Myeloid-derived suppressor cells (MDSCs) are generated under biological stress such as cancer, inflammatory tissue damage, and viral infection. In recent years, with occurrence of global infectious ...diseases, new discovery on MDSCs functions has been significantly expanded during viral infection and COVID-19. For a successful viral infection, pathogens viruses develop immune evasion strategies to avoid immune recognition. Numerous viruses induce the differentiation and expansion of MDSCs in order to suppress host immune responses including natural killer cells, antigen presenting cells, and T-cells. Moreover, MDSCs play an important role in regulation of immunopathogenesis by balancing viral infection and tissue damage. In this review article, we describe the overview of immunomodulation and genetic regulation of MDSCs during viral infection in the animal model and human studies. In addition, we include up-to-date review of role of MDSCs in SARS-CoV-2 infection and COVID-19. Finally, we discuss potential therapeutics targeting MDSCs.
Therapeutic proteins are indispensable in treating numerous human diseases. However, therapeutic proteins often suffer short serum half-life. In order to extend the serum half-life, a natural albumin ...ligand (a fatty acid) has been conjugated to small therapeutic peptides resulting in a prolonged serum half-life via binding to patients' serum albumin in vivo. However, fatty acid-conjugation has limited applicability due to lack of site-specificity resulting in the heterogeneity of conjugated proteins and a significant loss in pharmaceutical activity. In order to address these issues, we exploited the site-specific fatty acid-conjugation to a permissive site of a protein, using copper-catalyzed alkyne-azide cycloaddition, by linking a fatty acid derivative to p-ethynylphenylalanine incorporated into a protein using an engineered pair of yeast tRNA/aminoacyl tRNA synthetase. As a proof-of-concept, we show that single palmitic acid conjugated to superfolder green fluorescent protein (sfGFP) in a site-specific manner enhanced a protein's albumin-binding in vitro about 20 times and the serum half-life in vivo 5 times when compared to those of the unmodified sfGFP. Furthermore, the fatty acid conjugation did not cause a significant reduction in the fluorescence of sfGFP. Therefore, these results clearly indicate that the site-specific fatty acid-conjugation is a very promising strategy to prolong protein serum half-life in vivo without compromising its folded structure and activity.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Abstract
We explore the inboard-limited internal transport barrier (ITB) as an alternative advanced operation scenario for KSTAR. This paper presents in detail the progress of the ITB experiment at ...KSTAR. In an earlier study, the ITB formed in both ion and electron thermal channels, and an early neutral-beam injection (NBI) power of over 4 to 5 MW under a limited L-mode was crucial to ITB access. In the present study, we access the ITB experimentally with about 3 MW of NBI power by using the upper single null (USN), which is an unfavorable H-mode condition with a higher L–H power threshold. Finding an ITB access condition with a lower heating power should allow for a more efficient control of the heat flux and for maintaining stable plasma performance. The key control parameters of the experiment are the vertical position and the location of outboard striking point of the plasma. The shape-control attempts to divert the plasma to a vertically shifted USN with a marginal touch of the inboard limiter so that the plasma can remain in the L-mode at the boundary, while the striking-point control maintains the ITB performance for a longer period of time.
The rhesus monkey rhadinovirus (RRV), a γ2-herpesvirus of rhesus macaques, shares many biological features with the human pathogenic Kaposi's sarcoma-associated herpesvirus (KSHV). Both viruses, as ...well as the more distantly related Epstein-Barr virus, engage cellular receptors from the Eph family of receptor tyrosine kinases (Ephs). However, the importance of the Eph interaction for RRV entry varies between cell types suggesting the existence of Eph-independent entry pathways. We therefore aimed to identify additional cellular receptors for RRV by affinity enrichment and mass spectrometry. We identified an additional receptor family, the Plexin domain containing proteins 1 and 2 (Plxdc1/2) that bind the RRV gH/gL glycoprotein complex. Preincubation of RRV with soluble Plxdc2 decoy receptor reduced infection by ~60%, while overexpression of Plxdc1 and 2 dramatically enhanced RRV susceptibility and cell-cell fusion of otherwise marginally permissive Raji cells. While the Plxdc2 interaction is conserved between two RRV strains, 26-95 and 17577, Plxdc1 specifically interacts with RRV 26-95 gH. The Plxdc interaction is mediated by a short motif at the N-terminus of RRV gH that is partially conserved between isolate 26-95 and isolate 17577, but absent in KSHV gH. Mutation of this motif abrogated the interaction with Plxdc1/2 and reduced RRV infection in a cell type-specific manner. Taken together, our findings characterize Plxdc1/2 as novel interaction partners and entry receptors for RRV and support the concept of the N-terminal domain of the gammaherpesviral gH/gL complex as a multifunctional receptor-binding domain. Further, Plxdc1/2 usage defines an important biological difference between KSHV and RRV.