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In the existing large-scale distributed environments, there is still much room for improvement in the performance and computational efficiency of big data applications.However, performance analysis and optimization in large-scale environments requires a large number of human resources from domain experts.This paper proposes a general lowperformance query statement detection and optimization process for performance optimization in big data applications, summarizes four types of low-performance behaviors that significantly affect the performance of big data applications, and proposes specific optimization strategies for each type of low-performance behavior.Finally, through experimental evaluation, the effectiveness of the optimization scheme in actual large-scale cluster is verified.

Abstract Lung cancer is the primary cause of cancer-related death worldwide, and its global incidence and mortality rates remain high. The differential expression of circular RNAs (circRNAs) can affect the development of cancer, but the mechanisms by which circRNAs regulate lung cancer progression remain unclear. In this study, we identified circSORBS1, a circRNA that has not been previously described in lung cancer and is significantly underexpressed in lung cancer tissues, blood and cell lines, and the low expression of circSORBS1 correlated with tumour grade and prognosis. In vitro and in vivo functional experiments revealed that circSORBS1 overexpression inhibited cell proliferation and migration while enhancing apoptosis. Mechanistically, circSORBS1 acts as a sponge for miR-6779-5p, indirectly inhibiting RUFY3 mRNA degradation. Simultaneously, it binds to RUFY3 mRNA to enhance its stability. This dual regulatory mechanism leads to an increase in RUFY3 protein levels, which ultimately activates the YWHAE/BAD/BCL2 apoptotic signalling pathway and suppresses lung cancer progression. Our findings not only increase the knowledge about the regulatory pattern of circRNA expression but also provide new insights into the mechanisms by which circRNAs regulate lung cancer development.

BackgroundCo-use of alcohol and e-cigarettes (often called vaping) has been linked with long-term health outcomes, including increased risk for substance use disorder. Co-use may have been exacerbated by the COVID-19 pandemic. Social networking sites may offer insights into current perspectives on polysubstance use. ObjectiveThe aims of this study were to investigate concurrent mentions of vaping and alcohol on Twitter (subsequently rebranded X) during a time of changing vaping regulations in the United States and the emergence of the COVID-19 pandemic. MethodsTweets including both vape- and alcohol-related terms posted between October 2019 and September 2020 were analyzed using latent Dirichlet allocation modeling. Distinct topics were identified and described. ResultsThree topics were identified across 6437 tweets: (1) flavors and flavor ban (n=3334, 51.8% of tweets), (2) co-use discourse (n=1119, 17.4%), and (3) availability and access regulation (n=1984, 30.8%). Co-use discussions often portrayed co-use as positive and prosocial. Tweets focused on regulation often used alcohol regulations for comparison. Some focused on the perceived overregulation of vaping (compared to alcohol), while others supported limiting youth access but not at the expense of adult access (eg, stronger age verification over product bans). Across topics, vaping was typically portrayed as less harmful than alcohol use. The benefits of flavors for adult smoking cessation were also discussed. The distribution of topics across time varied across both pre– and post–regulatory change and pre– and post–COVID-19 pandemic declaration periods, suggesting shifts in topic focus salience across time. ConclusionsCo-use discussions on social media during this time of regulatory change and social upheaval typically portrayed both vaping and alcohol use in a positive light. It also included debates surrounding the differences in regulation of the 2 substances—particularly as it related to limiting youth access. Emergent themes from the analysis suggest that alcohol was perceived as more harmful but less regulated and more accessible to underage youth than vaping products. Frequent discussions and comparisons of the 2 substances as it relates to their regulation emphasize the still-evolving vaping policy landscape. Social media content analyses during times of change may help regulators and policy makers to better understand and respond to common concerns and potential misconceptions surrounding drug-related policies and accessibility.

Huntington’s disease (HD) is a progressive neurodegenerative disorder characterized by motor dysfunction and cognitive decline. While retinal abnormalities have been documented in some HD patients and animal models, the nature of these abnormalities—specifically whether they originate in the inner or outer retina—remains unclear, particularly regarding their progression with age. This study investigates the retinal structure and function in HD transgenic mice (R6/1) compared to C57BL/6 J control mice at 2, 4, and 6 months of age, encompassing both pre-symptomatic and symptomatic stages of HD. Pathological assessments of the striatum and evaluations of motor function confirmed significant HD-related alterations in R6/1 mice at 6 months. Visual function was subsequently analyzed, accompanied by immunofluorescent staining of retinal and optic nerve tissues over time. Our findings revealed that R6/1 mice exhibited pronounced HD symptoms at 6 months, characterized by neuronal loss in the striatum and impaired locomotor abilities. Functionally, visual acuity declined at 6 months, while retinal light responses began to deteriorate by 4 months. Structurally, R6/1 mice demonstrated a global reduction in cone opsin expression as early as 2 months, with a decrease in rhodopsin levels at 4 months, alongside a thinner retinal structure compared to controls. Notably, rod bipolar cell populations were decreased at 6 months, exhibiting shorter dendritic branches and reduced synaptic connections with photoreceptors in the outer retina. Additionally, ganglion cell numbers in the inner retina decreased at 6 months, accompanied by aberrant neural fibers in the optic nerve. Microglial activation was evident at 4 months, while astrocytic activation was observed at 6 months. Aggregates of mutant huntingtin (mHTT) were first detected in the ganglion cell layer and optic nerve at 2 months, subsequently disseminating throughout all retinal layers with advancing age. These results indicate that retinal pathology in R6/1 mice manifests earlier in the outer retina than in the inner retina, which does not align with the progression of mHTT aggregation. Consequently, the R6/1 mouse retina may serve as a more effective model for elucidating the mechanisms underlying HD and evaluating potential therapeutic strategies, rather than functioning as an early diagnostic tool for the disease.

Abstract Although the issue of embodied pollutants in China’s supply chains has garnered increasing attention, the dynamic changes occurring within them are unclear. Several existing studies analyze one-year or short-term data in supply chain. China’s overall CH4 emissions have risen from 41.1 Tg in 2000 to 60 Tg in 2020, so conducting long-term analyses can yield a deeper understanding of the dynamic changes across the entire supply chain from production to consumption. This study uses the environmentally extended input–output analysis (EEIOA) and structural path analysis (SPA) methods to investigate the dynamic variation of China’s embodied CH4 emissions in 20 industry sectors from 2000 to 2020, aiming to determine the key supply chain and key sectors. The results reveal that from the final demand perspective, consumption, investment and export drove 52.1%, 32%, and 15.9% of embodied CH4 emissions in 2020. The sector with the highest embodied CH4 emissions has changed from “Agriculture” in 2000 to “Construction” in 2010 to “Other service and activities” in 2020. The top listed supply chain path of embodied CH4 emissions has also evolved (starting from production to consumption) from “Agriculture → Rural consumption” in 2000 to “Agriculture → Food and tobacco → Urban consumption” in 2010 to “Agriculture → Urban consumption” in 2020. Notably, the high-ranked path, “Agriculture → Food and tobacco → Rural consumption”, shows that the embodied CH4 emission flowing between agriculture and the food industry cannot be ignored. The supply chain path “Coal Mining → Nonmetal Mineral Products → Construction → Capital Formation” has risen from 17th in 2000 to 3rd in 2020. Thus, it is necessary to control CH4 emissions from sectors upstream, which are predominantly influenced by the construction industry, and a coordinated effort between sectors is also required to effectively reduce emissions. By 2020, the CH4 emissions driven by urban consumption were 3.1 times that of rural consumption. This study provides a comprehensive analysis of China's supply chain over the past two decades. In particular, it suggests policy interventions by controlling critical supply chain paths and key sectors associated with embodied CH4 emission, thereby facilitating the coordinated reduction of anthropogenic CH4 emissions.

