A key factor for successful cancer immunotherapy (CIT) is the extent of antigen presentation by dendritic cells (DCs) that phagocytize tumor-associated antigens (TAA) in the tumor site and migrate to ...tumor draining lymph nodes (TDLN) for the activation of T cells. Although various types of adjuvant delivery have been studied to enhance the activity of the DCs, poor delivery efficiency and depleted population of tumor infiltrating DCs have limited the efficacy of CIT. Herein, we report a hypoxia-responsive mesoporous silica nanocarrier (denoted as CAGE) for an enhanced CIT assisted by photodynamic therapy (PDT). In this study, CAGE was designed as a hypoxia-responsive transforming carrier to improve the intracellular uptake of nanocarriers and the delivery of adjuvants to DCs. Furthermore, PDT was exploited for the generation of immunogenic debris and recruitment of DCs in a tumor site, followed by enhanced antigen presentation. Finally, a significant inhibition of tumor growth was observed in vivo, signifying that the PDT would be a promising solution for DC-based immunotherapy.
Human cytomegalovirus (HCMV) has evolved sophisticated immune evasion mechanisms that target both the innate and adaptive immune responses. However, how HCMV encoded proteins are involved in this ...immune escape is not clear. Here, we show that HCMV glycoprotein US9 inhibits the IFN-β response by targeting the mitochondrial antiviral-signaling protein (MAVS) and stimulator of interferon genes (STING)-mediated signaling pathways. US9 accumulation in mitochondria attenuates the mitochondrial membrane potential, leading to promotion of MAVS leakage from the mitochondria. Furthermore, US9 disrupts STING oligomerization and STING-TBK1 association through competitive interaction. Intriguingly, US9 blocks interferon regulatory factor 3 (IRF3) nuclear translocation and its cytoplasmic domain is essential for inhibiting IRF3 activation. Mutant HCMV lacking US7-16 is impaired in antagonism of MAVS/STING-mediated IFN-β expression, an effect that is reversible by the introduction of US9. Our findings indicate that HCMV US9 is an antagonist of IFN signaling to persistently evade host innate antiviral responses.
The mechanisms by which many human cytomegalovirus (HCMV)-encoded proteins help the virus to evade immune surveillance remain poorly understood. In particular, it is unknown whether HCMV proteins ...arrest Toll-like receptor (TLR) signaling pathways required for antiviral defense. Here, we report that US7 and US8 as key suppressors that bind both TLR3 and TLR4, facilitating their destabilization by distinct mechanisms. US7 exploits the ER-associated degradation components Derlin-1 and Sec61, promoting ubiquitination of TLR3 and TLR4. US8 not only disrupts the TLR3-UNC93B1 association but also targets TLR4 to the lysosome, resulting in rapid degradation of the TLR. Accordingly, a mutant HCMV lacking the US7-US16 region has an impaired ability to hinder TLR3 and TLR4 activation, and the impairment is reversed by the introduction of US7 or US8. Our findings reveal an inhibitory effect of HCMV on TLR signaling, which contributes to persistent avoidance of the host antiviral response to achieve viral latency.
The charge trapping characteristics of the high-k laminated traps with different thickness ratios were investigated in order to improve the distribution of threshold voltage and the charge loss ...problems in 3D NAND flash memories with TCAT structure. In this letter, the interfacial layers are formed between the HfO 2 /Al 2 O 3 laminated films, which increase trap sites and improve charge storage capability. In addition, due to the difference in bandgap between HfO 2 and Al 2 O 3 , the HfO 2 layer forms a deep quantum well and the Al 2 O 3 layer acts as a barrier to prevent the loss of electrons captured in the charge trapping layer. The barriers prevent trapped electrons from escaping to other layers. In other words, it reduces the loss of charges from the charge trapping layer to Si or gate electrode. Also, the number of interfaces and the ratio of appropriate laminate film thickness are important factors for obtaining good data retention characteristics. The experimental results show a higher charge storage density and a larger memory window of 11.5 V in the structure that has many interfaces and a 1/1 of HfO 2 /Al 2 O 3 thickness ratio. In this structure, the leakage current is 4.61<inline-formula> <tex-math notation="LaTeX">\times </tex-math></inline-formula> 10 −9 A/cm 2 and charge loss rate is 14.9%, which are the lowest values in tested structures. The proposed high-k laminated trap structure may be very useful in future 3D NAND flash memory device applications.
Autophagy is responsible for the bulk degradation of cytosolic constituents and plays an essential role in the intestinal epithelium by controlling beneficial host-bacterial relationships. Atg5 and ...Atg7 are thought to be critical for autophagy. However, Atg5- or Atg7-deficient cells still form autophagosomes and autolysosomes, and are capable of removing proteins or bacteria. Here, we report that human TRIM31 (tripartite motif), an intestine-specific protein localized in mitochondria, is essential for promoting lipopolysaccharide-induced Atg5/Atg7-independent autophagy. TRIM31 directly interacts with phosphatidylethanolamine in a palmitoylation-dependent manner, leading to induction of autolysosome formation. Depletion of endogenous TRIM31 significantly increases the number of intestinal epithelial cells containing invasive bacteria. Crohn's disease patients display TRIM31 downregulation. Human cytomegalovirus-infected intestinal cells show a decrease in TRIM31 expression as well as a significant increase in bacterial load, reversible by the introduction of wild-type TRIM31. We provide insight into an alternative autophagy pathway that protects against intestinal pathogenic bacterial infection.
