The ancestral retinoic acid receptor was a low-affinity sensor triggering neuronal differentiation.

Retinoic acid (RA) is an important intercellular signaling molecule in vertebrate development, with a well-established role in the regulation of hox genes during hindbrain patterning and in neurogenesis. However, the evolutionary origin of the RA signaling pathway remains elusive. To elucidate the evolution of the RA signaling system, we characterized RA metabolism and signaling in the marine annelid Platynereis dumerilii, a powerful model for evolution, development, and neurobiology. Binding assays and crystal structure analyses show that the annelid retinoic acid receptor (RAR) binds RA and activates transcription just as vertebrate RARs, yet with a different ligand-binding pocket and lower binding affinity, suggesting a permissive rather than instructive role of RA signaling. RAR knockdown and RA treatment of swimming annelid larvae further reveal that the RA signal is locally received in the medial neuroectoderm, where it controls neurogenesis and axon outgrowth, whereas the spatial colinear hox gene expression in the neuroectoderm remains unaffected. These findings suggest that one early role of the new RAR in bilaterian evolution was to control the spatially restricted onset of motor and interneuron differentiation in the developing ventral nerve cord and to indicate that the regulation of hox-controlled anterior-posterior patterning arose only at the base of the chordates, concomitant with a high-affinity RAR needed for the interpretation of a complex RA gradient

Adoption of digital tools in the context of the COVID-19 pandemic in the Region of the Americas - the Go.Data experience

The COVID-19 pandemic has accelerated the growth of digital health tools. Although a number of different tools exist to support field data collection in the context of outbreak response, they have not been sufficient. This prompted the World Health Organization (WHO) to collaborate with the Global Outbreak Alert and Response Network (GOARN) and GOARN partners to develop a comprehensive system, Go.Data. Go.Data, a digital tool for outbreak response has simplified how countries operationalize and monitor case and contact data. Since the start of the pandemic, WHO and GOARN partners have provided support to Go.Data projects in 65 countries and territories, yet the demand by countries to have documented success cases of Go.Data implementations continues to grow. This viewpoint documents the successful Go.Data implementation frameworks in two countries, Argentina and Guatemala and an academic institution, the University of Texas at Austin

The nuclear receptors of Biomphalaria glabrata and Lottia gigantea: Implications for developing new model organisms

© 2015 Kaur et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are creditedNuclear receptors (NRs) are transcription regulators involved in an array of diverse physiological functions including key roles in endocrine and metabolic function. The aim of this study was to identify nuclear receptors in the fully sequenced genome of the gastropod snail, Biomphalaria glabrata, intermediate host for Schistosoma mansoni and compare these to known vertebrate NRs, with a view to assessing the snail's potential as a invertebrate model organism for endocrine function, both as a prospective new test organism and to elucidate the fundamental genetic and mechanistic causes of disease. For comparative purposes, the genome of a second gastropod, the owl limpet, Lottia gigantea was also investigated for nuclear receptors. Thirty-nine and thirty-three putative NRs were identified from the B. glabrata and L. gigantea genomes respectively, based on the presence of a conserved DNA-binding domain and/or ligand-binding domain. Nuclear receptor transcript expression was confirmed and sequences were subjected to a comparative phylogenetic analysis, which demonstrated that these molluscs have representatives of all the major NR subfamilies (1-6). Many of the identified NRs are conserved between vertebrates and invertebrates, however differences exist, most notably, the absence of receptors of Group 3C, which includes some of the vertebrate endocrine hormone targets. The mollusc genomes also contain NR homologues that are present in insects and nematodes but not in vertebrates, such as Group 1J (HR48/DAF12/HR96). The identification of many shared receptors between humans and molluscs indicates the potential for molluscs as model organisms; however the absence of several steroid hormone receptors indicates snail endocrine systems are fundamentally different.The National Centre for the Replacement, Refinement and Reduction of Animals in Research, Grant Ref:G0900802 to CSJ, LRN, SJ & EJR [www.nc3rs.org.uk]