German pathologist Otto Aichel suggested, a century ago, that the cancer cell acquired its metastatic property from a leukocyte via cell-cell fusion. Since then, several revised versions of this theory have been proposed. Most of the proposals attribute the generation of the metastatic cancer cell to the fusion between a primary cancer cell and a macrophage. However, these theories have not addressed several issues, such as dormancy and stem cell-like self-renewal, of the metastatic cancer cell. On the other hand, recent studies have found that, like T- and B-/plasma cells, macrophages can also be categorized into naïve, effector, and memory/trained macrophages. As a memory/trained macrophage can enter dormancy/quiescence, be awakened from the dormancy/quiescence by acquainted primers, and re-populate via stem cell-like self-renewal, we, therefore, further specify that the macrophage fusing with the cancer cell and contributing to metastasis, belongs with the memory/trained macrophage, not other subtypes of macrophages. The current theory can explain many puzzling clinical features of cancer, including the paradoxal effects (recurrence vs. regression) of microbes on tumors, “spontaneous” and Coley’s toxin-induced tumor regression, anticancer activities of β-blockers and anti-inflammatory/anti-immune/antibiotic drugs, oncotaxis, surgery- and trauma-promoted metastasis, and impact of microbiota on tumors. Potential therapeutic strategies, such as Coley’s toxin-like preparations, are proposed. This is the last article of our trilogy on carcinogenesis theories.

Abstract China, as the world’s largest importer, heavily relies on agricultural products. However, the impact of China’s free trade agreements (FTAs) on greenhouse gas (GHG) emissions embodied in agricultural product imports has been overlooked. It’s crucial to analyze changes in embodied GHG emissions resulting from FTAs. We categorize 367 agricultural products into 15 categories and construct a dataset on the embodied GHG emissions of these products imported by China from 119 countries between 2000 and 2015. Using the Propensity Score Matching (PSM)-progressive difference-in-differences (DID) method, our findings indicate that China’s FTAs have double-edged impact on agricultural product imports. It has positively influenced imports, with a 12.22% annual growth rate, promoting economic integration. However, it has negatively affected GHG emissions, leading to a 53.00% increase in emissions from agricultural imports. These findings highlight the importance of addressing production and consumption in reducing GHG strategies with agricultural products.

Abstract Severe combined immunodeficiency (SCID) encompasses a range of inherited disorders that lead to a profound deterioration of the immune system. Among the pivotal genes associated with SCID, RAG1 and IL2RG play crucial roles. IL2RG is essential for the development, differentiation, and functioning of T, B, and NK cells, while RAG1 critically contributes to adaptive immunity by facilitating V(D)J recombination during the maturation of lymphocytes. Animal models carrying mutations in these genes exhibit notable deficiencies in their immune systems. Non-human primates (NHPs) are exceptionally well-suited models for biomedical research due to their genetic and physiological similarities to humans. Cytosine base editors (CBEs) serve as powerful tools for precisely and effectively modifying single-base mutations in the genome. Their successful implementation has been demonstrated in human cells, mice, and crop species. This study outlines the creation of an immunodeficient monkey model by deactivating both the IL2RG and RAG1 genes using the CBE4max system. The base-edited monkeys exhibited a severely compromised immune system characterized by lymphopenia, atrophy of lymphoid organs, and a deficiency of mature T cells. Furthermore, these base-edited monkeys were capable of hosting and supporting the growth of human breast cancer cells, leading to tumor formation. In summary, we have successfully developed an immunodeficient monkey model with the ability to foster tumor growth using the CBE4max system. These immunodeficiency monkeys show tremendous potential as valuable tools for advancing biomedical and translational research.

Precipitation data in urban hydrological models are derived from an ideal stormwater model, which has some uncertainties and limited prediction times. Therefore, to reliably forecast urban flooding, prolong prediction time periods, and better support associated research in urban flood forecasting, a combination of weather forecasts and urban hydrology is necessary. By applying comprehensive cloud microphysical schemes in the Weather Research and Forecasting (WRF) model to the predecessor torrential rainfall associated with Typhoon Khanun (2017), this study evaluated different configurations of atmospheric-hydrological simulations based on the WRF model and InfoWorks ICM. Results showed that the microphysics scheme could significantly affect spatial and temporal distributions of the simulated torrential rainfall. Generally, the combination of WRF and NSSL schemes produced better performance. Applying the NSSL scheme to the WRF model and combining it with the InfoWorks ICM system can reproduce torrential rainfall and urban flood formations.

Introduction: China, as the world’s largest emitter of carbon dioxide, faces significant challenges in agricultural greenhouse gas emissions. The Chinese government has been actively promoting household photovoltaic (PV) power generation, which has great potential for application in rural areas. This study aims to explore whether the promotion of household PV systems in rural areas has a positive impact on farmers’ low-carbon production behavior and to analyze the influencing factors and mechanisms. This research fills the research gap in the analysis of the promotion of household PV systems and farmers’ low-carbon production behavior, providing scientific evidence to support policymakers in promoting widespread use of household PV systems and facilitating the transition of farmers to low-carbon production methods.Methods: This study adopts a qualitative research method and analyzes interview data and semi-structured questionnaire survey data from 48 farmers. By collecting, organizing, comparing, and extracting information and employing the research process of grounded theory, the researchers summarize the model of household PV-driven low-carbon production behavior.Results: The study finds that the installation of household PV systems indeed promotes farmers to adopt more low-carbon production behaviors. Farmers who install household PV systems show a greater willingness to reduce the use of fertilizers and pesticides, conserve water resources, and improve land utilization, among others. They perceive the positive effects of household PV systems and their own capacity for environmental protection, enhancing confidence and motivation to engage in low-carbon production behaviors.Discussion: Existing research methods have mainly relied on theoretical deduction combined with quantitative empirical approaches when exploring farmers’ pro-environmental spillover behaviors. However, these methods often start from the perspectives of either egoism or altruism, resulting in biased tendencies toward negative spillover or positive spillover. Nevertheless, neither egoism nor altruism fully captures the decision-making process when deeply understanding farmers’ production, life, and decision-making processes. The installation of household PV systems can change factors such as farmers’ knowledge, skills, cognition, and resources, enhancing their green self-efficacy and helping them acquire more knowledge and skills in renewable energy. Therefore, this research adopts a qualitative research method to more accurately reflect farmers’ decision-making process and provides practical recommendations to promote farmers’ active transition to pro-environmental spillover behaviors.Conclusion: This study fills the research gap in the analysis of the promotion of household PV systems and farmers’ low-carbon production behavior, providing practical recommendations for policymakers to facilitate farmers’ positive behavioral changes. Qualitative research methods enable a more realistic understanding and promotion of farmers’ pro-environmental spillover behaviors by deeply understanding their contexts. The study offers targeted suggestions to policymakers to drive farmers’ transition to low-carbon production methods.

