A Genetic Screen for Attenuated Growth Identifies Genes Crucial for Intraerythrocytic Development of Plasmodium falciparum

A majority of the Plasmodium falciparum genome codes for genes with unknown functions, which presents a major challenge to understanding the parasite's biology. Large-scale functional analysis of the parasite genome is essential to pave the way for novel therapeutic intervention strategies against the disease and yet difficulties in genetic manipulation of this deadly human malaria parasite have been a major hindrance for functional analysis of its genome. Here, we used a forward functional genomic approach to study P. falciparum and identify genes important for optimal parasite development in the disease-causing, intraerythrocytic stages. We analyzed 123 piggyBac insertion mutants of P. falciparum for proliferation efficiency in the intraerythrocytic stages, in vitro. Almost 50% of the analyzed mutants showed significant reduction in proliferation efficiency, with 20% displaying severe defects. Functional categorization of genes in the severely attenuated mutants revealed significant enrichment for RNA binding proteins, suggesting the significance of post-transcriptional gene regulation in parasite development and emphasizing its importance as an antimalarial target. This study demonstrates the feasibility of much needed forward genetics approaches for P. falciparum to better characterize its genome and accelerate drug and vaccine development

GERMLINE GAIN-OF-FUNCTION MUTATIONS of ALK DISRUPT CENTRAL NERVOUS SYSTEM DEVELOPMENT

International audienceNeuroblastoma (NB) is a frequent embryonal tumour of sympathetic ganglia and adrenals with extremely variable outcome. Recently, somatic amplification and gain-of-function mutations of the anaplastic lymphoma receptor tyrosine kinase (ALK, MIM 105590) gene, either somatic or germline, were identified in a significant proportion of NB cases. Here we report a novel syndromic presentation associating congenital NB with severe encephalopathy and abnormal shape of the brainstem on brain MRI in two unrelated sporadic cases harbouring de novo, germline, heterozygous ALK gene mutations. Both mutations are gain-of-function mutations that have been reported in NB and NB cell lines. These observations further illustrate the role of oncogenes in both tumour predisposition and normal development, and shed light on the pleiotropic and activity-dependent role of ALK in humans. More generally, missing germline mutations relative to the spectrum of somatic mutations reported for a given oncogene may be a reflection of severe effects during embryonic development, and may prompt mutation screening in patients with extreme phenotypes

Biological Activities of Polyphenols from Grapes

The dietary consumption of grape and its products is associated with a lower incidence of degenerative diseases such as cardiovascular disease and certain types of cancers. Most recent interest has focused on the bioactive phenolic compounds in grape. Anthocyanins, flavanols, flavonols and resveratrol are the most important grape polyphenols because they possess many biological activities, such as antioxidant, cardioprotective, anticancer, anti-inflammation, antiaging and antimicrobial properties. This review summarizes current knowledge on the bioactivities of grape phenolics. The extraction, isolation and identification methods of polyphenols from grape as well as their bioavailability and potential toxicity also are included

Neuronal Oscillations Enhance Stimulus Discrimination by Ensuring Action Potential Precision

Although oscillations in membrane potential are a prominent feature of sensory, motor, and cognitive function, their precise role in signal processing remains elusive. Here we show, using a combination of in vivo, in vitro, and theoretical approaches, that both synaptically and intrinsically generated membrane potential oscillations dramatically improve action potential (AP) precision by removing the membrane potential variance associated with jitter-accumulating trains of APs. This increased AP precision occurred irrespective of cell type and—at oscillation frequencies ranging from 3 to 65 Hz—permitted accurate discernment of up to 1,000 different stimuli. At low oscillation frequencies, stimulus discrimination showed a clear phase dependence whereby inputs arriving during the trough and the early rising phase of an oscillation cycle were most robustly discriminated. Thus, by ensuring AP precision, membrane potential oscillations dramatically enhance the discriminatory capabilities of individual neurons and networks of cells and provide one attractive explanation for their abundance in neurophysiological systems

Eclipse in the Dark Years: Pick-up Flights, Routes of Resistance and the Free French

This article charts the importance of clandestine flights from Britain into occupied France during the Second World War as a route of resistance. These pick-up flights were coordinated from London and were an example of the inter-allied cooperation and Franco-British negotiation that took place between the BCRA, SIS, and SOE. The flights allowed General Charles de Gaulle to hold court with the leaders of resistance networks, smoothing problems on the route to a unified resistance council. Likewise, they allowed him to build bridges between vying factions in France and in London, drawing together the movements under his command and personalising the narrative of resistance. From busy London restaurants and family homes via secret flights to darkened fields in Occupied France, the route of these transfers shaped the character of resistance. This article draws out the personal interactions and connections that underpinned these networks and describes the enduring connections of this route of resistance, starting with the commemoration of Jean Moulin's crash landing at RAF Tangmere, the forward station for many of these flights

Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

Funder: NCI U24CA211006Abstract: The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts

