Unraveling the complex dynamics of signaling molecules in cellular signal transduction.

Signaling molecules in cellular responses to foreign stimuli are described as static up- or down-concentration changes during signal transduction. This is because analytical methods for transducing molecules are much slower than the signaling events. In this study, we develop a dynamic cell model and reveal the temporal regulation of signal transduction events in response to reactive oxygen species (ROS). The model contained a set of 10 batches of redox-modified cells that mimic the temporal ROS accumulation events. Validating this dynamic cell model, we discover that cells survive early ROS attacks by activating the Nrf2/polysulfide/p62/CDK1 pathway. Nearly all signaling molecules exhibit time-dependent V-shape or inverse V-shape activation/feedback regulation dynamics in response to ROS accumulation. The results show that the dynamic cell model approach is invaluable for revealing complex signal intensity- and time-dependent cell signaling events.

A zwitterionic solution for smart ionic liquids to evade cytotoxicity.

By linking the cation and anion motifs of ionic liquids (ILs), zwitterionic liquids (ZILs) exhibit at least 146-2740 and 112-1550 folds less cytotoxicity in human gastric and colon cells than those of the structurally related ILs. Computer simulation shows that ZIL molecules hardly penetrate the cell membranes in contrast to ILs. These findings reveal a novel mechanism for ZILs to evade cytotoxicity, establishing a structure-based design principle for the next generation of sustainable ZILs.

Computer-Aided Discovery of Potent Broad-Spectrum Vaccine Adjuvants.

Adjuvants stimulate the immune system to vigorously respond to a vaccine. While current adjuvants such as aluminum salts and oil-in-water emulsions have been used for decades, they do not generate broad and long-lasting responses in many vaccines. Consequently, more potent adjuvants are needed. Here, using computer-aided molecule design and machine learning, we discovered 2 new, broad-spectrum adjuvants that can boost vaccine responses. Our library containing 46 toll-like receptor (TLR)-targeting agonist ligands were assembled on Au nanoparticles. Comprehensive in vitro, ex vivo and in vivo studies showed both leads promoted dendritic cell activation via multiple TLRs and enhanced antigen presentation to T cells. When used together with tumor-specific antigens to immunize mice against B16-OVA melanoma and 4T1-PD1 breast cancer, both adjuvants unleashed strong immune responses that suppressed tumor growth and lung metastases. Our results show computer-aided design and screening can rapidly uncover potent adjuvants for tackling waning immunity in current vaccines.

Data storage mechanism of industrial IoT based on LRC sharding blockchain.

With the rapid development of Industry 4.0, the data security of Industrial Internet of Things in the Industry 4.0 environment has received widespread attention. Blockchain has the characteristics of decentralization and tamper-proof. Therefore, it has a natural advantage in solving the data security problem of Industrial Internet of Things. However, current blockchain technologies face challenges in providing consistency, scalability and data security at the same time in Industrial Internet of Things. To address the scalability problem and data security problem of Industrial Internet of Things, this paper constructs a highly scalable data storage mechanism for Industrial Internet of Things based on coded sharding blockchain. The mechanism uses coded sharding technology for data processing to improve the fault tolerance and storage load of the blockchain to solve the scalability problem. Then a cryptographic accumulator-based data storage scheme is designed which connects the cryptographic accumulator with the sharding nodes to save storage overhead and solve the security problem of data storage and verification. Finally, the scheme is proved to be security and the performance of the scheme is evaluated.

Verifiable Delay Function and Its Blockchain-Related Application: A Survey.

The concept of verifiable delay functions has received attention from researchers since it was first proposed in 2018. The applications of verifiable delay are also widespread in blockchain research, such as: computational timestamping, public random beacons, resource-efficient blockchains, and proofs of data replication. This paper introduces the concept of verifiable delay functions and systematically summarizes the types of verifiable delay functions. Firstly, the description and characteristics of verifiable delay functions are given, and weak verifiable delay functions, incremental verifiable delay functions, decodable verifiable delay functions, and trapdoor verifiable delay functions are introduced respectively. The construction of verifiable delay functions generally relies on two security assumptions: algebraic assumption or structural assumption. Then, the security assumptions of two different verifiable delay functions are described based on cryptography theory. Secondly, a post-quantum verifiable delay function based on super-singular isogeny is introduced. Finally, the paper summarizes the blockchain-related applications of verifiable delay functions.

