Bioadhesive Nanoparticles for Local Drug Delivery.

Local drug delivery is an effective strategy for achieving direct and instant therapeutic effects. Current clinical treatments have fallen short and are limited by traditional technologies. Bioadhesive nanoparticles (NPs), however, may be a promising carrier for optimized local drug delivery, offering prolonged drug retention time and steadily maintained therapeutic concentrations. In addition, the possibility of clinical applications of this platform are abundant, as most polymers used for bioadhesion are both biodegradable and biocompatible. This review highlights the major advances in the investigations of polymer-based bioadhesive nanoparticles and their innumerable applications in local drug delivery.

Chemical constituents from Lonicera japonica flower buds and their anti-hepatoma and anti-HBV activities.

Three new naturally occurring monoterpenoids, japopenoid A (1), japopenoid B (23) japopenoid C (24), and one new caffeoylquinic acid derivative (28), together with thirty-one known compounds (2-22, 25-27, 29-35), were isolated and identified from the flower buds of Lonicera japonica Thunb. Their structures were determined by extensive 1D and 2D NMR spectroscopic methods, high-resolution mass spectrometry, and the absolute configurations of 1, 23, 24 were determined by comparison of their electronic circular dichroism (ECD) spectrum with literature and theoretical calculation. Structurally, compound 1 is a monoterpenoid featured with an unusual tricyclic skeleton. All compounds (1-35) were evaluated for their cytotoxicities against human liver cancer cell lines (HepG 2 and SMMC-7721). Compound 12 exhibited the most potent activity with IC50 values of 26.54 ±â€¯1.95 and 8.72 ±â€¯1.57 µg/ml against HepG 2 and SMMC-7721, and the IC50 values of compound 13 were 26.54 ±â€¯1.95 and 12.35 ±â€¯1.43 µg/ml, respectively. Western blot results further proved that compound 13 induces hepatoma cell apoptosis via the intrinsic apoptosis pathway. In addition, most terpenoids showed inhibitory activity against HBsAg and HBeAg secretion, and HBV DNA replication. In particular, 25 µg/mlof compound 11 inhibits HBsAg and HBeAg secretion, and HBV DNA replication by 39.39 ±â€¯5.25, 15.64 ±â€¯1.25, and 16.13 ±â€¯4.10% compared to the control (p < 0.05). These results indicated that L. japonica flower buds could be served as functional food for anti-hepatoma and anti-HBV activities.

Role of Tibetan Buddhist monasteries in snow leopard conservation.

The snow leopard (Panthera uncia) inhabits the rugged mountains in 12 countries of Central Asia, including the Tibetan Plateau. Due to poaching, decreased abundance of prey, and habitat degradation, it was listed as endangered by the International Union for Conservation of Nature in 1972. Current conservation strategies, including nature reserves and incentive programs, have limited capacities to protect snow leopards. We investigated the role of Tibetan Buddhist monasteries in snow leopard conservation in the Sanjiangyuan region in China's Qinghai Province on the Tibetan Plateau. From 2009 to 2011, we systematically surveyed snow leopards in the Sanjiangyuan region. We used the MaxEnt model to determine the relation of their presence to environmental variables (e.g., elevation, ruggedness) and to predict snow leopard distribution. Model results showed 89,602 km(2) of snow leopard habitat in the Sanjiangyuan region, of which 7674 km(2) lay within Sanjiangyuan Nature Reserve's core zones. We analyzed the spatial relation between snow leopard habitat and Buddhist monasteries and found that 46% of monasteries were located in snow leopard habitat and 90% were within 5 km of snow leopard habitat. The 336 monasteries in the Sanjiangyuan region could protect more snow leopard habitat (8342 km(2) ) through social norms and active patrols than the nature reserve's core zones. We conducted 144 household interviews to identify local herders' attitudes and behavior toward snow leopards and other wildlife. Most local herders claimed that they did not kill wildlife, and 42% said they did not kill wildlife because it was a sin in Buddhism. Our results indicate monasteries play an important role in snow leopard conservation. Monastery-based snow leopard conservation could be extended to other Tibetan Buddhist regions that in total would encompass about 80% of the global range of snow leopards.

