MEDIATE - Molecular DockIng at homE: Turning collaborative simulations into therapeutic solutions

IntroductionCollaborative computing has attracted great interest in the possibility of joining the efforts of researchers worldwide. Its relevance has further increased during the pandemic crisis since it allows for the strengthening of scientific collaborations while avoiding physical interactions. Thus, the E4C consortium presents the MEDIATE initiative which invited researchers to contribute via their virtual screening simulations that will be combined with AI-based consensus approaches to provide robust and method-independent predictions. The best compounds will be tested, and the biological results will be shared with the scientific community.Areas coveredIn this paper, the MEDIATE initiative is described. This shares compounds' libraries and protein structures prepared to perform standardized virtual screenings. Preliminary analyses are also reported which provide encouraging results emphasizing the MEDIATE initiative's capacity to identify active compounds.Expert opinionStructure-based virtual screening is well-suited for collaborative projects provided that the participating researchers work on the same input file. Until now, such a strategy was rarely pursued and most initiatives in the field were organized as challenges. The MEDIATE platform is focused on SARS-CoV-2 targets but can be seen as a prototype which can be utilized to perform collaborative virtual screening campaigns in any therapeutic field by sharing the appropriate input files

Prediction Of Beef Fatty Acid Composition Using Near Infrared Spectroscopy: Effects Of Tissue And Sample Preparations

International audienceThe aims of the study were to determine the best site of bovine carcass for predicting fatty acid (FA) composition using a NIRS (near infrared spectroscopy) portable equipment and to study the effect of different methods of sample preparation. 78 animals were sampled from different types and rearing systems. Seven tissues (Longissimus thoracis, Infraspinatus, Diaphragma, Rectus abdominis, shoulder subcutaneous adipose tissue (SAT), intercostal SAT and intermuscular fat at the 5th rib) were measured after sampling and grinding in liquid nitrogen. The effect of samples preparation were measured on carcass (C0), muscle without grinding (B0), ground with a meat chopper (B1), ground with a knife mill (B2) on RA muscle. FA composition was assessed using gas chromatograph and the spectra were measured at wavelengths between 350 and 2500 nm. For adipose tissue, FA were not correctly predicted from NIRS. However, predictions were more satisfactory for the major FA (C16:0, C18:0, C18:1d9c), total saturated and monounsaturated FA of muscles. The results show a better prediction of FA composition concomitant with an increased gradient of sample homogenization. For other FA and especially polyunsaturated fatty acids, the performances were not satisfactory for quantitative purposes whatever the grinding method

Multivariate analysis of heavy metal contents in soils, sediments and water in the region of Meknes (Central Morocco)

International audienceConcentrations of Al, Fe, Cr, Cu, Ni, Pb and Zn in soils, sediments and water samples collected along the Oued Boufekrane river (Meknes, central Morocco) were determined. In soils, a homogeneous distribution of metal concentrations was observed throughout the study area except for Pb, which presents high enrichment at sites located at the vicinity of a main highway. In sediments, high enrichment, with respect to upstream sites, were observed downstream of the city of Meknes for Al, Cr, Fe and Ni and inside the city for Cu, Zn and Pb. In water samples, the metal contents showed to correlate with their homologues in sediments suggesting that the metal contents in water and sediments have identical origins. Descriptive statistics and multivariate analysis (principal factor method, PFM) were used to assist the interpretation of elemental data. This allowed the determination of the correlations between the metals and the identification of three main factor loadings controlling the metal variability in soils and sediments

BHRF1, a BCL2 viral homolog, disturbs mitochondrial dynamics and stimulates mitophagy to dampen type I IFN induction

Place: Philadelphia Publisher: Taylor & Francis Inc WOS:000546708500001Mitochondria respond to many cellular functions and act as central hubs in innate immunity against viruses. This response is notably due to their role in the activation of interferon (IFN) signaling pathways through the activity of MAVS (mitochondrial antiviral signaling protein) present at the mitochondrial surface. Here, we report that the BHRF1 protein, a BCL2 homolog encoded by Epstein-Barr virus (EBV), inhibits IFNB/IFN-beta induction by targeting the mitochondria. Indeed, we have demonstrated that BHRF1 expression modifies mitochondrial dynamics and stimulates DNM1L/Drp1-mediated mitochondrial fission. Concomitantly, we have shown that BHRF1 is pro-autophagic because it stimulates the autophagic flux by interacting with BECN1/Beclin 1. In response to the BHRF1-induced mitochondrial fission and macroautophagy/autophagy stimulation, BHRF1 drives mitochondrial network reorganization to form juxtanuclear mitochondrial aggregates known as mito-aggresomes. Mitophagy is a cellular process, which can specifically sequester and degrade mitochondria. Our confocal studies uncovered that numerous mitochondria are present in autophagosomes and acidic compartments using BHRF1-expressing cells. Moreover, mito-aggresome formation allows the induction of mitophagy and the accumulation of PINK1 at the mitochondria. As BHRF1 modulates the mitochondrial fate, we explored the effect of BHRF1 on innate immunity and showed that BHRF1 expression could prevent IFNB induction. Indeed, BHRF1 inhibits theIFNBpromoter activation and blocks the nuclear translocation of IRF3 (interferon regulatory factor 3). Thus, we concluded that BHRF1 can counteract innate immunity activation by inducing fission of the mitochondria to facilitate their sequestration in mitophagosomes for degradation

Massive clonal expansion of polycytotoxic skin and blood CD8+ T cells in patients with toxic epidermal necrolysis.

Toxic epidermal necrolysis (TEN) is a life-threatening cutaneous adverse drug reaction. To better understand why skin symptoms are so severe, we conducted a prospective immunophenotyping study on skin and blood. Mass cytometry results confirmed that effector memory polycytotoxic CD8+ T cells (CTLs) are the main leucocytes in TEN blisters at the acute phase. Deep T cell receptor (TCR) repertoire sequencing identified massive expansion of unique CDR3 clonotypes in blister cells. The same clones were highly expanded in patient's blood, and the degree of their expansion showed significant correlation with disease severity. By transducing α and β chains of the expanded clonotypes into a TCR-defective cell line, we confirmed that those cells were drug specific. Collectively, these results suggest that the relative clonal expansion and phenotype of skin-recruited CTLs condition the clinical presentation of cutaneous adverse drug reactions

Histone Acetylome-wide Association Study of Autism Spectrum Disorder

The association of histone modification changes with autism spectrum disorder (ASD) has not been systematically examined. We conducted a histone acetylome-wide association study (HAWAS) by performing H3K27ac chromatin immunoprecipitation sequencing (ChIP-seq) on 257 postmortem samples from ASD and matched control brains. Despite etiological heterogeneity, ≥68% of syndromic and idiopathic ASD cases shared a common acetylome signature at >5,000 cis-regulatory elements in prefrontal and temporal cortex. Similarly, multiple genes associated with rare genetic mutations in ASD showed common “epimutations.” Acetylome aberrations in ASD were not attributable to genetic differentiation at cis-SNPs and highlighted genes involved in synaptic transmission, ion transport, epilepsy, behavioral abnormality, chemokinesis, histone deacetylation, and immunity. By correlating histone acetylation with genotype, we discovered >2,000 histone acetylation quantitative trait loci (haQTLs) in human brain regions, including four candidate causal variants for psychiatric diseases. Due to the relative stability of histone modifications postmortem, we anticipate that the HAWAS approach will be applicable to multiple diseases.This article is freely available via Open Access. Click on the Additional Link above to access the full-text