High‐capacity sodium (Na) anodes suffer from dendrite growth due to the high reactivity, which can be overcome through inducing a stable NaF‐rich solid electrolyte interphase (SEI). Herein, we ...propose an additive strategy for realizing the anion‐enriched structure of Na+ solvation to obtain a NaF‐rich SEI. The electron‐withdrawing acetyl group in 4‐acetylpyridine (4‐APD) increases the coordination number of PF6− in the Na+ solvation sheath to facilitate PF6− to decompose into NaF. Thus, the NaF‐rich SEI with high mechanical stability and interfacial energy is formed to repress the growth of Na dendrites. With the 4‐APD‐contained electrolyte, the symmetric Na||Na cells show excellent cycling performance over 360 h at 1.0 mA cm−2. Meanwhile, excellent stability is also achieved for Na||Na3V2(PO4)2O2F full cells with high Coulombic efficiency (97 %) and capacity retention (91 %) after 200 cycles.
Owing to the anion‐enriched effect induced by 4‐acetylpyridine (4‐APD) additive, more PF6− could enter the inner Na+ solvation sheath to be decomposed into NaF on the Na anode surface, which could effectively repress the Na dendrite growth and boost the cycling performance of Na‐metal batteries.
Disruptive mutations in chromatin remodeler CHD8 cause autism spectrum disorders, exhibiting widespread white matter abnormalities; however, the underlying mechanisms remain elusive. We show that ...cell-type specific Chd8 deletion in oligodendrocyte progenitors, but not in neurons, results in myelination defects, revealing a cell-intrinsic dependence on CHD8 for oligodendrocyte lineage development, myelination and post-injury remyelination. CHD8 activates expression of BRG1-associated SWI/SNF complexes that in turn activate CHD7, thus initiating a successive chromatin remodeling cascade that orchestrates oligodendrocyte lineage progression. Genomic occupancy analyses reveal that CHD8 establishes an accessible chromatin landscape, and recruits MLL/KMT2 histone methyltransferase complexes distinctively around proximal promoters to promote oligodendrocyte differentiation. Inhibition of histone demethylase activity partially rescues myelination defects of CHD8-deficient mutants. Our data indicate that CHD8 exhibits a dual function through inducing a cascade of chromatin reprogramming and recruiting H3K4 histone methyltransferases to establish oligodendrocyte identity, suggesting potential strategies of therapeutic intervention for CHD8-associated white matter defects.
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•Autism-associated CHD8 required for oligodendrocyte development and survival•Chromatin regulator CHD8 required for OPC proliferation and remyelination•CHD8-BRG1-CHD7 cascade regulates oligodendroglial lineage progression•CHD8 recruits KMT2 histone methyltransferase to promote oligodendrocyte development
Mutations in chromatin regulator CHD8 are associated with autism and white matter abnormalities. Zhao et al. show that CHD8 functions in oligodendrocyte progenitors to promote oligodendrocyte lineage development, myelination, and post-injury remyelination by establishing an open chromatin landscape for a cascade of chromatin reprogramming events and recruiting KMT2 histone methyltransferase.
Necrotizing enterocolitis (NEC) is a severe gastrointestinal disease of the premature infant. One of the most important long-term complications observed in children who survive NEC early in life is ...the development of profound neurological impairments. However, the pathways leading to NEC-associated neurological impairments remain unknown, thus limiting the development of prevention strategies. We have recently shown that NEC development is dependent on the expression of the lipopolysaccharide receptor Toll-like receptor 4 (TLR4) on the intestinal epithelium, whose activation by bacteria in the newborn gut leads to mucosal inflammation. Here, we hypothesized that damage-induced production of TLR4 endogenous ligands in the intestine might lead to activation of microglial cells in the brain and promote cognitive impairments. We identified a gut-brain signaling axis in an NEC mouse model in which activation of intestinal TLR4 signaling led to release of high-mobility group box 1 in the intestine that, in turn, promoted microglial activation in the brain and neurological dysfunction. We further demonstrated that an orally administered dendrimer-based nanotherapeutic approach to targeting activated microglia could prevent NEC-associated neurological dysfunction in neonatal mice. These findings shed light on the molecular pathways leading to the development of NEC-associated brain injury, provide a rationale for early removal of diseased intestine in NEC, and indicate the potential of targeted therapies that protect the developing brain in the treatment of NEC in early childhood.
