Morphological change in an isolated population of red squirrels () in Britain.

The mechanical properties of dietary items are known to influence skull morphology, either through evolution or by phenotypic plasticity. Here, we investigated the impact of supplementary feeding of peanuts on the morphology of red squirrels () from five populations in Britain (North Scotland, Borders, Jersey and two temporally distinct populations from Formby (Merseyside)). Stable isotope analysis confirmed dietary ecology in 58 specimens.

An Update on the Nitrogen Heterocycle Compositions and Properties of U.S. FDA-Approved Pharmaceuticals (2013-2023).

This Perspective is a continuation of our analysis of U.S. FDA-approved small-molecule drugs (1938-2012) containing nitrogen heterocycles.

Beyond Rule of Five and PROTACs in Modern Drug Discovery: Polarity Reducers, Chameleonicity, and the Evolving Physicochemical Landscape.

Developing orally bioavailable drugs demands an understanding of absorption in early drug development. Traditional methods and physicochemical properties optimize absorption for rule of five (Ro5) compounds; beyond rule of five (bRo5) drugs necessitate advanced tools like the experimental measure of exposed polarity (EPSA) and the AbbVie multiparametric score (AB-MPS). Analyzing AB-MPS and EPSA against ∼1000 compounds with human absorption data and ∼10,000 AbbVie tool compounds (∼1000 proteolysis targeting chimeras or PROTACs, ∼7000 Ro5s, and ∼2000 bRo5s) revealed new patterns of physicochemical trends.

Mandibular characteristics of early Glires (Mammalia) reveal mixed rodent and lagomorph morphotypes.

Glires (rodents, lagomorphs and their fossil kin) is the most speciose and arguably most diversified clade of living placentals. Different lineages within the Glires evolved basically opposite chewing movements: a mostly transversal power stroke in lagomorphs, and a mostly proal power stroke in rodents, but the ancestral condition for Glires is still unclear. To address this knowledge gap, we studied the mandibles of Chinese Palaeocene Glires representing the duplicidentate (lagomorph-like; ) and simplicidentate (rodent-like; and ) lineages.

Feeding biomechanics reveals niche differentiation related to insular gigantism.

Insular gigantism is an evolutionary phenomenon whereby small animals become bigger on islands compared to their mainland relatives. The abundance of insular giant taxa in the fossil record suggests the presence of a universal "giant niche" present on islands, with resource limitation as a potential driver for this process. However, insular habitats are ecologically diverse, suggesting that island taxa adopt different survival strategies, including adaptations for foraging behaviors.

Masticatory biomechanics of red and grey squirrels ( and ) modelled with multibody dynamics analysis.

The process of feeding in mammals is achieved by moving the mandible relative to the cranium to bring the teeth into and out of occlusion. This process is especially complex in rodents which have a highly specialized configuration of jaw adductor muscles. Here, we used the computational technique of multi-body dynamics analysis (MDA) to model feeding in the red () and grey squirrel () and determine the relative contribution of each jaw-closing muscle in the generation of bite forces.

The evolution of unique cranial traits in leporid lagomorphs.

Background: The leporid lagomorphs (rabbits and hares) are adapted to running and leaping (some more than others) and consequently have unique anatomical features that distinguish them from ochotonid lagomorphs (pikas) and from their rodent relatives. Two traits that have received some attention are fenestration of the lateral wall of the maxilla and facial tilting. These features are known to correlate with specialised locomotory form in that the faster running species will generally have fenestration that occupies the dorsal and the anteroventral surface of the maxillary corpus and a more acute facial tilt angle.

Multidisciplinary Insights into the Structure-Function Relationship of the CYP2B6 Active Site.

Cytochrome P450 2B6 (CYP2B6) is a highly polymorphic human enzyme involved in the metabolism of many clinically relevant drugs, environmental toxins, and endogenous molecules with disparate structures. Over the last 20-plus years, in silico and in vitro studies of CYP2B6 using various ligands have provided foundational information regarding the substrate specificity and structure-function relationship of this enzyme. Approaches such as homology modeling, X-ray crystallography, molecular docking, and kinetic activity assays coupled with CYP2B6 mutagenesis have done much to characterize this originally neglected monooxygenase.

Effects of Electrode Support Structure on Electrode Microstructure, Transport Properties, and Gas Diffusion within the Gas Diffusion Layer.

The effects of gas diffusion layer (GDL) and electrode microstructure, which influence the catalyst layer and catalyst-membrane interface on the performance of a membrane electrode assembly (MEA) for gas-phase electrolysis and the separation of CO were experimentally characterized. Several types of GDL materials, with and without a microporous layer (MPL), were characterized using scanning electron microscopy (SEM) and Brunauer-Emmett-Teller (BET) surface area analysis. The diffusion of reactants through the GDL materials was measured to determine the effects on the microstructure and chemical properties on mass transport.

Identification and structure-based drug design of cell-active inhibitors of interleukin 17A at a novel C-terminal site.

Anti-IL17A therapies have proven effective for numerous inflammatory diseases including psoriasis, axial spondylitis and psoriatic arthritis. Modulating and/or antagonizing protein-protein interactions of IL17A cytokine binding to its cell surface receptors with oral therapies offers the promise to bring forward biologics-like efficacy in a pill to patients. We used an NMR-based fragment screen of recombinant IL17A to uncover starting points for small molecule IL17A antagonist discovery.

Body size, shape and ecology in tetrapods.

Body size and shape play fundamental roles in organismal function and it is expected that animals may possess body proportions that are well-suited to their ecological niche. Tetrapods exhibit a diverse array of body shapes, but to date this diversity in body proportions and its relationship to ecology have not been systematically quantified. Using whole-body skeletal models of 410 extinct and extant tetrapods, we show that allometric relationships vary across individual body segments thereby yielding changes in overall body shape as size increases.

