Search

Plasmodium falciparumerythrocyte membrane protein-1s (PfEMP1s), diverse malaria proteins expressed on the infected erythrocyte surface, play an important role in pathogenesis, mediating adhesion to host vascular endothelium. Antibodies to particular non-CD36-binding PfEMP1s are associated with protection against severe disease. We hypothesized that given lifelongP. falciparumexposure, Malian adults would have broad PfEMP1 serorecognition and high seroreactivity levels during follow-up, particularly to non-CD36-binding PfEMP1s such as those that attach to endothelial protein C receptor (EPCR) and intercellular adhesion molecule-1 (ICAM-1). Using a protein microarray, we determined serologic responses to 166 reference PfEMP1 fragments during a dry and subsequent malaria transmission season in Malian adults. Malian adult sera had PfEMP1 serologic responses throughout the year, with decreased reactivity to a small subset of PfEMP1 fragments during the dry season and increases in reactivity to a different subset of PfEMP1 fragments during the subsequent peak malaria transmission season, especially for intracellular PfEMP1 domains. For some individuals, PfEMP1 serologic responses increased after the dry season, suggesting antigenic switching during asymptomatic infection. Adults were more likely to experience variable serorecognition of CD36-binding PfEMP1s than non-CD36-binding PfEMP1s that bind EPCR or ICAM-1, which remained serorecognized throughout the year. Sustained seroreactivity to non-CD36-binding PfEMP1s throughout adulthood amid seasonal fluctuation patterns may reflect underlying protective severe malaria immunity and merits further investigation.

Purpose Molecular and cellular studies reported a role of cadmium in risk of advanced breast cancer (BC). However epidemiological evidence is limited. Our previous study suggests that cadmium might be related to a decreased risk of ER- and ER-PR- breast tumors. In this study, we further explored the association between long-term exposure to airborne cadmium and risk of BC by stage, grade of differentiation, and histological types at diagnosis. Methods A nested case-control study of 4,401 cases and 4,401 matched controls was conducted within the French E3N cohort. A Geographic Information System (GIS) based metric was employed to evaluate outdoor airborne exposure to cadmium. Multivariable adjusted odds ratios (OR) and 95% confidence intervals (CI) were estimated using conditional logistic regression models. Results There was no statistically significant association between cadmium exposure and stage of BC in the multivariable analyses. The adjusted ORs for the fifth versus first quintile were 1.02 (95% CI: 0.83–1.25), 1.11 (95% CI: 0.84–1.49), and 0.67 (95% CI: 0.37–1.24) for stages I, II, and III-IV BC, respectively. The subgroup analyses showed no statistically significant association between cadmium exposure and grade of differentiation of BC at diagnosis. However, further analyses by histological type suggested a positive dose-response association between cadmium and risk of invasive tubular carcinoma (ITC) BC (OR for the fifth versus first quintile = 3.44 (95% CI: 1.10–10.7)). Conclusions Our results do not support the hypothesis that airborne cadmium exposure may have a role in advanced BC risk, but suggest that cadmium may be associated with an increased risk of ITC. However, these results should be considered with caution, and more epidemiological studies are needed to confirm our findings and to improve our understanding of the effects of cadmium exposure according to several clinic-pathological characteristics of BC.

We report the investigation of the influence of periodic metallic arrays on the emission properties of organic emitters. Beforehand, the study of the coupling process between nanoparticles through the analysis of the extinction spectra related to Rayleigh anomalies indicate the crucial role of those latter in defining the nature of the excited grating modes. The obtained results emphasis that Rayleigh Anomalies can be considered as the intermediate between individual plasmonic and collective photonic responses. Thereafter, the experimental and numerical studies of the lattice modes and their associated effects on the lifetime and emission directivity of nearby emitters indicate that tuning the geometrical grating parameters offers a possibility to select a particular coupling process from a localized effect to a far field response. Depending on the coupling strength, the emission can be strongly altered by increasing the density of states or providing diffractive orders. Eventually, this study reports that the Rayleigh Anomalies play the role of an excitation source which drives the nanoparticles to act as a set of diffractive objects for shaping the emission to be highly directive.

