Small molecules disaggregate alpha-synuclein and prevent seeding from patient brain-derived fibrils.

The amyloid aggregation of alpha-synuclein within the brain is associated with the pathogenesis of Parkinson's disease (PD) and other related synucleinopathies, including multiple system atrophy (MSA). Alpha-synuclein aggregates are a major therapeutic target for treatment of these diseases. We identify two small molecules capable of disassembling preformed alpha-synuclein fibrils. The compounds, termed CNS-11 and CNS-11g, disaggregate recombinant alpha-synuclein fibrils in vitro, prevent the intracellular seeded aggregation of alpha-synuclein fibrils, and mitigate alpha-synuclein fibril cytotoxicity in neuronal cells. Furthermore, we demonstrate that both compounds disassemble fibrils extracted from MSA patient brains and prevent their intracellular seeding. They also reduce in vivo alpha-synuclein aggregates in C. elegans. Both compounds also penetrate brain tissue in mice. A molecular dynamics-based computational model suggests the compounds may exert their disaggregating effects on the N terminus of the fibril core. These compounds appear to be promising therapeutic leads for targeting alpha-synuclein for the treatment of synucleinopathies.

Cryo-EM structures of the D290V mutant of the hnRNPA2 low-complexity domain suggests how D290V affects phase separation and aggregation.

Heterogeneous nuclear ribonucleoprotein A2 (hnRNPA2) is a human ribonucleoprotein that transports RNA to designated locations for translation via its ability to phase separate. Its mutated form, D290V, is implicated in multisystem proteinopathy known to afflict two families, mainly with myopathy and Paget's disease of bone. Here, we investigate this mutant form of hnRNPA2 by determining cryo-EM structures of the recombinant D290V low complexity domain. We find that the mutant form of hnRNPA2 differs from the WT fibrils in four ways. In contrast to the WT fibrils, the PY-nuclear localization signals in the fibril cores of all three mutant polymorphs are less accessible to chaperones. Also, the mutant fibrils are more stable than WT fibrils as judged by phase separation, thermal stability, and energetic calculations. Similar to other pathogenic amyloids, the mutant fibrils are polymorphic. Thus, these structures offer evidence to explain how a D-to-V missense mutation diverts the assembly of reversible, functional amyloid-like fibrils into the assembly of pathogenic amyloid, and may shed light on analogous conversions occurring in other ribonucleoproteins that lead to neurological diseases such as amyotrophic lateral sclerosis and frontotemporal dementia.

Integrative physiology and transcriptome reveal salt-tolerance differences between two licorice species: Ion transport, Casparian strip formation and flavonoids biosynthesis.

BACKGROUND: Glycyrrhiza inflata Bat. and Glycyrrhiza uralensis Fisch. are both original plants of 'Gan Cao' in the Chinese Pharmacopoeia, and G. uralensis is currently the mainstream variety of licorice and has a long history of use in traditional Chinese medicine. Both of these species have shown some degree of tolerance to salinity, G. inflata exhibits higher salt tolerance than G. uralensis and can grow on saline meadow soils and crusty saline soils. However, the regulatory mechanism responsible for the differences in salt tolerance between different licorice species is unclear. Due to land area-related limitations, the excavation and cultivation of licorice varieties in saline-alkaline areas that both exhibit tolerance to salt and contain highly efficient active substances are needed. The systematic identification of the key genes and pathways associated with the differences in salt tolerance between these two licorice species will be beneficial for cultivating high-quality salt-tolerant licorice G. uralensis plant varieties and for the long-term development of the licorice industry. In this research, the differences in growth response indicators, ion accumulation, and transcription expression between the two licorice species were analyzed. RESULTS: This research included a comprehensive comparison of growth response indicators, including biomass, malondialdehyde (MDA) levels, and total flavonoids content, between two distinct licorice species and an analysis of their ion content and transcriptome expression. In contrast to the result found for G. uralensis, the salt treatment of G. inflata ensured the stable accumulation of biomass and total flavonoids at 0.5 d, 15 d, and 30 d and the restriction of Na+ to the roots while allowing for more K+ and Ca2+ accumulation. Notably, despite the increase in the Na+ concentration in the roots, the MDA concentration remained low. Transcriptome analysis revealed that the regulatory effects of growth and ion transport on the two licorice species were strongly correlated with the following pathways and relevant DEGs: the TCA cycle, the pentose phosphate pathway, and the photosynthetic carbon fixation pathway involved in carbon metabolism; Casparian strip formation (lignin oxidation and translocation, suberin formation) in response to Na+; K+ and Ca2+ translocation, organic solute synthesis (arginine, polyamines, GABA) in response to osmotic stresses; and the biosynthesis of the nonenzymatic antioxidants carotenoids and flavonoids in response to antioxidant stress. Furthermore, the differential expression of the DEGs related to ABA signaling in hormone transduction and the regulation of transcription factors such as the HSF and GRAS families may be associated with the remarkable salt tolerance of G. inflata. CONCLUSION: Compared with G. uralensis, G. inflata exhibits greater salt tolerance, which is primarily attributable to factors related to carbon metabolism, endodermal barrier formation and development, K+ and Ca2+ transport, biosynthesis of carotenoids and flavonoids, and regulation of signal transduction pathways and salt-responsive transcription factors. The formation of the Casparian strip, especially the transport and oxidation of lignin precursors, is likely the primary reason for the markedly higher amount of Na+ in the roots of G. inflata than in those of G. uralensis. The tendency of G. inflata to maintain low MDA levels in its roots under such conditions is closely related to the biosynthesis of flavonoids and carotenoids and the maintenance of the osmotic balance in roots by the absorption of more K+ and Ca2+ to meet growth needs. These findings may provide new insights for developing and cultivating G. uralensis plant species selected for cultivation in saline environments or soils managed through agronomic practices that involve the use of water with a high salt content.

