5683099 research outputs found
Sort by
Quantifying spectral information about source separation in multisource odour plumes.
No full textOdours released by objects in natural environments can contain information about their spatial locations. In particular, the correlation of odour concentration timeseries produced by two spatially separated sources contains information about the distance between the sources. For example, mice are able to distinguish correlated and anti-correlated odour fluctuations at frequencies up to 40 Hz, while insect olfactory receptor neurons can resolve fluctuations exceeding 100 Hz. Can this high-frequency acuity support odour source localization? Here we answer this question by quantifying the spatial information about source separation contained in the spectral constituents of correlations. We used computational fluid dynamics simulations of multisource plumes in two-dimensional chaotic flow environments to generate temporally complex, covarying odour concentration fields. By relating the correlation of these fields to the spectral decompositions of the associated odour concentration timeseries, and making simplifying assumptions about the statistics of these decompositions, we derived analytic expressions for the Fisher information contained in the spectral components of the correlations about source separation. We computed the Fisher information for a broad range of frequencies and source separations for three different source arrangements and found that high frequencies were more informative than low frequencies when sources were close relative to the sizes of the large eddies in the flow. We observed a qualitatively similar effect in an independent set of simulations with different geometry, but not for surrogate data with a similar power spectrum to our simulations but in which all frequencies were a priori equally informative. Our work suggests that the high-frequency acuity of olfactory systems may support high-resolution spatial localization of odour sources. We also provide a model of the distribution of the spectral components of correlations that is accurate over a broad range of frequencies and source separations. More broadly, our work establishes an approach for the quantification of the spatial information in odour concentration timeseries.</p
Discovering covalent cyclic peptide inhibitors of peptidyl arginine deiminase 4 (PADI4) using mRNA-display with a genetically encoded electrophilic warhead.
No full textCovalent drugs can achieve high potency with long dosing intervals. However, concerns remain about side-effects associated with off-target reactivity. Combining macrocyclic peptides with covalent warheads provides a solution to minimise off-target reactivity: the peptide enables highly specific target binding, positioning a weakly reactive warhead proximal to a suitable residue in the target. Here we demonstrate the direct discovery of covalent cyclic peptides using encoded libraries containing a weakly electrophilic cysteine-reactive fluoroamidine warhead. We combine direct incorporation of the warhead into peptide libraries using the flexible in vitro translation system with a peptide selection approach that identifies only covalent target binders. Using this approach, we identify potent and selective covalent inhibitors of the peptidyl arginine deiminase, PADI4 or PAD4, that react exclusively at the active site cysteine. We envisage this approach will enable covalent peptide inhibitor discovery for a range of related enzymes and expansion to alternative warheads in the future
Differential chromatin accessibility response to retinoic acid in neuroblastoma with ATRX in-frame-deletions versus ATRX loss-of-function.
No full textNeuroblastoma is a childhood cancer, arising in the developing sympathetic nervous system. Differentiation therapy with 13-cis-retinoic acid (RA) is given to children with neuroblastoma to prevent relapse, however there is little understanding of which patients benefit. ATRX alterations are identified in 10 % of high-risk neuroblastomas and associated with poor outcomes. The commonest type of ATRX alterations in neuroblastoma are in-frame multi-exon deletions, followed by nonsense mutations predicted to result in loss-of-function (ATRX LoF). We treated paired ATRX wild-type and LoF neuroblastoma cell-lines with RA: cells with ATRX LoF fail to upregulate direct RA target genes and show reduced chromatin accessibility differentiation and development related genes following RA treatment. Conversely, neuroblastoma models with in-frame deletions mount an appropriate epigenetic response to RA. Taken together this shows that the mechanism of differentiation in ATRX-altered neuroblastoma depends on the type of ATRX alteration, with implications relating to both oncogenesis and therapeutic response
June2024 Prections 12h-24h pulse
No full textStem cell differentiations June 2024. SAG pulse 12-24h.</p
Extrachromosomal DNA-driven oncogene spatial heterogeneity and evolution in glioblastoma.
