Enantioselective OTUD7B fragment discovery through chemoproteomics screening and high-throughput optimisation.

Deubiquitinating enzymes (DUBs) are key regulators of cellular homoeostasis, and their dysregulation is associated with several human diseases. The ovarian tumour protease (OTU) family of DUBs are biochemically well-characterised and of therapeutic interest, yet only a few tool compounds exist to study their cellular function and therapeutic potential. Here we present a chemoproteomics fragment screening platform for identifying novel DUB-specific hit matter, that combines activity-based protein profiling with high-throughput chemistry direct-to-biology optimisation to enable rapid elaboration of initial fragment hits against OTU DUBs. Applying these approaches, we identify an enantioselective covalent fragment for OTUD7B, and validate it using chemoproteomics and biochemical DUB activity assays

Targeting the PREX2/RAC1/PI3Kβ signaling axis confers sensitivity to clinically relevant therapeutic approaches in melanoma.

Metastatic melanoma remains a major clinical challenge. Large-scale genomic sequencing of melanoma has identified bona fide activating mutations in RAC1, which are associated with resistance to BRAF-targeting therapies. Targeting the RAC1-GTPase pathway, including the upstream activator PREX2 and the downstream effector PI3Kβ, could be a potential strategy for overcoming therapeutic resistance, limiting melanoma recurrence, and suppressing metastatic progression. Here, we used genetically engineered mouse models and patient-derived BRAFV600E-driven melanoma cell lines to dissect the role of PREX2 in melanomagenesis and response to therapy. While PREX2 was dispensable for the initiation and progression of melanoma, its loss conferred sensitivity to clinically relevant therapeutics targeting the MAPK pathway. Importantly, genetic and pharmacological targeting of PI3Kβ phenocopied PREX2 deficiency, sensitizing model systems to therapy. These data reveal a druggable PREX2/RAC1/PI3Kβ signaling axis in BRAF-mutant melanoma that could be exploited clinically

A novel SUN1-ALLAN complex coordinates segregation of the bipartite MTOC across the nuclear envelope during rapid closed mitosis in Plasmodium berghei.

Mitosis in eukaryotes involves reorganisation of the nuclear envelope (NE) and microtubule-organising centres (MTOCs). During male gametogenesis in Plasmodium, the causative agent of malaria, mitosis is exceptionally rapid and highly divergent. Within 8 min, the haploid male gametocyte genome undergoes three replication cycles (1N to 8N), while maintaining an intact NE. Axonemes assemble in the cytoplasm and connect to a bipartite MTOC-containing nuclear pole (NP) and cytoplasmic basal body, producing eight flagellated gametes. The mechanisms coordinating NE remodelling, MTOC dynamics, and flagellum assembly remain poorly understood. We identify the SUN1-ALLAN complex as a novel mediator of NE remodelling and bipartite MTOC coordination during Plasmodium berghei male gametogenesis. SUN1, a conserved NE protein, localises to dynamic loops and focal points at the nucleoplasmic face of the spindle poles. ALLAN, a divergent allantoicase, has a location like that of SUN1, and these proteins form a unique complex, detected by live-cell imaging, ultrastructural expansion microscopy, and interactomics. Deletion of either SUN1 or ALLAN genes disrupts nuclear MTOC organisation, leading to basal body mis-segregation, defective spindle assembly, and impaired spindle microtubule-kinetochore attachment, but axoneme formation remains intact. Ultrastructural analysis revealed nuclear and cytoplasmic MTOC miscoordination, producing aberrant flagellated gametes lacking nuclear material. These defects block development in the mosquito and parasite transmission, highlighting the essential functions of this complex

Timed chromatin invasion during mitosis governs prototype foamy virus integration site selection and infectivity.

Selection of a suitable chromatin environment during retroviral integration is a tightly regulated process. Most retroviruses, including spumaretroviruses, require mitosis for nuclear entry. However, whether intrinsic chromatin dynamics during mitosis modulates retroviral genome invasion is unknown. Previous work uncovered critical interactions of prototype foamy virus (PFV) Gag with nucleosomes via a highly conserved arginine anchor residue. Yet, the regulation of Gag-chromatin interaction and its functional consequences for spumaretrovirus biology remain obscure. Here, we investigated the kinetics of chromatin binding by Gag during mitosis and proviral integration in synchronized cells. We showed that alteration of Gag affinity for nucleosome binding induced untimely chromatin tethering during mitosis, decreased infectivity, and redistributed viral integration sites to markers associated with late replication timing of chromosomes. Mutant Gag proteins were, moreover, defective in their ability to displace the histone H4 tail from the nucleosome acidic patch of highly condensed chromatin. These data indicate that the chromatin landscape during Gag-nucleosome interactions is important for PFV integration site selection and that spumaretroviruses evolved high-affinity chromatin binding to overcome early mitosis chromatin condensation

Sequential transcriptional programs underpin activation of hippocampal stem cells.

