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Upon SARS-CoV-2 infection, viral intermediates specifically activate the IFN response through MDA5-mediated sensing and accordingly induce ADAR1 p150 expression, which might lead to viral A-to-I RNA editing. Here, we developed an RNA virus-specific editing identification pipeline, surveyed 7622 RNA-seq data from diverse types of samples infected with SARS-CoV-2, and constructed an atlas of A-to-I RNA editing sites in SARS-CoV-2. We found that A-to-I editing was dynamically regulated, varied between tissue and cell types, and was correlated with the intensity of innate immune response. On average, 91 editing events were deposited at viral dsRNA intermediates per sample. Moreover, editing hotspots were observed, including recoding sites in the spike gene that affect viral infectivity and antigenicity. Finally, we provided evidence that RNA editing accelerated SARS-CoV-2 evolution in humans during the epidemic. Our study highlights the ability of SARS-CoV-2 to hijack components of the host antiviral machinery to edit its genome and fuel its evolution, and also provides a framework and resource for studying viral RNA editing.

Deubiquitination plays an important role in the regulation of the crosstalk between macroautophagy/autophagy and innate immune signaling, yet its regulatory mechanisms are not fully understood. Here we identify the deubiquitinase OTUD7B as a negative regulator of antiviral immunity by targeting IRF3 (interferon regulatory factor 3) for selective autophagic degradation. Mechanistically, OTUD7B interacts with IRF3, and activates IRF3-associated cargo receptor SQSTM1/p62 (sequestosome 1) by removing its K63-linked poly-ubiquitin chains at lysine 7 (K7) to enhance SQSTM1 oligomerization. Moreover, viral infection increased the expression of OTUD7B, which forms a negative feedback loop by promoting IRF3 degradation to balance type I interferon (IFN) signaling. Taken together, our study reveals a specific role of OTUD7B in mediating the activation of cargo receptors in a substrate-dependent manner, which could be a potential target against excessive immune responses. Abbreviations: Baf A1: bafilomycin A1; CGAS: cyclic GMP-AMP synthase; DDX58/RIG-I: DExD/H-box helicase 58; DSS: dextran sodium sulfate; DUBs: deubiquitinating enzymes; GFP: green fluorescent protein; IFN: interferon; IKKi: IKBKB/IkappaB kinase inhibitor; IRF3: interferon regulatory factor 3; ISGs: interferon-stimulated genes; MAVS: mitochondrial antiviral signaling protein; MOI: multiplicity of infection; PAMPs: pathogen-associated molecular patterns; SeV: Sendai virus; siRNA: small interfering RNA; SQSTM1/p62: sequestosome 1; STING1: stimulator of interferon response cGAMP interactor 1; TBK1: TANK binding kinase 1; Ub: ubiquitin; WT: wild-type; VSV: vesicular stomatitis virus.

The substantial spatial and temporal variability of pesticides has led to large uncertainties when determining their peak aqueous concentrations. There is however a lack of large-scale studies dealing with accurate determination of annual maximum daily concentration (AMDC) across the landscape and over time based on the publicly available monitoring data. We developed a novel data-driven approach that firstly used time series modeling to generate AMDCs for qualified water monitoring sites in the conterminous U.S. With feature variables such as pesticide use and land cover compiled into the dataset, machine learning models using eXtreme Gradient Boosting (XGBoost) and Random Forest Regressor (RF) were then developed to estimate AMDCs in surface waters across the U.S. Both models exhibited significant predictability, while a hybrid model consisting of the average predictions by XGBoost and RF model had the highest prediction accuracy (mean absolute error (MAE): 1.23; R

Post-translational modifications (PTMs) of proteins are crucial to guarantee the proper biological functions in immune responses. Although protein phosphorylation has been extensively studied, our current knowledge of protein pyrophosphorylation, which occurs based on phosphorylation, is very limited. Protein pyrophosphorylation is originally considered to be a non-enzymatic process, and its function in immune signaling is unknown. Here, we identify a metabolic enzyme, UDP-N-acetylglucosamine pyrophosphorylase 1 (UAP1), as a pyrophosphorylase for protein serine pyrophosphorylation, by catalyzing the pyrophosphorylation of interferon regulatory factor 3 (IRF3) at serine (Ser) 386 to promote robust type I interferon (IFN) responses. Uap1 deficiency significantly impairs the activation of both DNA- and RNA-viruse-induced type I IFN pathways, and the Uap1-deficient mice are highly susceptible to lethal viral infection. Our findings demonstrate the function of protein pyrophosphorylation in the regulation of antiviral responses and provide insights into the crosstalk between metabolism and innate immunity.

