5683099 research outputs found
Sort by
Datasets associated with: Timely TGFβ signalling inhibition induces notochord
No full textDatasets associated with: Rito, T., Libby, A. R., Demuth, M., Domart, M. C., Cornwall-Scoones, J., & Briscoe, J. (2025). Timely TGFβ signalling inhibition induces notochord. Nature, 637(8046), 673-682.</p
Datasets associated with: MCM double hexamer loading visualized with human proteins
No full textDatasets associated with: Weissmann, F., Greiwe, J. F., Pühringer, T., Eastwood, E. L., Couves, E. C., Miller, T. C., ... & Costa, A. (2024). MCM double hexamer loading visualized with human proteins. Nature, 636(8042), 499-508.</p
Datasets associated with: CRISPR-Cas9 screening identifies KRAS-induced COX2 as a driver of immunotherapy resistance in lung cancer
No full textDatasets associated with: Boumelha, J., de Castro, A., Bah, N., Cha, H., de Carné Trécesson, S., Rana, S., ... & Downward, J. (2024). CRISPR–Cas9 screening identifies KRAS-induced COX2 as a driver of immunotherapy resistance in lung cancer. Cancer research, 84(14), 2231-2246.</p
Inactivation of airborne pathogen surrogates by triethylene glycol.
No full textThe COVID-19 outbreak brought to the fore the importance of airborne transmission in spreading human infectious diseases and highlighted the need for sustainable mitigation strategies. Triethylene glycol (TEG) has been documented as having microbicidal capabilities and has been proposed as one such mitigation strategy. Aerosolized TEG exhibits antimicrobial activity against airborne microorganisms. Grignard Pure Technology was developed to safely aerosolize TEG for decontamination of enclosed spaces. Here, we show that this TEG formulation effectively inactivates airborne microorganisms, resulting in 2 to 4.5 net log reduction in concentration of viable bacteria, viruses, and mycobacteria within 30-60 min at TEG concentration (aerosol + vapor) of ~0.7 mg/m3, which is well within the range considered safe for humans. Our data also demonstrate that aerosolizing both the test organisms and the antimicrobial product provides a more accurate and relevant measure of the product's efficacy for indoor usage than traditional surface-or solution-based disinfection assays. Accurate evaluation of antimicrobial efficacy is a crucial step in adopting novel interventions and tools to control airborne pathogens that pose a public health risk. Our findings argue that testing protocols must match the intended use of any intervention. Given the safety concerns of aerosolizing human pathogens for direct testing of airborne infectious burden, we also advance an approach for selecting suitable surrogate microorganisms based on their phenotypic and biophysical similarity to corresponding pathogenic species.IMPORTANCEDuring the COVID-19 pandemic, personal protective equipment, social distancing, and even vaccinations proved sub-optimal in controlling the spread of COVID-19. Public health practice and the hierarchy of controls emphasize primary prevention, whereby the pathogen is removed or destroyed before exposure to the public. Triethylene glycol (TEG) has the potential to inactivate airborne pathogens and limit their spread. TEG is designated a "safer chemical" by the US EPA and has been used for decades in aerosol deodorizers and theatrical special effects. This study shows that aerosolized TEG is highly effective at eliminating a wide spectrum of viable airborne pathogen surrogates at concentrations well below the threshold of safety concern. Thus, it may afford significant protection against the transmission of infectious agents with pandemic potential
A direct role for a mitochondrial targeting sequence in signalling stress.
No full textMitochondrial protein import is required for maintaining organellar function1. Perturbations in this process are associated with various physiological and disease conditions2. Several stress responses, including the mitochondrial compromised protein import response (mitoCPR), combat damage caused by mitochondrial protein import defects2. However, how this defect is sensed remains largely unknown. Here we reveal that the conserved mitochondrial Hsp70 co-chaperone, Mge1, acts as a stress messenger in budding yeast. During mitochondrial stress, unimported Mge1 entered the nucleus and triggered the transcription of mitoCPR target genes. This was mediated by the interaction of Mge1 with the transcription factor Pdr3 on DNA regulatory elements. The mitochondrial targeting sequence of Mge1 was both sufficient and essential for mitoCPR induction, demonstrating that in addition to their roles in mitochondrial protein import, targeting sequences can also function as signalling molecules. As protein import defects are a common consequence of various types of mitochondrial damage3,4, these findings suggest a novel function for the targeting sequence of Mge1 as an indicator of mitochondrial health
Hypoxic stress is an early pathogenic event in human VCP-mutant ALS astrocytes.
