@article{nokey,

title = {Tough, Resorbable Polycaprolactone-Based Bimodal Networks for Vat Polymerization 3D Printing},

doi = {10.1002/adfm.202213797},

year  = {2023},

date = {2023-03-27},

urldate = {2023-03-27},

journal = {Advanced Functional Materials},

volume = {33},

issue = {25},

pages = {2213797},

abstract = {Vat polymerization allows for the accurate and fast fabrication of personalized implants and devices. While the technology advances rapidly and more materials become available, the fabrication of flexible yet tough resorbable materials for biomedical applications remains a challenge. Here, a formulation that can be 3D printed with high accuracy using vat polymerization, yielding materials that are tough, degradable, and non-toxic is presented. This unique combination of properties is obtained by combining a long-chain polycaprolactone macromonomer with a small molecule cross-linker. A wide range of properties is achieved by tuning the ratio of these components. The use of benzyl alcohol as a non-volatile, benign solvent enables fabrication on a low-cost desktop 3D printer, with an exposure time of 8 s per 50-micron layer. The 3D-printed networks are tough and elastic with a tensile strength of 11 MPa at 116% elongation at break. Cells attach and proliferate on the networks with a viability of >91%. The networks are fully degradable to soluble products. This new 3D printable material opens up a range of opportunities in biomedical engineering and personalized medicine.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid36959177,

title = {Mena regulates nesprin-2 to control actin-nuclear lamina associations, trans-nuclear membrane signalling and gene expression},

author = {Frederic Li Mow Chee and Bruno Beernaert and Billie G C Griffith and Alexander E P Loftus and Yatendra Kumar and Jimi C Wills and Martin Lee and Jessica Valli and Ann P Wheeler and J Douglas Armstrong and Maddy Parsons and Irene M Leigh and Charlotte M Proby and Alex von Kriegsheim and Wendy A Bickmore and Margaret C Frame and Adam Byron},

doi = {10.1038/s41467-023-37021-x},

issn = {2041-1723},

year  = {2023},

date = {2023-03-01},

journal = {Nat Commun},

volume = {14},

number = {1},

pages = {1602},

abstract = {Interactions between cells and the extracellular matrix, mediated by integrin adhesion complexes, play key roles in fundamental cellular processes, including the sensing and transduction of mechanical cues. Here, we investigate systems-level changes in the integrin adhesome in patient-derived cutaneous squamous cell carcinoma cells and identify the actin regulatory protein Mena as a key node in the adhesion complex network. Mena is connected within a subnetwork of actin-binding proteins to the LINC complex component nesprin-2, with which it interacts and co-localises at the nuclear envelope. Moreover, Mena potentiates the interactions of nesprin-2 with the actin cytoskeleton and the nuclear lamina. CRISPR-mediated Mena depletion causes altered nuclear morphology, reduces tyrosine phosphorylation of the nuclear membrane protein emerin and downregulates expression of the immunomodulatory gene PTX3 via the recruitment of its enhancer to the nuclear periphery. We uncover an unexpected role for Mena at the nuclear membrane, where it controls nuclear architecture, chromatin repositioning and gene expression. Our findings identify an adhesion protein that regulates gene transcription via direct signalling across the nuclear envelope.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid36635604,

title = {Structural maturation of SYCP1-mediated meiotic chromosome synapsis by SYCE3},

author = {James H Crichton and James M Dunce and Orla M Dunne and Lucy J Salmon and Paul S Devenney and Jennifer Lawson and Ian R Adams and Owen R Davies},