In addition to investigating the virology of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), discovering the host–virus dependencies are essential to identify and design effective antiviral therapy strategy. Here, we report that the SARS-CoV-2 entry receptor, ACE2, conjugates with small ubiquitin-like modifier 3 (SUMO3) and provide evidence indicating that prevention of ACE2 SUMOylation can block SARS-CoV-2 infection. E3 SUMO ligase PIAS4 prompts the SUMOylation and stabilization of ACE2, whereas deSUMOylation enzyme SENP3 reverses this process. Conjugation of SUMO3 with ACE2 at lysine (K) 187 hampers the K48-linked ubiquitination of ACE2, thus suppressing its subsequent cargo receptor TOLLIP-dependent autophagic degradation. TOLLIP deficiency results in the stabilization of ACE2 and elevated SARS-CoV-2 infection. In conclusion, our findings suggest selective autophagic degradation of ACE2 orchestrated by SUMOylation and ubiquitination as a potential way to combat SARS-CoV-2 infection.

Acer truncatum Bunge and Xanthoceras sorbifolium Bunge are small deciduous trees distributed in East Asia and have high ecological and nutrient value due to their strong environmental adaptability and seed oil abundant in nervonic acid and unsaturated fatty acids. However, their natural distribution remains unclear, which will also be affected by the changing climatic conditions. The main purpose of this study was to map and predict the current and future potential suitable habitats of these two species using MaxEnt based on the presence location of species and environmental variables. The results showed that A. truncatum was more suitable for warm and humid climates and was more durable to climate change compared to X. sorbifolium. Under the current environmental conditions, the suitable habitat of A. truncatum was mainly concentrated in Inner Mongolia Plateau, Loess Plateau, Sichuan Basin, Northeast Plain, North China Plain, Korean Peninsula, as well as Japan, with an area of 115.39 × 104 km2. X. sorbifolium was mainly distributed in Inner Mongolia Plateau and Loess Plateau with an area of 146.15 × 104 km2. Under future climate scenarios, the model predicted that higher concentrations of greenhouse gas emissions could result in greater expansion of the potential distribution of both species. Meanwhile, the study also revealed that the two species migrated to the north by east to varying degrees with the change in suitable habitats. This work could provide scientific basis for resource protection and utilization of the two economic forest trees.

As a core kinase of antiviral immunity, the activity and stability of TANK-binding kinase 1 (TBK1) is tightly controlled by multiple post-translational modifications. Although it has been demonstrated that TBK1 stability can be regulated by ubiquitin-dependent proteasome pathway, it is unclear whether another important protein degradation pathway, autophagosome pathway, can specifically affect TBK1 degradation by cargo receptors. Here we report that E3 ubiquitin ligase NEDD4 functions as a negative regulator of type I interferon (IFN) signaling by targeting TBK1 for degradation at the late stage of viral infection, to prevent the host from excessive immune response. Mechanically NEDD4 catalyzes the K27-linked poly-ubiquitination of TBK1 at K344, which serves as a recognition signal for cargo receptor NDP52-mediated selective autophagic degradation. Taken together, our study reveals the regulatory role of NEDD4 in balancing TBK1-centered type I IFN activation and provides insights into the crosstalk between selective autophagy and antiviral signaling.

Foam targets are expected to be more efficient candidates than solid targets for laser produced plasma (LPP) for extreme ultraviolet (EUV) and x-ray radiation sources due to the expected plasma conditions that can be optimized regarding plasma opacities, volumetrics heating effects, and the produced ions debris characteristics. In this paper, a comparison of ion dynamics between low-density foam and solid Ni plasma was systematically investigated at CMUXE. The foam Ni target (density 0.6 g/cm3) and solid Ni target (density 8.9 g/cm3) were irradiated with 1064 nm Nd:YAG laser in vacuum. A Faraday cup (FC) was used to record the ion flux and time-of-flight (TOF) signals. A lower and wider TOF signal was observed for foam Ni plasma on the time scale. The average ion energy and peak of the TOF signal of solid Ni plasma were much higher than that of the foam Ni plasma. However, the total charge values between foam and solid Ni plasma were comparable indicating a more volumetric absorption of laser energy for foam Ni. The average ion energy and peak of the TOF signal of solid Ni showed a stronger angular and laser energy dependence than that of foam Ni. The plume shape of the solid Ni plasma appeared as an oblong ellipse at each time, while that of foam Ni plasma tended to be more circular, especially at early times. The results of mass ablation rate were consistent with the FC signals and showed a more intense plasma shielding for solid Ni.

