Blood-CNS barrier dysfunction in amyotrophic lateral sclerosis: Proposed mechanisms and clinical implications.

Peer reviewed: TrueThere is strong evidence for blood-brain and blood-spinal cord barrier dysfunction at the early stages of many neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Since impairment of the blood-central nervous system barrier (BCNSB) occurs during the pre-symptomatic stages of ALS, the mechanisms underlying this pathology are likely also involved in the ALS disease process. In this review, we explore how drivers of ALS disease, particularly mitochondrial dysfunction, astrocyte pathology and neuroinflammation, may contribute to BCNSB impairment. Mitochondria are highly abundant in BCNSB tissue and mitochondrial dysfunction in ALS contributes to motor neuron death. Likewise, astrocytes adopt key physical, transport and metabolic functions at the barrier, many of which are impaired in ALS. Astrocytes also show raised expression of inflammatory markers in ALS and ablating ALS-causing transgenes in astrocytes slows disease progression. In addition, key drivers of neuroinflammation, including TAR DNA-binding protein 43 (TDP-43) pathology, matrix metalloproteinase activation and systemic inflammation, affect BCNSB integrity in ALS. Finally, we discuss the translational implications of BCNSB dysfunction in ALS, including the development of biomarkers for disease onset and progression, approaches aimed at restoring BCNSB integrity and in vitro modelling of the neurogliovascular system

Coronal Heating as Determined by the Solar Flare Frequency Distribution Obtained by Aggregating Case Studies

Flare frequency distributions represent a key approach to addressing one of the largest problems in solar and stellar physics: determining the mechanism that counter-intuitively heats coronae to temperatures that are orders of magnitude hotter than the corresponding photospheres. It is widely accepted that the magnetic field is responsible for the heating, but there are two competing mechanisms that could explain it: nanoflares or Alfv\'en waves. To date, neither can be directly observed. Nanoflares are, by definition, extremely small, but their aggregate energy release could represent a substantial heating mechanism, presuming they are sufficiently abundant. One way to test this presumption is via the flare frequency distribution, which describes how often flares of various energies occur. If the slope of the power law fitting the flare frequency distribution is above a critical threshold, $\alpha=2$ as established in prior literature, then there should be a sufficient abundance of nanoflares to explain coronal heating. We performed $>$600 case studies of solar flares, made possible by an unprecedented number of data analysts via three semesters of an undergraduate physics laboratory course. This allowed us to include two crucial, but nontrivial, analysis methods: pre-flare baseline subtraction and computation of the flare energy, which requires determining flare start and stop times. We aggregated the results of these analyses into a statistical study to determine that $\alpha = 1.63 \pm 0.03$. This is below the critical threshold, suggesting that Alfv\'en waves are an important driver of coronal heating.Comment: 1,002 authors, 14 pages, 4 figures, 3 tables, published by The Astrophysical Journal on 2023-05-09, volume 948, page 7