Catalogue Search | MBRL
Are you sure you want to remove the book from the shelf?
{{itemTitle}}
930
result(s) for
"Yates, James"
Sort by:
Free Drug Theory – No Longer Just a Hypothesis?
The Free Drug Hypothesis is a well-established concept within the scientific lexicon pervading many areas of Drug Discovery and Development, and yet it is poorly defined by virtue of many variations appearing in the literature. Clearly, unbound drug is in dynamic equilibrium with respect to absorption, distribution, metabolism, elimination, and indeed, interaction with the desired pharmacological target. Binding interactions be they specific (e.g. high affinity) or nonspecific (e.g. lower affinity/higher capacity) are governed by the same fundamental physicochemical tenets including Hill-Langmuir Isotherms, the Law of Mass Action and Drug Receptor Theory. With this in mind, it is time to recognise a more coherent version and consider it the Free Drug Theory and a hypothesis no longer. Today, we have the experimental and modelling capabilities, pharmacological knowledge, and an improved understanding of unbound drug distribution (e.g. Kpuu) to raise the bar on our understanding and analysis of experimental data. The burden of proof should be to rule out mechanistic possibilities and/or experimental error before jumping to the conclusion that any observations contradict these fundamentals.
Journal Article
Ancient DNA data hold insights into past organisms and ecosystems — handle them with more care
DNA recovered from ancient remains is transforming our understanding of organisms and ecosystems from tens, thousands and even millions of years ago – but the growing volume of data must be better preserved.
DNA recovered from ancient remains is transforming our understanding of organisms and ecosystems from tens, thousands and even millions of years ago – but the growing volume of data must be better preserved.
Journal Article
Ecology, Not Host Phylogeny, Shapes the Oral Microbiome in Closely Related Species
Abstract
Host-associated microbiomes are essential for a multitude of biological processes. Placed at the contact zone between external and internal environments, the little-studied oral microbiome has important roles in host physiology and health. Here, we investigate the roles of host evolutionary relationships and ecology in shaping the oral microbiome in three closely related gorilla subspecies (mountain, Grauer's, and western lowland gorillas) using shotgun metagenomics of 46 museum-preserved dental calculus samples. We find that the oral microbiomes of mountain gorillas are functionally and taxonomically distinct from the other two subspecies, despite close evolutionary relationships and geographic proximity with Grauer's gorillas. Grauer's gorillas show intermediate bacterial taxonomic and functional, and dietary profiles. Altitudinal differences in gorilla subspecies ranges appear to explain these patterns, suggesting a close connection between dental calculus microbiomes and the environment, likely mediated through diet. This is further supported by the presence of gorilla subspecies-specific phyllosphere/rhizosphere taxa in the oral microbiome. Mountain gorillas show a high abundance of nitrate-reducing oral taxa, which may promote adaptation to a high-altitude lifestyle by modulating blood pressure. Our results suggest that ecology, rather than evolutionary relationships and geographic distribution, shape the oral microbiome in these closely related species.
Journal Article
Reproducible, portable, and efficient ancient genome reconstruction with nf-core/eager
The broadening utilisation of ancient DNA to address archaeological, palaeontological, and biological questions is resulting in a rising diversity in the size of laboratories and scale of analyses being performed. In the context of this heterogeneous landscape, we present an advanced, and entirely redesigned and extended version of the EAGER pipeline for the analysis of ancient genomic data. This Nextflow pipeline aims to address three main themes: accessibility and adaptability to different computing configurations, reproducibility to ensure robust analytical standards, and updating the pipeline to the latest routine ancient genomic practices. The new version of EAGER has been developed within the nf-core initiative to ensure high-quality software development and maintenance support; contributing to a long-term life-cycle for the pipeline. nf-core/eager will assist in ensuring that a wider range of ancient DNA analyses can be applied by a diverse range of research groups and fields.
Journal Article
Skipping a pillar does not make for strong foundations: Pharmacokinetic‐pharmacodynamic reasoning behind the shape of dose–response relationships in oncology
Dose–response analysis is often applied to the quantification of drug‐effect especially for slowly responding disease end points where a comparison is made across dose levels after a particular period of treatment. It has long been recognized that exposure – response is more appropriate than dose–response. However, trials necessarily are designed as dose–response experiments. Second, a wide range of functional forms are used to express relationships between dose and response. These considerations are also important for clinical development because pharmacokinetic (PK; and variability) plus pharmacokinetic‐pharmacodynamic modeling may allow one to anticipate the shape of the dose–response curve and so the trial design. Here, we describe how the location and steepness of the dose response is determined by the PKs of the compound being tested and its exposure‐response relationship in terms of potency (location), efficacy (maximum effect) and Hill coefficient (steepness). Thus, the location (50% effective dose [ED50]) is dependent not only on the potency (half‐maximal effective concentration) but also the compound's PKs. Similarly, the steepness of the dose response is shown to be a function of the half‐life of the drug. It is also shown that the shape of relationship varies dependent on the assumed time course of the disease. This is important in the context of drug‐discovery where the in vivo potencies of compounds are compared as well as when considering an analysis of summary data (for example, model‐based meta‐analysis) for clinical decision making.
Journal Article
Microbial differences between dental plaque and historic dental calculus are related to oral biofilm maturation stage
Background
Dental calculus, calcified oral plaque biofilm, contains microbial and host biomolecules that can be used to study historic microbiome communities and host responses. Dental calculus does not typically accumulate as much today as historically, and clinical oral microbiome research studies focus primarily on living dental plaque biofilm. However, plaque and calculus reflect different conditions of the oral biofilm, and the differences in microbial characteristics between the sample types have not yet been systematically explored. Here, we compare the microbial profiles of modern dental plaque, modern dental calculus, and historic dental calculus to establish expected differences between these substrates.
Results
Metagenomic data was generated from modern and historic calculus samples, and dental plaque metagenomic data was downloaded from the Human Microbiome Project. Microbial composition and functional profile were assessed. Metaproteomic data was obtained from a subset of historic calculus samples. Comparisons between microbial, protein, and metabolomic profiles revealed distinct taxonomic and metabolic functional profiles between plaque, modern calculus, and historic calculus, but not between calculus collected from healthy teeth and periodontal disease-affected teeth. Species co-exclusion was related to biofilm environment. Proteomic profiling revealed that healthy tooth samples contain low levels of bacterial virulence proteins and a robust innate immune response. Correlations between proteomic and metabolomic profiles suggest co-preservation of bacterial lipid membranes and membrane-associated proteins.
Conclusions
Overall, we find that there are systematic microbial differences between plaque and calculus related to biofilm physiology, and recognizing these differences is important for accurate data interpretation in studies comparing dental plaque and calculus.
Journal Article