Archaeal sequences have been detected in human colostrum and milk, but no studies have determined whether living archaea are present in either of these fluids. Methanogenic archaea are neglected since they are not detected by usual molecular and culture methods. By using improved DNA detection protocols and microbial culture techniques associated with antioxidants previously developed in our center, we investigated the presence of methanogenic archaea using culture and specific Methanobrevibacter smithii and Methanobrevibacter oralis real-time PCR in human colostrum and milk. M. smithii was isolated from 3 colostrum and 5 milk (day 10) samples. M. oralis was isolated from 1 milk sample. For 2 strains, the genome was sequenced, and the rhizome was similar to that of strains previously isolated from the human mouth and gut. M. smithii was detected in the colostrum or milk of 5/13 (38%) and 37/127 (29%) mothers by culture and qPCR, respectively. The different distribution of maternal body mass index according to the detection of M. smithii suggested an association with maternal metabolic phenotype. M. oralis was not detected by molecular methods. Our results suggest that breastfeeding may contribute to the vertical transmission of these microorganisms and may be essential to seed the infant’s microbiota with these neglected critical commensals from the first hour of life.

Water deficit stress at the early stage of development is one of the main factors limiting pearl millet production. One practice to counteract this limitation would be to resort to the application of hormones to stimulate plant growth and development at critical stages. Exogenous methyl jasmonate (MeJA) can improve drought tolerance by modulating signaling, metabolism, and photosynthesis pathways, therefore, we assumed that can occur in pearl millet during the early stage of development. To decipher the molecular mechanisms controlling these pathways, RNAseq was conducted in two pearl millet genotypes, drought-sensitive SosatC88 and drought-tolerant Souna3, in response to 200 μM of MeJA. Pairwise comparison between the MeJA-treated and non-treated plants revealed 3270 differentially expressed genes (DEGs) among 20,783 transcripts in SosatC88 and 127 DEGs out of 20,496 transcripts in Souna3. Gene ontology (GO) classification assigned most regulated DEGs in SosatC88 to heme binding, oxidation–reduction process, response to oxidative stress and membrane, and in Souna3 to terpene synthase activity, lyase activity, magnesium ion binding, and thylakoid. The Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis reveals that DEGs in SosatC88 are related to the oxidation–reduction process, the biosynthesis of other secondary metabolites, the signal transduction, and the metabolism of terpenoids, while in Souna3, DEGs are related to the metabolism of terpenoids and the energy metabolism. Two genes encoding a diterpenoid biosynthesis-related (Pgl_GLEAN_10009413) and a Glutathione S transferase T3 (Pgl_GLEAN_10034098) were contra-regulated between SosatC88 and Souna3. Additionally, five random genes differentially expressed by RNAseq were validated using qPCR, therefore, they are potential targets for the development of novel strategies breeding schemes for plant growth under water deficit stress. These insights into the molecular mechanisms of pearl millet genotype tolerance at the early stage of development contribute to the understanding of the role of hormones in adaptation to drought-prone environments.

Dengue virus is a major and rapidly growing public health concern in tropic and subtropic regions across the globe. In late 2018, Senegal experienced its largest dengue virus outbreak to date, covering several regions. However, little is known about the genetic diversity of dengue virus (DENV) in Senegal. Here we report complete viral genomes from 17 previously undetected DENV cases from the city of Thiès. In total we identified 19 cases of DENV in a cohort of 198 individuals with fever collected in October and November 2018. We detected 3 co-circulating serotypes; DENV 3 was the most frequent accounting for 11/17 sequences (65%), 4 (23%) were DENV2 and 2 (12%) were DENV1. Sequences were most similar to recent sequences from West Africa, suggesting ongoing local circulation of viral populations; however, detailed inference is limited by the scarcity of available genomic data. We did not find clear associations with reported clinical signs or symptoms, highlighting the importance of testing for diagnosing febrile diseases. Overall, these findings expand the known range of DENV in Senegal, and underscore the need for better genomic characterization of DENV in West Africa.