No full textAstrocytes are essential regulators of neuronal health, and their dysfunction contributes to neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). Using human induced pluripotent stem cell (iPSC)-derived astrocytes carrying ALS-associated VCP mutations, we uncover cell-autonomous activation of the hypoxia response under basal conditions. VCP-mutant astrocytes exhibit increased nuclear hypoxia-inducible factor (HIF)-1ɑ, mitochondrial depolarization, and lipid droplet accumulation. Mimicking hypoxia in control astrocytes by HIF-1ɑ stabilization with dimethyloxalylglycine recapitulates these phenotypes. Transcriptomic and CUT&RUN profiling reveal direct HIF-1ɑ binding to canonical hypoxia-responsive genes in VCP-mutant astrocytes and a transcriptional signature of metabolic reprogramming and mitochondrial dysfunction under normoxia. Furthermore, conditioned medium from hypoxia-exposed astrocytes fails to rescue RNA-binding protein mislocalization in motor neurons, unlike medium from healthy counterparts. Together, these findings demonstrate that aberrant HIF-1ɑ activation drives astrocytic dysfunction and compromises neuronal support, identifying hypoxic stress as an early and functionally consequential event in VCP-mutant ALS, with therapeutic implications for targeting HIF-1ɑ signaling
Multi-contrast X-ray microtomography of human lung specimens with an extended field-of-view.
No full textBACKGROUND: Phase-based X-ray microtomography is a powerful technique capable of quantitative volumetric imaging of lung tissue in health and disease. The maximum sample size is however limited by the fixed sizes of detectors and optical elements. Thus while high-resolution imaging can offer valuable microscale insights, it can be difficult to interpret without the context of the surrounding tissue. We propose a multi-contrast and multi-scale approach, combined with an offset geometry to extend the field-of-view (FOV). PURPOSE: FOV limitations make it a challenge to simultaneously achieve high spatial-resolution and image large samples. Our method doubles the possible FOV achievable for a given spatial-resolution, in a way compatible with multiple scales and imaging systems. METHODS: Multi-contrast whole sample volumetric images are acquired using a beam-tracking X-ray phase-contrast imaging(XPCI) system. Following this, a section of the same sample is imaged at higher resolution using an X-ray microscope with propagation-based imaging. The FOV of both methods is doubled using an offset center-of-rotation geometry, followed by weighted analytical reconstruction. RESULTS: We present exemplary multi-contrast reconstructions of resected human lung tissue at 10.5 μ m \umu{\rm m} voxel size across a 4.3 cm horizontal FOV, and at 450 nm voxel size for a 2.7 mm section of the same sample. This enables the visualization of a range of features, from the macro to the cellular scale. CONCLUSIONS: We demonstrate a versatile method to image large samples without sacrificing spatial-resolution. This method is directly compatible with complementary implementations of XPCI, and is easily adapted to a range of other systems
Deep learning assisted proton pure shift NMR spectroscopy.
No full textNuclear magnetic resonance spectroscopy (NMR) plays a key role for the analysis of a plethora of molecules, including natural products and drug-like organic molecules. For such cases, 1H NMR spectra have proven imperative because of their high sensitivity and atomic resolution. However, these spectra are complicated by overlapped complex multiplet patterns. Here we show a deep-learning approach, which transforms spin-echo modulated 1H NMR spectra into highly sensitive and high-resolution singlet NMR spectra, that is, virtual homonuclear decoupled pure shift spectra. The approach was evaluated on experimental NMR spectra of complex organic compounds, where it outperforms current methods. The method also predicts uncertainties of the transformation and therefore allows for quantifications, which is a key strength of NMR. We believe that our approach will provide significant advantages when characterizing low-sensitivity samples and systems with exchangeable protons, where signals are not observed in traditional pure-shift spectra and substantial overlaps hamper analysis from conventional spectra
Datasets and code associated with: Spatial multiplex analysis of lung cancer reveals that regulatory T cells attenuate KRAS-G12C inhibitor-induced immune responses.
No full textDatasets and code associated with: Cole, M., Anastasiou, P., Lee, C., Yu, X., De Castro, A., Roelink, J., ... & van Maldegem, F. (2024). Spatial multiplex analysis of lung cancer reveals that regulatory T cells attenuate KRAS-G12C inhibitor–induced immune responses. Science Advances, 10(44), eadl6464.</p
Investigations into multiple fission yeast chromosome size determinants.
No full textMitotic chromosome dimensions differ between species, and they differ between developmental stages within an organism. The physiological determinants of chromosome size remain poorly understood. Here, we investigate chromosome size determinants in the fission yeast Schizosaccharomyces pombe. Super-resolution microscopy and semi-automated measurements reveal that cell or nuclear volume in interphase, or the time spent in mitosis (both previously proposed chromosome size determinants), have little influence on resultant chromosome dimensions. Instead, levels of the chromosomal condensin complex affect chromosome size, with increasing condensin levels resulting in more compact, thinner and shorter, chromosomes. Our observations inform the understanding of how chromosome dimensions are controlled in an organism. They suggest that a chromosome-intrinsic mechanism sets chromosome size, more so than the environment in which chromosomes find themselves in