Deep Reinforcement Learning for Integration of Train Trajectory Optimization and Timetable Rescheduling Under Disturbances.

High-speed trains are susceptible to unexpected events such as strong winds and equipment failures, which can result in deviations from the scheduled timetable. As the density of traffic increases, these delays can quickly spread to other trains, eventually leading to conflicts in the timetable. To ensure the efficiency of high-speed railways, quickly resolving potential conflicts and generating appropriate rescheduling schemes are essential. The existing hierarchical structure of train control and online rescheduling tends to be inefficient in terms of information communication and can even lead to unfeasible rescheduled timetables and trajectories. To address these issues, an integrated structure of timetable rescheduling and train trajectory optimization is proposed by introducing the train minimum running time into the process of timetable rescheduling and using the adjusted running time as the objective of trajectory optimization. The integration model is formulated by considering the constraints of timetable rescheduling such as the maximum number of trains overtaking trains, platforms at stations, and the priority of the train, as well as the constraints of trajectory optimization. A deep reinforcement learning (DRL)-based approach is proposed to solve the problem. Numerical experiments are conducted on a segment of the Beijing-Shanghai high-speed railway line, using adapted data to demonstrate the effectiveness of the proposed method in rescheduling timetables and optimizing train trajectories. The results show that the integrated rescheduled timetable and the optimized train trajectory can be generated simultaneously and the computation time exhibits a linear increase with respect to the size of the problem.

hIMB1636-MMAE, a Novel TROP2-Targeting Antibody-Drug Conjugate Exerting Potent Antitumor Efficacy in Pancreatic Cancer.

Herein, we first prepared a novel anti-TROP2 antibody-drug conjugate (ADC) hIMB1636-MMAE using hIMB1636 antibody chemically coupled to monomethyl auristatin E (MMAE) via a Valine-Citrulline linker and then reported its characteristics and antitumor activity. With a DAR of 3.92, it binds specifically to both recombinant antigen (KD ∼ 0.687 nM) and cancer cells and could be internalized by target cells and selectively kill them with IC50 values at nanomolar/subnanomolar levels by inducing apoptosis and G2/M phase arrest. hIMB1636-MMAE also inhibited cell migration, induced ADCC effects, and had bystander effects. It displayed significant tumor-targeting ability and excellent tumor-suppressive effects in vivo, resulting in 5/8 tumor elimination at 12 mg/kg in the T3M4 xenograft model or complete tumor disappearance at 10 mg/kg in BxPc-3 xenografts in nude mice. Its half-life in mice was about 87 h. These data suggested that hIMB1636-MMAE was a promising candidate for the treatment of pancreatic cancer with TROP2 overexpression.

Dual-path multi-scale context dense aggregation network for retinal vessel segmentation.

There has been steady progress in the field of deep learning-based blood vessel segmentation. However, several challenging issues still continue to limit its progress, including inadequate sample sizes, the neglect of contextual information, and the loss of microvascular details. To address these limitations, we propose a dual-path deep learning framework for blood vessel segmentation. In our framework, the fundus images are divided into concentric patches with different scales to alleviate the overfitting problem. Then, a Multi-scale Context Dense Aggregation Network (MCDAU-Net) is proposed to accurately extract the blood vessel boundaries from these patches. In MCDAU-Net, a Cascaded Dilated Spatial Pyramid Pooling (CDSPP) module is designed and incorporated into intermediate layers of the model, enhancing the receptive field and producing feature maps enriched with contextual information. To improve segmentation performance for low-contrast vessels, we propose an InceptionConv (IConv) module, which can explore deeper semantic features and suppress the propagation of non-vessel information. Furthermore, we design a Multi-scale Adaptive Feature Aggregation (MAFA) module to fuse the multi-scale feature by assigning adaptive weight coefficients to different feature maps through skip connections. Finally, to explore the complementary contextual information and enhance the continuity of microvascular structures, a fusion module is designed to combine the segmentation results obtained from patches of different sizes, achieving fine microvascular segmentation performance. In order to assess the effectiveness of our approach, we conducted evaluations on three widely-used public datasets: DRIVE, CHASE-DB1, and STARE. Our findings reveal a remarkable advancement over the current state-of-the-art (SOTA) techniques, with the mean values of Se and F1 scores being an increase of 7.9% and 4.7%, respectively. The code is available at https://github.com/bai101315/MCDAU-Net.

Synthesis and electrochemical properties of Mn-doped Li2Mn0.1Ti1.9(PO4)3 materials.

