<div>Abstract<p>Nuclear receptor coactivator 2 (Ncoa2) is a member of the Ncoa family of coactivators, and we previously showed that Ncoa2 regulates the differentiation of induced regulatory T cells. However, it remains unknown if Ncoa2 plays a role in CD8<sup>+</sup> T-cell function. Here, we show that Ncoa2 promotes CD8<sup>+</sup> T cell–mediated immune responses against tumors by stimulating T-cell activation via upregulating PGC-1α expression to enhance mitochondrial function. Mice deficient in <i>Ncoa2</i> in T cells (<i>Ncoa2<sup>fl/fl</sup>/CD4<sup>Cre</sup></i>) displayed defective immune responses against implanted MC38 tumors, which associated with significantly reduced tumor-infiltrating CD8<sup>+</sup> T cells and decreased IFNγ production. Consistently, CD8<sup>+</sup> T cells from <i>Ncoa2<sup>fl/fl</sup>/CD4<sup>Cre</sup></i> mice failed to reject tumors after adoptive transfer into <i>Rag1<sup>−/−</sup></i> mice. Further, in response to TCR stimulation, <i>Ncoa2<sup>fl/fl</sup>/CD4<sup>Cre</sup></i> CD8<sup>+</sup> T cells failed to increase mitochondrial mass, showed impaired oxidative phosphorylation, and had lower expression of PGC-1α, a master regulator of mitochondrial biogenesis and function. Mechanically, T-cell activation–induced phosphorylation of CREB triggered the recruitment of Ncoa2 to bind to enhancers, thus, stimulating PGC-1α expression. Forced expression of PGC-1α in <i>Ncoa2<sup>fl/fl</sup>/CD4<sup>Cre</sup></i> CD8<sup>+</sup> T cells restored mitochondrial function, T-cell activation, IFNγ production, and antitumor immunity. This work informs the development of Ncoa2-based therapies that modulate CD8<sup>+</sup> T cell–mediated antitumor immune responses.</p></div>
The typical optical camera communication (OCC) modulation scheme is based on binary intensity modulation. To increase the transmission data rate, multi-level modulation format is highly desirable. In this work, we bring forward and demonstrate a rolling shutter 4-level pulse amplitude modulation (PAM4) demodulation scheme for OCC systems using pixel-per-symbol labeling neural network (PPSL-NN) for the first time up to the authors’ knowledge. A bit-rate distance product of 28.8 kbit/s • m per color is achieved. The proposed scheme is to calculate and re-sample the pixel-per-symbol (PPS) to make sure the same number of pixels in each PAM4 symbol is corresponding to a label for the neural network. Experiment results reveal that the proposed scheme can efficiently demodulate high speed PAM4 signal in the rolling shutter OCC pattern.
Native soy protein isolate (N-SPI) has a low denaturation point and low solubility, limiting its industrial application. The influence of different industrial modification methods (heat (H), alkaline (A), glycosylation (G), and oxidation (O)) on the structure of SPI, the properties of the gel, and the gel properties of soy protein isolate (SPI) in myofibril protein (MP) was evaluated. The study found that four industrial modifications did not influence the subunit composition of SPI. However, the four industrial modifications altered SPI's secondary structure and disulfide bond conformation content. A-SPI exhibits the highest surface hydrophobicity and I850/830 ratio but the lowest thermal stability. G-SPI exhibits the highest disulfide bond content and the best gel properties. Compared with MP gel, the addition of H-SPI, A-SPI, G-SPI, and O-SPI components significantly improved the properties of the gel. Additionally, MP-ASPI gel exhibits the best properties and microstructure. Overall, the four industrial modification effects may impact SPI's structure and gel properties in different ways. A-SPI could be a potential functionality-enhanced soy protein ingredient in comminuted meat products. The present study results will provide a theoretical basis for the industrialized production of SPI.
