Biology subjects

Noble, E.

Publications and source records attributed to Noble, E..

3 recordsLinked to original sources

bioRxiv2025

Hybrid Solid-Liquid Optics Enable Scalable, High-Resolution, Multi-Immersion Light-Sheet Microscopy

Modern biology increasingly depends on data-driven discovery, requiring scalable and affordable high-content 3D imaging across molecular to organ scales. Although tissue clearing, expansion microscopy, and light-sheet microscopy (LSM) enable subcellular-resolution imaging of intact specimens, their scalability remains fundamentally limited by detection optics: immersion objectives deliver high-resolution, aberration-free imaging but with short working distances, high cost, and multi-immersion incompatibility, while air objectives offer long working distances and portability at lower cost but suffer from severe aberrations and reduced photon collection when imaging immersed samples. We introduce the Hybrid Solid-Liquid Immersion Lens (HySIL) framework, which pairs an off-the-shelf solid optical component with a refractive index-matched liquid to precompensate aberrations and enhance resolution. Building on HySIL, we developed SCOPE and Super-SCOPE, objective-agnostic imaging devices achieving submicron lateral resolution (<0.75 {micro}m) across centimeter-scale samples using inexpensive air objectives with >30 mm working distances. Integration with a low-cost LSM platform yielded a compact, scalable system demonstrated for multi-immersion, multi-color, subcellular-resolution mapping of cleared or expanded mouse, salamander, and cavefish brains, human iPSC-derived organoids, and 3D histopathology of breast tissue. HySIL and SCOPE establish an accessible foundation for scalable, high-resolution volumetric imaging, advancing data-driven biological discovery.

bioengineering↗

bioRxiv2024

Induction and characterisation of Abeta and tau pathology in AppNL-F/NL-F mice following inoculation with Alzheimer's disease brain homogenate

Alzheimers disease (AD) is defined by the accumulation of neurofibrillary tangles containing hyperphosphorylated Tau and plaques containing Amyloid-{beta} (A{beta}). The aggregation of these two proteins is considered central to the disease. The lack of animal models that can recapitulate A{beta} and tau pathologies without overexpressing these proteins has hindered AD research. Accelerating pathology by inoculating A{beta} and tau seeds has helped to understand their prion-like propagation in the brain. Previous studies failed to characterise both A{beta} and tau pathologies in vivo upon inoculating AD brain homogenates. Here we present a longitudinal and systematic study; we inoculated the AppNL-F/NL-F knockin mice, which express humanised A{beta} and murine wild-type tau, with extracts from diseased human brains to analyse the contribution of A{beta} and tau assemblies to AD pathogenesis. We found that mice inoculated with AD brain extracts evinced early and prominent amyloid deposition, while those injected with control brain extracts or vehicle did not. Parenchymal and vascular amyloid accumulated in the same brain regions affected in control-inoculated AppNL-F/NL-F mice. However, the extent of vascular amyloid far exceeded that seen in AppNL-F/NL-Fmice injected with control brain extracts, and parenchymal deposits extended to a previously untargeted brain region - the cerebellum. An end-point titration of an AD brain homogenate in AppNL-F/NL-F mice demonstrated that human A{beta} seeds can be titrated in a prion-like fashion, which is useful for sample comparison, diagnostic and risk studies. Notably, the inoculation of AppNL-F/NL-F mice with AD brain homogenate induced intense tau phosphorylation, and provides more detailed context for the inoculation of AppNL-F/NL-F mice with human samples to study temporal and mechanistic relationships between A{beta} and tau pathology, vascular amyloid deposition and bioactivity of A{beta} seeds.

neuroscience↗

bioRxiv2022

Impact of cellular prion protein expression on disease progression and pathology in two mouse models of Alzheimer's disease

The aggregation of amyloid-{beta} (A{beta}) monomers increases their neurotoxicity, and these oligomeric species are thought to be central to the pathogenesis of Alzheimers disease. Unsurprisingly for such a complex disease, current Alzheimers disease mouse models fail to fully mimic the clinical disease in humans. Moreover, results obtained in a given mouse model are not always reproducible in a different model. Cellular prion protein (PrPC) is now an established receptor for A{beta} oligomers. However, different groups studying the A{beta}-PrPC interaction in vivo using a variety of mouse models have obtained contradictory results. Here we performed a longitudinal study in two commonly used AD mouse models using a range of biochemical, histological and behavioural techniques and found similar contradictory results and a possible explanation for the discrepancy. We propose that these two mouse models produce A{beta} oligomers with different conformations. Therefore, binding to PrPC and the subsequent activation of toxic signalling cascade will occur only when the A{beta} oligomer species with appropriate conformation are present. Hence, it is crucial to select the appropriate model producing the appropriate species of A{beta} oligomers to study specific aspects of {beta}-amyloidosis and its downstream pathways. Further conformational characterisation of A{beta} oligomers and their binding to PrPC is required to better understand A{beta} neurotoxicity.

neuroscience↗