Simulation combined model-based testing method for train control systems

A Train Control System (TCS) is utilised to guard the operational safety of the trains in railway systems. Therefore, functional testing is applied to verify consistency between the TCS and specification requirements. Traditional functional testing in TCSs is mainly based on manually designed test cases, which is becoming unsuitable for testing increasingly complex TCSs. Therefore, Model-Based Testing (MBT) methods have been introduced into TCS functional testing, to improve the efficiency and coverage of TCS testing, with application difficulties. To overcome the difficulties of applying MBT methods to test TCSs, the author introduces simulation combined MBT which combines an MBT method with simulation. Modelling method and implementation method for the proposed approach were explained in detail. Two case studies were undertaken to explore the effectiveness of the testing platform developed. The testing results obtained prove that the testing platform can be utilised to implement the functional testing of TCSs. To prove that the MBT platform is effective in detecting errors in the SUT, validation and verification was undertaken, which include validation of specification requirements and verification of the MBT platform. The testing performance is proven to be better than existing MBT methods in terms of coverage and efficiency

Multi-ancestry Mendelian randomization of omics traits revealing drug targets of COVID-19 severity

BACKGROUND: Recent omic studies prioritised several drug targets associated with coronavirus disease 2019 (COVID-19) severity. However, little evidence was provided to systematically estimate the effect of drug targets on COVID-19 severity in multiple ancestries. METHODS: In this study, we applied Mendelian randomization (MR) and colocalization approaches to understand the putative causal effects of 16,059 transcripts and 1608 proteins on COVID-19 severity in European and effects of 610 proteins on COVID-19 severity in African ancestry. We further integrated genetics, clinical and literature evidence to prioritise drug targets. Additional sensitivity analyses including multi-trait colocalization and phenome-wide MR were conducted to test for MR assumptions. FINDINGS: MR and colocalization prioritized four protein targets, FCRL3, ICAM5, ENTPD5 and OAS1 that showed effect on COVID-19 severity in European ancestry. One protein target, SERPINA1 showed a stronger effect in African ancestry but much weaker effect in European ancestry (odds ratio [OR] in Africans=0.369, 95%CI=0.203 to 0.668, P = 9.96 × 10(−4); OR in Europeans=1.021, 95%CI=0.901 to 1.157, P = 0.745), which suggested that increased level of SERPINA1 will reduce COVID-19 risk in African ancestry. One protein, ICAM1 showed suggestive effect on COVID-19 severity in both ancestries (OR in Europeans=1.152, 95%CI=1.063 to 1.249, P = 5.94 × 10(−4); OR in Africans=1.481, 95%CI=1.008 to 2.176; P = 0.045). The OAS1, SERPINA1 and ICAM1 effects were replicated using updated COVID-19 severity data in the two ancestries respectively, where alternative splicing events in OAS1 and ICAM1 also showed marginal effects on COVID-19 severity in Europeans. The phenome-wide MR of the prioritised targets on 622 complex traits provided information on potential beneficial effects on other diseases and suggested little evidence of adverse effects on major complications. INTERPRETATION: Our study identified six proteins as showing putative causal effects on COVID-19 severity. OAS1 and SERPINA1 were targets of existing drugs in trials as potential COVID-19 treatments. ICAM1, ICAM5 and FCRL3 are related to the immune system. Across the six targets, OAS1 has no reliable instrument in African ancestry; SERPINA1, FCRL3, ICAM5 and ENTPD5 showed a different level of putative causal evidence in European and African ancestries, which highlights the importance of more powerful ancestry-specific GWAS and value of multi-ancestry MR in informing the effects of drug targets on COVID-19 across different populations. This study provides a first step towards clinical investigation of beneficial and adverse effects of COVID-19 drug targets. FUNDING: No

Pretreatment with High-Dose Gamma Irradiation on Seeds Enhances the Tolerance of Sweet Osmanthus Seedlings to Salinity Stress

The landscape application of sweet osmanthus (Osmanthus fragrans) with flower fragrance and high ornamental value is severely limited by salinity stress. Gamma irradiation applied to seeds enhanced their tolerance to salinity stress as reported in other plants. In this study, O. fragrans ‘Huangchuang Jingui’ seeds were pretreated with different doses of gamma irradiation, and tolerance of the seedlings germinated from the irradiated seeds to salinity stress and the changes of reactive oxygen species (ROS) production and ROS scavenging systems induced by gamma irradiation were observed. The results showed that seed pretreatment with different doses of gamma irradiation enhanced the tolerance of sweet osmanthus seedlings to salinity stress, and the positive effect induced by gamma irradiation was more remarkable with the increase of radiation dose (50−150 Gy). The pretreatment with high-dose irradiation decreased O2− production under salinity stress and mitigated the oxidative damage marked by a lower malondialdehyde (MDA) level, which could be related to the significant increase of superoxide dismutase (SOD), peroxidase (POD) and catalase (CAT) activities in the seedlings germinated from the irradiated seeds compared to the corresponding control seedlings. In addition, the accumulation of proline in the irradiated seedlings may contribute to enhancing their tolerance to salt stress by the osmotic adjustment. The study demonstrated the importance of regulating plant ROS balance under salt stress and provided a potential approach to improve the tolerance of sweet osmanthus to salt stress

