Interleukin-1 receptor antagonist is upregulated during diet-induced obesity and regulates insulin sensitivity in rodents

Aims/hypothesis: The IL-1 receptor antagonist (IL-1Ra) is an anti-inflammatory cytokine known to antagonise the actions of IL-1. We have previously shown that IL-1Ra is markedly upregulated in the serum of obese patients, is correlated with BMI and insulin resistance, and is overexpressed in the white adipose tissue (WAT) of obese humans. The aim of this study was to examine the role of IL-1Ra in the regulation of glucose homeostasis in rodents. Methods: We assessed the expression of genes related to IL-1 signalling in the WAT of mice fed a high-fat diet, as well as the effect of Il1rn (the gene for IL-1Ra) deletion and treatment with IL-1Ra on glucose homeostasis in rodents. Results: We show that the expression of Il1rn and the gene encoding the inhibitory type II IL-1 receptor was upregulated in diet-induced obesity. The blood insulin:glucose ratio was significantly lower in Il1rn −/− animals, which is compatible with an increased sensitivity to insulin, reinforced by the fact that the insulin content and pancreatic islet morphology of Il1rn −/− animals were normal. In contrast, the administration of IL-1Ra to normal rats for 5days led to a decrease in the whole-body glucose disposal due to a selective decrease in muscle-specific glucose uptake. Conclusions/interpretation: The expression of genes encoding inhibitors of IL-1 signalling is upregulated in the WAT of mice with diet-induced obesity, and IL-1Ra reduces insulin sensitivity in rats through a muscle-specific decrease in glucose uptake. These results suggest that the markedly increased levels of IL-1Ra in human obesity might contribute to the development of insulin resistanc

Obstetrical and neonatal characteristics vary with birthweight in a cohort of 100 term newborns with symptomatic arterial ischemic stroke

ObjectivesMany questions remain regarding the mechanism of perinatal stroke. Methods In a series of 100 prospectively enrolled term neonates with symptomatic arterial ischemic stroke, we explored family antecedents, pregnancy and delivery conditions and clinical presenting features and distinguished features of the 50 larger infants with the remainder. Cardiac and cervical arterial imaging were performed in 70 and 51 cases. Results Previous fetal loss, first pregnancy, primiparity, twin-gestation, cesarean and traumatic delivery, neonatal distress, male sex and premature rupture of membranes were statistically more common than in the general population. Normal pregnancy proportion and mean birthweight were in the normal range, arguing against a vasculo-placental origin in the majority. Furthermore, there was an excess of large babies. The larger infants were more subject to suffer from acute perinatal events, with a trend for an excess of neonatal distress (p = 0.065) and for more severe presenting features (p = 0.027), while the lighter were more likely to have experienced longstanding obstetrical risk factors such as complicated pregnancy (p = 0.047) and tobacco exposure (p = 0.028). Cervical MR angiography showed an internal carotid occlusion in two babies, whereas echo-Doppler was always normal; in one case the two methods were discordant. Echocardiography was non-informative. Interpretation The data from this prospective cohort of neonates with stroke confirm that many obstetrical and perinatal factors are risk determinants. They also suggest that birthweight and gender may be biomarkers of two populations of neonates with different pathological mechanisms. MR angiography appears more sensitive than echo-Doppler for the exploration of the neonatal cervical vasculature

Phylogenetic Distribution and Evolutionary History of Bacterial DEAD-Box Proteins

