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Remyelination after white matter injury (WMI) often fails in diseases such as multiple sclerosis because of improper recruitment and repopulation of oligodendrocyte precursor cells (OPCs) in lesions. How OPCs elicit specific intracellular programs in response to a chemically and mechanically diverse environment to properly regenerate myelin remains unclear. OPCs construct primary cilia, specialized signaling compartments that transduce Hedgehog (Hh) and G-protein-coupled receptor (GPCR) signals. We investigated the role of primary cilia in the OPC response to WMI. Removing cilia from OPCs genetically via deletion of Ift88 results in OPCs failing to repopulate WMI lesions because of reduced proliferation. Interestingly, loss of cilia does not affect Hh signaling in OPCs or their responsiveness to Hh signals but instead leads to dysfunctional cyclic AMP (cAMP)-dependent cAMP response element-binding protein (CREB)-mediated transcription. Because inhibition of CREB activity in OPCs reduces proliferation, we propose that a GPCR/cAMP/CREB signaling axis initiated at OPC cilia orchestrates OPC proliferation during development and in response to WMI.

Oligodendrocyte precursor cells (OPCs) undergo an extensive and coordinated migration in the developing CNS, using the pre-formed scaffold of developed blood vessels as their physical substrate for migration. While OPC association with vasculature is critical for dispersal, equally important for permitting differentiation and proper myelination of target axons is their appropriate and timely detachment, but regulation of this process remains unclear. Here we demonstrate a correlation between the developmental formation of astrocytic endfeet on vessels and the termination of OPC perivascular migration. Ex vivo and in vivo live imaging shows that astrocyte endfeet physically displace OPCs from vasculature, and genetic abrogation of endfoot formation hinders both OPC detachment from vessels and subsequent differentiation. Astrocyte-derived semaphorins 3a and 6a act to repel OPCs from blood vessels at the cessation of their perivascular migration and, in so doing, permit subsequent OPC differentiation by insulating them from a maturation inhibitory endothelial niche.

Astrocytes become reactive in response to insults to the central nervous system by adopting context-specific cellular signatures and outputs, but a systematic understanding of the underlying molecular mechanisms is lacking. In this study, we developed CRISPR interference screening in human induced pluripotent stem cell-derived astrocytes coupled to single-cell transcriptomics to systematically interrogate cytokine-induced inflammatory astrocyte reactivity. We found that autocrine-paracrine IL-6 and interferon signaling downstream of canonical NF-κB activation drove two distinct inflammatory reactive signatures, one promoted by STAT3 and the other inhibited by STAT3. These signatures overlapped with those observed in other experimental contexts, including mouse models, and their markers were upregulated in human brains in Alzheimer's disease and hypoxic-ischemic encephalopathy. Furthermore, we validated that markers of these signatures were regulated by STAT3 in vivo using a mouse model of neuroinflammation. These results and the platform that we established have the potential to guide the development of therapeutics to selectively modulate different aspects of inflammatory astrocyte reactivity.

Oligodendrocyte (OL) maturation arrest in human white matter injury contributes significantly to the failure of endogenous remyelination in multiple sclerosis (MS) and newborn brain injuries such as hypoxic ischemic encephalopathy (HIE) that cause cerebral palsy. In this study, we identify an oligodendroglial-intrinsic factor that controls OL maturation specifically in the setting of injury. We find a requirement for the ring finger protein Rnf43 not in normal development but in neonatal hypoxic injury and remyelination in the adult mammalian CNS. Rnf43, but not the related Znrf3, is potently activated by Wnt signaling in OL progenitor cells (OPCs) and marks activated OPCs in human MS and HIE. Rnf43 is required in an injury-specific context, and it promotes OPC differentiation through negative regulation of Wnt signal strength in OPCs at the level of Fzd1 receptor presentation on the cell surface. Inhibition of Fzd1 using UM206 promotes remyelination following ex vivo and in vivo demyelinating injury.

This study aimed to investigate the necessity of measurement‐based patient‐specific quality assurance (PSQA) for online adaptive radiotherapy by analyzing measurement‐based PSQA results and calculation‐based 3D independent dose verification results with Elekta Unity MR‐Linac. There are two workflows for Elekta Unity enabled in the treatment planning system: adapt to position (ATP) and adapt to shape (ATS). ATP plans are those which have relatively slighter shifts from reference plans by adjusting beam shapes or weights, whereas ATS plans are the new plans optimized from the beginning with probable re‐contouring targets and organs‐at‐risk. PSQA gamma passing rates were measured using an MR‐compatible ArcCHECK diode array for 78 reference plans and corresponding 208 adaptive plans (129 ATP plans and 79 ATS plans) of Elekta Unity. Subsequently, the relationships between ATP, or ATS plans and reference plans were evaluated separately. The Pearson's r correlation coefficients between ATP or ATS adaptive plans and corresponding reference plans were also characterized using regression analysis. Moreover, the Bland–Altman plot method was used to describe the agreement of PSQA results between ATP or ATS adaptive plans and reference plans. Additionally, Monte Carlo‐based independent dose verification software ArcherQA was used to perform secondary dose check for adaptive plans. For ArcCHECK measurements, the average gamma passing rates (ArcCHECK vs. TPS) of PSQA (3%/2 mm criterion) were 99.51% ± 0.88% and 99.43% ± 0.54% for ATP and ATS plans, respectively, which were higher than the corresponding reference plans 99.34% ± 1.04% (p < 0.05) and 99.20% ± 0.71% (p < 0.05), respectively. The Pearson's r correlation coefficients were 0.720 between ATP and reference plans and 0.300 between ATS and reference plans with ArcCHECK, respectively. Furthermore, >95% of data points of differences between both ATP and ATS plans and reference plans were within ±2σ (standard deviation) of the mean difference between adaptive and reference plans with ArcCHECK measurements. With ArcherQA calculation, the average gamma passing rates (ArcherQA vs. TPS) were 98.23% ± 1.64% and 98.15% ± 1.07% for ATP and ATS adaptive plans, separately. It might be unnecessary to perform measurement‐based PSQA for both ATP and ATS adaptive plans for Unity if the gamma passing rates of both measurements of corresponding reference plans and independent dose verification of adaptive plans have high gamma passing rates. Periodic machine QA and verification of adaptive plans were recommended to ensure treatment safety. [ABSTRACT FROM AUTHOR]

Marek’s disease virus (MDV) can cause malignant T-cell lymphomas and immunosuppression in chickens. Macrophage migration inhibitory factor (MIF) not only plays a critical role in inhibiting T-cell responses, but also contributes to multiple aspects of tumour progression. The aim of this study was to reveal the potential role of MIF in the pathogenesis of MDV infection.