doi = {10.1038/s41594-022-00909-1},

issn = {1545-9985},

year  = {2023},

date = {2023-02-01},

journal = {Nat Struct Mol Biol},

volume = {30},

number = {2},

pages = {188--199},

abstract = {In meiosis, a supramolecular protein structure, the synaptonemal complex (SC), assembles between homologous chromosomes to facilitate their recombination. Mammalian SC formation is thought to involve hierarchical zipper-like assembly of an SYCP1 protein lattice that recruits stabilizing central element (CE) proteins as it extends. Here we combine biochemical approaches with separation-of-function mutagenesis in mice to show that, rather than stabilizing the SYCP1 lattice, the CE protein SYCE3 actively remodels this structure during synapsis. We find that SYCP1 tetramers undergo conformational change into 2:1 heterotrimers on SYCE3 binding, removing their assembly interfaces and disrupting the SYCP1 lattice. SYCE3 then establishes a new lattice by its self-assembly mimicking the role of the disrupted interface in tethering together SYCP1 dimers. SYCE3 also interacts with CE complexes SYCE1-SIX6OS1 and SYCE2-TEX12, providing a mechanism for their recruitment. Thus, SYCE3 remodels the SYCP1 lattice into a CE-binding integrated SYCP1-SYCE3 lattice to achieve long-range synapsis by a mature SC.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid37671010,

title = {Synaptic expression of TAR-DNA-binding protein 43 in the mouse spinal cord determined using super-resolution microscopy},

author = {Matthew J Broadhead and Ani Ayvazian-Hancock and Katherine Doucet and Owen Kantelberg and Lesley Motherwell and Fei Zhu and Seth G N Grant and Mathew H Horrocks and Gareth B Miles},

doi = {10.3389/fnmol.2023.1027898},

issn = {1662-5099},

year  = {2023},

date = {2023-01-01},

journal = {Front Mol Neurosci},

volume = {16},

pages = {1027898},

abstract = {Amyotrophic Lateral Sclerosis (ALS) is characterised by a loss of motor neurons in the brain and spinal cord that is preceded by early-stage changes in synapses that may be associated with TAR-DNA-Binding Protein 43 (TDP-43) pathology. Cellular inclusions of hyperphosphorylated TDP-43 (pTDP-43) are a key hallmark of neurodegenerative diseases such ALS. However, there has been little characterisation of the synaptic expression of TDP-43 inside subpopulations of spinal cord synapses. This study utilises a range of high-resolution and super-resolution microscopy techniques with immunolabelling, as well as an aptamer-based TDP-43 labelling strategy visualised with single-molecule localisation microscopy, to characterise and quantify the presence of pTDP-43 in populations of excitatory synapses near where motor neurons reside in the lateral ventral horn of the mouse lumbar spinal cord. We observe that TDP-43 is expressed in approximately half of spinal cord synapses as nanoscale clusters. Synaptic TDP-43 clusters are found most abundantly at synapses associated with VGLUT1-positive presynaptic terminals, compared to VGLUT2-associated synapses. Our nanoscopy techniques showed no difference in the subsynaptic expression of pTDP-43 in the ALS mouse model, SOD1, compared to healthy controls, despite prominent structural deficits in VGLUT1-associated synapses in SOD1 mice. This research characterises the basic synaptic expression of TDP-43 with nanoscale precision and provides a framework with which to investigate the potential relationship between TDP-43 pathology and synaptic pathology in neurodegenerative diseases.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid36476408,

title = {Oncogene expression from extrachromosomal DNA is driven by copy number amplification and does not require spatial clustering in glioblastoma stem cells},

author = {Karin Purshouse and Elias T Friman and Shelagh Boyle and Pooran Singh Dewari and Vivien Grant and Alhafidz Hamdan and Gillian M Morrison and Paul M Brennan and Sjoerd V Beentjes and Steven M Pollard and Wendy A Bickmore},

doi = {10.7554/eLife.80207},

issn = {2050-084X},

year  = {2022},

date = {2022-12-01},

journal = {Elife},

volume = {11},

abstract = {Extrachromosomal DNA (ecDNA) are frequently observed in human cancers and are responsible for high levels of oncogene expression. In glioblastoma (GBM), ecDNA copy number correlates with poor prognosis. It is hypothesized that their copy number, size, and chromatin accessibility facilitate clustering of ecDNA and colocalization with transcriptional hubs, and that this underpins their elevated transcriptional activity. Here, we use super-resolution imaging and quantitative image analysis to evaluate GBM stem cells harbouring distinct ecDNA species (). We find no evidence that ecDNA routinely cluster with one another or closely interact with transcriptional hubs. Cells with -containing ecDNA have increased  transcriptional output, but transcription per gene copy is similar in ecDNA compared to the endogenous chromosomal locus. These data suggest that it is the increased copy number of oncogene-harbouring ecDNA that primarily drives high levels of oncogene transcription, rather than specific interactions of ecDNA with each other or with high concentrations of the transcriptional machinery.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid35702882,

