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.

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.

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.

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.

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.

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.

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.

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.

Endoscopic prelacrimal recess approach adjunct with vestibular sulcus incision: case report of a minimally invasive access to remove infratemporal fossa tumor.

To remove tumor located at anterolateral-inferior of infratemporal fossa (ITF) with purely transnasal approach is still a great challenge because of the over lateral angulation. The aim of this study is to present our initial experience--endoscopic prelacrimal recess approach adjunct with vestibular sulcus incision as a simple and minimally invasive approach to remove tumor in this area. Tumor in anterolateral ITF can be well explored via endoscopic prelacrimal recess approach; a simple vestibular sulcus incision provides a second access for two-surgeon co-operation, so tumor can be removed conveniently with minimal invasion. It is a viable alternative to endoscopic extended medial maxillectomy approach or open approaches to this area.

Objective assessment of persistent rhinitis in Chinese and its relationship with serum indicators.

Persistent rhinitis (PR) is a chronic disease that affects millions of people. However, it lacks of a useful method, which can indicate the actual severity of the inflammation in PR patients. This study was designed to seek an examination which could reflect the actual severity of PR disease. The serum Phadiatop test, ECP level, four-phase rhinomanometry, and acoustic rhinometry were assessed in 91 adult patients with PR and 10 healthy controls. The serum total IgE was determined in some of the patients and all of the controls. The patients were divided into four groups: ARWO, ARWTO, NARWO and NARWTO. 40% (22/55) of AR and 33.3% (13/36) of NAR patients never complained of persistent nasal obstruction. Serum ECP levels were increased in the ARWO group. Serum total IgE was significantly elevated in the AR groups. MCA(1-Min) and MCA(1-T) were significantly reduced in the ARWO, ARWTO, and NARWO groups. NV(6-Min) and NV(6-T) were decreased in all PR groups, but only some of these differences were significant. In the ARWO group, MCA(2-Min) (r = -0.252), MCA(2-T) (r = -0.377), NV(6-Min) (r = -0.32), and NV(6-T) (r = -0.311) had significant relationships with serum ECP. We recommend acoustic rhinometry as a useful routine tool for the diagnosis of PR, even among patients without persistent subjective nasal obstruction. This technique might reveal the actual status of nasal congestion. An elevated serum ECP level might indicate severe AR and is negatively correlated with the results of acoustic rhinometry.

CD44 expression is predictive of poor prognosis in pharyngolaryngeal cancer: systematic review and meta-analysis.

Pharyngolaryngeal cancer is one of the most common head and neck cancer worldwide, and the early diagnosis and prognosis prediction are still difficult because of lacking in reliable cell markers. Although the expression of CD44 has been reported to correlate with poor prognosis of pharyngolaryngeal cancer in most literatures, some controversies still exist. Since the limited patient numbers within independent studies, here we performed a meta-analysis to clarify the correlations between CD44 expression and clinicopathological features and prognosis in pharyngolaryngeal cancer. A search of PubMed, ISI Web of Science and China National Knowledge Infrastructure databases (up to June 2013) was performed. Nineteen studies with 1,405 patients met the inclusion criteria. The expression of pan-CD44, including all variant isoforms, was detected in 58.0% (14.1-79.2%) specimens, while CD44-v6 (variant isoform 6 of CD44) was expressed in 54.8% (12-79.2%). In pooled analysis, CD44 expression was significantly associated with larger tumor size (T category, RR (relative risk) = 1.21, 95% CI: 1.01-1.46), lymph nodes metastasis (N category, RR = 1.94, 95% CI: 1.38-2.73) and poor prognosis [3-year overall survival (OS): RR = 0.70, 95% CI: 0.53-0.91; 5-year OS: RR = 0.66, 95% CI: 0.66-0.94]. In the stratified analysis of CD44 isoforms, high expression of CD44-v6 was related with a poor 5-year OS rate (RR = 0.53, 95% CI: 0.37-077). We propose that CD44 expression is associated with tumor size, lymph node metastasis, and poor prognosis in pharyngolaryngeal cancer patients.

The utility of repeated computed tomography to track a foreign body penetrating the esophagus to the level of the thyroid gland.

OBJECTIVE: Foreign body (FB) ingestion is a common problem in otolaryngology. One uncommon complication of FB ingestion is penetration to the level of the thyroid gland. To our knowledge, only 21 such cases have been reported in the literature. Here, we report a case of an esophageal FB penetrating to the level of the right thyroid gland. CASE REPORT: The patient was a 38-year-old woman in whom an esophageal FB penetrated to the level of the right thyroid gland. We traced the path to the thyroid gland using repeated computed tomography (CT) scans and demonstrated the importance of multiplanar reconstruction in locating the FB and formulating a precise surgical plan. CONCLUSIONS: To our knowledge, this is the first report of repeat CT scans being used to demonstrate the migratory route, over time, of a FB penetrating through the esophagus to the level of the thyroid gland. Our results suggest that multiplanar reconstruction may play a key role in the precise diagnosis of a FB at the level of the thyroid gland and may help surgeons choose the best approach for removal.

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.

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.

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.

Isolated inverting papilloma of the sphenoid sinus: clinical presentations, imaging manifestations, and therapeutic strategies.

BACKGROUND: Isolated inverting papilloma (IP) of the sphenoid sinus is rare, with about 50 patients reported in the English-language literature. With its rarity, scientists have paid less attention to the clinical and radiographic characteristics of isolated IPs arising from the sphenoid sinus. METHODS: We describe the clinical presentation, imaging manifestations, and surgical methods of isolated IPs from the sphenoid sinus in 3 patients and review the English-language literature from 1970 to 2011. RESULTS: In total, 59 cases of isolated sphenoid sinus IPs (including our cases) have been reported, 40 patients with computed tomography or magnetic resonance imaging details. The most common presentation is headache. Lesions were found in the sphenoethmoidal recess in 26 cases. In 8 patients who underwent enhanced magnetic resonance imaging, the tumor was obviously intensified. We found 26 patients with bony destruction, and 8 lesions revealed the correct tumor origin. CONCLUSIONS: A polyp-like mass in the sphenoethmoidal recess strongly implied the diagnosis of an IP in the sphenoid sinus. Bony destruction on computed tomography is a common characteristic of this disease and had a close relationship with the original tumor site in our study. Malignant transformation of IPs in the sphenoid sinus is much scarcer.

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.