Numerical modeling of coupled thermal-hydro-mechanical behavior of GMZ bentonite in the China-Mock-up test

peer reviewedGaomiaozi (GMZ) bentonite is currently considered as themost suitable buffermaterial for high-level radioactive waste geological repository in China. To investigate the long-term performance of GMZ bentonite under repository conditions, a large scale mock-up test has been carried out since 2011. In the test, a hydration systemand an electrical heater were employed to simulate the Thermal-Hydro-Mechanical (THM) coupled conditions near a repository. In this work, a numerical study is performed to reproduce the experimental data obtained in the first three years of the China-Mock-up experiment. The principle THM characteristics and parameters of the bentonite are presented. On this basis, a THM coupled constitutive model is introduced. With the proposed model, numerical simulations of the China-Mock-up test are carried out using LAGAMINE. The numerical data of temperature, relative humidity, and swelling pressure of the GMZ compacted bentonite are compared with the experimental ones.We discuss the effect of the balance between the drying effect and water penetration process on the THM behavior of the GMZ bentonite. The good agreement between the predicted and experimental results suggests that the proposed model can reproduce the fundamental behavior of GMZ compacted bentonite under coupled THM conditions

DNA Holliday Junction: History, Regulation and Bioactivity

DNA Holliday junction (HJ) is a four-way stranded DNA intermediate that formed in replication fork regression, homology-dependent repair and mitosis, performing a significant role in genomic stability. Failure to remove HJ can induce an acceptable replication fork stalling and DNA damage in normal cells, leading to a serious chromosomal aberration and even cell death in HJ nuclease-deficient tumor cells. Thus, HJ is becoming an attractive target in cancer therapy. However, the development of HJ-targeting ligand faces great challenges because of flexile cavities on the center of HJs. This review introduces the discovery history of HJ, elucidates the formation and dissociation procedures of HJ in corresponding bio-events, emphasizes the importance of prompt HJ-removing in genome stability, and summarizes recent advances in HJ-based ligand discovery. Our review indicate that target HJ is a promising approach in oncotherapy

China: Experience of radioactive waste (RAW) management

Zhiwen Fan, Yuemiao Liu, Ju Wang, Guogang Ren and William E. Lee, 'China: Experience of Radioactive waste (RAW) management', in William E. Lee, Michael I. Ojovan and Carol M. Jantzen, Eds., Radioactive waste management and contaminated site clean-up (Cambridge: Woodhead Publishing Limited 2013) ISBN: 9780857094353Progress in the management of China's radioactive waste (RAW) is described, including waste generation, waste management policy, and current practices in regional disposal of low and intermediate level waste (LILW) and development of a geological disposal facility for hight level waste (HlW)

CO2-Driven Hydraulic Fracturing Trajectories across a Preexisting Fracture

Defining the trajectory of hydraulic fractures crossing bedding planes and other fractures is a significant issue in determining the effectiveness of the stimulation. In this work, a damage evolution law is used to describe the initiation and propagation of the fracture. The model couples rock deformation and gas seepage using the finite element method and is validated against classical theoretical analysis. The simulation results define four basic intersection scenarios between the fluid-driven and preexisting fractures: (a) inserting—the hydraulic fracture inserts into a bedding plane and continues to propagate along it; (b) L-shaped crossing—the hydraulic fracture approaches the fracture/bedding plane then branches into the plane without crossing it; (c) T-shaped crossing—the hydraulic fracture approaches the fracture/bedding plane, branches into it, and crosses through it; (d) direct crossing—the hydraulic fracture crosses one or more bedding planes without branching into them. The intersection scenario changes from (a) → (b) → (c) → (d) in specimens with horizontal bedding planes when the stress ratio β (β=σy/σx) increases from 0.2 to 5. Similarly, the intersection type changes from (d) → (c) → (a) with an increase in the bedding plane angle α (0° → 90°). Stiffness of the bedding planes also exerts a significant influence on the propagation of hydraulic fractures. As the stiffness ratio E1¯/E2¯ increases from 0.1 to 0.4 and 0.8, the seepage area decreases from 22.2% to 41.8%, and the intersection type changes from a T-shaped crossing to a direct crossing

Identification of a novel heterogeneous nuclear ribonucleoprotein A2B1 (hnRNPA2B1) ligand that disrupts HnRNPA2B1/nucleic acid interactions to inhibit the MDMX-p53 axis in gastric cancer

Gastric carcinoma is a highly malignant tumor that still lacks effective molecular targets. Heterogeneous nuclear ribonucleoprotein A2B1 (hnRNPA2B1) is an essential oncogenic driver overexpressed in various cancers. The potential role of hnRNPA2B1 in oncotherapy has not been revealed because of the absence of active chemical molecules. In this study, we identified the pseudourea derivative XI-011 as a novel hnRNPA2B1 ligand using chemical proteomics. An interaction study indicated that XI-011 could bind the nucleotide-binding domain to disrupt the recruitment of hnRNPA2B1 to the promoter and untranslated region of the murine double minute X (MDMX) gene, thereby inhibiting its transcription. In addition, chemical targeting of hnRNPA2B1 recovered inactivated p53 and enhanced the therapeutic efficacy of apatinib in vivo. This work presented a novel strategy to restore p53 activity for the treatment of gastric cancers via chemically targeting hnRNPA2B1