We introduce a unified system for SCHOLAT to import information into Encyclopedia, called Semi-automatic Scholar Encyclopedia Generating System, which consists of four modules: website display page, backstage administration module, version comparison and website security module. Scholar Encyclopedia is implemented as a subsystem of Semi-automatic Scholar Encyclopedia Generating System. Scholar Encyclopedia is a scholar information website that has been independently compiled by the scholars and filled in by personal information. Scholar Encyclopedia Import Model consists of three modules: user evaluation, information import and manual review. At present, Semi-automatic Scholar Encyclopedia Generating System has been used, and the beta version of Scholar Encyclopedia has been deployed in our school network center. The online application shows that Scholar Encyclopedia Import Model has good accuracy and practicability.

The ongoing 2019 novel coronavirus disease (COVID-19) caused by SARS-CoV-2 has posed a worldwide pandemic and a major global public health threat. The severity and mortality of COVID-19 are associated with virus-induced dysfunctional inflammatory responses and cytokine storms. However, the interplay between host inflammatory responses and SARS-CoV-2 infection remains largely unknown. Here, we demonstrate that SARS-CoV-2 nucleocapsid (N) protein, the major structural protein of the virion, promotes the virus-triggered activation of NF-κB signaling. After binding to viral RNA, N protein robustly undergoes liquid–liquid phase separation (LLPS), which recruits TAK1 and IKK complex, the key kinases of NF-κB signaling, to enhance NF-κB activation. Moreover, 1,6-hexanediol, the inhibitor of LLPS, can attenuate the phase separation of N protein and restrict its regulatory functions in NF-κB activation. These results suggest that LLPS of N protein provides a platform to induce NF-κB hyper-activation, which could be a potential therapeutic target against COVID-19 severe pneumonia.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the ongoing coronavirus disease 2019 (COVID-19) pandemic. Alongside investigations into the virology of SARS-CoV-2, understanding the host–virus dependencies are vital for the identification and rational design of effective antiviral therapy. Here, we report the dominant SARS-CoV-2 entry receptor, ACE2, conjugates with small ubiquitin-like modifier 3 (SUMO3) through a proteome-wide protein interaction analysis. We further demonstrate that E3 SUMO ligase PIAS4 prompts the SUMOylation and stabilization of ACE2, whereas deSUMOylation enzyme SENP3 reverses this process. Conjugation of SUMO3 with ACE2 at lysine (K) 187 hampers the K48-linked ubiquitination of ACE2, thus suppressing its subsequent cargo receptor TOLLIP-dependent autophagic degradation. Pharmacological intervention of ACE2 SUMOylation blocks the entry of SARS-CoV-2 and viral infection-triggered immune responses. Collectively, our findings suggest selective autophagic degradation of ACE2 orchestrated by SUMOylation and ubiquitination can be targeted to future antiviral therapy of SARS-CoV-2.

To effectively incorporate in vitro-in silico-based methods into the regulation of consumer product safety, a quantitative connection between product phthalate concentrations and in vitro bioactivity data must be established for the general population. We developed, evaluated, and demonstrated a modeling framework that integrates exposure and pharmacokinetic models to convert product phthalate concentrations into population-scale risks for phthalates and their substitutes. A probabilistic exposure model was developed to generate the distribution of multi-route exposures based on product phthalate concentrations, chemical properties, and human activities. Pharmacokinetic models were developed to simulate population toxicokinetics using Bayesian analysis via the Markov chain Monte Carlo method. Both exposure and pharmacokinetic models demonstrated good predictive capability when compared with worldwide studies. The distributions of exposures and pharmacokinetics were integrated to predict the population distributions of internal dosimetry. The predicted distributions showed reasonable agreement with the U.S. biomonitoring surveys of urinary metabolites. The "source-tooutcome" local sensitivity analysis revealed that food contact materials had the greatest impact on body burden for di(2-ethylhexyl) adipate (DEHA), di-2-ethylhexyl phthalate (DEHP), di(isononyl) cyclohexane-1,2dicarboxylate (DINCH), and di(2-propylheptyl) phthalate (DPHP), whereas the body burden of diethyl phthalate (DEP) was most sensitive to the concentration in personal care products. The upper bounds of predicted plasma concentrations showed no overlap with ToxCast in vitro bioactivity values. Compared with the in vitro-toin vivo extrapolation (IVIVE) approach, the integrated modeling framework has significant advantages in mapping product phthalate concentrations to multi-route risks, and thus is of great significance for regulatory use with a relatively low input requirement. Further integration with new approach methodologies will facilitate these in vitro-in silico-based risk assessments for a broad range of products containing an equally broad range of chemicals. Published version

