A multiscale model of virus pandemic: Heterogeneous interactive entities in a globally connected world

This paper is devoted to the multidisciplinary modelling of a pandemic initiated by an aggressive virus, specifically the so-called SARS–CoV–2 Severe Acute Respiratory Syndrome, corona virus n.2. The study is developed within a multiscale framework accounting for the interaction of different spatial scales, from the small scale of the virus itself and cells, to the large scale of individuals and further up to the collective behaviour of populations. An interdisciplinary vision is developed thanks to the contributions of epidemiologists, immunologists and economists as well as those of mathematical modellers. The first part of the contents is devoted to understanding the complex features of the system and to the design of a modelling rationale. The modelling approach is treated in the second part of the paper by showing both how the virus propagates into infected individuals, successfully and not successfully recovered, and also the spatial patterns, which are subsequently studied by kinetic and lattice models. The third part reports the contribution of research in the fields of virology, epidemiology, immune competition, and economy focussed also on social behaviours. Finally, a critical analysis is proposed looking ahead to research perspectives.publishedVersionFil: Bellomo, Nicola. Universidad de Granada. Departamento de Matemática Aplicada; España.Fil: Bingham, Richard. University of York. Departments of Mathematics and Biology. Cross-disciplinary Centre for Systems Analysis; United Kingdom.Fil: Chaplain, Mark A. J. University of St Andrews. School of Mathematics and Statistics; Scotland.Fil: Dosi, Giovanni. Scuola Superiore Sant’Anna. Institute of Economics and EMbeDS; Italia.Fil: Forni, Guido. Accademia Nazionale dei Lincei; Italia.Fil: Knopoff, Damian A. Universidad Nacional de Córdoba. Facultad de Matemática, Astronomía, Física y Computación; Argentina.Fil: Knopoff, Damian A. Consejo Nacional de Investigaciones Científicas y Técnicas de Argentina. Centro de Investigacion y Estudios de Matematica; Argentina.Fil: Lowengrub, John. University California Irvine. Department of Mathematics; United States.Fil: Twarock, Reidun. University of York. Departments of Mathematics and Biology. Cross-disciplinary Centre for Systems Analysis; United Kingdom.Fil: Virgillito, Maria Enrica.Scuola Superiore Sant’Anna. Institute of Economics and EMbeDS; Italia

Epigenetic characterization of human hepatocyte subpopulations in context of complex metabolic diseases and during in vitro differentiation of hepatocyte-like cells

The comprehensive transcriptional and epigenetic characterization of human hepatocyte subpopulations is necessary to achieve a better understanding of regulatory processes in health and complex metabolic diseases as well as during in vitro differentiation. Based on integrative analysis of genome-wide sequencing data, this thesis aims to unravel hepatocyte heterogeneity in different biological contexts. A deeper understanding of spatial organization of cells in human tissues is an important challenge. Using a unique experimental set-up based on laser capture microdissection coupled to next generation sequencing, which preserves spatial orientation and still provides genome-wide data of well defined subpopulations, the first combined spatial analysis of transcriptomes and methylomes across three micro-dissected zones of human liver provides a wealth of new positional insights, both in health and in context of fatty liver disease. In addition, these spatial maps serve as reference for projection of single cell data into hepatic pseudospace, which is still a major challenge. Hence, a novel pseudospace inference approach, which considerably improves spatial reconstruction of single cells into tissue context, is demonstrated for human liver. Finally, the identification of underlying regulatory networks by integrative epigenomic analysis of in vitro differentiated hepatocyte-like cells contributes to the development of reasonable cell culture interventions to improve differentiation.Die umfassende transkriptionelle und epigenetische Charakterisierung humaner Leberzellsubpopulationen ist notwendig für die Aufklärung regulatorischer Prozesse in gesundem Gewebe, sowie im Zusammenhang mit komplexen metabolischen Erkrankungen und während der in vitro Differenzierung. Ziel dieser Arbeit ist es, basierend auf der integrativen Analyse genomweiter Sequenzierungsdaten, die Heterogenität von Leberzellen besser zu verstehen. Die räumliche Organisation von Zellen in humanem Gewebe stellt eine große Herausforderung dar. Mit Hilfe von Lasermikrodissektion gekoppelt an Hochdurchsatzsequenzierung ist es möglich definierte Subpopulationen hinsichtlich ihres Gewebekontextes zu analysieren. Somit konnte die erste räumliche Analyse von Transkriptom und Methylom dreier Zonen der humanen Leber erstellt werden, die eine Vielzahl neuer Erkenntnisse sowohl in gesundem Lebergewebe als auch in Zusammenhang mit Fettlebererkrankungen liefert. Außerdem wurde auf Grundlage dieser räumlichen Karten ein neuer Ansatz zur Projektion von Einzelzelldaten in den räumlichen Gewebekontext etabliert. Schließlich konnte durch die integrative Analyse der ausschlaggebenden regulatorischen Netzwerke während der in vitro Differenzierung von Hepatozyten-ähnlichen Zellen neue Strategien zur Verbesserung der Differenzierung entwickelt werden

