Biology subjects

Butler, R. J.

Publications and source records attributed to Butler, R. J..

6 recordsLinked to original sources

bioRxiv2026

A Kinetochore-Associated Proteasome Pool Drives a Second Pathway of Cohesin Removal during Meiosis

Accurate chromosome segregation requires the spatiotemporally regulated removal of sister chromatid cohesion. Cohesin cleavage by the endopeptidase separase depends on destruction of its inhibitor securin by the ubiquitin-proteasome system (UPS) and on phosphorylation-mediated priming of the cohesin kleisin subunit. Whether the UPS also contributes to cohesin priming has remained unknown. Here, we show that the 26S proteasome mediates cohesin removal during meiosis II through branches of two parallel pathways. Using separation-of-function mutants targeting either the proteasome's core or regulatory particles, we identify a proteasome function that is required specifically for centromeric cohesin removal during meiosis II but dispensable for separase activation. Defects in this proteasome function causes centromeric accumulation of phosphatase anchor shugoshin (Sgo1), impaired cleavage of meiotic kleisin Rec8, and frequent failure of sister chromatid segregation. Bypassing the requirement for Rec8 priming, either through a phosphomimetic rec8 allele or by separase-independent Rec8 cleavage, restores chromosome segregation, demonstrating that the proteasome mediates cohesin removal independently of its established role in activating separase. Consistent with a direct role, proteasomes localize prominently to kinetochores during meiosis II. Together, these findings identify the proteasome as a dual-function regulator that mediates both separase activation and cohesin priming, revealing how a single proteolytic machine coordinates the two molecular pathways underlying stepwise chromosome segregation during meiosis.

genetics↗

bioRxiv2026

Breaking the bottleneck: self-supervised deep learning framework for fully automated fossil CT segmentation

Semantic segmentation of domain-specific imaging data where labelled training examples are scarce and foreground-background contrast is low remains an open challenge in deep learning applied to science. Palaeontological computed tomography (CT) exemplifies this problem: digitally isolating fossilised bone from surrounding rock matrix is labour-intensive ([≥]100 hrs/dataset), subjective, and often reliant on expensive proprietary software, creating a "segmentation bottleneck" that prevents large-scale and rapid processing of CT data collections. Here we present a self-supervised, end-to-end framework combining SimCLR v1 contrastive pretraining with deterministic pseudo-label generation and U-Net refinement to fully automate fossil CT segmentation without manual annotation. Using 50,626 CT images from the Middle Jurassic Kilmaluag Formation spanning amphibians, reptiles, dinosaurs, and early mammals, the framework achieved a Dice coefficient of 93.66% and IoU of 82.42% on a held-out specimen not seen during training, comparable to the highest Dice and IoU values reported in recent Deep Learning-based fossil CT segmentation studies. Cross-taxon generalisation was validated geometrically on six fully external specimens, achieving sub-voxel mesh agreement with manually thresholded references. By eliminating the annotation requirement that has limited prior deep learning approaches in palaeontology, this framework reduces per-specimen processing from [~]100 person-hours to 6 hrs (one-time UNet training) +1-3 minutes (mesh generation per specimen), an essential first step towards batch processing and analysis of CT data for large-scale comparative and quantitative analyses.

paleontology↗

bioRxiv2023

Tozorakimab (MEDI3506): a dual-pharmacology anti-IL-33 antibody that inhibits IL-33 signalling via ST2 and RAGE/EGFR to reduce inflammation and epithelial dysfunction

Interleukin (IL)-33 is a broad-acting alarmin cytokine that can drive inflammatory responses following tissue damage or infection and is a promising target for treatment of inflammatory disease. Here, we describe the identification of tozorakimab (MEDI3506), a potent, human anti-IL-33 monoclonal antibody, which can inhibit reduced IL-33 (IL-33red) and oxidized IL-33 (IL-33ox) activities through distinct serum-stimulated 2 (ST2) and receptor for advanced glycation end products - epidermal growth factor receptor (RAGE-EGFR complex) signalling pathways. We hypothesized that a therapeutic antibody would require an affinity higher than that of ST2 for IL-33, with an association rate greater than 107 M-1 s-1, to effectively neutralize IL-33 following rapid release from damaged tissue. An innovative antibody generation campaign identified tozorakimab, an antibody with a femtomolar affinity for IL-33red and a fast association rate (8.5 x 107 M-1 s-1), which was comparable to soluble ST2. Tozorakimab potently inhibited ST2-dependent inflammatory responses driven by IL-33 in primary human cells and in a murine model of lung epithelial injury. Additionally, tozorakimab prevented the oxidation of IL-33 and its activity via the RAGE/EGFR signalling pathway, thus increasing in vitro epithelial cell migration and repair. Tozorakimab is a novel therapeutic agent with a dual mechanism of action that blocks IL-33red and IL-33ox signalling, offering potential to reduce inflammation and epithelial dysfunction in human disease.

immunology↗

bioRxiv2022

Early tetrapod diversification under neutral theory

Estimates of deep-time biodiversity typically rely on statistical methods to mitigate the impacts of sampling biases in the fossil record. However, these methods are limited by the spatial and temporal scale of the underlying data. Here we use a spatially explicit mechanistic model, based on neutral theory, to test hypotheses of early tetrapod diversity change during the late Carboniferous and early Permian, critical intervals for the diversification of vertebrate life on land. Our neutral simulations suggest, in contrast to previous studies, that increases in early tetrapod diversity were not driven by local endemism following the Carboniferous Rainforest Collapse. We show that apparent changes in face-value diversity can instead be explained by variation in sampling intensity through time. Our results further demonstrate the importance of accounting for sampling biases in analyses of the fossil record and demonstrate the vast potential of mechanistic models, including neutral models, for testing hypotheses in palaeobiology.

evolutionary biology↗

bioRxiv2019

A unique predator in a unique ecosystem: modelling the apex predator from the Late Cretaceous crocodyliform-dominated fauna in Brazil.

