•O-GlcNAcylation is an evolutionarily conserved, reversible protein modification regulated by OGT and OGA.•O-GlcNAcylation regulates fundamental biological processes in diverse cell types by sensing ...extracellular state.•O-GlcNAcylation is critical for proliferation, differentiation, and homeostatic maintenance of hematopoietic cells.•Aberrant O-GlcNAcylation is implicated in pathogenesis of hematologic malignancies through epigenetic dysregulation.
Posttranslational protein modification through addition of the O‐linked β-N-acetyl-D-glucosamine (O-GlcNAc) moiety to serine or threonine residues, termed O-GlcNAcylation, is a highly dynamic process conserved throughout eukaryotes. O-GlcNAcylation is reversibly catalyzed by a single pair of enzymes, O-GlcNAc transferase and O-GlcNAcase, and it acts as a fundamental regulator for a wide variety of biological processes including gene expression, cell cycle regulation, metabolism, stress response, cellular signaling, epigenetics, and proteostasis. O-GlcNAcylation is regulated by various intracellular or extracellular cues such as metabolic status, nutrient availability, and stress. Studies over decades have unveiled the profound biological significance of this unique protein modification in normal physiology and pathologic processes of diverse cell types or tissues. In hematopoiesis, recent studies have indicated the essential and pleiotropic roles of O-GlcNAcylation in differentiation, proliferation, and function of hematopoietic cells including T cells, B cells, myeloid progenitors, and hematopoietic stem and progenitor cells. Moreover, aberrant O-GlcNAcylation is implicated in the development of hematologic malignancies with dysregulated epigenetics, metabolism, and gene transcription. Thus, it is now recognized that O-GlcNAcylation is one of the key regulators of normal and malignant hematopoiesis.
Microglia are generally considered the immune cells of the central nervous system. Recent studies have demonstrated that under specific polarization conditions, microglia develop into two different ...phenotypes, termed M1‐like and M2‐like microglia. However, the phenotypic characteristics of M1‐like‐ and M2‐like‐polarized microglia and the mechanisms that regulate polarization are largely unknown. In this study, we characterized lipopolysaccharide‐treated M1‐like and IL‐4‐treated M2‐like microglia and investigated the mechanisms that regulate phenotypic switching. The addition of M2‐like microglial conditioned medium (CM) to primary neurons resulted in an increase in neurite length when compared with neurons treated with M1‐like microglial CM, possibly because of the enhanced secretion of neurotrophic factors by M2‐like microglia. M1‐like microglia were morphologically characterized by larger soma, whereas M2‐like microglia were characterized by long processes. M2‐like microglia exhibited greater phagocytic capacity than M1‐like microglia. These features switched in response to polarization cues. We found that expression of interferon regulatory factor 7 (IRF7) increased during the M2‐like to M1‐like switch in microglia in vitro and in vivo. Knockdown of IRF7 using siRNA suppressed the expression of M1 marker mRNA and reduced phosphorylation of STAT1. Our findings suggest that IRF7 signaling may play an important role in microglial polarization switching. GLIA 2015;63:595–610
Main Points
Microglial phenotypes are regulated by extracellular stimulus.
Interferon regulatory factor 7 is elevated in M1‐like microglia and is associated with microglial polarization.
Remyelination is disrupted in demyelinating diseases such as multiple sclerosis, but the underlying pathogenetic mechanisms are unclear. In this study, we employed the murine cuprizone model of ...demyelination, in which remyelination occurs after removal of the toxin from the diet, to examine the cellular and molecular changes during demyelination and remyelination. Microglia accumulated in the corpus callosum during weeks 2–4 of the cuprizone diet, and these cells remained activated 2 weeks after the change to the normal diet. To examine the role of microglia in remyelination, mice were treated with minocycline to inactivate these cells after cuprizone‐induced demyelination. Minocycline treatment reduced the number of CC1‐positive oligodendrocytes, as well as levels of myelin basic protein (MBP) and CNPase in the remyelination phase. The expression of CNTF mRNA in the corpus callosum increased after 4 weeks on the cuprizone diet and remained high 2 weeks after the change to the normal diet. Minocycline suppressed CNTF expression during the remyelination phase on the normal diet. Primary culture experiments showed that CNTF was produced by microglia in addition to astrocytes. In vitro, CNTF directly affected the differentiation of oligodendrocytic cells. These findings suggest that minocycline reduces remyelination by suppressing CNTF expression by microglia after cuprizone‐induced demyelination.