Salidroside protects Caenorhabditis elegans neurons from polyglutamine-mediated toxicity by reducing oxidative stress.

Polyglutamine (polyQ) aggregation plays a pivotal role in the pathological process of Huntington's disease and other polyQ disorders. Therefore, strategies aiming at restoring dysfunction and reducing stresses mediated by polyQ toxicity are of therapeutic interest for proteotoxicity diseases. Salidroside, a glycoside from Rhodiola rosea, has been shown to have a variety of bioactivities, including antioxidant activity. Using transgenic Caenorhabditis elegans models, we show here that salidroside is able to reduce neuronal death and behavioral dysfunction mediated by polyQ expressed in ASH neurons, but the neuroprotective effect is not associated with prevention of polyQ aggregation per se. Further experiments reveal that the neuroprotective effect of salidroside in C. elegans models involves its antioxidant capabilities, including decrease of ROS levels and paraquat-induced mortality, increase of antioxidant enzyme activities and reduction of lipid peroxidation. These results demonstrate that salidroside exerts its neuroprotective function against polyQ toxicity via oxidative stress pathways.

A nanocomposite hydrogel for co-delivery of multiple anti-biofilm therapeutics to enhance the treatment of bacterial biofilm-related infections.

The characteristics of biofilms have exacerbated the issue of clinical antibiotic resistance, rendering it a pressing challenge in need of resolution. The combination of biofilm-dispersing agents and antibiotics can eliminate biofilms and promote healing synergistically in infected wounds. In this study, we developed a novel nanocomposite hydrogel (NC gel) comprised of the poly(lactic acid)-hyperbranched polyglycerol (PLA-HPG) based bioadhesive nanoparticles (BNPs) and a hydrophilic carboxymethyl chitosan (CS) network. The NC gel was designed to co-deliver two biofilm-dispersing agents (an NO-donor SNO, and an α-amylase Am) and an antibiotic, cefepime (Cef), utilizing a synergistic anti-biofilm mechanism in which Am loosens the matrix structure and NO promotes the release of biofilm bacteria via quorum sensing, and Cef kills bacteria. The drug-loaded NC gel (SNO/BNP/CS@Am-Cef) demonstrated sustained drug release, minimal cytotoxicity, and increased drug-bacterial interactions at the site of infection. When applied to mice infected with methicillin-resistant Staphylococcus aureus (MRSA) biofilms in vivo, SNO/BNP/CS@Am-Cef enhanced biofilm elimination and promoted wound healing compared to traditional antibiotic treatments. Our work demonstrates the feasibility of the co-delivery of biofilm-dispersing agents and antibiotics using the NC gel and presents a promising approach for the polytherapy of bacterial biofilm-related infections.

Injectable Nanocomposite Hydrogels Improve Intraperitoneal Co-delivery of Chemotherapeutics and Immune Checkpoint Inhibitors for Enhanced Peritoneal Metastasis Therapy.

Intraperitoneal co-delivery of chemotherapeutic drugs (CDs) and immune checkpoint inhibitors (ICIs) brings hope to improve treatment outcomes in patients with peritoneal metastasis from ovarian cancer (OC). However, current intraperitoneal drug delivery systems face issues such as rapid drug clearance from lymphatic drainage, heterogeneous drug distribution, and uncontrolled release of therapeutic agents into the peritoneal cavity. Herein, we developed an injectable nanohydrogel by combining carboxymethyl chitosan (CMCS) with bioadhesive nanoparticles (BNPs) based on polylactic acid-hyperbranched polyglycerol. This system enables the codelivery of CD and ICI into the intraperitoneal space to extend drug retention. The nanohydrogel is formed by cross-linking of aldehyde groups on BNPs with amine groups on CMCS via reversible Schiff base bonds, with CD and ICI loaded separately into BNPs and CMCS network. BNP/CMCS nanohydrogel maintained the activity of the biomolecules and released drugs in a sustained manner over a 7 day period. The adhesive property, through the formation of Schiff bases with peritoneal tissues, confers BNPs with an extended residence time in the peritoneal cavity after being released from the nanohydrogel. In a mouse model, BNP/CMCS nanohydrogel loaded with paclitaxel (PTX) and anti-PD-1 antibodies (αPD-1) significantly suppressed peritoneal metastasis of OC compared to all other tested groups. In addition, no systemic toxicity of nanohydrogel-loaded PTX and αPD-1 was observed during the treatment, which supports potential translational applications of this delivery system.