title = {The Hippo pathway drives the cellular response to hydrostatic pressure},

author = {Jiwon Park and Siyang Jia and Donald Salter and Pierre Bagnaninchi and Carsten G Hansen},

doi = {10.15252/embj.2021108719},

issn = {1460-2075},

year  = {2022},

date = {2022-07-01},

journal = {EMBO J},

volume = {41},

number = {13},

pages = {e108719},

abstract = {Cells need to rapidly and precisely react to multiple mechanical and chemical stimuli in order to ensure precise context-dependent responses. This requires dynamic cellular signalling events that ensure homeostasis and plasticity when needed. A less well-understood process is cellular response to elevated interstitial fluid pressure, where the cell senses and responds to changes in extracellular hydrostatic pressure. Here, using quantitative label-free digital holographic imaging, combined with genome editing, biochemical assays and confocal imaging, we analyse the temporal cellular response to hydrostatic pressure. Upon elevated cyclic hydrostatic pressure, the cell responds by rapid, dramatic and reversible changes in cellular volume. We show that YAP and TAZ, the co-transcriptional regulators of the Hippo signalling pathway, control cell volume and that cells without YAP and TAZ have lower plasma membrane tension. We present direct evidence that YAP/TAZ drive the cellular response to hydrostatic pressure, a process that is at least partly mediated via clathrin-dependent endocytosis. Additionally, upon elevated oscillating hydrostatic pressure, YAP/TAZ are activated and induce TEAD-mediated transcription and expression of cellular components involved in dynamic regulation of cell volume and extracellular matrix. This cellular response confers a feedback loop that allows the cell to robustly respond to changes in interstitial fluid pressure.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid35305541,

title = {Selective vulnerability of tripartite synapses in amyotrophic lateral sclerosis},

author = {Matthew J Broadhead and Calum Bonthron and Julia Waddington and William V Smith and Maite F Lopez and Sarah Burley and Jessica Valli and Fei Zhu and Noboru H Komiyama and Colin Smith and Seth G N Grant and Gareth B Miles},

doi = {10.1007/s00401-022-02412-9},

issn = {1432-0533},

year  = {2022},

date = {2022-04-01},

journal = {Acta Neuropathol},

volume = {143},

number = {4},

pages = {471--486},

abstract = {Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disorder. Separate lines of evidence suggest that synapses and astrocytes play a role in the pathological mechanisms underlying ALS. Given that astrocytes make specialised contacts with some synapses, called tripartite synapses, we hypothesise that tripartite synapses could act as the fulcrum of disease in ALS. To test this hypothesis, we have performed an extensive microscopy-based investigation of synapses and tripartite synapses in the spinal cord of ALS model mice and post-mortem human tissue from ALS cases. We reveal widescale synaptic changes at the early symptomatic stages of the SOD1 mouse model. Super-resolution microscopy reveals that large complex postsynaptic structures are lost in ALS mice. Most surprisingly, tripartite synapses are selectively lost, while non-tripartite synapses remain in equal number to healthy controls. Finally, we also observe a similar selective loss of tripartite synapses in human post-mortem ALS spinal cords. From these data we conclude that tripartite synaptopathy is a key hallmark of ALS.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid35022745,

title = {Label2label: training a neural network to selectively restore cellular structures in fluorescence microscopy},

author = {Lisa Sophie Kölln and Omar Salem and Jessica Valli and Carsten Gram Hansen and Gail McConnell},