Can a robotic gripper only operate when attached to a robotic arm? The application space of the traditional gripper is limited by the robotic arm. Giving robot grippers the ability to move will expand their range of applications. Inspired by rich behavioral repertoire observed in octopus, we implement an integrated multifunctional soft robotic gripper with 6 independently controlled Arms. It can execute 8 different gripping actions for different objects, such as irregular rigid/soft objects, elongated objects with arbitrary orientation, and plane/curved objects with larger sizes than the grippers. Moreover, the soft gripper can realize omnidirectional crawling and swimming by itself. The soft gripper can perform highly integrated tasks of releasing, crawling, swimming, grasping, and retrieving objects in a confined underwater environment. Experimental results demonstrate that the integrated capabilities of multimodal adaptive grasping and omnidirectional motions enable dexterous manipulations that traditional robotic arms cannot achieve. The soft gripper may apply to highly integrated and labor-intensive tasks in unstructured underwater environments, including ocean litter collecting, capture fishery, and archeological exploration.

Abstract Accumulation of misfolded proteins leads to many neurodegenerative diseases that can be treated by lowering or removing mutant proteins. Huntington's disease (HD) is characterized by the intracellular accumulation of mutant huntingtin (mHTT) that can be soluble and aggregated in the central nervous system and causes neuronal damage and death. Here, an intracellular antibody (intrabody) fragment is generated that can specifically bind mHTT and link to the lysosome for degradation. It is found that delivery of this peptide by either brain injection or intravenous administration can efficiently clear the soluble and aggregated mHTT by activating the lysosomal degradation pathway, resulting in amelioration of gliosis and dyskinesia in HD knock‐in (KI‐140Q) mice. These findings suggest that the small intrabody peptide linked to lysosomes can effectively lower mutant proteins and provide a new approach for treating neurodegenerative diseases that are caused by the accumulation of mutant proteins.

Residential photovoltaics (PV) presents an effective means of achieving low-carbon development, owing to its installation flexibility and resource-saving properties. To explore the residents' behavioral intentions to purchase and install residential PV systems, this study collected 1424 samples and analyze the impact of different policies on residents' adoption of residential PV using the theory of TPB and the Partial Least Squares Structural Equation Model (PLS-SEM). The main conclusions are summarized as follows: (1) Bungalow residents exhibit a stronger inclination to install residential PV than building residents. (2) Perceived reward (PR) affects installation intention (II) more than perceived guide (PG) among bungalow residents. (3) Both PR and PG indirectly affect II through Perceived behavioral control (PBC) among bungalow residents. Economic policies, represented by PR, are likely to have more substantial indirect effects than propaganda and guidance policies. The findings suggest that China's recent residential PV installation policies should increase users' trust and guide the future decline of subsidy policy.

The Camellia weevil, Curculio chinensis (Chevrolat, 1978), is a dominant oligophagous pest that bores into the fruit of oil-tea Camellia. Genetic differentiation among populations in various hosts can easily occur, which hinders research on pest management. In this study, the genetic structure, genetic diversity, and phylogenetic structure of local C. chinensis populations were examined using 147 individuals (from 6 localities in Jiangxi), based on 2 mitochondrial COI markers. Results indicated that the C. chinensis population in Jiangxi exhibits a high haplotype diversity, especially for the populations from Cam. meiocarpa plantations. Structural differentiation was observed between Haplogroup 1 (73 individuals from Ganzhou, Jian, and Pingxiang) in the monoculture plantations of Cam. meiocarpa and Haplogroup 2 (75 individuals from Pingxiang and Jiujiang) in Cam. oleifera. Two haplogroups have recently undergone a demographic expansion, and Haplogroup 1 has shown a higher number of effective migrants than Haplogroup 2. This suggests that C. chinensis has been spreading from Cam. meiocarpa plantations to other oil-tea Camellia, such as Cam. oleifera. The increased cultivation of oil-tea Camellia in Jiangxi has contributed to a unique genetic structure within the C. chinensis population. This has, in turn, expanded the distribution of C. chinensis and increased migration between populations.

Abstract Asphalt pavement is vulnerable to the temperature rising and extremely high-temperature weather caused by climate change. The regulation techniques of asphalt pavement high temperature have become a growing concern to adapt to climate change. This paper reviewed the state of the art on regulating asphalt pavement high temperature. Firstly, the influencing factors and potential regulation paths of asphalt pavement temperature were summarized. The regulation techniques were categorized into two categories. One is to regulate the heat transfer process, including enhancing reflection, increasing thermal resistance, and evaporation cooling. The other is to regulate through heat collection and transfer or conversion, including embedded heat exchange system, phase change asphalt pavement, and thermoelectric system. Then, the regulation techniques in the literature were reviewed one by one in terms of cooling effects and pavement performance. The issues that still need to be improved were also discussed. Finally, the regulation techniques were compared from the perspectives of theoretical cooling effects, construction convenience, and required maintenance. It can provide reference for understanding the development status of asphalt pavement high temperature regulation techniques and technique selection in practice.

