International genome-wide meta-analysis identifies new primary biliary cirrhosis risk loci and targetable pathogenic pathways.

Primary biliary cirrhosis (PBC) is a classical autoimmune liver disease for which effective immunomodulatory therapy is lacking. Here we perform meta-analyses of discovery data sets from genome-wide association studies of European subjects (n=2,764 cases and 10,475 controls) followed by validation genotyping in an independent cohort (n=3,716 cases and 4,261 controls). We discover and validate six previously unknown risk loci for PBC (Pcombined<5 × 10(-8)) and used pathway analysis to identify JAK-STAT/IL12/IL27 signalling and cytokine-cytokine pathways, for which relevant therapies exist

The role of the T-box transcription factors Midline and H15 during epidermal growth factor receptor mediated epithelial patterning in «Drosophila melanogaster»

Axis specification in the Drosophila eggshell is achieved through localized activation of the epidermal growth factor receptor (EGFR) in the follicular epithelium by its ligand, Gurken (Grk), during oogenesis. Early activation of EGFR specifies posterior fates in the follicular epithelium. However at mid-oogenesis, graded EGFR activation in the dorsal anterior region of the epithelium will specify the dorsal anterior follicular cell fates. Recently we have shown that early EGFR signalling induces the expression of Midline and H15. These T-box transcription factors confer a molecular memory in posterior cells, preventing them from being specified as dorsal anterior follicle cells during the second phase of EGFR signalling. However the mechanism by which Midline and H15 restrict cellular response to EGFR at mid-oogenesis is not known. Furthermore, it is not known if this novel regulation of EGFR signalling by Midline and H15 represents a unique mechanism in oogenesis or if Midline and H15 are general regulators of EGFR signalling output in the patterning of Drosophila epithelia. My research has focused on developing tools to study the molecular mechanism by which Midline and H15 regulate EGFR signalling in oogenesis. I have also investigated other components of the EGFR pathway to understand how Mid and H15 regulate EGFR signalling output. These results have demonstrated that Midline and H15 do not regulate the levels of EGFR signalling but instead make cells refractory to the second phase of EGFR signalling. Additionally, these results have demonstrated that Pointed, a downstream effector of EGFR is able to regulate the expression of mid and H15 in oogenesis. Finally in order to determine whether Mid and H15 are general regulators of EGFR mediated epithelial patterning, I observed their expression, loss of function phenotypes and gain of function phenotypes during photoreceptor and vein specification. These results have demonstrated that Mid and H15 do not regulate EGFR mediated epithelial patterning in photoreceptor and vein specification during Drosophila development. Overall, these results have increased our understanding of the role mid and H15 play in EGFR mediated epithelial patterning.iPendant l’ovogénèse, la spécification des axes de la coquille de l’oeuf de la drosophile est accomplie par l’activation localisée du récepteur du facteur de croissance épidermale (EGFR) dans l’épithélium folliculaire, activation induite par le ligand Gurken (Grk). L’activation précoce d’EGFR spécifie les destinées cellulaires postérieures dans l’épithélium folliculaire. Toutefois, à la mi-parcours de l’ovogénèse, l’activation tardive graduée d’EGFR dans la région dorso-antérieure de l’épithélium spécifiera les destinées cellulaires du domaine dorso-antérieur. Nous avons récemment démontré que l’activation précoce d’EGFR induit l’expression de Midline (Mid) et de H15. Ces facteurs de transcription de type T-box dotent les cellules postérieures d’une mémoire moléculaire, ce qui empêche leur spécification en cellules du domaine dorso-antérieur pendant la phase tardive d’activation d’EGFR. Toutefois, le mécanisme par lequel Mid et H15 limitent la réponse cellulaire à la signalisation par EGFR à la mi-parcours de l’ovogénèse est encore inconnu. De plus, nous ne savons pas si ce nouveau mode de régulation de la signalisation d’EGFR par Mid et H15 représente un mécanisme unique à l’ovogénèse ou, au contraire, si Mid et H15 sont des régulateurs généraux du résultat de la signalisation d’EGFR dans la formation du patron des épithéliums chez la drosophile. Mon projet de recherche s’est porté sur la mise en place d’outils pour étudier le mécanisme moléculaire par lequel Mid et H15 régulent la voie de signalisation d’EGFR durant l’ovogénèse. J’ai aussi examiné d’autres composants de cette voie de signalisation dans le but de comprendre comment Mid et H15 modulent le résultat de la signalisation d’EGFR. Mes résultats ont démontré que Mid et H15 ne régulent pas les niveaux de signalisation d’EGFR, mais qu’ils rendent plutôt les cellules réfractaires à l’activation tardive de la voie de signalisation d’EGFR. De plus, mes résultats ont démontré que Pointed, un effecteur en aval d’EGFR, est capable de moduler l’expression de mid et de H15 durant l’ovogénèse. Finalement, de façon à déterminer si Mid et H15 sont des régulateurs généraux d’EGFR, j’ai étudié leur patron d’expression ainsi que les phénotypes d’une perte de fonction ou d’un gain de fonction pendant la spécification des veines et des photorécepteurs. Mes résultats ont démontré que Mid et H15 ne régulent pas la génération des patrons dûs à la signalisation d’EGFR durant le développement des veines et des photorécepteurs chez la drosophile. Dans leur ensemble, mes résulats contribuent à une meilleure compréhension des rôles que jouent mid et H15 pendant la formation des patrons de l’épithélium régulés par EGFR

