wheat breeding line Shaanmai 155. QYrSM155.1 was mapped to a 3.0-cM interval between the single-nucleotide polymorphism (SNP) markers AX-109583610 and AX-110907562 on chromosome arm 2BL. QYrSM155.2 was mapped to a 2.1-cM interval flanked by the SNP markers AX-110378556 and AX-86173526 on chromosome arm 7AS. A genome-wide association study was used to identify markers associated with APR in a panel of 411 spring wheat lines. Thirteen and 11 SNPs were significantly associated with QYrSM155.1 and QYrSM155.2, respectively, corresponding to physical intervals of 653.75–655.52 Mb on 2BL and 81.63–83.93 Mb on 7AS. To characterize the haplotype variation and the distribution of these QTL, haplotype analysis was performed based on these SNPs in an independent panel of 1,101 worldwide wheat accessions. Three major haplotypes (2B_h1, 2B_h2, and 2B_h3) for QYrSM155.1 and four major haplotypes (7A_h1, 7A_h2, 7A_h3, and 7A_h4) for QYrSM155.2 were identified. Accessions individually harboring QYrSM155.1_h1 and QYrSM155.2_h1 haplotypes and their combination displayed resistance. Additional assays of 1,306 current Chinese cultivars and breeding lines using markers flanking QYrSM155.1 and QYrSM155.2 indicated that the resistance haplotypes of the two QTL were present in respectively 1.45% and 14.16% of lines. Increasing resistance haplotype frequencies at these two loci using marker-assisted selection should benefit wheat production in China.

Adaptation to phytochemicals in herbivorous insects can influence tolerance to insecticides. However, it is unclear how insects use phytochemicals as cues to activate their metabolic detoxification systems. In this study, we found that dietary exposure to xanthotoxin enhanced tolerance of Spodoptera litura larvae to λ-cyhalothrin. Xanthotoxin ingestion significantly elevated the mRNA levels of 35 detoxification genes as well as the transcription factors Cap 'n' collar isoform-C (CncC) and its binding factor small muscle aponeurosis fibromatosis isoform-K (MafK). Additionally, xanthotoxin exposure increased the levels of reactive oxygen species (ROS), while ROS inhibitor N-acetylcysteine (NAC) treatment blocked xanthotoxin-induced expression of CncC, MafK, and detoxification genes and also prevented xanthotoxin-enhanced larval tolerance to λ-cyhalothrin. The 20-hydroxyecdysone (20E) signaling pathway was effectively activated by xanthotoxin, while blocking of 20E signaling transduction prevented xanthotoxin-enhanced larval tolerance to λ-cyhalothrin. Application of 20E induced the expression of multiple xanthotoxin-induced detoxification genes and enhanced λ-cyhalothrin tolerance in S. litura. NAC treatment blocked xanthotoxin-induced 20E synthesis, while the CncC agonist curcumin activated the 20E signaling pathway. These results indicate that the ROS/CncC pathway controls the induction of metabolic detoxification upon exposure to xanthotoxin, at least in part, through its regulation of the 20E signaling pathway.

The aim of this study is to explore whether or not the combined application of BS15 and H2 is capable to have a more effective control effect on SNE in broilers. A total of 240 1-day-old female chickens were randomly divided into 5 groups: (a) basal diet in negative control group (NC group); (b) basal diet + SNE infection (coccidiosis vaccine + CP) (PC group); (c) basal diet + SNE infection + H2 pre-treatment (BT group); (d) basal diet + SNE infection + BS15 pre-treatment (LT group); and (e) basal diet + SNE infection + H2 pre-treatment + BS15 pre-treatment (MT group). The results showed the MT group had the most positive effect on inhibiting the negative effect of growth performance at 42 days of age. In the detection of the NC, PC, and MT group indicators at 28 days of age, we found that MT group significantly promoted ileum tissue development of broilers, and the ileum of broilers in the MT group formed a flora structure different from NC and PC, although it was found that the MT group had no effect on the butyrate level in the cecum, but it could affect the serum immune level, such as significantly reducing the level of pro-inflammatory cytokine IL-8 and increasing the content of immunoglobulin IgM and IgG. In conclusion, the composite preparation of Lactobacillus johnsonii BS15 and Bacillus licheniformis H2 could effectively improve the growth performance against SNE broilers, which is possibly caused by the improvement of the immune levels, the reduction of inflammation levels, and the promotion of the intestinal development.

