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It is well described that certain group of patients do not display the typical symptoms of myocardial infarction (MI). Elderly patients, diabetics and those with previous coronary artery bypass graft surgery are at high risk for silent MI. The diagnosis of Acute MI in the emergency room (ER) is mainly based on the electrocardiogram (EKG) findings of ST elevations or new onset left bundle branch block which is supported by the clinical presentation and positive biomarkers when present. The diagnoses can sometimes become challenging when the patient is asymptomatic and has coincidental finding of hyperkalemia with diffuse ST segment elevations simulating that seen with electrolyte disturbance. Despite the well known pseudoinfarction pattern of hyperkalemia, acute MI should be ruled out first. A high index of suspicion is needed, especially in high risk patients. We think that in rare clinical situation when the diagnosis is in doubt, MI should be ruled out, as time has a high impact on patient mortality. An urgent bedside echocardiogram is very beneficial in excluding regional wall motion abnormalities and preventing any delay in destination therapy for transmural MI. We present a 67 years old female with history of diabetes and chronic kidney disease sent by her nephrologist to the ER for severe hyperkalemia (Potassium 7.2 milliequivalent/L). She was found to have ST elevations on EKG despite having no chest pain or distress. On cardiac catheterization she had a total occlusion of the proximal left circumflex artery, with a filling defect consistent with large thrombus. [ABSTRACT FROM AUTHOR] more...

Purpose Acute pericarditis is rather frequent. Annual incidence is estimated to 27.7 new cases per 100,000 inhabitants in Europe. About 5% of all non-ischemic chest pains admitted at emergencies could be pericarditis. Most of the patients are young patients, with a significant cost to society, particularly as regards hospitalizations. Indeed, pericarditis represents 1% of all hospitalizations in department of cardiology. It could be very interesting if clinical presentation and especially heart rate could help predict duration of hospitalizations. Methods Between March 2007 and February 2010, we conducted a retrospective study concerning all patients admitted in our center for acute pericarditis. Diagnosis criteria included 2 among the 4 following: typical chest pain, friction rub, pericardial effusion on echocardiography, or typical ECG findings. We evaluated hospital events (heart failure, acute pains, death) and biology during hospitalization (CRP on admission, on days 1, 2, 3, and especially peak). At one month, clinical events were recorded through phone calls when not noticed in clinical settings. Results We included 73 patients. Mean age was 41.0 y (CI 95% 37.2-44.8) and mean hospitalization duration was 3.5 d (2.5-4.5). Heart rate on admission was 88 bpm (83.6-92.4) and 71.8 bpm (68.9-74.7) on discharge. CRP peak was strongly correlated with heart rate (r=0.54; p<0.0001) and with hospitalization duration (r=0.8; p=0.007). Finally, we found a positive correlation between heart rate on admission and duration of hospitalizations (r=0,226; p<0.06). Fever was scarcely observed (21%), and was not correlated with heart rate and with CRP. Conclusion In acute pericarditis, cardiac frequency at admission is correlated with hospitalization duration, and could be a new prognostic marker. This point deserves to be explored, in order to reduce hospitalization duration. [ABSTRACT FROM AUTHOR] more...

Introduction Rest is usually recommended in acute pericarditis, as it could help to lower heart rate (HR) and contribute to limit "mechanical inflammation". Whether HR on admission could be correlated and perhaps participate to inflammation has not been reported. Methods Between March 2007 and February 2010, we conducted a retrospective study on all patients admitted in our center for acute pericarditis. Diagnosis criteria included 2 among the following: typical chest pain, friction rub, pericardial effusion on cardiac echography, or typical ECG findings. Primary endpoint was biology: CRP on admission, on days 1, 2, 3, and especially peak. We evaluated also recurrences and clinical events during hospitalization and at one month. Results We included 73 patients. Median age was 38.0 y (CI 25-75% 28.0-51.0) and median hospitalization duration was 2.0 d (1.5-3.0). 27% of the patients presented pericardial effusion. Heart rate on admission was 88.0 bpm (CI 25-75%: 76.0-100.0) and on discharge 72.0 (65.0-80.0)). Heart rate on admission was significantly correlated with CRP on admission (r=0.34, n=69; p=0.004), CRP peak (r=0.54; n=61; p<0.0001), CRP on discharge (r=0.32; p=0.021) and temperature on admission (r=0.40; n=39; p=0.01). Multivariate analysis showed that HR on admission is associated with an elevated CRP peak, independently of temperature on admission. Fever was scarcely observed (19.5%), and was neither correlated to HR nor CRP, after multivariate analysis. Conclusion In acute pericarditis, HR on admission is independently correlated with CRP levels. These observations could suggest a link between HR and pericardial inflammation. [ABSTRACT FROM AUTHOR] more...

