Genetic variations in genes involved in heparan sulphate biosynthesis are associated with Plasmodium falciparum parasitaemia: a familial study in Burkina Faso

<p>Abstract</p> <p>Background</p> <p>There is accumulating evidence that host heparan sulphate proteoglycans play an important role in the life cycle of <it>Plasmodium </it>through their heparan sulphate chains, suggesting that genetic variations in genes involved in heparan sulphate biosynthesis may influence parasitaemia. Interestingly, <it>Hs3st3a1 </it>and <it>Hs3st3b1 </it>encoding enzymes involved in the biosynthesis of heparan sulphate are located within a chromosomal region linked to <it>Plasmodium chabaudi </it>parasitaemia in mice. This suggests that <it>HS3ST3A1 </it>and <it>HS3ST3B1 </it>may influence <it>P. falciparum </it>parasitaemia in humans.</p> <p>Methods</p> <p>Polymorphisms within <it>HS3ST3A1 </it>and <it>HS3ST3B1 </it>were identified in 270 individuals belonging to 44 pedigrees and living in Burkina Faso. Linkage and association between parasitaemia and the polymorphisms were assessed with MERLIN and FBAT. A genetic interaction analysis was also conducted based on the PGMDR approach.</p> <p>Results</p> <p>Linkage between <it>P. falciparum </it>parasitaemia and the chromosomal region containing <it>HS3ST3A1 </it>and <it>HS3ST3B1 </it>was detected on the basis of the 20 SNPs identified. In addition, rs28470223 located within the promoter of HS3ST3A1 was associated with <it>P. falciparum </it>parasitaemia, whereas the PGMDR analysis revealed a genetic interaction between <it>HS3ST3A1 </it>and <it>HS3ST3B1</it>. Seventy-three significant multi-locus models were identified after correcting for multiple tests; 37 significant multi-locus models included rs28470223, whereas 38 multi-locus models contained at least one mis-sense mutation within HS3ST3B1.</p> <p>Conclusion</p> <p>Genetic variants of <it>HS3ST3A1 </it>and <it>HS3ST3B1 </it>are associated with <it>P. falciparum </it>parasitaemia. This suggests that those variants alter both the function of heparan sulphate proteoglycans and <it>P. falciparum </it>parasitaemia.</p

Striatal molecular signature of subchronic subthalamic nucleus high frequency stimulation in parkinsonian rat

International audienceThis study addresses the molecular mechanisms underlying the action of subthalamic nucleus high frequency stimulation (STN-HFS) in the treatment of Parkinson's disease and its interaction with levodopa (L-DOPA), focusing on the striatum. Striatal gene expression profile was assessed in rats with nigral dopamine neuron lesion, either treated or not, using agilent microarrays and qPCR verification. The treatments consisted in anti-akinetic STN-HFS (5 days), chronic L-DOPA treatment inducing dyskinesia (LIDs) or the combination of the two treatments that exacerbated LIDs. STN-HFS modulated 71 striatal genes. The main biological processes associated with the differentially expressed gene products include regulation of growth, of apoptosis and of synaptic transmission, and extracellular region is a major cellular component implicated. In particular, several of these genes have been shown to support survival or differentiation of striatal or of dopaminergic neurons. These results indicate that STN HFS may induce widespread anatomo-functional rearrangements in the striatum and create a molecular environment favorable for neuroprotection and neuroplasticity. STN-HFS and L-DOPA treatment share very few common gene regulation features indicating that the molecular substrates underlying their striatal action are mostly different; among the common effects is the down-regulation of Adrb1, which encodes the adrenergic beta-1-receptor, supporting a major role of this receptor in Parkinson's disease. In addition to genes already reported to be associated with LIDs (preprodynorphin, thyrotropin-releasing hormone, metabotropic glutamate receptor 4, cannabinoid receptor 1), the comparison between DOPA and DOPA/HFS identifies immunity-related genes as potential players in L-DOPA side effects

Gene expression profiling in blood from cerebral malaria patients and mild malaria patients living in Senegal

