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Benchmarking Skeletonization for Vascular Network Permeability
No full textPoster 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
High-resolution genomic history of early medieval Europe.
No full textMany known and unknown historical events have remained below detection thresholds of genetic studies because subtle ancestry changes are challenging to reconstruct. Methods based on shared haplotypes1,2 and rare variants3,4 improve power but are not explicitly temporal and have not been possible to adopt in unbiased ancestry models. Here we develop Twigstats, an approach of time-stratified ancestry analysis that can improve statistical power by an order of magnitude by focusing on coalescences in recent times, while remaining unbiased by population-specific drift. We apply this framework to 1,556 available ancient whole genomes from Europe in the historical period. We are able to model individual-level ancestry using preceding genomes to provide high resolution. During the first half of the first millennium CE, we observe at least two different streams of Scandinavian-related ancestry expanding across western, central and eastern Europe. By contrast, during the second half of the first millennium CE, ancestry patterns suggest the regional disappearance or substantial admixture of these ancestries. In Scandinavia, we document a major ancestry influx by approximately 800 CE, when a large proportion of Viking Age individuals carried ancestry from groups related to central Europe not seen in individuals from the early Iron Age. Our findings suggest that time-stratified ancestry analysis can provide a higher-resolution lens for genetic history
Redundant pathways for removal of defective RNA polymerase II complexes at a promoter-proximal pause checkpoint.
No full textThe biological purpose of Integrator and RNA polymerase II (RNAPII) promoter-proximal pausing remains uncertain. Here, we show that loss of INTS6 in human cells results in increased interaction of RNAPII with proteins that can mediate its dissociation from the DNA template, including the CRL3ARMC5 E3 ligase, which ubiquitylates CTD serine5-phosphorylated RPB1 for degradation. ARMC5-dependent RNAPII ubiquitylation is activated by defects in factors acting at the promoter-proximal pause, including Integrator, DSIF, and capping enzyme. This ARMC5 checkpoint normally curtails a sizeable fraction of RNAPII transcription, and ARMC5 knockout cells produce more uncapped transcripts. When both the Integrator and CRL3ARMC5 turnover mechanisms are compromised, cell growth ceases and RNAPII with high pausing propensity disperses from the promoter-proximal pause site into the gene body. These data support a model in which CRL3ARMC5 functions alongside Integrator in a checkpoint mechanism that removes faulty RNAPII complexes at promoter-proximal pause sites to safeguard transcription integrity
Real-time estimation of immunological responses against emerging SARS-CoV-2 variants in the UK: a mathematical modelling study.
No full textBACKGROUND: The emergence of SARS-CoV-2 variants and COVID-19 vaccination have resulted in complex exposure histories. Rapid assessment of the effects of these exposures on neutralising antibodies against SARS-CoV-2 infection is crucial for informing vaccine strategy and epidemic management. We aimed to investigate heterogeneity in individual-level and population-level antibody kinetics to emerging variants by previous SARS-CoV-2 exposure history, to examine implications for real-time estimation, and to examine the effects of vaccine-campaign timing. METHODS: Our Bayesian hierarchical model of antibody kinetics estimated neutralising-antibody trajectories against a panel of SARS-CoV-2 variants quantified with a live virus microneutralisation assay and informed by individual-level COVID-19 vaccination and SARS-CoV-2 infection histories. Antibody titre trajectories were modelled with a piecewise linear function that depended on the key biological quantities of an initial titre value, time the peak titre is reached, set-point time, and corresponding rates of increase and decrease for gradients between two timing parameters. All process parameters were estimated at both the individual level and the population level. We analysed data from participants in the University College London Hospitals-Francis