No full textUNLABELLED: Oncogenes amplified on extrachromosomal DNA (ecDNA) contribute to treatment resistance and poor survival across cancers. Currently, the spatiotemporal evolution of ecDNA remains poorly understood. In this study, we integrate computational modeling with samples from 94 treatment-naive human glioblastomas (GBM) to investigate the spatiotemporal evolution of ecDNA. We observe oncogene-specific patterns of ecDNA spatial heterogeneity, emerging from random ecDNA segregation and differing fitness advantages. Unlike PDGFRA-ecDNAs, EGFR-ecDNAs often accumulate prior to clonal expansions, conferring strong fitness advantages and reaching high abundances. In corroboration, we observe pretumor ecDNA accumulation in vivo in genetically engineered mouse neural stem cells. Variant and wild-type EGFR-ecDNAs often coexist in GBM. Those variant EGFR-ecDNAs, most commonly EGFRvIII-ecDNA, always derive from preexisting wild-type EGFR-ecDNAs, occur early, and reach high abundance. Our results suggest that the ecDNA oncogenic makeup determines unique evolutionary trajectories. New concepts such as ecDNA clonality and heteroplasmy require a refined evolutionary interpretation of genomic data in a large subset of GBMs. SIGNIFICANCE: We study spatial patterns of ecDNA-amplified oncogenes and their evolutionary properties in human GBM, revealing an ecDNA landscape and ecDNA oncogene-specific evolutionary histories. ecDNA accumulation can precede clonal expansion, facilitating the emergence of EGFR oncogenic variants, reframing our interpretation of genomic data in a large subset of GBMs. See related article by Korsah et al., p. XX
PhotoNeuro: A compact photodetector for synchronization of visual stimulus presentation during behavioural experiments in neuroscience
No full textPresenting visual stimuli in neuroscience experiments often requires precise temporal alignment between visual events and electrophysiological or behavioural recordings. This is typically achieved by combining analogue signals that convey timing information about the visual cue shown
on liquid crystal displays (LCDs), sensed via photodetectors and recorded through analogue-todigital
converter (ADC) acquisition boards. However, most commercial photodetector systems pose limitations such as high voltage requirements, large sensor footprints that interfere with stimulus presentation, and limited compatibility with open-source platforms. Here, we present a compact, low-cost photodetector system designed for compatibility with common 3.3–5 V microcontroller-based development boards (e.g., Arduino) and the open-source visual programming language Bonsai, widely used in neuroscience for experiment control. The circuit consists of
a photodiode, an amplification stage, and a low-pass filter, and can optionally incorporate an infrared filter—useful for experiments involving infrared touch displays. To facilitate reproducibility, we provide complete design files, a bill of materials and detailed building and operational instructions. We further introduce a four-channel variant, enabling the detection of four-bit binary signals for more complex synchronization needs. Validation and characterization of the device were performed through grayscale gamma correction analysis of LCD monitors using Bonsai. Additionally, we demonstrate the system’s utility in a head-fixed mouse experiment, synchronizing visual stimulus onset with neuronal recordings acquired via Neuropixels 2.0 probes. Performance comparisons with a commercial photodetector device indicate that our system achieves equivalent signal fidelity at a substantially lower cost, while maintaining a minimal footprint suitable for experimental use
The blood-brain barrier regulates brain tumor growth through the SLC36 amino acid transporter Pathetic in Drosophila.
No full textTumors adapt their metabolism to sustain increased proliferation, rendering them particularly vulnerable to fluctuations in nutrient availability. However, the role of the tumor microenvironment in modulating sensitivity to nutrient restriction (NR) remains poorly understood. Using a Drosophila brain dedifferentiation neural stem cell (NSC) tumor model induced by Prospero (Pros) inhibition, we show that tumor sensitivity to NR is governed by the blood-brain barrier (BBB) glia. We found that the SLC36 amino acid transporter Pathetic (Path) regulates brain branched-chain amino acids (BCAAs) levels. Under NR, while wild-type buffers against low nutrient levels by upregulating Path, tumor glia down-regulate Path. Furthermore, Path is specifically required by the tumor (but not wildtype) BBB; its downregulation causes reduced cell cycle progression of BBB glial cells and, in turn, restricts NSC tumor growth. Path influences BBB glial cell cycle via the BCAA-mTor-S6K pathway, and its expression is controlled by Ilp6 levels and the Insulin/PI3K pathway. Overexpression of Path is sufficient to counteract the inhibitory effects of NR on tumor growth. These findings suggest that Path levels at the glial niche BBB play a key role in determining tumor sensitivity to NR
KHNYN is a manganese-dependent endoribonuclease required for ZAP-mediated antiviral restriction.
