Neuroinflammation as a Key Driver of Secondary Neurodegeneration Following Stroke?

Ischaemic stroke involves the rapid onset of focal neurological dysfunction, most commonly due to an arterial blockage in a specific region of the brain. Stroke is a leading cause of death and common cause of disability, with over 17 million people worldwide suffering from a stroke each year. It is now well‐documented that neuroinflammation and immune mediators play a key role in acute and long‐term neuronal tissue damage and healing, not only in the infarct core but also in distal regions. Importantly, in these distal regions, termed sites of secondary neurodegeneration (SND), spikes in neuroinflammation may be seen sometime after the initial stroke onset, but prior to the presence of the neuronal tissue damage within these regions. However, it is key to acknowledge that, despite the mounting information describing neuroinflammation following ischaemic stroke, the exact mechanisms whereby inflammatory cells and their mediators drive stroke-induced neuroinflammation are still not fully understood. As a result, current anti‐inflammatory treatments have failed to show efficacy in clinical trials. In this review we discuss the complexities of post‐stroke neuroinflammation, specifically how it affects neuronal tissue and post‐stroke outcome acutely, chronically, and in sites of SND. We then discuss current and previously assessed anti‐inflammatory therapies, with a particular focus on how failed anti‐inflammatories may be repurposed to target SND‐associated neuroinflammation

SARS-CoV-2 susceptibility and COVID-19 disease severity are associated with genetic variants affecting gene expression in a variety of tissues

Variability in SARS-CoV-2 susceptibility and COVID-19 disease severity between individuals is partly due to genetic factors. Here, we identify 4 genomic loci with suggestive associations for SARS-CoV-2 susceptibility and 19 for COVID-19 disease severity. Four of these 23 loci likely have an ethnicity-specific component. Genome-wide association study (GWAS) signals in 11 loci colocalize with expression quantitative trait loci (eQTLs) associated with the expression of 20 genes in 62 tissues/cell types (range: 1:43 tissues/gene), including lung, brain, heart, muscle, and skin as well as the digestive system and immune system. We perform genetic fine mapping to compute 99% credible SNP sets, which identify 10 GWAS loci that have eight or fewer SNPs in the credible set, including three loci with one single likely causal SNP. Our study suggests that the diverse symptoms and disease severity of COVID-19 observed between individuals is associated with variants across the genome, affecting gene expression levels in a wide variety of tissue types

A first update on mapping the human genetic architecture of COVID-19

peer reviewe

Leakage beyond the primary lesion: A temporal analysis of cerebrovascular dysregulation at sites of hippocampal secondary neurodegeneration following cortical photothrombotic stroke

We have previously demonstrated that a cortical stroke causes persistent impairment of hippocampal-dependent cognitive tasks concomitant with secondary neurodegenerative processes such as amyloid-β accumulation in the hippocampus, a region remote from the primary infarct. Interestingly, there is emerging evidence suggesting that deposition of amyloid-β around cerebral vessels may lead to cerebrovascular structural changes, neurovascular dysfunction, and disruption of blood-brain barrier integrity. However, there is limited knowledge about the temporal changes of hippocampal cerebrovasculature after cortical stroke. In the current study, we aimed to characterise the spatiotemporal cerebrovascular changes after cortical stroke. This was done using the photothrombotic stroke model targeting the motor and somatosensory cortices of mice. Cerebrovascular morphology as well as the co-localisation of amyloid-β with vasculature and blood-brain barrier integrity were assessed in the cortex and hippocampal regions at 7, 28 and 84 days post-stroke. Our findings showed transient cerebrovascular remodelling in the peri-infarct area up to 28 days post-stroke. Importantly, the cerebrovascular changes were extended beyond the peri-infarct region to the ipsilateral hippocampus and were sustained out to 84 days post-stroke. When investigating vessel diameter, we showed a decrease at 84 days in the peri-infarct and CA1 regions that were exacerbated in vessels with amyloid-β deposition. Lastly, we showed sustained vascular leakage in the peri-infarct and ipsilateral hippocampus, indicative of a compromised blood-brain-barrier. Our findings indicate that hippocampal vasculature may represent an important therapeutic target to mitigate the progression of post-stroke cognitive impairment

KRAS Engages AGO2 to Enhance Cellular Transformation

SummaryOncogenic mutations in RAS provide a compelling yet intractable therapeutic target. Using co-immunoprecipitation mass spectrometry, we uncovered an interaction between RAS and Argonaute 2 (AGO2). Endogenously, RAS and AGO2 co-sediment and co-localize in the endoplasmic reticulum. The AGO2 N-terminal domain directly binds the Switch II region of KRAS, agnostic of nucleotide (GDP/GTP) binding. Functionally, AGO2 knockdown attenuates cell proliferation in mutant KRAS-dependent cells and AGO2 overexpression enhances KRASG12V-mediated transformation. Using AGO2−/− cells, we demonstrate that the RAS-AGO2 interaction is required for maximal mutant KRAS expression and cellular transformation. Mechanistically, oncogenic KRAS attenuates AGO2-mediated gene silencing. Overall, the functional interaction with AGO2 extends KRAS function beyond its canonical role in signaling

Piecewise linear approximation of protein structures using the principle of minimum message length

Simple and concise representations of protein-folding patterns provide powerful abstractions for visualizations, comparisons, classifications, searching and aligning structural data. Structures are often abstracted by replacing standard secondary structural features—that is, helices and strands of sheet—by vectors or linear segments. Relying solely on standard secondary structure may result in a significant loss of structural information. Further, traditional methods of simplification crucially depend on the consistency and accuracy of external methods to assign secondary structures to protein coordinate data. Although many methods exist automatically to identify secondary structure, the impreciseness of definitions, along with errors and inconsistencies in experimental structure data, drastically limit their applicability to generate reliable simplified representations, especially for structural comparison