doi = {10.1242/jcs.258994},

issn = {1477-9137},

year  = {2022},

date = {2022-02-01},

journal = {J Cell Sci},

volume = {135},

number = {3},

abstract = {Immunofluorescence microscopy is routinely used to visualise the spatial distribution of proteins that dictates their cellular function. However, unspecific antibody binding often results in high cytosolic background signals, decreasing the image contrast of a target structure. Recently, convolutional neural networks (CNNs) were successfully employed for image restoration in immunofluorescence microscopy, but current methods cannot correct for those background signals. We report a new method that trains a CNN to reduce unspecific signals in immunofluorescence images; we name this method label2label (L2L). In L2L, a CNN is trained with image pairs of two non-identical labels that target the same cellular structure. We show that after L2L training a network predicts images with significantly increased contrast of a target structure, which is further improved after implementing a multiscale structural similarity loss function. Here, our results suggest that sample differences in the training data decrease hallucination effects that are observed with other methods. We further assess the performance of a cycle generative adversarial network, and show that a CNN can be trained to separate structures in superposed immunofluorescence images of two targets.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid34668024,

title = {Particulate and drug-induced toxicity assessed in novel quadruple cell human primary hepatic disease models of steatosis and pre-fibrotic NASH},

author = {Ali Kermanizadeh and Jessica Valli and Katarzyna Sanchez and Simon Hutter and Agnieszka Pawlowska and Graeme Whyte and Wolfgang Moritz and Vicki Stone},

doi = {10.1007/s00204-021-03181-2},

issn = {1432-0738},

year  = {2022},

date = {2022-01-01},

journal = {Arch Toxicol},

volume = {96},

number = {1},

pages = {287--303},

abstract = {In an effort to replace, reduce and refine animal experimentation, there is an unmet need to advance current in vitro models that offer features with physiological relevance and enhanced predictivity of in vivo toxicological output. Hepatic toxicology is key following chemical, drug and nanomaterials (NMs) exposure, as the liver is vital in metabolic detoxification of chemicals as well as being a major site of xenobiotic accumulation (i.e., low solubility particulates). With the ever-increasing production of NMs, there is a necessity to evaluate the probability of consequential adverse effects, not only in health but also in clinically asymptomatic liver, as part of risk stratification strategies. In this study, two unique disease initiation and maintenance protocols were developed and utilised to mimic steatosis and pre-fibrotic NASH in scaffold-free 3D liver microtissues (MT) composed of primary human hepatocytes, hepatic stellate cells, Kupffer cells and sinusoidal endothelial cells. The characterized diseased MT were utilized for the toxicological assessment of a panel of xenobiotics. Highlights from the study included: 1. Clear experimental evidence for the pre-existing liver disease is important in the augmentation of xenobiotic-induced hepatotoxicity and 2. NMs are able to activate stellate cells. The data demonstrated that pre-existing disease is vital in the intensification of xenobiotic-induced liver damage. Therefore, it is imperative that all stages of the wide spectrum of liver disease are incorporated in risk assessment strategies. This is of significant consequence, as a substantial number of the general population suffer from sub-clinical liver injury without any apparent or diagnosed manifestations.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid34734804,

title = {A WDR35-dependent coat protein complex transports ciliary membrane cargo vesicles to cilia},

author = {Tooba Quidwai and Jiaolong Wang and Emma A Hall and Narcis A Petriman and Weihua Leng and Petra Kiesel and Jonathan N Wells and Laura C Murphy and Margaret A Keighren and Joseph A Marsh and Esben Lorentzen and Gaia Pigino and Pleasantine Mill},

doi = {10.7554/eLife.69786},

issn = {2050-084X},

year  = {2021},

date = {2021-11-01},

journal = {Elife},

volume = {10},

abstract = {Intraflagellar transport (IFT) is a highly conserved mechanism for motor-driven transport of cargo within cilia, but how this cargo is selectively transported to cilia is unclear. WDR35/IFT121 is a component of the IFT-A complex best known for its role in ciliary retrograde transport. In the absence of WDR35, small mutant cilia form but fail to enrich in diverse classes of ciliary membrane proteins. In  mouse mutants, the non-core IFT-A components are degraded and core components accumulate at the ciliary base. We reveal deep sequence homology of WDR35 and other IFT-A subunits to α and ß' COPI coatomer subunits and demonstrate an accumulation of 'coat-less' vesicles that fail to fuse with  mutant cilia. We determine that recombinant non-core IFT-As can bind directly to lipids and provide the first in situ evidence of a novel coat function for WDR35, likely with other IFT-A proteins, in delivering ciliary membrane cargo necessary for cilia elongation.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid34571955,

