Publication highlights

Researchers at the Crick and the Paul Scherrer Institute have developed a new imaging protocol to capture mouse brain cell connections in precise detail. Building on standard volume EM sample preparation protocols, they tested a new step - embedding the stained tissue using a resin developed in the nuclear and aerospace industries to protect against radiation. The samples were then imaged using X-rays in a synchrotron. The resulting images, produced using a specific type of X-ray imaging called X-ray ptychography, reached a resolution of 38nm. This was enough to show multiple elements of the mouse brain circuitry, including synapses, dendrites and axons.

Children born with mutations in the ARPC5 protein, which is part of the internal cytoskeleton, experience immunodeficiency and a high risk of sepsis. Researchers at the Crick investigated immune system function in mice with and without ARPC5 mutations, observing inflammation in adult mice with ARPC5 deficiency that mirrored that in humans. They showed that this was due to a big change in bacterial composition in the gut after weaning, triggering intestinal inflammation, as giving antibiotics to ARPC5-deficient mice at a critical four-week time point fully prevented the disease from developing. Finally, the team showed that macrophages with ARPC5 mutations had lost their usual shape and could no longer kill bacteria effectively, leading to an overwhelming response to the microbiome.

Researchers at the Crick have found that hunger can make virgin female mice aggressive towards pups, but only in certain hormonal states. These mice would usually ignore other females' pups or show parent-like caring behaviour. The team found that AgRP neurons mediated the effect of food deprivation on behaviour towards pups, by targeting the medial preoptic area. Mice at certain stages of the reproductive estrous cycle were more likely to become aggressive towards pups, dictated by the ratio of oestradiol and progesterone setting the responsiveness of MPOA neurons. They showed that hunger information carried by the AgRP neurons dampens neuronal activity in the MPOA, stimulating the switch from caring behaviour to pup-directed aggression. 

Lymph nodes are small organs distributed throughout the body that orchestrate immune processes. In response to infection, vaccination, or cancer, a germinal centre (GC) forms within them, driving the maturation of memory B cells and plasma cells. Because of their 3D structure and diverse cell types, GCs are ideal for 3D imaging. This protocol describes rapid, high-resolution multicolour imaging of whole immunised lymph nodes, covering harvesting, fixation, permeabilisation, staining, and clearing. Imaging is performed with a fluorescence lightsheet microscope, and analysis with Imaris. It quantifies GC B cells, plasma cells, and follicular T cells, and includes optimised stainings for visualising other lymph node structures.

Researchers at the Crick have discovered that the heart's own contractions trigger biological signals that guide the formation of a functional beating heart. Their study in zebrafish highlights the heart's ability to remodel and adapt to physiological demands and could also reveal what goes wrong during congenital heart conditions. They followed the early development of the heart's muscular structures, called trabeculae, in zebrafish using live 4D imaging. The team observed that trabeculae don't grow and develop by cell division, as previously thought. Instead, neighbouring cells are recruited to build trabecular complexity, thus increasing the heart's muscle mass and contractile efficiency. Finally, they uncovered a feedback mechanisms between heart contraction and its own development, dictating a healthy pace of growth.

Researchers have mapped the human metabolic pathways that Cryptosporidium, an intestinal parasite, requires to survive. They conducted a genome-scale screening experiment that involves systematically disabling nearly every protein-coding gene, individually, from human intestinal cells, before infecting the cells with Cryptosporidium. The team found that genes involved in making cholesterol appeared to have opposing effects - some boosting infection and others blocking it. This balance hinged on a molecule midway through the cholesterol production line, squalene. This molecule protects against oxidative stress by stimulating the production of glutathione, which Cryptosporidium needs but cannot make. This leaves the parasite dependent on glutathione from the host cell, a dependency which can be targeted with a high cholesterol drug called lapaquistat. This drug reduced infection in a mouse model of disease and completely blocked intestinal damage, suggesting it could be repurposed to fight Cryptosporidium.

Researchers at the Francis Crick Institute have shown that mice use chemical cues, including odours, to detect the social rank of an unfamiliar mouse and compare it to their own, using this information to determine their behaviour. They used a test where male mice enter a transparent tube at opposite ends, meeting in the middle. In this type of confrontation, a more submissive animal will typically retreat. Interactions between mice in the same cage were first used to rank each mouse, before observing that strangers could observe each other's rank and act accordingly. Putting the mice in the dark or removing their sex hormones had no impact, but when the researchers blocked the two chemosensory systems mice use, they could no longer recognise opponent rank, showing that both systems are used for rank recognition and can compensate if one is missing.