TRADD contributes to tumour suppression by regulating ULF-dependent p19Arf ubiquitylation

Tumour necrosis factor receptor (TNFR)-associated death domain (TRADD) protein is a central adaptor in the TNFR1 signalling complex that mediates both cell death and inflammatory signals. Here, we report that Tradd deficiency in mice accelerated tumour formation in a chemical-induced carcinogenesis model independently of TNFR1 signalling. In vitro, primary cells lacking TRADD were less susceptible to HRas-induced senescence and showed a reduced level of accumulation of the p19(Arf) tumour suppressor protein. Our data indicate that TRADD shuttles dynamically from the cytoplasm into the nucleus to modulate the interaction between p19(Arf) and its E3 ubiquitin ligase ULF, thereby promoting p19(Arf) protein stability and tumour suppression. These results reveal a previously unknown tumour-suppressive role for nuclear TRADD, augmenting its long-established cytoplasmic functions in inflammatory and immune signalling cascades. Our findings also make an important contribution to the rapidly expanding field of p19(Arf) post-translational regulation.     

Arabidopsis thaliana CENTRORADIALIS homologue (ATC) acts systemically to inhibit floral initiation in Arabidopsis

Floral initiation is orchestrated by systemic floral activators and inhibitors. This remote‐control system may integrate environmental cues to modulate floral initiation. Recently, FLOWERING LOCUS T (FT) was found to be a florigen. However, the identity of systemic floral inhibitor or anti‐florigen remains to be elucidated. Here we show that Arabidopsis thaliana CENTRORADIALIS homologue (ATC), an Arabidopsis FT homologue, may act in a non‐cell autonomous manner to inhibit floral initiation. Analysis of the ATC null mutant revealed that ATC is a short‐day‐induced floral inhibitor. Cell type‐specific expression showed that companion cells and apex that express ATC are sufficient to inhibit floral initiation. Histochemical analysis showed that the promoter activity of ATC was mainly found in vasculature but under the detection limit in apex, a finding that suggests that ATC may move from the vasculature to the apex to influence flowering. Consistent with this notion, Arabidopsis seedling grafting experiments demonstrated that ATC moved over a long distance and that floral inhibition by ATC is graft transmissible. ATC probably antagonizes FT activity, because both ATC and FT interact with FD and affect the same downstream meristem identity genes APETALA1, in an opposite manner. Thus, photoperiodic variations may trigger functionally opposite FT homologues to systemically influence floral initiation.     

Enhancing dopamine detection using a glassy carbon electrode modified with MWCNTs, quercetin, and Nafion

Glassy carbon (GC) electrode was modified using multi-wall carbon nanotubes (MWCNTs), quercetin (Q) and Nafion^® in this sequence. The thus modified electrode was used for the detection of dopamine (DA) in the presence of equimolar ascorbic acid (AA). It is demonstrated in this study that MWCNTs can increase the current response of DA by five-fold and Q can reduce the oxidation overpotential of DA by about 60 mV, compared to these parameters obtained with a bare GC electrode. It is also shown that a layer of Nafion^® can virtually eliminate the interference of AA for the detection of DA. The GC/MWCNTs/Q/Nafion^® electrode (hereafter also called composite electrode) shows a current density of about 900 μA cm⁻² for DA, compared to the value of 80 μA cm⁻² of the GC electrode and to the value of 390 μA cm⁻² of the GC/MWCNTs electrode. The 11-fold enhancement in the sensitivity of the GC electrode for DA determination is attributed to the composite modification of the electrode, and is substantiated through various cyclic voltammetric experiments. Cyclic voltammetry (CV) and linear sweep voltammetry were used to characterize the electrodes. Calibration curves of batch and flow systems were obtained by amperometry for the detection of DA. Additionally, the composite modified electrode was tested with a human serum sample for the determination of DA and was found to be promising at our preliminary experiments.     

Identification of 3-substituted N-benzhydryl-nortropane analogs as nociceptin receptor ligands for the management of cough and anxiety

A series of nortropane analogs based on previously reported compound 1 have been synthesized and shown to bind to the nociceptin receptor with high affinity. The synthesis and structure–activity relationships around the C-3 nortropane substitution are described. From the SAR study and hPXR screening effort, compound 15 was identified to possess potent oral antitussive and anxiolytic-like activities in the guinea pig models.     