title = {Identification and Characterization of an Affimer Affinity Reagent for the Detection of the cAMP Sensor, EPAC1},

author = {Hanna K Buist and Urszula Luchowska-Stańska and Boy van Basten and Jessica Valli and Brian O Smith and George S Baillie and Colin Rickman and Bryon Ricketts and Alex Davidson and Ryan Hannam and Joanne Sunderland and Stephen J Yarwood},

doi = {10.3390/cells10092307},

issn = {2073-4409},

year  = {2021},

date = {2021-09-01},

journal = {Cells},

volume = {10},

number = {9},

abstract = {An exchange protein directly activated by cAMP 1 (EPAC1) is an intracellular sensor for cAMP that is involved in a wide variety of cellular and physiological processes in health and disease. However, reagents are lacking to study its association with intracellular cAMP nanodomains. Here, we use non-antibody Affimer protein scaffolds to develop isoform-selective protein binders of EPAC1. Phage-display screens were carried out against purified, biotinylated human recombinant EPAC1ΔDEP protein (amino acids 149-811), which identified five potential EPAC1-selective Affimer binders. Dot blots and indirect ELISA assays were next used to identify Affimer 780A as the top EPAC1 binder. Mutagenesis studies further revealed a potential interaction site for 780A within the EPAC1 cyclic nucleotide binding domain (CNBD). In addition, 780A was shown to co-precipitate EPAC1 from transfected cells and co-localize with both wild-type EPAC1 and a mis-targeting mutant of EPAC1(K212R), predominantly in perinuclear and cytosolic regions of cells, respectively. As a novel EPAC1-selective binder, 780A therefore has the potential to be used in future studies to further understand compartmentalization of the cAMP-EPAC1 signaling system.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid34436832,

title = {Super-Resolution Fluorescence Microscopy Methods for Assessing Mouse Biology},

author = {Jessica Valli and Jeremy Sanderson},

doi = {10.1002/cpz1.224},

issn = {2691-1299},

year  = {2021},

date = {2021-08-01},

journal = {Curr Protoc},

volume = {1},

number = {8},

pages = {e224},

abstract = {Super-resolution (diffraction unlimited) microscopy was developed 15 years ago; the developers were awarded the Nobel Prize in Chemistry in recognition of their work in 2014. Super-resolution microscopy is increasingly being applied to diverse scientific fields, from single molecules to cell organelles, viruses, bacteria, plants, and animals, especially the mammalian model organism Mus musculus. In this review, we explain how super-resolution microscopy, along with fluorescence microscopy from which it grew, has aided the renaissance of the light microscope. We cover experiment planning and specimen preparation and explain structured illumination microscopy, super-resolution radial fluctuations, stimulated emission depletion microscopy, single-molecule localization microscopy, and super-resolution imaging by pixel reassignment. The final section of this review discusses the strengths and weaknesses of each super-resolution technique and how to choose the best approach for your research. © 2021 The Authors. Current Protocols published by Wiley Periodicals LLC.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid34015334,

title = {Seeing beyond the limit: A guide to choosing the right super-resolution microscopy technique},

author = {Jessica Valli and Adrian Garcia-Burgos and Liam M Rooney and Beatriz Vale de Melo E Oliveira and Rory R Duncan and Colin Rickman},

doi = {10.1016/j.jbc.2021.100791},

issn = {1083-351X},

year  = {2021},

date = {2021-07-01},

journal = {J Biol Chem},

volume = {297},

number = {1},

pages = {100791},

abstract = {Super-resolution microscopy has become an increasingly popular and robust tool across the life sciences to study minute cellular structures and processes. However, with the increasing number of available super-resolution techniques has come an increased complexity and burden of choice in planning imaging experiments. Choosing the right super-resolution technique to answer a given biological question is vital for understanding and interpreting biological relevance. This is an often-neglected and complex task that should take into account well-defined criteria (e.g., sample type, structure size, imaging requirements). Trade-offs in different imaging capabilities are inevitable; thus, many researchers still find it challenging to select the most suitable technique that will best answer their biological question. This review aims to provide an overview and clarify the concepts underlying the most commonly available super-resolution techniques as well as guide researchers through all aspects that should be considered before opting for a given technique.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid33829644,

