Critical role of the neutrophil-associated high-affinity receptor for IgE in the pathogenesis of experimental cerebral malaria

FcεR1-expressing neutrophils accumulate in the brain of mice infected with Plasmodium berghei (PbANKA) and promote the development of experimental cerebral malaria

A multi-scale analysis of bull sperm methylome revealed both species peculiarities and conserved tissue-specific

peer-reviewedBackground: Spermatozoa have a remarkable epigenome in line with their degree of specialization, their unique nature and different requirements for successful fertilization. Accordingly, perturbations in the establishment of DNA methylation patterns during male germ cell differentiation have been associated with infertility in several species.Background: Spermatozoa have a remarkable epigenResults: The quantification of DNA methylation at CCGG sites using luminometric methylation assay (LUMA) highlighted the undermethylation of bull sperm compared to the sperm of rams, stallions, mice, goats and men. Total blood cells displayed a similarly high level of methylation in bulls and rams, suggesting that undermethylation of the bovine genome was specific to sperm. Annotation of CCGG sites in different species revealed no striking bias in the distribution of genome features targeted by LUMA that could explain undermethylation of bull sperm. To map DNA methylation at a genome-wide scale, bull sperm was compared with bovine liver, fibroblasts and monocytes using reduced representation bisulfite sequencing (RRBS) and immunoprecipitation of methylated DNA followed by microarray hybridization (MeDIP-chip). These two methods exhibited differences in terms of genome coverage, and consistently, two independent sets of sequences differentially methylated in sperm and somatic cells were identified for RRBS and MeDIP-chip. Remarkably, in the two sets most of the differentially methylated sequences were hypomethylated in sperm. In agreement with previous studies in other species, the sequences that were specifically hypomethylated in bull sperm targeted processes relevant to the germline differentiation program (piRNA metabolism, meiosis, spermatogenesis) and sperm functions (cell adhesion, fertilization), as well as satellites and rDNA repeats. Conclusions: These results highlight the undermethylation of bull spermatozoa when compared with both bovine somatic cells and the sperm of other mammals, and raise questions regarding the dynamics of DNA methylation in bovine male germline. Whether sperm undermethylation has potential interactions with structural variation in the cattle genome may deserve further attention. While bull semen is widely used in artificial insemination, the literature describing DNA methylation in bull spermatozoa is still scarce. The purpose of this study was therefore to characterize the bull sperm methylome relative to both bovine somatic cells and the sperm of other mammals through a multiscale analysis

The Osteopontin Level in Liver, Adipose Tissue and Serum Is Correlated with Fibrosis in Patients with Alcoholic Liver Disease

<div><h3>Background</h3><p>Osteopontin (OPN) plays an important role in the progression of chronic liver diseases. We aimed to quantify the liver, adipose tissue and serum levels of OPN in heavy alcohol drinkers and to compare them with the histological severity of hepatic inflammation and fibrosis.</p> <h3>Methodology/Principal Findings</h3><p>OPN was evaluated in the serum of a retrospective and prospective group of 109 and 95 heavy alcohol drinkers, respectively, in the liver of 34 patients from the retrospective group, and in the liver and adipose tissue from an additional group of 38 heavy alcohol drinkers. Serum levels of OPN increased slightly with hepatic inflammation and progressively with the severity of hepatic fibrosis. Hepatic OPN expression correlated with hepatic inflammation, fibrosis, TGFβ expression, neutrophils accumulation and with the serum OPN level. Interestingly, adipose tissue OPN expression also correlated with hepatic fibrosis even after 7 days of alcohol abstinence. The elevated serum OPN level was an independent risk factor in estimating significant (F≥2) fibrosis in a model combining alkaline phosphatase, albumin, hemoglobin, OPN and FibroMeter® levels. OPN had an area under the receiving operator curve that estimated significant fibrosis of 0.89 and 0.88 in the retrospective and prospective groups, respectively. OPN, Hyaluronate (AUROC: 0.88), total Cytokeratin 18 (AUROC: 0.83) and FibroMeter® (AUROC: 0.90) estimated significance to the same extent in the retrospective group. Finally, the serum OPN levels also correlated with hepatic fibrosis and estimated significant (F≥2) fibrosis in 86 patients with chronic hepatitis C, which suggested that its elevated level could be a general response to chronic liver injury.</p> <h3>Conclusion/Significance</h3><p>OPN increased in the liver, adipose tissue and serum with liver fibrosis in alcoholic patients. Further, OPN is a new relevant biomarker for significant liver fibrosis. OPN could thus be an important actor in the pathogenesis of this chronic liver disease.</p> </div