Establishment and regulation of polar growth in Streptomyces

A fundamental question in developmental biology is how cells establish polarity, and most strikingly how cells grow polarly. From neuronal dendrites and root hairs to bud emergence and elongation of yeast, broadly conserved pathways control cell polarity in eukaryotes. In contrast, virtually nothing is known about the regulatory mechanisms controlling polar cell growth in prokaryotes. In evolutionary terms, the most ancient form of polar growth is found in the branching hyphae of the filamentous bacteria Streptomyces, and it is clear that the essential coiled-coil protein DivIVA, which forms part of a tip-organising, multiprotein polarisome complex, plays a key role in the control of cell polarity, apical growth and hyphal branching in Streptomyces coelicolor. I identified and characterised two regulatory mechanisms, both reminiscent of aspects of cell polarity control in eukaryotes. First, I show that the mechanistic basis of branch-site selection during hyphal growth in Streptomyces is a novel polarisome splitting mechanism, in which the apical tip polarisome splits to leave behind a small daughter polarisome on the lateral membrane as the tip grows away. This daughter polarisome gradually grows in size, and ultimately initiates the outgrowth of a new branch. Second, I show that the Ser/Thr protein kinase AfsK is part of an apparatus that controls the polarisome complex at the hyphal tip. Activated AfsK directly phosphorylates DivIVA and profoundly alters the subcellular localisation of DivIVA to establish multiple new sites of polar growth. Thereby, AfsK modulates apical growth and lateral branching during normal growth and cell wall stress. I suggest that this is part of a stress response that provides Streptomyces with a mechanism to dismantle the apical growth apparatus at established hyphal tips that encounter problems with cell wall synthesis (for example through exposure to an antibiotic or by hitting a physical obstacle in the soil) and instead direct emergence of new branches elsewhere along the hyphae

Wheat Improvement

This open-access textbook provides a comprehensive, up-to-date guide for students and practitioners wishing to access in a single volume the key disciplines and principles of wheat breeding. Wheat is a cornerstone of food security: it is the most widely grown of any crop and provides 20% of all human calories and protein. The authorship of this book includes world class researchers and breeders whose expertise spans cutting-edge academic science all the way to impacts in farmers’ fields. The book’s themes and authors were selected to provide a didactic work that considers the background to wheat improvement, current mainstream breeding approaches, and translational research and avant garde technologies that enable new breakthroughs in science to impact productivity. While the volume provides an overview for professionals interested in wheat, many of the ideas and methods presented are equally relevant to small grain cereals and crop improvement in general. The book is affordable, and because it is open access, can be readily shared and translated -- in whole or in part -- to university classes, members of breeding teams (from directors to technicians), conference participants, extension agents and farmers. Given the challenges currently faced by academia, industry and national wheat programs to produce higher crop yields --- often with less inputs and under increasingly harsher climates -- this volume is a timely addition to their toolkit

Genetics and Genomics of Forest Trees

Forest tree genetics and genomics are advancing at an accelerated rate, thanks to recent developments in high-throughput, next-generation sequencing capabilities, and novel biostatistical tools. Population and landscape genetics and genomics have seen the rise of new approaches implemented in large-scale studies that employ the use of genome-wide sampling. Such studies have started to discern the dynamics of neutral and adaptive variation in nature and the processes that underlie spatially explicit patterns of genetic and genomic variation in nature. The continuous development of genetic maps in forest trees and the expansion of QTL and association mapping approaches contribute to the unravelling of the genotype-phenotype relationship and lead to marker-assisted and genome-wide selection. However, major challenges lie ahead. Recent literature suggests that species demography and genetic diversity have been affected both by climatic oscillations and anthropogenically induced stresses in a way calls into question the possibility of future adaptation. Moreover, the pace of contemporary environmental change presents a great challenge to forest tree populations and their ability to adapt, taking into consideration their life history characteristics. Several questions emerge that include, but are not limited to, the interpretation of forest tree genome surveillance and their structural/functional properties, the adaptive and neutral processes that have shaped forest tree genomes, the analysis of phenotypic traits relevant to adaptation (especially adaptation under contemporary climate change), the link between epigenetics/epigenomics and phenotype/genotype, and the use of genetics/genomics as well as genetic monitoring to advance conservation priorities

Integrating genomics with the fossil record to explore the evolutionary history of Echinoidea

