Reduction of the ATPase inhibitory factor 1 (IF1) leads to visual impairment in vertebrates

In vertebrates, mitochondria are tightly preserved energy producing organelles, which sustain nervous system development and function. The understanding of proteins that regulate their homoeostasis in complex animals is therefore critical and doing so via means of systemic analysis pivotal to inform pathophysiological conditions associated with mitochondrial deficiency. With the goal to decipher the role of the ATPase inhibitory factor 1 (IF1) in brain development, we employed the zebrafish as elected model reporting that the Atpif1a−/− zebrafish mutant, pinotage (pnttq209), which lacks one of the two IF1 paralogous, exhibits visual impairment alongside increased apoptotic bodies and neuroinflammation in both brain and retina. This associates with increased processing of the dynamin-like GTPase optic atrophy 1 (OPA1), whose ablation is a direct cause of inherited optic atrophy. Defects in vision associated with the processing of OPA1 are specular in Atpif1−/− mice thus confirming a regulatory axis, which interlinks IF1 and OPA1 in the definition of mitochondrial fitness and specialised brain functions. This study unveils a functional relay between IF1 and OPA1 in central nervous system besides representing an example of how the zebrafish model could be harnessed to infer the activity of mitochondrial proteins during development

Defending the genome from the enemy within:mechanisms of retrotransposon suppression in the mouse germline

The viability of any species requires that the genome is kept stable as it is transmitted from generation to generation by the germ cells. One of the challenges to transgenerational genome stability is the potential mutagenic activity of transposable genetic elements, particularly retrotransposons. There are many different types of retrotransposon in mammalian genomes, and these target different points in germline development to amplify and integrate into new genomic locations. Germ cells, and their pluripotent developmental precursors, have evolved a variety of genome defence mechanisms that suppress retrotransposon activity and maintain genome stability across the generations. Here, we review recent advances in understanding how retrotransposon activity is suppressed in the mammalian germline, how genes involved in germline genome defence mechanisms are regulated, and the consequences of mutating these genome defence genes for the developing germline

The role of multiple marks in epigenetic silencing and the emergence of a stable bivalent chromatin state

We introduce and analyze a minimal model of epigenetic silencing in budding yeast, built upon known biomolecular interactions in the system. Doing so, we identify the epigenetic marks essential for the bistability of epigenetic states. The model explicitly incorporates two key chromatin marks, namely H4K16 acetylation and H3K79 methylation, and explores whether the presence of multiple marks lead to a qualitatively different systems behavior. We find that having both modifications is important for the robustness of epigenetic silencing. Besides the silenced and transcriptionally active fate of chromatin, our model leads to a novel state with bivalent (i.e., both active and silencing) marks under certain perturbations (knock-out mutations, inhibition or enhancement of enzymatic activity). The bivalent state appears under several perturbations and is shown to result in patchy silencing. We also show that the titration effect, owing to a limited supply of silencing proteins, can result in counter-intuitive responses. The design principles of the silencing system is systematically investigated and disparate experimental observations are assessed within a single theoretical framework. Specifically, we discuss the behavior of Sir protein recruitment, spreading and stability of silenced regions in commonly-studied mutants (e.g., sas2, dot1) illuminating the controversial role of Dot1 in the systems biology of yeast silencing.Comment: Supplementary Material, 14 page

Symptomatic and Asymptomatic Neurological Complications of Infective Endocarditis: Impact on Surgical Management and Prognosis

International audienceObjectives:Symptomatic neurological complications (NC) are a major cause of mortality in infective endocarditis (IE) but the impact of asymptomatic complications is unknown. We aimed to assess the impact of asymptomatic NC (AsNC) on the management and prognosis of IE.Methods: From the database of cases collected for a population-based study on IE, we selected 283 patients with definite left-sided IE who had undergone at least one neuroimaging procedure (cerebral CT scan and/or MRI) performed as part of initial evaluation.Results Among those 283 patients, 100 had symptomatic neurological complications (SNC) prior to the investigation, 35 had an asymptomatic neurological complications (AsNC), and 148 had a normal cerebral imaging (NoNC). The rate of valve surgery was 43% in the 100 patients with SNC, 77% in the 35 with AsNC, and 54% in the 148 with NoNC (p<0.001). In-hospital mortality was 42% in patients with SNC, 8.6% in patients with AsNC, and 16.9% in patients with NoNC (p<0.001). Among the 135 patients with NC, 95 had an indication for valve surgery (71%), which was performed in 70 of them (mortality 20%) and not performed in 25 (mortality 68%). In a multivariate adjusted analysis of the 135 patients with NC, age, renal failure, septic shock, and IE caused by S. aureus were independently associated with in-hospital and 1-year mortality. In addition SNC was an independent predictor of 1-year mortality.Conclusions The presence of NC was associated with a poorer prognosis when symptomatic. Patients with AsNC had the highest rate of valve surgery and the lowest mortality rate, which suggests a protective role of surgery guided by systematic neuroimaging results

Inferring stabilizing mutations from protein phylogenies : application to influenza hemagglutinin

