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Mechanical stress and cell fate acquisition during zebrafish trunk neural crest cell migration: Tissue bioimaging
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
BCL11A intellectual developmental disorder: defining the clinical spectrum and genotype-phenotype correlations.
No full textAn increasing number of individuals with intellectual developmental disorder (IDD) and heterozygous variants in BCL11A are identified, yet our knowledge of manifestations and mutational spectrum is lacking. To address this, we performed detailed analysis of 42 individuals with BCL11A-related IDD (BCL11A-IDD, a.k.a. Dias-Logan syndrome) ascertained through an international collaborative network, and reviewed 35 additional previously reported patients. Analysis of 77 affected individuals identified 60 unique disease-causing variants (30 frameshift, 7 missense, 6 splice-site, 17 stop-gain) and 8 unique BCL11A microdeletions. We define the most prevalent features of BCL11A-IDD: IDD, postnatal-onset microcephaly, hypotonia, behavioral abnormalities, autism spectrum disorder, and persistence of fetal hemoglobin (HbF), and identify autonomic dysregulation as new feature. BCL11A-IDD is distinguished from 2p16 microdeletion syndrome, which has a higher incidence of congenital anomalies. Our results underscore BCL11A as an important transcription factor in human hindbrain development, identifying a previously underrecognized phenotype of a small brainstem with a reduced pons/medulla ratio. Genotype-phenotype correlation revealed an isoform-dependent trend in severity of truncating variants: those affecting all isoforms are associated with higher frequency of hypotonia, and those affecting the long (BCL11A-L) and extra-long (-XL) isoforms, sparing the short (-S), are associated with higher frequency of postnatal microcephaly. With the largest international cohort to date, this study highlights persistence of fetal hemoglobin as a consistent biomarker and hindbrain abnormalities as a common feature. It contributes significantly to our understanding of BCL11A-IDD through an extensive unbiased multi-center assessment, providing valuable insights for diagnosis, management and counselling, and into BCL11A's role in brain development
Infecting minds: socio-contextual drivers of vaccine perceptions and attitudes among young and older adults living in urban and rural areas in KwaZulu-Natal, South Africa
No full textWe investigated how social and contextual factors, including a pandemic, shape vaccine perceptions and attitudes among people living in KwaZulu-Natal in South Africa. We assessed how participants’ views, acceptance, and uptake of vaccines for a range of infectious diseases, may be influenced by experiences and events linked to the COVID-19 pandemic.
Methods
We conducted 30 in-depth face-to-face and telephonic interviews with participants living in diverse rural and urban communities in two districts within KwaZulu-Natal. Participants were adults (≥ 18 years) consisting of ordinary citizens, traditional healers, and nurses. We combined non-representative convenience, snowballing and purposeful sampling techniques to recruit participants. Data collection was conducted in IsiZulu, and we used both inductive and deductive thematic analysis approaches to identify key themes linked to participants’ perceptions and attitudes towards vaccines.
Findings
Our study participants were mostly those who had accepted vaccination. The main reasons given for vaccine uptake included understanding the importance of vaccines for disease prevention and survival, and securing the health of family members, the fear of death, government campaigns, vaccine mandates and penalties. Older participants (≥ 40 years) demonstrated more positive attitudes towards vaccines. Most participants downplayed the role of culture and religion in attitudes towards vaccines. However, some of the drivers of vaccine hesitancy were having an ancestral calling, medical pluralism, or local myths around the treatment of infections such as influenza and mumps, and a perceived depopulation agenda couched in mistrust and the use of incentives and penalties to force people to accept COVID-19 vaccines.
Conclusion
Exploring what shapes attitudes towards vaccines in communities provides opportunities to understand the reasoning behind how people make decisions about whether to take a vaccine in different geographical and cultural spaces. The exploration of contexts, exposures and circumstances provide insights into perceptions and behaviour. Deeper engagement with local communities is crucial to develop evidence that can inform vaccine interventions. Assumptions about how culture and religion affect vaccine hesitancy or acceptance should be avoided in the process of developing such evidence
Caspase cleavage of influenza A virus M2 disrupts M2-LC3 interaction and regulates virion production.
