Crack patterns over uneven substrates.

Cracks in thin layers are influenced by what lies beneath them. From buried craters to crocodile skin, crack patterns are found over an enormous range of length scales. Regardless of absolute size, their substrates can dramatically influence how cracks form, guiding them in some cases, or shielding regions from them in others. Here we investigate how a substrate's shape affects the appearance of cracks above it, by preparing mud cracks over sinusoidally varying surfaces. We find that as the thickness of the cracking layer increases, the observed crack patterns change from wavy to ladder-like to isotropic. Two order parameters are introduced to measure the relative alignment of these crack networks, and, along with Fourier methods, are used to characterise the transitions between crack pattern types. Finally, we explain these results with a model, based on the Griffith criteria of fracture, that identifies the conditions for which straight or wavy cracks will be seen, and predicts how well-ordered the cracks will be. Our metrics and results can be applied to any situation where connected networks of cracks are expected, or found.

A mitochondrial inside-out iron-calcium signal reveals drug targets for Parkinson's disease.

Dysregulated iron or Ca2+ homeostasis has been reported in Parkinson's disease (PD) models. Here, we discover a connection between these two metals at the mitochondria. Elevation of iron levels causes inward mitochondrial Ca2+ overflow, through an interaction of Fe2+ with mitochondrial calcium uniporter (MCU). In PD neurons, iron accumulation-triggered Ca2+ influx across the mitochondrial surface leads to spatially confined Ca2+ elevation at the outer mitochondrial membrane, which is subsequently sensed by Miro1, a Ca2+-binding protein. A Miro1 blood test distinguishes PD patients from controls and responds to drug treatment. Miro1-based drug screens in PD cells discover Food and Drug Administration-approved T-type Ca2+-channel blockers. Human genetic analysis reveals enrichment of rare variants in T-type Ca2+-channel subtypes associated with PD status. Our results identify a molecular mechanism in PD pathophysiology and drug targets and candidates coupled with a convenient stratification method.

Miro1 Impairment in a Parkinson's At-Risk Cohort.

There is a lack of reliable molecular markers for Parkinson's disease (PD) patients and at-risk individuals. The detection of the pre-symptomatic population of PD will empower more effective clinical intervention to delay or prevent disease onset. We have previously found that the mitochondrial protein Miro1 is resistant to mitochondrial depolarization-induced degradation in fibroblasts from a large number of PD patients and several at-risk individuals. Therefore, Miro1 has the potential to molecularly label PD populations. In order to determine whether Miro1 could serve as a molecular marker for the risk of PD, here we examine the Miro1 response to mitochondrial depolarization by biochemical approaches in induced pluripotent stem cells from a cohort of at-risk individuals. Our results show that the Miro1 phenotype is significantly associated with PD risk. We propose that Miro1 is a promising molecular marker for detecting both PD and at-risk populations. Tracking this Miro1 marker could aid in diagnosis and Miro1-based drug discoveries.