DEAD-box proteins are found in all domains of life and participate in almost all cellular processes that involve RNA. The presence of DEAD and Helicase_C conserved domains distinguish these proteins. DEAD-box proteins exhibit RNA-dependent ATPase activity in vitro, and several also show RNA helicase activity. In this study, we analyzed the distribution and architecture of DEAD-box proteins among bacterial genomes to gain insight into the evolutionary pathways that have shaped their history. We identified 1,848 unique DEAD-box proteins from 563 bacterial genomes. Bacterial genomes can possess a single copy DEAD-box gene, or up to 12 copies of the gene, such as in Shewanella. The alignment of 1,208 sequences allowed us to perform a robust analysis of the hallmark motifs of DEAD-box proteins and determine the residues that occur at high frequency, some of which were previously overlooked. Bacterial DEAD-box proteins do not generally contain a conserved C-terminal domain, with the exception of some members that possess a DbpA RNA-binding domain (RBD). Phylogenetic analysis showed a separation of DbpA-RBD-containing and DbpA-RBD-lacking sequences and revealed a group of DEAD-box protein genes that expanded mainly in the Proteobacteria. Analysis of DEAD-box proteins from Firmicutes and γ-Proteobacteria, was used to deduce orthologous relationships of the well-studied DEAD-box proteins from Escherichia coli and Bacillus subtilis. These analyses suggest that DbpA-RBD is an ancestral domain that most likely emerged as a specialized domain of the RNA-dependent ATPases. Moreover, these data revealed numerous events of gene family expansion and reduction following speciation

Proteomic Analysis of S-Acylated Proteins in Human B Cells Reveals Palmitoylation of the Immune Regulators CD20 and CD23

S-palmitoylation is a reversible post-translational modification important for controlling the membrane targeting and function of numerous membrane proteins with diverse roles in signalling, scaffolding, and trafficking. We sought to identify novel palmitoylated proteins in B lymphocytes using acyl-biotin exchange chemistry, coupled with differential analysis by liquid-chromatography tandem mass spectrometry. In total, we identified 57 novel palmitoylated protein candidates from human EBV-transformed lymphoid cells. Two of them, namely CD20 and CD23 (low affinity immunoglobulin epsilon Fc receptor), are immune regulators that are effective/potential therapeutic targets for haematological malignancies, autoimmune diseases and allergic disorders. Palmitoylation of CD20 and CD23 was confirmed by heterologous expression of alanine mutants coupled with bioorthogonal metabolic labeling. This study demonstrates a new subset of palmitoylated proteins in B cells, illustrating the ubiquitous role of protein palmitoylation in immune regulation

Chemoproteomics reveals Toll-like receptor fatty acylation

Partial funding for Open Access provided by The Ohio State University Open Access Fund.Background: Palmitoylation is a 16-carbon lipid post-translational modification that increases protein hydrophobicity. This form of protein fatty acylation is emerging as a critical regulatory modification for multiple aspects of cellular interactions and signaling. Despite recent advances in the development of chemical tools for the rapid identification and visualization of palmitoylated proteins, the palmitoyl proteome has not been fully defined. Here we sought to identify and compare the palmitoylated proteins in murine fibroblasts and dendritic cells. Results: A total of 563 putative palmitoylation substrates were identified, more than 200 of which have not been previously suggested to be palmitoylated in past proteomic studies. Here we validate the palmitoylation of several new proteins including Toll-like receptors (TLRs) 2, 5 and 10, CD80, CD86, and NEDD4. Palmitoylation of TLR2, which was uniquely identified in dendritic cells, was mapped to a transmembrane domain-proximal cysteine. Inhibition of TLR2 S-palmitoylation pharmacologically or by cysteine mutagenesis led to decreased cell surface expression and a decreased inflammatory response to microbial ligands. Conclusions: This work identifies many fatty acylated proteins involved in fundamental cellular processes as well as cell type-specific functions, highlighting the value of examining the palmitoyl proteomes of multiple cell types. Spalmitoylation of TLR2 is a previously unknown immunoregulatory mechanism that represents an entirely novel avenue for modulation of TLR2 inflammatory activity.This work was supported by funding from the NIH/NIAID (grant R00AI095348 to J.S.Y.), the NIH/NIGMS (R01GM087544 to HCH), and the Ohio State University Public Health Preparedness for Infectious Diseases (PHPID) program. NMC is supported by the Ohio State University Systems and Integrative Biology Training Program (NIH/NIGMS grant T32GM068412). BWZ is a fellow of the National Science Foundation Graduate Research Fellowship Program (DGE-0937362)

A new Late Agenian (MN2a, Early Miocene) fossil assemblage from Wallenried (Molasse Basin, Canton Fribourg, Switzerland)