Contemporary Computational Applications and Tools in Drug Discovery.

In the past decade or so there has been a dramatic increase in the number of computational applications and tools that have been developed to enable medicinal chemists to prosecute modern drug discovery programs more efficiently. The upsurge of user-friendly, well-designed computational tools that enable structure-based drug design (SBDD) and cheminformatics (CI)-based drug design has equipped the medicinal chemist with an arsenal of tools and applications that significantly augments the entire design process, thereby enhancing the speed and efficiency of the design-make-test-analyze cycle. Modern computational applications and tools transcend all areas of drug discovery, and most savvy medicinal chemists can employ them effectively in a myriad of drug discovery applications.

Phenols in Pharmaceuticals: Analysis of a Recurring Motif.

Phenols and phenolic ethers are significant scaffolds recurring both in nature and among approved small-molecule pharmaceuticals. This compendium presents the first comprehensive compilation and analysis of the structures of U.S.

Mandible shape variation and feeding biomechanics in minks.

European and American minks are very similar in ecology, behavior and morphology. Both species hunt terrestrial vertebrates and aquatic prey, but the American mink is a more generalist predator which, among other factors, allows it to outcompete the European mink in areas where it has been introduced. We used 3D geometric morphometrics and estimates of muscle mechanical advantage to assess the degree of variation in mandibular morphology, and to determine whether such variation reflects dietary differences between the two species.

The biomechanical significance of the elongated rodent incisor root in the mandible during incision.

Rodents are characterised by a distinctive masticatory apparatus which includes a single pair of enlarged and continually growing incisors. This morphology, termed diprotodonty, has also independently evolved in a number of other mammals, including the aye-aye. This study examined the functional significance of the internal "root" of the elongated rodent-like incisor.

Cranial shape variation in mink: Separating two highly similar species.

European and American minks (Mustela lutreola and Neovison vison, respectively) are very similar in their ecology, behavior, and morphology. However, the American mink is a generalist predator and seems to adapt better to anthropized environments, allowing it to outcompete the European mink in areas where it has been introduced, threatening the survival of the native species. To assess whether morphological differences may be contributing to the success of the American mink relative to the European mink, we analyzed shape variation in the cranium of both species using 3D geometric morphometrics.

Back to the bones: do muscle area assessment techniques predict functional evolution across a macroevolutionary radiation?

Measures of attachment or accommodation area on the skeleton are a popular means of rapidly generating estimates of muscle proportions and functional performance for use in large-scale macroevolutionary studies. Herein, we provide the first evaluation of the accuracy of these muscle area assessment (MAA) techniques for estimating muscle proportions, force outputs and bone loading in a comparative macroevolutionary context using the rodent masticatory system as a case study. We find that MAA approaches perform poorly, yielding large absolute errors in muscle properties, bite force and particularly bone stress.

Landmark-free, parametric hypothesis tests regarding two-dimensional contour shapes using coherent point drift registration and statistical parametric mapping.

This paper proposes a computational framework for automated, landmark-free hypothesis testing of 2D contour shapes (i.e., shape outlines), and implements one realization of that framework.

Evolutionary biomechanics: hard tissues and soft evidence?

Biomechanical modelling is a powerful tool for quantifying the evolution of functional performance in extinct animals to understand key anatomical innovations and selective pressures driving major evolutionary radiations. However, the fossil record is composed predominantly of hard parts, forcing palaeontologists to reconstruct soft tissue properties in such models. Rarely are these reconstruction approaches validated on extant animals, despite soft tissue properties being highly determinant of functional performance.

Development of Orally Efficacious Allosteric Inhibitors of TNFα via Fragment-Based Drug Design.

Tumor necrosis factor α (TNFα) is a soluble cytokine that is directly involved in systemic inflammation through the regulation of the intracellular NF-κB and MAPK signaling pathways. The development of biologic drugs that inhibit TNFα has led to improved clinical outcomes for patients with rheumatoid arthritis and other chronic autoimmune diseases; however, TNFα has proven to be difficult to drug with small molecules. Herein, we present a two-phase, fragment-based drug discovery (FBDD) effort in which we first identified isoquinoline fragments that disrupt TNFα ligand-receptor binding through an allosteric desymmetrization mechanism as observed in high-resolution crystal structures.

Morphological divergence in giant fossil dormice.

Insular gigantism-evolutionary increases in body size from small-bodied mainland ancestors-is a conceptually significant, but poorly studied, evolutionary phenomenon. Gigantism is widespread on Mediterranean islands, particularly among fossil and extant dormice. These include an extant giant population of on Formentera, the giant Balearic genus † and the exceptionally large † of Pleistocene Sicily.

A Structural Analysis of the FDA Green Book-Approved Veterinary Drugs and Roles in Human Medicine.

The FDA Green Book is a list of all drug products that have been approved by the FDA for use in veterinary medicine. The Green Book, as published, lacks structural information corresponding to approved drugs. To address this gap, we have compiled the structural data for all FDA Green Book drugs approved through the end of 2019.

Escaping from Flatland: Substituted Bridged Pyrrolidine Fragments with Inherent Three-Dimensional Character.

The pressure to deliver new medicines to the patient continues to grow along with increases in compound failure rate, thus putting the current R&D model at risk. Analysis has shown that increasing the three-dimensionality of potential drug candidates decreases the risk of failure and improves binding selectivity and frequency. For this reason many workers have taken a new look at the power of photochemistry as a means to generate novel sp rich scaffolds for use in drug discovery programs.