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关键词： Androgenetic alopecia   minoxidil   finasteride   topical foam   phase 1   CG2001  

摘要： ObjectivesCompared with placebo, this phase I study evaluated the safety, tolerability, and pharmacokinetics of CG2001, a novel isopropyl alcohol-free minoxidil-finasteride combination topical foam, in Chinese males with androgenetic alopecia (AGA).MethodsIn this randomized, double-blind, placebo-controlled trial, 44 subjects received single and multiple doses across five cohorts with varying finasteride concentrations (0.025%-0.1%) and frequencies. Safety, tolerability, and pharmacokinetics were evaluated. The concentrations of minoxidil-finasteride were both measured.ResultsThe result shows that CG2001 was safe and well-tolerated, with no serious adverse events. Systemic minoxidil exposure was consistent across most dosages, while finasteride exposure increased dose- and frequency-dependently, though it remained markedly lower than that reported with oral administration. Steady state was achieved for both drugs after 7 days.ConculsionsThe favorable safety profile and reduced systemic finasteride exposure position CG2001 as a promising alternative, supporting further clinical development in a phase IIa trial, and provide a pharmacokinetic foundation for subsequent efficacy trials in patients with AGA.

关键词： Mountainous regions   landslide identification   SBAS-InSAR   LT-1   GNSS  

摘要： Interferometric Synthetic Aperture Radar (InSAR) is widely used for geological hazard monitoring, but its application remains difficult in mountainous regions due to steep terrain, dense vegetation, and rapid landslide events. China's Land Observation Satellite-1 (LT-1 a new-generation L-band radar, provides high spatial resolution and frequent revisit cycles, creating new opportunities for detecting landslides in complex terrain. This study employs LT-1 data to conduct long-term SBAS-InSAR landslide monitoring and validation, complemented by comparative assessments against Sentinel-1, ALOS-2, and GNSS observations. Results show that LT-1 detected 117 potential landslides, far more than Sentinel-1 in the same area. LT-1 maintained strong coherence and temporal stability even in steep, vegetated terrain, allowing reliable detection of slow-moving slope deformations. Case studies demonstrated the capability to detect subsidence rates exceeding 80 mm per year. GNSS and InSAR results showed strong agreement in both deformation trends and rainfall responses (r > 0.82, p < 0.01 supporting the reliability of the monitoring. Overall, the findings indicate that LT-1, when combined with SBAS-InSAR, can accurately capture cumulative surface and slope deformations.

摘要： Bovine alphaherpesvirus 1 (BoHV-1) is the causative agent of infectious bovine rhinotracheitis and reproductive disorders causing significant economic losses in the cattle industry. Both BoHV-1 glycoproteins B (gB) and D (gD) are targets of neutralizing antibodies and desirable antigens for subunit vaccine. In this study, a bivalent subunit vaccine was generated based on the ectodomain of gD and gB expressed by baculoviruses system. Compared with the inactivated vaccine, the bivalent subunit vaccine induced higher neutralizing antibody levels against both the BoHV-1 reference strain and the virulent BoHV-1 field strain. Following intranasally challenge with BoHV-1 J2303, the clinical signs and virus excretion were significantly reduced in rabbits vaccinated with this subunit vaccine whereas severe clinical symptoms appeared in the non-vaccinated rabbits, indicating that the bivalent subunit vaccine provides complete protection against virulent BoHV-1 infection. Considering that the respiratory symptoms caused by J2303 in rabbits is highly similar and even identical to those of cattle, our findings suggest that the bivalent subunit vaccine based on combination of gD with gB protein have promising application to BoHV-1control programs.

关键词： Pediatric pneumonia   ROS release   NETosis   mitochondrial dysfunction   inflammasome   pyroptosis   IRF1/MMP9 pathway  

摘要： While interferon regulatory factor 1 (IRF1) has been implicated in reactive oxygen species (ROS)-dependent neutrophil extracellular trap (NET) release during acute lung injury, its regulatory role in mitochondrial dysfunction-driven NETosis specific to pediatric pneumonia remains unexplored. Neutrophils were isolated from the bronchoalveolar lavage fluid (BALF) of pediatric pneumonia patients and the bone marrow of mice. IRF1 expression was quantified via qRT-PCR and Western blotting. Mitochondrial ROS (mtROS) and total ROS were measured by flow cytometry. Mitochondrial dysfunction was assessed by ATP quantification. NETosis was evaluated through immunofluorescence staining and ELISA quantification of neutrophil elastase (NE myeloperoxidase-DNA (MPO-DNA and citrullinated histone H3 (Cit-H3) levels. For in vivo studies, pneumonia-related lung injury was induced by intratracheal LPS instillation in mice, with pathological severity graded by H&E staining, pulmonary edema quantified via the wet/dry weight ratio, and inflammation assessed by the BALF protein concentration. Mechanistically, the IRF1/MMP9 interaction was predicted by bioinformatics (STRING database) and validated by co-immunoprecipitation (Co-IP) and immunofluorescence staining, while MMP9 overexpression was achieved via lentivirus transduction to delineate pathway regulation. IRF1 was significantly upregulated in BALF neutrophils from patients and correlated with elevated ROS production and mitochondrial dysfunction, as well as NETs release. IRF1 knockdown attenuated ROS-driven NETosis in vitro. Matrix metalloproteinase 9 (MMP9) was predicted to interact with IRF1, and MMP9 overexpression effectively reversed the beneficial effects of IRF1 deficiency on ROS release, mitochondrial dysfunction, neutrophil apoptosis, and NETosis. Consistently, in mouse models, MMP9 overexpression abolished the protective effects of IRF1 deficiency, exacerbating acute lung injury and restoring NETs levels in BALF.

