Studies on the association between MDM2 SNP309 (T > G) and gastric cancer have reported conflicting results. Thus, the aim of this study was to investigate whether MDM2 SNP309 is associated with susceptibility and prognosis of gastric carcinoma in Chinese patients.

Quantitative structure-activity relationships (QSAR) were developed to predict the inhibition ratio of pyrrolidine derivatives on matrix metalloproteinase via heuristic method (HM) and gene expression programming (GEP). The descriptors of 33 pyrrolidine derivatives were calculated by the software CODESSA, which can calculate quantum chemical, topological, geometrical, constitutional, and electrostatic descriptors. HM was also used for the preselection of 5 appropriate molecular descriptors. Linear and nonlinear QSAR models were developed based on the HM and GEP separately and two prediction models lead to a good correlation coefficient (R (2)) of 0.93 and 0.94. The two QSAR models are useful in predicting the inhibition ratio of pyrrolidine derivatives on matrix metalloproteinase during the discovery of new anticancer drugs and providing theory information for studying the new drugs.

Increasing demand for natural rubber prompts studies into the mechanisms governing the productivity of rubber tree (Heveabrasiliensis). It is very interesting to notice that a rubber tree of clone PR107 in Yunnan, China is reported to yield more than 20 times higher than the average rubber tree. This super-high-yielding (SHY) rubber tree (designated as SY107), produced 4.12 kg of latex (cytoplasm of rubber producing laticifers, containing about 30% of rubber) per tapping, more than 7-fold higher than that of the control. This rubber tree is therefore a good material to study how the rubber production is regulated at a molecular aspect. A comprehensive cDNA-AFLP transcript profiling was performed on the latex of SY107 and its average counterparts by using the 384 selective primer pairs for two restriction enzyme combinations (ApoI/MseI and TaqI/MseI). A total of 746 differentially expressed (DE) transcript-derived fragments (TDFs) were identified, of which the expression patterns of 453 TDFs were further confirmed by RT-PCR. These RT-PCR confirmed TDFs represented 352 non-redundant genes, of which 215 had known or partially known functions and were grouped into 10 functional categories. The top three largest categories were transcription and protein synthesis (representing 24.7% of the total genes), defense and stress (15.3%), and primary and secondary metabolism (14.0%). Detailed analysis of the DE-genes suggests notable characteristics of SHY phenotype in improved sucrose loading capability, rubber biosynthesis-preferred sugar utilization, enhanced general metabolism and timely stress alleviation. However, the SHY phenotype has little correlation with rubber-biosynthesis pathway genes.

Post-transcriptional regulation of mRNAs plays an essential role in the control of gene expression. mRNAs are regulated in ribonucleoprotein (RNP) complexes by RNA-binding proteins (RBPs) along with associated protein and noncoding RNA (ncRNA) cofactors. A global understanding of post-transcriptional control in any cell type requires identification of the components of all of its RNP complexes. We have previously shown that these complexes can be purified by immunoprecipitation using anti-RBP synthetic antibodies produced by phage display. To develop the large number of synthetic antibodies required for a global analysis of RNP complex composition, we have established a pipeline that combines (i) a computationally aided strategy for design of antigens located outside of annotated domains, (ii) high-throughput antigen expression and purification in Escherichia coli, and (iii) high-throughput antibody selection and screening. Using this pipeline, we have produced 279 antibodies against 61 different protein components of Drosophila melanogaster RNPs. Together with those produced in our low-throughput efforts, we have a panel of 311 antibodies for 67 RNP complex proteins. Tests of a subset of our antibodies demonstrated that 89% immunoprecipitate their endogenous target from embryo lysate. This panel of antibodies will serve as a resource for global studies of RNP complexes in Drosophila. Furthermore, our high-throughput pipeline permits efficient production of synthetic antibodies against any large set of proteins.

Increasing numbers of refractory or severe, even fatal, cases of Mycoplasma pneumoniae infections have been reported in recent years. Excessive inflammatory responses play a vital role in the pathogenesis of refractory M. pneumoniae pneumonia (RMPP). HMGB1 is an actively secreted cytokine produced by macrophages and other inflammatory cells that participates in various infectious diseases. The present study aimed to explore the role and clinical significance of HMGB1 in children with RMPP and the potential mechanism of HMGB1 expression.

