Matthew J.

Fu et al. develop CineMA, a foundation model pre-trained on 15 million cine cardiac MRI images. CineMA performs competitively in segmentation, disease detection, landmark localisation and prognostication across eight independent datasets, offering a versatile alternative to task-specific models.

G protein-coupled receptors (GPCRs) play key roles in physiology and are central targets for drug discovery and development1,2, but the design of protein agonists and antagonists has been challenging as GPCRs are integral membrane proteins and conformationally dynamic3–6. Here we describe computational de novo design methods and a high-throughput “receptor diversion” microscopy-based screen for generating GPCR binding miniproteins with high affinity, potency and selectivity. We design miniprotein agonists that activate receptors involved in itch and pain, as well as antagonists that inhibit receptors implicated in cancer, metabolic disorders such as diabetes and obesity, and migraine. Cryo-electron microscopy (cryo-EM) structures of five receptor-bound designs are close to the computational design models. A designed chemokine receptor antagonist mobilizes hematopoietic stem and progenitor cells in vivo at a level comparable to a clinically used drug, with fewer adverse effects.

β-sandwich domains of the intermediate immunoglobulin fold (IgI) are key building blocks of many large, multidomain proteins – such as titin. The uniformity of the basic fold of these domains does not seem to be an impediment to their adaptation to a wide variety of functions. IgI domains in different regions of titin have to fulfil distinct functions which is seen in subtle differences of sequence, structure and stability. This is particularly true for the N2A region whose IgI domains are subtly distinct from other parts of I-band titin. We have already shown the unusual structure and properties of IgI domain I83 which is able to bind to calcium and is part of a binding site for F-actin and p94. To continue our exploration of the titin IgI domains of the N2A region we describe here the solution NMR structure of domain I82 of murine titin. The structure of the murine domain is virtually identical to the human homologue. However, the NMR investigation reveals the existence of distinct conformers around a highly conserved glycine, part of the tyrosine corner motif at the junction of the EF-loop with the F-strand. 15N relaxation data show substantial line broadening for residues around this glycine, confirming conformational exchange on the fast-intermediate time scale. The unusual dynamics could for the first time explain the high level of conservation of the tyrosine corner glycine via a function in the folding of the domain.

Widespread declines in dissolved oxygen concentrations in lakes and rivers have ecological and socioeconomic consequences. This Review highlights spatial and temporal trends, climate and anthropogenic drivers, impacts and strategies for the management and mitigation of inland freshwater deoxygenation.

The time-of-flight imaging beamline VENUS at the Spallation Neutron Source of the Oak Ridge National Laboratory has recently entered the commissioning phase. Based on the experience acquired at the Spallation Neutron Source SNAP and the High Flux Isotope Reactor MARS...

Proteins that bind to a target protein of interest, termed “binders”, are essential components of biological research reagents and therapeutics. Ta...

Programmed cell death protein-1 (PD-1) expressed on activated T cells inhibits T cell function and proliferation to prevent an excessive immune res...

Purpose Accurate registration between pre-operative anatomical models and intra-operative endoscopic views is essential for reliable Augmented reality (AR) guidance in pituitary surgery. While coarse alignment can be achieved using external facial reconstruction, it does not account for relative motion between the face and internal surgical targets. Precise alignment at the sella region further remains challenging due to the lack of direct depth information in monocular endoscopy. Methods To identify an appropriate similarity metric for registration refinement, we conducted a grid search comparing monocular depth predictions from endoscopic images with depth rendered from a pre-operative 3D model. Normalised cross-correlation (NCC) demonstrated the most robust performance and was selected as the optimisation objective. A continuous optimisation framework was then implemented to iteratively refine translational pose parameters by maximising NCC, with optimisation applied periodically and propagated across frames for computational efficiency. Results Depth-based optimisation improved alignment at the surgical target, increasing DICE from 0.77 to 0.81, IoU from 0.63 to 0.68, and reducing centroid localisation error by 36%. Conclusion Overall, the proposed depth-based refinement improves target alignment in endoscopic AR guidance and demonstrates the potential of monocular depth cues for intra-operative registration correction.