Pharmacokinetics, pharmacodynamics, and safety of GS-3583, a FLT3 agonist Fc fusion protein, from single-ascending-dose phase I study in healthy participants.

Conventional dendritic cells subtype 1 (cDC1) play a vital role in the priming and expansion of tumor-specific CD8+ T cells and their recruitment to tumor microenvironment. However, cDC1s are often underrepresented in the microenvironment. Systemic administration of Fms-like tyrosine kinase 3 ligand, a hematopoietic growth factor that binds to FLT3 on myeloid and lymphoid progenitor cells, leads to cDC1 expansion in the periphery and recruitment into the microenvironment. FLT3 pathway stimulation using GS-3583, a novel FLT3 agonistic Fc fusion protein, has the potential to promote T-cell mediated antitumor activity. This was a first-in-human, placebo-controlled study of GS-3583 in healthy participants to evaluate the safety, pharmacokinetics (PK), and pharmacodynamic (PD) of escalating single doses (75-2000 µg) of GS-3583. Each dose cohort enrolled 8-12 healthy participants who received GS-3583 or placebo as single IV infusion at 3:1 ratio. As part of the PD evaluation, the changes in the number of cDC1 cells were investigated. GS-3583 was well-tolerated in healthy participants up to the highest evaluated dose (2000 µg). There have been no serious or grade III or higher adverse events. PK analysis suggested a dose-dependent increase in GS-3583 exposure with target-mediated disposition characteristics at low doses. PD analysis shows that administration of GS-3583 resulted in transient, dose-dependent increases in cDC1 cells that returned to baseline within 3 weeks of drug administration. The pharmacokinetics and pharmacodynamics of GS-3583 following single dosing were characterized in this study which enabled subsequent phase Ib assessments in patients with advanced solid tumors.

Targeting TRPV1 signaling: Galangin improves ethanol-induced gastric mucosal injury.

ETHNOPHARMACOLOGICAL RELEVANCE: Galangin, a bioactive compound extracted from Alpinia officinarum Hance (Zingiberaceae), a plant with significant ethnopharmacological importance, has been used for thousands of years as a spice, condiment, and medicinal agent for various conditions, including gastrointestinal disorders. Although there is evidence suggesting its potential to improve gastric ulcers, the molecular mechanisms underlying its anti-ulcer properties are not fully understood. OBJECTIVE: of the Study: This study aimed to investigate the effects of galangin on ethanol-induced acute gastric mucosal injury (AGMI) in mice and elucidate its molecular mechanisms. MATERIALS AND METHODS: Sixty BALB/c mice were randomly assigned into two main groups: a normal control group (n = 10) and an ethanol-induced group (n = 50). After establishing the AGMI model in mice using a combination of 40% ethanol and anhydrous ethanol, the ethanol-induced group was further subdivided into five subgroups (n = 10): an omeprazole control group (20 mg/kg), an untreated ethanol group, and three treatment groups receiving high-dose (50 mg/kg) or low-dose (25 mg/kg) galangin or capsazepine (CPZ, 2 mg/kg). The protective effects of galangin were evaluated through mucosal injury indices, hematoxylin and eosin staining, and quantification of inflammatory markers (IL-1ß, IL-6, IL-8, and TNF-α). Oxidative stress levels and matrix metalloproteinase activity were measured using specific assay kits. Molecular docking was conducted to assess the binding affinity of galangin to key proteins within the transient receptor potential vanilloid 1 (TRPV1) pathway. Real-time fluorescence quantitative PCR (qPCR) was used to determine mRNA expression levels of TRPV1, calmodulin (CaM), substance P (SP), and CGRP in gastric tissues. Protein expression levels of TRPV1, nerve growth factor (NGF), tropomyosin receptor kinase A (TRKA), transforming growth factor beta (TGF-ß), cyclooxygenase-2 (COX-2), and nuclear factor kappa B (NF-κB) were assessed through Western blot analysis. In cellular experiments, Culture of Human Gastric Epithelial Cells (GES-1) were treated with various concentrations of galangin after 7% ethanol induction. Cell proliferation, apoptosis, and migration were evaluated using Hoechst 33258 staining and transwell migration assays. TRPV1 protein expression was detected using immunofluorescence, and the expression levels of Bcl-2, BCL2-Associated X (BAX), and Caspase-3 were quantified by qPCR. Additionally, specific probe kits were used to measure intracellular calcium ions (Ca2+) and mitochondrial membrane potential. RESULTS: The findings indicate that galangin significantly improved mucosal pathology by reducing ulcer indices and inflammatory levels, while enhancing superoxide dismutase (SOD) activity and decreasing malondialdehyde (MDA) concentration. Galangin also reduced matrix metalloproteinase-2 (MMP-2), m metalloproteinase-9 (MMP-9) levels, promoting mucosal repair. At the cellular level, galangin decreased intracellular calcium ion concentration and mitigated the decline in mitochondrial membrane potential, enhance the restoration of mucosal cells, increased migration and proliferation, and reduced apoptosis. Molecularly, galangin demonstrated favorable binding to TRPV1, NGF, TRKA, TGF-ß, COX-2, and NF-κB, and reversed the elevated expression of these proteins. Additionally, galangin downregulated the mRNA expression of TRPV1, CaM, SP, CGRP, BAX, and Caspase-3 in gastric tissues/cells, while upregulating Bcl-2 mRNA expression. CONCLUSION: Galangin mitigates AGMI by inhibiting the overactivation of the TRPV1 pathway, thereby blocking aberrant signal transduction. This study suggests that galangin has therapeutic potential against ethanol-induced AGMI and may be a viable alternative for the treatment of alcohol-induced gastric mucosal injuries.