Comparative toxicity of [C8mim]Br and [C8py]Br in early developmental stages of zebrafish (Danio rerio) with focus on oxidative stress, apoptosis, and neurotoxicity.

The increasing production and usage of ionic liquids (ILs) have raised global ecotoxicological concerns regarding their release into the environment. While the effects of side chains on the IL-induced toxicity in various aquatic organisms have been well-recognized, the role of cationic cores in determining their ecotoxicity remains to be elucidated. Herein, the comparative bioavailability and toxicity of two ILs with different cationic cores but the same anion and side chain in zebrafish embryos were determined. 1-octyl-3-methylimidazolium bromide ([C8mim]Br) has higher accumulation in zebrafish, and triggered developmental toxicity by inducing oxidative stress and apoptosis. Meanwhile, 1-octyl-1-methylpyridium bromide ([C8py]Br) enhanced SOD activity and upregulated anti-apoptotic bcl-2 gene expression, contributing to its much lower neurodevelopmental toxicity. Our study demonstrates the vital role of cationic core in determining the developmental toxicity of ILs and highlights the need for further investigations into the toxicity of imidazolium and pyridinium based ILs in aquatic ecosystems.

Comparison of Bioabsorbable Steroid-Eluting Sinus Stents Versus Nasopore After Endoscopic Sinus Surgery: A Multicenter, Randomized, Controlled, Single-Blinded Clinical Trial.

OBJECTIVES: The aim of this study was to compare the efficacy of bioabsorbable steroid-eluting sinus stents versus absorbable Nasopore packs after endoscopic sinus surgery (ESS) for the treatment of chronic rhinosinusitis (CRS). METHODS: One hundred eighty-one patients with CRS who underwent ESS were randomly assigned to receive a steroid-eluting sinus stent in one ethmoid sinus cavity, whereas the contralateral control side received a Nasopore pack. Endoscopic evaluations were performed 14, 30, and 90 days after the ESS. Postoperative intervention, polyp formation, adhesions, and middle turbinate (MT) position were assessed as efficacy outcomes. RESULTS: The stents were successfully deployed in all 181 sinuses. Thirty days after the ESS, the stents significantly reduced the need for surgical intervention compared to the Nasopore (P < .0001). The percentage of cases with polyp formation was significantly lower on the stent sides compared with the Nasopore sides (P < .0001) at 14, 30, and 90 days after ESS. The percentage of severe adhesion was significantly lower on the stents sides than on the Nasopore sides at postoperative day 90 (P = .0003), whereas they were not significantly lower at postoperative days 14 and 30. There were no significant differences between the stent sides and the Nasopore sides regarding the frequency of MT lateralization at all end points. No device-related adverse events occurred. CONCLUSIONS: Our study demonstrated significant improvement in the early postoperative outcomes by reducing the need for postoperative surgical intervention and polyp formation using steroid-eluting stents when compared with absorbable Nasopore packs. The steroid-eluting sinus stents and the Nasopore packs were each effective in preserving the ethmoid sinus patency and in preventing MT lateralization. A further prospective cohort study with long-term postoperative outcomes is warranted.

Cytotoxicity Induction by the Oxidative Reactivity of Nanoparticles Revealed by a Combinatorial GNP Library with Diverse Redox Properties.

It is crucial to establish relationship between nanoparticle structures (or properties) and nanotoxicity. Previous investigations have shown that a nanoparticle's size, shape, surface and core materials all impact its toxicity. However, the relationship between the redox property of nanoparticles and their toxicity has not been established when all other nanoparticle properties are identical. Here, by synthesizing an 80-membered combinatorial gold nanoparticle (GNP) library with diverse redox properties, we systematically explored this causal relationship. The compelling results revealed that the oxidative reactivity of GNPs, rather than their other physicochemical properties, directly caused cytotoxicity via induction of cellular oxidative stress. Our results show that the redox diversity of nanoparticles is regulated by GNPs modified with redox reactive ligands.