The hunt for a higher power storage, relatively inexpensive, non-polluting battery technology is currently a pressing issue because of the rapid growth of the worldwide economic and the progressively significant environmental pollution. Among the possible nanomaterials for rechargeable batteries that can have heteroatoms applied to it in order to improve its electrochemical behavior is LixTiy(PO4)3. Carbon-coated Mn-doped Li2Mn0.1Ti1.9(PO4)3 materials was synthesized by spray drying method. The material was characterized by XRD, SEM, TEM, BET, TGA et al. Crystal data refinement results by Rietveld method showed that the symmetry space group is Pbcn.The lattice parameters of Li2Mn0.1Ti1.9(PO4)3 are a = 11.9372 Å, b = 8.5409 Å, c = 8.5979 Å, α = ß = γ = 90°, V = 876.59 Å3 and Z = 4). Rietveld refinement was performed, and the confidence factors are Rwp = 11.79%, Rp = 9.14%, and χ2 = 1.425. It was exhibited that LMTP0.1/CA-700 material has good crystallinity. Testing the cells with LAND test procedure (200 mA/g current density for 200 cycles), the LMTP0.1/CA-700 material has a discharge specific capacity of about 65 mAh/g. The capacity decayed by only 3% during the cycle. It has some potential application values as cathode of lithium ion battery in the future.

Excellent effects and possible mechanisms of action of a new antibody-drug conjugate against EGFR-positive triple-negative breast cancer.

BACKGROUND: Triple-negative breast cancer (TNBC) is the most aggressive subtype and occurs in approximately 15-20% of diagnosed breast cancers. TNBC is characterized by its highly metastatic and recurrent features, as well as a lack of specific targets and targeted therapeutics. Epidermal growth factor receptor (EGFR) is highly expressed in a variety of tumors, especially in TNBC. LR004-VC-MMAE is a new EGFR-targeting antibody-drug conjugate produced by our laboratory. This study aimed to evaluate its antitumor activities against EGFR-positive TNBC and further studied its possible mechanism of antitumor action. METHODS: LR004-VC-MMAE was prepared by coupling a cytotoxic payload (MMAE) to an anti-EGFR antibody (LR004) via a linker, and the drug-to-antibody ratio (DAR) was analyzed by HIC-HPLC. The gene expression of EGFR in a series of breast cancer cell lines was assessed using a publicly available microarray dataset (GSE41313) and Western blotting. MDA-MB-468 and MDA-MB-231 cells were treated with LR004-VC-MMAE (0, 0.0066, 0.066, 0.66, 6.6 nmol/L), and the inhibitory effects of LR004-VC-MMAE on cell proliferation were examined by CCK-8 and colony formation. The migration and invasion capacity of MDA-MB-468 and MDA-MB-231 cells were tested at different LR004-VC-MMAE concentrations (2.5 and 5 nmol/L) with wound healing and Transwell invasion assays. Flow cytometric analysis and tumorsphere-forming assays were used to detect the killing effects of LR004-VC-MMAE on cancer stem cells in MDA-MB-468 and MDA-MB-231 cells. The mouse xenograft models were also used to evaluate the antitumor efficacy of LR004-VC-MMAE in vivo. Briefly, BALB/c nude mice were subcutaneously inoculated with MDA-MB-468 or MDA-MB-231 cells. Then they were randomly divided into 4 groups (n = 6 per group) and treated with PBS, naked LR004 (10 mg/kg), LR004-VC-MMAE (10 mg/kg), or doxorubicin, respectively. Tumor sizes and the body weights of mice were measured every 4 days. The effects of LR004-VC-MMAE on apoptosis and cell cycle distribution were analyzed by flow cytometry. Western blotting was used to detect the effects of LR004-VC-MMAE on EGFR, ERK, MEK phosphorylation and tumor stemness marker gene expression. RESULTS: LR004-VC-MMAE with a DAR of 4.02 were obtained. The expression of EGFR was found to be significantly higher in TNBC cells compared with non-TNBC cells (P < 0.01). LR004-VC-MMAE inhibited the proliferation of EGFR-positive TNBC cells, and the IC50 values of MDA-MB-468 and MDA-MB-231 cells treated with LR004-VC-MMAE for 72 h were (0.13 ± 0.02) nmol/L and (0.66 ± 0.06) nmol/L, respectively, which were significantly lower than that of cells treated with MMAE [(3.20 ± 0.60) nmol/L, P < 0.01, and (6.60 ± 0.50) nmol/L, P < 0.001]. LR004-VC-MMAE effectively inhibited migration and invasion of MDA-MB-468 and MDA-MB-231 cells. Moreover, LR004-VC-MMAE also killed tumor stem cells in EGFR-positive TNBC cells and impaired their tumorsphere-forming ability. In TNBC xenograft models, LR004-VC-MMAE at 10 mg/kg significantly suppressed tumor growth and achieved complete tumor regression on day 36. Surprisingly, tumor recurrence was not observed until the end of the experiment on day 52. In a mechanistic study, we found that LR004-VC-MMAE significantly induced cell apoptosis and cell cycle arrest at G2/M phase in MDA-MB-468 [(34 ± 5)% vs. (12 ± 2)%, P < 0.001] and MDA-MB-231 [(27 ± 4)% vs. (18 ± 3)%, P < 0.01] cells. LR004-VC-MMAE also inhibited the activation of EGFR signaling and the expression of cancer stemness marker genes such as Oct4, Sox2, KLF4 and EpCAM. CONCLUSIONS: LR004-VC-MMAE showed effective antitumor activity by inhibiting the activation of EGFR signaling and the expression of cancer stemness marker genes. It might be a promising therapeutic candidate and provides a potential therapeutic avenue for the treatment of EGFR-positive TNBC.