BackgroundHealth warnings in tobacco advertisements provide health information while also increasing the perceived risks of tobacco use. However, existing federal laws requiring warnings on advertisements for tobacco products do not specify whether the rules apply to social media promotions. ObjectiveThis study aims to examine the current state of influencer promotions of little cigars and cigarillos (LCCs) on Instagram and the use of health warnings in influencer promotions. MethodsInstagram influencers were identified as those who were tagged by any of the 3 leading LCC brand Instagram pages between 2018 and 2021. Posts from identified influencers, which mentioned one of the three brands were considered LCC influencer promotions. A novel Warning Label Multi-Layer Image Identification computer vision algorithm was developed to measure the presence and properties of health warnings in a sample of 889 influencer posts. Negative binomial regressions were performed to examine the associations of health warning properties with post engagement (number of likes and comments). ResultsThe Warning Label Multi-Layer Image Identification algorithm was 99.3% accurate in detecting the presence of health warnings. Only 8.2% (n=73) of LCC influencer posts included a health warning. Influencer posts that contained health warnings received fewer likes (incidence rate ratio 0.59, P

Animal models are important for understanding the pathogenesis of human diseases and for developing and testing new drugs. Pigs have been widely used in the research on the cardiovascular, skin barrier, gastrointestinal, and central nervous systems as well as organ transplantation. Recently, pigs also become an attractive large animal model for the study of neurodegenerative diseases because their brains are very similar to human brains in terms of mass, gully pattern, vascularization, and the proportions of the gray and white matters. Although adeno-associated virus type 9 (AAV9) has been widely used to deliver transgenes in the brain, its utilization in large animal models remains to be fully characterized. Here, we report that intravenous injection of AAV9-GFP can lead to widespread expression of transgene in various organs in the pig. Importantly, GFP was highly expressed in various brain regions, especially the striatum, cortex, cerebellum, hippocampus, without detectable inflammatory responses. These results suggest that intravenous AAV9 administration can be used to establish large animal models of neurodegenerative diseases caused by gene mutations and to treat these animal models as well.

In order to achieve the “dual carbon goal”, the Chinese government is actively encouraging the adoption of household photovoltaic (PV) systems. While there has been considerable research on residents’ inclination to install PV, limited attention has been given to understanding how the installation and utilization of PV systems influence pro-environmental behaviors. Therefore, this paper aims to investigate the potential impact of pro-environmental behavior resulting from household PV installation on users’ green purchasing behavior. Based on the “learning by doing” theory, a survey was conducted with 1249 participants, and the generalized structural equation model was employed as our analytical approach. The findings of this research indicate that the adoption and utilization of household photovoltaic (PV) systems have a positive impact on green consumption. The test results demonstrate that the overall effect coefficient is 0.03, indicating that current PV promotion policies have an indirect impact on green consumption. Moreover, economic incentive policies have a more substantial influence than environmental publicity policies, with total indirect effect coefficients of 0.005 and 0.002, respectively. Based on the findings above, the following recommendations are proposed: (1) It is recommended to maintain stable economic incentives to promote the adoption of household PV systems. (2) Emphasizing the dissemination of knowledge and skills for promoting environmental protection should be prioritized. (3) Efforts should be made to align personal interests and societal interests with low-carbon policies.

To develop a clean and sustainable carbon anode material derived from biomass with desirable properties for lithium-ion batteries (LIBs), bio-nitrogen (N)-doped composite carbon nanofibrous mats (CNFMs) were made using natural cellulose (CE) and chitosan (CS) by means of two different electrospinning ways (single-nozzle and coaxial-nozzle) coupled with pyrolysis. The conventional CNFMs that had a CE/CS ratio of 5:5 showed the best electrochemical performance, corresponding to a high specific capacity of 327 mAh g−1 at 100 mA g−1, good rate performance with specific capacity of 399 mAh g−1 at 30 mA g−1 and 210 mA g−1 at 1000 mA g−1, as well as excellent cycling stability after 300 cycles. The core–shell CNFMs with a thick outer layer of CS and large average fiber diameter (316 nm) at the same CE/CS ratio had higher pyridinic-N and pyrrolic-N contents but a lower degree of graphitization and BET surface area compared to the conventional CNFMs. It was concluded that the bio-N in CS was more uniformly doped into the CNFMs by the single-nozzle electrospinning way than by the coaxial one, and thus more effectively promoted a comprehensive electrochemical performance.

Introduction The public most frequently associates tobacco use solely with pulmonary health risks, despite heart disease being the leading cause of death in smokers. The health perceptions of e-cigarettes, especially cardiovascular health, have not been well studied. We aimed to evaluate the prevalence and health perceptions of tweets related to cardiovascular, pulmonary, and brain health – three organ systems for which tobacco use is a major disease risk factor. Methods We examined the cardiovascular, pulmonary, and brain health perceptions of vaping and JUUL on Twitter, followed by a content analysis of tweets pertaining to the cardiovascular risks. A Twitter firehose API scraped about 6.2 million publicly available tweets from 2015–2019 that contained vaping-related terms, and a separate dataset of about 1.9 million tweets that contained the term JUUL. A quantitative content analysis (n=2145) of tweets was subsequently conducted to assess the health perceptions of vaping and JUUL. Two trained coders independently assessed the posts and Twitter profiles to determine age (

This study explores the effects of sentiment of Instagram images and captions on the sentiment of comments. All Instagram posts with the hashtag #mentalhealth and the associated metadata were scraped on World Mental Health Day. A mixed-method approach of a sentiment classifier and a quantitative content analysis of Instagram posts (N = 7,078) was used. Overall, our sample contained more positive sentiment posts and comments than negative ones, indicating a possible connection between mental health-related discourse and positive sentiment on Instagram. Images containing faces elicited more likes, comments and positive comments compared with images without faces. MANCOVA analyses of images with human faces found that emotional contagion from Instagram posts to comments was only observed when considering the sentiment of both images and captions. Congruency effects were seen for posts with both negative captions and images, which elicited more negative comments compared to emotionally incongruent posts. Theoretical implications of emotional contagion and real-life implications for mental health social media campaign design are discussed.

Abstract Introduction Marathon, as a long-distance aerobic exercise, has become a fashionable or popular sport. However, little is known about the holistic metabolic changes occurring within the serum metabolome of athletes after the completion of a marathon. Objectives The goal of current study was to have an in-depth understanding of the impact of marathon on human metabolomics as well as the relationships among a variety of metabolites. Methods The 20 studied subjects were all adult males who participated in a marathon. The serum samples of these participants were collected before and after the marathon and the biochemical metabolites in the serum were identified by an untargeted two-dimensional gas chromatography time-of-flight mass spectrometry. Results All participants completed the marathon within 3 h. Compared to those before exercise, serum urea and creatine kinase, as well as cortisol, elevated significantly (p

The tip of the red giant branch provides a luminous standard candle for calibrating distance ladders that reach Type Ia supernova (SN Ia) hosts. However, recent work reveals that tip measurements vary at the ∼0.1 mag level for different stellar populations and locations within a host, which may lead to inconsistencies along the distance ladder. We pursue a calibration of the tip using 11 Hubble Space Telescope fields around the maser host, NGC 4258, that is consistent with SN Ia hosts by standardizing tip measurements via their contrast ratios. We find F814W-band tips that exhibit a full 0.3 mag range and 0.1 mag dispersion. We do not find any correlation between H i column density and the apparent tip to 0.04 ± 0.03 mag/cm ^−2 . We search for a tip–contrast relation (TCR) and measure the TCR within the fields of NGC 4258 of −0.015 ± 0.008 mag/ R , where R is the contrast ratio. This value is consistent with the TCR originally discovered in the GHOSTS sample of −0.023 ± 0.005 mag/ R . Combining these measurements, we find a global TCR of −0.021 ± 0.004 mag/ R and a calibration of ${M}_{I}^{\mathrm{TRGB}}=-4.025\pm 0.035-(R-4)\times 0.021$ mag. We also use stellar models to simulate single age and metallicity stellar populations with [Fe/H] from −2.0 to −0.7 and ages from 3 to 12 Gyr and reconstruct the global TCR found here to a factor of ∼2. This work is combined in a companion analysis with tip measurements of nearby SN Ia hosts to measure H _0 .