Elucidation of the Critical Role of Core Materials in PM2.5-Induced Cytotoxicity by Interrogating Silica- and Carbon-Based Model PM2.5 Particle Libraries.

An insoluble core with adsorbed pollutants constitutes the most toxic part of PM2.5 particles. However, the toxicological difference between carbon and silica cores remains unknown. Here, we employed 32-membered carbon- and silica-based model PM2.5 libraries that each was loaded with four toxic airborne pollutants including Cr(VI), As(III), Pb2+, and BaP in all possible combinations to explore their contributions to cytotoxicity in normal human bronchial cells. The following three crucial findings were revealed: (1) more adsorption of polar pollutants in a silica core (such as Cr(VI), As(III), and Pb2+) and nonpolar ones in a carbon core (such as BaP); (2) about 41% more cell uptake of carbon- than silica-based particles; and (3) about 59% less toxicity in silica- than carbon-based particles when pollutants other than Cr(VI) were loaded. This was reversed after Cr(VI) loading (silica particles were 56% more toxic). The difference maker is that compared to stable silica, carbon particles reduce Cr(VI) to less toxic Cr(III). Our findings highlight the different roles of carbon and silica cores in inducing health risks of PM2.5 particles.

One Pot Synthesis of Large Gold Nanoparticles with Triple Functional Ferrocene Ligands.

In biomedical, toxicological, and optoelectronic applications, the size of nanoparticles is one of the decisive factors. Therefore, synthesis of nanoparticles with controlled sizes is required. The current methods for synthesis of larger gold nanoparticles (GNPs, ~200 nm) are complex and tedious, producing nanoparticles with a lower yield and more irregular shapes. Using ferrocene as a primary reducing agent and stabilizer, sodium citrate as a dispersant, and sodium borohydride as an accessory reducing agent, GNPs of 200 nm were synthesized in a one pot reaction. Besides the roles of reducing agent and GNP stabilizer, ferrocene also served a role of quantitative marker for ligand loading, allowing an accurate determinate of surface ligands.

Regulation of Cell Uptake and Cytotoxicity by Nanoparticle Core under the Controlled Shape, Size, and Surface Chemistries.

Nanoparticle structural parameters, such as size, surface chemistry, and shape, are well-recognized parameters that affect biological activities of nanoparticles. However, whether the core material of a nanoparticle also plays a role remains unknown. To answer this long-standing question, we synthesized and investigated a comprehensive library of 36 nanoparticles with all combinations of three types of core materials (Au, Pt, and Pd), two sizes (6 and 26 nm), and each conjugated with one of six surface ligands of different hydrophobicity. Using this systematic approach, we were able to identify cellular perturbation specifically attributed to core, size, or surface ligand. We discovered that core materials exhibited a comparable regulatory ability as surface ligand on cellular ROS generation and cytotoxicity. Pt nanoparticles were much more hydrophilic and showed much less cell uptake compared to Au and Pd nanoparticles with identical size, shape, and surface ligands. Furthermore, diverse core materials also regulated levels of cellular redox activities, resulting in different cytotoxicity. Specifically, Pd nanoparticles significantly reduced cellular H2O2 and promoted cell survival, while Au nanoparticles with identical size, shape, and surface ligand induced higher cellular oxidative stress and cytotoxicity. Our results demonstrate that nanoparticle core material is as important as other structural parameters in nanoparticle-cell interactions, making it also a necessary consideration when designing nanomedicines.

Universal nanohydrophobicity predictions using virtual nanoparticle library.

To facilitate the development of new nanomaterials, especially nanomedicines, a novel computational approach was developed to precisely predict the hydrophobicity of gold nanoparticles (GNPs). The core of this study was to develop a large virtual gold nanoparticle (vGNP) library with computational nanostructure simulations. Based on the vGNP library, a nanohydrophobicity model was developed and then validated against externally synthesized and tested GNPs. This approach and resulted model is an efficient and effective universal tool to visualize and predict critical physicochemical properties of new nanomaterials before synthesis, guiding nanomaterial design.