Coronary artery disease (CAD) is a leading cause of death worldwide and frequently associated with mitochondrial dysfunction. Detailed understanding of abnormalities in mitochondrial function that occur in patients with CAD is lacking. We evaluated mitochondrial damage, energy production, and mitochondrial complex activity in human non-CAD and CAD hearts. Fresh and frozen human heart tissue was used. Cell lysate or mitochondria were isolated using standard techniques. Mitochondrial DNA (mtDNA), NAD + and ATP levels, and mitochondrial oxidative phosphorylation capacity were evaluated. Proteins critical to the regulation of mitochondrial metabolism and function were also evaluated in tissue lysates. PCR analysis revealed an increase in mtDNA lesions and the frequency of mitochondrial common deletion, both established markers for impaired mitochondrial integrity in CAD compared to non-CAD patient samples. NAD+ and ATP levels were significantly decreased in CAD subjects compared to Non-CAD (NAD+ fold change: non-CAD 1.00 ± 0.17 vs. CAD 0.32 ± 0.12* and ATP fold change: non-CAD 1.00 ± 0.294 vs. CAD 0.01 ± 0.001*; N = 15, P

All tropically adapted humped cattle (Bos indicus or “zebu”), descend from a domestication process that took place >8,000 years ago in South Asia. Here we present an intercontinental survey of Y-chromosome diversity and a comprehensive reconstruction of male-lineage zebu cattle history and diversity patterns. Phylogenetic analysis revealed that all the zebu Y-chromosome haplotypes in our dataset group within three different lineages: Y3A, the most predominant and cosmopolitan lineage; Y3B, only observed in West Africa; and Y3C, predominant in South and Northeast India. The divergence times estimated for these three Zebu-specific lineages predate domestication. Coalescent demographic models support either de novo domestication of genetically divergent paternal lineages or more complex process including gene flow between wild and domestic animals. Our data suggest export of varied zebu lineages from domestication centres through time. The almost exclusive presence of Y3A haplotypes in East Africa is consistent with recent cattle restocking in this area. The cryptic presence of Y3B haplotypes in West Africa, found nowhere else, suggests that these haplotypes might represent the oldest zebu lineage introduced to Africa ca. 3,000 B.P. and subsequently replaced in most of the world. The informative ability of Interspersed Multilocus Microsatellites and Y-specific microsatellites to identify genetic structuring in cattle populations is confirmed.

Rabies is a generally fatal encephalitis caused by a negative-sense single-stranded RNA lyssavirus transmitted to humans mainly from dog bite. Despite the recommendation by WHO and OIE to use the direct immunofluorescence test as standard method, molecular diagnostic assays like reverse transcription quantitative polymerase chain reaction (RT-qPCR) are increasing as a confirmatory method. However, both technologies are inaccessible in resource-limited settings. Moreover, the available point-of-need molecular assay is of poor detection limit for African strains. Herein, we developed a reverse transcription recombinase polymerase amplification (RT-RPA) assay as potential point-of-need diagnostic tool for rapid detection of various strains of rabies virus including locally isolated African strains. The sensitivity and specificity of the method was evaluated using a molecular RNA standard and different Rabies-related viruses belonging to the Rhabdoviridea family, respectively. The RABV-RPA performances were evaluated on isolates representative of the existing diversity and viral dilutions spiked in non-neural clinical specimen. The results were compared with RT-qPCR as a gold standard. The RABV-RPA detected down to 4 RNA molecules per reaction in 95% of the cases in less than 10 min. The RABV-RPA assay is highly specific as various RABV isolates were identified, but no amplification was observed for other member of the Rhabdoviridea family. The sample background did not affect the performance of the RABV-RPA as down to 11 RNA molecules were identified, which is similar to the RT-qPCR results. Our developed assay is suitable for use in low-resource settings as a promising alternative tool for ante-mortem rabies diagnosis in humans for facilitating timely control decisions.

Vaccines based on Plasmodium falciparum apical membrane antigen 1 (AMA1) have failed due to extensive polymorphism in AMA1. To assess the strain-specificity of antibody responses to malaria infection and AMA1 vaccination, we designed protein and peptide microarrays representing hundreds of unique AMA1 variants. Following clinical malaria episodes, children had short-lived, sequence-independent increases in average whole-protein seroreactivity, as well as strain-specific responses to peptides representing diverse epitopes. Vaccination resulted in dramatically increased seroreactivity to all 263 AMA1 whole-protein variants. High-density peptide analysis revealed that vaccinated children had increases in seroreactivity to four distinct epitopes that exceeded responses to natural infection. A single amino acid change was critical to seroreactivity to peptides in a region of AMA1 associated with strain-specific vaccine efficacy. Antibody measurements using whole antigens may be biased towards conserved, immunodominant epitopes. Peptide microarrays may help to identify immunogenic epitopes, define correlates of vaccine protection, and measure strain-specific vaccine-induced antibodies.