Supplemental Information 1: Images of control and 9- cis

Trichoplax adhaerens, the only known species of Placozoa is likely to be closely related to an early metazoan that preceded branching of Cnidaria and Bilateria. This animal species is surprisingly well adapted to free life in the World Ocean inhabiting tidal costal zones of oceans and seas with warm to moderate temperatures and shallow waters. The genome of T. adhaerens (sp. Grell) includes four nuclear receptors, namely orthologue of RXR (NR2B), HNF4 (NR2A), COUP-TF (NR2F) and ERR (NR3B) that show a high degree of similarity with human orthologues. In the case of RXR, the sequence identity to human RXR alpha reaches 81% in the DNA binding domain and 70% in the ligand binding domain. We show that T. adhaerens RXR (TaRXR) binds 9-cis retinoic acid (9-cis-RA) with high affinity, as well as high specificity and that exposure of T. adhaerens to 9-cis-RA regulates the expression of the putative T. adhaerens orthologue of vertebrate L-malate-NADP+ oxidoreductase (EC 1.1.1.40) which in vertebrates is regulated by a heterodimer of RXR and thyroid hormone receptor. Treatment by 9-cis-RA alters the relative expression profile of T. adhaerens nuclear receptors, suggesting the existence of natural ligands. Keeping with this, algal food composition has a profound effect on T. adhaerens growth and appearance. We show that nanomolar concentrations of 9-cis-RA interfere with T. adhaerens growth response to specific algal food and causes growth arrest. Our results uncover an endocrine-like network of nuclear receptors sensitive to 9-cis-RA in T. adhaerens and support the existence of a ligand-sensitive network of nuclear receptors at the base of metazoan evolution

Effects of hospital facilities on patient outcomes after cancer surgery: an international, prospective, observational study

Background Early death after cancer surgery is higher in low-income and middle-income countries (LMICs) compared with in high-income countries, yet the impact of facility characteristics on early postoperative outcomes is unknown. The aim of this study was to examine the association between hospital infrastructure, resource availability, and processes on early outcomes after cancer surgery worldwide.Methods A multimethods analysis was performed as part of the GlobalSurg 3 study-a multicentre, international, prospective cohort study of patients who had surgery for breast, colorectal, or gastric cancer. The primary outcomes were 30-day mortality and 30-day major complication rates. Potentially beneficial hospital facilities were identified by variable selection to select those associated with 30-day mortality. Adjusted outcomes were determined using generalised estimating equations to account for patient characteristics and country-income group, with population stratification by hospital.Findings Between April 1, 2018, and April 23, 2019, facility-level data were collected for 9685 patients across 238 hospitals in 66 countries (91 hospitals in 20 high-income countries; 57 hospitals in 19 upper-middle-income countries; and 90 hospitals in 27 low-income to lower-middle-income countries). The availability of five hospital facilities was inversely associated with mortality: ultrasound, CT scanner, critical care unit, opioid analgesia, and oncologist. After adjustment for case-mix and country income group, hospitals with three or fewer of these facilities (62 hospitals, 1294 patients) had higher mortality compared with those with four or five (adjusted odds ratio [OR] 3.85 [95% CI 2.58-5.75]; p<0.0001), with excess mortality predominantly explained by a limited capacity to rescue following the development of major complications (63.0% vs 82.7%; OR 0.35 [0.23-0.53]; p<0.0001). Across LMICs, improvements in hospital facilities would prevent one to three deaths for every 100 patients undergoing surgery for cancer.Interpretation Hospitals with higher levels of infrastructure and resources have better outcomes after cancer surgery, independent of country income. Without urgent strengthening of hospital infrastructure and resources, the reductions in cancer-associated mortality associated with improved access will not be realised

Cloning retinoid and peroxisome proliferator-activated nuclear receptors of the Pacific oyster and in silico binding to environmental chemicals