Reactive navigation is the most researched navigation technique for underground vehicles. Local path planning is one of the main research difficulties in reactive navigation. At present, no technique can perfectly solve the problem of local path planning for the reactive navigation of underground vehicles. Aiming to address this problem, this paper proposes a new method for local path planning based on 2D LiDAR. First, we convert the LiDAR data into a binary image, and we then extract the skeleton of the binary image through a thinning algorithm. Finally, we extract the centerline of the current laneway from these skeletons and smooth the obtained roadway centerline as the current planned local path. Experiments show that the proposed method has high robustness and good performance. Additionally, the method can also be used for the global path planning of underground maps.

The cycle of biogenic elements in lakes is intimately linked with particulate organic matter (POM), which plays a critical role in ecosystem restoration and the control of eutrophication. However, little is known regarding the functionality of ecosystem degradation on the source of POM in the water of a karst lake. To fill this knowledge gap, herein we compared the temporal and spatial distribution characteristics of POM prior to and after ecosystem degradation in the karst lake Caohai Lake, located in the southwest of China, and analyzed the source of POM using a combination of carbon and nitrogen stable isotopes (δ13C–δ15N). Our results showed that the dissolved oxygen (DO) concentration and pH values decreased, and the concentrations of POM in water increased by 11% and 31% in the wet and dry seasons, respectively. The decrease in the δ13C value of POM was accompanied by the increase in the δ15N value of POM in the water of Caohai lake. Prior to the ecosystem’s degradation, sediment resuspension (28%) and submerged macrophytes (33%) were the dominant sources of POM in lake water. In contrast, sediment resuspension (51%) was the major source of POM after the ecosystem’s degradation. Environmental factors, including DO, turbidity, water depth, and water temperature, that are related to photosynthesis and sediment resuspension are the main factors controlling the spatiotemporal distribution of POM. The resuspension of sediment reduced the transparency of the water, limiting effective photosynthesis, impeding the survival of submerged macrophytes, and, consequently, deteriorating the ecosystem. We propose that the control of sediment resuspension is important for improving the water transparency that creates an appropriate habitat for the restoration of the submerged macrophyte community.

Combined use of in situ passivation and macrophytes is a valuable technology that exerts remarkable effects on aquatic systems. However, the effectiveness and ecological functions of this combined technology for macrophytes-dominated eutrophic (MDE) lakes with organophosphorus-controlled internal phosphorus (P) loading were poorly understood. In this study, aquatic simulation experiments were performed to study the combination of La-modified materials (LMM; La-modified bentonite (LMB), and La/Al co-modified attapulgite (LAA)) with macrophytes (Myriophyllum verticillatum L. (MVL), Hydrilla verticillata (Linn. f.) royle (HVR), and Ceratophyllum demersum L. (CDL)) for the control of P mobility in the water column, and to investigate the passivator effects on the physiological characteristics of macrophytes. The mineralization of organophosphates (BD−Po, HCl−Po, and Res−Po) is an important factor for maintaining high internal P loadings and overlying water P concentrations in the experiments. Compared with individual treatment groups, the reduction of internal P release flux and porewater SRP concentrations was more obvious in the combined treatments. Moreover, the redox-sensitive P forms transformation is more pronounced in the surface sediments. In the LAA+M group, internal P release flux was reduced by 55% and 55% compared with individual passivators and macrophytes retreatment groups, respectively. In contrast, the LMB+M group decreased by 16% and 46%, respectively. Simultaneously, LMM had less effect on macrophytes traits compared with individual macrophytes group and enhanced the absorption of phosphate by macrophytes. The phosphate content of macrophytes in the LAA+M and LMB+M groups increased by 24% and 11%, respectively, in comparison with the individual macrophytes group. Results concluded that the combination of passivator and macrophytes enhanced the effect of ecological restoration and exerts a synergistic effect on internal P pollution with macrophytes.

This study aims at developing a green sustainable bio-inspired composite film by combining the flexible chitin/silk fibroin matrix (CT/SF) and the rigid cellulose nanocrystals (CNC) with the multi-layer chiral nematic structure. The effects of CNC concentration on the chemical bonding, optical- and micro-morphology, thermal stability and mechanical properies of chitin/silk fibroin/cellulose nanocrystal (CT/SF/CNC) were comprehensively investigated. The results indicate that a critical concentration for CNC at 2 wt% can display the obvious iridescent color domains of biocomposite films with potential optical functional property. There is a color shift from blue to yellow-red corresponding to the higher concentrations at 3.5 and 5.0 wt%, respectively. The concentration of CNC also affects the transition of conformation of SF from the random to the β -turn as well as the bonding ability between SF and CT. The CT/SF/CNC-3.5 wt% with the excellent optical and mechanical properties as well as the improved thermal stability breaks the conventional conflict between increased strength and compromised ductility. Its tensile strength and elongation at break effectively elevate by 282% and 42%, respectively.

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In obesity, elevated insulin causes fatty liver by activating the gene encoding SREBP-1c, a transcription factor that enhances fatty acid synthesis. Two transcription factors, LXRα and C/EBPβ, are necessary but not sufficient for insulin induction of hepatic SREBP-1c mRNA. Here, we show that a third transcription factor, BHLHE40, is required. Immunoprecipitation revealed that BHLHE40 binds to C/EBPβ and LXRα in livers of rats that had fasted and then refed. Hepatic BHLHE40 mRNA rises rapidly when fasted rats are refed and when rat hepatocytes are incubated with insulin. Preventing this rise by gene knockout in mice or siRNAs in hepatocytes reduces the insulin-induced rise in SREBP-1c mRNA. Although BHLHE40 is necessary for insulin induction of SREBP-1c, it is not sufficient as demonstrated by failure of lentiviral BHLHE40 overexpression to increase hepatocyte SREBP-1c mRNA in the absence of insulin. Thus, an additional event is required for insulin to increase SREBP-1c mRNA.