Malignant peripheral nerve sheath tumor (MPNST) is an aggressive soft tissue sarcoma for which the only effective therapy is surgery. In 2016, an international meeting entitled "MPNST State of the ...Science: Outlining a Research Agenda for the Future" was convened to establish short- and long-term research priorities. Key recommendations included the: 1) development of standardized, cost-efficient fluorodeoxyglucose positron emission tomography and whole-body magnetic resonance imaging guidelines to evaluate masses concerning for MPNST; 2) development of better understanding and histologic criteria for the transformation of a plexiform neurofibroma to MPNST; 3) establishment of a centralized database to collect genetic, genomic, histologic, immunohistochemical, molecular, radiographic, treatment, and related clinical data from MPNST subspecialty centers in a standardized manner; 4) creation of accurate mouse models to study the plexiform neurofibroma-to-MPNST transition, MPNST metastasis, and drug resistance; 5) use of trial designs that minimize regulatory requirements, maximize availability to patients, consider novel secondary end points, and study patients with newly diagnosed disease. Lastly, in order to minimize delays in developing novel therapies and promote the most efficient use of research resources and patient samples, data sharing should be incentivized.
A major component of cells in tenosynovial giant cell tumor (TGCT) consists of bystander macrophages responding to CSF1 that is overproduced by a small number of neoplastic cells with a chromosomal ...translocation involving the CSF1 gene. An autocrine loop was postulated where the neoplastic cells would be stimulated through CSF1R expressed on their surface. Here, we use single-cell RNA sequencing (scRNA-seq) to investigate cellular interactions in TGCT.
A total of 18,788 single cells from three TGCT and two giant cell tumor of bone (GCTB) samples underwent scRNA-seq. The three TGCTs were additionally analyzed using long-read RNA sequencing. Immunofluorescence and IHC for a range of markers were used to validate and extend the scRNA-seq findings.
Two recurrent neoplastic cell populations were identified in TGCT that are highly similar to nonneoplastic synoviocytes. We identified GFPT2 as a marker that highlights the neoplastic cells in TCGT. We show that the neoplastic cells themselves do not express CSF1R. We identified overlapping MAB features between the giant cells in TGCT and GCTB.
The neoplastic cells in TGCT are highly similar to nonneoplastic synoviocytes. The lack of CSF1R on the neoplastic cells indicates they may be unaffected by current therapies. High expression of GFPT2 in the neoplastic cells is associated with activation of the YAP1/TAZ pathway. In addition, we identified expression of the platelet-derived growth factor receptor in the neoplastic cells. These findings suggest two additional pathways to target in this tumor.
The polycomb repressive complex 2 (PRC2) exerts oncogenic effects in many tumour types. However, loss-of-function mutations in PRC2 components occur in a subset of haematopoietic malignancies, ...suggesting that this complex plays a dichotomous and poorly understood role in cancer. Here we provide genomic, cellular, and mouse modelling data demonstrating that the polycomb group gene SUZ12 functions as tumour suppressor in PNS tumours, high-grade gliomas and melanomas by cooperating with mutations in NF1. NF1 encodes a Ras GTPase-activating protein (RasGAP) and its loss drives cancer by activating Ras. We show that SUZ12 loss potentiates the effects of NF1 mutations by amplifying Ras-driven transcription through effects on chromatin. Importantly, however, SUZ12 inactivation also triggers an epigenetic switch that sensitizes these cancers to bromodomain inhibitors. Collectively, these studies not only reveal an unexpected connection between the PRC2 complex, NF1 and Ras, but also identify a promising epigenetic-based therapeutic strategy that may be exploited for a variety of cancers.