Current challenges in capturing naive human pluripotent stem cells (hPSCs) suggest that the factors regulating human naive versus primed pluripotency remain incompletely defined. Here we demonstrate that the widely used Essential 8 minimal medium (E8) captures hPSCs at a naive-to-primed intermediate state of pluripotency expressing several naive-like developmental, bioenergetic, and epigenomic features despite providing primed-state-sustaining growth factor conditions. Transcriptionally, E8 hPSCs are marked by activated lipid biosynthesis and suppressed MAPK/TGF-β gene expression, resulting in endogenous ERK inhibition. These features are dependent on lipid-free culture conditions and are lost upon lipid exposure, whereas short-term pharmacological ERK inhibition restores naive-to-primed intermediate traits even in the presence of lipids. Finally, we identify de novo lipogenesis as a common transcriptional signature of E8 hPSCs and the pre-implantation human epiblast in vivo. These findings implicate exogenous lipid availability in regulating human pluripotency and define E8 hPSCs as a stable, naive-to-primed intermediate (NPI) pluripotent state.

Background: NO is an important cellular signaling molecule which is derived from L-arginine by nitric oxide synthase (NOS) and the effects of NOS signaling in lung injury is conflicting. The present study was designed to observe the effect of NOS and Arginase signaling in the occurrence and development of lung injury and its mechanism. Methods: An ozone-stressed lung injury animal model was established by exposure to 2.0 ppm O3 for 30 min every day for consecutive 12 day with or without the administration of NO precursor L-arginine or non-selective NOS inhibitor N-nitro-L-arginine methyl ester (L-NAME). Then, the lung histopathology, the releases of inflammatory mediators and the production of ROS were assayed by immunohistochemistry, ELISA and flow cytometry respectively. The activities and expression of NOS and Arginase were assayed by biochemical methods and western blot. Correspondingly, the release of 8-oxoguanine glycosylase 1(8-OxoG) and 8-oxoguanine glycosylase 1 (OGG1) were assayed by ELISA and western blot. The correlation between NOS/Arginase signaling with 8-OxoG/ OGG1 was also analyzed by Pearson correlation coefficients and immunofluorescence in NOS deficient bronchial epithelial cells. Results: In ozone-induced rat lung injury models, lung inflammation as well as lung architecture was disrupted in a time dependent manner. Ozone treatment with L-arginine showed a substantial attenuation of adverse lung histopathological changes and treatment with L-NAME promoted the inflammation and remodeling. Importantly, the expression of NOS was promoted by L-arginine and inhibited by L-NAME and the expression of Arginase was promoted by L-NAME treatment. Further, we observed significantly higher levels of 8-OxoG and lower levels of OGG1 in ozone group which was reversed by L-arginine and promoted by L-NAME. The expression of NOS is closely related with 8-OxoG /OCG1. Conclusion: These findings give further evidence that the NOS signaling is related with base excise repair.

Effect of micro ribonucleic acid (miR)-30 on the proliferation of trophoblasts in preeclampsia (PE) rats through the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway was studied. The miR-30 mimic was transfected into the trophoblast HTR8/SVNEO cell lines. The effects of expression level of miR-30 on the proliferation and hypoxia-induced apoptosis of HTR8/SVNEO cells were detected via methyl thiazolyl tetrazolium (MTT) assay and Annexin V/propidium iodide staining, respectively, using the flow cytometer. A total of 30 pregnant Sprague-Dawley rats were randomly divided into control group (CTL group, n=10), PE rat group (PE group, n=10) and PE + miR-30 Mimic group (PE+agomiR-30 group, n=10) using a random number table. The protein expression levels of phosphorylated ERK (p-ERK)1/2, ERK1/2, proliferating cell nuclear antigen (PCNA) and tubulin were determined using western blot analysis, and the mRNA expression level of ERK1/2 was detected via reverse transcription-quantitative polymerase chain reaction (RT-qPCR). The expression level of PCNA in tissues was detected via immunohistochemistry. The results of MTT assay showed that the proliferation of HTR8/SVNEO cells significantly declined in hypoxic environment, while miR-30 promoted the proliferation of HTR8/SVNEO cells and alleviated the hypoxia-induced inhibition on cell proliferation. It was found that the trophoblast apoptosis rate was increased in hypoxia group compared with that in CTL group, while it was significantly decreased in miR-30 Mimic group compared with that in hypoxia group. PE group had obviously decreased p-ERK and PCNA expression levels as well as p-ERK/ERK ratio in placental tissues compared with CTL group, while PE+agomiR-30 group had an obviously increased expression level of PCNA as well as p-ERK/ERK ratio in placental tissues compared with PE group. MiR-30 activates the MAPK/ERK signaling pathway and increases the expression level of PCNA through raising the p-ERK level and p-ERK/ERK ratio, thereby inhibiting cell apoptosis and promoting cell proliferation.

