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2025
- Book : ()
- Pub. Date : 2025
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2025
Non-centrosomal microtubule-organizing centers (ncMTOCs) are important for the function of differentiated cells. Yet, ncMTOCs are poorly understood. Previously, several components of the nuclear envelope (NE)-MTOC have been identified. However, the temporal localization of MTOC proteins and Golgi to the NE and factors controlling the switch from a centrosomal MTOC to a ncMTOC remain elusive. Here, we utilized the in vitro differentiation of C2C12 mouse myoblasts as a model system to study NE-MTOC formation. We find based on longitudinal co-immunofluorescence staining analyses that MTOC proteins are recruited in a sequential and gradual manner to the NE. AKAP9 localizes with the Golgi to the NE after the recruitment of MTOC proteins. Moreover, siRNA-mediated depletion experiments revealed that Mbnl2 is required for proper NE-MTOC formation by regulating the expression levels of AKAP6β. Finally, Mbnl2 depletion affects Pcnt isoform expression. Taken together, our results shed light on how mammals post-transcriptionally control the switch from a centrosomal MTOC to an NE-MTOC and identify Mbnl2 as a novel modulator of ncMTOCs in skeletal muscle cells.- Book : 14(4)
- Pub. Date : 2025
- Page : pp.237-237
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2025
- Book : ()
- Pub. Date : 2025
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2025
The ligand-binding domain (LBD) of the human nuclear receptor pregnane X receptor (PXR) is known to crystallize in two different crystal forms, P212121 or P43212, depending on the construct and the strategy used for protein production, as well as the presence or absence of the coactivator-derived peptide SRC-1. In order to facilitate biophysical and structural studies, a versatile construct was designed that allows access to both forms. This was achieved by introducing a thrombin cleavage site between the PXRLBD and the SRC-1 peptide fused to its C-terminus. Here, we describe the expression, purification and crystallization processes of this novel construct and report two new structures of PXRLBD that were obtained thanks to this strategy.- Book : 81(3)
- Pub. Date : 2025
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2025
Abstract
The dysregulation of YAP activity is implicated in abnormal organ size and the pathogenesis of diverse diseases, including cancer. However, the functional regulation of YAP activity by lncRNA-encoded peptides remains elusive. In this study, we report the identification of a small protein (93 aa) encoded by the lncRNA LINC01315. This small protein, termed YAPer-ORF, preferentially interacted with GNAQ/11 mutants to augment YAP activity. Mechanistically, YAPer-ORF was located in the nucleus and competed with YAP to bind the nuclear kinase PRP4K to hinder YAP phosphorylation. This decreased phosphorylation of YAP by YAPer-ORF promoted YAP retention in the nucleus and facilitated the expression of downstream target genes such as CCND1. In both cancerous and noncancerous models, YAPer-ORF prominently drove cell proliferation in a CCND1-dependent manner. Notably, cardiac-specific genetic knock-in of the human YAPer-ORF in mice significantly increased heart size through increased cardiomyocyte proliferation, underscoring the role of YAPer-ORF in cell proliferation. Moreover, treatment with an anti-YAPer-ORF neutralizing antibody effectively suppressed uveal melanoma growth, highlighting the therapeutic potential of targeting YAPer-ORF. These findings collectively establish YAPer-ORF as a critical regulator of YAP activity, further highlighting the disruption of YAPer-ORF activity as a potential therapeutic strategy against YAP-driven human cancers and developmental diseases.- Book : ()
- Pub. Date : 2025
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2025
- Book : 23(1)
- Pub. Date : 2025
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2025
Abstract
Electron cyclotron resonance heating (ECRH) staircase discharges in strongly shaped plasmas were performed at the full-tungsten ASDEX Upgrade tokamak to investigate the enhanced Dα (EDA) H-mode, a high-confinement regime without edge localized modes (ELMs) that exhibits numerous desirable qualities for future reactors. Heating power, fueling, and plasma current scans reveal rich dynamics as the plasma traverses different confinement regimes. The L-H transition typically occurs with a brief I-phase, sometimes followed by a short nonstationary ELM-free H-mode, before the quasi-coherent mode (QCM) sets in, marking the start of the EDA H-mode. After the pedestal fully develops, the plasma remains stationary until the heating power is raised above a certain threshold, causing ELMs. A novel criterion based on the normality of the divertor shunt current distribution is introduced to identify phases with ELMs, showing general applicability under a wide range of discharges and conditions. The no-ELM power boundary is found to increase with fueling, and too little deuterium gas puff results in a pathological nonstationary ELM-free H-mode without the QCM. Empirical scalings are derived for core, pedestal, and global parameters in EDA H-mode. These show, for example, that pedestal electron pressure increases sublinearly with power and almost quadratically with current. Line-averaged density is approximately proportional to plasma current but very weakly affected by power and fueling, whereas energy confinement time decreases sublinearly with power and increases supralinearly with current. The EDA H-mode achieves several reactor-relevant dimensionless parameters, most notably high Greenwald fraction and confinement enhancement factor over the entire heating power range. This dataset constitutes a versatile resource to plan EDA experiments in present and upcoming devices, also serving as a testbed for validating physics-based theories and models of the regime. Overall, the EDA H-mode remains promising and could become an important no-ELM scenario in future reactors such as SPARC and the full-tungsten ITER.- Book : ()
- Pub. Date : 2025
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2025
The concept of thyroid status is much broader than assessing the levels of thyroid stimulating hormone, free and bound thyroid hormones in the systemic circulation. It includes features of transport, tissue bioavailability, receptor interaction, metabolism, biomolecular mechanisms of action and inactivation, as well as the physiological or pathophysiological basis of changes in function and the pathomorphological substrate of diseases, including malignancies. Therefore, the question of the mechanisms through which thyroid status influences the processes of tumor initiation and promotion in the gastrointestinal tract is extremely relevant. Regarding colorectal cancer, an ambiguous link between thyroid status has been identified – in some studies, an increase in free T4 concentration and thyrotoxicosis are associated with a decreased risk of developing colon cancer, while in others, the administration of levothyroxine in hypothyroidism had a protective effect. The risk of gastric cancer is elevated in men living in regions with suboptimal or above-normal iodine consumption and suffering from various thyroid pathologies. This paper analyzes modern ideas about pathogenetic relationship between gastric and colon cancer and patients' thyroid status. It presents physiological and biochemical basics of thyroid status formation. Deiodinase expression profile in gastric and colon cancer is stated. The problem of iodine-induced disthyroidoses following radiation procedures using iodine-containing contrasts is described in detail.- Book : 26(4)
- Pub. Date : 2025
- Page : pp.478-483
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2025
- Book : ()
- Pub. Date : 2025
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2025
In this study, we employed the M-truncated fractional singular manifold
meth?od to analytically address the (2+1)-dimensional M-truncated fractional
Burgers equation. This approach involves reformulating the original
fractional differen?tial equation into a more tractable form through the
introduction of a singular manifold. This transformation simplifies the
problem and often leads to analytical solutions. We derive a general
solution expressed in terms of arbitrary functions, which enables us to
accommodate variations in system parameters or initial condi?tions. This
results in a versatile expression that captures a broad spectrum of
pos?sible solutions, providing a framework for analyzing the dynamics of
kink waves in the relevant fractional differential models. We also construct
multiple kink wave solutions, offering analytical representations of kink
wave behavior within these models. Notably, our findings revert to
well-established results when the fractional order is set to one, thereby
affirming the consistency of this method with existing theories and
validating our approach.- Book : 29(1 Part A)
- Pub. Date : 2025
- Page : pp.337-345
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