The Djallonké (West African Dwarf) sheep is a small-sized haired sheep resulting from a costly evolutionary process of natural adaptation to the harsh environment of West Africa including trypanosome challenge. However, genomic studies carried out in this sheep are scant. In this research, genomic data of 184 Djallonké sheep (and 12 Burkina-Sahel sheep as an outgroup) generated using medium-density SNP Chips were analyzed. Three different statistics (iHS, XP-EHH and nSL) were applied to identify candidate selection sweep regions spanning genes putatively associated with adaptation of sheep to the West African environment. A total of 207 candidate selection sweep regions were defined. Gene-annotation enrichment and functional annotation analyses allowed to identify three statistically significant functional clusters involving 12 candidate genes. Genes included in Functional Clusters associated to selection signatures were mainly related to metabolic response to stress, including regulation of oxidative and metabolic stress and thermotolerance. The bovine chromosomal areas carrying QTLs for cattle trypanotolerance were compared with the regions on which the orthologous functional candidate cattle genes were located. The importance of cattle BTA4 for trypanotolerant response might have been conserved between species. The current research provides new insights on the genomic basis for adaptation and highlights the importance of obtaining information from non-cosmopolite livestock populations managed in harsh environments.

Obese individuals without expected metabolic co-morbidities are referred to as metabolically healthy obese (MHO). The molecular mechanisms underlying this phenotype remain elusive. MicroRNAs may be involved in the MHO phenotype. To test this hypothesis, we screened 179 serum miRNAs in 20 African-American women (10 MHOs and 10 metabolically abnormal obese individuals -MAO). We identified 8 differentially expressed miRNAs (DEMs) with validation in an independent sample of 64 MHO and 34 MAO. Of the eight DEMs in the screening phase (p ≤ 0.05), miR-374a-5p remained significant (p = 0.04) with directional consistency in the validation sample. Ingenuity Pathway analysis revealed that miR-374a-5p putatively targeted 37 mRNAs (e.g. chemokines and transcription factors) which are members of canonical pathways involved in inflammation (IL-17A signaling) and lipid metabolism. Analysis restricted to adipocytes, the main source of circulating miRNAs in obesity, identified 3 mRNAs (CCL2, STEAP2, EN1) as the main target of miR-374a-5p. Evaluation of the 3 mRNAs in an independent sample showed that CCL2 was significantly downregulated (p = 0.0005). In summary, MiR-374a-5p is upregulated in MHO compared to MAO individuals and appears to show association with downregulation of pro-inflammatory markers that are linked to insulin resistance. Given the correlative nature of our findings, functional studies are needed.

Variant surface antigens (VSAs) play a critical role in severe malaria pathogenesis. Defining gaps, or “lacunae”, in immunity to these Plasmodium falciparum antigens in children with severe malaria would improve our understanding of vulnerability to severe malaria and how protective immunity develops. Using a protein microarray with 179 antigen variants from three VSA families as well as more than 300 variants of three other blood stage P. falciparum antigens, reactivity was measured in sera from Malian children with cerebral malaria or severe malarial anaemia and age-matched controls. Sera from children with severe malaria recognized fewer extracellular PfEMP1 fragments and were less reactive to specific fragments compared to controls. Following recovery from severe malaria, convalescent sera had increased reactivity to certain non-CD36 binding PfEMP1s, but not other malaria antigens. Sera from children with severe malarial anaemia reacted to fewer VSAs than did sera from children with cerebral malaria, and both of these groups had lacunae in their seroreactivity profiles in common with children who had both cerebral malaria and severe malarial anaemia. This microarray-based approach may identify a subset of VSAs that could inform the development of a vaccine to prevent severe disease or a diagnostic test to predict at-risk children.

