Computational studies of vascularized tumors

Cancer is a hard problem touching numerous branches of life science. One reason for the complexity of cancer is that tumors act across many different time and length scales ranging from the subcellular to the macroscopic level. Modern sciences still lack an integral understanding of cancer, however in recent years, increasing computational power enabled computational models to accompany and support conventional medical and biological methods bridging the scales from micro to macro. Here I report a multiscale computational model simulating the progression of solid tumors comprising the vasculature mimicked by artificial arterio-venous blood vessel networks. I present a numerical optimization procedure to determine radii of blood vessels in an artificial microcirculation based on physiological stimuli independently of Murray’s law. Comprising the blood vessels, the reported model enables the inspection of blood vessel remodeling dynamics (angiogenesis, vaso-dilation, vessel regression and collapse) during tumor growth. We successfully applied the method to simulated tumor blood vessel networks guided by optical mammography data. In subsequent model development, I included cellular details into the method enabling a computational study of the tumor microenvironment at cellular resolution. I found that small vascularized tumors at the angiogenic switch exhibit a large ecological niche diversity resulting in high evolutionary pressure favoring the colonal selecion hypothesis.Krebs ist ein schwieriges Thema und tritt in zahlreichen Gebieten auf. Ein Grund für die Komplexität des Tumorwachstums sind die unterschiedlichen Zeit- und Längenskalen. In der aktuellen Forschung fehlt immernoch ein ganzheitliches Verständnis von Krebs, obwohl die computergestützten Methoden in den vergangenen Jahren die konventionellen Methoden der Medizin und der Biologie erweitern und unterstützen. Damit wird die Kluft zwischen subzellulären und makroskopischen Prozessen bereits verringert. In der vorliegenden Arbeit dokumentiere ich ein computergestütztes Verfahren, welches das Tumorwachstum auf mehreren Skalen simuliert. Insbesondere wird das Blutgefäßsystem durch künstliche Gefäße nachgeahmt. Es wurde ein numerisches Optimierungsverfahren zur Bestimmung der Gefäßradien eines künstlichen Blutkreislaufes entwickelt, welches auf physiologischen Reizen basiert und unabhängig von Murray‘s Gesetz ist. Da das beschriebene Verfahren zur Simulation von Tumoren Blutgefäße beinhaltet, kann die Umbildung des Gefäßbaumes während des Tumorwachstums untersucht werden. Das Modell wurde erfolgreich mit krankhaften Gefäßsystemen verglichen. In der darauffolgenden Weiterentwicklung des Modells berücksichtigte ich zelluläre Feinheiten, die es mir erlaubten das Mikromilieu in zellulärer Auflösung zu untersuchen. Meine Resultate zeigen, dass bereits kleine Tumore eine hohe ökologische Vielfalt besitzen, was den Selektionsdruck erhöht und damit die Klon-Selektionstheorie begünstigt

Novel macrophage microbicidal responses against gram-positive bacteria

Antimicrobial resistance is a major global health threat, and there is growing interest in how modulation of the host immune response can enhance pathogen killing and reduce reliance on antimicrobials. One target cell is the macrophage; a key innate immune cell that possesses a range of microbicidal mechanisms and can combine responses for optimal pathogen killing. Streptococcus pneumoniae and Staphylococcus aureus are important gram-positive pathogens that represent differing intracellular burdens for the macrophage. A key macrophage microbicidal mechanism relevant to the killing of these pathogens is production of reactive oxygen species (ROS). While NADPH oxidase-derived ROS is an early response to infection, mitochondrial ROS (mROS) production is a later response and is enhanced during infection by alterations in mitochondrial dynamics. ROS and mROS can combine with other macrophage responses to facilitate pathogen killing, therefore the significance and potential for such interplay with other host defence mechanisms to enhance macrophage killing of pathogens such as S. pneumoniae and S. aureus is the focus of this thesis, with specific attention to mitochondrial-associated responses and the microbicidal and immunomodulatory host defence peptide cathelicidin. The data presented in this thesis show that expression of the CAMP gene, encoding cathelicidin, was upregulated by vitamin D in macrophages, was synergistically enhanced by bacterial infection or phenylbutyrate and was impaired by pro-inflammatory cytokines. Cathelicidin directly killed extracellular S. pneumoniae and contributed to early macrophage killing of intracellular S. aureus when bacterial burden was high. Mitochondrial adaptations to S. pneumoniae were more prevalent in macrophages during later stages of bacterial challenge and included increased mitochondrial fission and increased mROS production. Mitochondrial adaptations to S. aureus, which stresses macrophage microbicidal responses to a greater extent than S. pneumoniae, were observed during early stages of bacterial challenge. The regulators of canonical fission, dynamin-related protein 1 (Drp1) and mitochondrial fission factor (Mff), failed to influence overall levels of fission in the initial response to S. aureus. In contrast, Drp1 regulated localisation of mROS to intracellular S. aureus in a subset of macrophages, suggesting roles in mROS delivery to bacterial-containing phagolysosomes. In regard to mechanisms of mROS production, I have provided evidence that reverse electron transport (RET) occurs as an early response to S. pneumoniae challenge, but not late S. pneumoniae, or S. aureus challenge. S. aureus enhanced mROS production in macrophages, and while NADPH oxidase-derived ROS was the greater contributor to early killing of S. aureus, mROS also contributed to killing. Cathelicidin enhanced microbicidal responses against S. aureus particularly when NADPH oxidase-derived ROS generation was impaired, but also appeared to function as a brake on alterations in mitochondrial dynamics and mROS production in the presence of bacteria, therefore potentially regulating mitochondrial homeostasis. Results in this thesis demonstrate that macrophages use ROS, alterations in mitochondrial dynamics and mROS, and cathelicidin to combat S. pneumoniae and S. aureus infections with pathogen-dependent kinetics. Macrophages adapt responses to different pathogens to ensure a multi-layered immune response to clear pathogens. The work in this thesis provides greater insight into macrophage microbicidal responses to S. pneumoniae and S. aureus infection and could inform future therapeutic strategies to enhance macrophage microbicidal responses