Background: Kidney transplant recipients are currently treated with nonspecific immunosuppressants that cause severe systemic side effects. Current immunosuppressants were developed based on their effect on T-cell activation rather than the underlying mechanisms driving alloimmune responses. Thus, understanding the role of the intragraft microenvironment will help us identify more directed therapies with lower side effects., Methods: To understand the role of the alloimmune response and the intragraft microenvironment in cellular rejection progression, we conducted a Single nucleus RNA sequencing (snRNA-seq) on one human non-rejecting kidney allograft sample, one borderline sample, and T-cell mediated rejection (TCMR) sample (Banff IIa). We studied the differential gene expression and enriched pathways in different conditions, in addition to ligand-receptor (L-R) interactions., Results: Pathway analysis of T-cells in borderline sample showed enrichment for allograft rejection pathway, suggesting that the borderline sample reflects an early rejection. Hence, this allows for studying the early stages of cellular rejection. Moreover, we showed that focal adhesion (FA), IFNg pathways, and endomucin (EMCN) were significantly upregulated in endothelial cell clusters (ECs) of borderline compared to ECs TCMR. Furthermore, we found that pericytes in TCMR seem to favor endothelial permeability compared to borderline. Similarly, T-cells interaction with ECs in borderline differs from TCMR by involving DAMPS-TLRs interactions., Conclusion: Our data revealed novel roles of T-cells, ECs, and pericytes in cellular rejection progression, providing new clues on the pathophysiology of allograft rejection., Competing Interests: KV is employed by Q32 Bio Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Halawi, El Kurdi, Vernon, Solhjou, Choi, Saad, Younis, Elfekih, Mohammed, Deban, Weins, Abdi, Riella, De Serres, Cravedi, Greka, Khoueiry and Azzi.) more...

Acute gastroenteritis (AGE) is associated with significant global morbidity and mortality, especially among children under five years of age. Viruses are well established as etiologic agents of gastroenteritis since they are the most common pathogens that contribute to the disease burden in developing countries. Despite the advances in molecular diagnosis, a substantial proportion of AGE etiology remain unresolved. We implemented a viral metagenomics pipeline to determine the potential viral etiology associated with AGE among children under the age of five years in Qatar with undiagnosed etiology. Following enriching for the viral genome, ∼1.3 billion sequences were generated from 89 stool specimens using the Illumina HiSeq platform, of which 7% were mapped to viral genomes. Human viruses were detected in 34 specimens (38.2%); 14 were adenovirus, nine coxsackievirus A16, five rotavirus (G9P[8] and G4P[8]), four norovirus (GII), one influenza A virus (H3), and one respiratory syncytial virus A (RSVA). In conclusion, the viral metagenomics approach is useful for determining AGE's etiology when routine molecular diagnostic assays fail., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.) more...

