Phenolic composition and antiparasitic activity of plants from the Brazilian Northeast “Cerrado”

This work describes the antiparasitic and cytotoxic activities of three plant species from the Cerrado biome, Northeastern Brazil. Significant antiparasitic inhibition was observed against Trypanosoma cruzi (63.86%), Leishmania brasiliensis (92.20%) and Leishmania infantum (95.23%) when using ethanol extract from leaves of Guazuma ulmifolia Lam. (Malvaceae), at a concentration of 500 μg/mL. However, low levels of inhibition were observed when assessing leishmanicidal and trypanocidal (Clone CL-B5) activities of crude ethanol extracts from leaves and bast tissue of Luehea paniculata (Malvaceae) and leaves and bark of Prockia crucis (Salicaceae) at a concentration of 500 μg/mL. The extracts revealed the presence of phenolic acids such as gallic acid, chlorogenic acid, caffeic acid and rosmarinic acid, as well as flavonoids such as rutin, luteolin, apigenin and quercetin – the latter detected only in G. ulmifolia. G. ulmifolia extract displayed higher leishmanicidal activity probably due to the presence of quercetin, a potent known leishmanicidal compound. A cytotoxicity test indicated values over 50% at the highest concentration (1000 μg/mL) for all natural products, which were considered cytotoxic. This points out the need for further tests to enable future in vivo trials, including antineoplastic activity on human tumor cells.     

Fertilité et cancer du testicule. Impact des traitements

Objectives

To study the fertility of patients with testicular cancer.

Population and Method

The fertility of a consecutive series of 489 men treated for germ cell tumour of the testis in the Midi-Pyrénées region, between 1978 and 1998, was investigated by means of a questionnaire sent by mail to the patients. A participation rate of 95% was obtained.

Results

Information concerning fertility was obtained for 446 men. 90.1% of patients who had tried to have children prior to their testicular cancer had succeeded, but only 61.8% of men were able to have a child after treatment of their cancer. Radiotherapy and surgery of residual masses appear to be more harmful to fertility than BOE chemotherapy.

Conclusion

The population of men treated for testicular cancer present a high risk of infertility, as the fertility of these men decreases by about 30% after treatment.     

Heparan sulfate proteoglycan syndecan-3 is a novel receptor for GDNF, neurturin, and artemin

Glial cell line-derived neurotrophic factor (GDNF) family ligands (GFLs) are potent survival factors for dopaminergic neurons and motoneurons with therapeutic potential for Parkinson's disease. Soluble GFLs bind to a ligand-specific glycosylphosphatidylinositol-anchored coreceptor (GDNF family receptor α) and signal through the receptor tyrosine kinase RET. In this paper, we show that all immobilized matrix-bound GFLs, except persephin, use a fundamentally different receptor. They interact with syndecan-3, a transmembrane heparan sulfate (HS) proteoglycan, by binding to its HS chains with high affinity. GFL-syndecan-3 interaction mediates both cell spreading and neurite outgrowth with the involvement of Src kinase activation. GDNF promotes migration of cortical neurons in a syndecan-3-dependent manner, and in agreement, mice lacking syndecan-3 or GDNF have a reduced number of cortical γ-aminobutyric acid-releasing neurons, suggesting a central role for the two molecules in cortical development. Collectively, syndecan-3 may directly transduce GFL signals or serve as a coreceptor, presenting GFLs to the signaling receptor RET.     

HIV-1 Coreceptor Usage Assessment by Ultra-Deep Pyrosequencing and Response to Maraviroc

Background

Maraviroc is an HIV entry inhibitor that alters the conformation of CCR5 and is poorly efficient in patients infected by viruses that use CXCR4 as an entry coreceptor. The goal of this study was to assess the capacity of ultra-deep pyrosequencing (UDPS) and different data analysis approaches to characterize HIV tropism at baseline and predict the therapeutic outcome on maraviroc treatment.

Methods

113 patients with detectable HIV-1 RNA on HAART were treated with maraviroc. The virological response was assessed at months 1, 3 and 6. The sequence of the HIV V3 loop was determined at baseline and prediction of maraviroc response by different software and interpretation algorithms was analyzed.