Crosstalk between Interleukin-1 Receptor-Like 1 and Transforming Growth Factor-ß Receptor Signaling Promotes Renal Fibrosis

IL-33, a member of the IL-1 family, acts as an alarmin in immune response. Epithelial-mesenchymal transition and transforming growth factor-ß (TGF-ß)­induced fibroblast activation are key events in the development of renal interstitial fibrosis. The current study found increased expression of IL-33 and interleukin-1 receptor-like 1 (IL1RL1, alias ST2), the receptor for IL-33, in human fibrotic renal tissues. In addition, IL-33­ or ST2-deficient mice showed significantly reduced levels of fibronectin, α-smooth muscle actin, and vimentin, and increased E-cadherin levels. In HK-2 cells, IL-33 promotes the phosphorylation of the TGF-ß receptor (TGF-ßR), Smad2, and Smad3, and the production of extracellular matrix (ECM), with reduced expression of E-cadherin. Blocking TGF-ßR signaling or suppressing ST2 expression impeded Smad2 and Smad3 phosphorylation, thereby reducing ECM production, suggesting that IL-33­induced ECM synthesis requires cooperation between the two pathways. Mechanistically, IL-33 treatment induced a proximate interaction between ST2 and TGF-ßRs, activating downstream Smad2 and Smad3 for ECM production in renal epithelial cells. Collectively, this study identified a novel and essential role for IL-33 in promoting TGF-ß signaling and ECM production in the development of renal fibrosis. Therefore, targeting IL-33/ST2 signaling may be an effective therapeutic strategy for renal fibrosis.

Label-free Colorimetric Detection of Viral RNA Based on Clustered Regularly Interspaced Short Palindromic Repeats and Gold Nanoparticles with a Portable Device.

Viral infections, such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), are some of the most dangerous threats to humans. SARS-CoV-2 has caused a global pandemic, highlighting the unprecedented demand for rapid and portable diagnostic methods. To meet these requirements, we designed a label-free colorimetric platform that combines the clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR-associated proteins (Cas) 12a system for naked-eye detection (named LFP). This method utilizes reverse transcription loop-mediated isothermal amplification (RT-LAMP) and the trans-cleavage activity of the CRISPR/Cas12a system to increase the sensitivity and specificity of the reaction. This platform can detect as few as 4 copies/µL of RNA and produces no false positive results when tested against the influenza virus. To better meet the requirements of point-of-care (POC) detection, we developed a portable device that can be applied in resource-poor and densely populated regions. The LFP assay holds great potential for application in resource-limited settings, and the label-free gold nanoparticle (AuNPs) probe can reduce costs, making it suitable for large-scale screening. We expect that the LFP assay will be promising for the POC screening of COVID-19.

Curcumin affects autophagy of prolactinoma cells by upregulating miR-206 to exert antitumor effects.

