Potent anti-tumor effects of a dual specific oncolytic adenovirus expressing apoptin in vitro and in vivo

<p>Abstract</p> <p>Background</p> <p>Oncolytic virotherapy is an attractive drug platform of cancer gene therapy, but efficacy and specificity are important prerequisites for success of such strategies. Previous studies determined that Apoptin is a p53 independent, bcl-2 insensitive apoptotic protein with the ability to specifically induce apoptosis in tumor cells. Here, we generated a conditional replication-competent adenovirus (CRCA), designated Ad-hTERT-E1a-Apoptin, and investigated the effectiveness of the CRCA a gene therapy agent for further clinical trials.</p> <p>Results</p> <p>The observation that infection with Ad-hTERT-E1a-Apoptin significantly inhibited growth of the melanoma cells, protecting normal human epidermal melanocytes from growth inhibition confirmed cancer cell selective adenoviral replication, growth inhibition, and apoptosis induction of this therapeutic approach. The <it>in vivo </it>assays performed by using C57BL/6 mice containing established primary or metastatic tumors expanded the <it>in vitro </it>studies. When treated with Ad-hTERT-E1a-Apoptin, the subcutaneous primary tumor volume reduction was not only observed in intratumoral injection group but in systemic delivery mice. In the lung metastasis model, Ad-hTERT-E1a-Apoptin effectively suppressed pulmonary metastatic lesions. Furthermore, treatment of primary and metastatic models with Ad-hTERT-E1a-Apoptin increased mice survival.</p> <p>Conclusions</p> <p>These data further reinforce the previously research showing that an adenovirus expressing Apoptin is more effective and advocate the potential applications of Ad-hTERT-E1a-Apoptin in the treatment of neoplastic diseases in future clinical trials.</p

Optimization of International Roughness Index Model Parameters for Sustainable Runway

Pavement roughness is a critical airport pavement characteristic that has been linked to impacts such as safety and service life. A properly defined roughness evaluation method would reduce airport operational risk, prolong the life of aircraft landing gear, and optimize the decision-making process for pavement preservation, which together positively contribute to overall airport sustainability. In this study, we optimized the parameters of the International Roughness Index (IRI) model to resolve the current poor correlation between the IRI and aircraft vibration responses in order to adapt and extend the IRI’s use for airport runway roughness evaluation. We developed and validated a virtual prototype model based on ADAMS/Aircraft software for the Boeing 737–800 and then employed the model to predict the aircraft’s dynamic responses to runway pavement roughness. By developing a frequency response function for the standard 1/4 vehicle model, we obtained frequency response distribution curves for the IRI. Based on runway roughness data, we used fast Fourier transform to implement the frequency response distribution of the aircraft. We then utilized Particle Swarm Optimization to determine more appropriate IRI model parameters rather than modifying the model itself. Our case study results indicate that the correlation coefficient for the optimized IRI model and aircraft vibration response shows a qualitative leap from that of the original IRI model

Performance Assessment and Comparison of Two Piezoelectric Energy Harvesters Developed for Pavement Application: Case Study

To advance the development of piezoelectric energy harvesters, this study designed and manufactured bridge-unit-based and pile-unit-based piezoelectric devices. An indoor material testing system and accelerated pavement test equipment were used to test the electrical performance, mechanical performance, and electromechanical coupling performance of the devices. The results showed that the elastic modulus of the pile structure device was relatively higher than that of the bridge structure device. However, the elastic modulus of the two devices should be improved to avoid attenuation in the service performance and fatigue life caused by the stiffness difference. Furthermore, the electromechanical conversion coefficients of the two devices were smaller than 10% and insensitive to the load magnitude and load frequency. Moreover, the two devices can harvest 3.4 mW and 2.6 mW under the wheel load simulated by the one-third scale model mobile load simulator, thus meeting the supply requirements of low-power sensors. The elastic modulus, electromechanical conversion coefficients, and electric performance of the pile structure device were more reliable than those of the bridge structure device, indicating a better application prospect in road engineering

Systemic autoimmunity in TAM triple knockout mice causes inflammatory brain damage and cell death.

The Tyro3, Axl and Mertk (TAM) triply knockout (TKO) mice exhibit systemic autoimmune diseases, with characteristics of increased proinflammatory cytokine production, autoantibody deposition and autoreactive lymphocyte infiltration into a variety of tissues. Here we show that TKO mice produce high level of serum TNF-α and specific autoantibodies deposited onto brain blood vessels. The brain-blood barrier (BBB) in mutant brains exhibited increased permeability for Evans blue and fluorescent-dextran, suggesting a breakdown of the BBB in the mutant brains. Impaired BBB integrity facilitated autoreactive T cells infiltrating into all regions of the mutant brains. Brain autoimmune disorder caused accumulation of the ubiquitin-reactive aggregates in the mutant hippocampus, and early formation of autofluorescent lipofuscins in the neurons throughout the entire brains. Chronic neuroinflammation caused damage of the hippocampal mossy fibers and neuronal apoptotic death. This study shows that chronic systemic inflammation and autoimmune disorders in the TKO mice cause neuronal damage and death

Improvement of Boeing Bump Method Considering Aircraft Vibration Superposition Effect

