Fragile X quick-ish fix?

Scientists at the University of Edinburgh have demonstrated that they were able to restore learning abilities in a rat model of fragile X syndrome (FXS) through temporary treatment with the cholesterol-lowering agent lovastatin. FXS is the most common monogenic cause of intellectual disability and autism and has a multitude of symptoms, including learning disabilities. The authors hypothesized that temporary treatment during the developmental period where learning-related brain circuits are honed might lead to long-term improvements in learning abilities, and they tested their hypothesis by treating juvenile FXS rats with lovastatin, which has been shown to ameliorate FXS symptoms and has a known safety profile in children. They showed that such treatment restored the animals' abilities to learn associations, and observed "no regression of cognitive performance in the FXS rats over several months after treatment," leading them to conclude that the findings provide proof of concept that the impaired emergence of the cognitive repertoire in neurodevelopmental disorders may be prevented by brief, early pharmacological intervention. Their work appeared in the May 29, 2019, issue of Science Translational Medicine.

Fibroblasts specialize, too

Scientists at the University of Birmingham have shown that separate subsets of fibroblasts were responsible for driving inflammation and tissue damage in rheumatoid arthritis. Fibroblasts play a role in many inflammatory-mediated immune diseases, and in some of those diseases, different fibroblast subgroups with distinct gene expression profiles contribute to different aspects of disease. The researchers showed that fibroblasts expressing the surface markers THY1 affected inflammation but caused only minimal bone and cartilage damage in an animal model of rheumatoid arthritis, while the opposite was true of fibroblasts without THY1 expression. "The identification of [T-cell] subsets with non-overlapping effector functions has been pivotal to the development of targeted therapies in immune-mediated inflammatory diseases," the authors wrote. "Our findings describing anatomically discrete, functionally distinct fibroblast subsets with non-overlapping functions have important implications for cell-based therapies aimed at modulating inflammation and tissue damage." Their findings appeared in the May 30, 2019, issue of Nature.

Cracking influenza's egg code

Influenza vaccines are still produced by growing the influenza virus in eggs. The viruses are adapting to the egg environment as they are growing. Those adaptations, when they occur in the hemagglutinin that will serve as vaccine antigen, can change the hemagglutinin and compromise the vaccine's later ability to elicit an immune response. Now, researchers from the Scripps Research Institute and the University of Hong Kong have shown that they were able to prevent a common deleterious egg adaptation of the H3N2 virus by preemptively engineering another change into the viral hemagglutinin. The engineered change both preserved hemagglutinin's ability to serve as an antigen, and prevented the occurrence of the deleterious mutation, because H3N2 virus with both mutations was no longer able to infect cells and, therefore, could not survive. "Our results demonstrate that... interactions can be used to prevent the emergence of mutations that adversely alter antigenicity during egg adaptation," the authors wrote. Their findings appeared in the May 30, 2019, issue of Cell Host & Microbe.

'Perpetrators and targets' of CTLA4 signaling

Scientists at University College London have gained new insights into the functioning of checkpoint blocker CTLA4, which prevents T-cell activation and whose inhibition by Yervoy (ipilimumab) can unleash antitumor immune responses. However, the details of the mechanism, and even which T-cell subtypes rely most strongly on CTLA4 for their function, remain unclear. The researchers "set out to characterize both the perpetrators and cellular targets of CTLA4" in vivo. CTLA4 works by transendocytosis – that is, snatching surface molecules from other cells and internalizing them. The researchers demonstrated that CTLA4-dependent transendocytosis was primarily used by regulatory T cells to inhibit antigen-presenting dendritic cells. "Understanding the cellular targets of CTLA4–based regulation will be important for unraveling the synergy between therapeutic targeting of CTLA4 and programed cell death 1 (PD-1)," the authors wrote. They published their study in the May 31, 2019, issue of Science Immunology.

Healing bones during cancer remission

Bone damage is one of the frequent consequences of multiple myeloma, with well over three quarters of patients developing bone damage that can cause spinal cord compression and fractures, as well as severe pain. Puzzlingly, and unlike other cancers, bones do not heal even when patients are in remission after successful treatment. Researchers from the University of Edinburgh have demonstrated that myeloma cells could permanently reprogram fat cells in the bone marrow, and that those fat cells continued to secrete factors that activated bone-destroying osteoclasts and suppressed bone-building osteoblasts after the demise of the tumor cells themselves. Knocking out the methylating enzyme EZH2 in fat cells reversed bone damage in mouse models of multiple myeloma. The authors concluded that they have identified "a potential strategy for treatment of myeloma-induced bone disease," and potentially other cancer types that frequently metastasize to the bone. They reported their findings in the May 29, 2019, issue of Science Translational Medicine.