A cavitation jet can enhance food proteins' functionalities by regulating solvable oxidized soybean protein accumulates (SOSPI). We investigated the impacts of cavitation jet treatment on the emulsifying, structural and interfacial features of soluble soybean protein oxidation accumulate. Findings have shown that radicals in an oxidative environment not only induce proteins to form insoluble oxidative aggregates with a large particle size and high molecular weight, but also attack the protein side chains to form soluble small molecular weight protein aggregates. Emulsion prepared by SOSPI shows worse interface properties than OSPI. A cavitation jet at a short treating time (<6 min) has been shown to break the core aggregation skeleton of soybean protein insoluble aggregates, and insoluble aggregates into soluble aggregates resulting in an increase of emulsion activity (EAI) and constancy (ESI), and a decrease of interfacial tension from 25.15 to 20.19 mN/m. However, a cavitation jet at a long treating time (>6 min) would cause soluble oxidized aggregates to reaggregate through an anti-parallel intermolecular β-sheet, which resulted in lower EAI and ESI, and a higher interfacial tension (22.44 mN/m). The results showed that suitable cavitation jet treatment could adjust the structural and functional features of SOSPI by targeted regulated transformation between the soluble and insoluble components.
Massive GGGGCC (G4C2) repeat expansion in C9orf72 and the resulting loss of C9orf72 function are the key features of ~50% of inherited amyotrophic lateral sclerosis and frontotemporal dementia cases. However, the biological function of C9orf72 remains unclear. We previously found that C9orf72 can form a stable GTPase activating protein (GAP) complex with SMCR8 (Smith-Magenis chromosome region 8). Herein, we report that the C9orf72–SMCR8 complex is a major negative regulator of primary ciliogenesis, abnormalities in which lead to ciliopathies. Mechanistically, the C9orf72–SMCR8 complex suppresses the primary cilium as a RAB8A GAP. Moreover, based on biochemical analysis, we found that C9orf72 is the RAB8A binding subunit and that SMCR8 is the GAP subunit in the complex. We further found that the C9orf72–SMCR8 complex suppressed the primary cilium in multiple tissues from mice, including but not limited to the brain, kidney, and spleen. Importantly, cells with C9orf72 or SMCR8 knocked out were more sensitive to hedgehog signaling. These results reveal the unexpected impact of C9orf72 on primary ciliogenesis and elucidate the pathogenesis of diseases caused by the loss of C9orf72 function.
Here, we propose and demonstrate a performance degradation mitigation scheme in TV backlight and smart-phone-based visible light communication (VLC) system when the display content in the light-panel is dynamically changing. In order to evaluate the influence of the dynamic display contents to the VLC performance, we use a noise-ratio (NR) and noise-ratio standard deviation (NRSD) as the figure-of-merits for the bright-and-dark contrast of the display content; and the dispersal of the changing display content regarding the bright-and-dark contrast respectively. Performances of 4 dynamic display contents with different combinations of NR and NRSD are analyzed. They are: low NR and low NRSD (NR = 36.69%; NRSD = 0.0226); low NR and high NRSD (NR = 30.09%; NRSD = 0.2698); high NR and low NRSD (NR = 81.66%; NRSD = 0.0052); high NR and high NRSD (NR = 73.91%; and NRSD = 0.2717). The proposed scheme can work well; that is, even the transmission distance is up to 200 cm in both smart-phones. If the proposed scheme is not used, then high success rate can be observed only at the low NR and low NRSD display content when the transmission distance is < 100 cm.
The arginine dependency of cancer cells creates metabolic vulnerability. In this study, we examine the impact of arginine availability on DNA replication and genotoxicity resistance. Using DNA combing assays, we find that limiting extracellular arginine results in the arrest of cancer cells at S phase and a slowing or stalling of DNA replication. The translation of new histone H4 is arginine dependent and influences DNA replication. Increased proliferating cell nuclear antigen (PCNA) occupancy and helicase-like transcription factor (HLTF)-catalyzed PCNA K63-linked polyubiquitination protect arginine-starved cells from DNA damage. Arginine-deprived cancer cells display tolerance to genotoxicity in a PCNA K63-linked polyubiquitination-dependent manner. Our findings highlight the crucial role of extracellular arginine in nutrient-regulated DNA replication and provide potential avenues for the development of cancer treatments.