We explored the effects of curcumin on the aberrant biological behaviors of prolactinoma cells and the downstream pathways through which curcumin exerts its antitumor effects. We used quantitative reverse transcription-polymerase chain reaction assays to measure miR-206 expression levels in peripheral blood samples from patients with prolactinoma before and after curcumin treatment. We also investigated the proliferation level, viability, and invasion ability of groups of cells treated with different concentrations of curcumin using 3-(4,5)-dimethylthiahiazo (-z-y1)-3-di-phenytetrazoliumromide (MTT) assays, cell cloning assays, and Transwell assays, respectively. Furthermore, we determined the levels of autophagy-related proteins and protein kinase B/mammalian target of the rapamycin (Akt/mTOR) signaling pathway-related proteins in each group of treated cells by western blot. Curcumin treatment upregulated miR-206 expression levels in the peripheral blood of patients with prolactinoma and in GH3 cells. Knockdown of miR-206 expression enhanced the proliferation and invasive ability of GH3 cells, while curcumin treatment effectively inhibited the aberrant biological behavior of GH3 cells enhanced by miR-206 knockdown. miR-206 knockdown also activated the Akt/mTOR signaling pathway and inhibited autophagy in GH3 cells, and these changes were effectively reversed by curcumin treatment. Thus, curcumin inhibited the Akt/mTOR signaling pathway and promoted cell autophagy by miR-206 upregulation, resulting in antitumor effects that inhibited prolactinoma cell proliferation and invasion.

Comparative analysis of immunological changes following realgar and arsenic trioxide treatments in a murine model of myelodysplastic syndrome.

BACKGROUND: Myelodysplastic syndrome (MDS) is a prevalent hematological neoplastic disorder in clinics and its immunopathogenesis has garnered growing interest. Oral and intravenous arsenic agents have long been used to treat hematological malignancies. The main component of oral arsenic is realgar (arsenic disulfide), while arsenic trioxide is the main component of intravenous arsenic. METHODS: This study aimed to assess the effects of ATO and Realgar on the enhancement of peripheral blood, drug safety, and T cell immune status in the NUP98-HOXD13 (NHD13) mice model of MDS, specifically in the peripheral blood, spleen, and liver. RESULTS: The study findings indicate that realgar and arsenic trioxide (ATO) can improve peripheral hemogram in mice, whereas realgar promotes higher peripheral blood cell production than ATO. Furthermore, the clinical administration method and dose did not cause significant toxicity or side effects and thus can be considered safe. Coexistence and interconversion of hyperimmune function and immunosuppression in mice were also observed in this study. In addition, there were interactions between immune cells in the peripheral blood, spleen, and liver to regulate the immune balance of the body and activate immunity via T-cell activation. CONCLUSION: In summary, oral and intravenous arsenic agents are beneficial in improving peripheral hemogram and immunity in mice.

Recombinant outer membrane vesicles delivering eukaryotic expression plasmid of cytokines act as enhanced adjuvants against Helicobacter pylori infection in mice.

The widespread prevalence of Helicobacter pylori (H. pylori) infection remains a great challenge to human health. The existing vaccines are not ideal for preventing H. pylori infection; thus, exploring highly effective adjuvants may improve the immunoprotective efficacy of H. pylori vaccines. In a previous study, we found that the outer membrane vesicles (OMVs), a type of nanoscale particle spontaneously produced by Gram-negative bacteria, could act as adjuvants to boost the immune responses to vaccine antigens. In this study, we explored the potential application of OMVs as delivery vectors for adjuvant development. We constructed recombinant OMVs containing eukaryotic expression plasmid of cytokines, including interleukin 17A or interferon-γ, and evaluated their function as adjuvants in combination with inactivated whole-cell vaccine (WCV) or UreB as vaccine antigens. Our results showed that recombinant OMVs as adjuvants could induce stronger humoral and mucosal immune responses in mice than wild-type H. pylori OMVs and the cholera toxin (CT) adjuvant. Additionally, the recombinant OMVs significantly promoted Th1/Th2/Th17-type immune responses. Furthermore, the recombinant OMV adjuvant induced more potent clearance of H. pylori than CT and wild-type OMVs. Our findings suggest that the recombinant OMVs coupled with cytokines may become potent adjuvants for the development of novel and effective vaccines against H. pylori infection.