Cystic fibrosis is the most common life-limiting autosomal recessive disease in western countries with an incidence of 1:2500 in United States and 1:1000 in some European countries. Similar incidences were noted for the Middle East with variations from 1 in 2560 to 1 in 15,876 according to the degree of consanguinity. This is a preliminary systematic study that aims to assess the incidence and carrier rate of cystic fibrosis in the Middle Eastern Lebanese population; known for a high frequency of consanguinity. One hundred thirteen DNA samples were collected from neonatal blood cards obtained from newborns to healthy unrelated families with no previous history of Cystic fibrosis. Screening for Cystic Fibrosis-causing pathogenic variants was performed using next generation sequencing, and 17 different single nucleotide variants were detected, including six pathogenic and likely pathogenic. 5.5%-7% newborns were found to be carriers of a variant strongly suggestive of pathogenicity and comparable to published literature worldwide. This pilot analysis highlights the challenging interpretation of CFTR variants in a country underrepresented by large ethnic population analyses, and stresses the importance of premarital screening programs for Cystic fibrosis., (© 2021 John Wiley & Sons Ltd/University College London.) more...

Motivation: Identifying histone tail modifications using ChIP-seq is commonly used in time-series experiments in development and disease. These assays, however, cover specific time-points leaving intermediate or early stages with missing information. Although several machine learning methods were developed to predict histone marks, none exploited the dependence that exists in time-series experiments between data generated at specific time-points to extrapolate these findings to time-points where data cannot be generated for lack or scarcity of materials (i.e. early developmental stages)., Results: Here, we train a deep learning model named TempoMAGE, to predict the presence or absence of H3K27ac in open chromatin regions by integrating information from sequence, gene expression, chromatin accessibility and the estimated change in H3K27ac state from a reference time-point. We show that adding reference time-point information systematically improves the overall model's performance. In addition, sequence signatures extracted from our method were exclusive to the training dataset indicating that our model learned data-specific features. As an application, TempoMAGE was able to predict the activity of enhancers from pre-validated in-vivo dataset highlighting its ability to be used for functional annotation of putative enhancers., Availability and Implementation: TempoMAGE is freely available through GitHub at https://github.com/pkhoueiry/TempoMAGE., Supplementary Information: Supplementary data are available at Bioinformatics online., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.) more...

Introduction: Glioblastoma (GBM) is an aggressive brain tumor associated with high degree of resistance to treatment. Given its heterogeneity, it is important to understand the molecular landscape of this tumor for the development of more effective therapies. Because of the different genetic profiles of patients with GBM, we sought to identify genetic variants in Lebanese patients with GBM (LEB-GBM) and compare our findings to those in the Cancer Genome Atlas (TCGA)., Methods: We performed whole exome sequencing (WES) to identify somatic variants in a cohort of 60 patient-derived GBM samples. We focused our analysis on 50 commonly mutated GBM candidate genes and compared mutation signatures between our population and publicly available GBM data from TCGA. We also cross-tabulated biological covariates to assess for associations with overall survival, time to recurrence and follow-up duration., Results: We included 60 patient-derived GBM samples from 37 males and 23 females, with age ranging from 3 to 80 years (mean and median age at diagnosis were 51 and 56, respectively). Recurrent tumor formation was present in 94.8% of patients (n = 55/58). After filtering, we identified 360 somatic variants from 60 GBM patient samples. After filtering, we identified 360 somatic variants from 60 GBM patient samples. Most frequently mutated genes in our samples included ATRX, PCDHX11, PTEN, TP53, NF1, EGFR, PIK3CA, and SCN9A. Mutations in NLRP5 were associated with decreased overall survival among the Lebanese GBM cohort (p = 0.002). Mutations in NLRP5 were associated with decreased overall survival among the Lebanese GBM cohort (p = 0.002). EGFR and NF1 mutations were associated with the frontal lobe and temporal lobe in our LEB-GBM cohort, respectively., Conclusions: Our WES analysis confirmed the similarity in mutation signature of the LEB-GBM population with TCGA cohorts. It showed that 1 out of the 50 commonly GBM candidate gene mutations is associated with decreased overall survival among the Lebanese cohort. This study also highlights the need for studies with larger sample sizes to inform clinicians for better prognostication and management of Lebanese patients with GBM., Competing Interests: The authors have declared that no competing interests exist. more...

