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Subacute necrotizing encephalopathy, or Leigh syndrome (LS), is the most common pediatric presentation of genetic mitochondrial disease. LS is a multi‐system disorder with severe neurologic, metabolic, and musculoskeletal symptoms. The presence of progressive, symmetric, and necrotizing lesions in the brainstem are a defining feature of the disease, and the major cause of morbidity and mortality, but the mechanisms underlying their pathogenesis have been elusive. Recently, we demonstrated that high‐dose pexidartinib, a CSF1R inhibitor, prevents LS CNS lesions and systemic disease in the Ndufs4(−/−) mouse model of LS. While the dose–response in this study implicated peripheral immune cells, the immune populations involved have not yet been elucidated. Here, we used a targeted genetic tool, deletion of the colony‐stimulating Factor 1 receptor (CSF1R) macrophage super‐enhancer FIRE (Csf1rΔFIRE), to specifically deplete microglia and define the role of microglia in the pathogenesis of LS. Homozygosity for the Csf1rΔFIRE allele ablates microglia in both control and Ndufs4(−/−) animals, but onset of CNS lesions and sequalae in the Ndufs4(−/−), including mortality, are only marginally impacted by microglia depletion. The overall development of necrotizing CNS lesions is not altered, though microglia remain absent. Finally, histologic analysis of brainstem lesions provides direct evidence of a causal role for peripheral macrophages in the characteristic CNS lesions. These data demonstrate that peripheral macrophages play a key role in the pathogenesis of disease in the Ndufs4(−/−) model. Microglia and peripheral macrophages contribute to CNS pathology in the Ndufs4(−/−) mouse model of Leigh syndrome, while peripheral macrophages alone are sufficient to drive disease in microglia−deficient Ndufs4(−/−) animals. (A−B) Cortex of Ndufs4(−/−)/Csf1r (wt/wt) (A) and Ndufs4(−/−)/Csf1r (fr/fr) (B) mice stained for the pan−macrophage marker IBA1 (red) and the microglia−specific marker P2YR12 (green); DNA is co−stained with DAPI (blue). Microglia are absent by both IBA1 and P2YR12 staining in the Ndufs4(−/−)/Csf1r (fr/fr) cortex. (C−D) Brainstem lesions from Ndufs4(−/−)/Csf1r (wt/wt) (C) and Ndufs4(−/−)/Csf1r (fr/fr) (D) mice stained for the pan−macrophage marker IBA1 and the microglia−specific marker P2YR12. Cells positive for IBA1, the pan−macrophage marker, are present in both genotypes, while P2YR12 staining is absent in cells in the brainstem lesions of Ndufs4(−/−)/Csf1r (fr/fr) animals. Note: the P2YR12 staining surrounding the lesion site does not appear to be cellular in origin, and is thought to reflect the presence of aggregated platelets, which are P2YR12 positive. (E−F) Cortex of Ndufs4(−/−)/Csf1r (wt/wt) (E) and Ndufs4(−/−)/Csf1r (fr/fr) (F) mice stained for the pan−macrophage marker IBA1 (red) and the peripheral leukocyte marker CD45 (green); DNA is co−stained with DAPI (blue). Microglia are absent in the Ndufs4(−/−)/Csf1r (fr/fr) cortex, and microglia (by IBA1 posivitivy and morphology) do not express CD45 (E). A few compact cells with CD45 positivity are present in both genotypes, presumed to be circulating leukocytes. (G−H) Brainstem lesions in Ndufs4(−/−)/Csf1r (wt/wt) (G) and Ndufs4(−/−)/Csf1r (fr/fr) (H) mice stained for the pan−macrophage marker IBA1 and the peripheral leukocyte marker CD45. CD45 positive cells are present in both in the Ndufs4(−/−)/Csf1r (fr/fr) and Ndufs4(−/−)/Csf1r (wt/wt) lesions, while most or all IBA1 positive cells in the Ndufs4(−/−)/Csf1r (fr/fr) lesion appear to be positive for the peripheral leukocyte marker CD45. Co−staining of CD45 and IBA1 is indicative of peripheral macrophages.