Formin protein DIAPH1 positively regulates PD-L1 expression and predicts the therapeutic response to anti-PD-1/PD-L1 immunotherapy.

Formins are evolutionarily conserved genes and profoundly affect cancer progression. This study aims to explore the expressions, prognostic values, and immunological correlations of Formins in cancer. Specific Formins were dysregulated and immuno-biologically correlated in breast cancer (BRCA). Formins showed different expression patterns, namely some were enriched in immune cells while some were enriched in tumor cells. Among all Formins, DIAPH1 was enriched in tumor cells and associated with an inflamed tumor microenvironment (TME). DIAPH1 functioned as an oncogene in BRCA and mediated TGF-ß1-induced epithelial-mesenchymal transformation (EMT) and PD-L1 expression. Moreover, DIAPH1 was overexpressed in most cancers and functioned as a novel pan-cancer immuno-marker, which could predict the response to anti-PD-1/PD-L1 immunotherapy. Overall, DIAPH1 functions as an oncogene and is immunologically correlated, which could be utilized as an alternative biomarker for predicting the immunotherapeutic response.

Gastrointestinal microbiome of ARDS patients induces neuroinflammation and cognitive impairment in mice.

BACKGROUND: Acute respiratory distress syndrome (ARDS) is a respiratory failure syndrome that can cause many complications, impacting patients' quality of life. Behavioral and cognitive disorders have attracted increasing attention in patients with ARDS, but its potential mechanisms are still elusive. METHODS: Herein we transferred the faecal microbiota from patients with ARDS caused by community-acquired pneumonia (CAP) to antibiotics-treated recipient male mice to explore the microbiota-gut-brain mechanisms. Behavioral functions of mice were evaluated by the open field test, Morris water maze and Y-maze test. The structure and composition of the gut microbiota were analyzed by using 16S rRNA sequencing analysis. Microglia, astrocyte and neuron in the cortex and hippocampus were examined via immunofluorescent staining. RESULTS: We found that the major characteristic of the intestinal flora in ARDS/CAP patients was higher abundances of Gram-negative bacteria than normal controls. The gut microbiota derived from ARDS/CAP patients promoted neuroinflammation and behavioral dysfunctions in mice. Mice who underwent fecal transplant from ARDS/CAP patients had increased systemic lipopolysaccharide (LPS), systemic inflammation, and increased colonic barrier permeability. This may adversely impact blood barrier permeability and facilitate microglia activation, astrocyte proliferation, and loss of neurons. CONCLUSIONS: Our study proposes the role of the microbiota-gut-brain crosstalk on ARDS/CAP-associated behavioral impairments and suggests the gut microbiota as a potential target for the protection of brain health in ARDS patients in clinical practice.

Transient neonatal hyperglycemia induces metabolic shifts in the rat hippocampus: a 1H NMR-based metabolomics analysis.

Diabetes has been reported to induce brain metabolic disturbance, but the effect of transient neonatal hyperglycemia (TNH) on brain metabolism remains unclear. Herein the rats were treated with a single intraperitoneal injection of 100 µg/g body weight of streptozotocin within 12 h after birth and displayed a typical clinical characteristic of TNH. Then we used NMR-based metabolomics to examine the metabolic changes in the hippocampus between TNH and normal control (Ctrl) rats at postnatal 7 days (P7) and 21 days (P21). The results show that TNH rats had significantly increased levels of N-acetyl aspartate, glutamine, aspartate and choline in the hippocampus relative to Ctrl rats at P7. Moreover, we found that the levels of alanine, myo-inositol and choline were significantly lower in TNH rats, although their blood glucose levels have been recovered to the normal level at P21. Therefore, our results suggest that TNH may have a long-term effect on hippocampal metabolic changes mainly involving neurotransmitter metabolism and choline metabolism.

Do Socioeconomic Disparities Matter? Unraveling the Impacts of Online Vaccine Misinformation on Vaccination Intention During the COVID-19 Pandemic in China.