Response to the Dorsal Anterior Gradient of EGFR Signaling in Drosophila Oogenesis Is Prepatterned by Earlier Posterior EGFR Activation

Spatially restricted epidermal growth factor receptor (EGFR) activity plays a central role in patterning the follicular epithelium of the Drosophila ovary. In midoogenesis, localized EGFR activation is achieved by the graded dorsal anterior localization of its ligand, Gurken. Graded EGFR activity determines multiple dorsal anterior fates along the dorsal-ventral axis but cannot explain the sharp posterior limit of this domain. Here, we show that posterior follicle cells express the T-box transcription factors Midline and H15, which render cells unable to adopt a dorsal anterior fate in response to EGFR activation. The posterior expression of Midline and H15 is itself induced in early oogenesis by posteriorly localized EGFR signaling, defining a feedback loop in which early induction of Mid and H15 confers a molecular memory that fundamentally alters the outcome of later EGFR signaling. Spatial regulation of the EGFR pathway thus occurs both through localization of the ligand and through localized regulation of the cellular response

A Horizon Scan of Emerging Global Biological Conservation Issues for 2020.

In this horizon scan, we highlight 15 emerging issues of potential relevance to global conservation in 2020. Seven relate to potentially extensive changes in vegetation or ecological systems. These changes are either relatively new, for example, conversion of kelp forests to simpler macroalgal systems, or may occur in the future, for example, as a result of the derivation of nanocelluose from wood or the rapid expansion of small hydropower schemes. Other topics highlight potential changes in national legislation that may have global effect on international agreements. Our panel of 23 scientists and practitioners selected these issues using a modified version of the Delphi technique from a long-list of 89 potential topics.NERC and RSPB fundin

A horizon scan of global biological conservation issues for 2022

We present the results of our 13th annual horizon scan of issues likely to impact biodiversity conservation. Issues are either novel within the biological conservation sector or could cause a substantial step-change in impact, either globally or regionally. Our global panel of 26 scientists and practitioners identified 15 issues that we believe represent the highest priorities for tracking and action. Many of the issues we identified, including the impact of satellite megaconstellations, and the use of long-distance wireless energy transfer, have elements of threats and emerging opportunities. The recent state-sponsored application to commence deep-sea mining represents a significant step-change in impact. We hope that this horizon scan will increase research and policy attention on the highlighted issues.This exercise was coordinated by the Cambridge Conservation Initiative with funding offered by the Natural Environment Research Council and the RSPB (this funding was not needed because the proceedings were held online). We are grateful to everyone who submitted ideas to the exercise and the following who suggested a topic that made the final list: Jason Dinsdale (wireless energy infrastructure), Ian Francis (floating photovoltaics), Robin Freeman (airborne eDNA), Lizzie Garratt (environmental consequences of new refrigerants), Lammert Hilarides (mangrove expansion) and Jiping Shi (green ammonia). We would also like to thank Mick Clout who contributed to the process but was unable to attend the workshop and the referees for comments. The results, conclusions, and opinions expressed are those of the authors and do not necessarily reflect the views of any of their organisations. AT and WJS are funded by Arcadia

X Chromosome Contribution to the Genetic Architecture of Primary Biliary Cholangitis.

BACKGROUND & AIMS: Genome-wide association studies in primary biliary cholangitis (PBC) have failed to find X chromosome (chrX) variants associated with the disease. Here, we specifically explore the chrX contribution to PBC, a sexually dimorphic complex autoimmune disease. METHODS: We performed a chrX-wide association study, including genotype data from 5 genome-wide association studies (from Italy, United Kingdom, Canada, China, and Japan; 5244 case patients and 11,875 control individuals). RESULTS: Single-marker association analyses found approximately 100 loci displaying P < 5 × 10(-4), with the most significant being a signal within the OTUD5 gene (rs3027490; P = 4.80 × 10(-6); odds ratio [OR], 1.39; 95% confidence interval [CI], 1.028-1.88; Japanese cohort). Although the transethnic meta-analysis evidenced only a suggestive signal (rs2239452, mapping within the PIM2 gene; OR, 1.17; 95% CI, 1.09-1.26; P = 9.93 × 10(-8)), the population-specific meta-analysis showed a genome-wide significant locus in East Asian individuals pointing to the same region (rs7059064, mapping within the GRIPAP1 gene; P = 6.2 × 10(-9); OR, 1.33; 95% CI, 1.21-1.46). Indeed, rs7059064 tags a unique linkage disequilibrium block including 7 genes: TIMM17B, PQBP1, PIM2, SLC35A2, OTUD5, KCND1, and GRIPAP1, as well as a superenhancer (GH0XJ048933 within OTUD5) targeting all these genes. GH0XJ048933 is also predicted to target FOXP3, the main T-regulatory cell lineage specification factor. Consistently, OTUD5 and FOXP3 RNA levels were up-regulated in PBC case patients (1.75- and 1.64-fold, respectively). CONCLUSIONS: This work represents the first comprehensive study, to our knowledge, of the chrX contribution to the genetics of an autoimmune liver disease and shows a novel PBC-related genome-wide significant locus.The article is available via Open Access. Click on the 'Additional link' above to access the full-text.Published version, accepted versio