PACAP : a novel neuropeptide for pituitary gonadotroph maturation, function and regulation.

Pituitary adenylate cyclase-activating polypeptide (PACAP) is a 38-amino acid C-terminally a-amidated peptide that was first isolated from ovine hypothalamic extracts on the basis of its ability to stimulate cAMP production in anterior pituitary cells. As a member of the vasoactive intestinal polypeptide (VIP)/secretin/growth hormone-releasing hormone/glucagon superfamily, PACAP has been well conserved during evolution from sea squirt to humans, which suggests important biological functions. Two types of PACAP receptors have been characterized. PAC1-R is the only one PACAP-specific receptor with high affinity. Although PACAP was first found in hypothalamus, it is also expressed in the pituitary. In the research to be presented, PACAP and PAC1-R mRNA expression in the rodent pituitary and in gonadotroph cell lines were explored using semi-quantitative PCR, laser capture micro-dissection (LCM) and single cell PCR. The level of pituitary PACAP expression is high in the fetus and declines after birth. Most of pituitary PACAP is from gonadotrophs. PAC1-R in fetal pituitary exists as the Hop and short forms, and the level of the short form decreases after birth. The effects of PACAP on gonadotropins synthesis and secretion were studied in vivo and in vitro. The action of PACAP on LH and FSH was investigated utilizing micro-pump implanted, containing PACAP38 or the antagonist, PACAP 6-38, in pre-pubertal male rats. Protein and mRNA analysis revealed that PACAP suppresses FSH presumably through increased follistatin, but had no significant influence on LH. The existence of PACAP, therefore, likely contributes to maintain an appropriate gonadotropin environment during sexual development. We also studied pituitary cell cultures and gonadotroph cell lines to understand why PACAP expression in pituitary is high in the fetus, and declines at birth. PACAP was found to stimulate its own expression in that the PACAP 6-38 antagonist reduced the PACAP mRNA level in primary cell cultures, and PACAP38 induced high activity of PACAP promoter in gonadotroph cell lines. Furthermore, we found preliminary evidence to support the ideal that dopamine receptor 2 (Drd2) signaling may explain the neonatal decrease in pituitary PACAP mRNA levels. Finally, we propose that the decrease in PACAP results in a fall in pituitary follistatin, allowing for increased activin signaling which increases FSHß facilitates the sexual maturation of the gonads

Cyclodextrin-based biological stimuli-responsive carriers for smart and precision medicine

Spurred on by recent progress in nanotechnology and precision medicine, smart drug carriers are entering an entirely new era. Smart drug carriers have been widely studied in recent years as a result of their ability to control drug release under different microenvironments (such as pH, redox, and enzyme) in vivo. Host-guest interactions based on cyclodextrins have proven to be an efficient tool for fabricating smart drug carriers. Because of the application of host-guest interactions, many kinds of biological molecules or supramolecular building blocks can combine into an organic whole at the molecular level. In this review, the features, mechanisms of action, and potent applications of biological stimuli-responsive drug carriers based on cyclodextrins are discussed. In addition, some personal perspectives on this field are presented

Event-triggered dynamic output quantized control for 2-D switched systems

It is well known that designing mode-dependent event-triggered control (MDETC) brings challenging difficulties to theoretical analysis, especially for two-dimensional (2-D) switched systems. Therefore, for 2-D switched Fornasini–Marchesini local state-space (FMLSS) systems, this paper designs a MDETC to investigate global exponential stabilization almost surely (GES a.s.). A MDETC based on dynamic output quantization control scheme is designed, which not only has a wide range of practicability, but also greatly saves network bandwidth resources. By constructing mode-dependent Lyapunov functions that include two time directions, some novel sufficient conditions are provided such that the switched FMLSS system achieves GES a.s. Unlike most previous results, our results do not require each mode to be stable, not even after adding control. Finally, numerical experiments are provided to verify the validity of our main theoretical results

BONE MORPHOGENETIC PROTEIN-2 AND COLLAGEN TYPE 1 FROM DIFFERENT SOURCES OF DEMINERALIZED DENTINE MATRIX: RELEASE KINETIC AND CHEMOTAXIS POTENTIAL FOR OSTEOPROGENITOR CELLS