The presence of DNA in the cytoplasm is a danger signal that triggers immune and inflammatory responses. Cytosolic DNA binds to and activates cyclic GMP-AMP (cGAMP) synthase (cGAS), which produces the second messenger cGAMP. cGAMP binds to the adaptor protein STING and activates a signaling cascade that leads to the production of type I interferons and other cytokines. Here, we report the crystal structures of human cGAS in its apo form, representing its autoinhibited conformation as well as in its cGAMP- and sulfate-bound forms. These structures reveal switch-like conformational changes of an activation loop that result in the rearrangement of the catalytic site. The structure of DNA-bound cGAS reveals a complex composed of dimeric cGAS bound to two molecules of DNA. Functional analyses of cGAS mutants demonstrate that both the protein-protein interface and the two DNA binding surfaces are critical for cGAS activation. These results provide insights into the mechanism of DNA sensing by cGAS.

RNA virus infections are detected by the RIG-I family of receptors, which induce type-I interferons through the mitochondrial protein MAVS. MAVS forms large prion-like polymers that activate the cytosolic kinases IKK and TBK1, which in turn activate NF-κB and IRF3, respectively, to induce interferons. Here we show that MAVS polymers recruit several TRAF proteins, including TRAF2, TRAF5, and TRAF6, through distinct TRAF-binding motifs. Mutations of these motifs that disrupted MAVS binding to TRAFs abrogated its ability to activate IRF3. IRF3 activation was also abolished in cells lacking TRAF2, 5, and 6. These TRAF proteins promoted ubiquitination reactions that recruited NEMO to the MAVS signaling complex, leading to the activation of IKK and TBK1. These results delineate the mechanism of MAVS signaling and reveal that TRAF2, 5, and 6, which are normally associated with NF-κB activation, also play a crucial role in IRF3 activation in antiviral immune responses.

This paper addresses the consensus of second-order multiagent systems with general topology and time delay based on the nearest neighbor rule. By using the Laplace transform technique, it is proved that the second-order multi-agent system in the presence of time-delay can reach consensus if the network topology contains a globally reachable node and time delay is bounded. The bound of time-delay only depends on eigenvalues of the Laplacian matrix of the system. The main contribution of this paper is that the accurate state of the consensus center and the upper bound of the communication delay to make the agents reach consensus are given. Some numerical simulations are given to illustrate the theoretical results.

In clutter scenes, one or several targets need to be obtained, which is hard for robot manipulation task. Especially, when the targets are flat objects like book, plates, due to limitation of common robot end-effectors, it will be more challenging. By employing pre-grasp operation like sliding, it becomes feasible to rearrange objects and shift the target towards table edge, enabling the robot to grasp it from a lateral perspective. In this paper, the proposed method transfers the task into a Parameterized Action Markov Decision Process to solve the problem, which is based on deep reinforcement learning. The mask images are taken as one of observations to the network for avoiding the impact of noise of original image. In order to improve data utilization, the policy network predicts the parameters for the sliding primitive of each object, which is weight-sharing, and then the Q-network selects the optimal execution target. Meanwhile, extra reward mechanism is adopted for improving the efficiency of task actions to cope with multiple targets. In addition, an adaptive policy scaling algorithm is proposed to improve the speed and adaptability of policy training. In both simulation and real system, our method achieves a higher task success rate and requires fewer actions to accomplish the flat multi-target sliding manipulation task within clutter scene, which verifies the effectiveness of ours. [ABSTRACT FROM AUTHOR]

Drawing upon the literature on moral foundations theory and the social transmission of information, our study investigated the effects of values and emotions on the sharing of pro-vaping messages on Twitter. Tweets (N = 9,542) containing top pro-vaping hashtags during the time of e-cigarette or vaping use-associated lung injury (EVALI) and the federal vape bans were analyzed. A lexicon-based machine classifier customized to vaping discourse and the NRC Word-Emotion Association Lexicon were used to produce the frequencies of moral and emotional words in the corpus. Mixed-effects hurdle negative binomial models were performed to predict the likelihood of a post receiving one and more retweets. Results showed that moral foundations, particularly Authority/subversion and Care/harm, and emotions of anger and sadness predicted the sharing of pro-vaping tweets. Interaction effects indicated that both emotions had a stronger effect on eliciting shares when a post contained lower levels of moral foundations. This study provides insights into the mechanism of how pro-vaping messages are amplified on Twitter, emphasizing the roles of moral values and emotions in enabling the process. [ABSTRACT FROM AUTHOR]

INTRODUCTION The public most frequently associates tobacco use solely with pulmonary health risks, despite heart disease being the leading cause of death in smokers. The health perceptions of e-cigarettes, especially cardiovascular health, have not been well studied. We aimed to evaluate the prevalence and health perceptions of tweets related to cardiovascular, pulmonary, and brain health -- three organ systems for which tobacco use is a major disease risk factor. METHODS We examined the cardiovascular, pulmonary, and brain health perceptions of vaping and JUUL on Twitter, followed by a content analysis of tweets pertaining to the cardiovascular risks. A Twitter firehose API scraped about 6.2 million publicly available tweets from 2015-2019 that contained vaping-related terms, and a separate dataset of about 1.9 million tweets that contained the term JUUL. A quantitative content analysis (n=2145) of tweets was subsequently conducted to assess the health perceptions of vaping and JUUL. Two trained coders independently assessed the posts and Twitter profiles to determine age (<18 or ≥18 years), sex, race, sentiment towards JUUL, and vaping-related topics. RESULTS The majority of tweets containing vaping or JUUL-related terms did not also contain cardiovascular, pulmonary, or brain health terms (97.99% and 96.67%, respectively). Multiple linear regression analysis showed that youth (<18 years), females, non-White individuals, mention of a flavor, and mention of cardiovascular health harm words were associated with more positive sentiments towards JUUL. Pearson's chi-squared analyses indicated that youth were more likely to mention a JUUL flavor. Females and youth were more likely to reference cardiovascular terms with humor. CONCLUSIONS The cardiovascular health risks of vaping are not fully recognized by the public. Vulnerable populations such as youth and females reference JUUL with cardiovascular-related words that downplay the severity of tobacco as a major risk factor for cardiovascular disease. [ABSTRACT FROM AUTHOR]

Summer enrichment and residential programs can provide gifted students with positive social interactions and challenging curricula. However, little research has focused on gifted students' perceptions of the learning environment in such programs. This research project evaluated the psychometric properties and practical applications of the Student Perceptions of Classroom Quality (SPOCQ) instrument. The two studies used a total sample of 1,492 diverse, gifted students in Grades 5 through 12 who participated in a university-based enrichment residential program from 2010 through 2013. Confirmatory factor analysis results indicated that although the original model was a moderately good fit for the gifted student participants in 2010 to 2011, some items on the SPOCQ were classroom specific and did not apply to residential programs. Therefore, those items were revised and retested, and results showed that the modified model was a better fit for gifted student participants in 2012 to 2013. [ABSTRACT FROM AUTHOR]