Significance Drug repurposing effort for treatment of a new disease, such as COVID-19, usually starts from a virtual screening of existing drugs, followed by experimental validation, but the actual hit rate is generally rather low with traditional computational methods. It has been demonstrated that a new virtual screening approach with accelerated free energy perturbation-based absolute binding free energy (FEP-ABFE) predictions can reach an unprecedentedly high hit rate, leading to successful identification of 15 potent inhibitors of SARS-CoV-2 main protease (Mpro) from 25 computationally selected drugs under a threshold of Ki = 4 μM. The outcomes of this study are valuable for not only drug repurposing to treat COVID-19 but also demonstrating the promising potential of the FEP-ABFE prediction-based virtual screening approach., The COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a global crisis. There is no therapeutic treatment specific for COVID-19. It is highly desirable to identify potential antiviral agents against SARS-CoV-2 from existing drugs available for other diseases and thus repurpose them for treatment of COVID-19. In general, a drug repurposing effort for treatment of a new disease, such as COVID-19, usually starts from a virtual screening of existing drugs, followed by experimental validation, but the actual hit rate is generally rather low with traditional computational methods. Here we report a virtual screening approach with accelerated free energy perturbation-based absolute binding free energy (FEP-ABFE) predictions and its use in identifying drugs targeting SARS-CoV-2 main protease (Mpro). The accurate FEP-ABFE predictions were based on the use of a restraint energy distribution (RED) function, making the practical FEP-ABFE−based virtual screening of the existing drug library possible. As a result, out of 25 drugs predicted, 15 were confirmed as potent inhibitors of SARS-CoV-2 Mpro. The most potent one is dipyridamole (inhibitory constant Ki = 0.04 µM) which has shown promising therapeutic effects in subsequently conducted clinical studies for treatment of patients with COVID-19. Additionally, hydroxychloroquine (Ki = 0.36 µM) and chloroquine (Ki = 0.56 µM) were also found to potently inhibit SARS-CoV-2 Mpro. We anticipate that the FEP-ABFE prediction-based virtual screening approach will be useful in many other drug repurposing or discovery efforts.

IRF3 (interferon regulatory factor 3) is one of the most critical transcription factors in antiviral innate immune signaling, which is ubiquitously expressed in a variety of cells. Although it has been demonstrated that IRF3 can provoke multiple cellular processes during viral infection, including type I interferon (IFN) production, the mechanisms underlying the precise regulation of IRF3 activity are still not completely understood. Here, we report that selective macroautophagy/autophagy mediated by cargo receptor CALCOCO2/NDP52 promotes the degradation of IRF3 in a virus load-dependent manner. Deubiquitinase PSMD14/POH1 prevents IRF3 from autophagic degradation by cleaving the K27-linked poly-ubiquitin chains at lysine 313 on IRF3 to maintain its basal level and IRF3-mediated type I IFN activation. The autophagic degradation of IRF3 mediated by PSMD14 or CALCOCO2 ensures the precise control of IRF3 activity and fine-tunes the immune response against viral infection. Our study reveals the regulatory role of PSMD14 in balancing IRF3-centered IFN activation with immune suppression and provides insights into the crosstalk between selective autophagy and type I IFN signaling. ATG5: autophagy related gene 5; Baf A1: bafilomycin A1; BECN1: beclin 1; CALCOCO2/NDP52: calcium binding and coiled-coil domain 2; CGAS: cyclic GMP-AMP synthase; DDX58/RIG-I: DExD/H-box helicase 58; DUBs: deubiquitinating enzymes; IFN: interferon; IRF3: interferon regulatory factor 3; MAVS: mitochondrial antiviral signaling protein; MOI: multiplicity of infection; PAMPs: pathogen-associated molecule patterns; PBMC: peripheral blood mononuclear cell; PSMD14/POH1: proteasome 26S subunit, non-ATPase 14; RIPA: RLR-induced IRF3-mediated pathway of apoptosis; SeV: Sendai virus; SQSTM1/p62: sequestosome 1; STING1: stimulator of interferon response cGAMP interactor 1; TBK1: TANK binding kinase 1; Ub: ubiquitin; WT: wild type

