Estrogen-Related Receptor Alpha Modulates Lactate Dehydrogenase Activity in Thyroid Tumors

Metabolic modifications of tumor cells are hallmarks of cancer. They exhibit an altered metabolism that allows them to sustain higher proliferation rates in hostile environment outside the cell. In thyroid tumors, the expression of the estrogen-related receptor α (ERRα), a major factor of metabolic adaptation, is closely related to the oxidative metabolism and the proliferative status of the cells. To elucidate the role played by ERRα in the glycolytic adaptation of tumor cells, we focused on the regulation of lactate dehydrogenases A and B (LDHA, LDHB) and the LDHA/LDHB ratio. Our study included tissue samples from 10 classical and 10 oncocytic variants of follicular thyroid tumors and 10 normal thyroid tissues, as well as samples from three human thyroid tumor cell lines: FTC-133, XTC.UC1 and RO82W-1. We identified multiple cis-acting promoter elements for ERRα, in both the LDHA and LDHB genes. The interaction between ERRα and LDH promoters was confirmed by chromatin immunoprecipitation assays and in vitro analysis for LDHB. Using knock-in and knock-out cellular models, we found an inverse correlation between ERRα expression and LDH activity. This suggests that thyroid tumor cells may reprogram their metabolic pathways through the up-regulation of ERRα by a process distinct from that proposed by the recently revisited Warburg hypothesis.     

Stroma Cell-Derived Factor-1α Signaling Enhances Calcium Transients and Beating Frequency in Rat Neonatal Cardiomyocytes

Stroma cell-derived factor-1α (SDF-1α) is a cardioprotective chemokine, acting through its G-protein coupled receptor CXCR4. In experimental acute myocardial infarction, administration of SDF-1α induces an early improvement of systolic function which is difficult to explain solely by an anti-apoptotic and angiogenic effect. We wondered whether SDF-1α signaling might have direct effects on calcium transients and beating frequency.Primary rat neonatal cardiomyocytes were culture-expanded and characterized by immunofluorescence staining. Calcium sparks were studied by fluorescence microscopy after calcium loading with the Fluo-4 acetoxymethyl ester sensor. The cardiomyocyte enriched cellular suspension expressed troponin I and CXCR4 but was vimentin negative. Addition of SDF-1α in the medium increased cytoplasmic calcium release. The calcium response was completely abolished by using a neutralizing anti-CXCR4 antibody and partially suppressed and delayed by preincubation with an inositol triphosphate receptor (IP₃R) blocker, but not with a ryanodine receptor (RyR) antagonist. Calcium fluxes induced by caffeine, a RyR agonist, were decreased by an IP₃R blocker. Treatment with forskolin or SDF-1α increased cardiomyocyte beating frequency and their effects were additive. In vivo, treatment with SDF-1α increased left ventricular dP/dtmax.These results suggest that in rat neonatal cardiomyocytes, the SDF-1α/CXCR4 signaling increases calcium transients in an IP₃-gated fashion leading to a positive chronotropic and inotropic effect.     

IL-17RA in Non-Hematopoietic Cells Controls CXCL-1 and 5 Critical to Recruit Neutrophils to the Lung of Mycobacteria-Infected Mice during the Adaptive Immune Response

During chronic infection with Mycobacterium tuberculosis (Mtb), bacilli multiplication is constrained within lung granulomas until excessive inflammation destroys the lung. Neutrophils are recruited early and participate in granuloma formation, but excessive neutrophilia exacerbates the tuberculosis disease. Neutrophils thus appear as potential targets for therapeutic interventions, especially in patients for whom no antibiotic treatment is possible. Signals that regulate neutrophil recruitment to the lung during mycobacterial infection need to be better understood. We demonstrated here, in the mouse model, that neutrophils were recruited to the lung in two waves after intranasal infection with virulent Mtb or the live attenuated vaccine strain Bacillus Calmette Guérin (BCG). A first wave of neutrophils was swiftly recruited, followed by a subsequent adaptive wave that reached the lung together with IFN-γ- and IL-17A-producing T cells. Interestingly, the second neutrophil wave did not participate to mycobacteria control in the lung and established contacts with T cells. The adaptive wave was critically dependent on the expression of IL-17RA, the receptor for IL-17A, expressed in non-hematopoietic cells. In absence of this receptor, curtailed CXCL-1 and 5 production in the lung restrained neutrophil recruitment. CXCL-1 and 5 instillation reconstituted lung neutrophil recruitment in BCG-infected IL17RA-/- mice.     

Identification of Symptomatic Fetuses Infected with Cytomegalovirus Using Amniotic Fluid Peptide Biomarkers

Cytomegalovirus (CMV) is the most common cause of congenital infection, and is a major cause of sensorineural hearing loss and neurological disabilities. Evaluating the risk for a CMV infected fetus to develop severe clinical symptoms after birth is crucial to provide appropriate guidance to pregnant women who might have to consider termination of pregnancy or experimental prenatal medical therapies. However, establishing the prognosis before birth remains a challenge. This evaluation is currently based upon fetal imaging and fetal biological parameters, but the positive and negative predictive values of these parameters are not optimal, leaving room for the development of new prognostic factors. Here, we compared the amniotic fluid peptidome between asymptomatic fetuses who were born as asymptomatic neonates and symptomatic fetuses who were either terminated in view of severe cerebral lesions or born as severely symptomatic neonates. This comparison allowed us to identify a 34-peptide classifier in a discovery cohort of 13 symptomatic and 13 asymptomatic neonates. This classifier further yielded 89% sensitivity, 75% specificity and an area under the curve of 0.90 to segregate 9 severely symptomatic from 12 asymptomatic neonates in a validation cohort, showing an overall better performance than that of classical fetal laboratory parameters. Pathway analysis of the 34 peptides underlined the role of viral entry in fetuses with severe brain disease as well as the potential importance of both beta-2-microglobulin and adiponectin to protect the injured fetal brain infected with CMV. The results also suggested the mechanistic implication of the T calcium channel alpha-1G (CACNA1G) protein in the development of seizures in severely CMV infected children. These results open a new field for potential therapeutic options. In conclusion, this study demonstrates that amniotic fluid peptidome analysis can effectively predict the severity of congenital CMV infection. This peptidomic classifier may therefore be used in clinical settings during pregnancy to improve prenatal counseling.     