Inhibition of polyglutamine-mediated proteotoxicity by Astragalus membranaceus polysaccharide through the DAF-16/FOXO transcription factor in Caenorhabditis elegans.

Late-onset neurodegenerative diseases are characterized by progressive accumulation of aggregation-prone proteins and global disruption of the proteostasis network, e.g. abnormal polyQ (polyglutamine) aggregation in Huntington's disease. Astragalus membranaceus polysaccharide (astragalan) has recently been shown to modulate aging and proteotoxic stress pathways. Using Caenorhabditis elegans models, we now show that astragalan not only reduces polyQ aggregation, but also alleviates the associated neurotoxicity. We also reveal that astragalan can extend the adult lifespan of wild-type and polyQ nematodes, indicating a connection of its anti-aging benefit with the toxicity-suppressing effect. Further examination demonstrates that astragalan can extend the lifespan of daf-2 and age-1, but not daf-16, mutant nematodes of the insulin-like aging and stress pathway, suggesting a lifespan-regulation signalling independent of DAF (abnormal dauer formation)-2/IGF-1R (insulin-like growth factor 1 receptor), but dependent on the DAF-16/FOXO (forkhead box O) transcription factor, a pivotal integrator of divergent signalling pathways related to both lifespan regulation and stress resistance. We also show that a subset of DAF-16 downstream genes are regulated by astragalan, including the DAF-16 transcriptional target gene scl-20, which is itself constitutively up-regulated in transgenic polyQ nematodes. These findings, together with our previous work on LEA (late embryogenesis abundant) proteins and trehalose, provide a revealing insight into the potential of stress and lifespan regulators in the prevention of proteotoxic disorders.

PLA-HPG based coating enhanced anti-biofilm and wound healing of Shikonin in MRSA-infected burn wound.

Burn wounds are susceptible to bacterial infections, including Methicillin-resistant Staphylococcus aureus (MRSA), which typically form biofilms and exhibit drug resistance. They also have specific feature of abundant exudate, necessitating frequent drug administration. Shikonin (SKN) has been reported to reverse MRSA drug resistance and possesses anti-biofilm and wound healing properties, however, it suffers from drawbacks of low solubility and instability. In this study, we developed PLA-HPG based bioadhesive nanoparticles SKN/BNP, which demonstrated a drug loading capacity of about 3.6%, and exhibited sustained-release behavior of SKN. The aldehyde groups present on the surface of BNP improved the local adhesion of SKN/BNP both in vitro and in vivo, thereby reducing the frequency of drug dosing in exudate-rich burn wounds. BNP alone enhanced proliferation and migration of the fibroblast, while SKN/BNP promoted fibroblast proliferation and migration as well as angiogenesis. Due to its bioadhesive property, BNP directly interacted with biofilm and enhanced the efficacy of SKN against MRSA biofilm in vitro. In a mouse model of MRSA-infected burn wounds, SKN/BNP demonstrated improved anti-biofilm and wound healing efficiency. Overall, our findings suggest that SKN/BNP holds great promise as a novel and effective treatment option for clinical applications in MRSA-infected burn wounds.

Food webs reveal coexistence mechanisms and community organization in carnivores.