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Enhanced biological phosphorus removal (EBPR) relies on diverse but specialized microbial communities to mediate the cycling and ultimate removal of phosphorus from municipal wastewaters. However, ...little is known about microbial activity and dynamics in relation to process fluctuations in EBPR ecosystems. Here, we monitored temporal changes in microbial community structure and potential activity across each bioreactor zone in a pilot‐scale EBPR treatment plant by examining the ratio of small subunit ribosomal RNA (SSU rRNA) to SSU rRNA gene (rDNA) over a 120 day study period. Although the majority of operational taxonomic units (OTUs) in the EBPR ecosystem were rare, many maintained high potential activities based on SSU rRNA : rDNA ratios, suggesting that rare OTUs contribute substantially to protein synthesis potential in EBPR ecosystems. Few significant differences in OTU abundance and activity were observed between bioreactor redox zones, although differences in temporal activity were observed among phylogenetically cohesive OTUs. Moreover, observed temporal activity patterns could not be explained by measured process parameters, suggesting that other ecological drivers, such as grazing or viral lysis, modulated community interactions. Taken together, these results point towards complex interactions selected for within the EBPR ecosystem and highlight a previously unrecognized functional potential among low abundance microorganisms in engineered ecosystems.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Abstract
Suppression or mitigation of edge-localized mode (ELM) crashes is necessary for ITER. The strategy to suppress all the ELM crashes by the resonant magnetic perturbation (RMP) should be ...applied as soon as the first low-to-high confinement (L–H) transition occurs. A control algorithm based on real-time machine learning (ML) enables such an approach: it classifies the H-mode transition and the ELMy phase in real-time and automatically applies the preemptive RMP. This paper reports the algorithm design, which is now implemented in the KSTAR plasma-control system, and the corresponding experimental demonstration of typical high-
δ
KSTAR H-mode plasmas. As a result, all initial ELM crashes are suppressed with an acceptable safety factor at the edge (
q
95
) and with RMP field adjustment. Moreover, the ML-driven ELM crash suppression discharges remain stable without further degradation due to the regularization of the plasma pedestal.
In recent years, many subcellular proteins have emerged as promising therapeutic targets in oncology. One crucial target is the epidermal growth factor receptor. Inhibition of this receptor has ...significantly improved the survival rate of patients for many cancers. However, oncogenic mutations such as B-RAFV600E have rendered tumours resistant to this therapeutic approach. Therefore, this mutation has emerged as a potential target for cancer therapy. Sorafenib is developed to overcome the B-RAFV600E mutation and restore the response of the mutated tumour to therapy. Here, we explore the efficacy and distribution of sorafenib at a cellular level using colon cancer cell lines with B-RAFV600E or K-RASG12V mutations. The Raman results detected significant sorafenib-induced spectral differences in both cell lines. In addition, the western blot and real-time cell analysis in vitro assays revealed that the ERK phosphorylation and the cellular proliferation of cells are inhibited, respectively, in the sorafenib-treated cells. Thus, the observed Raman spectral changes illustrate the potent effect of sorafenib on cells despite the presence of the B-RAFV600E or K-RASG12V mutations. These results are in agreement with the clinical studies, where patients with the B-RAFV600E mutation respond to sorafenib. Furthermore, the Raman spectral imaging results have shown the uptake and the distribution of sorafenib in colon cancer cells with the B-RAFV600E mutation through its label-free marker bands in the fingerprint region. The present results of sorafenib efficacy and distribution in cells demonstrate the potential of Raman micro-spectroscopy as the in vitro assay for the assessment of drugs, which is important in drug discovery.
We report results of a search for oscillations involving a light sterile neutrino over distances of 1.04 and 735 km in a ν_{μ}-dominated beam with a peak energy of 3 GeV. The data, from an exposure ...of 10.56×10^{20} protons on target, are analyzed using a phenomenological model with one sterile neutrino. We constrain the mixing parameters θ_{24} and Δm_{41}^{2} and set limits on parameters of the four-dimensional Pontecorvo-Maki-Nakagawa-Sakata matrix, |U_{μ4}|^{2} and |U_{τ4}|^{2}, under the assumption that mixing between ν_{e} and ν_{s} is negligible (|U_{e4}|^{2}=0). No evidence for ν_{μ}→ν_{s} transitions is found and we set a world-leading limit on θ_{24} for values of Δm_{41}^{2}≲1 eV^{2}.
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CMK, CTK, FMFMET, IJS, NUK, PNG, UM
Nuclear fusion is one of the most attractive alternatives to carbon-dependent energy sources1. Harnessing energy from nuclear fusion in a large reactor scale, however, still presents many scientific ...challenges despite the many years of research and steady advances in magnetic confinement approaches. State-of-the-art magnetic fusion devices cannot yet achieve a sustainable fusion performance, which requires a high temperature above 100 million kelvin and sufficient control of instabilities to ensure steady-state operation on the order oftens of seconds2,3. Here we report experiments at the Korea Superconducting Tokamak Advanced Research4 device producing a plasma fusion regime that satisfies most ofthe above requirements: thanks to abundant fast ions stabilizing the core plasma turbulence, we generate plasmas at a temperature of 100 million kelvin lasting up to 20 seconds without plasma edge instabilities or impurity accumulation. A low plasma density combined with a moderate input power for operation is key to establishing this regime by preserving a high fraction of fast ions. This regime is rarely subject to disruption and can be sustained reliably even without a sophisticated control, and thus represents a promising path towards commercial fusion reactors.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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