To examine the role of microglia in remyelination, mice were treated with minocycline after cuprizone‐induced demyelination. Minocycline treatment reduced the number of oligodendrocytes and CNTF expression in the remyelination phase. In vitro, CNTF directly affected the differentiation of oligodendrocytic cells. These findings suggest that minocycline reduces remyelination by suppressing CNTF expression by microglia after cuprizone‐induced demyelination.
Purpose
Track structure simulation codes can accurately reproduce the stochastic nature of particle–matter interactions in order to evaluate quantitatively radiation damage in biological cells such ...as DNA strand breaks and base damage. Such simulations handle large numbers of secondary charged particles and molecular species created in the irradiated medium. Every particle and molecular species are tracked step‐by‐step using a Monte Carlo method to calculate energy loss patterns and spatial distributions of molecular species inside a cell nucleus with high spatial accuracy. The Geant4‐DNA extension of the Geant4 general‐purpose Monte Carlo simulation toolkit allows for such track structure simulations and can be run on CPUs. However, long execution times have been observed for the simulation of DNA damage in cells. We present in this work an improvement of the computing performance of such simulations using ultraparallel processing on a graphical processing unit (GPU).
Methods
A new Monte Carlo simulator named MPEXS‐DNA, allowing high computing performance by using a GPU, has been developed for track structure and radiolysis simulations at the subcellular scale. MPEXS‐DNA physics and chemical processes are based on Geant4‐DNA processes available in Geant4 version 10.02 p03. We have reimplemented the Geant4‐DNA process codes of the physics stage (electromagnetic processes of charged particles) and the chemical stage (diffusion and chemical reactions for molecular species) for microdosimetry simulation by using the CUDA language. MPEXS‐DNA can calculate a distribution of energy loss in the irradiated medium caused by charged particles and also simulate production, diffusion, and chemical interactions of molecular species from water radiolysis to quantitatively assess initial damage to DNA. The validation of MPEXS‐DNA physics and chemical simulations was performed by comparing various types of distributions, namely the radial dose distributions for the physics stage, and the G‐value profiles for each chemical product and their linear energy transfer dependency for the chemical stage, to existing experimental data and simulation results obtained by other simulation codes, including PARTRAC.
Results
For physics validation, radial dose distributions calculated by MPEXS‐DNA are consistent with experimental data and numerical simulations. For chemistry validation, MPEXS‐DNA can also reproduce G‐value profiles for each molecular species with the same tendency as existing experimental data. MPEXS‐DNA also agrees with simulations by PARTRAC reasonably well. However, we have confirmed that there are slight discrepancies in G‐value profiles calculated by MPEXS‐DNA for molecular species such as H2 and H2O2 when compared to experimental data and PARTRAC simulations. The differences in G‐value profiles between MPEXS‐DNA and PARTRAC are caused by the different chemical reactions considered. MPEXS‐DNA can drastically boost the computing performance of track structure and radiolysis simulations. By using NVIDIA's GPU devices adopting the Volta architecture, MPEXS‐DNA has achieved speedup factors up to 2900 against Geant4‐DNA simulations with a single CPU core.
Conclusion
The MPEXS‐DNA Monte Carlo simulation achieves similar accuracy to Monte Carlo simulations performed using other codes such as Geant4‐DNA and PARTRAC, and its predictions are consistent with experimental data. Notably, MPEXS‐DNA allows calculations that are, at maximum, 2900 times faster than conventional simulations using a CPU.