Efficacy and Safety of Sacituzumab Govitecan in Patients With Advanced Solid Tumors (TROPiCS-03): Analysis in Patients With Advanced Endometrial Cancer.

PURPOSE: Patients with advanced endometrial cancer (EC) who progress on or after platinum-based therapy and immunotherapy have poor prognosis. We report efficacy and safety of sacituzumab govitecan (SG), a trophoblast cell-surface antigen 2 (Trop-2)-directed antibody-drug conjugate, in patients with advanced EC. METHODS: TROPiCS-03 (ClinicalTrials.gov identifier: NCT03964727) is a multicohort, open-label, phase II basket study in patients with metastatic solid tumors. Eligible patients in the EC cohort received SG 10 mg/kg once on days 1 and 8 every 3 weeks. Primary end point was objective response rate (ORR) by investigator's assessment per RECIST v1.1. Secondary end points included clinical benefit rate (CBR; complete and partial response, and stable disease ≥6 months), duration of response (DOR), and progression-free survival (PFS) per investigator assessment, overall survival, and safety. Trop-2 expression of archival or baseline tumor specimens was analyzed by immunohistochemistry. RESULTS: At data extraction date, 41 patients were enrolled. Median follow-up was 5.8 months (range, 0.7-19.3); median previous therapies was three (range, 1-6); and 85% of patients received previous chemotherapy and immunotherapy. ORR was 22% (95% CI, 11 to 38); CBR was 32% (95% CI, 18 to 48). Median DOR was 8.8 months (95% CI, 2.8 to not estimable); median PFS was 4.8 months (95% CI, 2.8 to 9.8). Trop-2 exploratory analysis was conducted retrospectively for 39 patients. Tumor Trop-2 protein was highly expressed in EC, showing limited correlation with efficacy. Grade ≥3 treatment-related adverse events (TRAEs) occurred in 73% of patients. Study drug discontinuation due to TRAEs was 5%. Two deaths occurred, deemed unrelated to SG. CONCLUSION: Findings from TROPiCS-03 showed encouraging efficacy of SG with a manageable toxicity profile in a heavily pretreated population with advanced EC. Safety findings were consistent with the known SG safety profile.

Hydrogel Extinguishants.

