Myricetin improves endurance capacity and mitochondrial density by activating SIRT1 and PGC-1alpha

Robust mitochondrial respiration provides energy to support physical performance and physiological well-being, whereas mitochondrial malfunction is associated with various pathologies and reduced longevity. In the current study, we tested whether myricetin, a natural flavonol with diverse biological activities, may impact mitochondrial function and longevity. The mice were orally administered myricetin (50 mg/kg/day) for 3 weeks. Myricetin significantly potentiated aerobic capacity in mice, as evidenced by their increased running time and distance. The elevated mitochondrial function was associated with induction of genes for oxidative phosphorylation and mitochondrial biogenesis in metabolically active tissues. Importantly, myricetin treatment led to decreased PGC-1alpha acetylation through SIRT1 activation. Furthermore, myricetin significantly improved the healthspan and lifespan of wild-type, but not Sir-2.1-deficient, C. elegans. These results demonstrate that myricetin enhances mitochondrial activity, possibly by activating PGC-1alpha and SIRT1, to improve physical endurance, strongly suggesting myricetin as a mitochondria-activating agent

HARE: Explainable Hate Speech Detection with Step-by-Step Reasoning

With the proliferation of social media, accurate detection of hate speech has become critical to ensure safety online. To combat nuanced forms of hate speech, it is important to identify and thoroughly explain hate speech to help users understand its harmful effects. Recent benchmarks have attempted to tackle this issue by training generative models on free-text annotations of implications in hateful text. However, we find significant reasoning gaps in the existing annotations schemes, which may hinder the supervision of detection models. In this paper, we introduce a hate speech detection framework, HARE, which harnesses the reasoning capabilities of large language models (LLMs) to fill these gaps in explanations of hate speech, thus enabling effective supervision of detection models. Experiments on SBIC and Implicit Hate benchmarks show that our method, using model-generated data, consistently outperforms baselines, using existing free-text human annotations. Analysis demonstrates that our method enhances the explanation quality of trained models and improves generalization to unseen datasets. Our code is available at https://github.com/joonkeekim/hare-hate-speech.git.Comment: Findings of EMNLP 2023; The first three authors contribute equall

ReFine: Re-randomization before Fine-tuning for Cross-domain Few-shot Learning

Cross-domain few-shot learning (CD-FSL), where there are few target samples under extreme differences between source and target domains, has recently attracted huge attention. Recent studies on CD-FSL generally focus on transfer learning based approaches, where a neural network is pre-trained on popular labeled source domain datasets and then transferred to target domain data. Although the labeled datasets may provide suitable initial parameters for the target data, the domain difference between the source and target might hinder fine-tuning on the target domain. This paper proposes a simple yet powerful method that re-randomizes the parameters fitted on the source domain before adapting to the target data. The re-randomization resets source-specific parameters of the source pre-trained model and thus facilitates fine-tuning on the target domain, improving few-shot performance.Comment: CIKM 2022 Short; 5 pages, 3 figures, 4 table

Comparative Interactomes of VRK1 and VRK3 with Their Distinct Roles in the Cell Cycle of Liver Cancer

Vaccinia-related kinase 1 (VRK1) and VRK3 are members of the VRK family of serine/threonine kinases and are principally localized in the nucleus. Despite the crucial roles of VRK1/VRK3 in physiology and disease, the molecular and functional interactions of VRK1/VRK3 are poorly understood. Here, we identified over 200 unreported VRK1/VRK3-interacting candidate proteins by affinity purification and LC-MS/MS. The networks of VRK1 and VRK3 interactomes were found to be associated with important biological processes such as the cell cycle, DNA repair, chromatin assembly, and RNA processing. Interactions of interacting proteins with VRK1/VRK3 were confirmed by biochemical assays. We also found that phosphorylations of XRCC5 were regulated by both VRK1/VRK3, and that of CCNB1 was regulated by VRK3. In liver cancer cells and tissues, VRK1/VRK3 were highly upregulated and its depletion affected cell cycle progression in the different phases. VRK3 seemed to affect S phase progression and G2 or M phase entry and exit, whereas VRK1 affects G1/S transition in the liver cancer, which could be explained by different interacting candidate proteins. Thus, this study not only provides a resource for investigating the unidentified functions of VRK1/VRK3, but also an insight into the regulatory roles of VRK1/VRK3 in biological processes.11Ysciescopuskc

