Opportunities for Molecular Imaging in Multiple Sclerosis Management: Linking Probe to Treatment

Imaging has been a critical component of multiple sclerosis (MS) management for nearly 40 years. The visual information derived from structural MRI, that is, signs of blood-brain barrier disruption, inflammation and demyelination, and brain and spinal cord atrophy, are the primary metrics used to evaluate therapeutic efficacy in MS. The development of targeted imaging probes has expanded our ability to evaluate and monitor MS and its therapies at the molecular level. Most molecular imaging probes evaluated for MS applications are small molecules initially developed for PET, nearly half of which are derived from U.S. Food and Drug Administration-approved drugs and those currently undergoing clinical trials. Superparamagnetic and fluorinated particles have been used for tracking circulating immune cells (in situ labeling) and immunosuppressive or remyelinating therapeutic stem cells (ex vivo labeling) clinically using proton (hydrogen 1 [1H]) and preclinically using fluorine 19 MRI. Translocator protein PET and 1H MR spectroscopy have been demonstrated to complement imaging metrics from structural (gadolinium-enhanced) MRI in nine and six trials for MS disease-modifying therapies, respectively. Still, despite multiple demonstrations of the utility of molecular imaging probes to evaluate the target location and to elucidate the mechanisms of disease-modifying therapies for MS applications, their use has been sparse in both preclinical and clinical settings

Langerin-Heparin Interaction: Two Binding Sites for Small and Large Ligands as revealed by a combination of NMR Spectroscopy and Cross-Linking Mapping Experiments

Langerin is a C-type lectin present on Langerhans cells that mediates capture of pathogens in a carbohydrate-dependent manner, leading to subsequent internalization and elimination in the cellular organelles called Birbeck granules. This mechanism mediated by langerin was shown to constitute a natural barrier for HIV-1 particle transmission. Besides interacting specifically with high mannose and fucosylated neutral carbohydrate structures, langerin has the ability to bind sulfated carbohydrate ligands as 6-sulfated galactosides in the Ca2+ dependent binding site. Very recently langerin was demonstrated to interact with sulfated glycosaminoglycans (GAGs), in a Ca2+ independent way, resulting in the proposal of a new binding site for GAGs. Based on those results, we have conducted a structural study of the interactions of small heparin (HEP) like oligosaccharides with langerin in solution. Heparin-bead cross-linking experiments, an approach specifically designed to identify HEP/HS binding sites in proteins were first carried out and experimentally validated the previously proposed model for the interaction of Lg ECD with 6 kDa HEP. High-resolution NMR studies of a set of 8 synthetic HEP-like trisaccharides harboring different sulfation patterns demonstrated that all of them bound to langerin in a Ca2+ dependent way. The binding epitopes were determined by STD NMR and the bound conformations by transferred NOESY experiments. These experimental data were combined with docking and molecular dynamics and resulted in the proposal of a binding mode characterized by the coordination of calcium by the two equatorial hydroxyl groups OH3 and OH4 at the non-reducing end. The binding also includes the carboxylate group at the adjacent iduronate residue. Such epitope is shared by all the 8 ligands, explaining the absence of any impact on binding from their differences in substitution pattern. Finally, in contrast to the small trisaccharides, we demonstrated that a longer HEP-like hexasaccharide, bearing an additional O-sulfate group at the non-reducing end, which precludes binding to the Ca2+ site, interacts with langerin in the previously identified Ca2+ independent binding site

Metagenómica en la identificación de microorganismos que producen biodeterioro: patrimonio edificado con arquitectura en tierra, Vale Histórico Paulista (São Paulo, Brasil)

El objetivo de este trabajo es presentar resultados obtenidos mediante análisis por metagenómica como herramienta novedosa para la identificación taxonómica de hongos y bacterias a partir de biofilms en paredes de arquitectura en tierra (“pau-a-pique”, “taipa de pilão” y adobe), de edificaciones históricas del Vale Histórico Paulista, representativas del período colonial brasileño, Se extrajo el DNA total de los biofilms, que fue amplificado mediante primers específicos para regiones variables de los genes 16S y 18S ribosomal, y luego secuenciado obteniéndose bibliotecas del amplificado. El programa QIIME reveló la diversidad taxonómica en los distintos sustratos. Los géneros más abundantes de bacterias fueron: Aciditerrimonas, Blastococcus, Geodermatophilus, Arthrobacter, Micromonospora, Nocardioides, Propionibacterium, Pseudonocardia, Rubrobacter, Solirubrobacter, Thermoleophilum, Sphingobacterium, Sphaerobacter, Streptococcus, Gemmatimonas, Methylobacterium, Microvirga, Sphingomonas, Massilia, Klebsiella, Acinetobacter, Los géneros más abundantes de hongos: Passalora, Lacazia, Anisomeridium, Poliblastia, Hypocrea, Verrucaria, Caloplaca, Chaetomella, Meyerozima, Humicola, Oxyporus, Coriolopsis, Rhodotorula, Sporidiobolus, Trichosporon, Mucor, Syncephalastrum. Este trabajo es el primer reporte de comunidades microbianas a partir de paredes hechas con técnicas de arquitectura en tierra con el uso de metagenómica

