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ABSTRACTBackgroundConsidering the rise of new SARS-CoV-2 variants that have reduced the efficacy of COVID-19 vaccines, the development of new antiviral medications for the disease has become increasingly necessary. In this study, ASC10, a novel antiviral prodrug, was studied in a phase 1 trial in healthy Chinese participants.Research design and methodsPart 1 involved 60 participants, receiving 50–800 mg ASC10 or placebo twice daily for 5.5 days. Part 2, with 12 participants, explored ASC10 dosing in the fed/fasting states.ResultsASC10-A, the main pharmacologically active metabolite, rapidly appeared in plasma (Tmax: 1.00–2.00 h) and decreased (t1/2: 1.10–3.04 h) without accumulation. The Cmaxand area under the plasma concentration – time curve (AUC) of ASC10-A increased dose-dependently (50–800 mg BID) over 5.5 days, with no accumulation. The Tmaxwas slightly delayed in the fed state; however, the Cmaxand AUC were similar between the fed and fasting states. Adverse events (AEs) were comparable (ASC10/placebo, 66.7%) and mostly mild (95%).ConclusionASC10 was demonstrated to be safe and well tolerated and exhibited dose-proportional exposure and minimal food effects.Clinical trial registrationwww.clinicaltrials.govidentifier is NCT05523141.

In situoxygen generation is the most common strategy to boost reactive oxygen species (ROS) for enhancing the efficacy of phototherapy in cancer, including photodynamic therapy (PDT) and photothermal therapy (PTT). However, hyperoxidation or hyperthermia often triggers stress-defense pathways and promotes tumor cell survival, thus severely limiting the therapeutic efficacy. To overcome the tumor hypoxia and thermal resistance existing in phototherapy, we constructed a self-synergistic nanoplatform for tumors by incorporating brusatol, a nuclear factor erythroid 2-related factor (Nrf2) inhibitor, into the silica nanonetwork. It was then sequentially decorated with MnO2and the photosensitizer chlorin e6 (Ce6) and then coated with poly(ethylene glycol)-folate (PEG-FA)-functionalized polydopamine (PDA) (designated as brusatol/silica@MnO2/Ce6@PDA-PEG-FA). As an oxygen generator, MnO2can promote ROS production, which not only directly enhances Ce6-mediated PDT but also strengthens PDA-mediated PTT by attacking heat shock proteins (HSPs). Particularly, brusatol could efficiently inhibit the activation of Nrf2 defense pathway under hyperoxidation and hyperthermia and cause glutathione peroxidase 4 (GPX4) and ferritin heavy chain (FTH) inactivation, thereby inducing ferroptosis and ultimately enhancing the phototherapeutic effects. By exploiting these features, brusatol/silica@MnO2/Ce6@PDA-PEG-FA exhibited excellent antitumor efficacy with enhanced PDT and PTT both in in vitroand in vivostudies. Overall, our work highlights a promising strategy against hypoxia- and hyperthermia-associated resistance in phototherapy viasuppressing stress-defense system and inducing ferroptosis.