Results

UDPS followed by analysis with the Pyrotrop software or geno2pheno algorithm provided better prediction of the response to maraviroc than Sanger sequencing. We also found that the H34Y/S substitution in the V3 loop was the strongest individual predictor of maraviroc response, stronger than substitutions at positions 11 or 25 classically used in interpretation algorithms.

Conclusions

UDPS is a powerful tool that can be used with confidence to predict maraviroc response in HIV-1-infected patients. Improvement of the predictive value of interpretation algorithms is possible and our results suggest that adding the H34S/Y substitution would substantially improve the performance of the 11/25/charge rule.     

Developmental differences in genome replication program and origin activation

To ensure error-free duplication of all (epi)genetic information once per cell cycle, DNA replication follows a cell type and developmental stage specific spatio-temporal program. Here, we analyze the spatio-temporal DNA replication progression in (un)differentiated mouse embryonic stem (mES) cells. Whereas telomeres replicate throughout S-phase, we observe mid S-phase replication of (peri)centromeric heterochromatin in mES cells, which switches to late S-phase replication upon differentiation. This replication timing reversal correlates with and depends on an increase in condensation and a decrease in acetylation of chromatin. We further find synchronous duplication of the Y chromosome, marking the end of S-phase, irrespectively of the pluripotency state. Using a combination of single-molecule and super-resolution microscopy, we measure molecular properties of the mES cell replicon, the number of replication foci active in parallel and their spatial clustering. We conclude that each replication nanofocus in mES cells corresponds to an individual replicon, with up to one quarter representing unidirectional forks. Furthermore, with molecular combing and genome-wide origin mapping analyses, we find that mES cells activate twice as many origins spaced at half the distance than somatic cells. Altogether, our results highlight fundamental developmental differences on progression of genome replication and origin activation in pluripotent cells.     

Of rabbit and man: Comparative gene mapping

Summary Nineteen cell hybrids were obtained by fusing rabbit (Oryctolagus cuniculus, OCU) fibroblasts and a Chinese hamster cell line HGPRT. Eleven enzymatic markers were investigated for cosegregation analysis. Seven could be assigned to OCU chromosomes: LDHA to OCU1; LDHB and TPI to OCU4; PEPB, NP, and ITP to OCU16; and G6PD to OCUX. Two assignments were considered possible: MDH2 to OCU15, and GUK to OCU3 or 15. Two could not be assigned: MDH1 and PGD. These results are consistent with the OCU-HSA chromosome homocologies previously reported, except for PEPB.     

Topical application of a corticosteroid destabilizes the host-parasite relationship in an experimental model of the oral carrier state of Candida albicans

Abstract Using an experimental model in the mouse we have shown that both local and central lines of defense, involving CD4⁺ T cells, participate in a dynamic interaction to maintain a long-term carrier state of Candida albicans in the oral cavity. We have tested the impact of a predisposing factor to oral candidiasis in the form of a topical application of a corticosteroid (Topsyn^® gel) to the oral mucosa for 75 mice twice a day for a 20-day period. Very rapidly after the treatment was initiated, i.e. on day 4, the residual population of Candida increased up to 40-fold and by day 21, the population was 400-fold that of the carrier state. The resident population of intraepithelial CD4⁺ T cells in the oral mucosa virtually disappeared during the treatment. A topical corticosteroid application also resulted in a massive depletion of T cells in the lymph nodes and in the transient abrogation of the DTH reaction to Candida antigens. On cessation of treatment, normal levels of both Candida and intraepithelial CD4⁺ T cells were also quickly restored. These results suggest that resistance to superficial invasion by Candida is linked to the presence of an oral mucosal line of defense and that topical application of corticosteroids may dramatically shift the host-parasite relationship in favor of Candida .     

A cytogenetic survey of 110 baboons (Papio cynocephalus)

A cytogenetic investigation of 110 adult baboons (Papio cynocephalus) captured in Kenya and sacrificed at the Institut Pasteur, Paris, showed the absence of anomalies, numerical or structural bearing on nonheterochromatic material; a polymorphism of the AgNOR-positive secondary constriction of chromosome 5 in 12% of the animals; a polymorphism of a secondary constriction of chromosome 7 in 2% of the animals; a fragile site of chromosome 6 in one animal. We believe that our data show that cytogenetic observations in present day primates probably reflect their chromosomal evolution.