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The mistaken history of the Korean War : what we got wrong then and now
\"Intense propaganda and limited press coverage during the Korean War, coupled with vague objectives and an incomplete victory, resulted in a popular narrative of partial truth and factual omission. Battlefield stories--essentially true but often missing significant information--added an element of myth. Drawing on a range of sources, the author reexamines the war's causes, costs and outcomes\"-- Provided by publisher.
Book
APOE4/4 is linked to damaging lipid droplets in Alzheimer’s disease microglia
Several genetic risk factors for Alzheimer’s disease implicate genes involved in lipid metabolism and many of these lipid genes are highly expressed in glial cells
1
. However, the relationship between lipid metabolism in glia and Alzheimer’s disease pathology remains poorly understood. Through single-nucleus RNA sequencing of brain tissue in Alzheimer’s disease, we have identified a microglial state defined by the expression of the lipid droplet-associated enzyme ACSL1 with ACSL1-positive microglia being most abundant in patients with Alzheimer’s disease having the
APOE4/4
genotype. In human induced pluripotent stem cell-derived microglia, fibrillar Aβ induces
ACSL1
expression, triglyceride synthesis and lipid droplet accumulation in an APOE-dependent manner. Additionally, conditioned media from lipid droplet-containing microglia lead to Tau phosphorylation and neurotoxicity in an APOE-dependent manner. Our findings suggest a link between genetic risk factors for Alzheimer’s disease with microglial lipid droplet accumulation and neurotoxic microglia-derived factors, potentially providing therapeutic strategies for Alzheimer’s disease.
A microglial state, featuring lipid droplets and secretion of neurotoxic factors, is shown to be most prominent in people with Alzheimer’s disease who have the
APOE4
genotype.
Journal Article
A polarizing question: do M1 and M2 microglia exist?
In the twenty-first century, microglia came of age. Their remarkable ontogeny, unique functions and gene expression profile, process motility, and disease relevance have all been highlighted. Neuroscientists interested in microglia encounter an obsolete concept, M1/M2 polarization, suggesting experimental strategies that produce neither conceptual nor technical advances. Ransohoff's Perspective argues against applying this flawed paradigm.
Microglial research has entered a fertile, dynamic phase characterized by novel technologies including two-photon imaging, whole-genome transcriptomic and epigenomic analysis with complementary bioinformatics, unbiased proteomics, cytometry by time of flight (CyTOF; Fluidigm) cytometry, and complex high-content experimental models including slice culture and zebrafish. Against this vivid background of newly emerging data, investigators will encounter in the microglial research literature a body of published work using the terminology of macrophage polarization, most commonly into the M1 and M2 phenotypes. It is the assertion of this opinion piece that microglial polarization has not been established by research findings. Rather, the adoption of this schema was undertaken in an attempt to simplify data interpretation at a time when the ontogeny and functional significance of microglia had not yet been characterized. Now, terminology suggesting established meaningful pathways of microglial polarization hinders rather than aids research progress and should be discarded.
Journal Article
Transcriptional signature in microglia associated with Aβ plaque phagocytosis
The role of microglia cells in Alzheimer’s disease (AD) is well recognized, however their molecular and functional diversity remain unclear. Here, we isolated amyloid plaque-containing (using labelling with methoxy-XO4, XO4
+
) and non-containing (XO4
−
) microglia from an AD mouse model. Transcriptomics analysis identified different transcriptional trajectories in ageing and AD mice. XO4
+
microglial transcriptomes demonstrated dysregulated expression of genes associated with late onset AD. We further showed that the transcriptional program associated with XO4
+
microglia from mice is present in a subset of human microglia isolated from brains of individuals with AD. XO4
−
microglia displayed transcriptional signatures associated with accelerated ageing and contained more intracellular post-synaptic material than XO4
+
microglia, despite reduced active synaptosome phagocytosis. We identified HIF1α as potentially regulating synaptosome phagocytosis in vitro using primary human microglia, and BV2 mouse microglial cells. Together, these findings provide insight into molecular mechanisms underpinning the functional diversity of microglia in AD.
Microglia associated with Aβ plaques may have a distinct transcriptional signature compared to those in plaque-free areas of the brain in Alzheimer’s disease (AD) models. Here the authors show that amyloid plaque phagocytosis is associated with a specific microglia transcriptional signature in a mouse model of AD.
Journal Article
The Korean War : an international history
\"Although sixty-five years have passed since the armistice, the Korean conflict has never really ended. Tensions remain high on the peninsula as Washington and Pyongyang, as well as Seoul and Pyongyang, continue to face off. It is even more timely now to address the origins of the Korean War, the nature of the confrontation, and the ways in which it affects the geopolitical landscape of Northeast Asia and the Pacific region. With his unmatched ability to draw on sources from every country involved, Wada paints a rich and full portrait of a conflict that continues to generate controversy.\"-- Publisher's description.
Book
Dissection of artifactual and confounding glial signatures by single-cell sequencing of mouse and human brain
A key aspect of nearly all single-cell sequencing experiments is dissociation of intact tissues into single-cell suspensions. While many protocols have been optimized for optimal cell yield, they have often overlooked the effects that dissociation can have on ex vivo gene expression. Here, we demonstrate that use of enzymatic dissociation on brain tissue induces an aberrant ex vivo gene expression signature, most prominently in microglia, which is prevalent in published literature and can substantially confound downstream analyses. To address this issue, we present a rigorously validated protocol that preserves both in vivo transcriptional profiles and cell-type diversity and yield across tissue types and species. We also identify a similar signature in postmortem human brain single-nucleus RNA-sequencing datasets, and show that this signature is induced in freshly isolated human tissue by exposure to elevated temperatures ex vivo. Together, our results provide a methodological solution for preventing artifactual gene expression changes during fresh tissue digestion and a reference for future deeper analysis of the potential confounding states present in postmortem human samples.Marsh et al. demonstrate that enzymatic dissociation induces an aberrant ex vivo gene expression signature, most prominently in microglia, which when not addressed can substantially confound downstream analyses. They also identify a similar signature in postmortem human brain in snRNA-seq.
Journal Article
Microglia coordinate cellular interactions during spinal cord repair in mice
Traumatic spinal cord injury (SCI) triggers a neuro-inflammatory response dominated by tissue-resident microglia and monocyte derived macrophages (MDMs). Since activated microglia and MDMs are morphologically identical and express similar phenotypic markers in vivo, identifying injury responses specifically coordinated by microglia has historically been challenging. Here, we pharmacologically depleted microglia and use anatomical, histopathological, tract tracing, bulk and single cell RNA sequencing to reveal the cellular and molecular responses to SCI controlled by microglia. We show that microglia are vital for SCI recovery and coordinate injury responses in CNS-resident glia and infiltrating leukocytes. Depleting microglia exacerbates tissue damage and worsens functional recovery. Conversely, restoring select microglia-dependent signaling axes, identified through sequencing data, in microglia depleted mice prevents secondary damage and promotes recovery. Additional bioinformatics analyses reveal that optimal repair after SCI might be achieved by co-opting key ligand-receptor interactions between microglia, astrocytes and MDMs.
Here the authors show, using microglia-specific depletion techniques and single cell transcriptomics, that optimal repair after murine spinal cord injury (SCI) requires microglia.
Journal Article