Pleurésies purulentes communautaires de l'enfant et streptocoque A

Objectif : décrire les pleurésies purulentes communautaires de l'enfant en unité de réanimation pédiatrique (URP), et la place du streptocoque A dans ces pathologies. Patients et méthodes : soixante patients ont été hospitalisés en URP pour pleurésie purulente communautaire de 1997 à 2002 en Ile-de-France. Leurs dossiers ont été étudiés de façon rétrospective à l'aide d'une grille d'analyse regroupant des données cliniques, microbiologiques et thérapeutiques. Résultats : l'incidence était plus élevée en 2001-2002 que durant la période 1997-2000. Le taux de mortalité était de 1,7% (n=1). Un traitement par anti-inflammatoires non stéroïdiens était suivi avant l'admission dans 58% des cas renseignés. Les principaux germes retrouvés étaient le pneumocoque (33%), le staphylocoque doré (25%), le streptocoque A (22%) ; dans 18% des cas aucune bactérie n'était identifiée. Un drainage pleural était pratiqué dans 82% des cas, dont un tiers par technique chirurgicale. L'évolution respiratoire était favorable avec un recul de plus de deux ans. Conclusion : le nombre d'enfants admis en URP pour pleurésie purulente communautaire a augmenté entre 1997 et 2002. Le streptocoque A est devenu un germe fréquemment responsable. Ces modifications pourraient résulter de facteurs favorisants microbiologiques et médicamenteux telle l'utilisation d'anti-inflammatoires non stéroïdiens. Les indications et les modalités du drainage pleural restent controverséesTo describe the community-acquired pleural empyema of children in pediatric intensive care units (PICU), and the place of group A streptococcus (GAS) in these diseases. Sixty patients have been admitted in PICU for cummunity-acquired pleural empyema from 1997 to 2002 in Ile-de-France. There medical records have been retrospectively studied and clinical, microbiologic and therapeutic data collected. The incidence was higher in 2001-2002 than during the 1997-2000 period. The rate of mortality was 1,7 % (n=1). Nonsteroidal antiinflammatory agents (NSAI) were given before admission to 58 % of children whose case is known. The main bacteria found were pneumococcus (33 %)n staphylococcus (25 %), GAS (22 %) ; no germ was identified in 18 % of cases. Pleural evacuation was perfomed in 82 % of cases, one third of which by surgical method. Respiratory outcome was favourable after more than 2 years. The number of children admitted in PICU for community-acquired pleural empyema has increased between 1997 and 2002. GAS has become a frequently responsible germ of this disease. These changes could result from microbiologic favoring factors, and drugs'use like NSAI. The choice of modalities of pleural evacuation is still controversial.PARIS12-CRETEIL BU Médecine (940282101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Convulsions aux urgences pédiatriques de deux hôpitaux de La Réunion (St Denis et St Paul) (épidémiologie et prise en charge)

BORDEAUX2-BU Santé (330632101) / SudocSudocFranceF

Sketching techniques for very large matrix factorization

International audienc

Optimal level of nasal continuous positive airway pressure in severe viral bronchiolitis

Abstract Purpose: To determine the optimal level of nasal continuous positive airway pressure (nCPAP) in infants with severe hypercapnic viral bronchiolitis as assessed by the maximal unloading of the respiratory muscles and improvement of breathing pattern and gas exchange. Methods: A prospective physiological study in a tertiary paediatric intensive care unit (PICU). Breathing pattern, gas exchange, intrinsic end expiratory pressure (PEEPi) and respiratory muscle effort were measured in ten infants with severe hypercapnic viral bronchiolitis during spontaneous breathing (SB) and three increasing levels of nCPAP. Results: During SB, median PEEPi was 6 cmH 2 O (range 3.9-9.2 cmH 2 O), median respiratory rate was 78 breaths/min (range 41-96), median inspiratory time/total duty cycle (T i /T tot ) was 0.45 (range 0.40-0.48) and transcutaneous carbon dioxide pressure (P tc CO 2 ) was 61.5 mmHg (range 50-78). In all the infants, an nCPAP level of 7 cmH 2 O was associated with the greatest reduction in respiratory effort with a mean reduction in oesophageal and diaphragmatic pressure swings of 48 and 46%, respectively, and of the oesophageal and diaphragmatic pressure time product of 49 and 56%, respectively. During nCPAP, median respiratory rate decreased to 56 breaths/min (range 39-108, p \ 0.05), median T i /T tot decreased to 0.40 (range 0.34-0.44, p \ 0.50) and P tc CO 2 decreased to 49 mmHg (range 35-65, p \ 0.05). Only one infant with associated bacterial pneumonia required intubation and all the infants were discharged alive from the PICU after a median stay of 5.5 (range 3-27 days). Conclusion: In infants with hypercapnic respiratory failure due to acute viral bronchiolitis, an nCPAP level of 7 cmH 2 O is associated with the greatest unloading of the respiratory muscles and improvement of breathing pattern, as well as a favourable short-term clinical outcome. Keywords Nasal continuous positive airway pressure Á Intrinsic positive end expiratory pressure Á Bronchiolitis Á Work of breathing Á Childre