title = {Simultaneous multi-spectral, single-photon fluorescence imaging using a plasmonic colour filter array},

author = {Peter W R Connolly and Jessica Valli and Yash D Shah and Yoann Altmann and James Grant and Claudio Accarino and Colin Rickman and David R S Cumming and Gerald S Buller},

doi = {10.1002/jbio.202000505},

issn = {1864-0648},

year  = {2021},

date = {2021-07-01},

journal = {J Biophotonics},

volume = {14},

number = {7},

pages = {e202000505},

abstract = {We present the first realisation of simultaneous multi-spectral fluorescence imaging using a single-photon avalanche diode (SPAD) array, where the spectral unmixing is facilitated by a plasmonic metasurface mosaic colour filter array (CFA). A 64 × 64 pixel format silicon SPAD array is used to record widefield fluorescence and brightfield data from four biological samples. A plasmonic metasurface composed of an arrangement of circular and elliptical nanoholes etched into an aluminium thin film deposited on a glass substrate provides the high transmission efficiency CFA, enabling a bespoke spectral unmixing algorithm to reconstruct high fidelity, full colour images from as few as ∼3 photons per pixel. This approach points the way toward real-time, single-photon sensitive multi-spectral fluorescence imaging. Furthermore, this is possible without additional bulky components such as a filter wheel, prism or diffraction grating, nor the need for multiple sample exposures or multiple detectors.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid33734291,

title = {Parameter-free molecular super-structures quantification in single-molecule localization microscopy},

author = {Mattia Marenda and Elena Lazarova and Sebastian van de Linde and Nick Gilbert and Davide Michieletto},

doi = {10.1083/jcb.202010003},

issn = {1540-8140},

year  = {2021},

date = {2021-05-01},

journal = {J Cell Biol},

volume = {220},

number = {5},

abstract = {Understanding biological function requires the identification and characterization of complex patterns of molecules. Single-molecule localization microscopy (SMLM) can quantitatively measure molecular components and interactions at resolutions far beyond the diffraction limit, but this information is only useful if these patterns can be quantified and interpreted. We provide a new approach for the analysis of SMLM data that develops the concept of structures and super-structures formed by interconnected elements, such as smaller protein clusters. Using a formal framework and a parameter-free algorithm, (super-)structures formed from smaller components are found to be abundant in classes of nuclear proteins, such as heterogeneous nuclear ribonucleoprotein particles (hnRNPs), but are absent from ceramides located in the plasma membrane. We suggest that mesoscopic structures formed by interconnected protein clusters are common within the nucleus and have an important role in the organization and function of the genome. Our algorithm, SuperStructure, can be used to analyze and explore complex SMLM data and extract functionally relevant information.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid34035299,

title = {Cornelia de Lange syndrome-associated mutations cause a DNA damage signalling and repair defect},

author = {Gabrielle Olley and Madapura M Pradeepa and Graeme R Grimes and Sandra Piquet and Sophie E Polo and David R FitzPatrick and Wendy A Bickmore and Charlene Boumendil},

doi = {10.1038/s41467-021-23500-6},

issn = {2041-1723},

year  = {2021},

date = {2021-05-01},

journal = {Nat Commun},

volume = {12},

number = {1},

pages = {3127},

abstract = {Cornelia de Lange syndrome is a multisystem developmental disorder typically caused by mutations in the gene encoding the cohesin loader NIPBL. The associated phenotype is generally assumed to be the consequence of aberrant transcriptional regulation. Recently, we identified a missense mutation in BRD4 associated with a Cornelia de Lange-like syndrome that reduces BRD4 binding to acetylated histones. Here we show that, although this mutation reduces BRD4-occupancy at enhancers it does not affect transcription of the pluripotency network in mouse embryonic stem cells. Rather, it delays the cell cycle, increases DNA damage signalling, and perturbs regulation of DNA repair in mutant cells. This uncovers a role for BRD4 in DNA repair pathway choice. Furthermore, we find evidence of a similar increase in DNA damage signalling in cells derived from NIPBL-deficient individuals, suggesting that defective DNA damage signalling and repair is also a feature of typical Cornelia de Lange syndrome.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid33741926,

