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The metalloprotease ADAM17 is a key regulator of the TNFα, IL-6R and EGFR signaling pathways. The maturation and function of ADAM17 is controlled by the seven-membrane-spanning proteins iRhoms1 and 2. The functional properties of the ADAM17/iRhom1 and ADAM17/iRhom2 complexes differ, in that stimulated shedding of most ADAM17 substrates tested to date can be supported by iRhom2, whereas iRhom1 can only support stimulated shedding of very few ADAM17 substrates, such as TGFα. The first transmembrane domain (TMD1) of iRhom2 and the sole TMD of ADAM17 are important for the stimulated shedding of ADAM17 substrates by iRhom2. However, little is currently known about how the iRhoms interact with different substrates to control their stimulated shedding by ADAM17. To provide new insights into this topic, we tested how various chimeras between iRhom1 and iRhom2 affect the stimulated processing of the EGFR-ligands TGFα (iRhom1- or 2-dependent) and EREG (iRhom2-selective) by ADAM17. This uncovered an important role for the TMD7 of the iRhoms in determining their substrate selectivity. Computational methods utilized to characterize the iRhom1/2/substrate interactions suggest that the substrate selectivity is determined, at least in part, by a distinct accessibility of the substrate cleavage site to stimulated ADAM17. These studies not only provide new insights into why the substrate selectivity of stimulated iRhom2/ADAM17 differs from that of iRhom1/ADAM17, but also suggest new approaches for targeting the release of specific ADAM17 substrates. [ABSTRACT FROM AUTHOR]

Absent in melanoma 2 (AIM2), a key component of the IFI20X/IFI16 (PYHIN) protein family, is characterized as a DNA sensor to detect cytosolic bacteria and DNA viruses. However, little is known about its immunological role during pathogenic Clostridium perfringens (C. perfringens) infection, an extracellular bacterial pathogen. In a pathogenic C. perfringens gas gangrene model, Aim2−/− mice are more susceptible to pathogenic C. perfringens soft tissue infection, revealing the importance of AIM2 in host protection. Notably, Aim2 deficiency leads to a defect in bacterial killing and clearance. Our in vivo and in vitro findings further establish that inflammasome signaling is impaired in the absence of Aim2 in response to pathogenic C. perfringens. Mechanistically, inflammasome signaling downstream of active AIM2 promotes pathogen control. Importantly, pathogenic C. perfringens-derived genomic DNA triggers inflammasome signaling activation in an AIM2-dependent manner. Thus, these observations uncover a central role for AIM2 in host defense and triggering innate immunity to combat pathogenic C. perfringens infections. [ABSTRACT FROM AUTHOR]

Radiation therapy is a current standard-of-care treatment and is used widely for GBM patients. However, radiation therapy still remains a significant barrier to getting a successful outcome due to the therapeutic resistance and tumor recurrence. Understanding the underlying mechanisms of this resistance and recurrence would provide an efficient approach for improving the therapy for GBM treatment. Here, we identified a regulatory mechanism of CD44 which induces infiltration and mesenchymal shift of GBM. Ionizing radiation (IR)-induced K-RAS/ERK signaling activation elevates CD44 expression through downregulation of miR-202 and miR-185 expression. High expression of CD44 promotes SRC activation to induce cancer stemness and EMT features of GBM cells. In this study, we demonstrate that the K-RAS/ERK/CD44 axis is a key mechanism in regulating mesenchymal shift of GBM cells after irradiation. These findings suggest that blocking the K-RAS activation or CD44 expression could provide an efficient way for GBM treatment. [ABSTRACT FROM AUTHOR]