One selection pressure shaping sequence evolution is the requirement that a protein fold with sufficient stability to perform its biological functions. We present a conceptual framework that explains how this requirement causes the probability that a particular amino acid mutation is fixed during evolution to depend on its effect on protein stability. We mathematically formalize this framework to develop a Bayesian approach for inferring the stability effects of individual mutations from homologous protein sequences of known phylogeny. This approach is able to predict published experimentally measured mutational stability effects (ΔΔG values) with an accuracy that exceeds both a state-of-the-art physicochemical modeling program and the sequence-based consensus approach. As a further test, we use our phylogenetic inference approach to predict stabilizing mutations to influenza hemagglutinin. We introduce these mutations into a temperature-sensitive influenza virus with a defect in its hemagglutinin gene and experimentally demonstrate that some of the mutations allow the virus to grow at higher temperatures. Our work therefore describes a powerful new approach for predicting stabilizing mutations that can be successfully applied even to large, complex proteins such as hemagglutinin. This approach also makes a mathematical link between phylogenetics and experimentally measurable protein properties, potentially paving the way for more accurate analyses of molecular evolution

Expression, regulation and clinical significance of soluble and membrane CD14 receptors in pediatric inflammatory lung diseases

<p>Abstract</p> <p>Background</p> <p>Inflammatory lung diseases are a major morbidity factor in children. Therefore, novel strategies for early detection of inflammatory lung diseases are of high interest. Bacterial lipopolysaccharide (LPS) is recognized via Toll-like receptors and CD14. CD14 exists as a soluble (sCD14) and membrane-associated (mCD14) protein, present on the surface of leukocytes. Previous studies suggest sCD14 as potential marker for inflammatory diseases, but their potential role in pediatric lung diseases remained elusive. Therefore, we examined the expression, regulation and significance of sCD14 and mCD14 in pediatric lung diseases.</p> <p>Methods</p> <p>sCD14 levels were quantified in serum and bronchoalveolar lavage fluid (BALF) of children with infective (pneumonia, cystic fibrosis, CF) and non-infective (asthma) inflammatory lung diseases and healthy control subjects by ELISA. Membrane CD14 expression levels on monocytes in peripheral blood and on alveolar macrophages in BALF were quantified by flow cytometry. <it>In vitro </it>studies were performed to investigate which factors regulate sCD14 release and mCD14 expression.</p> <p>Results</p> <p>sCD14 serum levels were specifically increased in serum of children with pneumonia compared to CF, asthma and control subjects. <it>In vitro</it>, CpG induced the release of sCD14 levels in a protease-independent manner, whereas LPS-mediated mCD14 shedding was prevented by serine protease inhibition.</p> <p>Conclusions</p> <p>This study demonstrates for the first time the expression, regulation and clinical significance of soluble and membrane CD14 receptors in pediatric inflammatory lung diseases and suggests sCD14 as potential marker for pneumonia in children.</p

Expression, regulation and clinical significance of soluble and membrane CD14 receptors in pediatric inflammatory lung diseases

<p>Abstract</p> <p>Background</p> <p>Inflammatory lung diseases are a major morbidity factor in children. Therefore, novel strategies for early detection of inflammatory lung diseases are of high interest. Bacterial lipopolysaccharide (LPS) is recognized via Toll-like receptors and CD14. CD14 exists as a soluble (sCD14) and membrane-associated (mCD14) protein, present on the surface of leukocytes. Previous studies suggest sCD14 as potential marker for inflammatory diseases, but their potential role in pediatric lung diseases remained elusive. Therefore, we examined the expression, regulation and significance of sCD14 and mCD14 in pediatric lung diseases.</p> <p>Methods</p> <p>sCD14 levels were quantified in serum and bronchoalveolar lavage fluid (BALF) of children with infective (pneumonia, cystic fibrosis, CF) and non-infective (asthma) inflammatory lung diseases and healthy control subjects by ELISA. Membrane CD14 expression levels on monocytes in peripheral blood and on alveolar macrophages in BALF were quantified by flow cytometry. <it>In vitro </it>studies were performed to investigate which factors regulate sCD14 release and mCD14 expression.</p> <p>Results</p> <p>sCD14 serum levels were specifically increased in serum of children with pneumonia compared to CF, asthma and control subjects. <it>In vitro</it>, CpG induced the release of sCD14 levels in a protease-independent manner, whereas LPS-mediated mCD14 shedding was prevented by serine protease inhibition.</p> <p>Conclusions</p> <p>This study demonstrates for the first time the expression, regulation and clinical significance of soluble and membrane CD14 receptors in pediatric inflammatory lung diseases and suggests sCD14 as potential marker for pneumonia in children.</p

The Cornella Health Interview Survey Follow-Up (CHIS.FU) Study: design, methods, and response rate

BACKGROUND: The aim of this report is to describe the main characteristics of the design, including response rates, of the Cornella Health Interview Survey Follow-up Study. METHODS: The original cohort consisted of 2,500 subjects (1,263 women and 1,237 men) interviewed as part of the 1994 Cornella Health Interview Study. A record linkage to update the address and vital status of the cohort members was carried out using, first a deterministic method, and secondly a probabilistic one, based on each subject's first name and surnames. Subsequently, we attempted to locate the cohort members to conduct the phone follow-up interviews. A pilot study was carried out to test the overall feasibility and to modify some procedures before the field work began. RESULTS: After record linkage, 2,468 (98.7%) subjects were successfully traced. Of these, 91 (3.6%) were deceased, 259 (10.3%) had moved to other towns, and 50 (2.0%) had neither renewed their last municipal census documents nor declared having moved. After using different strategies to track and to retain cohort members, we traced 92% of the CHIS participants. From them, 1,605 subjects answered the follow-up questionnaire. CONCLUSION: The computerized record linkage maximized the success of the follow-up that was carried out 7 years after the baseline interview. The pilot study was useful to increase the efficiency in tracing and interviewing the respondents