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ABSTRACT Cullin-1 (Cul1), a cullin–RING ubiquitin ligase component, represses c-MYC activity in the nucleus. Orientia tsutsugamushi causes the potentially fatal rickettsiosis, scrub typhus. The obligate intracellular bacterium encodes an arsenal of ankyrin repeat-containing effectors (Anks), many of which carry a eukaryotic-like F-box motif that binds Cul1. O. tsutsugamushi reduces Cul1 levels in the nucleus. This phenomenon is not due to an alteration in Cul1 neddylation but is bacterial burden- and protein synthesis-dependent. Five of the 11 Anks capable of binding Cul1 (Ank1, Ank5, Ank6, Ank9, Ank17) sequester it in the cytoplasm when each is ectopically expressed. Ank1 and Ank6 proteins with alanine substitutions in their F-boxes that render them unable to bind Cul1 cannot exclude Cul1 from the nucleus. Coincident with the reduction of Cul1 in the nuclei of Orientia -infected cells, c-MYC nuclear levels are elevated, and Cul1 target genes are differentially expressed. Several of these genes regulate apoptosis. The resistance of O. tsutsugamushi -infected cells to staurosporine-induced apoptosis is recapitulated in uninfected cells expressing Ank1 or Ank6 but not alanine-substituted versions thereof that cannot bind Cul1. Other F-box-containing Anks that cannot bind or exclude Cul1 from the nucleus also fail to confer resistance to apoptosis. Overall, O. tsutsugamushi modulates the Cul1:c-MYC intranuclear balance as an anti-apoptotic strategy that is functionally linked to a subset of its F-box-containing Anks.

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ABSTRACTTo gain insight into biological mechanisms that cause resistance to DNA damage, we performed parallel pooled genetic CRISPR-Cas9 screening for survival in high risk HNSCC subtypes. Surprisingly, and in addition to ATM, DNAPK, and NFKB signaling, JAK1 was identified as a driver of tumor cell radiosensitivity. Knockout of JAK1 in HNSCC increases cell survival by enhancing the DNA damage-induced G2 arrest, and both knockout and JAK1 inhibition with abrocitinib prevent subsequent formation of radiation-induced micronuclei. Loss of JAK1 function does not affect canonical CDK1 signaling but does reduce activation of PLK1 and AURKA, kinases that regulate both G2 and M phase progression. Correspondingly, JAK1 KO was found to cause mitotic defects using both EdU labeling and live cell imaging techniques. Given this insight, we evaluated Kif18a inhibition as an approach to exacerbate mitotic stress and enhance the efficacy of radiation. These studies establish Kif18a inhibition as a novel strategy to counteract therapeutic resistance to DNA damage mediated by G2 cell cycle arrest.

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Honey bees extract sticky material from the exudates of different plants which transform afterwards to propolis. Propolis from several global locations has been shown to contain a wide variety of polyphenolic chemicals. Recent studies have revealed that propolis possesses antioxidant, anti-inflammatory, and immunomodulatory abilities. In laboratory animal studies, it has been demonstrated that propolis can enhance the functioning of the antioxidant defense system and decrease the activity of nuclear factor-kappa B. As a result, they can effectively alleviate the damage caused by exercise. One of the main flavonoids found in propolis, quercetin, has been demonstrated to enhance muscle mitochondrial biogenesis and exercise capacity. Propolis may aid athletes in preventing oxidative and inflammatory damage to their muscles during exercise and enhance their athletic performance. The goal of the current review was to evaluate how propolis consumption affected the molecular signaling associated with antioxidant/oxidant state, pro/anti-inflammatory cytokines, and anaerobic/aerobic endurance.

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This paper discusses the TM020 mode Higher-order Mode (HOM) damped cavity, which has a higher quality factor and lower characteristic impedance than the conventional TM010 mode. The unique electromagnetic field (EMF) distribution of the TM020 mode allows for an absorber to be placed at the magnetic field wave node, protecting the working mode while suppressing the HOMs. However, the introduction of high power input couplers and other structures can cause an asymmetrical EMF distribution, leading to operating mode leakage.To address this, EMF compensation methods are applied to the high power input coupler to achieve symmetrical EMF distribution, reducing operating mode loss. Overcoupling of the high power input coupler and the resonant cavity can significantly affect local EMF distribution, causing TM020 mode asymmetry. A tab structure at the coupler port are used to compensate for coupler-induced perturbations, attenuating EMF leakage.The paper proposes electromagnetic compensation structure schemes to mitigate working mode EMF leakage. The reliability of the scheme is demonstrated by the analysis of radiofrequency performance and other aspects through simulation software

• Book : 57(3)
• Pub. Date : 2025
• Page : pp.1-6
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Cold new early dark energy (cold NEDE) addresses the Hubble tension through a triggered vacuum phase transition in the dark sector. In this paper, we constrain a phenomenological fluid model using recent cosmic microwave background likelihoods based on Planck NPIPE data alongside baryonic acoustic oscillations (BAO) and supernovae data from Pantheon+. Exploiting the enhanced constraining power of the datasets, we introduce and study an extended version of the NEDE fluid model in which the equation of state parameter wNEDE, characterizing the fluid after the phase transition, is allowed to evolve with nonvanishing derivatives dwNEDE/dlna and d2wNEDE/d(lna)2. Our results indicate that data is compatible with a rather simple time dependence that could arise from a mixture of radiation and a stiff fluid. With the updated datasets, the base and extended models still show a significant reduction of the difference of the maximum tension from 6.3σ in ΛCDM down to 3.5σ with a small simultaneous reduction of the S8 tension, slightly improving over recent findings for the axionlike early dark energy model. Finally, we also provide a first test of the model against new BAO data from the dark energy spectroscopic instrument survey. Replacing the previous BAO constraints in our analysis with the new ones, the tension is further reduced to 2.6σ, reaffirming the cold NEDE model as a promising solution to the Hubble tension. Published by the American Physical Society 2025

• Book : 111(4)
• Pub. Date : 2025
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