International audienceBACKGROUND:Plasmodium falciparum malaria remains a major health problem in Africa. The mechanisms of pathogenesis are not fully understood. Transcriptomic studies may provide new insights into molecular pathways involved in the severe form of the disease.METHODS:Blood transcriptional levels were assessed in patients with cerebral malaria, non-cerebral malaria, or mild malaria by using microarray technology to look for gene expression profiles associated with clinical status. Multi-way ANOVA was used to extract differentially expressed genes. Network and pathways analyses were used to detect enrichment for biological pathways.RESULTS:We identified a set of 443 genes that were differentially expressed in the three patient groups after applying a false discovery rate of 10%. Since the cerebral patients displayed a particular transcriptional pattern, we focused our analysis on the differences between cerebral malaria patients and mild malaria patients. We further found 842 differentially expressed genes after applying a false discovery rate of 10%. Unsupervised hierarchical clustering of cerebral malaria-informative genes led to clustering of the cerebral malaria patients. The support vector machine method allowed us to correctly classify five out of six cerebral malaria patients and six of six mild malaria patients. Furthermore, the products of the differentially expressed genes were mapped onto a human protein-protein network. This led to the identification of the proteins with the highest number of interactions, including GSK3B, RELA, and APP. The enrichment analysis of the gene functional annotation indicates that genes involved in immune signalling pathways play a role in the occurrence of cerebral malaria. These include BCR-, TCR-, TLR-, cytokine-, FcεRI-, and FCGR- signalling pathways and natural killer cell cytotoxicity pathways, which are involved in the activation of immune cells. In addition, our results revealed an enrichment of genes involved in Alzheimer's disease.CONCLUSIONS:In the present study, we examine a set of genes whose expression differed in cerebral malaria patients and mild malaria patients. Moreover, our results provide new insights into the potential effect of the dysregulation of gene expression in immune pathways. Host genetic variation may partly explain such alteration of gene expression. Further studies are required to investigate this in African populations

In-flight calibration and verification of the Planck-LFI instrument

In this paper we discuss the Planck-LFI in-flight calibration campaign. After a brief overview of the ground test campaigns, we describe in detail the calibration and performance verification (CPV) phase, carried out in space during and just after the cool-down of LFI. We discuss in detail the functionality verification, the tuning of the front-end and warm electronics, the preliminary performance assessment and the thermal susceptibility tests. The logic, sequence, goals and results of the in-flight tests are discussed. All the calibration activities were successfully carried out and the instrument response was comparable to the one observed on ground. For some channels the in-flight tuning activity allowed us to improve significantly the noise performance.Comment: Long technical paper on Planck LFI in flight calibration campaign: 109 pages in this (not final) version, 100 page in the final JINST versio

Antibody Responses to <i>Schistosoma mansoni</i> Schistosomula Antigens

While antigens from Schistosoma schistosomula have been suggested as potential vaccine candidates, the association between antibody responses with schistosomula antigens and infection intensity at reinfection is not well known. Schistosoma mansoni-infected individuals were recruited from a schistosomiasis endemic area in Uganda (n = 372), treated with 40 mg/kg praziquantel (PZQ) and followed up at five weeks and at one year post-treatment. Pre-treatment and five weeks post-treatment immunoglobulin (Ig) E, IgG1 and IgG4 levels against recombinant schistosomula antigens rSmKK7, rSmLy6A, rSmLy6B and rSmTSP7 were measured using ELISA. Factors associated with detectable pre-treatment or post-treatment antibody response against the schistosomula antigens and the association between five-week antibody responses and one year post-treatment reinfection intensity among antibody responders were examined. Being male was associated with higher pre-treatment IgG1 to rSmKK7, rSmLy6a and AWA. Five weeks post-treatment antibody responses against schistosomula antigens were not associated with one year post-treatment reinfection intensity among antibody responders' antibody levels against rSmKK7, rSmLy6B and rSmTSP7 dropped, but increased against rSmLy6A, AWA and SEA at five weeks post-treatment among antibody responders. S. mansoni-infected individuals exhibit detectable antibody responses to schistosomula antigens that are affected by treatment. These findings indicate that schistosomula antigens induce highly varied antibody responses and could have implications for vaccine development

Deletion of Nkx2-5 in trabecular myocardium reveals the developmental origins of pathological heterogeneity associated with ventricular non-compaction cardiomyopathy.