Pavement evaluation is critical for the decision-making process of pavement preservation and rehabilitation. Roughness is a key airport pavement characteristic that has been linked to impacts such as safety and service life. The Boeing Bump is one of the few roughness evaluation methods that has been developed specifically for runways. Although it is superior to the widely used International Roughness Index (IRI), it does not take into account the superposition effect of continuous runway bumps. Based on the ADAMS/Aircraft virtual prototype platform, this paper establishes and verifies five typical models (B737, B747, B757, B777, and B787) and then analyzes the most unfavorable speed (in terms of aircraft vibration) of each model and the dynamic responses caused by multiple bumps. The original Boeing Bump is improved and optimized by determining dynamic response thresholds for the various aircraft types. The results show that the revised Boeing Bump is more realistic than the original version, especially with regard to medium and long wave bands

Random Vibration Analysis of a Coupled Aircraft/Runway Modeled System for Runway Evaluation

Runway roughness is one of the most critical performance factors for runway evaluation, which directly impacts airport operation safety and pavement preservation cost. Properly evaluated runway roughness could optimize the decision-making process for runway preservation and therefore reduce the life cycle cost of the runway pavement asset. In this paper, the excitation effect of runway roughness is analyzed using a coupled aircraft/runway system. The coupled system is composed of a two degrees-of-freedom (2-DOF) aircraft model and a typical asphalt runway structure model established under runway roughness random excitation in this work. The dynamic differential equations for the coupled system are derived based on D’Alembert’s principle. The system’s vibration responses are determined via the pseudo excitation method and three response laws, i.e., the center of gravity acceleration (CGA), the dynamic load coefficient (DLC) of the landing gear, and the runway structural displacement, which are investigated under different modes. The results show that the first-order mode of the runway structure, vertical deformation, is the most significant of the four modes. Moreover, uneven excitation has a significant effect on the distribution of the aircraft’s vibration response. Compared with a single aircraft system, the developed coupled aircraft/runway system has different dynamic responses, and the degree of difference depends on the taxiing speed. The coupled effect on the CGA increases significantly with an increase in speed, with up to a 7.3% percentage difference. The coupled effect on the DLC first increases and then decreases as the aircraft speed increases, reaching a maximum of about 6% percentage difference at 120 km/h

TKO mice produce increased proinflammatory cytokines.

<p>(A) TNF-α level in the WT and TKO mouse serum were measured by Ready-set-go ELISA kits (eBiosciences). Data are shown as means±SD, n = 9, p = 0.0002. (B) Thioglycollate-induced peritoneal macrophages (MФ) were treated with LPS for 2, 3, 4 and 5 hrs. TNF-α released into medium was measured as above. Data are shown as means ±SD for five wells per group in a single experiment and are representative of those in three experiments. N = 3, **P<0.001. (C) Real-time qPCR quantification of IL-1β and IL-6 mRNA in the lymph nodes. The total RNA was extracted by TRIzol and reversely transcribed using transcribed using qScript™ cDNA Supermix kit (Quanta Biosciences, MD). Real time qPCR was performed to measure the relative mRNA level of IL-1β and IL-6 genes in the WT (open) and TKO (solid) L.N. Data are shown as means ± SD, n = 3, *P<0.05, **P<0.002. Statistics was performed by the one-way ANOVA test using ProStat Ver 5.5.</p

Unraveling the Molecular Mechanisms of Tomatoes’ Defense against <i>Botrytis cinerea</i>: Insights from Transcriptome Analysis of Micro-Tom and Regular Tomato Varieties

Botrytis cinerea is a devastating fungal pathogen that causes severe economic losses in global tomato cultivation. Understanding the molecular mechanisms driving tomatoes’ response to this pathogen is crucial for developing effective strategies to counter it. Although the Micro-Tom (MT) cultivar has been used as a model, its stage-specific response to B. cinerea remains poorly understood. In this study, we examined the response of the MT and Ailsa Craig (AC) cultivars to B. cinerea at different time points (12–48 h post-infection (hpi)). Our results indicated that MT exhibited a stronger resistant phenotype at 18–24 hpi but became more susceptible to B. cinerea later (26–48 hpi) compared to AC. Transcriptome analysis revealed differential gene expression between MT at 24 hpi and AC at 22 hpi, with MT showing a greater number of differentially expressed genes (DEGs). Pathway and functional annotation analysis revealed significant differential gene expression in processes related to metabolism, biological regulation, detoxification, photosynthesis, and carbon metabolism, as well as some immune system-related genes. MT demonstrated an increased reliance on Ca2+ pathway-related proteins, such as CNGCs, CDPKs, and CaMCMLs, to resist B. cinerea invasion. B. cinerea infection induced the activation of PTI, ETI, and SA signaling pathways, involving the modulation of various genes such as FLS2, BAK1, CERK1, RPM, SGT1, and EDS1. Furthermore, transcription factors such as WRKY, MYB, NAC, and AUX/IAA families played crucial regulatory roles in tomatoes’ defense against B. cinerea. These findings provide valuable insights into the molecular mechanisms underlying tomatoes’ defense against B. cinerea and offer potential strategies to enhance plant resistance