Objectives: To determine the prevalence and prognostic value of MGMT promoter methylation and IDH1 mutation in glioblastoma multiforme (GBM) patients from the Middle East., Patients and Methods: Records of patients diagnosed between 2003 and 2015 were reviewed. MGMT promoter methylation was measured using methylation-specific polymerase chain reaction and IDH-1 mutation was reported. The primary endpoint was overall survival (OS)., Results: A total of 110 patients were included. The median age was 51 years and 71 patients (64.5%) were males. The median diameter of GBM was 4.6 cm and 29 patients (26.4%) had multifocal disease. Gross total resection was achieved in 38 patients (24.9%). All patients received adjuvant radiation therapy, and 96 patients (91.4%) received concomitant temozolomide. At a median follow up of 13.6 months, the median OS was 17.2 months, and the OS at 1 and 2 years were 71.6% and 34.8%, respectively. On multivariate analysis, age at diagnosis (HR 1.019; P = 0.044) and multifocality (HR 2.373; P = 0.001) were the only independent prognostic variables. MGMT promoter methylation was found in 28.2% of patients but did not significantly correlate with survival (HR 1.160; P = 0.635). IDH-1 mutation was found in 10% of patients was associated with a non-significant trend for survival improvement (HR 0.502; P = 0.151)., Conclusion: Patients with GBM from the Middle East have adequate survival outcomes when given the optimal treatment. In our patient population, MGMT promoter methylation did not seem to correlate with outcomes, but patients with IDH1 mutation had numerically higher survival outcomes., (Copyright © 2019 Elsevier B.V. All rights reserved.) more...

Transcription factor (TF) binding is determined by sequence as well as chromatin accessibility. Although the role of accessibility in shaping TF-binding landscapes is well recorded, its role in evolutionary divergence of TF binding, which in turn can alter cis-regulatory activities, is not well understood. In this work, we studied the evolution of genome-wide binding landscapes of five major TFs in the core network of mesoderm specification, between Drosophila melanogaster and Drosophila virilis, and examined its relationship to accessibility and sequence-level changes. We generated chromatin accessibility data from three important stages of embryogenesis in both Drosophila melanogaster and Drosophila virilis and recorded conservation and divergence patterns. We then used multivariable models to correlate accessibility and sequence changes to TF-binding divergence. We found that accessibility changes can in some cases, for example, for the master regulator Twist and for earlier developmental stages, more accurately predict binding change than is possible using TF-binding motif changes between orthologous enhancers. Accessibility changes also explain a significant portion of the codivergence of TF pairs. We noted that accessibility and motif changes offer complementary views of the evolution of TF binding and developed a combined model that captures the evolutionary data much more accurately than either view alone. Finally, we trained machine learning models to predict enhancer activity from TF binding and used these functional models to argue that motif and accessibility-based predictors of TF-binding change can substitute for experimentally measured binding change, for the purpose of predicting evolutionary changes in enhancer activity., (© The Author(s) 2019. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.) more...

Background: The overall 5-year survival of lung cancer remains dismal despite the current treatment regimens. Testing for driver mutations has become routine practice for oncologists due to the presence of targeted therapy readily available for patients. Deep targeted sequencing through next generation sequencing (NGS) is an adequate methodology to detect mutations at multi-genetic levels. The molecular pathology of non-small cell lung cancer (NSCLC) is poorly understood in the Middle East and, to date, no other reports have been published on deep targeted sequencing of lung adenocarcinoma (LUAD) tissues., Methods: Deep targeted sequencing using TruSeq Amplicon Cancer panel of 48 genes was performed on 85 formalin-fixed paraffin-embedded tissues from patients with LUAD who were treatment-naive at the time of the collection. Variants with an allele frequency higher than 10% were retained., Results: Variant calling identified a total of 2,455 variants of which missense mutations were the most frequent (75.6%). All of our samples showed at least one mutation in one of the 10 most commonly mutated genes with FLT3 being the gene with the highest mutation rate (67%). TP53, KRAS and STK11 were the second, third and fourth most commonly mutated genes, respectively while EGFR mutation rate reached 22.4%., Conclusions: To the best of our knowledge, this is the first hot spot profiling study on patients from this area. The frequencies of mutated genes presented in our study showed similarity to other reported outcomes. At least one mutation was detected in our cohort of LUAD., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare. more...