Concerns have been raised about whether and how groups at high risk of COVID-19 are more likely affected by online vaccine misinformation during the pandemic. This study examined the associations between exposure to online vaccine misinformation and vaccination intention through vaccination perceptions and investigated the moderating role of individuals' socioeconomic status. eHealth literacy was also investigated as a protective factor that mediated the effect of socioeconomic status. A survey of 1,700 Chinese netizens revealed that increased exposure to online COVID-19 vaccine misinformation predicted lower vaccination intention, which was mediated by negative attitudes, lowered subjective norms, lowered perceived benefits, and higher perceived barriers toward vaccination. Socio-economic status (i.e. education, income, and residence), in general, did not guarantee individuals against the negative impacts of vaccine misinformation. eHealth literacy is critical in reducing susceptibility to vaccine misinformation during the COVID-19 pandemic.

Heuristic Information Processing as a Mediating Factor in the Process of Exposure to COVID-19 Vaccine Information and Misinformation Sharing on Social Media.

Social media use for risk communication during the COVID-19 pandemic has caused considerable concerns about an overabundance of information, particularly misinformation. However, how exposure to COVID-19 information on social media can lead to subsequent misinformation sharing during the pandemic has received little research attention. This study adopted the social amplification of risk framework to delineate how exposure to COVID-19 vaccine information on social media can be associated with individuals' misinformation sharing through heuristic information processing. The role of social media trust was also examined. Results from an online survey (N = 1488) of Chinese Internet users revealed that exposure to COVID-19 vaccine information on social media was associated with misinformation sharing, mediated by both affect heuristics (i.e., negative affect toward the COVID-19 pandemic in general) and availability heuristics (i.e., perceived misinformation availability). Importantly, both high and low levels of trust in social media strengthened the mediating associations. While a low level of trust strengthened the association between exposure to COVID-19 vaccine information on social media and the affect heuristics, a high level of trust strengthened its association with the availability heuristics, both of which were associated with misinformation sharing. Our findings suggest that heuristic information processing is essential in amplifying the spread of misinformation after exposure to risk information on social media. It is also suggested that individuals should maintain a middle level of trust in social media, being open while critical of risk information on social media.

Potential Therapeutic Mechanism of Traditional Chinese Medicine on Diabetes in Rodents: A Review from an NMR-Based Metabolomics Perspective.

Traditional Chinese medicine (TCM) has been used to treat diabetes for a long time, but its application has not been widely accepted due to unstandardized product quality and complex pharmacological mechanisms. The modernization of TCM is crucial for its further development, and in recent years the metabolomics technique has largely driven its modernization. This review focuses on the application of NMR-based metabolomics in diabetic therapy using TCM. We identified a series of metabolic pathways that altered significantly after TCM treatment, providing a better understanding of the metabolic mechanisms of TCM for diabetes care.

Transcriptome revealed the molecular mechanism of Glycyrrhiza inflata root to maintain growth and development, absorb and distribute ions under salt stress.

BACKGROUND: Soil salinization extensively hampers the growth, yield, and quality of crops worldwide. The most effective strategies to counter this problem are a) development of crop cultivars with high salt tolerance and b) the plantation of salt-tolerant crops. Glycyrrhiza inflata, a traditional Chinese medicinal and primitive plant with salt tolerance and economic value, is among the most promising crops for improving saline-alkali wasteland. However, the underlying molecular mechanisms for the adaptive response of G. inflata to salinity stress remain largely unknown. RESULT: G. inflata retained a high concentration of Na+ in roots and maintained the absorption of K+, Ca2+, and Mg2+ under 150 mM NaCl induced salt stress. Transcriptomic analysis of G. inflata roots at different time points of salt stress (0 min, 30 min, and 24 h) was performed, which resulted in 70.77 Gb of clean data. Compared with the control, we detected 2645 and 574 differentially expressed genes (DEGs) at 30 min and 24 h post-salt-stress induction, respectively. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses revealed that G. inflata response to salt stress post 30 min and 24 h was remarkably distinct. Genes that were differentially expressed at 30 min post-salt stress induction were enriched in signal transduction, secondary metabolite synthesis, and ion transport. However, genes that were differentially expressed at 24 h post-salt-stress induction were enriched in phenylpropane biosynthesis and metabolism, fatty acid metabolism, glycerol metabolism, hormone signal transduction, wax, cutin, and cork biosynthesis. Besides, a total of 334 transcription factors (TFs) were altered in response to 30 min and 24 h of salt stress. Most of these TFs belonged to the MYB, WRKY, AP2-EREBP, C2H2, bHLH, bZIP, and NAC families. CONCLUSION: For the first time, this study elucidated the salt tolerance in G. inflata at the molecular level, including the activation of signaling pathways and genes that regulate the absorption and distribution of ions and root growth in G. inflata under salt stress conditions. These findings enhanced our understanding of the G. inflata salt tolerance and provided a theoretical basis for cultivating salt-tolerant crop varieties.