Development of Formation Flying CubeSats and Operation Systems for the CANYVAL-C Mission: Launch and Lessons Learned

The CubeSat Astronomy NASA and Yonsei using Virtual telescope ALignment for Coronagraph (CANYVAL-C) is a technology demonstration mission that shows the concept of a virtual space telescope using two CubeSats in formation flying. The final goal of the mission is to obtain several images of the solar corona during an artificial solar eclipse created by the two CubeSats, Timon (1U CubeSat) and Pumbaa (2U CubeSat). To implement this mission, two CubeSats in formation flying and a ground segment have been developed. The CubeSats were constructed mainly with commercial off the shelf components, sharing the bus architecture. The payload of each CubeSat is a visible camera and an occulter to block the light from the photosphere of the Sun. The occulter is composed of tape measures and a black-colored polyimide film; the system size is smaller than 0.5U (10 × 10 × 5 cm3) while it stowed and enlarged to 0.75 × 0.75 m2 after spreading the film. The 3D-printed propulsion system is smaller than 0.5U and facilitates accurate positioning maneuvers of Pumbaa. The on-board computer has multi-task processing capabilities and a space-saving configuration which is integrated with the GNSS receiver and the UHF transceiver. The core technology for the mission implementation is the precise formation flying guidance, navigation, and control system with a cold-gas propulsion system and an inter-satellite link system. The specification of each CubeSat system was evaluated using numerical simulations and ground testing. To operate CubeSats, the ground segment was constructed with some components, including the UHF ground station (UGS), flight dynamics system (FDS), mission analysis and planning system (MAPS), and spacecraft operation system (SOS). Each component works under the environment of an integrated graphic user interface. In particular, the UGS handles the RF communication, data storage, and instrument control for tracking CubeSats. The FDS processes the navigation data to precisely estimate absolute position and velocity. Then, the MAPS determines the allowable mission schedule and parameter set for implementing maneuvers of each CubeSat. Using the MAPS, feasibility of the mission operation canbe ensured through numerical simulations based on the solutions from the FDS. Finally, the SOS is the interface system between each component, processing telemetry and generating telecommand. The CubeSats were launched on March 22, 2021, by Soyuz-2.1a with a Fregat stage

xCT-Driven Expression of GPX4 Determines Sensitivity of Breast Cancer Cells to Ferroptosis Inducers

Inducers of ferroptosis such as the glutathione depleting agent Erastin and the GPX4 inhibitor Rsl-3 are being actively explored as potential therapeutics in various cancers, but the factors that determine their sensitivity are poorly understood. Here, we show that expression levels of both subunits of the cystine/glutamate antiporter xCT determine the expression of GPX4 in breast cancer, and that upregulation of the xCT/selenocysteine biosynthesis/GPX4 production axis paradoxically renders the cancer cells more sensitive to certain types of ferroptotic stimuli. We find that GPX4 is strongly upregulated in a subset of breast cancer tissues compared to matched normal samples, and that this is tightly correlated with the increased expression of the xCT subunits SLC7A11 and SLC3A2. Erastin depletes levels of the antioxidant selenoproteins GPX4 and GPX1 in breast cancer cells by inhibiting xCT-dependent extracellular reduction which is required for selenium uptake and selenocysteine biosynthesis. Unexpectedly, while breast cancer cells are resistant compared to nontransformed cells against oxidative stress inducing drugs, at the same time they are hypersensitive to lipid peroxidation and ferroptosis induced by Erastin or Rsl-3, indicating that they are \u27addicted\u27 to the xCT/GPX4 axis. Our findings provide a strategic basis for targeting the anti-ferroptotic machinery of breast cancer cells depending on their xCT status, which can be further explored