Macroautophagy/autophagy, a eukaryotic homeostatic process that sequesters cytoplasmic constituents for lysosomal degradation, is orchestrated by a number of autophagy-related (ATG) proteins tightly controlled by post-translational modifications. However, the involvement of reversible ubiquitination in the regulation of autophagy remains largely unclear. Here, we performed a single-guide RNA-based screening assay to investigate the functions of deubiquitinating enzymes (DUBs) in regulating autophagy. We identified previously unrecognized roles of several DUBs in modulating autophagy at multiple levels by targeting various ATG proteins. Mechanistically, we demonstrated that STAMBP/AMSH (STAM-binding protein) promotes the stabilization of ULK1 by removing its lysine 48 (K48)-linked ubiquitination, whereas OTUD7B mediates the degradation of PIK3 C3 by enhancing its K48-linked ubiquitination, thus positively or negatively affects autophagy flux, respectively. Together, our study elaborated on the broad involvement of DUBs in regulating autophagy and uncovered the critical roles of the reversible ubiquitination in the modification of ATG proteins. ATG: autophagy-related; Baf A1: bafilomycin A1; DUB: deubiquitinating enzyme; EBSS: Earle’s balanced salt solution; KO: knockout; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; OTUD7B: OTU domain-containing protein 7B; PIK3C3: phosphatidylinositol 3-kinase catalytic subunit type 3; sgRNA: single-guide RNA; SQSTM1/p62: sequestosome 1; STAMBP/AMSH: STAM-binding protein; ULK1: unc-51 like autophagy activating kinase 1; USP: ubiquitin specific peptidase.

The particle/gas partition coefficient Kp is an important parameter affecting the fate and transport of indoor semivolatile organic compounds (SVOCs) and resulting human exposure. Unfortunately, experimental measurements of Kp exist almost exclusively for atmospheric polycyclic aromatic hydrocarbons, with very few studies focusing on SVOCs that occur in indoor environments. A specially designed tube chamber operating in the laminar flow regime was developed to measure Kp of the plasticizer di-2-ethylhexyl phthalate (DEHP) for one inorganic (ammonium sulfate) and two organic (oleic acid and squalane) particles. The values of Kp for the organic particles (0.23 ± 0.13 m3/μg for oleic acid and 0.11 ± 0.10 m3/μg for squalane) are an order of magnitude higher than those for the inorganic particles (0.011 ± 0.004 m3/μg), suggesting that the process by which the particles accumulate SVOCs is different. A mechanistic model based on the experimental design reveals that the presence of the particles increases the ga...

Biogas from landfills and wastewater treatment facilities typically contain siloxane contaminants that can cause severe operational problems in engines and boilers when biogas is used as fuel. Likely due to their relatively low volatility, reliable siloxane sampling and analysis has proven challenging, and no standard sampling technique for gas-phase siloxanes exists, leading to high variability in analytical results. This study evaluates four techniques commonly used for sampling gas-phase siloxanes. Samples of a reference gas containing decamethylcyclopentasiloxane (D5) were taken using these techniques and measured D5 concentrations were compared to the reference gas D5 concentration. Methanol impingers and thermal desorption tubes proved to be most accurate and reliable, whereas Tedlar® bags and SUMMA canisters yielded lower D5 recovery rates due to adsorption to container surfaces. Based on these results, the methanol impinger and thermal desorption tube sampling methods appear to be more suitable for the quantitative analysis of gas-phase siloxanes in biogas.

Sorption of semivolatile organic compounds (SVOCs) onto interior surfaces, often referred to as the "sink effect", and their subsequent re-emission significantly affect the fate and transport of indoor SVOCs and the resulting human exposure. Unfortunately, experimental challenges and the large number of SVOC/surface combinations have impeded progress in understanding sorption of SVOCs on indoor surfaces. An experimental approach based on a diffusion model was thus developed to determine the surface/air partition coefficient K of di-2-ethylhexyl phthalate (DEHP) on typical impervious surfaces including aluminum, steel, glass, and acrylic. The results indicate that surface roughness plays an important role in the adsorption process. Although larger data sets are needed, the ability to predict K could be greatly improved by establishing the nature of the relationship between surface roughness and K for clean indoor surfaces. Furthermore, different surfaces exhibit nearly identical K values after being exposed to kitchen grime with values that are close to those reported for the octanol/air partition coefficient. This strongly supports the idea that interactions between gas-phase DEHP and soiled surfaces have been reduced to interactions with an organic film. Collectively, the results provide an improved understanding of equilibrium partitioning of SVOCs on impervious surfaces.