Platelet transcriptome profiles provide potential therapeutic targets for elderly acute myelocytic leukemia patients.

BACKGROUND: Acute myeloid leukemia (AML) is the most common acute leukemia in adults, with a median age of 68 in clinical diagnosis. About 60% patients are over 60 years old. There are various treatment options for AML patients. But for elderly patients, the complete remission rates are disappointing due to genetic, molecular, and age-related factors. Development of next-generation sequencing technologies makes it possible to seek individual strategies for patients in different ages. This study analyzed transcriptome profiles in platelets of AML patients in different ages for the first time. METHODS: Platelet RNA sequencing in AML of ten elderly and seven young patients were performed with Illumina TruSeq Stranded mRNA library Prep Kit and Illumina HiSeq4000 sequencing instrument. With the FASTQ sequencing data obtained, statistical analyses between elderly with young AML patients were analyzed by R program. GO and KEGG enrichment analyses were performed via R package clusterProfiler. TOP 10 down-regulated/up-regulated genes in elderly patients compared to young patients were selected with the threshold of |L2FC| > 2 and padj ≤ 0.0001. The down-regulated gene ATF4 was chosen by GSEA analysis and ROC analysis with AUC > 0.95. RESULTS: We found 3059 genes with differential transcript levels (GDTLs) in AML patients of different age. Among them, 2048 genes are down-regulated and 651 genes are up-regulated in elderly patients. We found that gene transcript profiles in elderly patients is obviously different from those in young patients, including a collection of down-regulated genes related to proteins processing in endoplasmic reticulum and immunity. We further identified that genes of pathway in cancer and mitogen activated protein kinase (MAPK) pathway, involved in natural immunity and metabolism, are significantly down-regulated in elderly patients. Among all screened genes with decreased transcript levels, we believe that activating transcription factor 4 (ATF4) is a biomarker indicating different chemotherapy strategies for elderly patients. CONCLUSIONS: In summary, gene transcript profiles are different in platelets of elderly and young AML patients. And ATF4 can be a useful biomarker indicating different chemotherapy strategies for AML patients with different ages.

Polydopamine-Based Nanoparticles for Photothermal Therapy/Chemotherapy and their Synergistic Therapy with Autophagy Inhibitor to Promote Antitumor Treatment.

Polydopamine (PDA) has attracted much attention recently due to its strong adhesion capability to most substrates. After combining with organic (such as organic metal framework, micelles, hydrogel, polypeptide copolymer) or inorganic nanomaterials (such as gold, silicon, carbon), polydopamine-based nanoparticles (PDA NPs) exhibit the merging of characteristics. Until now, the preparation methods, polymerization mechanism, and photothermal therapy (PTT) or chemotherapy (CT) applications of PDA NPs have been reported detailly. Since the PTT or CT treatment process is often accompanied by exogenous stimuli, tumor cells usually induce pro-survival autophagy to protect the cells from further damage, which will weaken the therapeutic effect. Therefore, an in-depth understanding of PDA NPs modulated PTT, CT, and autophagy is required. However, this association is rarely reviewed. Herein, we briefly described the relationship between PTT/CT, autophagy, and tumor treatment. Then, the outstanding performances of PDA NPs in PTT/CT and their combination with autophagy inhibitors for tumor synergistic therapy have been summarized. This work is expected to shed light on the multi-strategy antitumor therapy applications of PDA NPs.

Examining Twitter Discourse on Electronic Cigarette and Tobacco Consumption During National Cancer Prevention Month in 2018: Topic Modeling and Geospatial Analysis.