Virus-induced gene silencing (VIGS) is a natural defense mechanism of plants, which can cause sequence-specific degradation of viral RNA and is often used for studying the functional genome. At present, the VIGS system mediated by Tobacco rattle virus (TRV) has been successfully established in many plant species. However, the VIGS system in Chinese narcissus had not been reported yet. In this paper, the first use of the TRV-VIGS system in Chinese narcissus is described in detail. By injecting pTRV2-GFP into narcissus leaves, we confirmed that TRV could infect narcissus and move in narcissus plants. After the inoculation of pTRV2-NtPDS by two methods, phenomena such as photo-bleaching appeared in narcissus leaves and qRT-PCR results proved that PDS gene of narcissus was successfully silenced. Besides, pTRV2-NtMYB3 was inoculated into basal plates of narcissus to study the function of NtMYB3; the results showed that NtMYB3 is an inhibitor of flavonoids biosynthesis, which can increase the content of proanthocyanidins in basal plates of narcissus by repressing the expression level of NtFLS. These results indicate that the TRV-VIGS system has been successfully established in Chinese narcissus and successfully applied to the functional study of NtMYB3.

Purpose As a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), osimertinib has a powerful ability to penetrate the blood-brain barrier and a high potency for controlling brain metastases (BMs) from EGFR-mutant non-small cell lung cancer (NSCLC). The clinical value of cranial radiation therapy in osimertinib-treated NSCLC with BMs remains largely unknown. Methods and Materials Patients with NSCLC and BMs and receiving osimertinib treatment as the standard of care were retrospectively enrolled from 2 institutions. Cranial radiation therapy (RT; whole-brain radiation therapy [WBRT] or/and stereotactic radiosurgery [SRS]) performed before disease progression (PD) to osimertinib was categorized as upfront cranial radiation therapy (ucRT group), excluding those treatments performed during prior EGFR-TKI treatment. Overall survival (OS), progression-free survival (PFS), and the time to intracranial progression (iTTP) were compared between the 2 groups, with adjustment by covariates in propensity-score matched (PSM) analyses. The state of having 1 to 3 BM lesions, with a maximal size of ≤3 cm, was defined as having oligo-BM; otherwise; the cases were defined as having multiple BMs. Results Of the 205 patients enrolled, osimertinib was used as first-line therapy in 74 and second-line therapy in 131. There were 48 patients who received ucRTs, including WBRT in 24 and SRS in 24. All patients with oligo-BM in the ucRT group received SRS alone (n = 17), whereas most (n = 28; 90.3%) patients with multiple BMs received WBRT. Failure pattern analyses indicated that in the non-ucRT group, 40.2% of the initial PD involved the brain and 76.9% of the cranial PD involved the original sites, indicating the potential roles of ucRT. Indeed, the iTTP was significantly prolonged (P = .010) in the ucRT group among the whole population. In the PSM oligo-BM cohort, the ucRT group showed superior PFS (P = .033) and OS (P = .026) compared with the non-ucRT group, and the differences remained after multivariate Cox analyses. No such differences were observed in the subpopulation with multiple BMs. Conclusions In osimertinib-treated NSCLC patients with BMs, oligo-BM status could be used as a potential factor to select patients for upfront cranial RT. Further investigation by well-designed clinical trials is warranted.

β654-thalassemia is a prominent Chinese subtype of b-thalassemia, representing 17% of all cases of β-thalassemia in China. The molecular mechanism underlying this subtype involves the IVS-2-654 C→T mutation leading to aberrant β-globin RNA splicing. This results in an additional 73-nucleotide exon between exons 2 and 3 and leads to a severe thalassemia syndrome. Herein, we explored a CRISPR/Cas9 genome editing approach to eliminate the additional 73- nucleotide by targeting both the IVS-2-654 C→T and a cryptic acceptor splice site at IVS-2-579 in order to correct aberrant b-globin RNA splicing and ameliorate the clinical β-thalassemia syndrome in β654 mice. Gene-edited mice were generated by microinjection of sgRNA and Cas9 mRNA into one-cell embryos of β654 or control mice: 83.3% of live-born mice were gene-edited, 70% of which produced correctly spliced RNA. No off-target events were observed. The clinical symptoms, including hematologic parameters and tissue pathology of all of the edited β654 founders and their offspring were significantly improved compared to those of the non-edited β654 mice, consistent with the restoration of wild-type b-globin RNA expression. Notably, the survival rate of gene-edited heterozygous β654 mice increased significantly, and liveborn homozygous β654 mice were observed. Our study demonstrated a new and effective gene-editing approach that may provide groundwork for the exploration of β654-thalassemia therapy in the future.