Synthesis, characterization, and targeted chemotherapy of SCT200-linker-monomethyl auristatin E conjugates.

Antibody-drug conjugates (ADCs) are currently among the most successful and important strategies for treating patients with solid tumors. ADCs are composed of a monoclonal antibody and warhead, which are conjugated via a linker. Currently, monomethyl auristatin E (MMAE) is the most widely applied warhead in the development of ADCs. However, MMAE-based ADCs are generally constructed using the MC-VC-PABC linker, and this design has limited structural diversity and some disadvantages. Accordingly, in this study, we generated three types of novel linker-MMAE (with alterations in the spacer, catabolizing area, and self-immolative compared with MC-VC-PABC-MMAE) in ADCs, termed SCT200-linker-MMAE conjugates, and then evaluated the linker-drug plasma stability and the rate of drug release by cathepsin B. The binding ability, internalization rates, and efficacy of all SCT200-linker-MMAE ADCs were systematically studied, and the expression of apoptosis-associated proteins and the therapeutic efficacies of SCT200-M-2, -C-2, and -C-4 were evaluated. The results showed that the activities of some of these ADCs were increased for epidermal growth factor receptor-positive tumors. Moreover, the novel linkers designed in this study can be linked with other antibodies to treat other types of cancer. Overall, these findings provide important insights into the application of SCT200-based linkers in ADCs.

A novel potent metal-binding NDM-1 inhibitor was identified by fragment virtual, SPR and NMR screening.

NDM-1 can hydrolyze nearly all available ß-lactam antibiotics, including carbapenems. NDM-1 producing bacterial strains are worldwide threats. It is still very challenging to find a potent NDM-1 inhibitor for clinical use. In our study, we used a metal-binding pharmacophore (MBP) enriched virtual fragment library to screen NDM-1 hits. SPR screening helped to verify the MBP virtual hits and identified a new NDM-1 binder and weak inhibitor A1. A solution NMR study of 15N-labeled NDM-1 showed that A1 disturbed all three residues coordinating the second zinc ion (Zn2) in the active pocket of NDM-1. The perturbation only happened in the presence of zinc ion, indicating that A1 bound to Zn2. Based on the scaffold of A1, we designed and synthesized a series of NDM-1 inhibitors. Several compounds showed synergistic antibacterial activity with meropenem against NDM-1 producing K. pneumoniae.

Transcriptomic analysis of Momordica charantia polysaccharide on streptozotocin-induced diabetic rats.

Polysaccharides obtained from Momordica charantia have been shown to exert a hypoglycemic effect, thereby improving glucose metabolism. However, little is known regarding the molecular mechanisms underlying this process. In recent years, RNA sequencing (RNA-seq) has rapidly emerged as a major transcriptome profiling system. Herein, RNA-seq was utilized to obtain whole transcriptomes from the livers of SD rats with type 2 diabetes (DM) and type 2 diabetic rats treated with M. charantia polysaccharides (DMCPIIa). In total, 44,752,508-52,585,920 uniquely mapped reads were obtained, covering 85.54% of the annotated transcripts and representing 12,857 mRNA transcripts. Following analytical analysis, 17 differentially expressed genes (p < 0.05, false discovery rate q < 0.05) were identified in the DMCPIIa group relative to the DM group. Gene ontology and pathway analysis demonstrated that 17 differently expressed genes were enriched in specific biological processes mainly relating to glucose metabolism and fat metabolism (p < 0.05). Furthermore, a subset of the differential genes was selected for validation via real-time quantitative reverse-transcription PCR. Collectively, the integrated analysis of differential gene expression, data obtained herein and the examination of previously reported quantitative trait loci, and genome-wide association studies has suggested that pdk4, pkl, hsd11ß1, msmo1, rbp4 and fads2 may serve as promising candidates for the modulation of type 2 diabetes.

