Throughout the world social isolation and loneliness are common and both have several adverse impacts on health and wellbeing. We are designed to live in close-knit communities and we thrive in close ...co-operation, however, modern life isolates us from others. To reduce the burden of loneliness and social isolation we need to find strategies to reconnect people to each other, their place and provide a common purpose. Social movements aim to create healthier communities by connecting people to each other and giving people a common purpose. Interventions which create a social movement appear to be effective at engaging substantial portions of a community, however, it remains unclear why individuals are attracted to these initiatives, and if such reasons differ by sociodemographic characteristics. This study combined qualitative and quantitative methods to understand what motivated (different) people to take part in a social movement based intervention. This study suggests that it is not one but a combination of reasons people engage in interventions of this nature. This diversity needs to be acknowledged when promoting and communicating these interventions to potential participants to maximise engagement. Promoting an end reward or health/fitness may not be the most effective way to promote interventions to a large proportion of people. Instead, communications should be centred around what people value (i.e., being with their friends, doing what they enjoy and are good at).
Managed care of cephalopods can be complicated by numerous factors including infectious and non-infectious disease, environmental stressors, and anatomic and physiological changes associated with ...senescence. The current report describes a unique case of nephrolithiasis in a senescent, >2 yr old female Pacific octopus Enteroctopus dofleini housed in a public aquarium. Clinical signs included generalized external pallor, inappetence progressing to anorexia, lethargy, and a slow healing mantle abrasion over a period of a year. Due to the animal's declining condition, humane euthanasia was elected. At necropsy, multiple, small, approximately 1-5 mm diameter crystalline deposits were reported throughout all sections of the renal appendages. Histopathology identified a large crystal expanding and rupturing a focal tubule, causing necrosis, ulceration, and hemocytic infiltration. Crystalline stone analysis revealed that the nephrolith was composed of 100% ammonium acid urate. Additional changes to the digestive gland included marked atrophy with fibrosis correlated to the animal's history of hyporexia/anorexia secondary to senescence. To our knowledge, this is the first report of nephrolithiasis in E. dofleini.
Mutations within the kinase domain of the epidermal growth factor receptor (EGFR) are common oncogenic driver events in non-small cell lung cancer. Although the activation of EGFR in normal cells is ...primarily driven by growth-factor-binding-induced dimerization, mutations on different exons of the kinase domain of the receptor have been found to affect the equilibrium between its active and inactive conformations giving rise to growth-factor-independent kinase activation. Using molecular dynamics simulations combined with enhanced sampling techniques, we compare here the conformational landscape of the monomers and homodimers of the wild-type and mutated forms of EGFR ΔELREA and L858R, as well as of two exon 20 insertions, D770-N771insNPG, and A763-Y764insFQEA. The differences in the conformational energy landscapes are consistent with multiple mechanisms of action including the regulation of the hinge motion, the stabilization of the dimeric interface, and local unfolding transitions. Overall, a combination of different effects is caused by the mutations and leads to the observed aberrant signaling.
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•We newly developed 59 nuclear phylogenetic markers from a draft genome.•We used these to study aquatic insect diversification on Macaronesian islands.•Species tree reconstruction and ...concatenation resulted in fully resolved trees.•The Macaronesian islands have been colonized by at least three independent events.•Island-endemic speciation and trans-oceanic dispersal have been important processes.
The study of processes driving diversification requires a fully sampled and well resolved phylogeny, although a lack of phylogenetic markers remains a limitation for many non-model groups. Multilocus approaches to the study of recent diversification provide a powerful means to study the evolutionary process, but their application remains restricted because multiple unlinked loci with suitable variation for phylogenetic or coalescent analysis are not available for most non-model taxa. Here we identify novel, putative single-copy nuclear DNA (nDNA) phylogenetic markers to study the colonization and diversification of an aquatic insect species complex, Cloeon dipterum L. 1761 (Ephemeroptera: Baetidae), in Macaronesia. Whole-genome sequencing data from one member of the species complex were used to identify 59 nDNA loci (32,213 base pairs), followed by Sanger sequencing of 29 individuals sampled from 13 islands of three Macaronesian archipelagos. Multispecies coalescent analyses established six putative species. Three island species formed a monophyletic clade, with one species occurring on the Azores, Europe and North America. Ancestral state reconstruction indicated at least two colonization events from the mainland (to the Canaries, respectively Azores) and one within the archipelago (between Madeira and the Canaries). Random subsets of the 59 loci showed a positive linear relationship between number of loci and node support. In contrast, node support in the multispecies coalescent tree was negatively correlated with mean number of phylogenetically informative sites per locus, suggesting a complex relationship between tree resolution and marker variability. Our approach highlights the value of combining genomics, coalescent-based phylogeography, species delimitation, and phylogenetic reconstruction to resolve recent diversification events in an archipelago species complex.