Comparative analysis of maternal-fetal interface in preeclampsia and preterm labor

The maternal-fetal interface, a chimeric structure, is formed when fetal cytotrophoblasts (CTBs) from the placenta invade the uterine wall and its resident vasculature. In preeclampsia (PE), interstitial and endovascular invasion are often shallow, and fewer spiral arterioles are breached in toto. Our previous work has shown that faulty CTB differentiation to an invasive phenotype is a contributing factor. Here, we have tested the hypothesis that the constellation of morphological and molecular defects that are associated with PE are unique to this condition. Specifically, we have compared the histology of the maternal-fetal interface and CTB expression of stage-specific antigens in PE and in preterm labor (PTL) with or without inflammation. In the absence of inflammation, biopsies obtained after PTL were near normal at histological and molecular levels. In accord with previously published data, PE had severe negative effects on the endpoints analyzed. Biopsies obtained after PTL with inflammation had an intermediate phenotype. Our results suggest that the maternal-fetal interface from cases of PTL without inflammation can be used for comparative purposes, e.g., as age-matched controls, in studies of the effects of PE on cells in this region. This work was supported by the Intramural Division of NICHD (Perinatology Research Branch) and HD 30367.     

Application of dental stem cells in three-dimensional tissue regeneration

Dental stem cells can differentiate into different types of cells. Dental pulp stem cells, stem cells from human exfoliated deciduous teeth, periodontal ligament stem cells, stem cells from apical papilla, and dental follicle progenitor cells are five different types of dental stem cells that have been identified during different stages of tooth development. The availability of dental stem cells from discarded or removed teeth makes them promising candidates for tissue engineering. In recent years, three-dimensional (3D) tissue scaffolds have been used to reconstruct and restore different anatomical defects. With rapid advances in 3D tissue engineering, dental stem cells have been used in the regeneration of 3D engineered tissue. This review presents an overview of different types of dental stem cells used in 3D tissue regeneration, which are currently the most common type of stem cells used to treat human tissue conditions.     

Two new species and a new record of the genus Sinogastromyzon (Teleostei: Balitoridae) from Yunnan, China

Two new species and a new record of Sinogastromyzon are described from Lixianjiang River of Yunnan province, China. Sinogastromyzon lixianjiangensis, new species, can be distinguished from its congeners by the following characters: pectoral fin with XIII–XIV, 15–17 rays; pelvic fin with X–XI, 10–12 rays; 60–65 lateral-line scales; no scales on the dorsum of paired fins or the region between axilla of pectoral fin and pelvic-fin origin; tip of pelvic fin close to anus; tip of anal fin close to caudal-fin base; anal-fin origin nearer to the caudal-fin base than to the posterior pelvic-fin base; anus nearer to anal-fin origin than to the posterior pelvic-fin base; dorsal side of the body with 9–11 black blotches. Sinogastromyzon macrostoma, new species can be distinguished from its congeners by the following characters: pectoral fin with XII–XIV, 12–15 rays; pelvic fin with VII–IX, 11–13 rays; 48–56 lateral-line scales; mouth extremely big, slightly arched; no scales on the dorsum of paired fins or the region between axilla of pectoral fin and pelvic-fin origin; tip of pelvic fin far beyond anus; tip of anal fin far from caudal-fin base; anal-fin origin about midway between the posterior pelvic-fin base and caudal-fin base; anus nearer to posterior pelvic-fin base than to anal-fin origin; dorsal side of the body uniformly gray, without regular blotches in formalin preserved specimen. Sinogastromyzon cf. multiocellum is firstly recorded in China.     

Pyrazoloquinolines as PDE10A inhibitors: discovery of a tool compound

A series of pyrazoloquinolines, possessing (hetero)arylhydroxymethyl substituents at the quinoline C-4 position were evaluated as PDE10A inhibitors. Among these, methylpyrimidyl analogue 15 was identified as having good rodent and monkey exposure, and a MED of 10 mg/kg in an in vivo model.     

Structure elucidation of Sch 538415, a novel acyl carrier protein synthase inhibitor from a microorganism

A novel acyl carrier protein synthase inhibitor, Sch 538415 (1), was isolated from an unidentified bacterial microbe. Structure elucidation of 1 was accomplished based on analysis of spectroscopic data including UV, MS and 2D-NMR spectra. Compound 1 exhibited inhibitory activity in the acyl carrier protein synthase (AcpS) assay with an IC(50) value of 4.19 microM and showed antibacterial activity against Staphylococcus aureus in the agar diffusion assay.