Leigh syndrome (LS) is the most common pediatric presentation of genetic mitochondrial disease and characterized by neurological and metabolic abnormalities. The hallmark of the disease is the presence of progressive, bilateral, symmetric neurodegenerative lesions in the brainstem and/or basal ganglia. Recent studies in the Ndufs4 (-/-) mouse model of LS indicate that disease is causally driven by the immune system. Both microglia and peripherally originating macrophages are enriched in the lesions of Ndufs4 (-/-) mice and pharmacologic elimination of these cell types prevents disease indicating a crucial role for innate immune cells. Here, we investigated the role of the adaptive immune system in Ndufs4 (-/-) disease pathogenesis. We crossed Ndufs4 (-/-) mice with mice expressing a null form of interleukin 2 receptor gamma ( Il2rg ) and monitored disease onset and progression. Il2rg knockout (KO) mice have dramatically depleted numbers of B-, T-, the adaptive immune system’s key cellular actors, and NK-cells. We observed no difference in neurological disease progression or overall survival between Ndufs4 (-/-)/ Il2rg (WT) and Ndufs4 (-/-)/ Il2rg (KO) mice, strongly suggesting that T cells, B cells, and NK cells do not play a significant role in CNS disease pathogenesis in Ndufs4 (-/-) mice. Combined with previous studies indicating a causal role for macrophages, we conclude that LS CNS pathology is primarily driven by the monocyte/macrophage innate immune system.

Leigh syndrome (LS) is the most common pediatric presentation of genetic mitochondrial disease and characterized by neurological and metabolic abnormalities. The hallmark of the disease is the presence of progressive, bilateral, symmetric neurodegenerative lesions in the brainstem and/or basal ganglia. Recent studies in the Ndufs4(-/-) mouse model of LS indicate that disease is causally driven by the immune system. Both microglia and peripherally originating macrophages are enriched in the lesions of Ndufs4(-/-) mice and pharmacologic elimination of these cell types prevents disease indicating a crucial role for innate immune cells. Here, we investigated the role of the adaptive immune system in Ndufs4(-/-) disease pathogenesis. We crossed Ndufs4(-/-) mice with mice expressing a null form of interleukin 2 receptor gamma (Il2rg) and monitored disease onset and progression. Il2rg knockout (KO) mice have dramatically depleted numbers of B-, T-, the adaptive immune system's key cellular actors, and NK-cells. We observed no difference in neurological disease progression or overall survival between Ndufs4(-/-)/Il2rg(WT) and Ndufs4(-/-)/Il2rg(KO) mice, strongly suggesting that T cells, B cells, and NK cells do not play a significant role in CNS disease pathogenesis in Ndufs4(-/-) mice. Combined with previous studies indicating a causal role for macrophages, we conclude that LS CNS pathology is primarily driven by the monocyte/macrophage innate immune system.

Flare frequency distributions represent a key approach to addressing one of the largest problems in solar and stellar physics: determining the mechanism that counterintuitively 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 Alfvén 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, α = 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: preflare 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 α = 1.63 ± 0.03. This is below the critical threshold, suggesting that Alfvén waves are an important driver of coronal heating.

Primary genetic mitochondrial diseases (GMDs) are a clinically and genetically diverse group of diseases estimated to impact over 1 in 4,000 individuals. Leigh syndrome (LS) is the most common pediatric presentation of GMD. LS typically presents within the first years of life and is a severe progressive multi-system disorder. Symmetric progressive inflammatory brain lesions are a defining feature of the disease. Patients can also present with seizures, metabolic dysfunction, muscle weakness, and other symptoms. No effective clinical treatments currently exist. Recent data from the (-/-) mouse model shows that peripheral macrophages contribute to brain lesions in LS, that disease is causally driven by innate immune populations, and that depletion of innate immune cells prevents LS disease. However, the precise mechanisms underlying immune activation remain unknown. Certain mitochondrial macromolecules retain bacterial signatures and can act as potent agonists for innate immune pathways. For example, cytoplasmic mitochondrial RNA and mitochondrial DNA are detected by Toll-like receptors (TLRs) 7 and 9, respectively, at the endosome. Accordingly, these are considered strong candidates for mediating innate immune activation in LS. Here, we generated TLR signaling deficient (-/-)/ (-/-) animals to assess whether TLR signaling plays a role in disease onset or progression in LS. Loss of in (-/-) animals statistically significantly increased survival and delayed the onset of some symptoms, but the benefits were modest compared to CSF1R inhibition from prior work. We conclude that -mediated immune signaling is not a primary driver of LS. Notably, prophylactic enrofloxacin treatment, which was necessary for production of innate immune deficient (-/-) animals, modestly decreased survival and accelerated disease. The impact of enrofloxacin and similar drugs in the context of mitochondrial disease warrants further investigation.