In this experiment, laying hens were divided into a high productive group (group H) and a low productive group (group L). The purpose of this experiment was to screen and isolate a potential probiotic associated with the laying rate from group H by comparing the results via 16S rDNA high-throughput sequencing. The high-throughput sequencing analysis results showed that there were some differences in the composition of the gut microbiome between groups H and L on the Phylum and Genus levels. Through isolation and identification, we screened 16 lactobacilli strains. Among the 16 strains, S5 showed good acid tolerance, bile salt tolerance, and cholesterol degradation. Therefore, we chose strain S5 (identified as Limosilactobacillus oris, named Limosilactobacillus oris BSLO 1801) as a potential probiotic to promote the productivity of ordinary laying hens. During the animal experiment, 288 Hy-line white hens (30 weeks old) were divided into four groups, with six replications (n = 12) per group. The control group received the basic diet, and the treatment groups received the same basic diet supplemented with 107 CFU/kg, 108 CFU/kg, and 109 CFU/kg of BSLO 1801. The laying hens were acclimated to the environment for 1 week before the initiation of the experiment. Dietary supplementation with 107 CFU/kg and 109 CFU/kg of BSLO 1801 increased the laying rate significantly, and the potential probiotic improved the egg weight in all treatment groups. Additionally, the cholesterol content of the yolk dropped significantly in the 109 CFU/kg group, and the weight of egg yolk was significantly increased in all treatment groups. However, no significant differences in eggshell strength, eggshell thickness, protein height, and Haugh unit were observed among the four groups. These results revealed that lactobacilli spp. are important bacteria of the intestinal microbiome in highly productive laying hens, and BSLO 1801 was isolated as a potential probiotic. Through these animal experiments, we also found that adding BSLO 1801 to the basic diet of laying hens could effectively improve the laying rate, average egg weight, and yolk weight and reduce the cholesterol content in egg yolk.

Circular RNA-synaptosome associated protein 47 (circ-SNAP47; Hsa_circ_0016760) is oncogenic in non-small-cell lung cancer (NSCLC); however, its role is undescribed in cis-diamminedichloroplatinum II (DDP) resistance. We attempted to investigate its expression, role and mechanism in DDP-tolerant NSCLC. As a result, circ-SNAP47 expression was upregulated in human DDP-tolerant NSCLC tissues and cells, accompanied with WEE1 G2 checkpoint kinase (WEE1) upregulation and microRNA (miR)-625-5p downregulation. Functionally, interfering circ-SNAP47 and/or restoring miR-625-5p curbed the 50% inhibitory concentration of DDP, colony formation, cell proliferation and invasion, accompanied with apoptotic rate promotion and depressions of multidrug resistance (MDR) markers MDR1 and MRP1, anti-apoptosis protein Bcl-2, and pro-invasion protein MMP9. Notably, circ-SNAP47 interference suppressed xenograft tumor growth of DDP-tolerant NSCLC cells by elevating miR-625-5p and descending WEE1. Mechanistically, circ-SNAP47 directly targeted miR-625-5p, and miR-625-5p further targeted WEE1. Therefore, circ-SNAP47-miR-625-5p-WEE1 axis might participate in chemoresistance and progression of DDP-tolerant NSCLC.

