Molecular Evolution Of Fibropapilloma-Associated Herpesviruses Infecting Juvenile Green And Loggerhead Sea Turtles

Chelonid Alphaherpesvirus 5 (ChHV5) has long been associated with fibropapillomatosis (FP) tumor disease in marine turtles. Presenting primarily in juvenile animals, FP results in fibromas of the skin, connective tissue, and internal organs, which may indirectly affect fitness by obstructing normal turtle processes. ChHV5 is near-universally present in tumorous tissues taken from affected animals, often at very high concentrations. However, there is also considerable asymptomatic carriage amongst healthy marine turtles, suggesting that asymptomatic hosts play an important role in disease ecology. Currently, there is a paucity of studies investigating variation in viral genetics between diseased and asymptomatic hosts, which could potentially explain why only some ChHV5 infections lead to tumor formation. Here, we generated a database containing DNA from over 400 tissue samples taken from green and loggerhead marine turtles, including multiple tissue types, a twenty year time span, and both diseased and asymptomatic animals. We used two molecular detection techniques, quantitative (q)PCR and nested PCR, to characterize the presence and genetic lineage of ChHV5 in each sample. We found that nested PCR across multiple loci out-performed qPCR and is a more powerful technique for determining infection status. Phylogenetic reconstruction of three viral loci from all ChHV5-positive samples indicated widespread panmixia of viral lineages, with samples taken across decades, species, disease states, and tissues all falling within the same evolutionary lineages. Haplotype networks produced similar results in that viral haplotypes were shared across species, tissue types and disease states with no evidence that viral lineages associated significantly with disease dynamics. Additionally, tests of selection on viral gene trees indicated signals of selection dividing major clades, though this selection did not divide sample categories. Based on these data, neither the presence of ChHV5 infection nor neutral genetic divergence between viral lineages infecting a juvenile marine turtle is sufficient to explain the development of FP within an individual

Investigating the Mental Health Impacts of Climate Change in Youth: Design and Implementation of the International Changing Worlds Study

As climate change continues unabated, research is increasingly focused on capturing and quantifying the lesser-known psychological responses and mental health implications of this humanitarian and environmental crisis. There has been a particular interest in the experiences of young people, who are more vulnerable for a range of reasons, including their developmental stage, the high rates of mental health conditions among this population, and their relative lack of agency to address climate threats. The different geographic and sociocultural settings in which people are coming of age afford certain opportunities and present distinct challenges and exposures to climate hazards. Understanding the diversity of lived experiences is vitally important for informing evidence-based, locally led psychosocial support and social and climate policies. In this Project Report we describe the design and implementation of the “Changing Worlds” study, focusing on our experiences and personal reflections as a transdisciplinary collaboration representing the UK, India, Trinidad and Tobago, Guyana, Barbados, the Philippines, and the USA. The project was conceived within the planetary health paradigm, aimed at characterizing and quantifying the impacts of human-mediated environmental systems changes on youth mental health and wellbeing. With input from local youth representatives, we designed and delivered a series of locally adapted surveys asking young people about their mental health and wellbeing, as well as their thoughts, emotions, and perceived agency in relation to the climate crisis and the global COVID-19 pandemic. This project report outlines the principles that guided the study design and describes the conceptual and practical hurdles we navigated as a distributed and interdisciplinary research collaboration working in different institutional, social, and research governance settings. Finally, we highlight lessons learned, specify our recommendations for other collaborative research projects in this space, and touch upon the next steps for our work. This project explicitly balances context sensitivity and the need for quantitative, globally comparable data on how youth are responding to and coping with environmental change, inspiring a new vision for a global community of practice on mental health in climate change

Comparative performances of machine learning methods for classifying Crohn Disease patients using genome-wide genotyping data