A
bstract
We study the odd spin structure contributions to the multiloop amplitudes of light-cone gauge superstring field theory. We show that they coincide with the amplitudes in the conformal gauge ...with two of the vertex operators chosen to be in the pictures different from the standard choice, namely (−1, −1) picture in the type II case and −1 picture in the heterotic case. We also show that the contact term divergences can be regularized in the same way as in the amplitudes for the even structures and we get the amplitudes which coincide with those obtained from the first-quantized approach.
Geant4 is a toolkit for the simulation of the passage of particles through matter. Its areas of application include high energy, nuclear and accelerator physics, as well as studies in medical and ...space science. In this article, the recent developments of Geant4, especially new functionalities and applications using parallel computing, are explained.
The transcription factor IRF8 is essential for the development of monocytes and dendritic cells (DCs), whereas it inhibits neutrophilic differentiation. It is unclear how Irf8 expression is regulated ...and how this single transcription factor supports the generation of both monocytes and DCs. Here, we identified a RUNX-CBFβ-driven enhancer 56 kb downstream of the Irf8 transcription start site. Deletion of this enhancer in vivo significantly decreased Irf8 expression throughout the myeloid lineage from the progenitor stages, thus resulting in loss of common DC progenitors and overproduction of Ly6C
monocytes. We demonstrated that high, low or null expression of IRF8 in hematopoietic progenitor cells promotes differentiation toward type 1 conventional DCs, Ly6C
monocytes or neutrophils, respectively, via epigenetic regulation of distinct sets of enhancers in cooperation with other transcription factors. Our results illustrate the mechanism through which IRF8 controls the lineage choice in a dose-dependent manner within the myeloid cell system.
After allogeneic hematopoietic stem cell transplantation (HSCT), human herpesvirus-6 (HHV-6) can cause serious central nervous system (CNS) disorder and typically presents as encephalitis. Another ...manifestation of HHV-6 is myelitis, which has not been fully evaluated. In this study, we retrospectively analyzed 19 patients who developed HHV-6 myelitis after allogeneic HSCT. Median onset was 20 days after transplantation (range, 13-31), with a cumulative incidence of 4.1% at day 40 after transplantation. Median age at transplant was 50 years (range, 17-61). Median copy number of HHV-6 DNA was 3000 copies/ml in cerebrospinal fluid (CSF; range, 200-100,000). The most common symptoms were pruritus, pain of the extremities/back, and numbness. Three patients subsequently developed encephalitis in the clinical course of myelitis; their HHV-6 copy numbers in CSF had been higher than 10,000 copies/ml at the onset of myelitis. Antiviral agents were initiated shortly after onset in all patients, resulting in recovery. These results suggest that myelitis would be an important subtype of HHV-6-associated CNS disorders after allogeneic HSCT, whose prognosis could be favorable by an early intervention. Transplant physicians should recognize early posttransplant neurological symptoms such as pruritus, pain, or numbness as possible signs of HHV-6 myelitis, which could also progress to encephalitis.
Chronic myeloid leukemia (CML) is a form of myeloproliferative neoplasm caused by the oncogenic tyrosine kinase BCR-ABL. Although tyrosine kinase inhibitors have dramatically improved the prognosis ...of patients with CML, several problems such as resistance and recurrence still exist. Immunological control may contribute to solving these problems, and it is important to understand why CML patients fail to spontaneously develop anti-tumor immunity. Here, we show that differentiation of conventional dendritic cells (cDCs), which are vital for anti-tumor immunity, is restricted from an early stage of hematopoiesis in CML. In addition, we found that monocytes and basophils, which are increased in CML patients, express high levels of PD-L1, an immune checkpoint molecule that inhibits T cell responses. Moreover, RNA-sequencing analysis revealed that basophils express genes related to poor prognosis in CML. Our data suggest that BCR-ABL not only disrupts the "accelerator" (i.e., cDCs) but also applies the "brake" (i.e., monocytes and basophils) of anti-tumor immunity, compromising the defense against CML cells.
PDF
