Histological 3D reconstruction and in vivo lineage tracing of the human endometrium

Regular menstrual shedding and repair of the endometrial functionalis is unique to humans and higher‐order primates. The current consensus postulates endometrial glands to have a single‐tubular architecture, where multi‐potential stem cells reside in the blind‐ending glandular‐bases. Utilising fixed samples from patients, we have studied the three‐dimensional (3D) micro‐architecture of the human endometrium. We demonstrate that some non‐branching, single, vertical functionalis glands originate from a complex horizontally interconnecting network of basalis glands. The existence of a multipotent endometrial epithelial stem cell capable of regenerating the entire complement of glandular lineages was demonstrated by in vivo lineage tracing, using naturally occurring somatic mitochondrial DNA mutations as clonal markers. Vertical tracking of mutated clones showed that at least one stem‐cell population resides in the basalis glands. These novel findings provide insight into the efficient and scar‐less regenerative potential of the human endometrium

Histological 3D reconstruction and in vivo lineage tracing of the human endometrium

Regular menstrual shedding and repair of the endometrial functionalis is unique to humans and higher‐order primates. The current consensus postulates endometrial glands to have a single‐tubular architecture, where multi‐potential stem cells reside in the blind‐ending glandular‐bases. Utilising fixed samples from patients, we have studied the three‐dimensional (3D) micro‐architecture of the human endometrium. We demonstrate that some non‐branching, single, vertical functionalis glands originate from a complex horizontally interconnecting network of basalis glands. The existence of a multipotent endometrial epithelial stem cell capable of regenerating the entire complement of glandular lineages was demonstrated by in vivo lineage tracing, using naturally occurring somatic mitochondrial DNA mutations as clonal markers. Vertical tracking of mutated clones showed that at least one stem‐cell population resides in the basalis glands. These novel findings provide insight into the efficient and scar‐less regenerative potential of the human endometrium

The Barrett's Gland in Phenotype Space

Barrett's esophagus is characterized by the erosive replacement of esophageal squamous epithelium by a range of metaplastic glandular phenotypes. These glandular phenotypes likely change over time, and their distribution varies along the Barrett's segment. Although much recent work has addressed Barrett's esophagus from the genomic viewpoint-its genotype space-the fact that the phenotype of Barrett's esophagus is nonstatic points to conversion between phenotypes and suggests that Barrett's esophagus also exists in phenotype space. Here we explore this latter concept, investigating the scope of glandular phenotypes in Barrett's esophagus and how they exist in physical and temporal space as well as their evolution and their life history. We conclude that individual Barrett's glands are clonal units; because of this important fact, we propose that it is the Barrett's gland that is the unit of selection in phenotypic and indeed neoplastic progression. Transition between metaplastic phenotypes may be governed by neutral drift akin to niche turnover in normal and dysplastic niches. In consequence, the phenotype of Barrett's glands assumes considerable importance, and we make a strong plea for the integration of the Barrett's gland in both genotype and phenotype space in future work

Evolution of oesophageal adenocarcinoma from metaplastic columnar epithelium without goblet cells in Barrett's oesophagus

Supported by the Dutch Cancer Society (KWF) and Cancer Research UK (CR-UK). This work was supported by Cancer Research UK (grant number A14895

A direct interaction between fascin and microtubules contributes to adhesion dynamics and cell migration

Fascin is an actin-binding and bundling protein that is highly upregulated in most epithelial cancers. Fascin promotes cell migration and adhesion dynamics in vitro and tumour cell metastasis in vivo. However, potential non-actin bundling roles for fascin remain unknown. Here we show for the first time that fascin can directly interact with the microtubule cytoskeleton and that this does not depend upon fascin-actin bundling. Microtubule binding contributes to fascin-dependent control of focal adhesion dynamics and cell migration speed. We also show that fascin forms a complex with focal adhesion kinase (FAK) and Src, and that this signalling pathway lies downstream of fascin-microtubule association in the control of adhesion stability. These findings shed light on new non actin-dependent roles for fascin and may have implications for the design of therapies to target fascin in metastatic disease

Quantification of crypt and stem cell evolution in the normal and neoplastic human colon.

Human intestinal stem cell and crypt dynamics remain poorly characterized because transgenic lineage-tracing methods are impractical in humans. Here, we have circumvented this problem by quantitatively using somatic mtDNA mutations to trace clonal lineages. By analyzing clonal imprints on the walls of colonic crypts, we show that human intestinal stem cells conform to one-dimensional neutral drift dynamics with a "functional" stem cell number of five to six in both normal patients and individuals with familial adenomatous polyposis (germline APC(-/+)). Furthermore, we show that, in adenomatous crypts (APC(-/-)), there is a proportionate increase in both functional stem cell number and the loss/replacement rate. Finally, by analyzing fields of mtDNA mutant crypts, we show that a normal colon crypt divides around once every 30-40 years, and the division rate is increased in adenomas by at least an order of magnitude. These data provide in vivo quantification of human intestinal stem cell and crypt dynamics.This study was supported by Cancer Research UK (to A.-M.B. and N.A.W.), the Medical Research Council (to B.C. and S.A.C.M.), the Engineering and Physical Sciences Research Council (to A.G.F.), Microsoft Research (to A.G.F.), the National Institute for Health Research University College London Hospitals Biomedical Research Centre (to M.R.J.), the Dutch Cancer Research Foundation (to M.J.), the Wellcome Trust (to B.D.S.), and Higher Education Funding Council for England (to T.A.G.)

Moral enhancement: do means matter morally?

One of the reasons why moral enhancement may be controversial, is because the advantages of moral enhancement may fall upon society rather than on those who are enhanced. If directed at individuals with certain counter-moral traits it may have direct societal benefits by lowering immoral behavior and increasing public safety, but it is not directly clear if this also benefits the individual in question. In this paper, we will discuss what we consider to be moral enhancement, how different means may be used to achieve it and whether the means we employ to reach moral enhancement matter morally. Are certain means to achieve moral enhancement wrong in themselves? Are certain means to achieve moral enhancement better than others, and if so, why? More specifically, we will investigate whether the difference between direct and indirect moral enhancement matters morally. Is it the case that indirect means are morally preferable to direct means of moral enhancement and can we indeed pinpoint relevant intrinsic, moral differences between both? We argue that the distinction between direct and indirect means is indeed morally relevant, but only insofar as it tracks an underlying distinction between active and passive interventions. Although passive interventions can be ethical provided specific safeguards are put in place, these interventions exhibit a greater potential to compromise autonomy and disrupt identity

Assessing Vaccination Sentiments with Online Social Media: Implications for Infectious Disease Dynamics and Control

There is great interest in the dynamics of health behaviors in social networks and how they affect collective public health outcomes, but measuring population health behaviors over time and space requires substantial resources. Here, we use publicly available data from 101,853 users of online social media collected over a time period of almost six months to measure the spatio-temporal sentiment towards a new vaccine. We validated our approach by identifying a strong correlation between sentiments expressed online and CDC- estimated vaccination rates by region. Analysis of the network of opinionated users showed that information flows more often between users who share the same sentiments - and less often between users who do not share the same sentiments - than expected by chance alone. We also found that most communities are dominated by either positive or negative sentiments towards the novel vaccine. Simulations of infectious disease transmission show that if clusters of negative vaccine sentiments lead to clusters of unprotected individuals, the likelihood of disease outbreaks are greatly increased. Online social media provide unprecedented access to data allowing for inexpensive and efficient tools to identify target areas for intervention efforts and to evaluate their effectiveness.Comment: Accepted for publication in PLoS Computational Biolog