Insights into the Mechanism of Bovine CD38/NAD+Glycohydrolase from the X-Ray Structures of Its Michaelis Complex and Covalently-Trapped Intermediates

Bovine CD38/NAD+glycohydrolase (bCD38) catalyses the hydrolysis of NAD+ into nicotinamide and ADP-ribose and the formation of cyclic ADP-ribose (cADPR). We solved the crystal structures of the mono N-glycosylated forms of the ecto-domain of bCD38 or the catalytic residue mutant Glu218Gln in their apo state or bound to aFNAD or rFNAD, two 2′-fluorinated analogs of NAD+. Both compounds behave as mechanism-based inhibitors, allowing the trapping of a reaction intermediate covalently linked to Glu218. Compared to the non-covalent (Michaelis) complex, the ligands adopt a more folded conformation in the covalent complexes. Altogether these crystallographic snapshots along the reaction pathway reveal the drastic conformational rearrangements undergone by the ligand during catalysis with the repositioning of its adenine ring from a solvent-exposed position stacked against Trp168 to a more buried position stacked against Trp181. This adenine flipping between conserved tryptophans is a prerequisite for the proper positioning of the N1 of the adenine ring to perform the nucleophilic attack on the C1′ of the ribofuranoside ring ultimately yielding cADPR. In all structures, however, the adenine ring adopts the most thermodynamically favorable anti conformation, explaining why cyclization, which requires a syn conformation, remains a rare alternate event in the reactions catalyzed by bCD38 (cADPR represents only 1% of the reaction products). In the Michaelis complex, the substrate is bound in a constrained conformation; the enzyme uses this ground-state destabilization, in addition to a hydrophobic environment and desolvation of the nicotinamide-ribosyl bond, to destabilize the scissile bond leading to the formation of a ribooxocarbenium ion intermediate. The Glu218 side chain stabilizes this reaction intermediate and plays another important role during catalysis by polarizing the 2′-OH of the substrate NAD+. Based on our structural analysis and data on active site mutants, we propose a detailed analysis of the catalytic mechanism

The Evolution of Primate Short-Term Memory.

Short-term memory is implicated in a range of cognitive abilities and is critical for understanding primate cognitive evolution. To investigate the effects of phylogeny, ecology and sociality on short-term memory, we tested the largest and most diverse primate sample to date (421 non-human primates across 41 species) in an experimental delayed-response task. Our results confirm previous findings that longer delays decrease memory performance across species and taxa. Our analyses demonstrate a considerable contribution of phylogeny over ecological and social factors on the distribution of short-term memory performance in primates; closely related species had more similar short-term memory abilities. Overall, individuals in the branch of Hominoidea performed better compared to Cercopithecoidea, who in turn performed above Platyrrhini and Strepsirrhini. Interdependencies between phylogeny and socioecology of a given species presented an obstacle to disentangling the effects of each of these factors on the evolution of short-term memory capacity. However, this study offers an important step forward in understanding the interspecies and individual variation in short-term memory ability by providing the first phylogenetic reconstruction of this trait’s evolutionary history. The dataset constitutes a unique resource for studying the evolution of primate cognition and the role of short-term memory in other cognitive abilities.info:eu-repo/semantics/publishedVersio

The Evolution of Primate Short-Term Memory

Short-term memory is implicated in a range of cognitive abilities and is critical for understanding primate cognitive evolution. To investigate the effects of phylogeny, ecology and sociality on short-term memory, we tested the largest and most diverse primate sample to date (421 non-human primates across 41 species) in an experimental delayed-response task. Our results confirm previous findings that longer delays decrease memory performance across species and taxa. Our analyses demonstrate a considerable contribution of phylogeny over ecological and social factors on the distribution of short-term memory performance in primates; closely related species had more similar short-term memory abilities. Overall, individuals in the branch of Hominoidea performed better compared to Cercopithecoidea, who in turn performed above Platyrrhini and Strepsirrhini. Interdependencies between phylogeny and socioecology of a given species presented an obstacle to disentangling the effects of each of these factors on the evolution of short-term memory capacity. However, this study offers an important step forward in understanding the interspecies and individual variation in short-term memory ability by providing the first phylogenetic reconstruction of this trait’s evolutionary history. The dataset constitutes a unique resource for studying the evolution of primate cognition and the role of short-term memory in other cognitive abilities