Crick Institute Legacy study cohort (NCT04750356) who underwent surveillance for SARS-CoV-2 either through asymptomatic mandatory occupational health screening once per week between April 1, 2020, and May 31, 2022, or symptom-based testing between April 1, 2020, and Feb 1, 2023. People included in the Legacy study were either Crick employees or health-care workers at three London hospitals, older than 18 years, and gave written informed consent. Legacy excluded people who were unable or unwilling to give informed consent and those not employed by a qualifying institution. We segmented data to include vaccination events occurring up to 150 days before the emergence of three variants of concern: delta, BA.2, and XBB 1.5. We split the data for each wave into two categories: real-time and retrospective. The real-time dataset contained neutralising-antibody titres collected up to the date of emergence in each wave; the retrospective dataset contained all samples until the next SARS-CoV-2 exposure of each individual, whether vaccination or infection. FINDINGS: We included data from 335 participants in the delta wave analysis, 223 (67%) of whom were female and 112 (33%) of whom were male (median age 40 years, IQR 22-58); data from 385 participants in the BA.2 wave analysis, 271 (70%) of whom were female and 114 (30%) of whom were male (41 years, 22-60); and data from 248 participants in the XBB 1.5 wave analysis, 191 (77%) of whom were female, 56 (23%) of whom were male, and one (<1%) of whom preferred not to say (40 years, 21-59). Overall, we included 968 exposures (vaccinations) across 1895 serum samples in the model. For the delta wave, we estimated peak titre values as 490·0 IC50 (95% credible interval 224·3-1515·9) for people with no previous infection and as 702·4 IC50 (300·8-2322·7) for people with a previous infection before omicron; the delta wave did not include people with a previous omicron infection. For the BA.2 wave, we estimated peak titre values as 858·1 IC50 (689·8-1363·2) for people with no previous infection, 1020·7 IC50 (725·9-1722·6) for people with a previous infection before omicron, and 1422·0 IC50 (679·2-3027·3) for people with a previous omicron infection. For the XBB 1.5 wave, we estimated peak titre values as 703·2 IC50 (415·0-3197·8) for people with no previous infection, 1215·9 IC50 (511·6-7338·7) for people with a previous infection before omicron, and 1556·3 IC50 (757·2-7907·9) for people with a previous omicron infection. INTERPRETATION: Our study shows the feasibility of real-time estimation of antibody kinetics before SARS-CoV-2 variant emergence. This estimation is valuable for understanding how specific combinations of SARS-CoV-2 exposures influence antibody kinetics and for examining how COVID-19 vaccination-campaign timing could affect population-level immunity to emerging variants. FUNDING: Wellcome Trust, National Institute for Health Research University College London Hospitals Biomedical Research Centre, UK Research and Innovation, UK Medical Research Council, Francis Crick Institute, and Genotype-to-Phenotype National Virology Consortium
A constitutive interferon-high immunophenotype defines response to immunotherapy in colorectal cancer
No full textFewer than 50% of metastatic deficient mismatch repair (dMMR) colorectal cancer (CRC) patients respond to immune checkpoint inhibition (ICI). Identifying and expanding this patient population remains a pressing clinical need. Here, we report that an interferon-high immunophenotype locally enriched in cytotoxic lymphocytes and antigen-presenting macrophages is required for response. This immunophenotype is not exclusive to dMMR CRCs but comprises a subset of MMR proficient (pMMR) CRCs. Single-cell spatial analysis and in vitro cell co-cultures indicate that interferon-producing cytotoxic T cells induce overexpression of antigen presentation in adjacent macrophages and tumor cells, including MHC class II invariant chain CD74. dMMR CRCs expressing high levels of CD74 respond to ICI and a subset of CD74 high pMMR CRC patients show better progression free survival when treated with ICI. Therefore, CD74 abundance can identify the constitutive interferon-high immunophenotype determining clinical benefit in CRC, independently of tumor mutational burden or MMR status
Why transport matters: an update on carrier proteins in Apicomplexan parasites.