Objective: To investigate the release of bone morphogenetic protein-2 (BMP-2) and collagen type I proteins (COL1) from different sources ofdemineralized dentine matrix (DDM) and their chemotaxis to mouse osteoprogenitor cells.Methods: The release kinetic of BMP-2 and COL1 was measured from custom-made DDM (CMDDM) and commercially available DDM (CADDM).Using Urist physicochemical method, CMDDM was collected from the extracted teeth in a certified dental clinic. Levels of BMP-2 and COL1 releasedwere measured at days 1, 2, 3, 5, 7, 9, 11, and 13. Next, mouse osteoprogenitor cells, MC3T3-E1, were cultured with a variety of materials as follows:CMDDM, CADDM, Bio-Oss®, and blank control in transwell system. The number of cell migration was determined by crystal violet staining to explorechemotaxis of different DDMs to mouse osteoprogenitor cells.Results: BMP-2 was detected at 588.32 ± 14.53 pg/ml from 5 g of CMDDM. In the release kinetic assay, the concentration of BMP-2 in the CMDDMgroup increased rapidly and peaked at 113.9 pg/ml on day 5, almost four times higher than that of CADDM. The release of COL1 showed similarpattern in both CMDDM and CADDM; however, the amount was significantly higher in the CMDDM group. In cell culture experiment, the number ofmigrated MC3T3-E1 was ranked as the highest in CMDDM, followed by CADDM and Bio-Oss® (p<0.05).Conclusion: CMDDM released BMP-2 and COL1 greater than CADDM, which can induce more osteoblast-like cell migration. These results demonstrateda release kinetic of proteins and osteoinductivity of CMDDM, which supports a benefit of using autogenous bone graft

The study of GPX3 methylation in patients with Kashin-Beck Disease and its mechanism in chondrocyte apoptosis

Objective Selenium deficiency is a risk factor for Kashin-Beck Disease (KBD), an endemic osteoarthropathy. Although promoter hypermethylation of glutathione peroxidase 3 (GPX3) (a selenoprotein) has been identified in several cancers, little is known about promoter methylation and expression of GPX3 and their relation to selenium in KBD. The present study was thus conducted to investigate this research question. Methods Methylation and expressions of GPX3 in whole blood drawn from 288 KBD patients and 362 healthy controls and in chondrocyte cell line were evaluated using methylation-specific PCR and qRT-PCR, respectively. The protein levels of PI3K/Akt/c-fos signaling in the whole blood and chondrocyte cell line were determined with Western blotting. Chondrocytes apoptosis were detected by Hoechst 33342 and Annexin V-FITC/PI staining. Results GPX3 methylation was increased, GPX3 mRNA was decreased, and protein levels in the PI3K/Akt/c-fos signaling pathway were up-regulated in the whole blood collected from KBD patients as compared with healthy controls. Similar results were obtained for chondrocytes injured by oxidative stress. There was a significant, decreasing trend in GPX3 expression across groups of unmethylation, partial methylation, and complete methylation for GPX3, in sequence. Compared with unmethylation group, protein levels in PI3K/Akt/c-fos pathway were enhanced in partial and complete methylation groups. Treatment of chondrocytes with sodium selenite resulted in reduced methylation and increased expression of GPX3 as well as down-regulated level of PI3K/Akt/c-fos proteins. Conclusions The methylation and expression of GPX3 and expression of PI3K/Akt/c-fos pathway are altered in KBD and these changes are reversible by selenium supplementation

cAMP/CREB-regulated LINC00473 marks LKB1-inactivated lung cancer and mediates tumor growth

The LKB1 tumor suppressor gene is frequently mutated and inactivated in non–small cell lung cancer (NSCLC). Loss of LKB1 promotes cancer progression and influences therapeutic responses in preclinical studies; however, specific targeted therapies for lung cancer with LKB1 inactivation are currently unavailable. Here, we have identified a long noncoding RNA (lncRNA) signature that is associated with the loss of LKB1 function. We discovered that LINC00473 is consistently the most highly induced gene in LKB1-inactivated human primary NSCLC samples and derived cell lines. Elevated LINC00473 expression correlated with poor prognosis, and sustained LINC00473 expression was required for the growth and survival of LKB1-inactivated NSCLC cells. Mechanistically, LINC00473 was induced by LKB1 inactivation and subsequent cyclic AMP–responsive element–binding protein (CREB)/CREB-regulated transcription coactivator (CRTC) activation. We determined that LINC00473 is a nuclear lncRNA and interacts with NONO, a component of the cAMP signaling pathway, thereby facilitating CRTC/CREB-mediated transcription. Collectively, our study demonstrates that LINC00473 expression potentially serves as a robust biomarker for tumor LKB1 functional status that can be integrated into clinical trials for patient selection and treatment evaluation, and implicates LINC00473 as a therapeutic target for LKB1-inactivated NSCLC