Biotechnology to Combat COVID-19

This book provides an inclusive and comprehensive discussion of the transmission, science, biology, genome sequencing, diagnostics, and therapeutics of COVID-19. It also discusses public and government health measures and the roles of media as well as the impact of society on the ongoing efforts to combat the global pandemic. It addresses almost every topic that has been studied so far in the research on SARS-CoV-2 to gain insights into the fundamentals of the disease and mitigation strategies. This volume is a useful resource for virologists, epidemiologists, biologists, medical professionals, public health and government professionals, and all global citizens who have endured and battled against the pandemic

Molecular phylogeny of horseshoe crab using mitochondrial Cox1 gene as a benchmark sequence

An effort to assess the utility of 650 bp Cytochrome C oxidase subunit I (DNA barcode) gene in delineating the members horseshoe crabs (Family: xiphosura) with closely related sister taxa was made. A total of 33 sequences were extracted from National Center for Biotechnological Information (NCBI) which include horseshoe crabs, beetles, common crabs and scorpion sequences. Constructed phylogram showed beetles are closely related with horseshoe crabs than common crabs. Scorpion spp were distantly related to xiphosurans. Phylogram and observed genetic distance (GD) date were also revealed that Limulus polyphemus was closely related with Tachypleus tridentatus than with T.gigas. Carcinoscorpius rotundicauda was distantly related with L.polyphemus. The observed mean Genetic Distance (GD) value was higher in 3rd codon position in all the selected group of organisms. Among the horseshoe crabs high GC content was observed in L.polyphemus (38.32%) and lowest was observed in T.tridentatus (32.35%). We conclude that COI sequencing (barcoding) could be used in identifying and delineating evolutionary relatedness with closely related specie

Crab and cockle shells as heterogeneous catalysts in the production of biodiesel

In the present study, the waste crab and cockle shells were utilized as source of calcium oxide to transesterify palm olein into methyl esters (biodiesel). Characterization results revealed that the main component of the shells are calcium carbonate which transformed into calcium oxide upon activated above 700 °C for 2 h. Parametric studies have been investigated and optimal conditions were found to be catalyst amount, 5 wt.% and methanol/oil mass ratio, 0.5:1. The waste catalysts perform equally well as laboratory CaO, thus creating another low-cost catalyst source for producing biodiesel. Reusability results confirmed that the prepared catalyst is able to be reemployed up to five times. Statistical analysis has been performed using a Central Composite Design to evaluate the contribution and performance of the parameters on biodiesel purity

Multimetal smithing : An urban craft in rural settings?

Multimetal smithing should be defined as the use of more than one metal and/or different metalworking techniques within thesame crafts-milieu. This complex metalworking has long been linked to centrality, central places and urbanity in Scandinavia.It has been extensively argued that fine casting and smithing, as well as manufacture utilizing precious metals was exclusivelyundertaken within early urban settings or the “central places” pre-dating these. Furthermore, the presence of complex metalcraftsmanship has been used as a driving indicator of the political, social and economic superiority of certain sites, therebyenhancing their identity as “centralities”.Recent research has come to challenge the universality of this link between urbanity, centrality and complex metalworkingas sites in rural settings with evidence of multimetal smithing are being identified. This shows that the relationship between thecraft and centrality (urbanity) must be nuanced and that perhaps multimetal craftsmanship should be reconsidered as an urbanindicator.The thesis project “From Crucible and onto Anvil” started in 2015 and focuses on sites housing remains of multimetalcraftsmanship dating primarily from 500-1000 AD. Within the project a comprehensive survey of sites will be used to evaluate thepresence of multimetal craftsmanship in the landscape. Sites in selected target areas will also be subject to intra-site analysisfocusing on workshop organisation, production output, metalworking techniques and chronological variances.A key aim in the project is to elucidate the conceptual aspects of complex metalworking. The term multimetality is used toanalytically frame all the societal and economic aspects of multimetal craftsmanship. Through this inclusive perspective both thecraftsmanship and the metalworkers behind it are positioned within the overall socioeconomic framework. The metalworkers,their skills and competences as well as the products of their labour are viewed as dynamic actors in the landscape and on thearenas of political economy of the Late Iron Age.The survey has already revealed interesting aspects concerning multimetal smithing and urbanity. Although the multimetalsites do cluster against areas of early urban development there are also other patterns emerging. Multimetal craftsmanship – both as practice and concept – was well represented in both rural peripheral settings and urban crafts-milieus. This means that therole of multimetality as part of an “urban conceptual package” is crucial to investigate. Such an approach will have the dual endsof properly understanding the craft and its societal implications, but also further the knowledge of the phenomenon of urbanityas a whole. Was multimetal smithing part of an “urban package” that spread into the rural landscape? Did the multimetality differbetween urban and rural crafts-milieus? How does early urbanity relate to the chronology of multimetal craftsmanship?This paper aims to counter these questions using examples from the survey of multimetal sites conducted within the thesisproject. A comparison between selected sites will be presented. The purpose of this is to evaluate the role of multimetality withinthe “urban package” and discuss the role of complex metalworking in the establishment of urban arenas of interaction in LateIron Age Scandinavia