Major depressive disorder is a common but devastating mental disorder, and recent evidence shows that neuroinflammation may play a pivotal role in the etiology of depression. Astragaloside IV (AS-IV) is an active component purifed from Astragalus membranaceus(Fisch) Bge, which has shown anti-inflammatory, anti-oxidative and anti-apoptotic effects. In this study, we explored whether AS-IV produced antidepressant effects via its inhibition of neuroinflammation in mouse models of depression. Depressive-like behaviors including decreased sucrose consumption, reduced locomotor activity and increased immobility time were induced in mice using repeated restraint stress (RRS). We found that administration of AS-IV (16, 32 and 64 mg·kg-1·d-1, ig) significantly attenuated RRS-induced depressive-like behaviors. Furthermore, AS-IV administration significantly reduced the levels of TNF-α and IL-1β, increased PPARγ expression and GSK3β phosphorylation, decreased NF-κB phosphorylation, and reduced NOD-, LRR- and pyrin domain-containingprotein 3 (NLRP3) inflammasome and caspase-1 p20 generation in the hippocampus of the mice. LPS-induced depression-like behaviors were induced by LPS injection (1 mg·kg-1·d-1, ip), which were ameliorated by administration of AS-IV (20, 40 mg·kg-1·d-1, ig). The results of the LPS-induced mouse model were in accordance with those acquired from the RRS-induced mouse model: LPS injection significantly increased TNF-α and IL-1β expression in the mouse hippocampus, which was reversed by administration of AS-IV. Moreover, administration of AS-IV significantly increased PPARγ expression and GSK3β phosphorylation, and decreased NF-κB phosphorylation and NLRP3 inflammasome. These results suggest that AS-IV is a potential drug against depression, and its antidepressant effects are partially mediated by inhibition of neuroinflammation via the upregulation of PPARγ expression.

B4C ceramic tapes were prepared by aqueous tape-casting with boron carbide powders as starting material, deionized water as solvent, polymine (PEI) as dispersant, polyethylene glycol (PEG) as plasticizer, poval (PVA) or gelatin as binders. The influences of pH, dispersant content, kind and content of binder on the stability and rheological property of tape slurries were studied. The experimental results indicated that, when the pH was ranged in 3-4, the slurries with good stability and good rheology could be obtained with 0.8 wt% PEI, 4.0 wt% PVA or 6.5 wt% gelatin. PVA as binder made cast tape with certain strength, and gelatin as binder made cast tape with poor strength.

In our country, crop straw output more than 600 million tons per year, which is a huge amount of renewable biological resources, and the prospect of energy-oriented using is promising. This paper have analyzed the main way and technology of crop straw energy-oriented using, carried on the thorough research on the technology of crop straw curing molding for energy-oriented using, and proposed the basic train of thought of promoting our country straw curing molding for energy-oriented using technology development.

With full development of 350km/h high-speed rail network in China, further research in the key technology of 380km/h or higher super-speed rail system has become crucial. Applying the simulation of pantograph-catenary interaction based on infinite element method, this paper simulated the dynamic performance of pantograph-catenary system for high-tension overhead contact system at over 350km/h. The research findings showed that wave propagation speed can still serve as a brief computing method for the running speed within the range of 350-400km/h. When the running speed reaches 80% of the wave propagation speed or higher, the current-carrying quality of double-pantograph-catenaries system might not satisfy the standard of EN 50367 all the time.

Objective The risk factors associated with iodine contrast extravasation immediately after endovascular thrombectomy (EVT) and subsequent hemorrhagic transformation within 24 hours remain unclear.Methods Mixed images, iodine overlay maps, and virtual non-contrast images were reconstructed from 106 consecutive acute ischemic stroke patients who underwent dual energy computed tomography immediately and 24 hours after EVT. Multivariate analyses of clinical and radiological data were performed to explore independent predictors of iodine contrast extravasation and hemorrhagic transformation.Results Sixty-eight (64.2%) patients exhibited pure iodine contrast extravasation after EVT; 30.9% developed hemorrhagic transformation within 24 hours after EVT. The number of stent retriever passes was independently associated with both iodine contrast extravasation (odds ratio 1.608; 95% confidence interval (CI) 1.047–2.469) and subsequent hemorrhagic transformation (odds ratio 1.477; 95% CI 1.003–2.175). Patients with more than two stent retriever passes were more likely to exhibit iodine contrast extravasation (sensitivity = 68.2%, specificity = 81.5%), while those with more than three stent retriever passes more often exhibited hemorrhage after iodine contrast extravasation (sensitivity = 64.6%, specificity = 87.2%).Conclusions The number of stent retriever passes was an independent predictor for both iodine contrast extravasation and subsequent hemorrhagic transformation.