Sequence variation within enhancers plays a major role in both evolution and disease, yet its functional impact on transcription factor (TF) occupancy and enhancer activity remains poorly understood. Here, we assayed the binding of five essential TFs over multiple stages of embryogenesis in two distant Drosophila species (with 1.4 substitutions per neutral site), identifying thousands of orthologous enhancers with conserved or diverged combinatorial occupancy. We used these binding signatures to dissect two properties of developmental enhancers: (1) potential TF cooperativity, using signatures of co-associations and co-divergence in TF occupancy. This revealed conserved combinatorial binding despite sequence divergence, suggesting protein-protein interactions sustain conserved collective occupancy. (2) Enhancer in-vivo activity, revealing orthologous enhancers with conserved activity despite divergence in TF occupancy. Taken together, we identify enhancers with diverged motifs yet conserved occupancy and others with diverged occupancy yet conserved activity, emphasising the need to functionally measure the effect of divergence on enhancer activity. more...

Embryogenesis is remarkably robust to segregating mutations and environmental variation; under a range of conditions, embryos of a given species develop into stereotypically patterned organisms. Such robustness is thought to be conferred, in part, through elements within regulatory networks that perform similar, redundant tasks. Redundant enhancers (or "shadow" enhancers), for example, can confer precision and robustness to gene expression, at least at individual, well-studied loci. However, the extent to which enhancer redundancy exists and can thereby have a major impact on developmental robustness remains unknown. Here, we systematically assessed this, identifying over 1,000 predicted shadow enhancers during Drosophila mesoderm development. The activity of 23 elements, associated with five genes, was examined in transgenic embryos, while natural structural variation among individuals was used to assess their ability to buffer against genetic variation. Our results reveal three clear properties of enhancer redundancy within developmental systems. First, it is much more pervasive than previously anticipated, with 64% of loci examined having shadow enhancers. Their spatial redundancy is often partial in nature, while the non-overlapping function may explain why these enhancers are maintained within a population. Second, over 70% of loci do not follow the simple situation of having only two shadow enhancers-often there are three (rols), four (CadN and ade5), or five (Traf1), at least one of which can be deleted with no obvious phenotypic effects. Third, although shadow enhancers can buffer variation, patterns of segregating variation suggest that they play a more complex role in development than generally considered., (Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.) more...

Genome-wide resources, such as collections of cDNA clones encoding for complete proteins (full-ORF clones), are crucial tools for studying the evolution of gene function and genetic interactions. Non-model organisms, in particular marine organisms, provide a rich source of functional diversity. Marine organism genomes are, however, frequently highly polymorphic and encode proteins that diverge significantly from those of well-annotated model genomes. The construction of full-ORF clone collections from non-model organisms is hindered by the difficulty of predicting accurately the N-terminal ends of proteins, and distinguishing recent paralogs from highly polymorphic alleles. We report a computational strategy that overcomes these difficulties, and allows for accurate gene level clustering of transcript data followed by the automated identification of full-ORFs with correct 5'- and 3'-ends. It is robust to polymorphism, includes paralog calling and does not require evolutionary proximity to well annotated model organisms. We developed this pipeline for the ascidian Ciona intestinalis, a highly polymorphic member of the divergent sister group of the vertebrates, emerging as a powerful model organism to study chordate gene function, Gene Regulatory Networks and molecular mechanisms underlying human pathologies. Using this pipeline we have generated the first full-ORF collection for a highly polymorphic marine invertebrate. It contains 19,163 full-ORF cDNA clones covering 60% of Ciona coding genes, and full-ORF orthologs for approximately half of curated human disease-associated genes., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.) more...

