Altered topological blueprint of trabecular bone associates with skeletal pathology in humans.

Bone is a hierarchically organized biological material, and its strength is usually attributed to overt factors such as mass, density, and composition. Here we investigate a covert factor - the topological blueprint, or the network organization pattern of trabecular bone. This generally conserved metric of an edge-and-node simplified presentation of trabecular bone relates to the average coordination/valence of nodes and the equiangular 3D offset of trabeculae emanating from these nodes. We compare the topological blueprint of trabecular bone in presumably normal, fractured osteoporotic, and osteoarthritic samples (all from human femoral head, cross-sectional study). We show that bone topology is altered similarly in both fragility fracture and in joint degeneration. Decoupled from the morphological descriptors, the topological blueprint subjected to simulated loading associates with an abnormal distribution of strain, local stress concentrations and lower resistance to the standardized load in pathological samples, in comparison with normal samples. These topological effects show no correlation with classic morphological descriptors of trabecular bone. The negative effect of the altered topological blueprint may, or may not, be partly compensated for by the morphological parameters. Thus, naturally occurring optimization of trabecular topology, or a lack thereof in skeletal disease, might be an additional, previously unaccounted for, contributor to the biomechanical performance of bone, and might be considered as a factor in the life-long pathophysiological trajectory of common bone ailments.

Daily light exposure in morning-type and evening-type individuals.

Morning-type individuals (M-types) have earlier sleep schedules than do evening types (E-types) and therefore differ in their exposure to the external light-dark cycle. M-types and E-types usually differ in their endogenous circadian phase as well, but whether this is the cause or the consequence of the difference in light exposure remains controversial. In this study, ambulatory monitoring was used to measure 24-h light exposure in M-type and E-type subjects for 7 consecutive days. The circadian phase of each subject was then estimated in the laboratory using the dim-light melatonin onset in saliva (DLMO) and the core body temperature minimum (Tmin). On average, M-types had earlier sleep schedules and earlier circadian phases than E-types. They also showed more minutes of daily bright light exposure (> 1000 lux) than E-types. As expected, the 24-h patterns of light exposure analyzed in relation to clock time indicated that M-types were exposed to more light in the morning than E-types and that the reverse was true in the late evening. However, there was no significant difference when the light profiles were analyzed in relation to circadian phase, suggesting that, on average, the circadian pacemaker of both M-types and E-types was similarly entrained to the light-dark cycle they usually experience. Some M-types and E-types had different sleep schedules but similar circadian phases. These subjects also had identical light profiles in relation to their circadian phase. By contrast, M-types and E-types with very early or very late circadian phases showed large differences in their profiles of light exposure in relation to their circadian phase. This observation suggests that in these individuals, early or late circadian phases are related to relatively short and long circadian periods and that a phase-delaying profile of light exposure in M-types and a phase-advancing profile in E-types are necessary to ensure a stable entrainment to the 24-h day.

Basal somatodendritic dopamine release requires snare proteins.

Dopaminergic neurons have the capacity to release dopamine not only from their axon terminals, but also from their somatodendritic compartment. The actual mechanism of somatodendritic dopamine release has remained controversial. Here we established for the first time a rat primary neuron culture model to investigate this phenomenon and use it to study the mechanism under conditions of non-stimulated spontaneous firing (1-2 Hz). We found that we can selectively measure somatodendritic dopamine release by lowering extracellular calcium to 0.5 mm, thus confirming the previously established differential calcium sensitivity of somatodendritic and terminal release. Dopamine release measured under these conditions was dependent on firing activity and independent of reverse transport through the plasma membrane. We found that treatment with botulinum neurotoxins A and B strongly reduced somatodendritic dopamine release, thus demonstrating the requirement for SNARE proteins SNAP-25 and synaptobrevin. Our work is the first to provide such direct and unambiguous evidence for the involvement of an exocytotic mechanism in basal spontaneous somatodendritic dopamine release.