Left ventricular non-compaction (LVNC) is a rare cardiomyopathy associated with a hypertrabeculated phenotype and a large spectrum of symptoms. It is still unclear whether LVNC results from a defect of ventricular trabeculae development and the mechanistic basis that underlies the varying severity of this pathology is unknown. To investigate these issues, we inactivated the cardiac transcription factor Nkx2-5 in trabecular myocardium at different stages of trabecular morphogenesis using an inducible Cx40-creERT2 allele. Conditional deletion of Nkx2-5 at embryonic stages, during trabecular formation, provokes a severe hypertrabeculated phenotype associated with subendocardial fibrosis and Purkinje fiber hypoplasia. A milder phenotype was observed after Nkx2-5 deletion at fetal stages, during trabecular compaction. A longitudinal study of cardiac function in adult Nkx2-5 conditional mutant mice demonstrates that excessive trabeculation is associated with complex ventricular conduction defects, progressively leading to strain defects, and, in 50% of mutant mice, to heart failure. Progressive impaired cardiac function correlates with conduction and strain defects independently of the degree of hypertrabeculation. Transcriptomic analysis of molecular pathways reflects myocardial remodeling with a larger number of differentially expressed genes in the severe versus mild phenotype and identifies Six1 as being upregulated in hypertrabeculated hearts. Our results provide insights into the etiology of LVNC and link its pathogenicity with compromised trabecular development including compaction defects and ventricular conduction system hypoplasia

Known Allergen Structures Predict Schistosoma mansoni IgE-Binding Antigens in Human Infection

This is the final published paper. The article was originally published in Frontiers in Immunology 6:26, 03 February 2015, doi: 10.3389/fimmu.2015.00026The IgE response has been associated with both allergic reactions and immunity to metazoan\ud parasites. Recently, we hypothesized that all environmental allergens bear structural\ud homology to IgE-binding antigens from metazoan parasites and that this homology defines\ud the relatively small number of protein families containing allergenic targets. In this study,\ud known allergen structures (Pfam domains) from major environmental allergen families were\ud used to predict allergen-like (SmProfilin, SmVAL-6, SmLipocalin, SmHSP20, Sm triosephosphate\ud isomerase, SmThioredoxin, Sm superoxide dismutase, SmCyclophilin, and Sm phosphoglycerate\ud kinase) and non-allergen-like [Sm dynein light chain (SmDLC), SmAldolase\ud SmAK, SmUbiquitin, and Sm14-3-3] proteins in Schistosoma mansoni. Recombinant antigens\ud were produced in Escherichia coli and IgG1, IgG4, and IgE responses against them\ud measured in a cohort of people (n = 222) infected with S. mansoni. All allergen-like antigens\ud were targeted by IgE responses in infected subjects, whilst IgE responses to the nonallergen-like\ud antigens, SmAK, SmUbiquitin, and Sm14-3-3 were essentially absent being of\ud both low prevalence and magnitude.Two new IgE-binding Pfam domain families, not previously\ud described in allergen family databases, were also found, with prevalent IgE responses\ud against SmDLC (PF01221) and SmAldolase (PF00274). Finally, it was demonstrated that\ud immunoregulatory serological processes typically associated with allergens also occurred\ud in responses to allergen-like proteins in S. mansoni infections, including the production of\ud IgG4 in people responding with IgE and the down-regulation of IgE in response to increased\ud antigen exposure from S. mansoni eggs. This study establishes that structures of known\ud allergens can be used to predict IgE responses against homologous parasite allergen-like\ud molecules (parallergens) and that serological responses with IgE/IgG4 to parallergens mirror\ud those seen against allergens, supporting our hypothesis that allergenicity is rooted in\ud expression of certain protein domain families in metazoan parasites.We would like to thank the people of Namoni Village for their\ud time and co-operation in the study as well as the field workers\ud of the Ugandan Virus Research Institute and the Kenyan Medical\ud Research Institute. Thanks go also to Shona Wilson, Joseph\ud Mwatha, and Timothy Kamau, for their knowledge and skill in\ud collecting and preparing samples for the study. We would also\ud like to thank Maureen Laidlaw of the Schistosomiasis Research\ud Group (University of Cambridge) for her expert technical assistance;\ud Undergraduate students Aws Sadik, Matthew J Murray,\ud Emma Robbins, and Emily Day for their hard work during final\ud year projects in the Schistosomiasis Research Group; and Prof.\ud Dame Janet Thornton at the European Bioinformatics Institute\ud for her continued help and support. This work was supported by\ud the Wellcome Trust via program WT 083931/Z/07/Z and project\ud WT 094317/Z/10/Z grants and by the European Commission via\ud FP7-CP-IP-SICA scheme grant 242107

Rac1 and Rac3 isoform activation is involved in the invasive and metastatic phenotype of human breast cancer cells

