Basal and luminal are two molecular subtypes of breast cancer with opposite histoclinical features. We report a combined, high-resolution analysis of genome copy number and gene expression in primary basal and luminal breast cancers. First, we identified and compared genomic alterations in 45 basal and 48 luminal tumors by using 244K oligonucleotide array comparative genomic hybridization (aCGH). We found various genome gains and losses and rare high-level gene amplifications that may provide therapeutic targets. We show that gain of 10p is a new alteration in basal breast cancer and that a subregion of the 8p12 amplification is specific of luminal tumors. Rare high-level amplifications contained BCL2L2, CCNE, EGFR, FGFR2, IGF1R, NOTCH2, and PIK3CA. Potential gene breaks involved ETV6 and FLT3. Second, we analyzed both aCGH and gene expression profiles for 42 basal and 32 luminal breast cancers. The results support the existence of specific oncogenic pathways in basal and luminal breast cancers, involving several potential oncogenes and tumor suppressor genes (TSG). In basal tumors, 73 candidate oncogenes were identified in chromosome regions 1q21-23, 10p14, and 12p13 and 28 candidate TSG in regions 4q32-34 and 5q11-23. In luminal breast cancers, 33 potential oncogenes were identified in 1q21-23, 8p12-q21, 11q13, and 16p12-13 and 61 candidate TSG in 16q12-13, 16q22-24, and 17p13. HORMAD1 (P = 6.5 Â 10 À5 ) and ZNF703 (P = 7 Â 10 À4

BackgroundPlasmodium ovale is one of the five malaria species infecting humans. Recent data have shown that the name of this neglected species masks two distinct genotypes also called curtisi and wallikeri. Some authors show that these species could be sympatric. These two subspecies are not differentiated by microscopy techniques and malaria rapid diagnostic tests. This diagnostic defect is the result of low parasitaemia, antigenic polymorphism and absence of antibodies performance and requires the use of sequencing techniques. An accurate and easy discrimination detection method is necessary.MethodsA new molecular assay was developed to easily identify the two genotypes of P. ovale. This tool allowed the study of 90 blood samples containing P. ovale, confirmed by molecular biology techniques, which were obtained from patients with imported malaria.ResultsThe new marker was validated on well genotyped samples. The genotype of 90 P. ovale samples mainly imported from the Ivory Coast and the Comoros Islands was easily and quickly realized. The distribution of the two subspecies was described with a significant number of samples and showed that the two genotypes were present in the studied countries.ConclusionThis work confirms the presence of the two species in the same country for the first time, in the Ivory Coast and the Comoros Islands. A better genotyping of P. ovale types may improve a better characterization of the clinical pathophysiology for each.

One of the most important public health problems in the world today is the emergence and dissemination of drug-resistant malaria parasites. Plasmodium falciparum is the causative agent of the most lethal form of human malaria. New anti-malarial strategies are urgently required, and their design and development require the identification of potential therapeutic targets. However, the molecular mechanisms controlling the life cycle of the malaria parasite are still poorly understood. The published genome sequence of P. falciparum and previous studies have revealed that several homologues of eukaryotic signalling proteins, such as protein kinases, are relatively conserved. Protein kinases are now widely recognized as important drug targets in protozoan parasites. Cyclic AMP-dependent protein kinase (PKA) is implicated in numerous processes in mammalian cells, and the regulatory mechanisms of the cAMP pathway have been characterized. P. falciparum cAMP-dependent protein kinase plays an important role in the parasite's life cycle and thus represents an attractive target for the development of anti-malarial drugs. In this review, we focus on the P. falciparum cAMP/PKA pathway to provide new insights and an improved understanding of this signalling cascade.