Background. Breast cancer (BRCA) is one of the most common cancers and the leading cause of cancer-related death in women. RNA-binding proteins (RBPs) play an important role in the emergence and pathogenesis of tumors. The target RNAs of RBPs are very diverse; in addition to binding to mRNA, RBPs also bind to noncoding RNA. Noncoding RNA can cause secondary structures that can bind to RBPs and regulate multiple processes such as splicing, RNA modification, protein localization, and chromosomes remodeling, which can lead to tumor initiation, progression, and invasion. Methods. (1) BRCA data were downloaded from The Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium (ICGC) databases and were used as training and testing datasets, respectively. (2) The prognostic RBPs-related genes were screened according to the overlapping differentially expressed genes (DEGs) from the TCGA database. (3) Univariate Cox proportional hazard regression was performed to identify the genes with significant prognostic value. (4) Further, we used the LASSO regression to construct a prognostic signature and validated the signature in the TCGA and ICGC cohort. (5) Besides, we also performed prognostic analysis, expression level verification, immune cell correlation analysis, and drug correlation analysis of the genes in the model. Results. Four genes (MRPL13, IGF2BP1, BRCA1, and MAEL) were identified as prognostic gene signatures. The prognostic model has been validated in the TCGA and ICGC cohorts. The risk score calculated with four genes signatures could largely predict overall survival for 1, 3, and 5 years in patients with BRCA. The calibration plot demonstrated outstanding consistency between the prediction and actual observation. The findings of online database verification revealed that these four genes were significantly highly expressed in tumors. Also, we observed their significant correlations with some immune cells and also potential correlations with some drugs. Conclusion. We constructed a 4-RBPs-based prognostic signature to predict the prognosis of BRCA patients, and it has the potential for treating and diagnosing BRCA.

To assess the value of procalcitonin (PCT) as an early biomarker for predicting urosepsis caused by Gram-negative (GN) bacteria, Gram-positive (GP) bacteria and fungi following mini-percutaneous nephrolithotomy (mPCNL) and flexible ureteroscopy (FURS).A total number of 356 patients with positive preoperative UC (urine cultures) who underwent mPCNL and FURS between June 2017 and January 2021 were retrospectively analyzed. Univariable analysis and multivariable logistic regression analysis were conducted to compare the predictors for urosepsis caused by different organisms. Furthermore, the nomogram was established as a predicted model for urosepsis.Among 356 positive UC, 265 (74.4%) were positive for GN bacteria, 77 (21.4%) for GP bacteria and 14 (3.9%) for fungal pathogens. Escherichia coli (48.9%) were the predominant pathogens and Enterococcus (54/77) were the most common GP bacteria. Multivariate logistic regression analysis showed that positive nitrite (OR 3.31, 95% CI 1.20-9.14; P = 0.021), operative time 90 min (OR 3.10, 95% CI 1.10-8.75, P = 0.033) and postoperative PCT 0.1 ng/mL (OR 56.18, 95% CI 15.20-207.64, P 0.001) were associated with postoperative urosepsis originated in GN infections, while urosepsis caused by GP bacteria and fungi was not associated with PCT 0.1 ng/mL (P = 0.198), only stone burden 800 mmFor patients with positive preoperative UC, postoperative PCT 0.1 ng/mL was an independent risk factor of post-PCNL and post-FURS urosepsis caused by GN bacteria rather than GP bacteria and fungi.

Objectives 6-Hydroxykynurenic acid (6-HKA) is an organic acid component in extracts of Ginkgo biloba leaves and acts as a major contributor to neurorestorative effects, while its oral bioavailability was low. Therefore, using prodrug method to improve the bioavailability and brain content of 6-HKA is significant. Methods Three structural modified compounds of 6-HKA were synthesized, and ultra performance liquid chromatography-tandem mass spectrometry methods for quantification of these structural modified compounds in rat plasma and rat brain homogenate were established and comprehensively validated. The methods were effectively applied to investigate the effects of structural modification on apparent permeability coefficients in cells, the pharmacokinetics and the brain distribution in rats. Key findings The results illustrated that esterification can greatly improve the apparent permeability coefficient and bioavailability of 6-HKA. Comparing with direct oral administration of 6-HKA, the bioavailability of isopropyl ester was greatly improved (from 3.96 ± 1.45% to 41.8 ± 15.3%), and the contents of 6-HKA in rat brains (49.7 ± 9.2 ng/g brain) were significantly higher after oral administration. Conclusions The bioavailability and the brain content of 6-HKA can be improved by the prodrug method. Among three structural modified compounds, isopropyl-esterified 6-HKA was the most promising treatment.

The environmental and physicochemical characteristics and fungal communities of two batches of Chinese Luzhou-flavored Daqu were investigated during the fermentation stage and storage period. The D...