title = {Red blood cell mannoses as phagocytic ligands mediating both sickle cell anaemia and malaria resistance},

author = {Huan Cao and Aristotelis Antonopoulos and Sadie Henderson and Heather Wassall and John Brewin and Alanna Masson and Jenna Shepherd and Gabriela Konieczny and Bhinal Patel and Maria-Louise Williams and Adam Davie and Megan A Forrester and Lindsay Hall and Beverley Minter and Dimitris Tampakis and Michael Moss and Charlotte Lennon and Wendy Pickford and Lars Erwig and Beverley Robertson and Anne Dell and Gordon D Brown and Heather M Wilson and David C Rees and Stuart M Haslam and J Alexandra Rowe and Robert N Barker and Mark A Vickers},

doi = {10.1038/s41467-021-21814-z},

issn = {2041-1723},

year  = {2021},

date = {2021-03-01},

journal = {Nat Commun},

volume = {12},

number = {1},

pages = {1792},

abstract = {In both sickle cell disease and malaria, red blood cells (RBCs) are phagocytosed in the spleen, but receptor-ligand pairs mediating uptake have not been identified. Here, we report that patches of high mannose N-glycans (ManGlcNAc), expressed on diseased or oxidized RBC surfaces, bind the mannose receptor (CD206) on phagocytes to mediate clearance. We find that extravascular hemolysis in sickle cell disease correlates with high mannose glycan levels on RBCs. Furthermore, Plasmodium falciparum-infected RBCs expose surface mannose N-glycans, which occur at significantly higher levels on infected RBCs from sickle cell trait subjects compared to those lacking hemoglobin S. The glycans are associated with high molecular weight complexes and protease-resistant, lower molecular weight fragments containing spectrin. Recognition of surface N-linked high mannose glycans as a response to cellular stress is a molecular mechanism common to both the pathogenesis of sickle cell disease and resistance to severe malaria in sickle cell trait.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid33230297,

title = {cGAS-mediated induction of type I interferon due to inborn errors of histone pre-mRNA processing},

author = {Carolina Uggenti and Alice Lepelley and Marine Depp and Andrew P Badrock and Mathieu P Rodero and Marie-Thérèse El-Daher and Gillian I Rice and Somdutta Dhir and Ann P Wheeler and Ashish Dhir and Waad Albawardi and Marie-Louise Frémond and Luis Seabra and Jennifer Doig and Natalie Blair and Maria José Martin-Niclos and Erika Della Mina and Alejandro Rubio-Roldán and Jose L García-Pérez and Duncan Sproul and Jan Rehwinkel and Jonny Hertzog and Anne Boland-Auge and Robert Olaso and Jean-François Deleuze and Julien Baruteau and Karine Brochard and Jonathan Buckley and Vanessa Cavallera and Cristina Cereda and Liesbeth M H De Waele and Angus Dobbie and Diane Doummar and Frances Elmslie and Margarete Koch-Hogrebe and Ram Kumar and Kate Lamb and John H Livingston and Anirban Majumdar and Charles Marques Lorenço and Simona Orcesi and Sylviane Peudenier and Kevin Rostasy and Caroline A Salmon and Christiaan Scott and Davide Tonduti and Guy Touati and Marialuisa Valente and Hélio van der Linden and Hilde Van Esch and Marie Vermelle and Kate Webb and Andrew P Jackson and Martin A M Reijns and Nick Gilbert and Yanick J Crow},