Introduction and Objective: Drug-induced thrombocytopenia is a common adverse effect reported in the literature. Typically patients present with a low platelet count with signs and symptoms ranging from bruising to bleeding, and major organ damage. Penicillin-induced thrombocytopenia previously reported in the literature is explained primarily through the hapten-dependent antibody process. The goal of this report is to present a case of an amoxicillin/clavulanic acid-induced thrombocytopenia., Case Presentation: A 23-year-old male presented to the emergency department with bruises on his arms and legs after completing a full course of amoxicillin/clavulanic acid of 625 mg twice a day for 5 days for tonsillitis. After several tests, the patient was diagnosed with thrombocytopenia induced by amoxicillin/clavulanic acid. The patient was treated with a corticosteroids taper regimen for 3 weeks. He was discharged after 3 days of inpatient treatment with instructions to avoid physical activity for 2 weeks. Two weeks post discharge, the follow-up showed that the platelet count had increased., Discussion: Penicillin-induced thrombocytopenia has been previously reported in the inpatient setting where bleeding was observed. However, the patient in this case report presented with bruises on his arms and legs. The diagnosis was made by the process of elimination; not all possible tests were conducted. The patient was prescribed corticosteroids that are not indicated for drug-induced thrombocytopenia. The Naranjo scale showed that this is a probable adverse event of amoxicillin/clavulanic acid., Conclusion: This is a unique case where amoxicillin/clavulanic acid was reported to be a probable cause of thrombocytopenia in an outpatient setting without signs of bleeding and without concomitant medications. more...

Objectives: Hospital surveillance systems have been established to monitor occupational blood exposures. We compare short-term monitoring with long-term monitoring of data analysis over 11 years and 21 institutions to identify variations in the number of reported exposures., Methods: Short-term monitoring examines the current number of exposures compared to their average over previous years. Long-term monitoring detects trends over several years by various exposure characteristics (place, staff, procedure, etc) through estimating rates of change and using the best linear unbiased predictors (BLUPs) to prevent artefactual trends due to the many categories for each characteristic. Graphical representations of estimated rates help detect change and differences in rates of change., Results: Annual monitoring allowed detection of significant changes in the number of reported exposures. Long-term monitoring identified moderate trends over time. The BLUP corrected the estimate of each specific annual rate of change and allowed all other rates to reduce the random variability around the mean change for more specificity. League tables showed significant increases or decreases compared to no change. League tables for two-by-two comparisons allowed reliable comparisons between estimates of the rates of change, although with spurious ranking. Funnel plots enabled quick detection of changes in trends within specified confidence intervals. Long-term trends agreed with the dominant type of annual changes over the 11&emsp14;years but were not as sensitive., Conclusions: The two methods have different uses. Both are helpful for assessing short-term sudden and long-term minor changes in number of exposures, possibly reflecting the success or otherwise of introducing specific safety devices or guidelines. more...

Developmental biology aims to understand how the dynamics of embryonic shapes and organ functions are encoded in linear DNA molecules. Thanks to recent progress in genomics and imaging technologies, systemic approaches are now used in parallel with small-scale studies to establish links between genomic information and phenotypes, often described at the subcellular level. Current model organism databases, however, do not integrate heterogeneous data sets at different scales into a global view of the developmental program. Here, we present a novel, generic digital system, NISEED, and its implementation, ANISEED, to ascidians, which are invertebrate chordates suitable for developmental systems biology approaches. ANISEED hosts an unprecedented combination of anatomical and molecular data on ascidian development. This includes the first detailed anatomical ontologies for these embryos, and quantitative geometrical descriptions of developing cells obtained from reconstructed three-dimensional (3D) embryos up to the gastrula stages. Fully annotated gene model sets are linked to 30,000 high-resolution spatial gene expression patterns in wild-type and experimentally manipulated conditions and to 528 experimentally validated cis-regulatory regions imported from specialized databases or extracted from 160 literature articles. This highly structured data set can be explored via a Developmental Browser, a Genome Browser, and a 3D Virtual Embryo module. We show how integration of heterogeneous data in ANISEED can provide a system-level understanding of the developmental program through the automatic inference of gene regulatory interactions, the identification of inducing signals, and the discovery and explanation of novel asymmetric divisions. more...