Ultrafine particle libraries for exploring mechanisms of PM2.5-induced toxicity in human cells.

Air pollution worldwide, especially in China and India, has caused serious health issues. Because PM2.5 particles consist of solid particles of diverse properties with payloads of inorganic, organic and biological pollutants, it is still not known what the major toxic components are and how these components induce toxicities. To explore this complex issue, we apply reductionism principle and an ultrafine particle library approach in this work. From investigation of 63 diversely functionalized ultrafine particles (FUPs) with adsorbed key pollutants, our findings indicate that 1) only certain pollutants in the payloads of PM2.5 are responsible for causing cellular oxidative stress, cell apoptosis, and cytotoxicity while the particle carriers are much less toxic; 2) pollutant-induced cellular oxidative stress and oxidative stress-triggered apoptosis are identified as one of the dominant mechanisms for PM2.5-induced cytotoxicity; 3) each specific toxic component on PM2.5 (such as As, Pb, Cr or BaP) mainly affects its specific target organ(s) and, adding together, these pollutants may cause synergistic or just additive effects. Our findings demonstrate that reductionism concept and model PM2.5 particle library approach are very effective in our endeavor to search for a better understanding of PM2.5-induced health effects.

Management of maxillary sinus inverted papilloma via endoscopic partial medial maxillectomy with an inferior turbinate reversing approach.

The aim of this study is to evaluate the efficacy of endoscopic treatment for maxillary inverted papilloma (IP) through partial medial maxillectomy with an inferior turbinate reversing approach. A retrospective analysis of patients treated in our institution for maxillary sinus IP between July 2011 and August 2015 was performed. Demographics, operative technique, characteristics of tumors, complications, postoperative follow-up, and recurrence were evaluated. Twenty-two patients were enrolled in the study. All tumor attachments were identified intraoperatively. Adequate visualization was obtained following our approach. All inferior turbinate and nasolacrimal ducts were preserved. The median follow-up time was 41 months. One recurrence occurred at the follow-up time of 27 months. Postoperative hemorrhage and numbness at the ipsilateral frontal teeth were reported in two and one patients, respectively. Endoscopic surgery through partial medial maxillectomy using an inferior turbinate reversing approach provides full access to the maxillary sinus and preserves the inferior turbinate and nasolacrimal duct.

Toward a systematic exploration of nano-bio interactions.

Many studies of nanomaterials make non-systematic alterations of nanoparticle physicochemical properties. Given the immense size of the property space for nanomaterials, such approaches are not very useful in elucidating fundamental relationships between inherent physicochemical properties of these materials and their interactions with, and effects on, biological systems. Data driven artificial intelligence methods such as machine learning algorithms have proven highly effective in generating models with good predictivity and some degree of interpretability. They can provide a viable method of reducing or eliminating animal testing. However, careful experimental design with the modelling of the results in mind is a proven and efficient way of exploring large materials spaces. This approach, coupled with high speed automated experimental synthesis and characterization technologies now appearing, is the fastest route to developing models that regulatory bodies may find useful. We advocate greatly increased focus on systematic modification of physicochemical properties of nanoparticles combined with comprehensive biological evaluation and computational analysis. This is essential to obtain better mechanistic understanding of nano-bio interactions, and to derive quantitatively predictive and robust models for the properties of nanomaterials that have useful domains of applicability.

Different roles of Staphylococcus aureus enterotoxin in different subtypes of nasal polyps.

