Oxidative stress is a central part of innate immune-induced neurodegeneration. However, the transcriptomic landscape of central nervous system (CNS) innate immune cells contributing to oxidative ...stress is unknown, and therapies to target their neurotoxic functions are not widely available. Here, we provide the oxidative stress innate immune cell atlas in neuroinflammatory disease and report the discovery of new druggable pathways. Transcriptional profiling of oxidative stress-producing CNS innate immune cells identified a core oxidative stress gene signature coupled to coagulation and glutathione-pathway genes shared between a microglia cluster and infiltrating macrophages. Tox-seq followed by a microglia high-throughput screen and oxidative stress gene network analysis identified the glutathione-regulating compound acivicin, with potent therapeutic effects that decrease oxidative stress and axonal damage in chronic and relapsing multiple sclerosis models. Thus, oxidative stress transcriptomics identified neurotoxic CNS innate immune populations and may enable discovery of selective neuroprotective strategies.
Recent studies suggest that mitochondria can be transferred between cells to support the survival of metabolically compromised cells. However, whether intercellular mitochondria transfer occurs in ...white adipose tissue (WAT) or regulates metabolic homeostasis in vivo remains unknown. We found that macrophages acquire mitochondria from neighboring adipocytes in vivo and that this process defines a transcriptionally distinct macrophage subpopulation. A genome-wide CRISPR-Cas9 knockout screen revealed that mitochondria uptake depends on heparan sulfates (HS). High-fat diet (HFD)-induced obese mice exhibit lower HS levels on WAT macrophages and decreased intercellular mitochondria transfer from adipocytes to macrophages. Deletion of the HS biosynthetic gene Ext1 in myeloid cells decreases mitochondria uptake by WAT macrophages, increases WAT mass, lowers energy expenditure, and exacerbates HFD-induced obesity in vivo. Collectively, this study suggests that adipocytes and macrophages employ intercellular mitochondria transfer as a mechanism of immunometabolic crosstalk that regulates metabolic homeostasis and is impaired in obesity.
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•Adipocytes transfer their mitochondria to macrophages in vivo•Mitochondria transfer from adipocytes to macrophages is decreased in obesity•Mitochondria uptake by macrophages is mediated by heparan sulfates•Mice that lack heparan sulfates on macrophages exhibit metabolic dysfunction
Brestoff et al. show that adipose-tissue-resident macrophages acquire mitochondria from neighboring adipocytes in a heparan-sulfate-dependent process that is impaired in obesity. Genetic disruption of mitochondria uptake by macrophages reduces energy expenditure and exacerbates diet-induced obesity in mice, indicating that intercellular mitochondria transfer to macrophages mediates systemic metabolic homeostasis.
Objective
Rates of worsening and evolution to secondary progressive multiple sclerosis (MS) may be substantially lower in actively treated patients compared to natural history studies from the ...pretreatment era. Nonetheless, in our recently reported prospective cohort, more than half of patients with relapsing MS accumulated significant new disability by the 10th year of follow‐up. Notably, “no evidence of disease activity” at 2 years did not predict long‐term stability. Here, we determined to what extent clinical relapses and radiographic evidence of disease activity contribute to long‐term disability accumulation.
Methods
Disability progression was defined as an increase in Expanded Disability Status Scale (EDSS) of 1.5, 1.0, or 0.5 (or greater) from baseline EDSS = 0, 1.0–5.0, and 5.5 or higher, respectively, assessed from baseline to year 5 (±1 year) and sustained to year 10 (±1 year). Longitudinal analysis of relative brain volume loss used a linear mixed model with sex, age, disease duration, and HLA‐DRB1*15:01 as covariates.
Results
Relapses were associated with a transient increase in disability over 1‐year intervals (p = 0.012) but not with confirmed disability progression (p = 0.551). Relative brain volume declined at a greater rate among individuals with disability progression compared to those who remained stable (p < 0.05).