Background: Transcription initiation is controlled by cis-regulatory modules. Although these modules are usually made of clusters of short transcription factor binding sites, a small minority of such clusters in the genome have cis-regulatory activity. This paradox is currently unsolved., Results: To identify what discriminates active from inactive clusters, we focused our attention on short topologically unconstrained clusters of two ETS and two GATA binding sites, similar to the early neural enhancer of Ciona intestinalis Otx. We first computationally identified 55 such clusters, conserved between the two Ciona genomes. In vivo assay of the activity of 19 hits identified three novel early neural enhancers, all located next to genes coexpressed with Otx. Optimization of ETS and GATA binding sites was not always sufficient to confer activity to inactive clusters. Rather, a dinucleotide sequence code associated to nucleosome depletion showed a robust correlation with enhancer potential. Identification of a large collection of Ciona regulatory regions revealed that predicted nucleosome depletion constitutes a general signature of Ciona enhancers, which is conserved between orthologous loci in the two Ciona genomes and which partitions conserved noncoding sequences into a major nucleosome-bound fraction and a minor nucleosome-free fraction with higher cis-regulatory potential. We also found this signature in a large fraction of short Drosophila cis-regulatory modules., Conclusion: This study indicates that a sequence-based dinucleotide signature, previously associated with nucleosome depletion and independent of transcription factor binding sites, contributes to the definition of a local cis-regulatory potential in two metazoa, Ciona intestinalis and Drosophila melanogaster., ((c) 2010 Elsevier Ltd. All rights reserved.) more...

Background: Carbonyl derivatives are mainly formed by direct metal-catalysed oxidation (MCO) attacks on the amino-acid side chains of proline, arginine, lysine and threonine residues. For reasons unknown, only some proteins are prone to carbonylation., Methodology/principal Findings: we used mass spectrometry analysis to identify carbonylated sites in: BSA that had undergone in vitro MCO, and 23 carbonylated proteins in Escherichia coli. The presence of a carbonylated site rendered the neighbouring carbonylatable site more prone to carbonylation. Most carbonylated sites were present within hot spots of carbonylation. These observations led us to suggest rules for identifying sites more prone to carbonylation. We used these rules to design an in silico model (available at http://www.lcb.cnrs-mrs.fr/CSPD/), allowing an effective and accurate prediction of sites and of proteins more prone to carbonylation in the E. coli proteome., Conclusions/significance: We observed that proteins evolve to either selectively maintain or lose predicted hot spots of carbonylation depending on their biological function. As our predictive model also allows efficient detection of carbonylated proteins in Bacillus subtilis, we believe that our model may be extended to direct MCO attacks in all organisms. more...

Anteroposterior patterning of the ectoderm in the invertebrate chordate Ciona intestinalis first relies on key zygotic activators, such as FoxA, and later on the coordinated responses to inducing signals from the underlying mesendoderm. Here, we focus on a mechanism of coordination of these responses by looking at the cis-regulatory logics of Ci-Rora and Ci-Rorb, which are coding for putative non-canonical transmembrane Wnt receptors, and are present in tandem along the C. intestinalis chromosome 08q. We showed that during cleavage stages, both Ci-Rora and Ci-Rorb genes are initially expressed in all blastomeres of the anterior ectoderm (a-line), as sFRP1/5 (Lamy, C., Rothbächer, U., Caillol, D., Lemaire, P., 2006. Ci-FoxA-a is the earliest zygotic determinant of the ascidian anterior ectoderm and directly activates Ci-sFRP1/5. Development 133, 2835-2844.). We then carried out a functional analysis of cis-regulatory regions and showed that both genes have elements enriched in Ci-FoxA-a binding sites. We dissected one of these early enhancers, and showed that it is directly activated by Ci-FoxA-a, as one sFRP1/5 cis-regulatory element. We also showed that although FoxA binding sites are abundant in genomes, dense clusters of these sites are found upstream from very few genes, and have a high predictive value of a-line expression. These data indicate an important role for FoxA in anterior specification, via the transcriptional regulation of target genes belonging to various signalling pathways. more...