Chronic rhinosinusitis with nasal polyps (CRSwNP) is a multifactorial disease. The pathogenesis of CRSwNP remains unclear. This study was designed to investigate the role of inflammation and Staphylococcus aureus enterotoxin (SE) in this disease. The study included a total of 74 patients with CRSwNP and 6 controls. A serum Phadiatop assay was conducted to detect atopy status, and serum eosinophil cationic protein (ECP) and total immunoglobulin (Ig)E levels were determined using ELISA. SEA, SEB, total IgE, ECP and myeloperoxidase (MPO) levels in nasal tissue supernatant were measured using ELISA. The results indicated that 15 (22.1%) patients had systemic allergies. On the basis of the ECP/MPO ratio, the patients were divided into an eosinophilic CRSwNP group (n=18) and a non-eosinophilic CRSwNP group (n=56). The total ECP/MPO ratio was 0.572, with a notable bias toward neutrophilic inflammation. The supernatant ECP and MPO levels were elevated in the CRSwNP group compared with the control group, but no significant difference in the serum total IgE and ECP levels were observed between the CRSwNP and control groups. In addition, the non-eosinophilic and eosinophilic CRSwNP groups showed significant elevations in supernatant total IgE, SEA and SEB levels compared with the control group. Thus, it may be concluded that allergy is a common pathogenesis of CRSwNP, and neutrophilic inflammation is present in most Chinese CRSwNP patients. Additionally, local indicators reflect the inflammatory status more accurately than do serum indicators. SEs may act as an infection factor rather than as a superantigen in Chinese non-eosinophilic CRSwNP patients. Thus, long-term antibiotic therapy may be an option for Chinese non-eosinophilic CRSwNP patients.

Copper(II)-Silver(I) Macrocyclic Metal-Organic Framework: A Highly Efficient Reusable Triplet Oxygen Collector and Singlet Oxygen Generator.

The generation of highly reactive oxygen (1O2) is very significant for a variety of applications such as degradation, bleaching, chemical synthesis, photodynamic therapy for tumor treatment, and others. Herein, we report a novel peroxide-dianion-embedded bimetallic macrocycle, [O22-@Ag4Cu4L4]2+ (2), that can completely release the inserted peroxide dianion as the singlet oxygen (1O2) via a H+-assisted disproportionation process in methanol. Notably, the resulting empty Ag4Cu4L4(ClO4)4 (3) is able to trap oxygen (3O2) from air and fixes it in the macrocycle host as a peroxide dianion; furthermore, it releases it as 1O2 again in the presence of H+. So, the bimetallic macrocycle [Ag4Cu4L4]4+ herein behaves as a highly efficient reusable triplet oxygen receptor and singlet oxygen generator.

Understanding of the low temperature auto-oxidation scheme of sec-alcohols based on a Cu(II)-MOF with open metal sites.

A Cu(II)-MOF (1') with open metal sites was readily obtained by removing the coordinated water molecule at 120 °C. It can be used as a probe to evidence the sec-alkyl hydroperoxide species generated from room temperature sec-alcohol auto-oxidation in air. The formed alkyl hydroperoxides can be effectively catalyzed by 1' to decompose into molecular oxygen and corresponding sec-alcohols under ambient conditions.

A case report of an inflammatory myofibroblastic tumor of the neck: A focus on the computed tomography and magnetic resonance imaging findings.

Inflammatory myofibroblastic tumors (IMTs) of the neck are rare, with only a few patients reported in the literature. The present study discusses the clinical manifestations, radiographic characteristics and management of these tumors, with a focus on imaging modalities. A case of IMT of the neck is presented and the associated literature is reviewed. In total, seven patients in seven English-language studies, including the present case, and one patient in one Chinese-language study were found. On CT scans, all tumors appeared as soft-tissue densities. Upon magnetic resonance imaging (MRI), all tumors displayed a heterogeneous hypointense-isointense signal on T1-weighted sequences and an isointense-hyperintense signal on T2-weighted sequences. All tumors showed enhancement on enhanced CT and MR images. The imaging features of the neck IMTs can be summarized as follows: i) When enhanced, the tumor displays enhancement on CT and MR images; ii) MRI is superior to CT scans in the differential diagnosis of this disease; iii) in general, the lesion displays a hypointense-isointense signal on T1-weighted sequences and an isointense-hyperintense signal on T2-weighted sequences; iv) due to the fibrous tissue in the tumor, delayed enhancement may be observed on gadolinium-enhanced MR images; and v) due to its benign or intermediate features, the tumor is usually a well-defined mass.