CD11c, also known as integrin alpha X, is the most widely used defining marker for dendritic cells (DCs). CD11c can bind complement iC3b and mediate phagocytosis in vitro, for which it is also referred to as complement receptor 4. However, the functions of this prominent marker protein in DCs, especially in vivo, remain poorly defined. Here, in the process of studying DC activation and immune responses induced by cells lacking self-CD47, we found that DC capture of CD47-deficient cells and DC activation was dependent on the integrin-signaling adaptor Talin1. Specifically, CD11c and its partner Itgb2 were required for DC capture of CD47-deficient cells. CD11b was not necessary for this process but could partially compensate in the absence of CD11c. Mice with DCs lacking Talin1, Itgb2, or CD11c were defective in supporting T-cell proliferation and differentiation induced by CD47-deficient cell associated antigen. These findings establish a critical role for CD11c in DC antigen uptake and activation in vivo. They may also contribute to understanding the functional mechanism of CD47-blockade therapies. [ABSTRACT FROM AUTHOR]

Cyclic GMP-AMP containing a unique combination of mixed phosphodiester linkages (2'3'-cGAMP) is an endogenous second messenger molecule that activates the type-I IFN pathway upon binding to the homodimer of the adaptor protein STING on the surface of endoplasmic reticulum membrane. However, the preferential binding of the asymmetric ligand 2'3'-cGAMP to the symmetric dimer of STING represents a physicochemical enigma. Here we show that 2'3'-cGAMP, but not its linkage isomers, adopts an organized free-ligand conformation that resembles the STING-bound conformation and pays low entropy and enthalpy costs in converting into the active conformation. Our results demonstrate that analyses of free-ligand conformations can be as important as analyses of protein conformations in understanding protein-ligand interactions. [ABSTRACT FROM AUTHOR]

Invasion of microbial DNA into the cytoplasm of animal cells triggers a cascade of host immune reactions that help clear the infection; however, self DNA in the cytoplasm can cause autoimmune diseases. Biochemical approaches led to the identification of cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) synthase (cGAS) as a cytosolic DNA sensor that triggers innate immune responses. Here, we show that cells from cGAS-deficient (cGas-/-) mice, including fibroblasts, macrophages, and dendritic cells, failed to produce type I interferons and other cytokines in response to DNA transfection or DNA virus infection. cGas-/- mice were more susceptible to lethal infection with herpes simplex virus 1 (HSV1) than wild-type mice. We also show that cGAMP is an adjuvant that boosts antigen-specific T cell activation and antibody production in mice. [ABSTRACT FROM AUTHOR]

Retroviruses, including HIV, can activate innate immune responses, but the host sensors for retroviruses are largely unknown. Here we show that HIV infection activates cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) synthase (cGAS) to produce cGAMP, which binds to and activates the adaptor protein STING to induce type I interferons and other cytokines. Inhibitors of HIV reverse transcriptase, but not integrase, abrogated interferon-ß induction by the virus, suggesting that the reverse-transcribed HIV DNA triggers the innate immune response. Knockout or knockdown of cGAS in mouse or human cell lines blocked cytokine induction by HIV, murine leukemia virus, and simian immunodeficiency virus. These results indicate that cGAS is an innate immune sensor of HIV and other retroviruses. [ABSTRACT FROM AUTHOR]

Neurons from the brains of Alzheimer's disease (AD) and related tauopathy patients contain neurofibrillary tangles composed of hyperphosphorylated tau protein. Tau normally stabilizes microtubules (MTs); however, tau hyperphosphorylation leads to loss of this function with consequent MT destabilization and neuronal dysfunction. Accordingly, MT-stabilizing drugs such as paclitaxel and epothilone D have been shown as possible therapies for AD and related tauopathies. However, MT-stabilizing drugs have common side effects such as neuropathy and neutropenia. To find previously undescribed suppressors of tau-induced MT defects, we established a Drosophila model ectopically expressing human tau in muscle cells, which allow for clear visualization of the MT network. Overexpressed tau was hyperphosphorylated and resulted in decreased MT density and greater fragmentation, consistent with previous reports in AD patients and mouse models. From a genetic screen, we found that a histone deacetylase 6 (HDAC6) null mutation rescued tau-induced MT defects in both muscles and neurons. Genetic and pharmacological inhibition of the tubulin-specific deacetylase activity of HDAC6 indicates that the rescue effect may be mediated by increased MT acetylation. These findings reveal HDAC6 as a unique potential drug target for AD and related tauopathies. [ABSTRACT FROM AUTHOR]

Cytosolic DNA induces type I interferons and other cytokines that are important for antimicrobial defense but can also result in autoimmunity. This DNA signaling pathway requires the adaptor protein STING and the transcription factor IRF3, but the mechanism of DNA sensing is unclear. We found that mammalian cytosolic extracts synthesized cyclic guanosine monophosphate-adenosine monophosphate (cyclic GMP-AMP, or cGAMP) in vitro from adenosine triphosphate and guanosine triphosphate in the presence of DNA but not RNA. DNA transfection or DNA virus infection of mammalian cells also triggered cGAMP production. cGAMP bound to STING, leading to the activation of IRF3 and induction of interferon-β. Thus, cGAMP in metazoans and functions as an endogenous second messenger that triggers interferon production in response to cytosolic DNA. [ABSTRACT FROM AUTHOR]

The presence of DNA in the cytoplasm of mammalian cells is a danger signal that triggers, host immune responses such as the production of type I interferons. Cytosolic DNA induces interferons through the production of cyclic guanosine monophosphate-adenosine monophosphate (cyclic GMP-AMP, or cGAMP), which binds to and activates the adaptor protein STING. Through biochemical fractionation and quantitative mass spectrometry, we identified a cGAMP synthase (cGAS), which belongs to the nucleotidyltransferase family. Overexpression of cGAS activated the transcription factor IRF3 and induced interferon-p in a STING-dependent manner. Knockdown of cGAS inhibited IRF3 activation and interferon-p induction by DNA transfection or DNA virus infection. cGAS bound to DNA in the cytoplasm and catalyzed cGAMP synthesis. These results indicate that cGAS is a cytosolic DNA sensor that induces interferons by producing the second messenger cGAMP. [ABSTRACT FROM AUTHOR]