The exploitation of clean and efficient fire extinguishing materials has substantial implications for improving disaster prevention, mitigation, and relief capabilities, maintaining public safety, and protecting people's lives and property as well as the natural environment. Natural polymer hydrogel with high water containment, excellent film formation, high heat insulation, ecofriendliness, and degradability has huge potential in achieving new breakthroughs for developing clean and efficient fire extinguishing materials and products. In recent years, the exploitation of hydrogel extinguishing materials and the fabrication of products has attracted great attention, gradually replacing traditional fire extinguishing products. In this perspective, an in-depth review of the evolution of hydrogels applied for fire extinguishing and prevention is presented. Firstly, the extinguishing principles of hydrogel extinguishants are explained. Secondly, the preparation strategies and evaluation system of the hydrogel extinguishants are emphatically discussed. Although great progress has been made in developing high-performance hydrogel extinguishants, it remains challenging to develop cost-effective, degradable, and easy-to-use hydrogel extinguishants. Additionally, we highlight the importance of considering the commercial aspects of hydrogel extinguishants. Looking into the future, hydrogel extinguishants are promising, but continued investment in research and development is necessary to overcome the challenges.

Analgesic and anti-inflammatory effects of galangin: a potential pathway to inhibit transient receptor potential vanilloid 1 receptor activation.

Background: Galangin, commonly employed in traditional Chinese medicine for its diverse medicinal properties, exhibits potential in treating inflammatory pain. Nevertheless, its mechanism of action remains unclear. Methods: Mice were randomly divided into 4 groups for 7 days: a normal control group, a galangin-treated (25 and 50 mg/kg), and a positive control celecoxib (20 mg/kg). Analgesic and anti-inflammatory effects were evaluated using a hot plate test, acetic acid-induced writhing test, acetic acid-induced vascular permeability test, formalininduced paw licking test, and carrageenan-induced paw swelling test. The interplay between galangin, transient receptor potential vanilloid 1 (TRPV1), NF-κB, COX-2, and TNF-α proteins was evaluated via molecular docking. COX- 2, PGE2, IL-1ß, IL-6, and TNF-α levels in serum were measured using ELISA after capsaicin administration (200 nmol/L). TRPV1 expression in the dorsal root ganglion was analyzed by Western blot. The quantities of substance P (SP) and calcitonin gene-related peptide (CGRP) were assessed using qPCR. Results: Galangin reduced hot plate-induced licking latency, acetic acid-induced contortions, carrageenantriggered foot inflammation, and capillary permeability in mice. It exhibited favorable affinity towards TRPV1, NF- κB, COX-2, and TNF-α, resulting in decreased levels of COX-2, PGE2, IL-1ß, IL-6, and TNF-α in serum following capsaicin stimulation. Galangin effectively suppressed the upregulation of TRPV1 protein and associated receptor neuropeptides CGRP and SP mRNA, while concurrently inhibiting the expression of NF-κB, TNF-α, COX-2, and PGE2 mRNA. Conclusions: Galangin exerts its anti-inflammatory pain effects by inhibiting TRPV1 activation and regulating COX-2, NF-κB/TNF-α expression, providing evidence for the use of galangin in the management of inflammatory pain.

Oral PD-L1 inhibitor GS-4224 selectively engages PD-L1 high cells and elicits pharmacodynamic responses in patients with advanced solid tumors.