Autophagy, an evolutionarily conserved cargo degradation process, is responsible to remove superfluous and unwanted cytoplasmic materials and maintain cellular homeostasis. Autophagy can be highly selective and target specific cargoes by utilizing multiple cargo receptors, which bind both ubiquitinated cargoes and autophagosomes. Mounting evidence has revealed the deep involvement of selective autophagy in innate immunity upon pathogen invasion, including eliminating microbial pathogens, initiating the anti-microbe responses, and inhibiting excessive immune responses. Given the importance of selective autophagy in innate immunity, how cargo receptors deliver pathogens and intracellular host constitutes to autophagosomes during infection remains to be elucidated. In this review, we summarize current evidence for the regulation of innate immunity by selective autophagy and try to elucidate the mechanisms employed by cargo receptor network in mediating diverse innate immune responses.

Certain processes in indoor air, such as deposition, partitioning, and heterogeneous reactions, involve interactions with surfaces. We have characterized the surface area, volume, shape, and material of objects in 10 bedrooms, nine kitchens, and three offices. The resolution of the measurements was ∼1 cm. The ratio of surface area with contents to that without contents did not vary by type of room and averaged 1.5 ± 0.3 (mean ± standard deviation) across all rooms. The ratio of the volume minus contents to nominal volume averaged 0.9 ± 0.1 and was lower for kitchens compared to bedrooms and offices. Ignoring contents, the surface-area-to-volume ratio was 1.8 ± 0.3 m−1; accounting for contents, the ratio was 3.2 ± 1.2 m−1, or 78% higher. These two ratios did not vary by type of room and were similar to those measured for 33 rooms in another study. Due to substantial differences in the design and contents of kitchens, their ratios had the highest variability among the three room types. The most common shape of surfaces was flat rectangular, while each room also had many irregularly-shaped objects. Paint-covered surfaces and stained wood were the two most common materials in each room, accounting for an average of 42% and 22% of total surface area, respectively, although the distribution of materials varied by room type. These findings have important implications for understanding the chemistry of indoor environments, as the available surface area for deposition, partitioning, and reactions is higher and more complex than assumed in simple models.

Autophagy, an evolutionarily conserved cargo degradation process, is responsible to remove superfluous and unwanted cytoplasmic materials and maintain cellular homeostasis. Autophagy can be highly selective and target specific cargoes by utilizing multiple cargo receptors, which bind both ubiquitinated cargoes and autophagosomes. Mounting evidence has revealed the deep involvement of selective autophagy in innate immunity upon pathogen invasion, including eliminating microbial pathogens, initiating the anti-microbe responses, and inhibiting excessive immune responses. Given the importance of selective autophagy in innate immunity, how cargo receptors deliver pathogens and intracellular host constitutes to autophagosomes during infection remains to be elucidated. In this review, we summarize current evidence for the regulation of innate immunity by selective autophagy and try to elucidate the mechanisms employed by cargo receptor network in mediating diverse innate immune responses.

The immune system plays a critical role in defense against invading pathogens, and its function must be strictly controlled to maintain intracellular homeostasis. Once suffering microbial invasion or receiving danger signals, the immune system initiates the responses timely. After the threat removal, the immune system should be shut down to avoid the harm caused by excessive immune activation. Additionally, the immune system needs to be internally adjusted so that it does not respond to self-antigens to avoid autoimmune diseases. The states of nonresponse in immunity are termed as immune tolerance. Numerous studies indicated that macroautophagy (hereafter named as autophagy) is involved in T cells and B cells related immune tolerance. Recently, more and more researches demonstrated that autophagy is not only capable of nonselective degradation of cellular macromolecular components but also responsible for sorting and transporting autophagic substrates through a group of cargo receptors for selective degradation, which is called as selective autophagy. Recent studies indicated that selective autophagy can effectively regulate the immune tolerance and avoid over-activation of immune response by targeting multiple receptors and effectors of immune cells. In this chapter, we will focus on how autophagy participates explicitly in the adaptive and innate immune tolerance.