Abstract Background Tauopathies are neurodegenerative diseases that are associated with the pathological accumulation of tau-containing tangles in the brain. Tauopathy can impair cognitive and motor functions and has been observed in Alzheimer’s disease (AD) and frontotemporal dementia (FTD). The aetiology of tauopathy remains mysterious; however, recent studies suggest that the autophagic-endolysosomal function plays an essential role in the degradation and transmission of pathological tau. We previously demonstrated that tetrandrine could ameliorate memory functions and clear amyloid plaques in transgenic AD mice by restoring autophagic-endolysosomal function. However, the efficacy of tetrandrine and the associated therapeutic mechanism in tauopathies have not been evaluated and elucidated. Methods Novel object recognition, fear conditioning and electrophysiology were used to evaluate the effects of tetrandrine on memory functions in transgenic tau mice. Western blotting and immunofluorescence staining were employed to determine the effect of tetrandrine on autophagy and tau clearance in vivo. Calcium (Ca2+) imaging and flow cytometry were used to delineate the role of pathological tau and tetrandrine in lysosomal Ca2+ and pH homeostasis. Biochemical BiFC fluorescence, Western blotting and immunofluorescence staining were used to evaluate degradation of hyperphosphorylated tau in vitro, whereas coculture of brain slices with isolated microglia was used to evaluate tau clearance ex vivo. Results We observed that tetrandrine treatment mitigated tau tangle development and corrected memory impairment in Thy1-hTau.P301S transgenic mice. Mechanistically, we showed that mutant tau expression disrupts lysosome pH by increasing two-pore channel 2 (TPC2)-mediated Ca2+ release, thereby contributing to lysosome alkalinization. Tetrandrine inhibits TPC2, thereby restoring the lysosomal pH, promotes tau degradation via autophagy, and ameliorates tau aggregation. Furthermore, in an ex vivo assay, we demonstrated that tetrandrine treatment promotes pathological tau clearance by microglia. Conclusions Together, these findings suggest that pathological tau disturbs endolysosomal homeostasis to impair tau clearance. This impairment results in a vicious cycle that accelerates disease pathogenesis. The success of tetrandrine in reducing tau aggregation suggests first, that tetrandrine could be an effective drug for tauopathies and second, that rescuing lysosomal Ca2+ homeostasis, thereby restoring ALP function, could be an effective general strategy for the development of novel therapies for tauopathies.

Asthma is a chronic inflammatory disease characterized by airway hypersensitivity and remodeling. The current treatments provide only short-term benefits and may have undesirable side effects; thus, alternative or supplementary therapy is needed. Because intracellular calcium (Ca2+) signaling plays an essential role in regulating the contractility and remodeling of airway smooth muscle cells, the targeting of Ca2+ signaling is a potential therapeutic strategy for asthma. Houttuynia cordata is a traditional Chinese herb that is used to treat asthma due to its anti-allergic and anti-inflammatory properties. We hypothesized that H. cordata might modulate intracellular Ca2+ signaling and could help relieve asthmatic airway remodeling. We found that the mRNA and protein levels of inositol trisphosphate receptors (IP3Rs) were elevated in interleukin-stimulated primary human bronchial smooth muscle cells and a house dust mite–sensitized model of asthma. The upregulation of IP3R expression enhanced intracellular Ca2+ release upon stimulation and contributed to airway remodeling in asthma. Intriguingly, pretreatment with H. cordata essential oil rectified the disruption of Ca2+ signaling, mitigated asthma development, and prevented airway narrowing. Furthermore, our analysis suggested that houttuynin/2-undecanone could be the bioactive component in H. cordata essential oil because we found similar IP3R suppression in response to the commercially available derivative sodium houttuyfonate. An in silico analysis showed that houttuynin, which downregulates IP3R expression, binds to the IP3 binding domain of IP3R and may mediate a direct inhibitory effect. In summary, our findings suggest that H. cordata is a potential alternative treatment choice that may reduce asthma severity by targeting the dysregulation of Ca2+ signaling.

Alzheimer's disease (AD), characterized by the accumulation of protein aggregates including phosphorylated Tau aggregates, is the most common neurodegenerative disorder with limited therapeutic agents. Autophagy plays a critical role in the degradation of phosphorylated Tau aggregates, and transcription factor EB (TFEB) is a master regulator of autophagy and lysosomal biogenesis. Thus, small-molecule autophagy enhancers targeting TFEB hold promise for AD therapy. Here, we found that celastrol, an active ingredient isolated from the root extracts of Tripterygium wilfordii (Lei Gong Teng in Chinese) enhanced TFEB-mediated autophagy and lysosomal biogenesis in vitro and in mouse brains. Importantly, celastrol reduced phosphorylated Tau aggregates and attenuated memory dysfunction and cognitive deficits in P301S Tau and 3xTg mice, two commonly used AD animal models. Mechanistical studies suggest that TFEB-mediated autophagy-lysosomal pathway is responsible for phosphorylated Tau degradation in response to celastrol. Overall, our findings indicate that Celastrol is a novel TFEB activator that promotes the degradation of phosphorylated Tau aggregates and improves memory in AD animal models. Therefore, Celastrol shows potential as a novel agent for the treatment and/or prevention of AD and other tauopathies.

During virus infection, the adaptor proteins MAVS and STING transduce signals from the cytosolic nucleic acid sensors RIG-I and cGAS, respectively, to induce type I interferons (IFNs) and other antiviral molecules. Here we show that MAVS and STING harbor two conserved serine and threonine clusters that are phosphorylated by the kinases IKK and/or TBK1 in response to stimulation. Phosphorylated MAVS and STING then bind to a positively charged surface of interferon regulatory factor 3 (IRF3) and thereby recruit IRF3 for its phosphorylation and activation by TBK1.We further show that TRIF, an adaptor protein in Toll-like receptor signaling, activates IRF3 through a similar phosphorylation-dependent mechanism. These results reveal that phosphorylation of innate adaptor proteins is an essential and conserved mechanism that selectively recruits IRF3 to activate the type I IFN pathway. [ABSTRACT FROM AUTHOR]

Neuroinflammation is the precursor for several neurodegenerative diseases (NDDs), such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and multiple sclerosis (MS). Targeting neuroinflammation has emerged as a promising strategy to address a wide range of CNS pathologies. These NDDs still present significant challenges in terms of limited and ineffective diagnosis and treatment options, driving the need to explore innovative and novel therapeutic alternatives. Aptamers are single-stranded nucleic acids that offer the potential for addressing these challenges through diagnostic and therapeutic applications. In this review, we summarize diagnostic and therapeutic aptamers for inflammatory biomolecules, as well as the inflammatory cells in NDDs. We also discussed the potential of short nucleotides for Aptamer-Based Targeted Brain Delivery through their unique features and modifications, as well as their ability to penetrate the blood-brain barrier. Moreover, the unprecedented opportunities and substantial challenges of using aptamers as therapeutic agents, such as drug efficacy, safety considerations, and pharmacokinetics, are also discussed. Taken together, this review assesses the potential of aptamers as a pioneering approach for target delivery to the CNS and the treatment of neuroinflammation and NDDs.