Colonization front of the understorey palm Astrocaryum sciophilum in a pristine rain forest of French Guiana

Aims Astrocaryum sciophilum (Miq.) Pulle (Arecaceae) is an understorey palm, endemic to north‐eastern South America with a patchy distribution. We tested the hypothesis that the spatial distribution of this palm species is not in equilibrium but is slowly colonizing the forest understorey. Location Inventories and seed dispersal studies were conducted in the undisturbed tropical forest close to the Nouragues research station, French Guiana. Additional data were collected in the entire territory of French Guiana. Methods We studied the demography of A. sciophilum on a 20‐ha plot located at the edge of its distribution. The age of the palms was estimated by postulating an exponentially decreasing abundance by age class. Direct seed dispersal experiments were also conducted, to estimate dispersal parameters. The seeds of A. sciophilum were dispersed only by rodents. This information was used to parameterize a forest growth simulator, to study the spatial spread of this species. Results Within the sampling plot, the density of A. sciophilum dropped sharply from about 500 individuals per hectare to zero. The maturation age was estimated to be 170 ± 70 years, and over 55 years with 95% confidence. Seed‐dispersal experiments yielded an average seed dispersal distance of 11 m and a maximum estimated dispersal distance of 125 m across a generational span of 55 years to maturity. Therefore, the maximal estimated colonization speed is 2.3 m/y. Conclusions Empirical results and numerical simulations suggest that the boundary of the A. sciophilum population is a colonization front, and that the range of this species is slowly expanding. The implications of this result in respect of palaeoenvironmental changes in this region are discussed.     

Induction of antiproliferative effect by diosgenin through activation of p53,release of apoptosis-inducing factor （AIF） and modulation of caspase-3 activity in different human cancer cells

Previously, we demonstrated that a plant steroid, diosgenin, altered cell cycle distribution and induced apoptosis in the human osteosarcoma 1547 cell line. The objective of this study was to investigate if the antiproliferative effect of diosgenin was similar for different human cancer cell lines such as laryngocarcinoma HEp-2 and melanoma M4Beu cells. Moreover, this work essentially focused on the mitochondrial pathway. We found that diosgenin had an important and similar antiproliferative effect on different types of cancer cells. In addition, our new results show that diosgenin-induced apoptosis is caspase-3 dependent with a fall of mitochondrial membrane potential, nuclear localization of AIF and poly (ADP-ribose) polymerase cleavage. Diosgenin treatment also induces p53 activation and cell cycle arrest in the different cell lines studied.     

Induction of iron regulatory protein 1 RNA-binding activity by nitric oxide is associated with a concomitant increase in the labile iron pool: implications for DNA damage

Iron regulatory protein 1 (IRP1) is a bifunctional [4Fe-4S] protein that controls iron homeostasis. Switching off its function from an aconitase to an apo-IRP1 interacting with iron-responsive element-containing mRNAs depends on the reduced availability of iron in labile iron pool (LIP). Although the modulation of IRP1 by nitric oxide has been characterized, its impact on LIP remains unknown. Here, we show that inhibition of IRP1 aconitase activity and induction of its IRE-binding activity during exposure of L5178Y mouse lymphoma cells to NO are associated with an increase in LIP levels. Removal of NO resulted in a reverse regulation of IRP1 activities accompanied by a decrease of LIP. The increased iron burden in LIP caused by NO exacerbated hydrogen peroxide-induced genotoxicity in L5178Y cells. We demonstrate that the increase in LIP levels in response to chronic but not burst exposure of L5178Y cells to NO is associated with alterations in the expression of proteins involved in iron metabolism.     

Synthesis and in vitro pharmacological studies of new C(2) modified salvinorin A analogues

Salvinorin A is the most potent naturally occurring opioid agonist yet discovered with high selectivity and affinity for kappa-opioid receptor. To explore its structure and activity relationships, a series of salvinorin A derivatives modified at the C2 position were prepared and studied. These salvinorin A derivatives were screened for binding and functional activities at the human kappa-opioid receptor. Compound 4, containing a methoxymethyl group at the 2-position, was a full kappa-agonist with an EC50 value at 0.6 nM, which is about 7 times more potent than salvinorin A.     