No full textInfluenza A virus (IAV) Matrix 2 protein (M2) is an ion channel, required for efficient viral entry and egress. M2 interacts with the small ubiquitin-like LC3 protein through a cytoplasmic C-terminal LC3-interacting region (LIR). Here, we report that M2 is cleaved by caspases, abolishing the M2-LC3 interaction. A crystal structure of the M2 LIR in complex with LC3 indicates the caspase cleavage tetrapeptide motif (82SAVD85) is an unstructured linear motif that does not overlap with the LIR. IAV mutant expressing a permanently truncated M2, mimicking caspase cleavage, exhibit defects in M2 plasma membrane transport, viral filament formation, and virion production. Our results reveal a dynamic regulation of the M2-LC3 interaction by caspases. This highlights the role of host proteases in regulating IAV exit, relating virion production with host cell state
Clonal driver neoantigen loss under EGFR TKI and immune selection pressures.
No full textNeoantigen vaccines are under investigation for various cancers, including epidermal growth factor receptor (EGFR)-driven lung cancers1,2. We tracked the phylogenetic history of an EGFR mutant lung cancer treated with erlotinib, osimertinib, radiotherapy and a personalized neopeptide vaccine (NPV) targeting ten somatic mutations, including EGFR exon 19 deletion (ex19del). The ex19del mutation was clonal, but is likely to have appeared after a whole-genome doubling (WGD) event. Following osimertinib and NPV treatment, loss of the ex19del mutation was identified in a progressing small-cell-transformed liver metastasis. Circulating tumour DNA analyses tracking 467 somatic variants revealed the presence of this EGFR wild-type clone before vaccination and its expansion during osimertinib/NPV therapy. Despite systemic T cell reactivity to the vaccine-targeted ex19del neoantigen, the NPV failed to halt disease progression. The liver metastasis lost vaccine-targeted neoantigens through chromosomal instability and exhibited a hostile microenvironment, characterized by limited immune infiltration, low CXCL9 and elevated M2 macrophage levels. Neoantigens arising post-WGD were more likely to be absent in the progressing liver metastasis than those occurring pre-WGD, suggesting that prioritizing pre-WGD neoantigens may improve vaccine design. Data from the TRACERx 421 cohort3 provide evidence that pre-WGD mutations better represent clonal variants, and owing to their presence at multiple copy numbers, are less likely to be lost in metastatic transition. These data highlight the power of phylogenetic disease tracking and functional T cell profiling to understand mechanisms of immune escape during combination therapies.</p
Data associated with "A multimodal imaging pipeline to decipher cell-specific metabolic functions and tissue microenvironment dynamics"
No full textSEM image with cells of interest (B cells – blue, T cells – red, Tumour cells – green) identified by confocal fluorescence analysis. Raw images from NanoSIMS showing isotope ratios for the B cell and T cell that are denoted in the SEM image. This data is associated with the manuscript - "A multimodal imaging pipeline to decipher cell-specific metabolic functions and tissue microenvironment dynamics"</p
Frictiotaxis underlies focal adhesion-independent durotaxis.
No full textCells move directionally along gradients of substrate stiffness - a process called durotaxis. In the situations studied so far, durotaxis relies on cell-substrate focal adhesions to sense stiffness and transmit forces that drive directed motion. However, whether and how durotaxis can take place in the absence of focal adhesions remains unclear. Here, we show that confined cells can perform durotaxis despite lacking focal adhesions. This durotactic migration depends on an asymmetric myosin distribution and actomyosin retrograde flow. We propose that the mechanism of this focal adhesion-independent durotaxis is that stiffer substrates offer higher friction. We put forward a physical model that predicts that non-adherent cells polarise and migrate towards regions of higher friction - a process that we call frictiotaxis. We demonstrate frictiotaxis in experiments by showing that cells migrate up a friction gradient even when stiffness is uniform. Our results broaden the potential of durotaxis to guide any cell that contacts a substrate, and they reveal a mode of directed migration based on friction. These findings have implications for cell migration during development, immune response and cancer progression, which usually takes place in confined environments that favour adhesion-independent amoeboid migration
Discovery and optimisation of a covalent ligand for TRIM25 and its application to targeted protein ubiquitination.
