Mitochondrial phosphoenolpyruvate carboxykinase (PEPCK-M) and serine biosynthetic pathway genes are co-ordinately increased during anabolic agent-induced skeletal muscle growth

We aimed to identify novel molecular mechanisms for muscle growth during administration of anabolic agents. Growing pigs (Duroc/(Landrace/Large-White)) were administered Ractopamine (a beta-adrenergic agonist; BA; 20ppm in feed) or Reporcin (recombinant growth hormone; GH; 10mg/48hours injected) and compared to a control cohort (feed only; no injections) over a 27-day time course (1, 3, 7, 13 or 27-days). Longissimus Dorsi muscle gene expression was analyzed using Agilent porcine transcriptome microarrays and clusters of genes displaying similar expression profiles were identified using a modified maSigPro clustering algorithm. Anabolic agents increased carcass (p=0.002) and muscle weights (Vastus Lateralis: p<0.001; Semitendinosus: p=0.075). Skeletal muscle mRNA expression of serine/one-carbon/glycine biosynthesis pathway genes (Phgdh, Psat1 and Psph) and the gluconeogenic enzyme, phosphoenolpyruvate carboxykinase-M (Pck2/PEPCK-M), increased during treatment with BA, and to a lesser extent GH (p<0.001, treatment x time interaction). Treatment with BA, but not GH, caused a 2-fold increase in phosphoglycerate dehydrogenase (PHGDH) protein expression at days 3 (p<0.05) and 7 (p<0.01), and a 2-fold increase in PEPCK-M protein expression at day 7 (p<0.01). BA treated pigs exhibit a profound increase in expression of PHGDH and PEPCK-M in skeletal muscle, implicating a role for biosynthetic metabolic pathways in muscle growth

Otitis Media in a New Mouse Model for CHARGE Syndrome with a Deletion in the Chd7 Gene

Otitis media is a middle ear disease common in children under three years old. Otitis media can occur in normal individuals with no other symptoms or syndromes, but it is often seen in individuals clinically diagnosed with genetic diseases such as CHARGE syndrome, a complex genetic disease caused by mutation in the Chd7 gene and characterized by multiple birth defects. Although otitis media is common in human CHARGE syndrome patients, it has not been reported in mouse models of CHARGE syndrome. In this study, we report a mouse model with a spontaneous deletion mutation in the Chd7 gene and with chronic otitis media of early onset age accompanied by hearing loss. These mice also exhibit morphological alteration in the Eustachian tubes, dysregulation of epithelial proliferation, and decreased density of middle ear cilia. Gene expression profiling revealed up-regulation of Muc5ac, Muc5b and Tgf-β1 transcripts, the products of which are involved in mucin production and TGF pathway regulation. This is the first mouse model of CHARGE syndrome reported to show otitis media with effusion and it will be valuable for studying the etiology of otitis media and other symptoms in CHARGE syndrome

Multiple Organ System Defects and Transcriptional Dysregulation in the Nipbl+/− Mouse, a Model of Cornelia de Lange Syndrome

Cornelia de Lange Syndrome (CdLS) is a multi-organ system birth defects disorder linked, in at least half of cases, to heterozygous mutations in the NIPBL gene. In animals and fungi, orthologs of NIPBL regulate cohesin, a complex of proteins that is essential for chromosome cohesion and is also implicated in DNA repair and transcriptional regulation. Mice heterozygous for a gene-trap mutation in Nipbl were produced and exhibited defects characteristic of CdLS, including small size, craniofacial anomalies, microbrachycephaly, heart defects, hearing abnormalities, delayed bone maturation, reduced body fat, behavioral disturbances, and high mortality (75–80%) during the first weeks of life. These phenotypes arose despite a decrease in Nipbl transcript levels of only ∼30%, implying extreme sensitivity of development to small changes in Nipbl activity. Gene expression profiling demonstrated that Nipbl deficiency leads to modest but significant transcriptional dysregulation of many genes. Expression changes at the protocadherin beta (Pcdhb) locus, as well as at other loci, support the view that NIPBL influences long-range chromosomal regulatory interactions. In addition, evidence is presented that reduced expression of genes involved in adipogenic differentiation may underlie the low amounts of body fat observed both in Nipbl+/− mice and in individuals with CdLS

Gene Therapy Restores Auditory and Vestibular Function in a Mouse Model of Usher Syndrome Type 1c

Because there are currently no biological treatments for deafness, we sought to advance gene therapy approaches to treat genetic deafness. We reasoned that gene delivery systems that target auditory and vestibular sensory cells with high efficiency would be required to restore complex auditory and balance function. We focused on Usher Syndrome, a devastating genetic disorder that causes blindness, balance disorders and profound deafness, and used a knock-in mouse model, Ush1c c.216G>A, which carries a cryptic splice site mutation found in French-Acadian patients with Usher Syndrome type IC (USH1C). Following delivery of wild-type Ush1c into the inner ears of neonatal Ush1c c.216G>A mice, we find recovery of gene and protein expression, restoration of sensory cell function, rescue of complex auditory function and recovery of hearing and balance behavior to near wild-type levels. The data represent unprecedented recovery of inner ear function and suggest that biological therapies to treat deafness may be suitable for translation to humans with genetic inner ear disorders

Flodoard of Rheims and the Historiography of the Tenth-Century West

Flodoard of Rheims is one of the most important authors of tenth-century Europe, and the only contemporary historian to document the momentous struggles between kings and nobles in Francia in the wake of the demise of the Carolingian Empire. Flodoard’s era stands at the center of major historiographical debates concerning the nature of political and social change and the origins of European institutions. Yet, despite his singularity, his substantial histories have received little attention from scholars examining the profound transformations of the period. Exploring this discrepancy, this article offers an overview of Flodoard’s career and reviews how his histories have been invoked in some of the great scholarly debates about tenth-century Europe. It further proposes to recontextualize Flodoard and to reread his histories from the bottom up in order to gain a subtler understanding of how one contemporary perceived and represented the dramatic events and changes taking place around him

Multi-level high-voltage power supply for dea application

In order to reap the benefits of Dielectric Elastomer Actuator (DEA) high energy density, the electronics powering the actuator should be as small as possible. Knowing that only a small fraction of the energy delivered to DEAs is effectively converted into mechanical energy, the power supply has to be highly efficient and bidirectional in order to recover the unused energy, which requires more volume. Furthermore, DEA applications call for high voltage (up to 18kV for a 200um film), but as the voltage increases, so does the volume. In addition, there are no MOS transistors rated above 4.5kV, which limits our options. Since these goals are contradictory, we need to demonstrate the feasibility of DEA integration and find its limits. Therefore we present a prototype of Multi-Level Converter designed for DEA, which is a bidirectional structure that has proven to be especially effective in the power electronics field. A Multi-Level Converter overcomes the voltage limitation by equally distributing the desired voltage among levels; because the voltage of each level is sufficiently low, smaller available parts can now be used. Our prototype includes 20 levels of 1kV each. A numerical study of this topology has demonstrated that the efficiency is above 90%. Upcoming experimental works will discuss the advantages and the drawbacks of such Multi-Level Converters. Finally, the volume of the DEA will be compared with the volume of electronics

Environmental transition during Early Holocene: the impact of RCCs on the Moulouya basin (NE Morocco)

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Evolution holocène du bassin de l’oued Tabouda (Oriental, Maroc) : premiers résultats

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Willgerodt-Kingdler's microwave-enhanced synthesis of thioamide derivatives

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