Cholestasis is challenging to treat due to lacked effective drugs. N-(3,4,5-trichlorophenyl)-2 (3-nitrobenzenesulfonamido) benzamide, abbreviated as IMB16-4, which may be effective for the treatment of cholestasis. However, its poor solubility and bioavailability seriously obstruct the research programs.

In recent years, reports of refractory Mycoplasma pneumoniae pneumonia (RMPP) have gradually increased, including reports on how these conditions threaten the lives of children. However, the specific mechanism of Mycoplasma pneumoniae pneumonia (MPP) remains unclear. This study aimed to investigate the relationship between community-acquired respiratory distress syndrome toxin (CARDS TX) and High-mobility group box protein 1-Toll-like receptors-Myeloid differentiation factor 88 (HMGB1-TLRs-MyD88) in MPP and to examine the immune pathogenesis of Mycoplasma pneumoniae infection.

Zika virus (ZIKV) infects fetal and adult human brain and is associated with serious neurological complications. To date, no therapeutic treatment is available to treat ZIKV-infected patients. We performed a high-content chemical screen using human pluripotent stem cell-derived cortical neural progenitor cells (hNPCs) and found that hippeastrine hydrobromide (HH) and amodiaquine dihydrochloride dihydrate (AQ) can inhibit ZIKV infection in hNPCs. Further validation showed that HH also rescues ZIKV-induced growth and differentiation defects in hNPCs and human fetal-like forebrain organoids. Finally, HH and AQ inhibit ZIKV infection in adult mouse brain in vivo. Strikingly, HH suppresses viral propagation when administered to adult mice with active ZIKV infection, highlighting its therapeutic potential. Our approach highlights the power of stem cell-based screens and validation in human forebrain organoids and mouse models in identifying drug candidates for treating ZIKV infection and related neurological complications in fetal and adult patients.

Background. The roles of the sympathetic and parasympathetic systems in mediating the effect of electroacupuncture (EA) at ST37 on jejunal motility have yet to be demonstrated. Aim. We used rats and mice to investigate the effect and mechanism of action of EA at ST37 on jejunal motility. Methods. Jejunal motility was recorded by a balloon placed in the jejunum and connected to a biological signal collection system through a transducer. The effects of EA (3 mA) at ST37 were evaluated in Sprague-Dawley rats without drugs and with the administration of clenbuterol, propranolol, acetylcholine, and atropine. Further, the efficacy of EA at different intensities (1/2/4/6/8 mA) was measured in wild-type mice and β1β2-/- mice and M2M3-/- mice. Results. In Sprague-Dawley rats, the excitatory effect of EA at ST37 on jejunal motility disappeared in the presence of the muscarinic receptor antagonist atropine. EA at ST37 was less effective in M2M3-/- mice than in wild-type mice. Furthermore, to a certain extent, there existed "intensity-response" relationship between jejunal motility and EA. Conclusions. EA at ST37 can enhance jejunal motility in rats and mice mainly via excitation of the parasympathetic pathway. There is an "intensity-response" relationship between EA and effect on jejunal motility.

To explore the roles of Toll-like receptor (TLR)2 in Th2 cytokine production and immunoglobulin (Ig) class switching following ovalbumin (OVA) sensitization.

Oncogenes only transform cells under certain cellular contexts, a phenomenon called oncogenic competence. Using a combination of a human pluripotent stem cell–derived cancer model along with zebrafish transgenesis, we demonstrate that the transforming ability of BRAFV600E along with additional mutations depends on the intrinsic transcriptional program present in the cell of origin. In both systems, melanocytes are less responsive to mutations, whereas both neural crest and melanoblast populations are readily transformed. Profiling reveals that progenitors have higher expression of chromatin-modifying enzymes such as ATAD2, a melanoma competence factor that forms a complex with SOX10 and allows for expression of downstream oncogenic and neural crest programs. These data suggest that oncogenic competence is mediated by regulation of developmental chromatin factors, which then allow for proper response to those oncogenes.

The anesthetic states are accompanied by functional alterations. However, the dose-related adaptive alterations in the higher-order network under anesthesia, e. g. default mode network (DMN), are poorly revealed.