No full textThe tripartite motif (TRIM) family of RING-type E3 ligases catalyses the formation of many different types of ubiquitin chains, and as such, plays important roles in diverse cellular functions, ranging from immune regulation to cancer signalling pathways. Few ligands have been discovered for TRIM E3 ligases, and these E3s are under-represented in the rapidly expanding field of induced proximity. Here we present the identification of a novel covalent ligand for the PRYSPRY substrate binding domain of TRIM25. We employ covalent fragment screening coupled with high-throughput chemistry direct-to-biology optimisation to efficiently elaborate covalent fragment hits. We demonstrate that our optimised ligand enhances the in vitro auto-ubiquitination activity of TRIM25 and engages TRIM25 in live cells. We also present the X-ray crystal structure of TRIM25 PRYSPRY in complex with this covalent ligand. Finally, we incorporate our optimised ligand into heterobifunctional proximity-inducing compounds and demonstrate the in vitro targeted ubiquitination of a neosubstrate by TRIM25
Experimental comparison of X-ray ptychographic and holographic nanotomography of metal-stained neuronal tissue
No full textHard X-ray nanotomography is a promising technology for nondestructive imaging of biological tissues with three-dimensional isotropic resolution. The implementation of fourth-generation synchrotron sources brings coherent X-ray microscopy to the central stage and fosters further development of this class of techniques. Here, we present an experimental comparison of X-ray near-field ptychography and X-ray holography, two high-resolution X-ray microscopy techniques applied under cryogenic conditions to the exact same sample at two different synchrotron sources. Using a heavy-metal-stained, resin-embedded brain tissue sample, we obtain similar contrast and spatial resolutions at equivalent radiation doses with these two approaches. We discuss the current benefits and limitations of the two methods. These results provide a basis for developments in X-ray microscopy of biological samples at present and future beamlines of fourth-generation synchrotron sources
Swine influenza virus surveillance programme pilot to assess the risk for animal and public health, the Netherlands, 2022 to 2023
No full textBackground: Swine influenza has a considerable impact on pig populations and poses a pandemic threat to humans. However, little is known about the influenza A viruses circulating among pigs in the Netherlands.
Aim: We piloted a surveillance programme aimed at enabling swine influenza A virus (swIAV) surveillance in the Netherlands: investigated prevalence, genomic characteristics and recent evolution of circulating swIAV variants and compared them with relevant human and swine influenza viruses from the Netherlands and other European countries.
Methods: We collected and tested respiratory samples from pigs (2019–2023) for swIAV, characterised the viruses with molecular and virological methods and shared molecular data of swine and relevant human influenza A viruses in a national platform.
Results: We detected swIAV throughout the year in 342 (42%) of 824 respiratory samples from 90 farms. Complete genome sequencing identified 73 H1N1, 51 H1N2 and one H3N2 viruses. Phylogenetic analyses identified viruses from each of the three H1 swine lineages (1A/B/C) and four subclades. Viruses from the 1A lineage clustered into three subgroups with distinct antigenic properties, which seemed descendent from separate introductions of human seasonal A(H1N1) pdm09 viruses. Phenotypically, no reduced susceptibility to existing antiviral drugs oseltamivir and zanamivir was found.
Conclusion: We provided insights into swIAVs in pigs in the Netherlands, including antiviral susceptibility and antigenic differences. It highlighted occasional virus transmission between humans and pigs. Sharing swIAV data at a national level will be continued to reduce influenza burden in swine and support identification and characterisation of emerging swIAVs with zoonotic potential