BACKGROUND: Checkpoint inhibitors targeting the programmed cell death 1 (PD-1)/programmed cell death 1 ligand 1 (PD-L1) pathway are effective therapies in a range of immunogenic cancer types. Blocking this pathway with an oral therapy could benefit patients through greater convenience, particularly in combination regimens, and allow flexible management of immune-mediated toxicities. METHODS: PD-L1 binding activity was assessed in engineered dimerization and primary cell target occupancy assays. Preclinical antitumor activity was evaluated in ex vivo and in vivo human PD-L1-expressing tumor models. Human safety, tolerability, pharmacokinetics, and biomarker activity were evaluated in an open-label, multicenter, sequential dose-escalation study in patients with advanced solid tumors. Biomarkers evaluated included target occupancy, flow cytometric immunophenotyping, plasma cytokine measurements, and T-cell receptor sequencing. RESULTS: GS-4224 binding caused dimerization of PD-L1, blocking its interaction with PD-1 and leading to reversal of T-cell inhibition and increased tumor killing in vitro and in vivo. The potency of GS-4224 was dependent on the density of cell surface PD-L1, with binding being most potent on PD-L1-high cells. In a phase 1 dose-escalation study in patients with advanced solid tumors, treatment was well tolerated at doses of 400-1,500 mg once daily. Administration of GS-4224 was associated with a dose-dependent increase in plasma GS-4224 exposure and reduction in free PD-L1 on peripheral blood T cells, an increase in Ki67 among the PD-1-positive T-cell subsets, and elevated plasma cytokines and chemokines. CONCLUSIONS: GS-4224 is a novel, orally bioavailable small molecule inhibitor of PD-L1. GS-4224 showed evidence of expected on-target biomarker activity, including engagement of PD-L1 and induction of immune-related pharmacodynamic responses consistent with PD-L1 blockade. TRIAL REGISTRATION NUMBER: NCT04049617.

Phase I Study of GS-3583, an FMS-like Tyrosine Kinase 3 Agonist Fc Fusion Protein, in Patients with Advanced Solid Tumors.

PURPOSE: GS-3583, an FMS-like tyrosine kinase 3 (FLT3) agonist Fc fusion protein, expanded conventional dendritic cells (cDC) in the periphery of healthy volunteers, suggesting potential for GS-3583 to increase cDCs in the tumor microenvironment and promote T cell-mediated antitumor activity in cancer patients. This phase Ib open-label study assessed GS-3583 in adults with advanced solid tumors. PATIENTS AND METHODS: Multiple escalating doses of GS-3583 (standard 3+3 design) were administered intravenously on days 1 and 15 of cycle 1 and day 1 of each subsequent 28-day cycle for up to 52 weeks. Dose-limiting toxicity (DLT) was evaluated during the first 28 days of GS-3583 at each dose level. RESULTS: Thirteen participants enrolled in four dose-escalation cohorts, after which the study was terminated following safety review. Median (range) age was 71 (44-79), and 7 (54%) participants were male. There were no DLTs. Seven participants had grade ≥3 AEs; 2 participants had grade 5 AEs, including a second primary malignancy (acute myeloid leukemia) considered treatment-related. Dose-dependent increase in GS-3583 serum exposure was observed in the dose range of 2-20 mg with GS-3583 accumulation at higher dose levels. Expansions of cDCs occurred at all four doses with a dose-dependent trend in the durability of the cDC expansion. CONCLUSIONS: GS-3583 was relatively well tolerated and induced dose-dependent expansion of cDCs in the periphery of patients with advanced solid tumors. However, development of a second primary malignancy provides a cautionary tale for the FLT3 agonist mechanism. See related commentary by Raeder and Drazer, p. 2857.

Components study on gastroprotective effect and holistic mechanism of the herbal pair Alpinia officinarum - Cyperus rotundus based on spectrum-effect relationship and integrated transcriptome and metabolome analyses.