This is the final version of the article. Available from Public Library of Science via the DOI in this record.Disruption of nuclear receptors, a transcription factor superfamily regulating gene expression in animals, is one proposed mechanism through which pollution causes effects in aquatic invertebrates. Environmental pollutants have the ability to interfere with the receptor's functions through direct binding and inducing incorrect signals. Limited knowledge of invertebrate endocrinology and molecular regulatory mechanisms, however, impede the understanding of endocrine disruptive effects in many aquatic invertebrate species. Here, we isolated three nuclear receptors of the Pacific oyster, Crassostrea gigas: two isoforms of the retinoid X receptor, CgRXR-1 and CgRXR-2, a retinoic acid receptor ortholog CgRAR, and a peroxisome proliferator-activated receptor ortholog CgPPAR. Computer modelling of the receptors based on 3D crystal structures of human proteins was used to predict each receptor's ability to bind to different ligands in silico. CgRXR showed high potential to bind and be activated by 9-cis retinoic acid and the organotin tributyltin (TBT). Computer modelling of CgRAR revealed six residues in the ligand binding domain, which prevent the successful interaction with natural and synthetic retinoid ligands. This supports an existing theory of loss of retinoid binding in molluscan RARs. Modelling of CgPPAR was less reliable due to high discrepancies in sequence to its human ortholog. Yet, there are suggestions of binding to TBT, but not to rosiglitazone. The effect of potential receptor ligands on early oyster development was assessed after 24h of chemical exposure. TBT oxide (0.2μg/l), all-trans retinoic acid (ATRA) (0.06 mg/L) and perfluorooctanoic acid (20 mg/L) showed high effects on development (>74% abnormal developed D-shelled larvae), while rosiglitazone (40 mg/L) showed no effect. The results are discussed in relation to a putative direct (TBT) disruption effect on nuclear receptors. The inability of direct binding of ATRA to CgRAR suggests either a disruptive effect through a pathway excluding nuclear receptors or an indirect interaction. Our findings provide valuable information on potential mechanisms of molluscan nuclear receptors and the effects of environmental pollution on aquatic invertebrates.The study was funded by the Centre for Environment, Fisheries and Aquaculture Science (Cefas; https://www.cefas.co.uk) and by the University of Exeter (http://www.exeter.ac.uk)

Evolution du récepteur de l'acide rétinoïque

L’acide rétinoïque (AR) est un morphogène dérivé de la vitamine A qui contrôle des processus clés au niveau cellulaire et pendant le développement embryonnaire des chordés. Chez les vertébrés les principaux acteurs de la voie de signalisation de l’AR sont les récepteurs de l’acide rétinoïque (RAR) et les récepteurs des x rétinoïdes (RXR). L’évolution de RAR est encore très mal connue cependant, des données récentes indiquent qu’il est également présent chez des animaux non-chordés. Suggérant ainsi, que l’origine évolutive de RAR et de la voie de signalisation de l’AR est plus ancienne qu’initialement prévu. Durant ma thèse j’ai pu retracer l’histoire évolutive de ce récepteur depuis son origine chez Urbilateria jusqu'à sa diversification, suite aux duplications génomiques chez les vertébrés. En caractérisant les RARs d’un annélide, un mollusque et un oursin j’ai démontré que chez l’annélide et l’oursin RAR est activé par l’AR, contrairement au RAR de mollusque qui n’est pas fonctionnel avec l’AR. De plus, des études menées chez l’annélide ont montré que les gènes régulés par l’AR chez cette espèce sont différents de ceux régulés chez les vertébrés. Ces données permettent donc de s’interroger sur la fonction ancestrale probable que ce récepteur avait chez Urbilateria. Finalement, la caractérisation moléculaire des RAR de cyclostomes nous a permis d’étudier l’impact des duplications génomiques sur l’évolution de la poche de liaison au ligand. Ainsi, les résultats obtenus pendant ma thèse permettent de mieux comprendre les relations entre le récepteur et son ligand ainsi que de découvrir de nouveaux aspects sur la fonction de RAR en présence de ligands non-classiques.Retinoic acid (RA) is a fat-soluble morphogen derived from vitamin A that controls key cellular and developmental processes in chordates. In vertebrates, the major actors of the RA signaling pathway are the retinoic acid receptors (RARs) and the retinoid X receptors (RXRs). The evolution of RAR is still poorly understood, however, recently RARs have been identified in the genome of non-chordate species, suggesting that RAR and the RA pathway might have a more ancient evolutionary origin than previously thought. The work presented in this manuscript allowed us to retrace the evolutionary history of RAR from its origin in Urbilateria to its diversification following whole genome duplication events in vertebrates. We describe the characterization of the RARs from an annelid, a mollusk and a sea urchin. We showed that the receptors from the annelid and the sea urchin are functional RARs, however, the receptor from the mollusk is not functional with RA. Studies carried out in the annelid revealed that the signaling pathways regulated by RA in this species are different to the ones it regulates in vertebrates. These observations raise questions about the function of RA and RAR on the embryonic development of non-chordate species and their possible function in Urbilateria. Finally, the molecular characterization of cyclostome RARs allowed us to characterize the impact of whole genome duplications on the evolution of the ligand-binding pocket. Altogether, these data will allow us to better understand the relationship between the receptor and its ligand and to reveal novel insights on the function of RAR in response to non-classical ligands