Human Streptococcus suis Outbreak, Sichuan, China

Streptococcus suis outbreak was associated with exposure to sick or dead pigs

Long Noncoding RNA FAM201A Mediates the Radiosensitivity of Esophageal Squamous Cell Cancer by Regulating ATM and mTOR Expression via miR-101

Background: The aim of the present study was to identify the potential long non-coding (lnc.)-RNA and its associated molecular mechanisms involved in the regulation of the radiosensitivity of esophageal squamous cell cancer (ESCC) in order to assess whether it could be a biomarker for the prediction of the response to radiotherapy and prognosis in patients with ESCC.Methods: Microarrays and bioinformatics analysis were utilized to screen the potential lncRNAs associated with radiosensitivity in radiosensitive (n = 3) and radioresistant (n = 3) ESCC tumor tissues. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was performed in 35 ESCC tumor tissues (20 radiosensitive and 15 radioresistant tissues, respectively) to validate the lncRNA that contributed the most to the radiosensitivity of ESCC (named the candidate lncRNA). MTT, flow cytometry, and western blot assays were conducted to assess the effect of the candidate lncRNA on radiosensitivity in vitro in ECA109/ECA109R ESCC cells. A mouse xenograft model was established to confirm the function of the candidate lncRNA in the radiosensitivity of ESCC in vivo. The putative downstream target genes regulated by the candidate lncRNA were predicted using Starbase 2.0 software and the TargetScan database. The interactions between the candidate lncRNA and the putative downstream target genes were examined by Luciferase reporter assay, and were confirmed by PCR.Results: A total of 113 aberrantly expressed lncRNAs were identified by microarray analysis, of which family with sequence similarity 201-member A (FAM201A) was identified as the lncRNA that contributed the most to the radiosensitivity of ESCC. FAM201A was upregulated in radioresistant ESCC tumor tissues and had a poorer short-term response to radiotherapy resulting in inferior overall survival. FAM201A knockdown enhanced the radiosensitivity of ECA109/ECA109R cells by upregulating ataxia telangiectasia mutated (ATM) and mammalian target of rapamycin (mTOR) expression via the negative regulation of miR-101 expression. The mouse xenograft model demonstrated that FAM201A knockdown improved the radiosensitivity of ESCC.Conclusion: The lncRNA FAM201A, which mediated the radiosensitivity of ESCC by regulating ATM and mTOR expression via miR-101 in the present study, may be a potential biomarker for predicting radiosensitivity and patient prognosis, and may be a therapeutic target for enhancing cancer radiosensitivity in ESCC

Seroprevalence of Pandemic (H1N1) 2009 in Pregnant Women in China: An Observational Study

BACKGROUND: We investigated the seropositive rates and persistence of antibody against pandemic (H1N1) 2009 virus (pH1N1) in pregnant women and voluntary blood donors after the second wave of the pandemic in Nanjing, China. METHODOLOGY/PRINCIPAL FINDINGS: Serum samples of unvaccinated pregnant women (n = 720) and voluntary blood donors (n = 320) were collected after the second wave of 2009 pandemic in Nanjing. All samples were tested against pH1N1 strain (A/California/7/2009) with hemagglutination inhibition assay. A significant decline in seropositive rates, from above 50% to about 20%, was observed in pregnant women and voluntary blood donors fifteen weeks after the second wave of the pandemic. A quarter of the samples were tested against a seasonal H1N1 strain (A/Brisbane/59/2007). The antibody titers against pH1N1 strain were found to correlate positively with those against seasonal H1N1 strain. The correlation was modest but statistically significant. CONCLUSIONS AND SIGNIFICANCE: The high seropositive rates in both pregnant women and voluntary blood donors suggested that the pH1N1 virus had widely spread in these two populations. Immunity derived from natural infection seemed not to be persistent well

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe