The E3 Ubiquitin Ligase AMFR and INSIG1 Bridge the Activation of TBK1 Kinase by Modifying the Adaptor STING

SummaryStimulator of interferon genes (STING, also known as MITA, ERIS, or MPYS) is essential for host immune responses triggered by microbial DNAs. However, the regulatory mechanisms underlying STING-mediated signaling are not fully understood. We report here that, upon cytoplasmic DNA stimulation, the endoplasmic reticulum (ER) protein AMFR was recruited to and interacted with STING in an insulin-induced gene 1 (INSIG1)-dependent manner. AMFR and INSIG1, an E3 ubiquitin ligase complex, then catalyzed the K27-linked polyubiquitination of STING. This modification served as an anchoring platform for recruiting TANK-binding kinase 1 (TBK1) and facilitating its translocation to the perinuclear microsomes. Depletion of AMFR or INSIG1 impaired STING-mediated antiviral gene induction. Consistently, myeloid-cell-specific Insig1−/− mice were more susceptible to herpes simplex virus 1 (HSV-1) infection than wild-type mice. This study uncovers an essential role of the ER proteins AMFR and INSIG1 in innate immunity, revealing an important missing link in the STING signaling pathway

Nudel and FAK as Antagonizing Strength Modulators of Nascent Adhesions through Paxillin

Competition for binding to the cellular protein paxillin by the proteins Nudel and focal adhesion kinase is important for the proper regulation of cell adhesion and migration

Distinct Chemokine Signaling Regulates Integrin Ligand Specificity to Dictate Tissue-Specific Lymphocyte Homing

SummaryImmune surveillance and host defense depend on the precisely regulated trafficking of lymphocytes. Integrin α4β7 mediates lymphocyte homing to the gut through its interaction with mucosal vascular address in cell adhesion molecule-1 (MAdCAM-1). α4β7 also binds vascular cell adhesion molecule-1 (VCAM-1), which is expressed in other tissues. To maintain the tissue specificity of lymphocyte homing, α4β7 must distinguish one ligand from the other. Here, we demonstrate that α4β7 is activated by different chemokines in a ligand-specific manner. CCL25 stimulation promotes α4β7-mediated lymphocyte adhesion to MAdCAM-1 but suppresses adhesion to VCAM-1, whereas CXCL10 stimulation has the opposite effect. Using separate pathways, CCL25 and CXCL10 stimulate differential phosphorylation states of the β7 tail and distinct talin and kindlin-3 binding patterns, resulting in different binding affinities of MAdCAM-1 and VCAM-1 to α4β7. Thus, our findings provide a mechanism for lymphocyte traffic control through the unique ligand-specific regulation of integrin adhesion by different chemokines

Layer-by-layer deposition of bioactive layers on magnesium alloy stent materials to improve corrosion resistance and biocompatibility

Magnesium alloy is considered as one of the ideal cardiovascular stent materials owing to its good mechanical properties and biodegradability. However, the in vivo rapid degradation rate and the insufficient biocompatibility restrict its clinical applications. In this study, the magnesium alloy (AZ31B) was modified by combining the surface chemical treatment and in-situ self-assembly of 16-phosphonyl-hexadecanoic acid, followed by the immobilization of chitosan-functionalized graphene oxide (GOCS). Heparin (Hep) and GOCS were alternatively immobilized on the GOCS-modified surface through layer by layer (LBL) to construct the GOCS/Hep bioactive multilayer coating, and the corrosion resistance and biocompatibility were extensively explored. The results showed that the GOCS/Hep bioactive multilayer coating can endow magnesium alloys with an excellent in vitro corrosion resistance. The GOCS/Hep multilayer coating can significantly reduce the hemolysis rate and the platelet adhesion and activation, resulting in an excellent blood compatibility. In addition, the multilayer coating can not only enhance the adhesion and proliferation of the endothelial cells, but also promote the vascular endothelial growth factor (VEGF) and nitric oxide (NO) expression of the attached endothelial cells on the surfaces. Therefore, the method of the present study can be used to simultaneously control the corrosion resistance and improve the biocompatibility of the magnesium alloys, which is expected to promote the application of magnesium alloys in biomaterials or medical devices, especially cardiovascular stent

A Comprehensive Survey of Immune Cytolytic Activity-Associated Gene Co-Expression Networks across 17 Tumor and Normal Tissue Types