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 Alfvén 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 Alfvén waves are an important driver of coronal heating.

Leigh syndrome (LS) is the most common pediatric presentation of genetic mitochondrial disease. LS is a multi-system disease characterized by severe neurologic and metabolic abnormalities. The defining feature of the disease is the presence of symmetric, bilateral, progressive necrotizing lesions in the brain stem, cerebellum, and basal ganglia. The pathogenic mechanisms underlying disease initiation and progression in LS have yet to be elucidated. Recent evidence demonstrates that the immune system plays a key role in LS pathogenesis. Treatment with the macrophage-depleting Csf1r inhibitor pexidartinib prevents disease in the Ndufs4(-/-) mouse model of LS, but the mechanisms leading to immune activation and governing disease progression remain to be elucidated. In recent work, the cytokines IFNγ and IFNγ-induced protein 10 (IP10) were found to be significantly elevated in Ndufs4(-/-) brainstem. Given their role as macrophage-activating factors, here we sought to assess the role of IFNγ and IP10 in LS using by generating Ndufs4(-/-)/Ifng(-/-) and Ndufs4(-/-)/IP10(-/-) double knockout lines. We find that IP10 alone does not significantly impact the onset or progression of disease in the Ndufs4(-/-) model, while IFNγ loss significantly, but modestly, improves survival. These data indicate that IFNγ contributes to pathology, but that IFNγ and IP10 are both dispensable for overall disease course of LS. Our findings support some role for IFNγ targeting therapies in the management of mitochondrial disease, but suggest they may provide only modest benefits, at least in LS.

In WSe 2 monolayers, strain has been used to control the energy of excitons, induce funneling, and realize single-photon sources. Here, we developed a technique for probing the dynamics of free excitons in nanoscale strain landscapes in such monolayers. A nanosculpted tapered optical fiber is used to simultaneously generate strain and probe the near-field optical response of WSe 2 monolayers at 5 K. When the monolayer is pushed by the fiber, its lowest energy states shift by as much as 390 meV (>20% of the bandgap of a WSe 2 monolayer). Polarization and lifetime measurements of these red-shifting peaks indicate they originate from dark excitons. We conclude free dark excitons are funneled to high-strain regions during their long lifetime and are the principal participants in drift and diffusion at cryogenic temperatures. This insight supports proposals on the origin of single-photon sources in WSe 2 and demonstrates a route towards exciton traps for exciton condensation. Here, the authors use a tapered optical fibre to create a dynamic, reversible strain in a suspended WSe 2 monolayer, and observe that dark excitons are funnelled to high-strain regions and are the principal participants in drift and diffusion at cryogenic temperatures.

Metabolic pathways and inflammatory processes are under circadian regulation. Rhythmic immune cell recruitment is known to impact infection outcomes, but whether the circadian clock modulates immunometabolism remains unclear. We find that the molecular clock Bmal1 is induced by inflammatory stimulants, including Ifn-γ/lipopolysaccharide (M1) and tumor-conditioned medium, to maintain mitochondrial metabolism under metabolically stressed conditions in mouse macrophages. Upon M1 stimulation, myeloid-specific Bmal1 knockout (M-BKO) renders macrophages unable to sustain mitochondrial function, enhancing succinate dehydrogenase (SDH)-mediated mitochondrial production of reactive oxygen species as well as Hif-1α-dependent metabolic reprogramming and inflammatory damage. In tumor-associated macrophages, aberrant Hif-1α activation and metabolic dysregulation by M-BKO contribute to an immunosuppressive tumor microenvironment. Consequently, M-BKO increases melanoma tumor burden, whereas administering the SDH inhibitor dimethyl malonate suppresses tumor growth. Therefore, Bmal1 functions as a metabolic checkpoint that integrates macrophage mitochondrial metabolism, redox homeostasis and effector functions. This Bmal1-Hif-1α regulatory loop may provide therapeutic opportunities for inflammatory diseases and immunotherapy.