Clonage par simple-hybride de facteurs de transcription régulant le gène de la tyrosine hydroxylase (TH) de rat

Tyrosine hydroxylase is the rate limiting enzyme in catecholamine biosynthesis, a major group of neurotransmitters including dopamine, norepinephrine and epinephrine.The aim of our work was to isolate transcription factors potentially implicated in the cell-specific expression of the rat TH gene. For this purpose, we used the yeast one-hybrid system to identify proteins interacting with 2 important elements present in the TH promoter : the E box and the octameric/heptameric sequences. Three cDNA clones were obtained from 2 different cDNA libraries (whole adult rat brain and embryonic rat mesencephalon). The first cDNA corresponds to rITF2, a bHLH factor which ability to bind to the TH E box has previously been described. The second one is Lhx9, a LIM homeobox protein. Finally, the third cDNA, which we named ZENON, encodes a novel zinc finger protein showing a neuronal specific expression. These 3 factors were further characterized, revealing quite interesting features. They bind specifically to the TH promoter and are able to modulate TH gene transcription in cell lines. All 3 clones exhibit complex and changing expression patterns throughout development, however this expression is not restricted to catecholaminergic cells. To better understand the function of these factors in TH cell-specific expression, the E box and the octameric/heptameric sequences were characterized in vivo in transgenic mice. The E box plays a subtle role in peripheral catecholaminergic cells, suggesting intricate mechanisms involved in TH cell-specific expression.This work brings to light the difficulties underlying the search for transcription factors implicated in cell-specific expression mechanisms. Furthermore, our data defines a new zinc finger protein family, of which ZENON is the first member.La tyrosine hydroxylase (TH) est l'enzyme clé de la biosynthèse des catécholamines, classe fondamentale de neurotransmetteurs regroupant la dopamine, la noradrénaline et l'adrénaline. Une expression atypique des catécholamines pourrait conduire à de nombreuses complications neuropsychiatriques. L'étude des facteurs qui régulent le gène de la TH est donc déterminante.Ce travail a pour objectif l'isolement de facteurs de transcription potentiellement impliqués dans l'expression cellulaire restreinte du gène TH de rat. Dans ce but, nous avons développé une stratégie de simple-hybride dans la levure en utilisant la boîte E et les sites octamérique/heptamérique du promoteur TH comme cibles. Deux banques d'ADN complémentaire différentes ont été criblées, issues respectivement de cerveau de rat adulte et de mésencéphale embryonnaire. Ces criblages ont conduit à l'identification de 3 facteurs de transcription candidats : rITF2, un facteur bHLH ubiquitaire déjà décrit pour son aptitude à interagir avec la boîte E du promoteur TH, Lhx9, une protéine LIM à homéodomaine, et ZENON, une nouvelle protéine à doigts de zinc spécifiquement exprimée dans les neurones. La caractérisation de ces 3 facteurs a révélé des propriétés tout à fait intéressantes. Ils sont capables d'interagir spécifiquement avec le promoteur TH, et modulent la transcription du gène TH dans des lignées cellulaires. Leurs patrons d'expression sont complexes et s'inscrivent dans une dynamique développementale très particulière, mais ne sont pas spécifiques du système catécholaminergique. Pour comprendre le rôle de ces facteurs dans l'expression cellulaire restreinte de la TH, nous avons mené une étude de transgenèse des sites cibles utilisés en simple-hybride. La boîte E joue un rôle subtil dans le système catécholaminergique périphérique, illustrant la complexité des mécanismes conduisant à l'expression cellulaire restreinte de la TH. Ce travail souligne les difficultés rencontrées pour isoler des facteurs de transcription impliqués dans des processus d'expression cellulaire restreinte et définit une nouvelle famille de protéines à doigts de zinc, dont ZENON, le premier membre, semble lié au phénotype neuronal. L'identification et l'étude d'autres protéines appartenant à cette famille pourraient donc s'avérer capitales pour la compréhension des mécanismes impliqués dans la mise en place et le maintien des caractères neuronaux au cours du développement

Inter-individual variability in the bull sperm methylome: what does it tells about the animal and which practical applications?

International audienc

The epigenome of male germ cells in ruminants

International audienc