Globally, massive carnivore guild extirpations have led to trophic downgrading and compromised ecosystem services. However, the complexity of multi-carnivore food webs complicates accurate identification of species interactions and community organization. Here, we used fecal DNA metabarcoding to investigate three communities that together encompass eight large- and meso-carnivore species and their 44 prey taxa of the Qinghai-Tibet Plateau (QTP), one of the last places on Earth that still harbors intact carnivore assemblages. Quantitative food-web analyses revealed pronounced interspecific variations in the carnivores' prey compositions and dietary partitioning both between and within guilds. Additionally, body masses of the carnivores and their prey exhibited consistent hump-shaped correlations across communities. Overall, differences in prey diversity, size category, and proportional utilization among the carnivore species result in trophic niche segregation that likely promotes carnivore coexistence in the harsh QTP environment. Network structure analyses detected significant modularity in all food webs but nestedness in only one. Furthermore, network characterization identified pikas (Ochotona spp.), bharal (Pseudois nayaur), and domestic yak (Bos grunniens) as potential keystone prey across the areas. Our results paint a holistic and detailed picture of the QTP carnivore assemblages' trophic networks and demonstrate that the combined use of the molecular dietary approach and network analysis can generate structural insights into carnivore coexistence and can identify functionally important species in complex communities. Such knowledge can help safeguard carnivore guild integrity and enhance community resilience to environmental perturbations in the sensitive QTP ecosystems.

JFD, a Novel Natural Inhibitor of Keap1 Alkylation, Suppresses Intracellular Mycobacterium Tuberculosis Growth through Keap1/Nrf2/SOD2-Mediated ROS Accumulation.

It is an effective strategy to treat tuberculosis by enhancing reactive oxygen species- (ROS-) mediated killing of Mycobacterium tuberculosis in macrophages, but there are no current therapeutic agents targeting this pathway. Honeysuckle has been used as the traditional medicine for tuberculosis treatment for 1500 years. Japoflavone D (JFD) is a novel biflavonoid isolated from Honeysuckle promoting ROS accumulation by Nrf2 pathway in hepatocarcinoma cells. However, its activity to kill M. tuberculosis in macrophages and molecular mechanism has not been reported. Our results showed that JFD enhances the M. tuberculosis elimination by boosting ROS levels in THP-1 cells. Moreover, the massive ROS accumulation activates p38 to induce apoptosis. Notably, the mechanism revealed that JFD suppresses the nuclear transport of Nrf2, thereby inhibiting SOD2 transcription, leading to a large ROS accumulation. Further studies showed that JFD disrupts the Keap1 alkylation at specific residues Cys14, Cys257, and Cys319, which is crucial for Nrf2 activation, thereby interrupts the nuclear transport of Nrf2. In pharmacokinetic study, JFD can stay as the prototype for 24 h in mice and can be excreted in feces without any toxicity. Our data reveal for the first time that a novel biflavonoid JFD as a potent inhibitor of Keap1 alkylation can suppress the nuclear transport of Nrf2. And it is the first research of the inhibitor of Keap1 alkylation. Furthermore, JFD robustly promotes M. tuberculosis elimination from macrophages by inhibiting Keap1/Nrf2/SOD2 pathway, resulting in the ROS accumulation. This work identified Keap1 alkylation as a new drug target for tuberculosis and provides a preliminary basis for the development of antituberculosis lead compounds based on JFD.

Research on safety of the intended functionality of automobile AEB perception system in typical dangerous scenarios of two-wheelers.

The statistical analysis was conducted on data of accident scenarios between cars and two-wheelers from National Automobile Accident In-depth Investigation System (NAIS) database in order to study safety of intended functionality of Autonomous emergency braking (AEB) perception system in typical dangerous scenarios of cars and two-wheelers. 11 scenario-related variables were selected, and 6 types of typical scenarios were obtained through cluster analysis and manual classification. The 6 types of typical scenarios were built by the automatic driving simulation software PreScan, and the AEB longitudinal control algorithm was built in Matlab/Simulink. Batch simulation script files were written, and the relative location distribution of car and two-wheeler with different time to collision (TTC) was obtained by batch simulation. Furthermore, the effects of car velocity, two-wheeler velocity and cyclist casualties on the parameter configuration of the perception system were analyzed. Under the premise of satisfying safety of intended functionality of the perception system, the optimal sensor detection scheme at different TTCs was obtained by comprehensively considering the death accident detection rate, detection area, and standard deviation. The results show that when the detection rate is 90%, the AEB system can adopt the detection scheme of long-range radar and short-range radar. The field of view (FOV) and detection range of the short range radar are 133.6° and 38.1 m, and those of the long range radar are 84.5° and 74.3 m. And when the detection rate was close to 100%, a single sensor can be used, and the detection parameters are 150° and 77.6 m. It provides reference for parameter optimization of AEB perception system.

