ABSTRACT
This paper presents a generic analytical framework tailored for surrogate safety measures (SSMs) that is versatile across various highway geometries, capable of encompassing vehicle dynamics of differing dimensionality and fidelity, and suitable for dynamic, real-world environments. The framework incorporates a generic vehicle movement model, accommodating a spectrum of scenarios with varying degrees of complexity and dimensionality, facilitating the estimation of future vehicle trajectory evolution. It establishes a generic mathematical criterion to denote potential collisions, characterized by the spatial overlap between a vehicle and any other entity. A collision risk is present if the collision criterion is met at any non-negative estimated future time point, with the minimum threshold representing the remaining time to collision. The framework's proficiency spans from conventional one-dimensional (1D) SSMs to extended multi-dimensional, high-fidelity SSMs. Its validity is corroborated through simulation experiments that assess the precision of the framework when linearization is performed on the vehicle movement model. The outcomes showcase remarkable accuracy in estimating vehicle trajectory evolution and the time remaining before potential collisions occur, comparing to high-accuracy numerical integration solutions. The necessity of higher-dimensional and higher-fidelity SSMs is highlighted through a comparison of conventional 1D SSMs and extended three-dimensional (3D) SSMs. The results showed that using 1D SSMs over 3D SSMs could be off by 300% for Time-to-Collision (TTC) values larger than 1.5 s and about 20% for TTC values below 1.5 s. In other words, conventional 1D SSMs can yield highly inaccurate and unreliable results when assessing collision proximity and substantially misjudge the count of conflicts with predefined threshold (e.g., below 1.5s). Furthermore, the framework's practical application is demonstrated through a case study that actively evaluates all potential conflicts, underscoring its effectiveness in dynamic, real-world traffic situations.
Subject(s)
Accidents, Traffic , Humans , Accidents, Traffic/prevention & control , Biomechanical Phenomena , Computer Simulation , Models, Theoretical , SafetyABSTRACT
Nonalcoholic steatohepatitis (NASH) represents a severe disease subtype of nonalcoholic fatty liver disease (NAFLD) that is thought to be highly associated with systemic metabolic abnormalities. It is characterized by a series of substantial liver damage, including hepatocellular steatosis, inflammation, and fibrosis. The end stage of NASH, in some cases, may result in cirrhosis and hepatocellular carcinoma (HCC). Nowadays a large number of investigations are actively under way to test various therapeutic strategies, including emerging oligonucleotide drugs (e.g., antisense oligonucleotide, small interfering RNA, microRNA, mimic/inhibitor RNA, and small activating RNA) that have shown high potential in treating this fatal liver disease. This article systematically reviews the pathogenesis of NASH/NAFLD, the promising druggable targets proven by current studies in chemical compounds or biological drug development, and the feasibility and limitations of oligonucleotide-based therapeutic approaches under clinical or pre-clinical studies.
ABSTRACT
Novel CHCHD2 mutations causing C-terminal truncation and interrupted CHCHD2 protein stability in Parkinson's disease (PD) patients were previously found. However, there is limited understanding of the underlying mechanism and impact of subsequent CHCHD2 loss-of-function on PD pathogenesis. The current study further identified the crucial motif (aa125-133) responsible for diminished CHCHD2 expression and the molecular interplay within the C1QBP/CHCHD2/CHCHD10 complex to regulate mitochondrial functions. Specifically, CHCHD2 deficiency led to decreased neural cell viability and mitochondrial structural and functional impairments, paralleling the upregulation of autophagy under cellular stresses. Meanwhile, as a binding partner of CHCHD2, C1QBP was found to regulate the stability of CHCHD2 and CHCHD10 proteins to maintain the integrity of the C1QBP/CHCHD2/CHCHD10 complex. Moreover, C1QBP-silenced neural cells displayed severe cell death phenotype along with mitochondrial damage that initiated a significant mitophagy process. Taken together, the evidence obtained from our in vitro and in vivo studies emphasized the critical role of CHCHD2 in regulating mitochondria functions via coordination among CHCHD2, CHCHD10, and C1QBP, suggesting the potential mechanism by which CHCHD2 function loss takes part in the progression of neurodegenerative diseases.
ABSTRACT
Additives may be present in amounts higher than 50% within plastic objects. Additives in plastics can be gradually released from microplastics (MPs) into the aquatic environment during their aging and fragmentation because most of them do not chemically react with the polymers. Some are known to be hazardous substances, which can cause toxicity effects on organisms and pose ecological risks. In this paper, the application of functional additives in MPs and their leaching in the environment are first summarized followed by their release mechanisms including photooxidation, chemical oxidation, biochemical degradation, and physical abrasion. Important factors affecting the additive release from MPs are also reviewed. Generally, smaller particle size, light irradiation, high temperature, dissolved organic matter (DOM) existence and alkaline conditions can promote the release of chemicals from MPs. In addition, the release of additives is also influenced by the polymer's structure, electrolyte types, as well as salinity. These additives may transfer into the organisms after ingestion and disrupt various biological processes, leading to developmental malformations and toxicity in offspring. Nonetheless, challenges on the toxicity of chemicals in MPs remain hindering the risk assessment on human health from MPs in the environment. Future research is suggested to strengthen research on the leaching experiment in the actual environment, develop more techniques and analysis methods to identify leaching products, and evaluate the toxicity effects of additives from MPs based on more model organisms. The work gives a comprehensive overview of current process for MP additive release in natural waters, summarizes their toxicity effects on organisms, and provides recommendations for future research.
Subject(s)
Microplastics , Water Pollutants, Chemical , Humans , Microplastics/chemistry , Plastics/toxicity , Water Pollutants, Chemical/analysis , Polymers , Hazardous Substances/analysisABSTRACT
Sepsis is a life-threatening organ dysfunction associated with macrophage overactivation. Targeted therapy against macrophages is considered a promising strategy for sepsis treatment. Mollugin (MLG), a compound extracted from traditional Chinese medicine Rubia cordifolia L., possesses anti-tumor and anti-inflammatory activities. This study aimed to investigate the anti-inflammatory effects and mechanisms of MLG in macrophages and its therapeutic role in CLP-induced sepsis in mice. The results demonstrated that MLG downregulated the inflammatory response induced by LPS or tumor necrosis factor α (TNF-α) in macrophages. Mechanistically, MLG suppressed the phosphorylation of TAK1, the upstream modulator of IKKα/ß and MAPKs, thereby inhibiting the pro-inflammatory signaling transduction of NF-κB and MAPKs. Additionally, MLG also activated the Nrf2 antioxidant pathway, reducing intracellular reactive oxygen species. CETSA and molecular docking analyses revealed that MLG could effectively bind to TAK1 and Keap1, which may be involved in the inhibition of TAK1- NF-κB/MAPKs and activation of Nrf2 mediated by MLG. Animal study demonstrated that MLG ameliorated inflammatory injury of lung and liver in CLP-induced sepsis mice probably by reducing the levels of pro-inflammatory cytokines. Therefore, our study suggests that bi-directional roles of MLG in improving sepsis via blocking the TAK1-NF-κB/MAPKs and activating Nrf2 pathways, indicating its potential as a promising candidate drug for sepsis treatment.