Early Medieval Muslim Graves in France: First Archaeological,Anthropological and Palaeogenomic Evidence

The rapid Arab-Islamic conquest during the early Middle Ages led to major political and cultural changes in the Mediterranean world. Although the early medieval Muslim presence in the Iberian Peninsula is now well documented, based in the evaluation of archeological and historical sources, the Muslim expansion in the area north of the Pyrenees has only been documented so far through textual sources or rare archaeological data. Our study provides the first archaeo-anthropological testimony of the Muslim establishment in South of France through the multidisciplinary analysis of three graves excavated at Nimes. First, we argue in favor of burials that followed Islamic rites and then note the presence of a community practicing Muslim traditions in Nimes. Second, the radiometric dates obtained from all three human skeletons (between the 7th and the 9th centuries AD) echo historical sources documenting an early Muslim presence in southern Gaul (i.e., the first half of 8th century AD). Finally, palaeogenomic analyses conducted on the human remains provide arguments in favor of a North African ancestry of the three individuals, at least considering the paternal lineages. Given all of these data, we propose that the skeletons from the Nimes burials belonged to Berbers integrated into the Umayyad army during the Arab expansion in North Africa. Our discovery not only discusses the first anthropological and genetic data concerning the Muslim occupation of the Visigothic territory of Septimania but also highlights the complexity of the relationship between the two communities during this period.     

Biological Status and Dietary Intakes of Iron,Zinc and Vitamin A among Women and Preschool Children in Rural Burkina Faso

Background

Food-based approaches such as biofortification are meant to sustainably address micronutrient deficiencies in poor settings. Knowing more about micronutrient intakes and deficiencies is a prerequisite to designing and evaluating interventions.

Objective

The objectives of the study were to assess biological status and dietary intakes of iron, zinc and vitamin A among women and children aged 36–59 months in rural Burkina Faso and to study relationships between intake and status to better inform future food-based interventions.

Design

A cross-sectional survey was carried out in two rural provinces of Burkina Faso on a random cluster sample of 480 mother-child pairs. Dietary data was obtained by 24-hour recalls repeated on a random sub-selection of 37.5% of subjects to allow calculation of nutrient’s probability of adequacy (PA). Biomarkers were measured on a sub-sample of 180 mother-child pairs. Blood samples were analyzed for hemoglobin, serum ferritin, soluble transferrin receptors (sTfR), C-reactive protein, alpha-1-glycoprotein, serum zinc concentration (SZnC) and retinol. For each micronutrient the relationship between biomarker and dietary intake was investigated by multiple linear regression models accounting for inflammatory biomarkers.

Results

Mean PA for iron, zinc and vitamin A was 0.49, 0.87 and 0.21 among women and 0.61, 0.95 and 0.33 among children, respectively. Prevalence of anemia, corrected low serum ferritin and high sTfR was 37.6%, 4.0% and 77.5% among women and 72.1%, 1.5% and 87.6% among children, respectively. Prevalence of low SZnC and corrected low serum retinol was 39.4% and 12.0% among women and 63.7% and 24.8% among children, respectively. There was a tendency for a positive relationship between vitamin A intakes and serum retinol among women (β = 0.0003, P = 0.06). Otherwise, no link was found between micronutrients biomarkers and intakes.

Conclusion

Our study depicted different images of micronutrient deficiencies when based on dietary intakes or biomarkers results, thus highlighting the need for more suitable biomarkers and more precise measures of absorbable micronutrient intakes at the individual level. It thus points to challenges in the design and evaluation of future biofortification or other food-based interventions in rural areas of Burkina Faso.     

TMEM45A Is Dispensable for Epidermal Morphogenesis,Keratinization and Barrier Formation

TMEM45A gene encodes an initially uncharacterized predicted transmembrane protein. We previously showed that this gene is highly expressed in keratinocytes where its expression correlates with keratinization, suggesting a role in normal epidermal physiology. To test this hypothesis, we generated TMEM45A knockout mice and found that these mice develop without any evident phenotype. The morphology of the epidermis assessed by histology and by labelling differentiation markers in immunofluorescence was not altered. Toluidine blue permeability assay showed that the epidermal barrier develops normally during embryonic development. We also showed that depletion of TMEM45A in human keratinocytes does not alter their potential to form in vitro 3D-reconstructed epidermis. Indeed, epidermis with normal morphogenesis were generated from TMEM45A-silenced keratinocytes. Their expression of differentiation markers quantified by RT-qPCR and evidenced by immunofluorescence labelling as well as their barrier function estimated by Lucifer yellow permeability were similar to the control epidermis. In summary, TMEM45A gene expression is dispensable for epidermal morphogenesis, keratinization and barrier formation. If this protein plays a role in the epidermis, its experimental depletion can possibly be compensated by other proteins in the two experimental models analyzed in this study.