Genus Lonicera: New drug discovery from traditional usage to modern chemical and pharmacological research.

BACKGROUND: Lonicera Linn. belonging to the family Caprifoliaceae, the largest genus in the plant family, includes about more than 200 species, which are mainly distributed in northern Africa, North America, Europe and Asia. Some species of this genus have been usually used in traditional Chinese medicine as well as functional foods, cosmetics and other applications, such as L. japonica Thunb. Bioactive components and pharmacological activities of the genus Lonicera plants have received an increasing interest from the scientific community. Thus, a comprehensive and systematic review on their traditional usage in China, chemical components, and their pharmacological properties of their whole plants, bioactive extracts, and bioactive isolates including partial structure-activity relationships from the genus is indispensable. METHODS: Information on genus Lonicera of this systematic electronic literature search was gathered via the published articles, patents, clinical trials website (https://clinicaltrials.gov/) and several online bibliographic databases (PubMed, Sci Finder, Research Gate, Science Direct, CNKI, Web of Science and Google Scholar). The following keywords were used for the online search: Lonicera, phytochemical composition, Lonicerae japonica, Lonicera review articles, bioactivities of Lonicera, anti-inflammatory, antiviral, antimicrobial, anticancer, hepatoprotective, antioxidant, neuroprotective, anti-diabetic, and clinical trials. This review paper consists of a total of 225 papers covering the Lonicera genus from 1800 to 2021, including research articles, reviews, patents, and book chapters. RESULTS: In this review (1800s-2021), about 420 components from the genus of Lonicera Linn. including 87 flavonoids, 222 terpenoids, 51 organic acids, and other compounds, together with their pharmacological activities including anti-inflammatory, antiviral, antimicrobial, anticancer, hepatoprotective, antioxidant, neuroprotective, antidiabetic, anti-allergic, immunomodulatory effects, and toxicity were summarized. CONCLUSION: The relationship is discussed among their traditional usage, their pharmacological properties, and their chemical components, which indicate the genus Lonicera have a large prospect in terms of new drug exploitation, especially in COVID-19 treatment.

Tubuloside B, isolated from Cistanche tubulosa, a promising agent against M1 macrophage activation via synergistically targeting Mob1 and ERK1/2.

Targeting macrophage M1 polarization is a promising strategy with fewer detrimental effects in COVID-19 curation. Phenylethanoid glycosides (PhGs) of Cistanche tubulosa are a botanical drug to possess various anti-inflammation-related functions, such as immunomodulating, hepatoprotective or neuroprotective functions, whereas their anti-inflammatory activity is rarely understood. A search into their anti-inflammatory characteristics led to the isolation of 49 PhGs along with 15 new PhGs. Their inhibitory effects against M1 polarization induced by LPS plus IFN-γ were explored in RAW264.7 macrophages. Of these PhGs, tubuloside B (Tub B) exerted substantial NO scavenging effect both in chemical- and cell-based assays, and it inhibited massive production of cytokines and chemokines. Tub B decreased ERK1/2 phosphorylation via direct binding and inhibited the MAPK signaling pathway. Tub B also directly binded to Mob1 protein, thereby increased the stability and level of Mob1 protein by inhibiting ubiquitinated degradation. Mob1 was pivotal for the anti-inflammatory activity of Tub B, and it acted independently of the canonical Hippo-YAP pathway. Moreover, ERK1/2 and Mob1 also had a synergic effect on modulating the inflammatory response. Finally, these effects of Tub B were verified in mice with LPS-induced systemic inflammatory response syndrome. Taken together, these results indicated that Tub B acted as a promising agent against M1 macrophage activation by synergistically targeting ERK1/2 and Mob1, and that it may potentially be a drug candidate to prevent/treat inflammatory diseases, especially in COVID-19.

Topical formulation based on disease-specific nanoparticles for single-dose cure of psoriasis.