Many circRNA transcriptome data were deposited in public resources, but these data show great heterogeneity. Researchers without bioinformatics skills have difficulty in investigating these invaluable data or their own data. Here, we specifically designed circMine (http://hpcc.siat.ac.cn/circmine and http://www.biomedical-web.com/circmine/) that provides 1 821 448 entries formed by 136 871 circRNAs, 87 diseases and 120 circRNA transcriptome datasets of 1107 samples across 31 human body sites. circMine further provides 13 online analytical functions to comprehensively investigate these datasets to evaluate the clinical and biological significance of circRNA. To improve the data applicability, each dataset was standardized and annotated with relevant clinical information. All of the 13 analytic functions allow users to group samples based on their clinical data and assign different parameters for different analyses, and enable them to perform these analyses using their own circRNA transcriptomes. Moreover, three additional tools were developed in circMine to systematically discover the circRNA–miRNA interaction and circRNA translatability. For example, we systematically discovered five potential translatable circRNAs associated with prostate cancer progression using circMine. In summary, circMine provides user-friendly web interfaces to browse, search, analyze and download data freely, and submit new data for further integration, and it can be an important resource to discover significant circRNA in different diseases.

Intestinal stem cell (ISC) differentiation is regulated precisely by a niche in the crypt, where lymphocytes may interact with stem and transient amplifying (TA) cells. However, whether and how lymphocyte–stem/TA cell contact affects ISC differentiation is largely unknown. Here, we uncover a novel role of T cell–stem/TA cell contact in ISC fate decisions. We show that intestinal lymphocyte depletion results in skewed ISC differentiation in mice, which can be rescued by T cell transfer. Mechanistically, integrin αEβ7 expressed on T cells binds to E-cadherin on ISCs and TA cells, triggering E-cadherin endocytosis and the consequent Wnt and Notch signaling alterations. Blocking αEβ7−E-cadherin adhesion suppresses Wnt signaling and promotes Notch signaling in ISCs and TA cells, leading to defective ISC differentiation. Thus, αEβ7(+) T cells regulate ISC differentiation at single-cell level through cell–cell contact-mediated αEβ7−E-cadherin adhesion signaling, highlighting a critical role of the T cell–stem/TA cell contact in maintaining intestinal homeostasis.

Application of differentiation therapy targeting cellular plasticity for the treatment of solid malignancies has been lagging. Nasopharyngeal carcinoma (NPC) is a distinctive cancer with poor differentiation and high prevalence of Epstein-Barr virus (EBV) infection. Here, we show that the expression of EBV latent protein LMP1 induces dedifferentiated and stem-like status with high plasticity through the transcriptional inhibition of CEBPA. Mechanistically, LMP1 upregulates STAT5A and recruits HDAC1/2 to the CEBPA locus to reduce its histone acetylation. HDAC inhibition restored CEBPA expression, reversing cellular dedifferentiation and stem-like status in mouse xenograft models. These findings provide a novel mechanistic epigenetic-based insight into virus-induced cellular plasticity and propose a promising concept of differentiation therapy in solid tumor by using HDAC inhibitors to target cellular plasticity.

Objective: As the world's food safety and environmental safety problems become increasingly severe, the agricultural sectors of various countries are also paying closer attention to the use of biofertilizers and biocontrol agents. Rhizosphere bacteria are a significant source of commonly used biofertilizers and biocontrol agents. This study aims to describe the genome and genomic traits of a biocontrol agent in the genus Bacillus.Results: In this paper, a strain of Bacillus amyloliquefaciens IBFCBF-5 was isolated and identified to have an inhibitory effect on several common oomycete and fungal pathogens Phytophthora capsica, Sclerotinia sclerotiorum, Colletotrichum gloeosporioides, and Fusarium oxysporum f.sp. cucumerinum. The genome of strain IBFCB-5 was sequenced, and the assembled genome was 4,338,658bp, with a G+C content of 46.05%. The IBFCBF-5 genome contains abundant GH, GT, CE, PL, AA, and CBM gene families, potentially degrading cellulose and hemicellulose, chitin, starch, xylan, peptidoglycan, etc. In addition, 14 lipopeptide and polypeptide antibiotic gene clusters were found in IBFCBF-5, including those coding for the synthesis of several known antifungal and antibacterial compounds Fengycin, Bacilysin, Bacillibactin, and plantazolicin.Conclusion: Our results show that Bacillus amyloliquefaciens IBFCBF-5 has a broad-spectrum antifungal ability and that its genome contains many genes coding for antimicrobial metabolites.