Interpretation
Long‐term worsening is common in relapsing MS patients, is largely independent of relapse activity, and is associated with accelerated brain atrophy. We propose the term silent progression to describe the insidious disability that accrues in many patients who satisfy traditional criteria for relapsing–remitting MS. Ann Neurol 2019;85:653–666
Dwarf satellite galaxies are thought to be the remnants of the population of primordial structures that coalesced to form giant galaxies like the Milky Way. It has previously been suspected that ...dwarf galaxies may not be isotropically distributed around our Galaxy, because several are correlated with streams of H I emission, and may form coplanar groups. These suspicions are supported by recent analyses. It has been claimed that the apparently planar distribution of satellites is not predicted within standard cosmology, and cannot simply represent a memory of past coherent accretion. However, other studies dispute this conclusion. Here we report the existence of a planar subgroup of satellites in the Andromeda galaxy (M 31), comprising about half of the population. The structure is at least 400 kiloparsecs in diameter, but also extremely thin, with a perpendicular scatter of less than 14.1 kiloparsecs. Radial velocity measurements reveal that the satellites in this structure have the same sense of rotation about their host. This shows conclusively that substantial numbers of dwarf satellite galaxies share the same dynamical orbital properties and direction of angular momentum. Intriguingly, the plane we identify is approximately aligned with the pole of the Milky Way's disk and with the vector between the Milky Way and Andromeda.
Here, we evaluate the contribution of AT-rich interaction domain-containing protein 1A (
), the most frequently mutated member of the SWItch/sucrose non-fermentable (SWI/SNF) complex, in pancreatic ...homeostasis and pancreatic ductal adenocarcinoma (PDAC) pathogenesis using mouse models.
Mice with a targeted deletion of
in the pancreas by itself and in the context of two common genetic alterations in PDAC,
and
, were followed longitudinally. Pancreases were examined and analysed for proliferation, response to injury and tumourigenesis. Cancer cell lines derived from these models were analysed for clonogenic, migratory, invasive and transcriptomic changes.
deletion in the pancreas results in progressive acinar-to-ductal metaplasia (ADM), loss of acinar mass, diminished acinar regeneration in response to injury and ductal cell expansion. Mutant
cooperates with homozygous deletion of
, leading to intraductal papillary mucinous neoplasm (IPMN).
loss in the context of mutant
and
leads to shorter tumour latency, with the resulting tumours being poorly differentiated. Cancer cell lines derived from
-mutant tumours are more mesenchymal, migratory, invasive and capable of anchorage-independent growth; gene expression analysis showed activation of epithelial-mesenchymal transition (EMT) and stem cell identity pathways that are partially dependent on
loss for dysregulation.
ARID1A plays a key role in pancreatic acinar homeostasis and response to injury. Furthermore, ARID1A restrains oncogenic KRAS-driven formation of premalignant proliferative IPMN.
-deficient PDACs are poorly differentiated and have mesenchymal features conferring migratory/invasive and stem-like properties.
Cultivated strawberry emerged from the hybridization of two wild octoploid species, both descendants from the merger of four diploid progenitor species into a single nucleus more than 1 million years ...ago. Here we report a near-complete chromosome-scale assembly for cultivated octoploid strawberry (Fragaria × ananassa) and uncovered the origin and evolutionary processes that shaped this complex allopolyploid. We identified the extant relatives of each diploid progenitor species and provide support for the North American origin of octoploid strawberry. We examined the dynamics among the four subgenomes in octoploid strawberry and uncovered the presence of a single dominant subgenome with significantly greater gene content, gene expression abundance, and biased exchanges between homoeologous chromosomes, as compared with the other subgenomes. Pathway analysis showed that certain metabolomic and disease-resistance traits are largely controlled by the dominant subgenome. These findings and the reference genome should serve as a powerful platform for future evolutionary studies and enable molecular breeding in strawberry.
SARS-CoV-2 mRNA vaccines have shown remarkable clinical efficacy, but questions remain about the nature and kinetics of T cell priming. We performed longitudinal antigen-specific T cell analyses on ...healthy SARS-CoV-2-naive and recovered individuals prior to and following mRNA prime and boost vaccination. Vaccination induced rapid antigen-specific CD4+ T cell responses in naive subjects after the first dose, whereas CD8+ T cell responses developed gradually and were variable in magnitude. Vaccine-induced Th1 and Tfh cell responses following the first dose correlated with post-boost CD8+ T cells and neutralizing antibodies, respectively. Integrated analysis revealed coordinated immune responses with distinct trajectories in SARS-CoV-2-naive and recovered individuals. Last, whereas booster vaccination improved T cell responses in SARS-CoV-2-naive subjects, the second dose had little effect in SARS-CoV-2-recovered individuals. These findings highlight the role of rapidly primed CD4+ T cells in coordinating responses to the second vaccine dose in SARS-CoV-2-naive individuals.