ETHNOPHARMACOLOGICAL RELEVANCE: The herbal pair Alpinia officinarum-Cyperus rotundus (HPAC) has an extended history of use in the treatment of gastric ulcers, and its curative effect is definite. AIM OF THE STUDY: To explore the material basis and holistic mechanism of HPAC on ethanol-induced gastric ulcers. MATERIALS AND METHODS: Three chemometrics, GRA, OPLS, and BCA, were used to construct the spectrum-effect relationship between the HPLC fingerprints of HPAC extracts and the bioactivity indices (cell viability; the levels of TNF-α, IL-6, COX-2, and PGE2; and wound healing rate) against GES-1 cell damage to screen the bioactive ingredients. The bioactive components were isolated and validated in vitro. Simultaneously, the effects of HPAC with concentrated bioactive ingredients was tested on ethanol-induced gastric ulcers in vivo, and the mechanism was investigated using transcriptomics and metabolomics. The mechanism was further validated by Western blotting. Finally, the contents of the main components of HPAC were determined before and after compatibility. RESULTS: Twelve bioactive components were screened, and the structures of nine compounds were confirmed. An in vitro verification test showed that DPHA and galangin could protect GES-1 cells from injury, and that their content increased after compatibility. The CH2Cl2 fraction of HPAC (HP-CH2Cl2) can protect mice from ethanol-induced gastric mucosal injury by reducing hemorrhage and decreasing inflammatory cell infiltration. Western blot analysis indicated that this fraction may up-regulate TRPV1 protein and down-regulate PI3K and AKT proteins. CONCLUSIONS: DPHA and galangin may be the bioactive components against ethanol-induced GES-1 cell injury. HP-CH2Cl2 may exert gastroprotective effects by regulating PI3K, AKT and TRPV1 proteins.

Impacted spike frequency adaptation associated with reduction of KCNQ2/3 exacerbates seizure activity in temporal lobe epilepsy.

Numerous epilepsy-related genes have been identified in recent decades by unbiased genome-wide screens. However, the available druggable targets for temporal lobe epilepsy (TLE) remain limited. Furthermore, a substantial pool of candidate genes potentially applicable to TLE therapy awaits further validation. In this study, we reveal the significant role of KCNQ2 and KCNQ3, two M-type potassium channel genes, in the onset of seizures in TLE. Our investigation began with a quantitative analysis of two publicly available TLE patient databases to establish a correlation between seizure onset and the downregulated expression of KCNQ2/3. We then replicated these pathological changes in a pilocarpine seizure mouse model and observed a decrease in spike frequency adaptation due to the affected M-currents in dentate gyrus granule neurons. In addition, we performed a small-scale simulation of the dentate gyrus network and confirmed that the impaired spike frequency adaptation of granule cells facilitated epileptiform activity throughout the network. This, in turn, resulted in prolonged seizure duration and reduced interictal intervals. Our findings shed light on an underlying mechanism contributing to ictogenesis in the TLE hippocampus and suggest a promising target for the development of antiepileptic drugs.

Cytotoxic Indole Diterpenoids from a Sphagneticola trilobata-Derived Fungus Aspergillus sp. PQJ-1.

Two new indole diterpene derivatives, 5S-hydroxy-ß-aflatrem (1) and 14R-hydroxy-ß-aflatrem (2), along with one known analogue, 14-(N,N-dimethl-L-valyloxy)paspalinine (3), were isolated from the fermentation broth of the fungus Aspergillus sp. PQJ-1 derived from Sphagneticola trilobata. The structures of the new compounds were elucidated from spectroscopic data and ECD spectroscopic analyses. All the compounds (1-3) were evaluated for their cytotoxicity against A549, Hela, Hep G2, and MCF-7 cell lines. Compounds 1 and 2 exhibited selective inhibition against Hela cells. Further studies showed that 1 significantly induced apoptosis and suppressed migration and invasion in Hela cells. Moreover, 1 could up-regulate pro-apoptotic genes BAX and Caspase-3 and down-regulate anti-apoptotic genes Bcl-xL and XIXP.

Engineering of a GSH activatable photosensitizer for enhanced photodynamic therapy through disrupting redox homeostasis.