The bromodomain-containing proteins are a ligandable family of epigenetic readers, which play important roles in oncological, cardiovascular, and inflammatory diseases. Achieving selective inhibition ...of specific bromodomains is challenging, due to the limited understanding of compound and target selectivity features. In this study we build and benchmark proteochemometric (PCM) classification models on bioactivity data for 15,350 data points across 31 bromodomains, using both compound fingerprints and binding site protein descriptors as input variables, achieving a maximum performance as measured by the Matthew’s Correlation Coefficient (MCC) of 0.83 on the external test set. We also find that histone peptide binding data can be used as a target descriptor to build a high performing PCM model (MCC 0.80), showing the transferability of peptide interaction information to modeling small-molecule bioactivity. 1,139 compounds were selected for prospective experimental testing by performing a virtual screen using model predictions and implementing conformal prediction, which resulted in 319 correctly predicted compound-target pair actives and the correct prediction for certain selectivity profile combinations of the four bromodomains tested against. We identify that conformal prediction can be used to fine-tune the balance between hit retrieval and hit structural diversity in a virtual screening setting. PCM can be applied to future virtual screening and compound design, including off-target prediction for bromodomains.
is an invertebrate model organism used in many areas of biology including developmental biology and the identification of molecular mechanisms and pathways. However, several experimental approaches ...require large quantities of worms, which is limiting and time-consuming. We present a protocol that uses modern fermentation methodology to effectively produce large numbers of
using a 7-l bioreactor in a fed-batch cultivation procedure. The production is modular and flexible as well as being a self-controlled system, thus not much labor is required until harvesting
. The high-yield worm cultivation is flexible and simple to amend, and now allows for the extended application of
as a model organism and expression system, including large-scale protein production.
The Canary Islands and Madeira are reportedly home to seven recognised species of baetid mayflies (Ephemeroptera, Baetidae), two of which also occur on the European mainland. Their species status ...remains unsure, and loss of habitat suggests they are of conservation concern. We applied morphological characters and a general mixed Yule‐coalescent (gmyc) model analysis of the cytochrome c oxidase subunit 1 (cox1) gene to delineate putative species within morphologically cryptic species groups Baetis (Rhodobaetis) and Cloeon dipterum s.l. We used a three‐gene mitochondrial data set (1450 base pairs) to infer phylogenetic relationships and a molecular clock calibrated using island geological ages to infer colonisation history. Genetic and morphological evidence indicated the presence of 12 putative species, 11 of which were endemic to the islands. Only Baetis atlanticus, on Madeira, also occurs on the European mainland. Two lineages (B. pseudorhodani s.l. and B. canariensis s.l.) appear to have arisen in the past 15 million years (mya) and diversified in parallel throughout the Canary Islands. Within the canariensis lineage, sister species occur on the island of Gran Canaria and in North Africa. Pronounced island endemism contradicts previous taxonomic work, which reported a depauperate fauna that included several mainland species. Recent diversification among islands and a close link to North Africa suggest a complex evolutionary history. Owing to their small population size and ongoing habitat alteration, several of these island endemics are among the most endangered aquatic insects in Europe.
To improve our ability to extrapolate preclinical toxicity to humans, there is a need to understand and quantify the concordance of adverse events (AEs) between animal models and clinical studies. In ...the present work, we discovered 3011 statistically significant associations between preclinical and clinical AEs caused by drugs reported in the PharmaPendium database of which 2952 were new associations between toxicities encoded by different Medical Dictionary for Regulatory Activities terms across species. To find plausible and testable candidate off-target drug activities for the derived associations, we investigated the genetic overlap between the genes linked to both a preclinical and a clinical AE and the protein targets found to interact with one or more drugs causing both AEs. We discuss three associations from the analysis in more detail for which novel candidate off-target drug activities could be identified, namely, the association of preclinical mutagenicity readouts with clinical teratospermia and ovarian failure, the association of preclinical reflexes abnormal with clinical poor-quality sleep, and the association of preclinical psychomotor hyperactivity with clinical drug withdrawal syndrome. Our analysis successfully identified a total of 77% of known safety targets currently tested in in vitro screening panels plus an additional 431 genes which were proposed for investigation as future safety targets for different clinical toxicities. This work provides new translational toxicity relationships beyond AE term-matching, the results of which can be used for risk profiling of future new chemical entities for clinical studies and for the development of future in vitro safety panels.
ATAD2 is an epigenetic bromodomain-containing target which is overexpressed in many cancers and has been suggested as a potential oncology target. While several small molecule inhibitors have been ...described in the literature, their cellular activity has proved to be underwhelming. In this work, we describe the identification of a novel series of ATAD2 inhibitors by high throughput screening, confirmation of the bromodomain region as the site of action, and the optimization campaign undertaken to improve the potency, selectivity, and permeability of the initial hit. The result is compound 5 (AZ13824374), a highly potent and selective ATAD2 inhibitor which shows cellular target engagement and antiproliferative activity in a range of breast cancer models.
Inhibition of class IIa histone deacetylase (HDAC) enzymes have been suggested as a therapeutic strategy for a number of diseases, including Huntington’s disease. Catalytic-site small molecule ...inhibitors of the class IIa HDAC4, -5, -7, and -9 were developed. These trisubstituted diarylcyclopropanehydroxamic acids were designed to exploit a lower pocket that is characteristic for the class IIa HDACs, not present in other HDAC classes. Selected inhibitors were cocrystallized with the catalytic domain of human HDAC4. We describe the first HDAC4 catalytic domain crystal structure in a “closed-loop” form, which in our view represents the biologically relevant conformation. We have demonstrated that these molecules can differentiate class IIa HDACs from class I and class IIb subtypes. They exhibited pharmacokinetic properties that should enable the assessment of their therapeutic benefit in both peripheral and CNS disorders. These selective inhibitors provide a means for evaluating potential efficacy in preclinical models in vivo.
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