The cortical actin cytoskeleton plays a critical role in maintaining intestinal epithelial integrity, and the loss of this architecture leads to chronic inflammation, as seen in inflammatory bowel ...disease (IBD). However, the exact mechanisms underlying aberrant actin remodeling in pathological states remain largely unknown. Here, we show that a subset of patients with IBD exhibits substantially higher levels of tripartite motif-containing protein 40 (TRIM40), a gene that is hardly detectable in healthy individuals. TRIM40 is an E3 ligase that directly targets Rho-associated coiled-coil-containing protein kinase 1 (ROCK1), an essential kinase involved in promoting cell-cell junctions, markedly decreasing the phosphorylation of key signaling factors critical for cortical actin formation and stabilization. This causes failure of the epithelial barrier function, thereby promoting a long-lived inflammatory response. A mutant TRIM40 lacking the RING, B-box, or C-terminal domains has impaired ability to accelerate ROCK1 degradation-driven cortical actin disruption. Accordingly, Trim40-deficient male mice are highly resistant to dextran sulfate sodium (DSS)-induced colitis. Our findings highlight that aberrant upregulation of TRIM40, which is epigenetically silenced under healthy conditions, drives IBD by subverting cortical actin formation and exacerbating epithelial barrier dysfunction.
Eosinophils play proinflammatory roles in helminth infections and allergic diseases. Under steady-state conditions, eosinophils are abundantly found in the small intestinal lamina propria, but their ...physiological function is largely unexplored. In this study, we found that small intestinal eosinophils down-regulate Th17 cells. Th17 cells in the small intestine were markedly increased in the ΔdblGATA-1 mice lacking eosinophils, and an inverse correlation was observed between the number of eosinophils and that of Th17 cells in the small intestine of wild-type mice. In addition, small intestinal eosinophils suppressed the in vitro differentiation of Th17 cells, as well as IL-17 production by small intestinal CD4(+)T cells. Unlike other small intestinal immune cells or circulating eosinophils, we found that small intestinal eosinophils have a unique ability to constitutively secrete high levels of IL-1 receptor antagonist (IL-1Ra), a natural inhibitor of IL-1β. Moreover, small intestinal eosinophils isolated from IL-1Ra-deficient mice failed to suppress Th17 cells. Collectively, our results demonstrate that small intestinal eosinophils play a pivotal role in the maintenance of intestinal homeostasis by regulating Th17 cells via production of IL-1Ra.
Many efficient catalytic methods for the introduction of trifluoromethyl group (CF3) have been reported. Among them, the addition of CF3 and other components to alkenes is well known, and many ...components such as azides, cyanides, amines, and halides have been inserted into alkenes with CF3. However, to date the double catalytic insertion of CF3 into an alkene is unknown. Herein, we report the catalytic 1,2‐bistrifluoromethylations of alkenes catalyzed by Copper (Cu). We used two CF3 sources, namely Umemoto's reagent and (trifluoromethyl)trimethylsilane (TMSCF3). Each reagent plays a unique role during this transformation; Umemoto's reagent generates CF3 radicals, while TMSCF3 is used to form CF3 anions. Copper (I) bromide (CuBr) exhibited the best catalytic activity for this reaction. We believe that CuBr oxidizes the alkyl radical, which is produced by the addition of the CF3 radical to the alkene, to the corresponding alkyl cation, which then reacts with the CF3 anion from TMSCF3 to produce the desired product. This reaction tolerates a diverse set of substrates bearing functional groups such as amides, esters, ethers, ketones, protected amines, tertiary amines, and phthalimides; hence this transformation is widely applicable to a wide variety of substrates.
Abstract
Inflammatory cytokines are key signaling molecules that can promote an immune response, thus their RNA turnover must be tightly controlled during infection. Most studies investigate the RNA ...decay pathways in the cytosol or nucleoplasm but never focused on the nucleolus. Although this organelle has well-studied roles in ribosome biogenesis and cellular stress sensing, the mechanism of RNA decay within the nucleolus is not completely understood. Here, we report that the nucleolus is an essential site of inflammatory pre-mRNA instability during infection. RNA-sequencing analysis reveals that not only do inflammatory genes have higher intronic read densities compared with non-inflammatory genes, but their pre-mRNAs are highly enriched in nucleoli during infection. Notably, nucleolin (NCL) acts as a guide factor for recruiting cytosine or uracil (C/U)-rich sequence-containing inflammatory pre-mRNAs and the Rrp6-exosome complex to the nucleolus through a physical interaction, thereby enabling targeted RNA delivery to Rrp6-exosomes and subsequent degradation. Consequently,
Ncl
depletion causes aberrant hyperinflammation, resulting in a severe lethality in response to LPS. Importantly, the dynamics of NCL post-translational modifications determine its functional activity in phases of LPS. This process represents a nucleolus-dependent pathway for maintaining inflammatory gene expression integrity and immunological homeostasis during infection.
In 2019, an outbreak of Spodoptera frugiperda (Smith) was first reported in Korea. This study aimed to determine the growth rate and feeding amount of S. frugiperda by temperature to establish the ...right time window for its control and management. Linear regression analysis was used to determine the growth period and thermal requirements of S. frugiperda. The longest growth period of 97.2 ± 1.2 days was observed at 16 °C, and the shortest growth period of 15.5 ± 0.7 days was observed at 36 °C. In terms of each growth stage, the pupal period was the longest at all temperatures, followed by the egg period. The maximum corn leaf feeding amount (6.61 g) was observed for the larvae grown at 16 °C, and the minimum (2.9 g) was observed at 36 °C. However, the daily feeding amount of S. frugiperda larvae was the highest at 28 °C and 32 °C. The hatching rate according to temperature exceeded 70% at 24 °C, 28 °C, and 32 °C, and the survival rate of larvae and pupae was 100% at 24 °C to 32 °C. Based on these results, a temperature range of 28 °C to 32 °C is proposed as the optimum temperature for the growth of S. frugiperda.
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