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Twisted gastrulation (TWSG1) is an evolutionarily conserved secreted glycoprotein which controls signaling by Bone Morphogenetic Proteins (BMPs). TWSG1 binds BMPs and their antagonist Chordin to control BMP signaling during embryonic development, kidney regeneration and cancer. We report crystal structures of TWSG1 alone and in complex with a BMP ligand, Growth Differentiation Factor 5. TWSG1 is composed of two distinct, disulfide-rich domains. The TWSG1 N-terminal domain occupies the BMP type 1 receptor binding site on BMPs, whereas the C-terminal domain binds to a Chordin family member. We show that TWSG1 inhibits BMP function in cellular signaling assays and mouse colon organoids. This inhibitory function is abolished in a TWSG1 mutant that cannot bind BMPs. The same mutation in the Drosophila TWSG1 ortholog Tsg fails to mediate BMP gradient formation required for dorsal-ventral axis patterning of the early embryo. Our studies reveal the evolutionarily conserved mechanism of BMP signaling inhibition by TWSG1., (© 2024. The Author(s).)

Background: An understanding and appreciation of scientific research is a key quality of the modern clinician. Yet the Medical Schools Council has previously reported a reduction in the number of clinicians performing research. To explore the reasons for this difficulty, this multicentre, cross-sectional study aims to determine the medical student involvement and perceptions of research and research-orientated careers. It will additionally identify perceived barriers and incentives to participating in research as a student., Methods and Analysis: This cross-sectional study of medical students at UK medical schools recognised by the General Medical Council will be administered using an online questionnaire. This will be disseminated nationally over a 2-month period through collaborative university medical school and student networks. The primary outcome is to determine the extent to which medical students are currently involved in research. Secondary outcomes include identifying the personal and demographic factors involved in incentivising and deterring medical students from becoming involved in research during medical school. This will be achieved using a selection of Likert scale, multiple-choice and free text questions. Ordinal logistic regression analysis will be performed to understand the association between specific factors and student involvement in research. This study will also characterise the proportion of medical students who are currently interested in conducting research in the future., Ethics and Dissemination: Ethics approval has been obtained from the Medical Sciences Interdivisional Research Ethics Committee, Oxford, England. The results will be disseminated via publication in a peer-reviewed medical journal and may be presented at local, regional, national and international conferences by medical student collaborators., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.)