BackgroundOver its life cycle, the Plasmodium falciparum parasite is exposed to different environmental conditions, particularly to variations in O2 pressure. For example, the parasite circulates in human venous blood at 5% O2 pressure and in arterial blood, particularly in the lungs, at 13% O2 pressure. Moreover, the parasite is exposed to 21% O2 levels in the salivary glands of mosquitoes.MethodsTo study the metabolic adaptation of P. falciparum to different oxygen pressures during the intraerythrocytic cycle, a combined approach using transcriptomic and proteomic techniques was undertaken.ResultsEven though hyperoxia lengthens the parasitic cycle, significant transcriptional changes were detected in hyperoxic conditions in the late-ring stage. Using PS 6.0™ software (Ariadne Genomics) for microarray analysis, this study demonstrate up-expression of genes involved in antioxidant systems and down-expression of genes involved in the digestive vacuole metabolism and the glycolysis in favour of mitochondrial respiration. Proteomic analysis revealed increased levels of heat shock proteins, and decreased levels of glycolytic enzymes. Some of this regulation reflected post-transcriptional modifications during the hyperoxia response.ConclusionsThese results seem to indicate that hyperoxia activates antioxidant defence systems in parasites to preserve the integrity of its cellular structures. Moreover, environmental constraints seem to induce an energetic metabolism adaptation of P. falciparum. This study provides a better understanding of the adaptive capabilities of P. falciparum to environmental changes and may lead to the development of novel therapeutic targets.

A recessive mutation of Arabidopsis designated sas1 (for sodium overaccumulation in shoot) that was mapped to the bottom of chromosome III resulted in a two-to sevenfold overaccumulation of Na ؉ in shoots compared with wild-type plants. sas1 is a pleiotropic mutation that also caused severe growth reduction. The impact of NaCl stress on growth was similar for sas1 and wild-type plants; however, with regard to survival, sas1 plants displayed increased sensitivity to NaCl and LiCl treatments compared with wild-type plants. sas1 mutants overaccumulated Na ؉ and its toxic structural analog Li ؉ , but not K ؉ , Mg 2 ؉ , or Ca 2 ؉ . Sodium accumulated preferentially over K ؉ in a similar manner for sas1 and wild-type plants. Sodium overaccumulation occurred in all of the aerial organs of intact sas1 plants but not in roots. Sodium-treated leaf fragments or calli displayed similar Na ؉ accumulation levels for sas1 and wild-type tissues. This suggested that the sas1 mutation impaired Na ؉ long-distance transport from roots to shoots. The transpiration stream was similar in sas1 and wild-type plants, whereas the Na ؉ concentration in the xylem sap of sas1 plants was 5.5-fold higher than that of wild-type plants. These results suggest that the sas1 mutation disrupts control of the radial transport of Na ؉ from the soil solution to the xylem vessels. INTRODUCTIONAmong abiotic stresses, salinity is one of the major causes of yield losses of crop plants (Boyer, 1982). Salt stress is a polymorphous stress that reduces yield through three direct effects: osmotic stress, nutritional stress, and ion toxicity. It is widely thought that breeding for salt tolerance will involve developing a pyramiding strategy for selecting favorable combinations of traits, each of which would improve one of the physiological adaptations to salt stress (Yeo and Flowers, 1986). However, it is not clear which traits are appropriate for use in breeding programs to improve salt tolerance. Many physiological and molecular responses to salinity have been described (Greenway and Munns, 1980;Munns, 1993;Yeo, 1998), but their effects on the improvement of salt tolerance have seldom been demonstrated. This observation made clear the necessity of developing genetic approaches to establish which responses are physiologically relevant to salt tolerance (Epstein et al., 1980).The contributions of different physiological responses to salt tolerance were analyzed recently in genetic studies with a number of different variants (mutants or transgenic plants). The advantages of using mutants are that no prior knowledge of the molecular bases of the mechanism of interest is necessary and that mutants can reveal mechanisms previously unknown to be involved in salt tolerance. The identification and characterization of salt-tolerant and salt-hypersensitive mutants have drawn attention to several matters: (1) the control of Cl Ϫ transport from root to shoot (Abel, 1969); (2) the overaccumulation of proline (Kueh and Bright, 1982); (3) the overaccumulation of Na ϩ and K ϩ ...