The discovery of fluoropyridine-based inhibitors of the Factor VIIa/TF complex

The activated Factor VII/tissue factor complex (FVIIa/TF) plays a key role in the formation of blood clots. Inhibition of this complex may lead to new antithrombotic drugs. An X-ray crystal structure of a fluoropyridine-based FVIIa/TF inhibitor bound in the active site of the enzyme complex suggested that incorporation of substitution at the 5-position of the hydroxybenzoic acid side chain could lead to the formation of more potent inhibitors through interactions with the S1'/S2' pocket.     

Structural properties of polyubiquitin chains in solution

Because polyubiquitin chain structure modulates Ub-mediated signaling, knowledge of the physiological conformations of chain signals should provide insights into specific recognition. Here, we characterized the solution conformations of K48-linked Ub(2) and Ub(4) using a combination of NMR techniques, including chemical shift mapping of the interdomain interface, domain orientation measurements on the basis of 15N relaxation and residual dipolar couplings, and the solvent accessibility studies. Our data indicate a switch in the conformation of Ub(2), from open to closed, with increasing pH. The closed conformation features a well-defined interface that is related to, but distinguishable from, that observed in the Ub(2) crystal structure. This interface is dynamic in solution, such that important hydrophobic residues (L8, I44, V70) that are sequestered at the interface in the closed conformation may be accessible for direct interactions with recognition factors. Our results suggest that the distal two units of Ub(4), which is the minimum signal for efficient proteasomal degradation, may adopt the closed Ub(2) conformation.     

Residual Tumor Cells That Drive Disease Relapse after Chemotherapy Do Not Have Enhanced Tumor Initiating Capacity

Although chemotherapy is used to treat most advanced solid tumors, recurrent disease is still the major cause of cancer-related mortality. Cancer stem cells (CSCs) have been the focus of intense research in recent years because they provide a possible explanation for disease relapse. However, the precise role of CSCs in recurrent disease remains poorly understood and surprisingly little attention has been focused on studying the cells responsible for re-initiating tumor growth within the original host after chemotherapy treatment. We utilized both xenograft and genetically engineered mouse models of non-small cell lung cancer (NSCLC) to characterize the residual tumor cells that survive chemotherapy treatment and go on to cause tumor regrowth, which we refer to as tumor re-initiating cells (TRICs). We set out to determine whether TRICs display characteristics of CSCs, and whether assays used to define CSCs also provide an accurate readout of a cell’s ability to cause tumor recurrence. We did not find consistent enrichment of CSC marker positive cells or enhanced tumor initiating potential in TRICs. However, TRICs from all models do appear to be in EMT, a state that has been linked to chemoresistance in numerous types of cancer. Thus, the standard CSC assays may not accurately reflect a cell’s ability to drive disease recurrence.     

The effects of electromyographic feedback training on suppression of the oral-lingual movements associated with tardive dyskinesia

The efficacy of electromyographic feedback training in reducing the magnitude and frequency of the oral-lingual movements associated with tardive dyskinesia (TD) was investigated in a groups design. Twenty adult male inpatients diagnosed as having TD using the Abnormal Involuntary Movements Scale (AIMS) were randomly assigned to one of two treatment conditions. Following identification, all participants were initially reduced to the lowest effective dosage of neuroleptics, and then discontinued from anticholinergics. Following one month on this regimen, they were given a course of feedback training consisting of ten 14-minute sessions. Group one participants were provided with a tone contingent upon oral-lingual movements above a yoked threshold. Group two participants were given noncontingent feedback tones generated randomly. Weekly AIMS were administered as well as an initial baseline during each session to determine current level of oral-lingual activity. An analysis of session effects indicated significantly more suppression of oral-lingual activity in the contingent group versus the noncontingent feedback group. Jaw and forehead activity also measured showed reductions of similar magnitudes for both groups.This work was sponsored in part by a Research Advisory Grant from the Department of Veterans Affairs awarded to Joanne Intrator. We gratefully acknowledge the valuable contributions of K. Duvvi, S. Kemble, and L. Kolman.