BACKGROUND: Examining public perception of tobacco products is critical for effective tobacco policy making and public education outreach. While the link between traditional tobacco products and lung cancer is well established, it is not known how the public perceives the association between electronic cigarettes (e-cigarettes) and lung cancer. In addition, it is unclear how members of the public interact with official messages during cancer campaigns on tobacco consumption and lung cancer. OBJECTIVE: In this study, we aimed to analyze e-cigarette and smoking tweets in the context of lung cancer during National Cancer Prevention Month in 2018 and examine how e-cigarette and traditional tobacco product discussions relate to implementation of tobacco control policies across different states in the United States. METHODS: We mined tweets that contained the term "lung cancer" on Twitter from February to March 2018. The data set contained 13,946 publicly available tweets that occurred during National Cancer Prevention Month (February 2018), and 10,153 tweets that occurred during March 2018. E-cigarette-related and smoking-related tweets were retrieved, using topic modeling and geospatial analysis. RESULTS: Debates on harmfulness (454/915, 49.7%), personal experiences (316/915, 34.5%), and e-cigarette risks (145/915, 15.8%) were the major themes of e-cigarette tweets related to lung cancer. Policy discussions (2251/3870, 58.1%), smoking risks (843/3870, 21.8%), and personal experiences (776/3870, 20.1%) were the major themes of smoking tweets related to lung cancer. Geospatial analysis showed that discussion on e-cigarette risks was positively correlated with the number of state-level smoke-free policies enacted for e-cigarettes. In particular, the number of indoor and on campus smoke-free policies was related to the number of tweets on e-cigarette risks (smoke-free indoor, r49=0.33, P=.02; smoke-free campus, r49=0.32, P=.02). The total number of e-cigarette policies was also positively related to the number of tweets on e-cigarette risks (r49=0.32, P=.02). In contrast, the number of smoking policies was not significantly associated with any of the smoking themes in the lung cancer discourse (P>.13). CONCLUSIONS: Though people recognized the importance of traditional tobacco control policies in reducing lung cancer incidences, their views on e-cigarette risks were divided, and discussions on the importance of e-cigarette policy control were missing from public discourse. Findings suggest the need for health organizations to continuously engage the public in discussions on the potential health risks of e-cigarettes and raise awareness of the insidious lobbying efforts from the tobacco industry.

Improved Particle Swarm Optimization Based on Entropy and Its Application in Implicit Generalized Predictive Control.

Setting sights on the problem of input-output constraints in most industrial systems, an implicit generalized predictive control algorithm based on an improved particle swarm optimization algorithm (PSO) is presented in this paper. PSO has the advantages of high precision and fast convergence speed in solving constraint problems. In order to effectively avoid the problems of premature and slow operation in the later stage, combined with the idea of the entropy of system (SR), a new weight attenuation strategy and local jump out optimization strategy are introduced into PSO. The velocity update mechanism is cancelled, and the algorithm is adjusted respectively in the iterative process and after falling into local optimization. The improved PSO is used to optimize the performance index in predictive control. The combination of PSO and gradient optimization for rolling-horizon improves the optimization effect of the algorithm. The simulation results show that the system overshoot is reduced by about 7.5% and the settling time is reduced by about 6% compared with the implicit generalized predictive control algorithm based on particle swarm optimization algorithm (PSO-IGPC).

Cav-1 participates in the development of diabetic neuropathy pain through the TLR4 signaling pathway.

This study aims to determine whether caveolin-1 (Cav-1) participates in the process of diabetic neuropathic pain by directly regulating the expression of toll-like receptor 4 (TLR4) and the subsequent phosphorylation of N-methyl-D-aspartate receptor 2B subunit (NR2B) in the spinal cord. Male Sprague-Dawley rats (120-150 g) were continuously fed with high-fat and high-sugar diet for 8 weeks, and received a single low-dose of intraperitoneal streptozocin injection in preparation for the type-II diabetes model. Then, these rats were divided into five groups according to the level of blood glucose, and the mechanical withdrawal threshold and thermal withdrawal latency values. The pain thresholds were measured at 3, 7, and 14 days after animal grouping. Then, eight rats were randomly chosen from each group and killed. Lumbar segments 4-6 of the spinal cord were removed for western blot analysis and immunofluorescence assay. Cav-1 was persistently upregulated in the spinal cord after diabetic neuropathic pain in rats. The downregulation of Cav-1 through the subcutaneous injection of Cav-1 inhibitor daidzein ameliorated the pain hypersensitivity and TLR4 expression in the spinal cord in diabetic neuropathic pain (DNP) rats. Furthermore, it was found that Cav-1 directly bound with TLR4, and the subsequent phosphorylation of NR2B in the spinal cord contributed to the modulation of DNP. These findings suggest that Cav-1 plays a vital role in DNP processing at least in part by directly regulating the expression of TLR4, and through the subsequent phosphorylation of NR2B in the spinal cord.