ABSTRACTTheropod dinosaurs were relatively scarce in the Late Cretaceous ecosystems of southeast Brazil. Instead, hypercarnivorous crocodyliforms known as baurusuchids were abundant and probably occupied the ecological role of apex predators. Baurusuchids exhibited a series of morphological adaptations hypothesised to be associated with this ecological role, but quantitative biomechanical analyses of their morphology have so far been lacking. Here, we employ a biomechanical modelling approach, applying finite element analysis (FEA) to models of the skull and mandibles of a baurusuchid specimen. This allowed us to characterise the craniomandibular apparatus of baurusuchids, as well as to compare the functional morphology of the group to that of other archosaurian carnivores, such as theropods and crocodylians. Our results support the ecological role of baurusuchids as specialised apex predators in the continental Late Cretaceous ecosystems of South America. With a relatively weak bite force (∼600 N), baurusuchids’ predation strategies likely relied on other morphological specializations, such as ziphodont dentition and strong cervical musculature. Comparative assessments of the stress distribution and magnitude of scaled models of other predators (the theropod Allosaurus fragilis and the living crocodylian Alligator mississippiensis) consistently show different responses to loadings under the same functional scenarios, suggesting distinct predatory behaviours for these animals. The unique selective pressures in the arid to semi-arid Late Cretaceous ecosystems of southeast Brazil, which were dominated by crocodyliforms, possibly drove the emergence and evolution of the biomechanical features seen in baurusuchids, which are distinct from those previously reported for other predatory taxa.View Full Text

paleontology↗

bioRxiv2018

The multi-peak adaptive landscape of crocodylomorph body size evolution

Background Little is known about the long-term patterns of body size evolution in Crocodylomorpha, the > 200-million-year-old group that includes living crocodylians and their extinct relatives. Extant crocodylians are mostly large-bodied (3–7 m) predators. However, extinct crocodylomorphs exhibit a wider range of phenotypes, and many of the earliest taxa were much smaller (< 1.2 m). This suggests a pattern of size increase through time that could be caused by multi-lineage evolutionary trends of size increase or by selective extinction of small-bodied species. In this study, we characterise patterns of crocodylomorph body size evolution using a model fitting-approach (with cranial measurements serving as proxies). We also estimate body size disparity through time and quantitatively test hypotheses of biotic and abiotic factors as potential drivers of crocodylomorph body size evolution.Results Crocodylomorphs reached an early peak in body size disparity during the Late Jurassic, and underwent essentially continually decreases in disparity since then. A multi-peak Ornstein-Uhlenbeck model outperforms all other evolutionary models fitted to our data (including both uniform and non-uniform), indicating that the macroevolutionary dynamics of crocodylomorph body size are better described within the concept of an adaptive landscape, with most body size variation emerging after shifts to new macroevolutionary regimes (analogous to adaptive zones). We did not find support for a consistent evolutionary trend towards larger sizes among lineages (i.e., Cope’s rule), or strong correlations of body size with climate. Instead, the intermediate to large body sizes of some crocodylomorphs are better explained by group-specific adaptations. In particular, the evolution of a more aquatic lifestyle (especially marine) correlates with increases in average body size, though not without exceptions.Conclusions Shifts between macroevolutionary regimes provide a better explanation of crocodylomorph body size evolution than do climatic factors, suggesting a central role for lineage-specific adaptations rather than climatic forcing. Shifts leading to larger body sizes occurred in most aquatic and semi-aquatic groups. This, combined with extinctions of groups occupying smaller body size regimes (particularly during the Late Cretaceous and Cenozoic), gave rise to the upward-shifted body size distribution of extant crocodylomorphs compared to their smaller-bodied terrestrial ancestors.AbbreviationsCranial measurementsDCLdorsal cranial lengthODCLorbito-cranial lengthEvolutionary modelsBMBrownian motionEBEarly burstOUOrnstein-UhlenbeckBMSmulti-regime BM model that allows parameter σ2 to varyOUMVmulti-regime OU model that allows θ and σ2 to varyOUMAmulti-regime OU model in which θ and α can varyOUMVAOU model in which all three parameters (θ, α and σ2) can varyModel parametersθtrait optimum of OU-based modelsαattraction parameter of OU-based modelsσ2Brownian variance or rate parameter of BM or OU-based modelsμevolutionary trend parameter of BM-based modelsZ0estimated trait value at the root of the tree of OU-based modelsOptimality criteriaAICAkaike’s information criterionAICcAkaike’s information criterion for finite sample sizesBICBayesian information criterionpBICphylogenetic Bayesian information criterionView Full Text

paleontology↗