Ancient Mycobacterium leprae genome reveals medieval English red squirrels as animal leprosy host

Leprosy, one of the oldest recorded diseases in human history, remains prevalent in Asia, Africa, and South America, with over 200,000 cases every year. Although ancient DNA (aDNA) approaches on the major causative agent, Mycobacterium leprae, have elucidated the disease's evolutionary history the role of animal hosts and interspecies transmission in the past remains unexplored. Research has uncovered relationships between medieval strains isolated from archaeological human remains and modern animal hosts such as the red squirrel in England. However, the time frame, distribution, and direction of transmissions remains unknown. Here, we studied 25 human and 12 squirrel samples from two archaeological sites in Winchester, a medieval English city well known for its leprosarium and connections to the fur trade. We reconstructed four medieval M. leprae genomes, including one from a red squirrel, at a 2.2-fold average coverage. Our analysis revealed a phylogenetic placement of all strains on branch 3 as well as a close relationship between the squirrel strain and one newly reconstructed medieval human strain. In particular, the medieval squirrel strain is more closely related to some medieval human strains from Winchester than to modern red squirrel strains from England, indicating a yet-undetected circulation of M. leprae in non-human hosts in the Middle Ages. Our study represents the first One Health approach for M. leprae in archaeology, which is centered around a medieval animal host strain, and highlights the future capability of such approaches to understand the disease's zoonotic past and current potential.ISSN:0960-9822ISSN:1879-044

Scoring of senescence signalling in multiple human tumour gene expression datasets, identification of a correlation between senescence score and drug toxicity in the NCI60 panel and a pro-inflammatory signature correlating with survival advantage in peritoneal mesothelioma

Background: Cellular senescence is a major barrier to tumour progression, though its role in pathogenesis of cancer and other diseases is poorly understood in vivo. Improved understanding of the degree to which latent senescence signalling persists in tumours might identify intervention strategies to provoke "accelerated senescence" responses as a therapeutic outcome. Senescence involves convergence of multiple pathways and requires ongoing dynamic signalling throughout its establishment and maintenance. Recent discovery of several new markers allows for an expression profiling approach to study specific senescence phenotypes in relevant tissue samples. We adopted a "senescence scoring" methodology based on expression profiles of multiple senescence markers to examine the degree to which signals of damage-associated or secretory senescence persist in various human tumours. Results: We first show that scoring captures differential induction of damage or inflammatory pathways in a series of public datasets involving radiotherapy of colon adenocarcinoma, chemotherapy of breast cancer cells, replicative senescence of mesenchymal stem cells, and progression of melanoma. We extended these results to investigate correlations between senescence score and growth inhibition in response to similar to 1500 compounds in the NCI60 panel. Scoring of our own mesenchymal tumour dataset highlighted differential expression of secretory signalling pathways between distinct subgroups of MPNST, liposarcomas and peritoneal mesothelioma. Furthermore, a proinflammatory signature yielded by hierarchical clustering of secretory markers showed prognostic significance in mesothelioma. Conclusions: We find that "senescence scoring" accurately reports senescence signalling in a variety of situations where senescence would be expected to occur and highlights differential expression of damage associated and secretory senescence pathways in a context-dependent manner

Charity and Conquest: Leprosaria in Early Norman England

APPEAL FROM THE SECOND JUDICIAL DISTRICT COURT IN AND FOR WEBER COUNTY, OGDEN DEPARTMENT, STATE OF UTAH JUDGE ROGER S. DUTSO