Abstract Redox balance is the critical liaison for cancer homeostasis. Moderate increases in reactive oxygen species (ROS) levels can lead to cancer formation and progression. However, a disproportional increase of ROS levels changes equilibrium in cell redox status and leads to cancer cell death. Therefore, exogenous agents or antioxidant inhibitors which augment ROS generation become a potential new way to target cancer cells. We have found excessive accumulation of cellular proteins during arginine starvation causes stresses on the endoplasmic reticulum (ER) protein folding machinery resulting in elevated ROS levels. In this study, we continue to examine that arginine starvation-attenuated heme oxygenase-1 (HO-1) translation exacerbates the high ROS level to kill the cancer cells. In addition, HO-1 translational downregulation is due to arginine starvation-induced O-GlcNAcylation of eIF2α at S219, T239, and T241 residues. Loss of O-GlcNAcylation at eIF2α significantly rescues arginine starvation-reduced HO-1 protein level, resulting in better recovery and migratory properties from starvation and lower ROS level. In addition, arginine starvation-induced O-GlcNAcylation of eIF2α to suppress HO-1 translation is independent of its phosphorylation at S51, which is another stress-stimuli modification that regulates eIF2 involved protein translation. Arginine starvation exploits O-GlcNAcylation to antagonize eIF2α phosphorylation-induced HO-1 expression. Taken together, arginine starvation is a potential anti-cancer therapy in which induced eIF2α O-GlcNAcylation presents itself as a critical role for metabolic adaptation and tumor growth by dysregulating the antioxidant protein in cancer cells. Citation Format: Yu-Wen Hung, Yi-Chang Wang, David K. Ann. eIF2α O-GlcNAcylation promotes oxidative stress in arginine-starved triple-negative breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5809.
Abstract We have previously demonstrated that USP24 is involved in cancer progression. Here, we found that USP24 expression is upregulated in M2 macrophages and lung cancer cells. Conditioned medium from USP24-knockdown M2 macrophages decreases the migratory and chemotactic activity of lung cancer cells and the angiogenic properties of human microvascular endothelial cell 1 (HMEC-1). IL-6 expression is significantly decreased in USP24-knockdown M2 macrophages and lung cancer cells, and IL-6-replenished conditioned medium restores the migratory, chemotactic and angiogenetic properties of the cells. USP24 stabilizes p300 and β-TrCP to increase the levels of histone-3 acetylation and NF-κB, and decreases the levels of DNMT1 and IκB, thereby increasing IL-6 transcription in M2 macrophages and lung cancer cells, results in cancer malignancy finally. IL-6 has previously been a target for cancer drug development. Here, we provide direct evidence to support that USP24 promotes IL-6 expression, which might be beneficial for cancer therapy.
Sphingolipids are ubiquitous components of membranes and function as bioactive lipid signaling molecules. Here, through genetic screening and lipidomics analyses, we find that the endoplasmic reticulum (ER) calcium channel Csg2 integrates sphingolipid metabolism with autophagy by regulating ER calcium homeostasis in the yeast Saccharomyces cerevisiae. Csg2 functions as a calcium release channel and maintains calcium homeostasis in the ER, which enables normal functioning of the essential sphingolipid synthase Aur1. Under starvation conditions, deletion of Csg2 causes increases in calcium levels in the ER and then disturbs Aur1 stability, leading to accumulation of the bioactive sphingolipid phytosphingosine, which specifically and completely blocks autophagy and induces loss of starvation resistance in cells. Our findings indicate that calcium homeostasis in the ER mediated by the channel Csg2 translates sphingolipid metabolism into autophagy regulation, further supporting the role of the ER as a signaling hub for calcium homeostasis, sphingolipid metabolism and autophagy.
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