Beyond 1D and oversimplified kinematics: A generic analytical framework for surrogate safety measures.

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.

Oligonucleotide therapies for nonalcoholic steatohepatitis.

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.

Loss of CHCHD2 Stability Coordinates with C1QBP/CHCHD2/CHCHD10 Complex Impairment to Mediate PD-Linked Mitochondrial Dysfunction.

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.

Various additive release from microplastics and their toxicity in aquatic environments.

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.

Mollugin prevents CLP-induced sepsis in mice by inhibiting TAK1-NF-κB/MAPKs pathways and activating Keap1-Nrf2 pathway in macrophages.

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.

Achievable rate as affected by active elements distribution in reconfigurable intelligent surfaces for wireless communication.

To increase constantly the achievable rate of reconfigurable intelligent surfaces (RISs)-assisted communication systems, the traditional approaches are to deploy a few active elements randomly on the passive RISs. However, the effect of the geometry distribution of the deployment of the active elements is ignored in performance analysis. In this article, three types of geometry distribution with active elements on RISs, denoted as random distribution, uniform distribution, and eight-queens distribution, are discussed to analyze the affect on achievable rate in RISs-assisted wireless communications. Specifically, the optimal achievable rate is obtained according to the predefined codebook, and the codebook is determined by the reflection beamforming codeword related to the active elements geometry distribution in RISs. Simulation results show that different geometry distribution of active elements in RISs causes different influences to achievable rates. The eight-queens distribution proposed in this article for active elements in RISs brings the highest achievable rate compared with random distribution and uniform distribution. In the passive RISs surface, the distribution of a few active elements is limited by the eight-queens, further enhancing the achievable rate of the wireless communication system. This method has a 7% improvement over the conventional method.

An Ultra-Energy-Efficient and High Accuracy ECG Classification Processor With SNN Inference Assisted by On-Chip ANN Learning.

The ECG classification processor is a key component in wearable intelligent ECG monitoring devices which monitor the ECG signals in real time and detect the abnormality automatically. The state-of-the-art ECG classification processors for wearable intelligent ECG monitoring devices are faced with two challenges, including ultra-low energy consumption demand and high classification accuracy demand against patient-to-patient variability. To address the above two challenges, in this work, an ultra-energy-efficient ECG classification processor with high classification accuracy is proposed. Several design techniques have been proposed, including a reconfigurable SNN/ANN inference architecture for reducing energy consumption while maintaining classification accuracy, a reconfigurable on-chip learning architecture for improving the classification accuracy against patent-to-patient variability, and a dual-purpose binary encoding scheme of ECG heartbeats for further reducing the energy consumption. Fabricated with a 28nm CMOS technology, the proposed design consumes extremely low classification energy (0.3µJ) while achieving high classification accuracy (97.36%) against patient-to-patient variability, outperforming several state-of-the-art designs.

Hepatocellular BChE as a therapeutic target to ameliorate hypercholesterolemia through PRMT5 selective degradation to restore LDL receptor transcription.

AIMS: Individuals with nonalcoholic hepatosteatosis (NAFLD) have a worse atherogenic lipoprotein profile and are susceptible to cardiovascular diseases. The MEK-ERK signaling cascades are central regulators of the levels of LDL receptor (LDLR), a major determinant of circulating cholesterol. It is elusive how hepatic steatosis contributes to dyslipidemia, especially hypercholesterolemia. MAIN METHODS: The effects of BChE on signaling pathways were determined by immunoblotting in a BChE knockout hepatocyte cell line. DiI-LDL probe was used to explore the effect of BChE expression on LDL internalization. Co-immunoprecipitation and LC-MS were used to explore the interacting proteins with BChE. Finally, a hepatocyte-restricted BChE silencing mouse model was established by AAV8-Tbg-shRNA, and the hypercholesterolemia was induced by 65% kcal% high-fat, high-sucrose diet feeding. MAIN FINDINGS: Here we demonstrate that butyrylcholinesterase (BChE) governs the LDL receptor levels and LDL uptake capacity through the MEK-ERK signaling cascades to promote Ldlr transcription. BChE interacts and co-localizes with PRMT5, a protein methylation modifier controlling the ERK signaling. PRMT5 regulates LDLR-dependent LDL uptake and is a substrate of chaperone-mediated autophagy (CMA). BChE deficiency induces the PRTM5 degradation dependent on CMA activity, possibly through facilitating the HSC70 (Heat shock cognate 71 kDa) recognition of PRMT5. Remarkably, in vivo hepatocyte-restricted BChE silencing reduces plasma cholesterol levels substantially. In contrast, the BChE knockout mice are predisposed to hypercholesterolemia. SIGNIFICANCE: Taken together, these findings outline a regulatory role for the BChE-PRMT5-ERK-LDLR axis in hepatocyte cholesterol metabolism, and suggest that targeting liver BChE is an effective therapeutic strategy to treat hypercholesterolemia.

