Jeune asphyxiating thoracic dystrophy (ATD) is an autosomal-recessive chondrodysplasia characterized by short ribs and a narrow thorax, short long bones, inconstant polydactyly, and trident acetabular roof. ATD is closely related to the short rib polydactyly syndrome (SRP) type III, which is a more severe condition characterized by early prenatal expression and lethality and variable malformations. We first excluded IFT80 in a series of 26 fetuses and children belonging to 14 families diagnosed with either ATD or SRP type III. Studying a consanguineous family from Morocco, we mapped an ATD gene to chromosome 11q14.3-q23.1 in a 20.4 Mb region and identified homozygous mutations in the cytoplasmic dynein 2 heavy chain 1 (DYNC2H1) gene in the affected children. Compound heterozygosity for DYNC2H1 mutations was also identified in four additional families. Among the five families, 3/5 were diagnosed with ATD and 2/5 included pregnancies terminated for SRP type III. DYNC2H1 is a component of a cytoplasmic dynein complex and is directly involved in the generation and maintenance of cilia. From this study, we conclude that ATD and SRP type III are variants of a single disorder belonging to the ciliopathy group.

The cytosolic RIG-I (retinoic acid-inducible gene I) receptor plays a pivotal role in the initiation of the immune response against RNA virus infection by recognizing short 5=-triphosphate (5=ppp)-containing viral RNA and activating the host antiviral innate response. In the present study, we generated novel 5=ppp RIG-I agonists of varieous lengths, structures, and sequences and evaluated the generation of the antiviral and inflammatory responses in human epithelial A549 cells, human innate immune primary cells, and murine models of influenza and chikungunya viral pathogenesis. A 99-nucleotide, uridine-rich hairpin 5=pppRNA termed M8 stimulated an extensive and robust interferon response compared to other modified 5=pppRNA structures, RIG-I aptamers, or poly(I·C). Interestingly, manipulation of the primary RNA sequence alone was sufficient to modulate antiviral activity and inflammatory response, in a manner dependent exclusively on RIG-I and independent of MDA5 and TLR3. Both prophylactic and therapeutic administration of M8 effectively inhibited influenza virus and dengue virus replication in vitro. Furthermore, multiple strains of influenza virus that were resistant to oseltamivir, an FDA-approved therapeutic treatment for influenza, were highly sensitive to inhibition by M8. Finally, prophylactic M8 treatment in vivo prolonged survival and reduced lung viral titers of mice challenged with influenza virus, as well as reducing chikungunya virus-associated foot swelling and viral load. Altogether, these results demonstrate that 5=pppRNA can be rationally designed to achieve a maximal RIG-I-mediated protective antiviral response against human-pathogenic RNA viruses. IMPORTANCEThe development of novel therapeutics to treat human-pathogenic RNA viral infections is an important goal to reduce spread of infection and to improve human health and safety. This study investigated the design of an RNA agonist with enhanced antiviral and inflammatory properties against influenza, dengue, and chikungunya viruses. A novel, sequence-dependent, uridine-rich RIG-I agonist generated a protective antiviral response in vitro and in vivo and was effective at concentrations 100-fold lower than prototype sequences or other RNA agonists, highlighting the robust activity and potential clinical use of the 5=pppRNA against RNA virus infection. Altogether, the results identify a novel, sequence-specific RIG-I agonist as an attractive therapeutic candidate for the treatment of a broad range of RNA viruses, a pressing issue in which a need for new and more effective options persists.H uman-pathogenic RNA viral infections, including influenza, dengue, and chikungunya, pose significant threats to human health and safety. For this reason, the development of prophylactic and therapeutic antivirals to treat and limit spread of infection remains a growing unmet medical need. Currently, there are no therapeutics for the prevention or treatment of dengue or chikungunya infections, and approved antiviral compounds to treat influenza have si...

Oncolytic viruses (OVs) offer a promising therapeutic approach to treat multiple types of cancer. In this study, we show that the manipulation of the antioxidant network via transcription factor Nrf2 augments vesicular stomatitis virus Δ51 (VSVΔ51) replication and sensitizes cancer cells to viral oncolysis. Activation of Nrf2 signaling by the antioxidant compound sulforaphane (SFN) leads to enhanced VSVΔ51 spread in OV-resistant cancer cells and improves the therapeutic outcome in different murine syngeneic and xenograft tumor models. Chemoresistant A549 lung cancer cells that display constitutive dominant hyperactivation of Nrf2 signaling are particularly vulnerable to VSVΔ51 oncolysis. Mechanistically, enhanced Nrf2 signaling stimulated viral replication in cancer cells and disrupted the type I IFN response via increased autophagy. This study reveals a previously unappreciated role for Nrf2 in the regulation of autophagy and the innate antiviral response that complements the therapeutic potential of VSV-directed oncolysis against multiple types of OV-resistant or chemoresistant cancer.