No full textThe movement of molecules across the membranous barriers of a cell is fundamental to cellular homeostasis in every living organism. This vital process is facilitated through a mechanistically diverse class of proteins, collectively known as membrane transporters. Among these are so-called carrier proteins that can function in passive and active transport mechanisms. They exhibit high substrate specificity and undergo conformational changes to transfer a specific solute across the membrane, thereby facilitating diffusion or actively transporting a molecule under energy expenditure or against an established electrochemical gradient. Apicomplexan parasites invest up to 5% of their genome to encode for membrane transporters; however, only a few have been fully characterised, and their specific mechanisms remain largely unknown. Recent advances in structural biology and the application of state-of-the-art genomic editing tools have greatly accelerated investigations into the intricate mechanisms of Apicomplexan carrier proteins. Understanding the molecular 'ins and outs' of membrane transporters is fundamental to inform the rational design of inhibitors, as well as to overcome antimicrobial resistance
PDZ-directed substrate recruitment is the primary determinant of specific 4E-BP1 dephosphorylation by PP1-Neurabin
No full textPhosphoprotein phosphatase 1 (PP1) relies on association with PP1-interacting proteins (PIPs) to generate substrate-specific PIP/PP1 holoenzymes, but the lack of well-defined substrates has hindered elucidation of the mechanisms involved. We previously demonstrated that the Phactr1 PIP confers sequence specificity on the Phactr1/PP1 holoenzyme by remodelling the PP1 hydrophobic substrate groove. Phactr1 defines a group of ‘RVxF-ΦΦ-R-W’ PIPs that all interact with PP1 in a similar fashion. Here, we use a PP1-PIP fusion approach to address sequence specificity and identify substrates of the RVxF-ΦΦ-R-W family PIPs. We show that the four Phactr proteins confer identical sequence specificities on their holoenzymes. We identify the 4E-BP and p70 S6K translational regulators as substrates for the Neurabin/Spinophilin PIPs, implicated in neuronal plasticity, pointing to a role for their holoenzymes in mTORC1-dependent translational control. Biochemical and structural experiments show that in contrast to the Phactrs, substrate recruitment and catalytic efficiency of the PP1-Neurabin and PP1-Spinophilin fusions is primarily determined by substrate interaction with the PDZ domain adjoining their RVxF-ΦΦ-R-W motifs, rather than by recognition of the remodelled PP1 hydrophobic groove. Thus, even PIPs that interact with PP1 in a similar manner use different mechanisms to ensure substrate selectivity
Tumor microenvironments with an active type I IFN response are sensitive to inhibitors of heme degradation.
No full textThe tumor microenvironment (TME) is highly heterogeneous and can dictate the success of therapeutic interventions. Identifying TMEs that are susceptible to specific therapeutic interventions paves the way for more personalized and effective treatments. In this study, using a spontaneous murine model of breast cancer, we characterize a TME that is responsive to inhibitors of the heme degradation pathway mediated by heme oxygenase (HO), resulting in CD8+ T- and NK-cell-dependent tumor control. A hallmark of this TME is a chronic type-I interferon (IFN) signal that is directly involved in orchestrating the anti-tumor immune response. Importantly, we identify that similar TMEs exist in human breast cancer which are associated with patient prognosis. Leveraging these observations, we demonstrate that combining a STING agonist, which induces type-I IFN responses, with an HO inhibitor produces a synergistic effect leading to superior tumor control. This study highlights HO activity as a potential resistance mechanism for type-I IFN responses in cancer offering a novel avenue for overcoming immune evasion in cancer therapy
Orbitrap noise structure and method for noise unbiased multivariate analysis.
No full textOrbitrap mass spectrometry is widely used in the life-sciences. However, like all mass spectrometers, non-uniform (heteroscedastic) noise introduces bias in multivariate analysis complicating data interpretation. Here, we study the noise structure of an Orbitrap mass analyser integrated into a secondary ion mass spectrometer (OrbiSIMS). Using a stable primary ion beam to provide a well-controlled source of ions from a silver sample, we find that noise has three characteristic regimes: at low signals the Orbitrap detector noise and a censoring algorithm dominates; at intermediate signals counting noise specific to the ion emission process is most significant; and at high signals additional sources of measurement variation become important. Using this understanding, we developed a generative model for Orbitrap data that accounts for the noise distribution and introduce a scaling method, termed WSoR, to reduce the effects of noise bias in multivariate analysis. We compare WSoR performance with no-scaling and existing scaling methods for three biological imaging data sets including drosophila central nervous system, mouse testis and a desorption electrospray ionisation (DESI) image of a rat liver. WSoR consistently performed best at discriminating chemical information from noise. The performance of the other methods varied on a case-by-case basis, complicating the analysis
A unified model for cohesin function in sisterchromatid cohesion and chromatin loop formation.
No full textThe ring-shaped cohesin complex topologically entraps two DNAs to establish sister chromatid cohesion. Cohesin also shapes the interphase chromatin landscape by forming DNA loops, which it is thought to achieve using an in vitro-observed loop extrusion mechanism. However, recent studies revealed that loop-extrusion-deficient cohesin retains its ability to form chromatin loops, suggesting a divergence of in vitro and in vivo loop formation. Instead of loop extrusion, we examine whether cohesin forms chromatin loops by a mechanism akin to sister chromatid cohesion establishment: sequential topological capture of two DNAs. We explore similarities and differences between the "loop capture" and the "loop extrusion" model, how they compare at explaining experimental observations, and how future approaches can delineate their possible respective contributions. We extend our DNA-DNA capture model for cohesin function to related structural maintenance of chromosomes (SMC) family members, condensin, the Smc5-Smc6 complex, and bacterial SMC complexes