Although disrupted redox homeostasis has emerged as a promising approach for tumor therapy, most existing photosensitizers are not able to simultaneously improve the reactive oxygen species level and reduce the glutathione (GSH) level. Therefore, designing photosensitizers that can achieve these two aspects of this goal is still urgent and challenging. In this work, an organic activatable near-infrared (NIR) photosensitizer, CyI-S-diCF3, is developed for GSH depletion-assisted enhanced photodynamic therapy. CyI-S-diCF3, composed of an iodinated heptamethine cyanine skeleton linked with a recognition unit of 3,5-bis(trifluoromethyl)benzenethiol, can specifically react with GSH by nucleophilic substitution, resulting in intracellular GSH depletion and redox imbalance. Moreover, the activated photosensitizer can produce abundant singlet oxygen (1O2) under NIR light irradiation, further heightening the cellular oxidative stress. By this unique nature, CyI-S-diCF3 exhibits excellent toxicity to cancer cells, followed by inducing earlier apoptosis. Thus, our study may propose a new strategy to design an activatable photosensitizer for breaking the redox homeostasis in tumor cells.

Isoindigo-Thiophene D-A-D-Type Conjugated Polymers: Electrosynthesis and Electrochromic Performances.

Four novel isoindigo-thiophene D-A-D-type precursors are synthesized by Stille coupling and electrosynthesized to yield corresponding hybrid polymers with favorable electrochemical and electrochromic performances. Intrinsic structure-property relationships of precursors and corresponding polymers, including surface morphology, band gaps, electrochemical properties, and electrochromic behaviors, are systematically investigated. The resultant isoindigo-thiophene D-A-D-type polymer combines the merits of isoindigo and polythiophene, including the excellent stability of isoindigo-based polymers and the extraordinary electrochromic stability of polythiophene. The low onset oxidation potential of precursors ranges from 1.10 to 1.15 V vs. Ag/AgCl, contributing to the electrodeposition of high-quality polymer films. Further kinetic studies illustrate that isoindigo-thiophene D-A-D-type polymers possess favorable electrochromic performances, including high optical contrast (53%, 1000 nm), fast switching time (0.8 s), and high coloration efficiency (124 cm2 C-1). These features of isoindigo-thiophene D-A-D-type conjugated polymers could provide a possibility for rational design and application as electrochromic materials.

Gastric protective effect of Alpinia officinarum flavonoids: mediating TLR4/NF-κB and TRPV1 signalling pathways and gastric mucosal healing.

CONTEXT: Our previous studies have found that total flavonoid of Alpinia officinarum Hance (Zingiberaceae) (F.AOH) had protective effects on gastric ulcer (GU). OBJECTIVE: To investigate the protective mechanism of F.AOH on acetic acid-induced chronic GUs in rats and ethanol-induced GES-1 cells damage. MATERIALS AND METHODS: In vivo: Gastric damage was induced in SD rats by administering acetic acid after oral treatment with F-AOH at 54, 27 and 13.5 mg/kg (2 weeks of continuous gavage). After a comprehensive evaluation of rats' serum and gastric tissue-related indicators, gene transcriptome sequencing, qPCR and Western blotting were used to investigate the mechanism further. In vivo: GES-1 cells were incubated with F-AOH (8, 4 and 2 µg/mL) for 16 h and treated with 7% ethanol for 4 h. Transwell and flow cytometry were employed to detect migration and apoptosis of cells. RESULTS: F.AOH effectively reduced the area of GUs in rats (from 11.2 ± 1.89 to 2.19 ± 0.95), reversing ethanol-induced cells apoptosis (from 23 ± 1.3 to 8.11 ± 0.93%). It also inhibited the expression of endothelin-1 (ET-1) and iNOS proteins, decreasing the levels of TNF-α IL-6 in serum, improving oxidative stress levels and increasing the expression of Bcl-2/Bax dimer genes. In addition, 4005 differentially expressed genes between the acetic acid model and the drug groups. Through experimental verification, F.AOH can inhibit the activation of TLR4/NF-κB signalling pathway and TRPV1 receptor. CONCLUSIONS: F.AOH, as an effective gastric protective plant component, had potential therapeutic value in anti-inflammatory pain and antioxidative stress gastrointestinal diseases.

Large-fused-ring-based D-A type electrochromic polymer with magenta/yellowish green/cyan three-color transitions.