Lycophytes are an ancient clade of the non-flowering vascular plants with chromosome numbers that vary from tens to hundreds. They are an excellent study system for examining whole-genome duplications (WGDs), or polyploidization, in spore-dispersed vascular plants. However, a lack of genome sequence data limits the reliable detection of very ancient WGDs, small-scale duplications (SSDs), and recent WGDs. Here, we integrated phylogenomic analysis and the distribution of synonymous substitutions per synonymous sites (Ks) of the transcriptomes of 13 species of lycophytes to identify, locate, and date multiple WGDs in the lycophyte family Lycopodiaceae. Additionally, we examined the genus Phlegmariurus for signs of genetic discordance, which can provide valuable insight into the underlying causes of such conflict (e.g., hybridization, incomplete lineage sorting, or horizontal gene transfer).We found strong evidence that two WGD events occurred along the phylogenetic backbone of Lycopodiaceae, with one occurring in the common ancestor of extant Phlegmariurus (Lycopodiaceae) approximately 22–23 million years ago (Mya) and the other occurring in the common ancestor of Lycopodiaceae around 206–214 Mya. Interestingly, we found significant genetic discordance in the genus Phlegmariurus, indicating that the genus has a complex evolutionary history. This study provides molecular evidence for multiple WGDs in Lycopodiaceae and offers phylogenetic clues to the evolutionary history of Lycopodiaceae.

Aim This study investigates the effects of ginsenoside Rb1 (GsRb1) on methamphetamine (METH)-induced toxicity in SH-SY5Y neuroblastoma cells and METH-induced conditioned place preference (CPP) in adult Sprague-Dawley rats. It also examines whether GsRb1 can regulate these effects through the NR2B/ERK/CREB/BDNF signaling pathways. Methods SH-SY5Y cells were pretreated with GsRb1 (20 μM and 40 μM) for 1 h, followed by METH treatment (2 mM) for 24 h. Rats were treated with METH (2 mg/kg) or saline on alternating days for 10 days to allow CPP to be examined. GsRb1 (5, 10, and 20 mg/kg) was injected intraperitoneally 1 h before METH or saline. Western blot was used to examine the protein expression of NR2B, ERK, P-ERK, CREB, P-CREB, and BDNF in the SH-SY5Y cells and the rats' hippocampus, nucleus accumbens (NAc), and prefrontal cortex (PFC). Results METH dose-dependently reduced the viability of SH-SY5Y cells. Pretreatment of cells with 40 μM of GsRb1 increased cell viability and reduced the expression of METH-induced NR2B, p-ERK, p-CREB and BDNF. GsRb1 also attenuated the expression of METH CPP in a dose-dependent manner in rats. Further, GsRb1 dose-dependently reduced the expression of METH-induced NR2B, p-ERK, p-CREB, and BDNF in the PFC, hippocampus, and NAc of rats. Conclusion GsRb1 regulated METH-induced neurotoxicity in vitro and METH-induced CPP through the NR2B/ERK/CREB/BDNF regulatory pathway. GsRb1 could be a therapeutic target for treating METH-induced neurotoxicity or METH addiction.