Regeneration of CNS myelin involves differentiation of oligodendrocytes from oligodendrocyte progenitor cells. In multiple sclerosis, remyelination can fail despite abundant oligodendrocyte ...progenitor cells, suggesting impairment of oligodendrocyte differentiation. T cells infiltrate the CNS in multiple sclerosis, yet little is known about T cell functions in remyelination. We report that regulatory T cells (T
) promote oligodendrocyte differentiation and (re)myelination. T
-deficient mice exhibited substantially impaired remyelination and oligodendrocyte differentiation, which was rescued by adoptive transfer of T
. In brain slice cultures, T
accelerated developmental myelination and remyelination, even in the absence of overt inflammation. T
directly promoted oligodendrocyte progenitor cell differentiation and myelination in vitro. We identified CCN3 as a T
-derived mediator of oligodendrocyte differentiation and myelination in vitro. These findings reveal a new regenerative function of T
in the CNS, distinct from immunomodulation. Although the cells were originally named 'T
' to reflect immunoregulatory roles, this also captures emerging, regenerative T
functions.
Although complex inflammatory-like alterations are observed around the amyloid plaques of Alzheimer’s disease (AD), little is known about the molecular changes and cellular interactions that ...characterize this response. We investigate here, in an AD mouse model, the transcriptional changes occurring in tissue domains in a 100-μm diameter around amyloid plaques using spatial transcriptomics. We demonstrate early alterations in a gene co-expression network enriched for myelin and oligodendrocyte genes (OLIGs), whereas a multicellular gene co-expression network of plaque-induced genes (PIGs) involving the complement system, oxidative stress, lysosomes, and inflammation is prominent in the later phase of the disease. We confirm the majority of the observed alterations at the cellular level using in situ sequencing on mouse and human brain sections. Genome-wide spatial transcriptomics analysis provides an unprecedented approach to untangle the dysregulated cellular network in the vicinity of pathogenic hallmarks of AD and other brain diseases.
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•Spatial transcriptomics identifies a plaque-induced gene (PIG) network•Spatial transcriptomics identifies an oligodendrocyte gene (OLIG) response in AD•In situ sequencing in mouse and human confirms these responses at single-cell level•PIG and OLIG responses are conserved over different neurodegenerative diseases
A combination of spatial transcriptomics and in situ sequencing on mouse and human brain demonstrates multicellular gene co-expression networks in Alzheimer’s disease, two of which are induced by accumulating amyloid plaques. A plaque-induced gene (PIG) network mainly involving micro- and astroglia and an oligodendrocyte gene (OLIG) and myelination response are identified.
Background
Malignant peripheral nerve sheath tumors (MPNST) are a rare form of soft tissue sarcoma with few studies reporting on patient outcomes and prognostic variables.
Methods
A retrospective ...review of 175 patients diagnosed with MPNST from 1985 to 2010 was performed. Patient, tumor, and treatment characteristics were evaluated to identify prognostic variables.
Results
The median age of our study population was 44 years, and 51% were female. Median tumor size was 6 cm, and 61% of patients had high-grade tumors. Tumors were most commonly located on the extremities (45%), then trunk (34%) and head/neck (19%). The majority of patients underwent surgical resection (95%) and adjuvant treatment with chemotherapy (6%), radiation (42%) or both (22%). Margin status was R0 in 69%, R1 in 2%, R2 in 9%, and unknown in 20%. The local recurrence rate was 22%, and 5- and 10-year disease-specific survival (DSS) were 60% and 45%, respectively. On univariate analysis, no predictors for local recurrence were identified. Tumor size ≥5 cm, high tumor grade, tumor location, presence of neurofibromatosis type 1, local recurrence, and adjuvant chemotherapy were all associated with DSS. On multivariate analysis, size ≥5 cm hazard ratio (HR) = 6.1, 95% confidence interval (CI) 1.5–25.0, local recurrence (HR = 4.4, 95% CI 1.7–11.4), high tumor grade (HR = 3.8, 95% CI 1.1–13.2), and truncal location (HR = 3.7, 95% CI 1.1–12.7) were poor prognostic indicators for DSS.
Conclusions
High tumor grade and tumor size ≥5 cm predict adverse DSS for MPNST. In the context of a multidisciplinary treatment regimen, local recurrence and survival outcomes at 5 and 10 years were better than previously reported for MPNST.
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