No full textZinc finger antiviral protein (ZAP) is a cytoplasmic protein central to host innate immunity to viral infection. ZAP has no intrinsic catalytic activity but inhibits viral replication by binding to CpG dinucleotides in cytoplasmic viral RNA and recruiting other factors to inhibit protein synthesis and target the RNA for degradation. KHNYN is a ZAP-binding protein required for ZAP-restriction of CpG-rich viral genomes. It contains an extended diKH, PIN nuclease, and CUElike domain, each of which are required for ZAP restriction of viral replication. Here, we report a structural, enzymological, and virological study of KHNYN's essential PIN nuclease domain. Our crystal structure reveals an extended PIN domain (ex-PIN) containing a conserved N-terminal arm region required for domain stability and an active site tetra-Asp motif, which are both required for antiviral activity. Unlike the weak activity recently reported for the PIN domain, we demonstrate that the KHNYN ex-PIN domain is a highly active Mn2+-dependent single-stranded RNA endonuclease that cleaves with a preference for ApC, ApA, and UpA dinucleotides. These observations extend our view of KHNYN antiviral activity and suggest an unforeseen role for activation by manganese ions in the ZAP-KHNYN antiviral response
User-centred design and development of a smartphone application (OverSight) for digital phenotyping in ophthalmology
No full textBackground: Visual impairment can significantly impact an individual’s daily activities. Patients require regular monitoring, typically occurring within hospital eye services. Capacity constraints have necessitated innovative solutions to improve patient care. Existing digital solutions rely on task-based digital home monitoring such as visual acuity testing. These require active involvement from patients and do not typically offer an indication of quality of life. Digital phenotyping refers to the use of personal digital devices to quantify passive behaviour for detecting clinically significant changes in vision and act as biomarkers for disease. Its uniqueness lies in the ability to detect changes passively. The objective was to co-design an accessible smartphone app (OverSight) for the purposes of digital phenotyping in people with sight impairment. Methods: Development of OverSight included stakeholder consultations following principles of user-centred design. Apple iOS software frameworks (HealthKit, ResearchKit, and SensorKit) and a SwiftUI developer toolkit were used to enable the collection of active and passive data streams. Accessibility and usability were assessed using the System Usability Scale (SUS) and feedback following a 3-month pilot study. Consultations with patients informed the design of OverSight, including preferred survey scheduling and the relevancy of patient support resources. Results: Twenty visually impaired participants (mean age 42 ± 19 years) were recruited to the pilot study. The average score on the SUS was 76.8 (±8.9), indicating good usability. There was a statistically significant moderate negative correlation between SUS scores and visual acuity in both the better (r = −0.494; p ≤ 0.001) and worse eye (r = −0.421; p ≤ 0.001). Conclusions: OverSight offers promising potential for collecting patient-generated health data for the purposes of digital phenotyping in patients with eye disease. Through further testing and validation, this novel approach to patient care may ultimately provide opportunities for remote monitoring in ophthalmology
Generation of a human induced pluripotent stem cell line (CRICKi021-A) from a patient with Ullrich congenital muscular dystrophy carrying a pathogenic mutation in the COL6A1 gene.
No full textUllrich congenital muscular dystrophy (UCMD) represents the most severe subtype of collagen VI-related dystrophies (COL6-RDs), a spectrum of rare extracellular matrix disorders affecting skeletal muscle and connective tissue. Here, we generated an induced pluripotent stem cell (iPSC) line (CRICKi021-A) from a UCMD patient with de novo dominant-negative mutation in COL6A1 gene by reprogramming dermal fibroblasts using a non-integrating mRNA-based protocol. The resulting human iPSCs displayed normal morphology, expressed pluripotency-associated markers and differentiated into the three germ layers. This new COL6A1-mutant iPSC line can be employed for disease modelling and for investigating potential therapies for COL6-RDs