Background: The marine algae are considered a diverse source of bioactive compounds. Many active compounds have been isolated from algae and show good biological activities. Materials and Methods: The aim of this study is to detect the antiviral and anticancer activities in some extracts of marine algae. Extraction, purification and identification of some marine algae common in Egypt were conducted. Extraction of Ulva lactuca, Sargassum dentifolium, and Cystoseiara myrica was conducted. A sequence of extractions, including extraction by ethanol, boiling water, hydrochloric acid and sodium hydroxide were carried out. The obtained extracts were evaluated for their antitumour and antiviral activities against liver tumour cells, brain tumour cell lines, measles virus, mumps virus and hepatitis B virus (HBV). The extracts of the best activities were subjected for purification by size exclusion chromatography and anion exchange chromatography for ethanolic extracts or precipitation by cetylpyridinium chloride (CPC) then by size exclusion chromatography and anion exchange chromatography for aqueous extracts. Separation by GLS/MS was performed. The structures of the active compounds have been identified through different chemical analyses, including sugar analysis, configurational analysis, High-Performance Liquid Chromatography (HPLC), infrared spectroscopy (IR), Gas-Liquid Chromatography-Mass Spectroscopy (GLC-MS) and 1H,13C nuclear magnetic resonance (NMR) at ZV. Results: The active compounds from the water extracts have been identified mainly as polysaccharides and sulphated polysaccharides. The antitumour and the antiviral activities of ethanolic extracts are attributable to compound identified as Ethyl Palmitate. These natural compounds did not show cytotoxic effect. Conclusion: These outputs could be preliminary for further biological studies aiming to therapeutic application.

Background: Baicalin, a flavonoid glycoside compound present in Scutellaria baicalensis, has shown a wide spectrum of biological activities, but its liposolubility, water-solubility and mucosal permeability are all very poor, which leads to the low concentration in brain and poor bioavailability by oral or intravenous injective administration. Objective: The primary objective of this study was to formulate the Scutellaria baicalensis extract (SBE) with phospholipid to yield Scutellaria baicalensis extract-phospholipid complex (SBEPC) , and to evaluate its pharmacodynamics in the middle cerebral artery occlusion (MCAO). Methods: The optimal preparation technology of SBEPC was obtained through single-factor test and central composite design-response surface methodology (CCD-RSM), and was characterized with various analytical techniques including SEM, FT-IR and NMR. The storage conditions of SBEPC were established through stability study and the MCAO rat model was investigated through conducting pharmacodynamic studies to screen the appropriate administration and dose of SBEPC as well as to verify the neuroprotective effect of SBEPC on cerebral ischemia-reperfusion injury. Results: The optimized preparation conditions of SBEPC were summarized as follows: the ratio of phospholipids to drug was 2:1, the drug concentration was 3.5 mg/ml, the reaction temperature was 50 °C, and the entrapment efficiency was over 93.00%. Stability studies have demonstrated that SBEPC should be stored under 40 °C in a dry and ventilated place away from light and below 37% humidity. Furthermore, pharmacodynamic studies have found that, compared with SBE, SBEPC could introduce drugs into the brain and better exert the neuroprotective effect on MCAO rats, and the optimal administration and dose concentration of SBEPC were nasal administration and 40 mg/ml, respectively. Conclusion: These findings demonstrate that SBEPC is successfully prepared by CCD-RSM. SBEPC can enhance drugs' ability to enter the brain and improve the bioavailability of drugs in brain, and can effectively exert the neuroprotective effect on cerebral ischemia-reperfusion injury as compared with SBE.

Acute myocardial infarction (AMI) remains a dominant origin of morbidity, mortality and disability worldwide. Increases in reactive oxygen species (ROS) are key contributor to excessive cardiac injury after AMI. Here we developed an immobilized enzyme with Superoxide Dismutase (SOD) activity cross-link with Zr-based metal-organic framework (ZrMOF) (SOD-ZrMOF) for mitigate ROS-caused injury. In vitro and in vivo evidence indicates that SOD-ZrMOF exhibits excellent biocompatibility. By efficiently scavenging ROS and suppressing oxidative stress, SOD-ZrMOF can protect the function of mitochondria, reduce cell death and alleviate inflammation. More excitingly, long-term study using an animal model of AMI demonstrated that SOD-ZrMOF can reduce the infarct area, protect cardiac function, promote angiogenesis and inhibit pathological myocardial remodeling. Therefore, SOD-ZrMOF holds great potential as an efficacious and safe nanomaterial treatment for AMI., Graphical abstract Image 1, Highlights • We synthesized a superoxide dismutase immobilized nanocomposite with enhanced stability. • We tested the biocompatibility of SOD-ZrMOF and found it could promote the cell viability and proliferation of H9c2 cells. • SOD-ZrMOF shows excellent performance in protecting mitochondrial function of CMs by eliminating excessive ROS under hypoxia. • SOD-ZrMOF exhibited therapeutic effects on MI heart through inhibiting oxidative stress injury by NF-κB/HIF-1α pathway.