First-line treatments for mild to moderate psoriasis are typically topical formulations containing corticosteroids, however, the therapeutic efficacy of these formulations is compromised by limited penetration and skin retention. Even more challenging, off-target corticosteroids are known to adversely affect healthy skin, including induction of epidermal and dermal atrophy. Here, we report a nanoparticle-based topical formulation that cures psoriasis in a single dose, but leaves healthy skin intact. Specifically, we developed tris(hydroxymethyl)aminomethane-modified bioadhesive nanoparticles (Tris-BNPs) that exploit the high permeability characteristic of psoriasis to penetrate only psoriatic skin but not the healthy skin. Furthermore, as Tris-BNPs diffuse and penetrate into the epidermis, the Tris molecules slowly diffuse away, exposing the aldehyde groups of BNPs, which can bind to amine groups present within lesional skin, leading to long local retention of BNPs in lesions of psoriatic skin. The accumulated BNPs within lesions release corticosteroids over a ~ 3 day period to maintain local drug concentration above the therapeutic level. In addition to deeper penetration and longer retention compared with commercial psoriasis treatments, the topical applied Tris-BNPs were not affected by sweating, humidity, or active wiping due to their preferential accumulation between the stratum corneum and the basal cells of the epidermis. Overall, Tris-BNP as a topical formulation hold promise to overcome the limitations of current psoriasis treatment.

The costs and benefits of primary prevention of zoonotic pandemics.

The lives lost and economic costs of viral zoonotic pandemics have steadily increased over the past century. Prominent policymakers have promoted plans that argue the best ways to address future pandemic catastrophes should entail, "detecting and containing emerging zoonotic threats." In other words, we should take actions only after humans get sick. We sharply disagree. Humans have extensive contact with wildlife known to harbor vast numbers of viruses, many of which have not yet spilled into humans. We compute the annualized damages from emerging viral zoonoses. We explore three practical actions to minimize the impact of future pandemics: better surveillance of pathogen spillover and development of global databases of virus genomics and serology, better management of wildlife trade, and substantial reduction of deforestation. We find that these primary pandemic prevention actions cost less than 1/20th the value of lives lost each year to emerging viral zoonoses and have substantial cobenefits.

Why do we need a wildlife consumption ban in China?

The COVID-19 pandemic is an alarm call to all on the risks of zoonotic diseases and the delicate relationship between nature and human health. In response, China has taken a proactive step by issuing a legal decision to ban consumption of terrestrial wildlife. However, concerns have been raised and opponents of bans argue that well-regulated trade should be promoted instead. By analyzing China's legal framework and management system regulating wildlife trade, together with state and provincial-level wildlife-trade licenses and wildlife criminal cases, we argue that current wildlife trade regulations do not function as expected. This is due to outdated protected species lists, insufficient cross-sector collaboration, and weak restrictions and law enforcement on farming and trading of species. The lack of quarantine standards for wildlife and increased wildlife farming in recent years pose great risks for food safety and public health. In addition, wildlife consumption is neither required for subsistence nor an essential part of Chinese diets. All these facts make the ban necessary to provoke improvement in wildlife management, such as updating protected species lists, revising laws and changing consumption behaviors. Nonetheless, the ban is not sufficient to address all the problems. To sustain the efficacy of the change, we propose that a long-term mechanism to reduce the demand and improve effective management is needed.

Research of fatal car-to-pedestrian precrash scenarios for the testing of the active safety system in China.

Road safety remains a challenge with numerous Vulnerable Road Users (VRUs) suffering from injuries and death every year. Pedestrian protection using active safety systems, such as Automated Emergency Braking (AEB), is an effective measure to combat the situation. Furthermore, the perception of precrash scenarios plays an important role in active safety research. It is essential to understand and define precrash scenarios. This study aimed to apply the obtained typical car-to-pedestrian precrash scenarios from Chinese severely injured pedestrian traffic accidents to develop and test active safety systems. The National Automobile Accident In-Depth Investigation System (NAIS) recorded 467 cases from 2011 to 2018 in China, and 12 items were selected from the NAIS database as description variables for the precrash scenario. The items were divided into four categories: car, pedestrian, road, and environment. Group decision theory was applied to evaluate the importance of each variable in its category. A total of 34 basic scenarios were defined and obtained according to the extracted significant variables. These basic scenarios represented diverse fatal scenarios in China which are crucial for autonomous driving. The frequency distribution of the scenarios demonstrated that the top five scenarios covered 85.3 % of the total. Five scenarios were identified to have the common characteristic of cars going straight. Additionally, 13 detailed scenarios were obtained from the five basic scenarios by using cluster and frequency analyses. In contrast to the New Car Assessment Program (NCAP) test scenarios, weather and lighting conditions were considered in these 13 scenarios, and the driving speed before the crash were mostly distributed in the range of 40-80 km/h (20-60 km/h in the NCAP). Meanwhile, both walking and running were commonly recorded for pedestrians to cross the street from the nearside, compared with records of walking only to cross from the nearside in the NCAP. These results contribute to a reference for test scenarios of pedestrian AEB or Forward Collision Warning (FCW) in China.