The proposition of non-fullerene acceptors (NFAs) in organic solar cells has made great progress in the raise of power conversion efficiency, and it also broadens the ways for searching and designing new acceptor molecules. In this work, the design of novel NFAs with required properties is performed with the conditional generative model constructed from a convolutional neural network (CNN). The temporal CNN is firstly trained to be a good string-based molecular conditional generative model to directly generate the desired molecules. The reliability of generated molecular properties is then demonstrated by a graph-based prediction model and evaluated with quantum chemical calculations. Specifically, the global attention mechanism is incorporated in the prediction model to pool the extracted information of molecular structures and provide interpretability. By combining the generative and prediction models, thousands of NFAs with required frontier molecular orbital energies are generated. The generated new molecules essentially explore the chemical space and enrich the database of transformation rules for molecular design. The conditional generation model can also be trained to generate the molecules from molecular fragments, and the contribution of molecular fragments to the properties is subsequently predicted by the prediction model. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is one of the most aggressive human cancers with a high frequency of post-surgical recurrence. It is very critical to diagnose HCC recurrence at an early stage for a better therapeutic treatment. In this study, we examined the microRNA (miRNA) expression profiling in tumor tissues obtained from early and late recurrent HCC patients post-resection, using a microarray assay. A total of 32 miRNAs were identified to be differentially expressed during the progression of recurrence. Among these, 16 miRNAs were upregulated and 16 were downregulated. In addition, this miRNA expression signature was further validated by quantitative real-time polymerase chain reaction (qRT-PCR) analysis. Moreover, functional annotation of predicted target genes of these recurrent HCC-related miRNAs indicates that multiple biological pathways (i.e., focal adhesion pathway, cancer-related pathways and mitogen-activated protein kinase (MAPK) signaling) that are all critical for cancer development and progression, may participate in the recurrence of HCC. Our data suggest potential molecular mechanisms underpinning miRNA-controlled HCC recurrence, and support the notion that miRNA expression signature and miRNA-based therapy can be useful tools for a better diagnosis and treatment stratification of this disease. [ABSTRACT FROM AUTHOR]

Translational photopharmacological applications are limited through irradiation by light showing wavelengths within the bio-optical window. To achieve sufficient tissue penetration, using wavelengths >500 nm is mandatory. Nevertheless, the majority of photopharmacological compounds respond to irradiation with more energetic UV light, which shows only a minor depth of tissue penetration in the µm range. Thus, we became interested in UV light containing Cherenkov radiation (CR) induced as a by-product by clinically employed radionuclides labeling specific tissues. Therefore, CR may be applicable in novel photopharmacological approaches. To provide evidence for the hypothesis, we verified the clinically established radionuclides 68Ga and 90Y but not 18F in clinically used activities to be capable of generating CR in aqueous solutions. We then investigated whether the generated CR was able to photoactivate the caged kinase inhibitor cagedAZD5438 as a photoresponsive model system. Herein, 21% uncaging of the model system cagedAZD5438 occurred by incubation with 90Y, along with a non-specific compound decomposition for 68Ga and partly for 90Y. The findings suggest that the combination of a clinically employed radionuclide with an optimized photoresponsive agent could be beneficial for highly focused photopharmacological therapies. [ABSTRACT FROM AUTHOR]

As a polyene antibiotic of great pharmaceutical significance, pimaricin has been extensively studied to enhance its productivity and effectiveness. In our previous studies, pre-reaction state (PRS) has been validated as one of the significant conformational categories before macrocyclization, and is critical to mutual recognition and catalytic preparation in thioesterase (TE)-catalyzed systems. In our study, molecular dynamics (MD) simulations were conducted on pimaricin TE-polyketide complex and PRS, as well as pre-organization state (POS), a molecular conformation possessing a pivotal intra-molecular hydrogen bond, were detected. Conformational transition between POS and PRS was observed in one of the simulations, and POS was calculated to be energetically more stable than PRS by 4.58 kcal/mol. The structural characteristics of PRS and POS-based hydrogen-bonding, and hydrophobic interactions were uncovered, and additional simulations were carried out to rationalize the functions of several key residues (Q29, M210, and R186). Binding energies, obtained from MM/PBSA calculations, were further decomposed to residues, in order to reveal their roles in product release. Our study advanced a comprehensive understanding of pimaricin TE-catalyzed macrocyclization from the perspectives of conformational change, protein-polyketide recognition, and product release, and provided potential residues for rational modification of pimaricin TE. [ABSTRACT FROM AUTHOR]