Pathogenic variants of sphingomyelin synthase SMS2 disrupt lipid landscapes in the secretory pathway

Sphingomyelin is a dominant sphingolipid in mammalian cells. Its production in the trans-Golgi traps cholesterol synthesized in the ER to promote formation of a sphingomyelin/sterol gradient along the secretory pathway. This gradient marks a fundamental transition in physical membrane properties that help specify organelle identify and function. We previously identified mutations in sphingomyelin synthase SMS2 that cause osteoporosis and skeletal dysplasia. Here, we show that SMS2 variants linked to the most severe bone phenotypes retain full enzymatic activity but fail to leave the ER owing to a defective autonomous ER export signal. Cells harboring pathogenic SMS2 variants accumulate sphingomyelin in the ER and display a disrupted transbilayer sphingomyelin asymmetry. These aberrant sphingomyelin distributions also occur in patient-derived fibroblasts and are accompanied by imbalances in cholesterol organization, glycerophospholipid profiles, and lipid order in the secretory pathway. We postulate that pathogenic SMS2 variants undermine the capacity of osteogenic cells to uphold nonrandom lipid distributions that are critical for their bone forming activity.Peer reviewe

Graphic rules in planning: a critical exploration of normative drawings starting from zoning maps and form-based codes

This article is focused on the rules that we create using drawings (designs, pictures, paintings, etc.) which will be termed ‘graphic rules’. Its attention is therefore not simply on the use of images in normative documents but also ‘as law’. We will delve into one of these types of graphic rules: that is, graphic rules used in urban planning. The fact that graphic rules are widespread in planning practices, and indeed typical of them, makes rules of this kind a particularly significant field of interest for planning theory. An important point to stress is that while analysis of images used descriptively has been under way for some time (although in many respects it is anything but conclusive, despite what is generally thought), analysis of images used as rules is still in its infancy. To gain deeper understanding of these particular and widespread forms of (graphic) rules is therefore both theoretically and practically important

The Zoning Map and American City Form

This paper investigates a common mode of visual communication in planning practice, the use of maps to regulate urban development. Holding equal legal status with the text, the zoning map was invented in the early twentieth century as a tool for implementing municipal policy and, although debated, modified, and sometimes repurposed over the past nine decades, it remains standard. Mundane and largely taken for granted, the zoning map itself has aroused little scholarly interest. However, as an image of the city and as a graphic intermediary used in administrative processes, it reveals how planning thought is embedded in planning tools