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Aberrant alternative splicing (AS) events have been identified in a variety of cancers. Although somatic mutations of splicing factors and dysregulation of RNA-binding proteins (RBPs) have been linked to AS and tumor malignancy, it remains unclear how upstream mechanisms contribute to cancer development via alternative gene splicing. In this issue of the JCI, Wenrui Zhang and colleagues identified the role of asparagine endopeptidase (AEP), an intracellular cysteine endopeptidase, in promoting solid tumor-associated RNA splicing. The authors demonstrated that tumor environmental factors such as oxygen and nutrient deprivation induce the activity of AEP in a HIFIA-dependent manner. The activated AEP, in turn, cleaves an RNA helicase DDX3X to promote its nuclear retention. The authors further showed that this DDX3X nuclear fraction engages with splicing machinery to induce AS events in several cancer cells. These findings suggest that targeting an AEP-dependent aberrant RNA splicing cascade may facilitate therapeutics for solid tumors., Aberrant RNA splicing in cancers Alternative splicing (AS) is a critical cellular process that contributes to the encoding capacity of transcriptomes of eukaryotic cells (1). Recently, high-throughput sequencing and genome-wide [...]

The Qinghai–Tibet Plateau (QTP) is the highest altitude plateau in the world, characterized by strong solar radiation and large diurnal temperature differences and so on, which brings a great negative impact on the temperature and thermal stress field of asphalt pavement. The purpose of this study is to analyze the temperature field and thermal stress status of asphalt pavement in the QTP to provide a reference for pavement design and maintenance in high-altitude areas. The finite element method was applied to establish the temperature field model to study the distribution and variation of pavement temperature. On this basis, the influence of cooling amplitude on pavement thermal stress was studied during cold waves. In addition to this, the key internal factors affecting the thermal stress of pavement, such as surface thickness, surface temperature shrinkage coefficient, surface modulus, and base modulus, were analyzed by an orthogonal test. It was found that temperature and solar radiation have a significant effect on the pavement temperature field. When the cold wave came, the cooling rate had a considerable impact on the thermal stress of the pavement, that is, every 5 °C increase in cooling rate would increase the thermal stress by more than 50%. The temperature shrinkage coefficient and surface modulus of the surface layer material had the greatest influence on the pavement thermal stress. The thermal stress could be reduced by more than 0.4 Mpa for every 5 × 10−6/°C reduction in the surface temperature shrinkage coefficient or every 1000 Mpa reduction in the surface modulus. This study can provide a reference for improving the temperature field and thermal stress field of asphalt pavement in the plateau area. [ABSTRACT FROM AUTHOR]

Although Western diet and dysbiosis are the most prominent environmental factors associated with inflammatory bowel diseases (IBDs), the corresponding host factors and cellular mechanisms remain poorly defined. Here we report that the TSC1/mTOR pathway in the gut epithelium represents a metabolic and innate immune checkpoint for intestinal dysfunction and inflammation. mTOR hyperactivation triggered by Western diet or Tsc1 ablation led to epithelium necroptosis, barrier disruption, and predisposition to dextran sulfate sodium-induced colitis and inflammation-associated colon cancer. Mechanistically, our results uncovered a critical role for TSC1/mTOR in restraining the expression and activation of RIPK3 in the gut epithelium through TRIM11-mediated ubiquitination and autophagy-dependent degradation. Notably, microbiota depletion by antibiotics or gnotobiotics attenuated RIPK3 expression and activation, thereby alleviating epithelial necroptosis and colitis driven by mTOR hyperactivation. mTOR primarily impinged on RIPK3 to potentiate necroptosis induced by TNF and by microbial pathogen-associated molecular patterns (PAMPs), and hyperactive mTOR and aberrant necroptosis were intertwined in human IBDs. Together, our data reveal a previously unsuspected link between the Western diet, microbiota, and necroptosis and identify the mTOR/RIPK3/necroptosis axis as a driving force for intestinal inflammation and cancer., Introduction Inflammatory bowel diseases (IBDs), comprising Crohn's disease and ulcerative colitis, are chronic and relapsing inflammatory disorders manifested in the gastrointestinal (GI) tract (1, 2). Despite a continuous increase in [...]

This study introduces a single-layer patterned graphene metamaterial, composed of a graphene ring (GR), two parallel graphene strips (TPGSs), two vertical graphene strips (TVGSs), and a graphene block (GB), which achieves triple plasmon-induced transparency (TPIT) in the terahertz (THz) frequency range using coupled mode theory (CMT) and the finite-difference time-domain (FDTD) technique. Moreover, a synchronized electro-optical switch with four modulation modes is implemented by dynamically adjusting graphene's Fermi level, exhibiting modulation degrees of amplitude (MDA) of 88.3%, 94.7%, 86.9%, and 89.0% at 1.69 THz, 3.14 THz, 3.95 THz, and 4.67 THz, respectively. In addition, the modes excited by TPGSs and TVGSs interconvert due to the proposed structure's symmetry, accounting for the polarization insensitivity of TPIT. The enhanced MDA and polarization insensitivity of the electro-optical switch presented in this study significantly surpass those of comparable electro-optical switches. As a result, the polarization insensitivity of multiple optical switches to incident light fields offers a promising approach for designing optoelectronic devices. [ABSTRACT FROM AUTHOR]