(µ-1,4,7,10-Tetra-oxacyclo-dodeca-ne)bis-[(1,4,7,10-tetra-oxacyclo-dodeca-ne)lithium] bis-(perchlorate).

12-Crown-4 ether (12C4) and LiClO(4) combine to form the ionic title compound, [Li(2)(C(8)H(16)O(4))(3)](ClO(4))(2), which is com-posed of discrete Li/12C4 cations and perchlorate anions. In the [Li(2)(12C4)(3)](2+) cation there are two peripheral 12C4 ligands, which each form four Li-O bonds with only one Li(+) atom. Additionally there is a central 12C4 in which diagonal O atoms form one Li-O bond each with both Li(+) atoms. Therefore each Li(+) atom is penta-coordinated in a distorted square-pyramidal geometry, forming four longer bonds to the O atoms on the peripheral 12C4 and one shorter bond to an O atom of the central 12C4. The cation occupies a crystallographic inversion centre located at the center of the ring of the central 12C4 ligand. The Li(+) atom lies above the cavity of the peripheral 12C4 by 0.815 (2) Šbecause it is too large to fit in the cavity.

(1,4,7,10-Tetra-oxacyclo-dodeca-ne)(trideuteroacetonitrile)lithium perchlorate.

In the title compound, [Li(C(8)H(16)O(4))(CD(3)CN)]ClO(4), the Li atom is penta-coordinate. The O atoms of the 12-crown-4 ether form the basal plane, whereas the N atom of the trideutero-aceto-nitrile occupies the apical position. The Li(+) atom is displaced by 0.794 (6) Štoward the apical position from the plane formed by the O atoms because the Li(+) atom is too large to fit in the cavity of the 12-crown-4 ether, resulting in a distorted square-pyramidal geometry about the Li(+) atom.

Mining and comparative analysis of typical pre-crash scenarios from IGLAD.

Scenario-based testing is crucial for considering the intended functional safety of automated driving vehicles. For the first time, pre-crash scenario mining research was conducted using worldwide accident data obtained from the Initiative for the Global Harmonization of Accident Data (IGLAD). First, data from the IGLAD database were analyzed and divided into four categories based on differences in traffic environments among countries and regions. Second, according to actual accident characteristics, fields and methods of clustering were selected, and 21 typical pre-crash scenarios were obtained using clustering and analysis. Finally, the typical scenarios were analyzed and compared in detail. Four conclusions were drawn as follows: 1. Considerable differences exist in traffic participant types, accident forms, and typical scenarios across countries and regions. 2. The third group of countries (3-G, represented by China and Brazil) in which accidents and pre-crash scenarios are the most representative and diverse is an ideal data source for the international scenario research. 3. The typical scenarios mined through clustering were highly consistent with the new test scenarios added in the Euro-NCAP 2025 Roadmap, but a few typical scenario elements which are critical for safety evaluations were still not covered in Roadmap. 4. Data from the IGLAD database still lacks a few important pieces of information for scenario research, such as obstruction of visual field due to obstacles, and the data representativeness need to be improved, therefore we recommend that IGLAD database adds some new data parameters to fit the further scenario research, and propose distribution requirements of accident data considering scenario elements. The analysis methods and conclusions presented used in this study could serve as guidelines or references for automated vehicle safety evaluations.