Abstract: Crohn Disease (CD) is a complex genetic disorder for which more than 140 genes have been identified using genome wide association studies (GWAS). However, the genetic architecture of the trait remains largely unknown. The recent development of machine learning (ML) approaches incited us to apply them to classify healthy and diseased people according to their genomic information. The Immunochip dataset containing 18,227 CD patients and 34,050 healthy controls enrolled and genotyped by the international Inflammatory Bowel Disease genetic consortium (IIBDGC) has been re-analyzed using a set of ML methods: penalized logistic regression (LR), gradient boosted trees (GBT) and artificial neural networks (NN). The main score used to compare the methods was the Area Under the ROC Curve (AUC) statistics. The impact of quality control (QC), imputing and coding methods on LR results showed that QC methods and imputation of missing genotypes may artificially increase the scores. At the opposite, neither the patient/control ratio nor marker preselection or coding strategies significantly affected the results. LR methods, including Lasso, Ridge and ElasticNet provided similar results with a maximum AUC of 0.80. GBT methods like XGBoost, LightGBM and CatBoost, together with dense NN with one or more hidden layers, provided similar AUC values, suggesting limited epistatic effects in the genetic architecture of the trait. ML methods detected near all the genetic variants previously identified by GWAS among the best predictors plus additional predictors with lower effects. The robustness and complementarity of the different methods are also studied. Compared to LR, non-linear models such as GBT or NN may provide robust complementary approaches to identify and classify genetic markers

Antisense approach to inflammatory bowel disease: Prospects and challenges

Despite the great success of anti-tumour necrosis factor-based therapies, the treatment of Crohn's disease (CD) and ulcerative colitis (UC) still remains a challenge for clinicians, as these drugs are not effective in all patients, their efficacy may wane with time, and their use can increase the risk of adverse events and be associated with the development of new immune-mediated diseases. Therefore, new therapeutic targets are currently being investigated both in pre-clinical studies and in clinical trials. Among the technologies used to build new therapeutic compounds, the antisense oligonucleotide (ASO) approach is slowly gaining space in the field of inflammatory bowel diseases (IBDs), and three ASOs have been investigated in clinical trials. Systemic administration of alicaforsen targeting intercellular adhesion molecule-1, a protein involved in the recruitment of leukocytes to inflamed intestine, was not effective in CD, even though the same compound was of benefit when given as an enema to UC patients. DIMS0150, targeting nuclear factor (NF) κB-p65, a transcription factor that promotes pro-inflammatory responses, was very promising in pre-clinical studies and is currently being tested in clinical trials. Oral mongersen, targeting Smad7, an intracellular protein that inhibits transforming growth factor (TGF)-β1 activity, was safe and well tolerated by CD patients, and the results of a phase II clinical trial showed the efficacy of the drug in inducing clinical remission in patients with active disease. In this leading article, we review the rationale and the clinical data available regarding these three agents, and we discuss the challenge of using ASOs in IBD

HLA-DQA1-HLA-DRB1 variants confer susceptibility to pancreatitis induced by thiopurine immunosuppressants

Pancreatitis occurs in approximately 4% of patients treated with the thiopurines azathioprine or mercaptopurine. Its development is unpredictable and almost always leads to drug withdrawal. We identified patients with inflammatory bowel disease (IBD) who had developed pancreatitis within 3 months of starting these drugs from 168 sites around the world. After detailed case adjudication, we performed a genome-wide association study on 172 cases and 2,035 controls with IBD. We identified strong evidence of association within the class II HLA region, with the most significant association identified at rs2647087 (odds ratio 2.59, 95% confidence interval 2.07-3.26, P = 2 x 10(-16)). We replicated these findings in an independent set of 78 cases and 472 controls with IBD matched for drug exposure. Fine mapping of the HLA region identified association with the HLA-DQA1*02:01-HLA-DRB1*07:01 haplotype. Patients heterozygous at rs2647087 have a 9% risk of developing pancreatitis after administration of a thiopurine, whereas homozygotes have a 17% risk