SIRT6 Depletion Suppresses Tumor Growth by Promoting Cellular Senescence Induced by DNA Damage in HCC

The role of Sirtuin 6 (SIRT6) as a tumor suppressor or oncogene in liver cancer remains controversial. Thus, we identified the specific role of SIRT6 in the progression of hepatocellular carcinoma (HCC). SIRT6 expression was significantly higher in HCC cell lines and HCC tissues from 138 patients than in an immortalized hepatocyte cell line, THLE-2 and non-tumor tissues, respectively. SIRT6 knockdown by shRNA suppressed the growth of HCC cells and inhibited HCC tumor growth in vivo. In addition, SIRT6 silencing significantly prevented the growth of HCC cell lines by inducing cellular senescence in the p16/Rb- and p53/p21-pathway independent manners. Microarray analysis revealed that the expression of genes involved in nucleosome assembly was apparently altered in SIRT6-depleted Hep3B cells. SIRT6 knockdown promoted G2/M phase arrest and downregulation of genes encoding histone variants associated with nucleosome assembly, which could be attributed to DNA damage. Taken together, our findings suggest that SIRT6 acts as a tumor promoter by preventing DNA damage and cellular senescence, indicating that SIRT6 represents a potential therapeutic target for the treatment of HCC.11137Ysciescopu

DISC1 Modulates Neuronal Stress Responses by Gate-Keeping ER-Mitochondria Ca2+ Transfer through the MAM

A wide range of Ca2+-mediated functions are enabled by the dynamic properties of Ca2+, all of which are dependent on the endoplasmic reticulum (ER) and mitochondria. Disrupted-in-schizophrenia 1 (DISC1) is a scaffold protein that is involved in the function of intracellular organelles and is linked to cognitive and emotional deficits. Here, we demonstrate that DISC1 localizes to the mitochondria-associated ER membrane (MAM). At the MAM, DISC1 interacts with IP3R1 and downregulates its ligand binding, modulating ER-mitochondria Ca2+ transfer through the MAM. The disrupted regulation of Ca2+ transfer caused by DISC1 dysfunction leads to abnormal Ca2+ accumulation in mitochondria following oxidative stress, which impairs mitochondrial functions. DISC1 dysfunction alters corticosterone-induced mitochondrial Ca2+ accumulation in an oxidative stress-dependent manner. Together, these findings link stress-associated neural stimuli with intracellular ER-mitochondria Ca2+ crosstalk via DISC1, providing mechanistic insight into how environmental risk factors can be interpreted by intracellular pathways under the control of genetic components in neurons.114sciescopu

Myricetin improves endurance capacity and mitochondrial density by activating SIRT1 and PGC-1α

1132Nsciescopu

Cancer Metabolism: Fueling More than Just Growth

The early landmark discoveries in cancer metabolism research have uncovered metabolic processes that support rapid proliferation, such as aerobic glycolysis (Warburg effect), glutaminolysis, and increased nucleotide biosynthesis. However, there are limitations to the effectiveness of specifically targeting the metabolic processes which support rapid proliferation. First, as other normal proliferative tissues also share similar metabolic features, they may also be affected by such treatments. Secondly, targeting proliferative metabolism may only target the highly proliferating bulk tumor cells and not the slower-growing, clinically relevant cancer stem cell subpopulations which may be required for an effective cure. An emerging body of research indicates that altered metabolism plays key roles in supporting proliferation-independent functions of cancer such as cell survival within the ischemic and acidic tumor microenvironment, immune system evasion, and maintenance of the cancer stem cell state. As these aspects of cancer cell metabolism are critical for tumor maintenance yet are less likely to be relevant in normal cells, they represent attractive targets for cancer therapy