The particle-gas partition coefficient (Kp) and mass accommodation coefficient (α) are two parameters characterizing the gas-particle interaction of semi-volatile organic compounds (SVOCs). Most of the available methods for measuring Kp require equilibrium at the chamber outlet, implying substantial preliminary testing. The need to separate gas-phase and particle-phase SVOCs also reduces the method accuracy. Few studies measuring α for indoor-related SVOCs are available, and they usually ignore the wall loss of SVOCs, resulting in reduced measurement accuracy. To overcome these deficiencies, we developed a dynamic method coupling a laminar flow tube chamber and an SVOC mass transfer model. Using the interaction between gas-phase di-2-ethylhexyl phthalate (DEHP) and (NH4)2SO4 particles (with diameters in the range of 10–600 nm) as an example, experiments were performed to evaluate the effectiveness and accuracy of the dynamic method. For the experimental conditions investigated (temperature = 25 °C and relative humidity 4)2SO4 particles is governed by surface adsorption because (NH4)2SO4 particles are in solid state. In this case, gas-particle partitioning should be characterized by the surface-area-normalized partition coefficient (KpA). KpA and α were measured to be 260 ± 80 m and 0.20 ± 0.05, respectively. Both are consistent with results reported in the literature. The method applicability for other SVOC-particle combinations and the improvement of method accuracy require further study. Copyright © 2019 American Association for Aerosol Research

Chromatin modifications, such as histone acetylation, ubiquitination, and methylation, play fundamental roles in maintaining chromatin architecture and regulating gene transcription. Although their crosstalk in chromatin remodeling has been gradually uncovered, the functional relationship between histone ubiquitination and methylation in regulating immunity and inflammation remains unclear. Here, it is reported that USP38 is a novel histone deubiquitinase that works together with the histone H3K4 modifier KDM5B to orchestrate inflammatory responses. USP38 specifically removes the monoubiquitin on H2B at lysine 120, which functions as a prerequisite for the subsequent recruitment of demethylase KDM5B to the promoters of proinflammatory cytokines Il6 and Il23a during LPS stimulation. KDM5B in turn inhibits the binding of NF‐κB transcription factors to the Il6 and Il23a promoters by reducing H3K4 trimethylation. Furthermore, USP38 can bind to KDM5B and prevent it from proteasomal degradation, which further enhances the function of KDM5B in the regulation of inflammation‐related genes. Loss of Usp38 in mice markedly enhances susceptibility to endotoxin shock and acute colitis, and these mice display a more severe inflammatory phenotype compared to wild‐type mice. The studies identify USP38‐KDM5B as a distinct chromatin modification complex that restrains inflammatory responses through manipulating the crosstalk of histone ubiquitination and methylation., USP38 is a novel histone deubiquitinase of H2B that couples the regulation of histone ubiquitination (H2Bub) and methylation (H3K4me3) with KDM5B to selectively inhibit the transcription of the proinflammatory cytokines and prevent excessive inflammation. USP38 deficiency in mice enhances the inflammatory response, and renders animals more susceptible to acute inflammation and dextran sulfate sodium‐induced acute colitis.

Phthalates and alternative plasticizers are semivolatile organic compounds (SVOCs), an important class of indoor pollutants that may have significant adverse effects on human health. Unfortunately, models that predict emissions of and the resulting exposure to SVOCs have substantial uncertainties. One reason is that the characteristics governing emissions, transport, and exposure are usually strongly dependent on vapor pressure. Furthermore, available data for phthalates exhibit significant variability, and vapor pressures for the various alternatives are usually unavailable. For these reasons, a new approach based on modeling of the evaporation process was developed to determine vapor pressures of phthalates and alternate plasticizers. A laminar flow forced convection model was used in the design of a partial saturator (PS) tube. The mass transfer mechanisms in the PS tube are accurately modeled and enable the determination of vapor pressure even when the carrier gas is not completely saturated, avoiding the complicated procedure to establish vapor saturation. The measured vapor pressures ranged from about 10(-2) to 10(-7) Pa. Compared to the traditional gas saturation method, the model-based approach is advantageous in terms of both predictability and simplicity. The knowledge provides new insight into experimental design and a sound basis for further method development.