Evolution du récepteur de l'acide rétinoïque

Retinoic acid (RA) is a fat-soluble morphogen derived from vitamin A that controls key cellular and developmental processes in chordates. In vertebrates, the major actors of the RA signaling pathway are the retinoic acid receptors (RARs) and the retinoid X receptors (RXRs). The evolution of RAR is still poorly understood, however, recently RARs have been identified in the genome of non-chordate species, suggesting that RAR and the RA pathway might have a more ancient evolutionary origin than previously thought. The work presented in this manuscript allowed us to retrace the evolutionary history of RAR from its origin in Urbilateria to its diversification following whole genome duplication events in vertebrates. We describe the characterization of the RARs from an annelid, a mollusk and a sea urchin. We showed that the receptors from the annelid and the sea urchin are functional RARs, however, the receptor from the mollusk is not functional with RA. Studies carried out in the annelid revealed that the signaling pathways regulated by RA in this species are different to the ones it regulates in vertebrates. These observations raise questions about the function of RA and RAR on the embryonic development of non-chordate species and their possible function in Urbilateria. Finally, the molecular characterization of cyclostome RARs allowed us to characterize the impact of whole genome duplications on the evolution of the ligand-binding pocket. Altogether, these data will allow us to better understand the relationship between the receptor and its ligand and to reveal novel insights on the function of RAR in response to non-classical ligands.L’acide rétinoïque (AR) est un morphogène dérivé de la vitamine A qui contrôle des processus clés au niveau cellulaire et pendant le développement embryonnaire des chordés. Chez les vertébrés les principaux acteurs de la voie de signalisation de l’AR sont les récepteurs de l’acide rétinoïque (RAR) et les récepteurs des x rétinoïdes (RXR). L’évolution de RAR est encore très mal connue cependant, des données récentes indiquent qu’il est également présent chez des animaux non-chordés. Suggérant ainsi, que l’origine évolutive de RAR et de la voie de signalisation de l’AR est plus ancienne qu’initialement prévu. Durant ma thèse j’ai pu retracer l’histoire évolutive de ce récepteur depuis son origine chez Urbilateria jusqu'à sa diversification, suite aux duplications génomiques chez les vertébrés. En caractérisant les RARs d’un annélide, un mollusque et un oursin j’ai démontré que chez l’annélide et l’oursin RAR est activé par l’AR, contrairement au RAR de mollusque qui n’est pas fonctionnel avec l’AR. De plus, des études menées chez l’annélide ont montré que les gènes régulés par l’AR chez cette espèce sont différents de ceux régulés chez les vertébrés. Ces données permettent donc de s’interroger sur la fonction ancestrale probable que ce récepteur avait chez Urbilateria. Finalement, la caractérisation moléculaire des RAR de cyclostomes nous a permis d’étudier l’impact des duplications génomiques sur l’évolution de la poche de liaison au ligand. Ainsi, les résultats obtenus pendant ma thèse permettent de mieux comprendre les relations entre le récepteur et son ligand ainsi que de découvrir de nouveaux aspects sur la fonction de RAR en présence de ligands non-classiques