Large-fused-ring-based conjugated polymers possess wide application prospects in optoelectronic devices due to their high charge transport and wide optical absorption. In this paper, three low-bandgap donor-acceptor (D-A) type polymers PBIT-X (X = 1, 2, 3) based on alkylated benzodithiophene and tris(thienothiophene) as donors and thiadiazol-quinoxaline as an acceptor were synthesized via Stille coupling polymerization at different (donor/acceptor) D/A molar feed ratios. The band gaps of PBIT-1, PBIT-2, PBIT-3 were 1.10 eV, 1.04 eV and 1.02 eV, respectively. Spectroelectrochemistry studies showed that the three D-A type polymers have dual bands located in visible and near-infrared regions in the neutral state. The three D-A type polymers possess good electrochromic properties, such as an optical contrast of 56% and response time of 0.3 s. In particular, PBIT-3 could achieve three color changes from magenta to yellowish green to cyan during the oxidation process. The results indicate that these D-A type conjugated polymers based on large fused-ring units exhibit multiple color changes, endowing them with huge potential applications in visible and near-infrared electrochromic devices.

Toward High-Performance Electrochromic Conjugated Polymers: Influence of Local Chemical Environment and Side-Chain Engineering.

Three homologous electrochromic conjugated polymers, each containing an asymmetric building block but decorated with distinct alkyl chains, were designed and synthesized using electrochemical polymerization in this study. The corresponding monomers, namely T610FBTT810, DT6FBT, and DT48FBT, comprise the same backbone structure, i.e., an asymmetric 5-fluorobenzo[c][1,2,5]thiadiazole unit substituted by two thiophene terminals, but were decorated with different types of alkyl chain (hexyl, 2-butyloctyl, 2-hexyldecyl, or 2-octyldecyl). The effects of the side-chain structure and asymmetric repeating unit on the optical absorption, electrochemistry, morphology, and electrochromic properties were investigated comparatively. It was found that the electrochromism conjugated polymer, originating from DT6FBT with the shortest and linear alkyl chain, exhibits the best electrochromic performance with a 25% optical contrast ratio and a 0.3 s response time. The flexible electrochromic device of PDT6FBT achieved reversible colors of navy and cyan between the neutral and oxidized states, consistent with the non-device phenomenon. These results demonstrate that subtle modification of the side chain is able to change the electrochromic properties of conjugated polymers.

Truxene-Centered Electron Acceptors for Non-Fullerene Solar Cells: Alkyl Chain and Branched Arm Engineering.

A series of symmetrical truxene-centered and 3-ethylrhodanine end-capped electron acceptors with high absorption coefficient, namely Tr(Hex)6-3RD, Tr(Dec)6-3RD, and Tr(Hex)6-6RD, were prepared and constructed for non-fullerene solar cells. To satisfy solution-processability, multiple energy levels, and suitable morphology, these three acceptors were comparatively studied through alkyl chain (hexyl/decyl) and branched-arm engineering (three/six branched arms). The six-bladed propeller acceptor of Tr(Hex)6-6RD recorded the power conversion efficiency (PCE) of 1.1% blending with PTB7-Th without additional additives and post-processing. This work highly broadens the potential applications of star-shaped truxene building blocks in the fields of organic electronics.

Midkine-Notch2 Pathway Mediates Excessive Proliferation of Airway Smooth Muscle Cells in Chronic Obstructive Lung Disease.