Polymer/clay nanocomposite (PCN) membranes are useful as barrier materials to reduce the permeability of gases and vapors through polymer materials. Extensive studies have focused on theoretical prediction of the effective diffusion coefficients based on the clay fraction and distribution within the polymer matrix. However, existing models are based on highly idealized geometries of the PCN membranes, and are not in agreement with experimental data as a consequence. A simple and novel numerical method based on a two-dimensional representation of the barrier membrane is developed to predict gas permeability in PCN. Employing Transmission Electron Microscopy (TEM), the nano-structure of PCN is captured and transformed into mathematical morphology data. Based on the image matrix, the barrier property of PCN was numerically modelled and generally agrees well with experimental measurements from the literature for volatile organic compounds. Because the geometry of barrier polymers can be easily captured by TEM, the proposed method should be applicable to different PCN membranes to quickly estimate the barrier properties for gases and vapors.

In article number 2002680, Jun Cui and co‐workers identify a new histone modifier‐USP38, that modulates histone ubiquitination and methylation to resolve inflammatory response. USP38 acts as a “Safety Machine” which shuts down the inflammation by de‐ubiquitinating histone H2B and stabilizes KDM5B to de‐methylate H3K4, which blocks the transcription of pro‐inflammatory genes. The USP38‐KDM5B complex might be a potential clinical target for therapy against inflammatory diseases. [Image: see text]

Summary: The class III phosphoinositide 3-kinase vacuolar protein sorting 34 (VPS34) is a core protein of autophagy initiation, yet the regulatory mechanisms responsible for its stringent control remain poorly understood. Here, we report that the E3 ubiquitin ligase NEDD4-1 promotes the autophagy flux by targeting VPS34. NEDD4-1 undergoes lysine 29 (K29)-linked auto-ubiquitination at K1279 and serves as a scaffold for recruiting the ubiquitin-specific protease 13 (USP13) to form an NEDD4-1-USP13 deubiquitination complex, which subsequently stabilizes VPS34 to promote autophagy through removing the K48-linked poly-ubiquitin chains from VPS34 at K419. Knockout of either NEDD4-1 or USP13 increased K48-linked ubiquitination and degradation of VPS34, thus attenuating the formation of the autophagosome. Our results identify an essential role for NEDD4-1 in regulating autophagy, which provides molecular insights into the mechanisms by which ubiquitination regulates autophagy flux. : Xie et al. demonstrate that HECT ubiquitin E3 ligase NEDD4-1 undergoes lysine 29 (K29)-linked auto-ubiquitination and serves as a scaffold to recruit the ubiquitin-specific protease 13 (USP13) to form a deubiquitination complex, which subsequently stabilizes VPS34 to promote autophagy through the removal of K48-linked poly-ubiquitin chains on VPS34. Keywords: autophagy, VPS34, NEDD4-1, USP13, deubiquitination complex, auto-ubiquitination

Viral infection triggers host innate immune responses, which primarily include the activation of type I interferon (IFN) signaling and inflammasomes. Here, we report that Zika virus (ZIKV) infection triggers NLRP3 inflammasome activation, which is further enhanced by viral non‐structural protein NS1 to benefit its replication. NS1 recruits the host deubiquitinase USP8 to cleave K11‐linked poly‐ubiquitin chains from caspase‐1 at Lys134, thus inhibiting the proteasomal degradation of caspase‐1. The enhanced stabilization of caspase‐1 by NS1 promotes the cleavage of cGAS, which recognizes mitochondrial DNA release and initiates type I IFN signaling during ZIKV infection. NLRP3 deficiency increases type I IFN production and strengthens host resistance to ZIKV in vitro and in vivo . Taken together, our work unravels a novel antagonistic mechanism employed by ZIKV to suppress host immune response by manipulating the interplay between inflammasome and type I IFN signaling, which might guide the rational design of therapeutics in the future.

Phthalates and phthalate alternatives are semivolatile organic compounds (SVOCs) present in many PVC products as plasticizers to enhance product performance. Knowledge of the mass-transfer parameters, including the equilibrium concentration in the air in contact with the product surface (y0), will greatly improve the ability to estimate the emission rate of SVOCs from these products and to assess human exposure. The objective of this study was to measure y0 for different PVC products and to evaluate its relationship with the material-phase concentrations (C0). Also, C0 and y0 data from other sources were included, resulting in a substantially larger data set (Ntotal = 34, T = 25 °C) than found in previous studies. The results show that the material/gas equilibrium relationship does not follow Raoult’s law and that therefore the assumption of an ideal solution is invalid. Instead, Henry’s law applies, and the Henry’s law constant for all target SVOCs consists of the respective pure liquid vapor pressure an...