Conserved and divergent arms of the antiviral response in the duplicated genomes of salmonid fishes

Funding Information: This work was funded by the European Union's Horizon 2020 research and innovation program under grant agreement No 817923 (AQUAFAANG), by ANR (ANR-21-CE35-0019, LipofishVac), by the Eranet ICRAD-Nucnanofish (ANR_13001498 and BBSRC_ICRAD BB/V019902/1), by the BBSRC Institutional strategic programme award (BBS/E/D/20002174) and by institutional grants from INRAE. We thank Drs Hugues Roest Crollius, Camille Berthelot, Alexandra Louis and Elise Parey for sharing synteny-based corrected data produced by SCORPiOs, and Louis du Pasquier for insightful discussions.Peer reviewedPublisher PD

Maternal Adiposity Influences Neonatal Brain Functional Connectivity

The neural mechanisms associated with obesity have been extensively studied, but the impact of maternal obesity on fetal and neonatal brain development remains poorly understood. In this study of full-term neonates, we aimed to detect potential neonatal functional connectivity alterations associated with maternal adiposity, quantified via body-mass-index (BMI) and body-fat-mass (BFM) percentage, based on seed-based and graph theoretical analysis using resting-state fMRI data. Our results revealed significant neonatal functional connectivity alterations in all four functional domains that are implicated in adult obesity: sensory cue processing, reward processing, cognitive control, and motor control. Moreover, some of the detected areas showing regional functional connectivity alterations also showed global degree and efficiency differences. These findings provide important clues to the potential neural basis for cognitive and mental health development in offspring of obese mothers and may lead to the derivation of imaging-based biomarkers for the early identification of risks for timely intervention

Mendelian randomization study of B-type natriuretic peptide and type 2 diabetes: evidence of causal association from population studies

<p>Background: Genetic and epidemiological evidence suggests an inverse association between B-type natriuretic peptide (BNP) levels in blood and risk of type 2 diabetes (T2D), but the prospective association of BNP with T2D is uncertain, and it is unclear whether the association is confounded.</p> <p>Methods and Findings: We analysed the association between levels of the N-terminal fragment of pro-BNP (NT-pro-BNP) in blood and risk of incident T2D in a prospective case-cohort study and genotyped the variant rs198389 within the BNP locus in three T2D case-control studies. We combined our results with existing data in a meta-analysis of 11 case-control studies. Using a Mendelian randomization approach, we compared the observed association between rs198389 and T2D to that expected from the NT-pro-BNP level to T2D association and the NT-pro-BNP difference per C allele of rs198389. In participants of our case-cohort study who were free of T2D and cardiovascular disease at baseline, we observed a 21% (95% CI 3%-36%) decreased risk of incident T2D per one standard deviation (SD) higher log-transformed NT-pro-BNP levels in analysis adjusted for age, sex, body mass index, systolic blood pressure, smoking, family history of T2D, history of hypertension, and levels of triglycerides, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol. The association between rs198389 and T2D observed in case-control studies (odds ratio = 0.94 per C allele, 95% CI 0.91-0.97) was similar to that expected (0.96, 0.93-0.98) based on the pooled estimate for the log-NT-pro-BNP level to T2D association derived from a meta-analysis of our study and published data (hazard ratio = 0.82 per SD, 0.74-0.90) and the difference in NT-pro-BNP levels (0.22 SD, 0.15-0.29) per C allele of rs198389. No significant associations were observed between the rs198389 genotype and potential confounders.</p> <p>Conclusions: Our results provide evidence for a potential causal role of the BNP system in the aetiology of T2D. Further studies are needed to investigate the mechanisms underlying this association and possibilities for preventive interventions.</p&gt