CNPase, a 2',3'-Cyclic-nucleotide 3'-phosphodiesterase, as a Therapeutic Target to Attenuate Cardiac Hypertrophy by Enhancing Mitochondrial Energy Production.

Heart failure is the end-stage of all cardiovascular diseases with a ~25% 5-year survival rate, and insufficient mitochondrial energy production to meet myocardial demand is the hallmark of heart failure. Mitochondrial components involved in the regulation of ATP production remain to be fully elucidated. Recently, roles of 2',3'-cyclic nucleotide-3'-phosphodiesterase (CNPase) in the pathophysiological processes of heart diseases have emerged, implicated by evidence that mitochondrial CNPase proteins are associated with mitochondrial integrity under metabolic stress. In this study, a zebrafish heart failure model was established, by employing antisense morpholino oligonucleotides and the CRISPR-Cas9 gene-editing system, which recapitulates heart failure phenotypes including heart dysfunction, pericardial edema, ventricular enlargement, bradycardia, and premature death. The translational implications of CNPase in the pathophysiological process of heart failure were tested in a pressure overload-induced heart hypertrophy model, which was carried out in rats through transverse abdominal aorta constriction (TAAC). AAV9-mediated myocardial delivery of CNPase mitigated the hypertrophic response through the specific hydrolysis of 2'-3'-cyclic nucleotides, supported by the decrease of cardiac hypertrophy and fibrosis, the integrity of mitochondrial ultrastructure, and indicators of heart contractility in the AAV9-TAAC group. Finally, the biometrics of a mitochondrial respiration assay carried out on a Seahorse cellular energy analyzer demonstrated that CNPase protects mitochondrial respiration and ATP production from AngII-induced metabolic stress. In summary, this study provides mechanistic insights into CNPase-2',3'-cyclic nucleotide metabolism that protects the heart from energy starvation and suggests novel therapeutic approaches to treat heart failure by targeting CNPase activity.

Molecular cloning and characterization of an atypical butyrylcholinesterase-like protein in zebrafish.

Cholinesterases act as bio scavengers to clear organophosphorus (OP) compounds and prodrugs. The butyrylcholinesterase (BChE) gene has been found in several types of teleost fish but this gene has yet to be identified in cyprinid fish. Indeed, BChE homologs have not been found in the zebrafish (Danio rerio) genomic database. Here, we demonstrate that BChE activity is present in zebrafish, in line with other groups' findings. Using in-gel native-PAGE enzymatic activity staining and LC-MS/MS technique, an atypical BChE-like protein was identified in zebrafish. The si:ch211-93f2.1 gene was cloned, and His-tagged recombinant protein was expressed using the Pichia yeast system. The purified protein (molecular weight ~ 180 kDa) showed BChE activity, and degraded acetylcholinesterase (ACh) at a higher rate than BCh. However, phylogram analysis shows that this novel cholinesterase shared an evolutionary origin with carboxylic esterase rather than BChE. The zebrafish BChE-like protein shares structural characteristics with cholinesterase and carboxylesterase. The 2-arachidonoylglycerol (2-AG), nicosulfuron, and triacetin exhibited a higher binding affinity to the zebrafish BChE-like protein than BCh and ACh. With the identification of BChE-like protein in zebrafish, this study could shed light on the origin of BChE and may contribute towards the development of a BChE knockout zebrafish model for sensitive drug or toxin screening.