The Plasmodium falciparum mitochondrion is an organelle that presents structural and physiological characteristics different from mitochondria in other eukaryotes. Moreover, there are substantial differences in the properties of asexual and sexual mitochondria. One of the reasons is the adaptation of the parasite to different environments, in particular the great differences in oxygen tension between the host and the mosquito. In this review, we present a synthesis of the recent data on the ultrastructure, the genome and the physiology of the mitochondrion. We try to clarify the mitochondrial role in the intraerythrocytic environment and particularly focus on mitochondrial metabolic pathways that relate to oxidative phosphorylation, including the tricarboxylic acid cycle, de novo pyrimidine biosynthesis via dihydroorotate dehydrogenase and the particularities of the electron transport chain. In addition, we provide details on certain characteristics like the lack of pyruvate dehydrogenase, the existence of a rotenone-insensitive NADH-dehydrogenase, the possible existence of an alternative oxidase, and uncoupled proteins. Such unique particularities of parasite mitochondria could be promising targets for development of a new therapy. The elucidation of the role of this organelle in microaerophilic respiratory metabolism and the association of antimalarial drugs with hyperbaric oxygen therapy might provide new treatments for infection by P. falciparum.

A recessive mutation of Arabidopsis designated sas1 (for sodium overaccumulation in shoot) that was mapped to the bottom of chromosome III resulted in a two- to sevenfold overaccumulation of Na(+) in shoots compared with wild-type plants. sas1 is a pleiotropic mutation that also caused severe growth reduction. The impact of NaCl stress on growth was similar for sas1 and wild-type plants; however, with regard to survival, sas1 plants displayed increased sensitivity to NaCl and LiCl treatments compared with wild-type plants. sas1 mutants overaccumulated Na(+) and its toxic structural analog Li(+), but not K(+), Mg(2)+, or Ca(2)+. Sodium accumulated preferentially over K(+) in a similar manner for sas1 and wild-type plants. Sodium overaccumulation occurred in all of the aerial organs of intact sas1 plants but not in roots. Sodium-treated leaf fragments or calli displayed similar Na(+) accumulation levels for sas1 and wild-type tissues. This suggested that the sas1 mutation impaired Na(+) long-distance transport from roots to shoots. The transpiration stream was similar in sas1 and wild-type plants, whereas the Na(+) concentration in the xylem sap of sas1 plants was 5.5-fold higher than that of wild-type plants. These results suggest that the sas1 mutation disrupts control of the radial transport of Na(+) from the soil solution to the xylem vessels.

The emergence and dissemination of drug-resistant malaria parasites represent one of the most important problems in malaria case management. Plasmodium falciparum is the causative agent of the most lethal form of human malaria. The molecular mechanisms that control the life cycle of the malaria parasite are still poorly understood. The published genome sequence (P. falciparum strain 3D7) reveals that several homologs of eukaryotic signaling proteins, such as protein kinases and phosphatases, are conserved in P. falciparum. Proteins kinases are now widely recognized as valuable drug targets in protozoan parasites. In this study, gene silencing with double-stranded RNA (dsRNA) and microarray techniques were used to study the biological function of the cAMP-dependent protein kinase catalytic subunit (PfPKAc) in the parasite erythrocytic life cycle. Treatment of parasites with PfPKAc dsRNA resulted in a marked reduction of endogenous PfPKAc mRNA associated with a compensatory decrease of PfPKAr mRNA followed by morphological changes in schizont stages and cell cycle arrest. The global effects of gene silencing were also investigated using a P. falciparum pan-genomic microarray. Transcriptomic analysis showed that the expression of 329 genes was altered in response to downregulation of PfPKAc mRNA particularly genes in specific metabolic pathways linked with merozoite invasion processes, the calcium/calmodulin signaling, and kinases network and mitochondrial functions.