Echinoidea constitutes one of five major clades of living echinoderms, marine animals uniquely characterized by a pentaradial symmetry. Approximately 1,000 living and 10,000 extinct species have been described, including many commonly known as sea urchins, heart urchins and sand dollars. Today, echinoids are ubiquitous in benthic marine environments, where they strongly affect the functioning of biodiverse communities such as coral reefs and kelp forests. Given the quality of their fossil record, their remarkable morphological complexity and our thorough understanding of their development, echinoids provide unparalleled opportunities to explore evolutionary questions in deep-time, providing access to the developmental and morphological underpinnings of evolutionary innovation. These questions cannot be addressed without first resolving the phylogenetic relationships among living and extinct lineages. The goal of this dissertation is to advance our understanding of echinoid relationships and evolutionary history, as well as to explore more broadly the integration of phylogenomic, morphological and paleontological data in phylogenetic reconstruction and macroevolutionary inference.In Chapter 1, I report the results of the first phylogenomic analysis of echinoids based on the sequencing of 17 novel echinoid transcriptomes. Phylogenetic analyses of this data resolve the position of several clades—including the sand dollars—in disagreement with traditional morphological hypotheses. I demonstrate the presence of a strong phylogenetic signal for these novel resolutions, and explore scenarios to reconcile these findings with morphological evidence. In Chapter 7, I extend this approach with a more thorough taxon sampling, resulting in a robust topology with a near-complete sampling of major echinoid lineages. This effort reveals that apatopygids, a clade of three species with previously unclear affinities, represent the only living descendants of a once diverse Mesozoic clade. I also perform a thorough time calibration analysis, quantifying the relative effects of choosing among alternative models of molecular evolution, gene samples and clock priors. I introduce the concept of a chronospace and use it to reveal that only the last among the aforementioned choices affects significantly our understanding of echinoid diversification. Molecular clocks unambiguously support late Permian and late Cretaceous origins for crown group echinoids and sand dollars, respectively, implying long ghost ranges for both. Fossils have been shown to improve the accuracy of phylogenetic comparative methods, warranting their inclusion alongside extant terminals when exploring evolutionary processes across deep timescales. However, their impact on topological inference remains controversial. I explore this topic in Chapter 3 with the use of simulations, which show that morphological phylogenies are more accurate when fossil taxa are incorporated. I also show that tip-dated Bayesian inference, which takes stratigraphic information from fossils into account, outperforms uncalibrated methods. This approach is complemented in Chapter 2 with the analysis of empirical datasets, confirming that incorporating fossils reshapes phylogenies in a manner that is entirely distinct from increased sampling of extant taxa, a result largely attributable to the occurrence of distinctive character combinations among fossils. Even though phylogenomic and paleontological data are complementary resources for unraveling the relationships and divergence times of lineages, few studies have attempted to fully integrate them. Chapter 4 revisits the phylogeny of crown group Echinoidea using a total-evidence dating approach combining phylogenomic, morphological and stratigraphic information. To this end, I develop a method (genesortR) for subsampling molecular datasets that selects loci with high phylogenetic signal and low systematic biases. The results demonstrate that combining different data sources increases topological accuracy and helps resolve phylogenetic conflicts. Notably, I present a new hypothesis for the origin and early morphological evolution of the sand dollars and close allies. In Chapter 6, I compare the behavior of genesortR against alternative subsampling strategies across a sample of phylogenomic matrices. I find this method to systematically outperform random loci selection, unlike commonly-used approaches that target specific evolutionary rates or minimize sources of systematic error. I conclude that these methods should not be used indiscriminately, and that multivariate methods of phylogenomic subsampling should be favored. Finally, in Chapter 5, I explore the macroevolutionary dynamics of echinoid body size across 270 million years using data for more than 5,000 specimens in a phylogenetically explicit context. I also develop a method (extendedSurface) for parameterizing adaptive landscapes that overcomes issues with existing approaches and finds better fitting models. While echinoid body size has been largely constrained to evolve within a single adaptive peak, the disparity of the clade was generated by regime shifts driving the repeated evolution of miniaturized and gigantic forms. Most innovations occurred during the latter half of the Mesozoic, and were followed by a drastic slowdown in the aftermath of the Cretaceous-Paleogene mass extinction

Volume 1

"Europe’s Lost Frontiers was the largest directed archaeological research project undertaken in Europe to investigate the inundated landscapes of the Early Holocene North Sea – the area frequently referred to as ‘Doggerland’. Funded through a European Research Council Advanced Grant (project number 670518), the project ran from 2015 to 2021, and involved more than 30 academics, representing institutions spread geographically from Ireland to China. A vast area of the seabed was mapped, and multiple ship expeditions were launched to retrieve sediment cores from the valleys of the lost prehistoric landscapes of the North Sea. This data has now been analysed to provide evidence of how the land was transformed in the face of climate change and rising sea levels. This volume is the first in a series of monographs dedicated to the analysis and interpretation of data generated by the project. As a precursor to the publication of the detailed results, it provides the context of the study and method statements. Later volumes will present the mapping, palaeoenvironment, geomorphology and modelling programmes of Europe’s Lost Frontiers. The results of the project confirm that these landscapes, long held to be inaccessible to archaeology, can be studied directly and provide an archaeological narrative. This data will become increasingly important at a time when contemporary climate change and geo-political crises are pushing development within the North Sea at an unprecedented rate, and when the opportunities to explore this unique, heritage landscape may be significantly limited in the future.