Inflammation-induced proliferation of airway smooth muscle cells (ASMCs) and subsequent airway remodeling is a hallmark of chronic obstructive lung disease (COPD). The role of midkine (MK) in COPD is unclear. In this work, we explored the role of MK-Notch2 signaling in COPD by inhibiting the expression of MK using lentivirus shRNA in ASMCs in vitro and instillation of AAV9-MK in the airway of a COPD rat model in vivo. The results demonstrated that LPS decreased ASMC migration and proliferation, increased apoptosis and induced the expression of MK and Notch2 signaling molecules. Inhibition of MK exacerbated the changes in migration and proliferation but decreased the expression of MK and Notch2 signaling molecules. Rats treated with smoke fumigation and LPS showed features of COPD. The small airways of COPD rats were remodeled and lung function was significantly reduced. The expressions of TGF-ß, ICAM-1, HA, MMP-9, PC-III, and LN in BALF and the expression of MK and Notch2 signaling molecules were significantly increased in the COPD rats compared with controls. Inhibition of MK reversed these changes. In conclusion, the MK-Notch2 pathway plays a key role in airway remodeling induced by ASMC proliferation. Targeting the MK-Notch2 pathway may be a new strategy for improving airway remodeling and preventing progressive decline of pulmonary function in COPD.

Self-Healing Silver Nanowires and Reduced Graphene Oxide/Polyurethane Composite Film Based on the Diels-Alder Reaction under Infrared Radiation.

The hybrid composite of silver nanowires (AgNWs) and reduced graphene oxide (RGO) was synthesized in situ by an improved polyol-thermal method. The AgNWs-RGO with mass contents of 5-37 wt% was added into the thermo-reversible Diels-Alder reaction polyurethane (DA-PU) matrix with the AgNWs as the main conductor and the RGO as the auxiliary conductor to prepare self-healing composite conductive films. Further, the electrical conductivity, thermal conductivity, mechanical properties, infrared thermal response, and self-healing property of the composite film under infrared light irradiation were studied. The experimental results demonstrate that the AgNWs-RGO endows the composite film with good electrical and thermal conductivity and infrared thermal response ability, while the mechanical properties of the composite film decrease as the AgNWs-RGO mass content increases. The self-healing efficiency of the composite film is higher than that of the pure DA-PU under infrared light irradiation due to the good infrared photothermal response ability of the AgNWs-RGO. When the mass content of AgNWs-RGO in the composite film was 25 wt%, the AgNWs-RGO showed good dispersion in composite films, and the resistivity, thermal conductivity, and tensile strength of the composite film were 0.544 Ω·m, 0.3039 W·m-1·K-1, and 9.05 MPa, respectively. The infrared photothermal conversion temperature of the composite film is 158.5 °C (3450 lux for 1 min), and the infrared photothermal self-healing efficiency is 118% (3450 lux for 600 s). The AgNWs-RGO also improves the multiple self-healing ability of the composite film. The use of a high mass content of AgNWs-RGO in the composite film is beneficial in obtaining high multiple self-healing efficiencies. The first and the fifth infrared thermal self-healing efficiencies of the composite film with AgNWs-RGO of 35 wt% are 105% and 86%, respectively, and the resistivity of the composite film changes little and still maintains good conductivity.

Near-Infrared-Light-Assisted Self-Healing Graphene-Thermopolyurethane Composite Films.

Graphene-thermopolyurethane (G-TPU) composite films were fabricated and the effects of the TPU initial concentration, characteristics of TPU, and graphene loading on the electrical, mechanical, thermal, infrared thermal response and near-infrared-light-assisted self-healing properties of the composite films were investigated in detail. The experimental results demonstrate that the comprehensive performances of the composite film are related to the initial concentration of the TPU solution and the characteristics of the TPU and the graphene loading. The composite film prepared from TPU solution with low initial concentration can have conductivity under the condition of low graphene content. However, the composite film prepared with appropriate initial concentration of TPU solution and high graphene loading is conducive to obtain high conductivity. After 60 s of near-infrared illumination, the temperature of the composite film first increases and then decreases with the increase in graphene loading until it reaches saturation. The near-infrared light thermal response of the composite film with high graphene loading is related to the initial concentration of TPU solution, while the near-IR thermal response of the composite film with low graphene loading is independent of the initial concentration of TPU. The surface micro-cracks of the composite film almost disappeared after 10 min of near-infrared illumination. The resistance of the conductive composite film increases after healed. The composite film prepared with low melting point TPU is more favorable to obtain high near-IR thermal self-healing efficiency.