Excavations of two fossiliferous layers in the Wallenried sand- and marl pit produced a very diversified vertebrate fauna. New material allows the reassessment of the taxonomic position of the ruminant taxa Andegameryx andegaviensis and endemic Friburgomeryx wallenriedensis. An emended diagnosis for the second species is provided and additional material of large and small mammals, as well as ectothermic vertebrates, is described. The recorded Lagomorpha show interesting morphological deviations from other Central European material, and probably represent a unique transitional assemblage with a co-occurrence of Titanomys, Lagopsis and Prolagus. Rodentia and Eulipotyphla belong to typical and well-known species of the Agenian of the Swiss Molasse Basin. Abundant small mammal teeth have allowed us to pinpoint the biostratigraphic age of Wallenried to late MN2a. The biostratigraphic age conforms to data derived from the charophyte assemblages and confirms the oldest occurrence of venomous snake fangs. The palaeoenvironmental context is quite complex. Sedimentary structures and fauna (fishes, frogs, salamanders, ostracods) are characteristic for a humid, lacustrine environment within a flood plain system

De novo TBR1 variants cause a neurocognitive phenotype with ID and autistic traits:report of 25 new individuals and review of the literature

TBR1, a T-box transcription factor expressed in the cerebral cortex, regulates the expression of several candidate genes for autism spectrum disorders (ASD). Although TBR1 has been reported as a high-confidence risk gene for ASD and intellectual disability (ID) in functional and clinical reports since 2011, TBR1 has only recently been recorded as a human disease gene in the OMIM database. Currently, the neurodevelopmental disorders and structural brain anomalies associated with TBR1 variants are not well characterized. Through international data sharing, we collected data from 25 unreported individuals and compared them with data from the literature. We evaluated structural brain anomalies in seven individuals by analysis of MRI images, and compared these with anomalies observed in TBR1 mutant mice. The phenotype included ID in all individuals, associated to autistic traits in 76% of them. No recognizable facial phenotype could be identified. MRI analysis revealed a reduction of the anterior commissure and suggested new features including dysplastic hippocampus and subtle neocortical dysgenesis. This report supports the role of TBR1 in ID associated with autistic traits and suggests new structural brain malformations in humans. We hope this work will help geneticists to interpret TBR1 variants and diagnose ASD probands

Biostratigraphical correlations between the Organyà section (Catalonian Pyrenees, NE Spain) and SE France during Valanginian - Aptian times

Between 1998 and 2000 the well-known Organyà section (Catalonian Pyrenees) was the subject of three important publications (of which two were doctoral theses) dealing with the Valanginian – Aptian stratigraphy. The two theses came to completely different conclusions concerning the biostratigraphy of the Hostal Nou Formation and the lower part of the Prada Formation. It thus appeared necessary to reinterpret the data published in these two theses in the light of the results obtained in SE France, especially on the orbitolinid biostratigraphy (related to the ammonite scale) and on sequence stratigraphy. The present paper demonstrates that the series of the Berriasian-Valanginian and Urgonian platform carbonates of the Organyà section and SE France present a remarkable stratigraphic identity. Key words: Catalonian Pyrenees (Spain), Organyà, Hostal Nou, Prada, Subalpine Chains (France), Jura, Urgonian, Valanginian, Hauterivian, Barremian, Aptian.Entre 1998 y 2000 el célebre corte d'Organyà (Pirineo catalan) ha sido objeto de tres importantes publicaciones (entre ellas dos tesis doctorales) que se ocupan del intervalo estratigráfico Valanginiense – Aptiense. Estas dos tesis llegan a conclusiones diametralmente opuestas en lo referente a la bioestratigrafía de la Formación Hostal Nou y la parte inferior de la Formación Prada. Por ese motivo hemos reinterpretado los datos publicados en las dos tesis, comparándolos con los resultados recientemente obtenidos en el Sudeste de Francia, que se refieren a la bioestratigrafía con orbitolínidos y a la estratigrafía secuencial. El resultado es que las series d'Organyà y las de la plataforma berriasiense-valanginiense y urgoniana del Sudeste de Francia presentan una notable identidad estratigráfica. Palabras clave: Pirineo Catalán (España), Organyà, Hostal Nou, Prada, Cadenas Subalpinas (Francia), Jura, Urgoniano, Valanginiense, Hauteriviense, Barremiense, Aptiense