Adult neural stem cells exist on a continuum from deep to shallow quiescence that changes in response to injury or aging; however, the transcription factors controlling these stepwise transitions have not been identified. Single-cell transcriptomic analyses of mice with loss of function or increased levels of the essential activation factor Ascl1 reveal that Ascl1 promotes the activation of hippocampal neural stem cells by driving these cells out of deep quiescence, despite its low protein expression in this state. Subsequently, during the transition from deep to shallow quiescence, Ascl1 induces the expression of Mycn, which drives progression through shallow quiescent states toward a proliferating state. Together, these results define the required sequence of transcription factors during hippocampal neural stem cell activation and establish a combinatorial code for classifying these cells into deep and shallow quiescence

Major transitions in sociocultural evolution

Recent years have seen growing interest in applying the Evolutionary Transitions in Individuality (ETI) framework to human sociocultural evolution. Proponents argue that human societies exhibit features—such as multilevel organisation, cooperation, and division of labour—sufficiently analogous to biological ETIs to warrant theoretical extension. This paper critically assesses such claims and argues that they rest on a fundamental misapplication of the ETI framework. Drawing on recent work in cultural evolution, I show that sociocultural systems typically lack the core conditions required for an ETI, including autonomous reproduction at the group level and the operation of natural selection in the reproductive mode. Attempts to relax these criteria risk undermining the coherence of the framework itself. I conclude that while the broader MET framework may still have value for understanding sociocultural change, the specific explanatory structure of ETI theory does not transfer

Mechanochemical coupling of cell shape and organ function optimizes heart size and contractile efficiency in zebrafish.

How simple tissue primordia sculpt complex functional organs, robustly and reproducibly, remains elusive. During zebrafish development, the embryonic myocardial wall matures into an intricate 3D architecture, composed of an outer compact layer enveloping an inner layer of multicellular trabecular ridges. How these tissue layers acquire their characteristic form suited for their function remains an open question. Here, we find that multiscale mechanochemical coupling and an emergent tissue-scale morphological transition steer functional maturation of the developing zebrafish heart. Single-celled trabecular seeds recruit outer compact layer cells to mature into clonally heterogeneous multicellular ridges, thereby amplifying cardiac contractile forces. In response, the remaining compact layer cells are stretched, which impedes their further recruitment, thereby constraining trabecular ridge density. Concomitantly, Notch-dependent actomyosin dampening triggers a sharp transition in myocardial tissue area, activating rapid organ growth that expands blood-filling capacity. Thus, multiscale self-organizing interactions optimize heart size and contractile efficiency to support embryonic life

Mechanical stress and cell fate acquisition during zebrafish trunk neural crest cell migration: Tissue bioimaging

Poster presented as part of the Crick BioImage Analysis Symposium 2025.Permission has been given by authors to upload to Crick Figshare. Copyright remains with the original authors.</p

Exenatide once weekly in the treatment of patients with multiple system atrophy.

OBJECTIVE: Exenatide, a glucagon-like peptide-1 (GLP-1) receptor agonist, has neuroprotective effects in preclinical models of multiple system atrophy (MSA). We investigated these effects in a proof-of-concept clinical trial. METHODS: In this single-center, randomized, open label trial, participants with MSA were randomly assigned (1:1) to receive subcutaneous injections of exenatide 2 mg weekly for 48 weeks, or as controls, followed by a 48-week washout period. The primary outcome was the Unified Multiple System Atrophy Rating Scale (UMSARS) parts I + II combined score at 48 weeks. Objective secondary outcome measures included the numbers of participants losing ambulation; scoring ≥ 3 on UMSARS part I items for falls, speech, swallowing, as well as timed walking and measures of quality of life and cognition. RESULTS: Between September 23, 2020, and May 6, 2022, 50 participants were recruited (25 in each group). At 48 weeks, UMSARS parts I + II scores had worsened by 6.1 points (95% confidence interval [CI] = 3.0 to 9.3, SD = 6.9) in the exenatide group and by 13 3 points (95% CI = 9.2 to 17.3, SD = 9.4) in the control group, an adjusted mean difference of -7.4 points (-11.3 to -3.6, p = 0.0003). There were no statistically significant differences at either 48 or 96 weeks in the secondary outcome measures. Biomarker analysis of neurofilament light chain and cerebral spinal fluid (CSF) alpha-synuclein oligomer load, sensor-derived gait measures, and imaging findings were also similar between groups. INTERPRETATION: Exenatide was associated with positive effects on participant-reported symptoms and clinician-rated MSA severity. In contrast, none of the objective comparisons differed according to randomization. Given the open label trial design, the discrepancy between the primary outcome and the objective measures may be explicable as placebo effects/observer bias. ANN NEUROL 2025

Spatiotemporal orchestration of mitosis by cyclin-dependent kinase.

Mitotic onset is a critical transition for eukaryotic cell proliferation. The commonly held view of mitotic control is that the master regulator, cyclin-dependent kinase (CDK), is first activated in the cytoplasm, at the centrosome, initiating mitosis1-3. Bistability in CDK activation ensures that the transition is irreversible, but how this unfolds in a spatially compartmentalized cell is unknown4-8. Here, using fission yeast, we show that CDK is first activated in the nucleus, and that the bistable responses differ markedly between the nucleus and the cytoplasm, with a stronger response in the nucleus driving mitotic signal propagation from there to the cytoplasm. Abolishing cyclin-CDK localization to the centrosome led to activation occurring only in the nucleus, spatially uncoupling the nucleus and cytoplasm mitotically, suggesting that centrosomal cyclin-CDK acts as a 'signal relayer'. We propose that the key mitotic regulatory system operates in the nucleus in proximity to DNA, which enables incomplete DNA replication and DNA damage to be effectively monitored to preserve genome integrity and to integrate ploidy within the CDK control network. This spatiotemporal regulatory framework establishes core principles for control of the onset of mitosis and highlights that the CDK control system operates within distinct regulatory domains in the nucleus and cytoplasm