关键词： Tubulin polymerisation inhibitor   colchicine-binding site   imidazopyridine   molecular docking   antiproliferative activity  

摘要： Tubulin, the fundamental component of microtubules, remains a critical target in anticancer therapy. The development of small-molecule tubulin polymerization inhibitors continues to drive the discovery of novel chemotherapeutic agents. Through systematic analysis of known tubulin inhibitors and in silico binding pocket models, a focused series of 6-aryl-3-(3,4,5-trimethoxyphenyl)imidazo[1,2-a]pyridine derivatives was rationally designed and synthesized. Compound 8o exhibited superior antiproliferative potency, with IC5. values of 0.050-0.078 & micro;M against HeLa, HCT116, and MCF-7 cancer cell lines. Mechanistic investigations confirmed that 8o effectively inhibits tubulin polymerization, disrupts the microtubule cytoskeleton, induces G(2)/M phase arrest, and triggers apoptosis. Preliminary physicochemical assessment indicated that 8o adheres to Lipinski's rule of five, supporting favorable drug-likeness. Collectively, these findings identify 8o as a potent, drug-like colchicine-site tubulin inhibitor with compelling anticancer efficacy, meriting further investigation as a promising lead compound.

关键词： antiretroviral therapy   developing countries   dolutegravir   RCT   second-line  

摘要： Background Longer-term outcome data following second-line antiretroviral therapy initiation in resource-limited settings is limited, especially in regions where genotypic resistance is inaccessible. This analysis evaluated extended efficacy and tolerability data from the D2EFT study. Methods D2EFT is a completed, multicenter, phase IIIB/IV, randomized, open-label trial in 14 low- and middle-income countries. People with human immunodeficiency virus (HIV) who had failed first-line non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimens were switched to 1 of ritonavir-boosted darunavir plus 2 nucleoside reverse transcriptase inhibitors (DRV/r + 2NRTIs ritonavir-boosted darunavir plus dolutegravir (DTG + DRV/r or dolutegravir with tenofovir disoproxil fumarate plus either lamivudine or emtricitabine (DTG + TDF/XTC with or without pre-switch genotyping. Here we report virological suppression at 96 weeks, defined as HIV RNA <50 copies/mL in a modified intention-to-treat population. Results Between November 2017 and January 2022, 1190 participants were screened, 828 were randomized, and 826 were included in the analysis. At week 96, the proportions of participants with HIV RNA <50 copies/mL were 191/251 (76.1%) in DRV/r + 2NRTIs, 215/251 (85.7%) in DTG + DRV/r, and 231/283 (81.6%) in DTG + TDF/XTC. The treatment differences (95% confidence intervals [CIs in proportions achieving virological suppression were 9.6% (2.7, 16.4) in DTG + DRV/r and 9.0% (1.4, 16.6) in DTG + TDF/XTC, compared to DRV/r + 2NRTIs. Intermediate or high-level dolutegravir resistance was identified in 3/27 (13%) of virological failures in individuals taking DTG + TDF/XTC but in no one taking DTG + DRV/r. No darunavir resistance was observed. Conclusions After 96 weeks of follow-up, DTG + DRV/r and DTG + TDF/XTC demonstrated virological superiority over DRV/r + 2NRTIs after first-line NNRTI-failure. However, emerging dolutegravir resistance, which was observed only in individuals taking D

关键词： High pressure   Infrared spectroscopy   Nonclassical hydrogen bond   Phase transition   Polymorphism   Synchrotron X-ray diffraction  

摘要： The crystal structural stability and optical properties of N,N´-diphenyl-1,4-phenylenediamine (C₁₈H₁₆N₂, B3) under high pressure are investigated using in situ high-pressure Infrared (IR) absorption spectroscopy, synchrotron angular-dispersive X-ray diffraction (ADXRD), photoluminescence (PL) spectroscopy, and Ultraviolet–visible (UV–vis) absorption spectroscopy. The results show that enhanced N−H···π and C−H···π nonclassical hydrogen bonds under high pressure induce a Phase I (orthorhombic) to Phase II (triclinic) transition in B3 crystals, initiating at approximately 1.8 GPa and completing around 5.9 GPa, accompanied by a ∼2.00% collapse in the normalized unit cell volume. Moreover, the continuous enhancement of intermolecular interactions results in a red shift and eventual quenching of the PL emission throughout the compression process. This study provides a spectroscopic and structural basis for understanding how weak N−H···π and C−H···π interactions drive phase transitions and modulate the optical properties of organic supramolecular polymorphs under high pressure.

关键词： Control parameters   Fractional bernoulli polynomials   General class of nonlinear systems of (2+1)-dimensional fractional differential equations   Optimization  

摘要： In recent years, the inherent numerical challenges associated with investigating systems of $(2+1)$-dimensional fractional differential equations have made them a subject of limited study. This paper marks the first introduction of a general class of nonlinear systems of $(2+1)$-dimensional fractional differential equations that encompass initial and boundary conditions. The approach begins by expanding the unknown functions using fractional Bernoulli polynomials as basis functions. Subsequently, an optimization problem is formulated utilizing these expansions and the operational matrices of the fractional derivatives. This formulation is then solved using the Lagrange multiplier algorithm, transforming the optimization problem into a system of nonlinear algebraic equations. Furthermore, the convergence analysis of the obtained approximate solution via the proposed technique is explored. Finally, the numerical algorithm’s validity is assessed through a numerical example.