doi = {10.1038/s41588-020-00737-3},

issn = {1546-1718},

year  = {2020},

date = {2020-12-01},

journal = {Nat Genet},

volume = {52},

number = {12},

pages = {1364--1372},

abstract = {Inappropriate stimulation or defective negative regulation of the type I interferon response can lead to autoinflammation. In genetically uncharacterized cases of the type I interferonopathy Aicardi-Goutières syndrome, we identified biallelic mutations in LSM11 and RNU7-1, which encode components of the replication-dependent histone pre-mRNA-processing complex. Mutations were associated with the misprocessing of canonical histone transcripts and a disturbance of linker histone stoichiometry. Additionally, we observed an altered distribution of nuclear cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS) and enhanced interferon signaling mediated by the cGAS-stimulator of interferon genes (STING) pathway in patient-derived fibroblasts. Finally, we established that chromatin without linker histone stimulates cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) production in vitro more efficiently. We conclude that nuclear histones, as key constituents of chromatin, are essential in suppressing the immunogenicity of self-DNA.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid32616520,

title = {Identification of a localized nonsense-mediated decay pathway at the endoplasmic reticulum},

author = {Dasa Longman and Kathryn A Jackson-Jones and Magdalena M Maslon and Laura C Murphy and Robert S Young and Jack J Stoddart and Nele Hug and Martin S Taylor and Dimitrios K Papadopoulos and Javier F Cáceres},

doi = {10.1101/gad.338061.120},

issn = {1549-5477},

year  = {2020},

date = {2020-08-01},

journal = {Genes Dev},

volume = {34},

number = {15-16},

pages = {1075--1088},

abstract = {Nonsense-mediated decay (NMD) is a translation-dependent RNA quality control mechanism that occurs in the cytoplasm. However, it is unknown how NMD regulates the stability of RNAs translated at the endoplasmic reticulum (ER). Here, we identify a localized NMD pathway dedicated to ER-translated mRNAs. We previously identified NBAS, a component of the Syntaxin 18 complex involved in Golgi-to-ER trafficking, as a novel NMD factor. Furthermore, we show that NBAS fulfills an independent function in NMD. This ER-NMD pathway requires the interaction of NBAS with the core NMD factor UPF1, which is partially localized at the ER in the proximity of the translocon. NBAS and UPF1 coregulate the stability of ER-associated transcripts, in particular those associated with the cellular stress response. We propose a model where NBAS recruits UPF1 to the membrane of the ER and activates an ER-dedicated NMD pathway, thus providing an ER-protective function by ensuring quality control of ER-translated mRNAs.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid32652076,

title = {PRL3-DDX21 Transcriptional Control of Endolysosomal Genes Restricts Melanocyte Stem Cell Differentiation},

author = {Jeanette A Johansson and Kerrie L Marie and Yuting Lu and Alessandro Brombin and Cristina Santoriello and Zhiqiang Zeng and Judith Zich and Philippe Gautier and Alex von Kriegsheim and Hannah Brunsdon and Ann P Wheeler and Marcel Dreger and Douglas R Houston and Christopher M Dooley and Andrew H Sims and Elisabeth M Busch-Nentwich and Leonard I Zon and Robert S Illingworth and E Elizabeth Patton},

doi = {10.1016/j.devcel.2020.06.013},

issn = {1878-1551},

year  = {2020},

date = {2020-08-01},

journal = {Dev Cell},

volume = {54},

number = {3},

pages = {317--332.e9},

abstract = {Melanocytes, replenished throughout life by melanocyte stem cells (MSCs), play a critical role in pigmentation and melanoma. Here, we reveal a function for the metastasis-associated phosphatase of regenerating liver 3 (PRL3) in MSC regeneration. We show that PRL3 binds to the RNA helicase DDX21, thereby restricting productive transcription by RNAPII at master transcription factor (MITF)-regulated endolysosomal vesicle genes. In zebrafish, this mechanism controls premature melanoblast expansion and differentiation from MSCs. In melanoma patients, restricted transcription of this endolysosomal vesicle pathway is a hallmark of PRL3-high melanomas. Our work presents the conceptual advance that PRL3-mediated control of transcriptional elongation is a differentiation checkpoint mechanism for activated MSCs and has clinical relevance for the activity of PRL3 in regenerating tissue and cancer.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}