To learn about the gene structure, phylogenetic evolution, and function under biotic and abiotic stresses of BTB (Bric-a-Brac/Tramtrack/Broad Complex) genes in Paulownia fortunei, a whole-genome sequence evaluation was carried out, and a total of 62 PfBTB genes were identified. The phylogenetic analysis showed that PfBTB proteins are divided into eight groups, and these proteins are highly conserved. PfBTB genes were unevenly distributed on 17 chromosomes. The colinearity analysis found that fragment replication and tandem replication are the main modes of gene amplification in the PfBTB family. The analysis of cis-acting elements suggests that PfBTB genes may be involved in a variety of biological processes. The transcriptomic analysis results showed that PfBTB3/12/14/16/19/36/44 responded to Paulownia witches' broom (PaWB), while PfBTB1/4/17/43 responded to drought stress, and the RT-qPCR results further support the reliability of transcriptome data. In addition, the association analysis between miRNA and transcriptome revealed a 91-pair targeting relationship between miRNAs and PfBTBs. In conclusion, the BTB genes in Paulownia are systematically identified in this research. This work provides useful knowledge to more fully appreciate the potential functions of these genes and their possible roles in the occurrence of PaWB and in response to stress.

Studies defining normal and disrupted human neural crest cell development have been challenging given its early timing and intricacy of development. Consequently, insight into the early disruptive events causing a neural crest related disease such as pediatric cancer neuroblastoma is limited. To overcome this problem, we developed an in vitro differentiation model to recapitulate the normal in vivo developmental process of the sympathoadrenal lineage which gives rise to neuroblastoma. We used human in vitro pluripotent stem cells and single-cell RNA sequencing to recapitulate the molecular events during sympathoadrenal development. We provide a detailed map of dynamically regulated transcriptomes during sympathoblast formation and illustrate the power of this model to study early events of the development of human neuroblastoma, identifying a distinct subpopulation of cell marked by SOX2 expression in developing sympathoblast obtained from patient derived iPSC cells harboring a germline activating mutation in the anaplastic lymphoma kinase (ALK) gene.

The biological function of TRIM39, a member of TRIM family, remains largely unexplored in cancer, especially in colorectal cancer (CRC). In this study, we show that TRIM39 is upregulated in tumor tissues compared to adjacent normal tissues and associated with poor prognosis in CRC. Functional studies demonstrate that TRIM39 deficiency restrains CRC progression in vitro and in vivo. Our results further find that TRIM39 is a positive regulator of autophagosome-lysosome fusion. Mechanistically, TRIM39 interacts with Rab7 and promotes its activity via inhibiting its ubiquitination at lysine 191 residue. Depletion of TRIM39 inhibits CRC progression and autophagic flux in a Rab7 activity-dependent manner. Moreover, TRIM39 deficiency suppresses CRC progression through inhibiting autophagic degradation of p53. Thus, our findings uncover the roles as well as the relevant mechanisms of TRIM39 in CRC and establish a functional relationship between autophagy and CRC progression, which may provide promising approaches for the treatment of CRC.

Previous studies have demonstrated that both CS and LiCl possess anti-Alzheimer's disease (AD) activities. We prepared chondroitin sulfate-Li (CS-Li) and investigated its effect on AD and explored the possible mechanisms both in vitro and in vivo. We found that CS-Li could inhibit amyloid β (Aβ) aggregation and protect SH-SY5Y cells from Aβ 1-42-induced cytotoxicity in vitro. In D-gal and AlCl3-induced AD mouse model, CS-Li improves the spatial learning and memory abilities of AD mice, reverses the nuclear pyknosis and cell edema, and increases the survival rate of neurons in hippocampus of mice. Moreover, CS-Li significantly increased the levels of GSH-Px, Na+/K+-ATPase, and ChAT and decreased the levels of MDA and AchE in AD mice. Western blot results demonstrated that CS-Li could decrease the hyperphosphorylation of tau (Ser396/Ser404) by regulating the expression of p-GSK-3β (Ser9) and PP2A and inhibit the expression of proinflammatory factors through inhibiting NF-κB nuclear translocation by activating the MAPK signaling pathways. In a word, CS-Li can delay AD development through multitarget processes, including Aβ aggregation inhibition, oxidative stress damage, tau hyperphosphorylation, and inflammatory response, thereby improves learning and memory abilities.

Gastrointestinal motility disorder has been demonstrated to be regulated by acupuncture treatment. The mechanisms underlying the effects of acupuncture stimulation of abdominal and lower limb acupoints on gastrointestinal motility have been thoroughly studied; however, the physiology underlying the effects of acupuncture on the forelimbs to mediate gastrointestinal motility requires further exploration. The aim of this study was to determine whether electroacupuncture (EA) at LI11 promotes jejunal motility, whether the parasympathetic pathway participates in this effect, and if so, which somatic afferent nerve fibres are involved.