INTRODUCTION: The metastatic progression of cancer is a direct result of the disregulation of numerous cellular signaling pathways, including those associated with adhesion, migration, and invasion. Members of the Rac family of small GTPases are known to act as regulators of actin cytoskeletal structures and strongly influence the cellular processes of integrin-mediated adhesion and migration. Even though hyperactivated Rac proteins have been shown to influence metastatic processes, these proteins have never been directly linked to metastatic progression. METHODS: To investigate a role for Rac and Cdc42 in metastatic breast cancer cell invasion and migration, relative endogenous Rac or Cdc42 activity was determined in a panel of metastatic variants of the MDA-MB-435 metastatic human breast cancer cell line using a p21-binding domain-PAK pull down assay. To investigate the migratory and invasive potential of the Rac isoforms in human breast cancer, namely Rac1 and the subsequently cloned Rac3, we stably expressed either dominant active Rac1 or dominant active Rac3 into the least metastatic cell variant. Dominant negative Rac1 or dominant negative Rac3 were stably expressed in the most metastatic cell variant. Cell lines expressing mutant Rac1 or Rac3 were analyzed using in vitro adhesion, migration and invasion assays. RESULTS: We show that increased activation of Rac proteins directly correlates with increasing metastatic potential in a panel of cell variants derived from a single metastatic breast cancer cell line (MDA-MB-435). The same correlation could not be found with activated Cdc42. Expression of a dominant active Rac1 or a dominant active Rac3 resulted in a more invasive and motile phenotype. Moreover, expression of either dominant negative Rac1 or dominant negative Rac3 into the most metastatic cell variant resulted in decreased invasive and motile properties. CONCLUSION: This study correlates endogenous Rac activity with high metastatic potential and implicates Rac in the regulation of cell migration and invasion in metastatic breast cancer cells. Taken together, these results suggest a role for both the Rac1 and Rac3 GTPases in human breast cancer progression

NCR3 polymorphism, haematological parameters, and severe malaria in Senegalese patients

Background Host factors, including host genetic variation, have been shown to influence the outcome of Plasmodium falciparum infection. Genome-wide linkage studies have mapped mild malaria resistance genes on chromosome 6p21, whereas NCR3-412 polymorphism (rs2736191) lying within this region was found to be associated with mild malaria. Methods Blood samples were taken from 188 Plasmodium falciparum malaria patients (76 mild malaria patients, 85 cerebral malaria patients, and 27 severe non-cerebral malaria patients). NCR3-412 (rs2736191) was analysed by sequencing, and haematological parameters were measured. Finally, their association with clinical phenotypes was assessed. Results We evidenced an association of thrombocytopenia with both cerebral malaria and severe non-cerebral malaria, and of an association of high leukocyte count with cerebral malaria. Additionally, we found no association of NCR3-412 with either cerebral malaria, severe non-cerebral malaria, or severe malaria after grouping cerebral malaria and severe non-cerebral malaria patients. Conclusions Our results suggest that NCR3 genetic variation has no effect, or only a small effect on the occurrence of severe malaria, although it has been strongly associated with mild malaria. We discuss the biological meaning of these results. Besides, we confirmed the association of thrombocytopenia and high leukocyte count with severe malaria phenotypes

alpha-decay of excited states in 11C and 11B

Studies of the 16O(9Be,alpha7Be)14C and 7Li(9Be,alpha7Li)5He reactions at E{beam}=70 MeV have been performed using resonant particle spectroscopy techniques. The 11C excited states decaying into alpha+7Be(gs) are observed at 8.65, 9.85, 10.7 and 12.1 MeV as well as possible states at 12.6 and 13.4 MeV. This result is the first observation of alpha-decay for excited states above 9 MeV. The alpha+7Li(gs) decay of 11B excited states at 9.2, 10.3, 10.55, 11.2, (11.4), 11.8, 12.5,(13.0), 13.1, (14.0), 14.35, (17.4) and (18.6) MeV is observed. The decay processes are used to indicate the possible three-centre 2alpha+3He(3H) cluster structure of observed states. Two rotational bands corresponding to very deformed structures are suggested for the positive-parity states. Excitations of some observed T=1/2 resonances coincide with the energies of T=3/2 states which are the isobaric analogs of the lowest 11Be states. Some of these states may have mixed isospin.Comment: accepted for publication in Nuclear Physics