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•mRNA vaccines generate antigen-specific T cells in a coordinated immune response•Vaccine-induced T cells resemble the durable memory cells primed by infection•Th1 and cTfh cell responses to the first dose correlate with second-dose responses•SARS-CoV-2-recovered individuals benefit from the first but not the second dose
SARS-CoV-2 mRNA vaccines have demonstrated remarkable efficacy, but T cell responses to vaccination have not been well studied. In a longitudinal cohort, Painter et al. show that mRNA vaccines activate SARS-CoV-2-specific T cells that could contribute to durable immunity. The findings highlight the central role of T cells in the two-dose vaccine regimen for individuals not previously infected with SARS-CoV-2.
Many present-day aquatic ecosystems are defined by anthropogenic activities such as the introduction of non-native species, habitat loss, and eutrophication. On Prince Edward Island, Canada, ...non-native rainbow trout (
Oncorhynchus mykiss
) have established in highly agricultural coastal watersheds. We used acoustic telemetry with continual oxygen and temperature monitoring to explore the relationship between rainbow trout movements, low dissolved oxygen, high temperature, and other environmental parameters in the eutrophic Dunk River estuary. We tested the hypothesis that rainbow trout capitalize on increased productivity from nutrient stimulation but face a trade-off with disturbed water quality. We divided the salinity transition gradient into zones representing the transition from freshwater to seawater and established that temperature and hypoxia increased with salinity. During hypoxic periods, movements decreased, and residence increased in low salinity habitat (< 1 Practical Salinity Units, PSU) Movement between zones increased from September to November, when conditions improved. A boosted regression tree model showed that dissolved oxygen, discharge, and temperature were related to occupancy which was greatest at dissolved oxygen levels > 6 mg L
−1
, discharge averaging 2 m
3
s
−1
, and temperatures below 23 °C. This study provides insights into the success of rainbow trout in eutrophic estuaries.
Molecular signatures have identified several subsets of diffuse large B cell lymphoma (DLBCL) and rational targets within the B cell receptor (BCR) signaling axis. The OxPhos-DLBCL subset, which ...harbors the signature of genes involved in mitochondrial metabolism, is insensitive to inhibition of BCR survival signaling but is functionally undefined. We show that, compared with BCR-DLBCLs, OxPhos-DLBCLs display enhanced mitochondrial energy transduction, greater incorporation of nutrient-derived carbons into the tricarboxylic acid cycle, and increased glutathione levels. Moreover, perturbation of the fatty acid oxidation program and glutathione synthesis proved selectively toxic to this tumor subset. Our analysis provides evidence for distinct metabolic fingerprints and associated survival mechanisms in DLBCL and may have therapeutic implications.
► Glucose and fatty acids are differentially utilized in molecular subsets of DLBCL ► Mitochondria are predominant in the metabolic signature of BCR-independent DLBCLs ► Fatty acid oxidation and glutathione synthesis are relevant to OxPhos-DLBCL survival ► Fuel utilization pathways define additional levels of heterogeneity in DLBCL
Classical Hodgkin lymphoma (cHL) and mediastinal large B-cell lymphoma (MLBCL) are lymphoid malignancies with certain shared clinical, histologic, and molecular features. Primary cHLs and MLBCLs ...include variable numbers of malignant cells within an inflammatory infiltrate, suggesting that these tumors escape immune surveillance. Herein, we integrate high-resolution copy number data with transcriptional profiles and identify the immunoregulatory genes, PD-L1 and PD-L2, as key targets at the 9p24.1 amplification peak in HL and MLBCL cell lines. We extend these findings to laser-capture microdissected primary Hodgkin Reed-Sternberg cells and primary MLBCLs and find that programmed cell death-1 (PD-1) ligand/9p24.1 amplification is restricted to nodular sclerosing HL, the cHL subtype most closely related to MLBCL. Using quantitative immunohistochemical methods, we document the association between 9p24.1 copy number and PD-1 ligand expression in primary tumors. In cHL and MLBCL, the extended 9p24.1 amplification region also included the Janus kinase 2 (JAK2) locus. Of note, JAK2 amplification increased protein expression and activity, specifically induced PD-1 ligand transcription and enhanced sensitivity to JAK2 inhibition. Therefore, 9p24.1 amplification is a disease-specific structural alteration that increases both the gene dosage of PD-1 ligands and their induction by JAK2, defining the PD-1 pathway and JAK2 as complementary rational therapeutic targets.
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