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BackgroundThe cause of isolated gonadotropin-independent precocious puberty (PP) with an ovarian cyst is unknown in the majority of cases. Here, we describe 11 new cases of peripheral PP and, based on phenotypes observed in mouse models, we tested the hypothesis that mutations in the GNAS1, NR5A1, LHCGR, FSHR, NR5A1, StAR, DMRT4 and NOBOX may be associated with this phenotype.Methodology/Principal Findings11 girls with gonadotropin-independent PP were included in this study. Three girls were seen for a history of prenatal ovarian cyst, 6 girls for breast development, and 2 girls for vaginal bleeding. With one exception, all girls were seen before 8 years of age. In 8 cases, an ovarian cyst was detected, and in one case, suspected. One other case has polycystic ovaries, and the remaining case was referred for vaginal bleeding. Four patients had a familial history of ovarian anomalies and/or infertility. Mutations in the coding sequences of the candidate genes GNAS1, NR5A1, LHCGR, FSHR, NR5A1, StAR, DMRT4 and NOBOX were not observed.Conclusions/SignificanceOvarian PP shows markedly different clinical features from central PP. Our data suggest that mutations in the GNAS1, NR5A1, LHCGR, FSHR StAR, DMRT4 and NOBOX genes are not responsible for ovarian PP. Further research, including the identification of familial cases, is needed to understand the etiology of ovarian PP.

Ce document est protégé par la loi sur le droit d'auteur. L'utilisation des services d'Érudit (y compris la reproduction) est assujettie à sa politique d'utilisation que vous pouvez consulter en ligne.https://apropos.erudit.org/fr/usagers/politique-dutilisation/ Cet article est diffusé et préservé par Érudit.Érudit est un consortium interuniversitaire sans but lucratif composé de l'Université de Montréal, l'Université Laval et l'Université du Québec à Montréal. Il a pour mission la promotion et la valorisation de la recherche. le bien-être du patient, l'autonomie du patient, la sécurité publique, la justice distributive, la qualité des interventions, la pratique compétente, l'indépendance professionnelle, l'honnêteté et le professionnalisme. Bien que les ergothérapeutes aient à coeur le bien-être des patients, plusieurs éléments semblent contribuer à cet état de fait, comme les situations de double allégeance vécues par les ergothérapeutes, l'ingérence des tiers payeurs dans le processus clinique et le mode de financement des cliniques. Plus encore, les enjeux éthiques de la pratique privée de l'ergothérapie sont principalement de nature macroscopique. La capacité des ergothérapeutes à percevoir certains de ces enjeux semble être reliée à certaines de leurs caractéristiques, en l'occurrence leur sensibilité éthique et le fait qu'ils soient novices. Les résultats de cette étude rejoignent en général ceux décrits dans les écrits en physiothérapie et montrent le manque de soutien offert aux ergothérapeutes, notamment aux novices, pour surmonter ces enjeux avec aisance et efficacité. Résumé AbstractAu Québec, 31% des ergothérapeutes travaillent dans le secteur privé, lequel est en constante croissance. À ce jour, aucune étude n'a spécifiquement répertorié les enjeux éthiques de cette pratique. Cette étude avait pour objectif d'explorer ces enjeux, c'est-à-dire les situations susceptibles de compromettre le respect d'une valeur é t h i q u e . O p t a n t p o u r u n d e v i s d ' i n s p i r a t i o n phénoménologique, sept ergothérapeutes ont été rencontrés dans le cadre d'entrevues individuelles semidirigées. Basé sur le cadre conceptuel de Swisher et ses collaborateurs, le canevas d'entrevue a permis d'identifier différents types d'enjeux éthiques. Les résultats attestent que plusieurs valeurs sont suscept ibles d'être compromises, soit : le bien-être du patient, l'autonomie du patient, la sécurité publique, la justice distributive, la qualité des interventions, la pratique compétente, l'indépendance professionnelle, l'honnêteté et le professionnalisme. Bien que les ergothérapeutes aient à coeur le bien-être des patients, plusieurs éléments semblent contribuer à cet état de fait, comme les situations de double allégeance vécues par les ergothérapeutes, l'ingérence des tiers payeurs dans le processus clinique et le mode de financement des cliniques. Plus encore, les enjeux éthiques de la pratique privée de l'ergothérapie sont principalement de nature macroscopique. La capacité des ergothérapeutes à percevoir cert...

ABSTRACT. In post‐embryonic development, the visual system of the cricket Nemobius sylvestris (Bosc) shows a regular increase in the length and number of the ommatidia and a decrease of inter‐ommatidial angle so that the adult's is a third of the value in the first larval instar. Further, a 20° widening of the binocular visual field, in the horizontal plane at least, and a three‐fold increase of the inter‐ocular distance improve the potential for binocular vision. Behavioural experiments showed that the insect orientates with differing precision depending on the distances to targets of constant angular size. Further, in a choice situation between two such vertical targets, the cricket orientates most strongly towards the closer of the two, even at target distances of 52 and 130 cm from its point of decision. In fixed tethered animals, discrimination between a close and a distant target is still possible, but disappears when the head is waxed to the thorax, so that any relative movement between the animal and the object is prevented. As these capabilities exceed the possibilities of binocular triangulation, the possible role of other mechanisms is discussed, particularly that involving movement parallax using both eyes.

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