Cytolytic immune activity in solid tissue can be quantified by transcript levels of two genes, GZMA and PRF1, which is named the CYT score. A previous study has investigated the molecular and genetic properties of tumors associated CYT, but a systematic exploration of how co-expression networks across different tumors are shaped by anti-tumor immunity is lacking. Here, we examined the connectivity and biological themes of CYT-associated modules in gene co-expression networks of 14 tumor and 3 matched normal tissues constructed from the RNA-Seq data of the “The Cancer Genome Atlas” project. We first found that tumors networks have more diverse CYT-correlated modules than normal networks. We next identified and investigated tissue-specific CYT-associated modules across 14 tumor types. Finally, a common CYT-associated network across 14 tumor types was constructed. Two common modules have mixed signs of correlation with CYT in different tumors. Given the tumors and normal tissues surveyed, our study presents a systematic view of the regulation of cytolytic immune activity across multiple tumor tissues

A calculation model of the mean flow velocity of overland flow considering a variety of grass covers and raindrop’s characteristics

The effect of vegetation distribution patterns, coverage, and raindrop impact on the overland flow velocity is highly intricate. To quantify these effects, a rigorous experimental campaign was conducted involving five rainfall intensities (ranging between 60 and 120 mm h−1), six vegetation patterns (diamond pattern - DP, random pattern - RP, checkerboard pattern - CP, vertical strip pattern aligned with the slope direction - VP, step strip pattern - SP, banded pattern perpendicular to the slope direction - BP), five vegetation coverage (ranging between 30% and 70%) and three slope gradients (ranging between 8.72% and 25.88%). The results obtained show that the BP configuration has the best flow velocity reduction effect, which can lessen the flow velocity by 58.68% - 69.27% compared with the bare slope, while the change for VP is only 4.80% - 6.30%. This indicates that BP yields significant soil and water conservation benefits. Furthermore, when the vegetation coverage is 30%, a concentrated flow formed between the vegetation patches under the RP and CP configurations, resulting in a higher overland flow velocity greater than the one recorded for the bare slope, which is unfavorable for soil and water conservation and should be avoided. Finally, a model was established to predict flow velocity and it was built by combining the equations of momentum and mechanical balance. After having calibrated the model and assessed its performance against research data available in literature, it was possible to confirm its reliability and consistency. These findings provide scientific guidance for assessing the soil and water conservation effectiveness of different vegetation patterns

SIGANEO: Similarity network with GAN enhancement for immunogenic neoepitope prediction

Target selection of the personalized cancer neoantigen vaccine, which is highly dependent on computational prediction algorithms, is crucial for its clinical efficacy. Due to the limited number of experimentally validated immunogenic neoepitopes as well as the complexity of neoantigens in eliciting T cell response, the accuracy of neoepitope immunogenicity prediction methods requires persistent efforts for improvement. We present a deep learning framework for neoepitope immunogenicity prediction – SIGANEO by integrating GAN-like network with similarity network to address issues of missing values and limited data concerning neoantigen prediction. This framework exhibits superior performance over competing machine-learning-based neoantigen prediction algorithms over an independent test dataset from TESLA consortium. Particularly for the clinical setting of neoantigen vaccine where only the top 10 and 20 predictions are selected for vaccine production, SIGANEO achieves significantly better accuracy for predicting experimentally validated neoepitopes. Our work demonstrates that deep learning techniques can greatly boost the accuracy of target identification for cancer neoantigen vaccine

Encapsulation and Protection of Ultrathin Two-Dimensional Porous Organic Nanosheets within Biocompatible Metal-Organic Frameworks for Live-Cell Imaging

10.1021/acs.chemmater.9b01642CHEMISTRY OF MATERIALS31134897-491

Epicutaneous immunization with modified vaccinia Ankara viral vectors generates superior T cell immunity against a respiratory viral challenge

Abstract Modified Vaccinia Ankara (MVA) was recently approved as a smallpox vaccine. Variola is transmitted by respiratory droplets and MVA immunization by skin scarification (s.s.) protected mice far more effectively against lethal respiratory challenge with vaccinia virus (VACV) than any other route of delivery, and at lower doses. Comparisons of s.s. with intradermal, subcutaneous, or intramuscular routes showed that MVAOVA s.s.-generated T cells were both more abundant and transcriptionally unique. MVAOVA s.s. produced greater numbers of lung Ova-specific CD8+ TRM and was superior in protecting mice against lethal VACVOVA respiratory challenge. Nearly as many lung TRM were generated with MVAOVA s.s. immunization compared to intra-tracheal immunization with MVAOVA and both routes vaccination protected mice against lethal pulmonary challenge with VACVOVA. Strikingly, MVAOVA s.s.-generated effector T cells exhibited overlapping gene transcriptional profiles to those generated via intra-tracheal immunization. Overall, our data suggest that heterologous MVA vectors immunized via s.s. are uniquely well-suited as vaccine vectors for respiratory pathogens, which may be relevant to COVID-19. In addition, MVA delivered via s.s. could represent a more effective dose-sparing smallpox vaccine