P. falciparum virulence is related to adhesion and sequestration of infected erythrocytes (IE) in deep vascular beds, but the endothelial receptors involved in severe malaria remain unclear. In the largest ever study of clinical isolates, we surveyed adhesion of freshly collected IE from children under 5 years of age in Mali to identify novel vascular receptors, and examined the effects of host age, hemoglobin type, blood group and severe malaria on levels of IE adhesion to a panel of endothelial receptors. Several novel molecules, including integrin α3β1, VE-cadherin, ICAM-2, junctional adhesion molecule-B (JAM-B), laminin, and cellular fibronectin, supported binding of IE from children. Severe malaria was not significantly associated with levels of IE adhesion to any of the 19 receptors. Hemoglobin AC, which reduces severe malaria risk, reduced IE binding to the receptors CD36 and integrin α5β1, while hemoglobin AS did not modify IE adhesion to any receptors. Blood groups A, AB and B significantly reduced IE binding to ICAM-1. Severe malaria risk varies with age, but age significantly impacted the level of IE binding to only a few receptors: IE binding to JAM-B decreased with age, while binding to CD36 and integrin α5β1 significantly increased with age.

Iron deficiency is the most common nutrient deficiency worldwide and routine supplementation is standard policy for pregnant mothers and children in most low-income countries. However, iron lies at the center of host-pathogen competition for nutritional resources and recent trials of iron administration in African and Asian children have resulted in significant excesses of serious adverse events including hospitalizations and deaths. Increased rates of malaria, respiratory infections, severe diarrhea and febrile illnesses of unknown origin have all been reported, but the mechanisms are unclear. We here investigated the ex vivo growth characteristics of exemplar sentinel bacteria in adult sera collected before and 4 h after oral supplementation with 2 mg/kg iron as ferrous sulfate. Escherichia coli, Yersinia enterocolitica and Salmonella enterica serovar Typhimurium (all gram-negative bacteria) and Staphylococcus epidermidis (gram-positive) showed markedly elevated growth in serum collected after iron supplementation. Growth rates were very strongly correlated with transferrin saturation (p Staphylococcus aureus, which preferentially scavenges heme iron, was unaffected. These data suggest that even modest oral supplements with highly soluble (non-physiological) iron, as typically used in low-income settings, could promote bacteremia by accelerating early phase bacterial growth prior to the induction of immune defenses.

Rift Valley Fever virus (RVFV) is a member of Bunyaviridae family that causes a febrile disease affecting mainly ruminants and occasionally humans in Africa, with symptoms that range from mid to severe. RVFV has a tri-segmented ssRNA genome that permits reassortment and could generate more virulent strains. In this study, we reveal the importance of reassortment for RVFV evolution using viral gene genealogy inference and phylodynamics. We uncovered seven events of reassortment that originated RVFV lineages with discordant origins among segments. Moreover, we also found that despite similar selection regimens, the three segments have distinct evolutionary dynamics; the longer segment L evolves at a significant lower rate. Episodes of discordance between population size estimates per segment also coincided with reassortment dating. Our results show that RVFV segments are decoupled enough to have distinct demographic histories and to evolve under different molecular rates.

Dietary methionine restriction (MR) in rodents increased lifespan despite higher heart-to-body weight ratio (w/w) and hyperhomocysteinemia, which are symptoms associated with increased risk for cardiovascular disease. We investigated this paradoxical effect of MR on cardiac function using young, old and apolipoprotein E-deficient (ApoE-KO) mice. Indeed, MR animals exhibited higher heart-to-body weight ratio (w/w) and hyperhomocysteinemia with a molecular pattern consistent with cardiac stress while maintaining the integrity of cardiac structure. Baseline cardiac function, which was measured by non-invasive electrocardiography (ECG), showed that young MR mice had prolonged QRS intervals compared with control-fed (CF) mice, whereas old and ApoE-KO mice showed similar results for both groups. Following β-adrenergic challenge, responses of MR mice were either similar or attenuated compared with CF mice. Cardiac contractility, which was measured by isolated heart retrograde perfusion, was similar in both groups of old mice. Finally, the MR diet induced secretion of cardioprotective hormones, adiponectin and fibroblast growth factor 21 (FGF21), in MR mice with concomitant alterations in cardiac metabolic molecular signatures. Our findings demonstrate that MR diet does not alter cardiac function in mice despite the presence of hyperhomocysteinemia because of the adaptive responses of increased adiponectin and FGF21 levels.