Characterization of Momordica charantia L. polysaccharide and its protective effect on pancreatic cells injury in STZ-induced diabetic mice.

A polysaccharide with a molecular weight of 13,029Da was isolated from Momordica charantia (MCP) fruit and purified by ion-exchange and size-exclusion chromatography. The isolated polysaccharide MCPIIa contained L-Rha, D-GalA, D-Gal, D-Xyl, L-Ara in a molar ratio of 12:3.05:19.89:5.95:56. IR spectrum and NMR studies indicated that the MCPIIa sugar units were linked, via ß-glycosidic bonds, to a large number of arabinofuranose, glucuronic acid, and xylopyranosyl residues. In addition, the hypoglycemic effect of MCPIIa was investigated in streptozotocin (STZ)-induced diabetic mice. After STZ-induction, MCPIIa (100, 200, or 300mg/kg body weight) was administered orally, once daily, for 28days. Glycemia in STZ-diabetogenic mice was significantly reduced, and compared with diabetes mellitus (DM) mice, serum insulin concentration increased significantly, following MCPIIa administration. Transmission electron microscopy showed an alleviation of STZ-lesions in pancreatic tissue from mice treated with MCPIIa. These results indicate that MCPIIa may be useful as an anti-diabetic agent.

Robust fault detection for the dynamics of high-speed train with multi-source finite frequency interference.

This paper proposes a composite fault detection scheme for the dynamics of high-speed train (HST), using an unknown input observer-like (UIO-like) fault detection filter, in the presence of wind gust and operating noises which are modeled as disturbance generated by exogenous system and unknown multi-source disturbance within finite frequency domain. Using system input and system output measurements, the fault detection filter is designed to generate the needed residual signals. In order to decouple disturbance from residual signals without truncating the influence of faults, this paper proposes a method to partition the disturbance into two parts. One subset of the disturbance does not appear in residual dynamics, and the influence of the other subset is constrained by H∞ performance index in a finite frequency domain. A set of detection subspaces are defined, and every different fault is assigned to its own detection subspace to guarantee the residual signals are diagonally affected promptly by the faults. Simulations are conducted to demonstrate the effectiveness and merits of the proposed method.

[Expression and correlation of cyclooxygenase-2 and vascular endothelial growth factor in nasopharyngeal carcinoma-].

OBJECTIVE: To evaluate the Expression and correlation of cyclooxygenase-2 (COX-2) and vascular endothelial growth factor receptor (VEGF) in nasopharyngeal carcinoma. METHOD: In this study, expression levels of COX-2, VEGF were examined in 58 patients with nasopharyngeal carcinoma and 38 patients with inflammation in nasopharyngeal mucosa by immunohistochemistry method. RESULT: The expression of COX-2, VEGF were higher in nasopharyngeal carcinoma than those in nasopharyngeal mucosa (P < 0.05), and they had some correlation with the invasion and lymphatic metastasis and with the clinical stage of nasopharyngeal carcinoma (P < 0.05). The expression of COX-2 was positively correlated with that of VEGF (P < 0.05). CONCLUSION: The coexpression of COX-2 and VEGF may play animportant role in the carcinogenesis and development of nasopharyngeal carcinoma, and they may prom (see text) lymph node metastasis of nasopharyngeal carcinoma.

[The expression and relationship of cyclooxygenase-2 and latent membrane protein-1 in nasopharyngeal carcinoma].

OBJECTIVE: To discuss the expression and correlation of COX2 and LMP1 in NPC. METHOD: Fifty-three nasopharyngeal biopsy specimens of NPC patients who had been diagnosed definitely with pathology in our department from 2000 to 2005, and 8 nasopharyngeal biopsy specimens of chronic nasopharyngitis patients were collected. The expression of COX2, LMP1 were detected with streptavidin peroxidase immunohistochemistry staining. All the datas were analyzed with SPSS 12.0. RESULT: The positive expression rate of COX2 was 71.70% (38/53), and that of LMP1 was 66.04% (35/53) of Nasopharyngeal carcinoma tissue. The higher expression rate was detected in neck lymph nodes metastasis group of nasopharyngeal carcinoma (P<0.05). While the expression rate of COX2, LMP1 was no significant relation with age, gender, clinical stage and pathological classification (P>0.05). The expression of COX2 and LMP1 showed positive correlation (gamma = 0.797, P<0.01). CONCLUSION: COX2 and LMP1 were highly expressed in nasopharyngeal carcinoma cells. The expressions of COX2 and LMP1 was significantly associated with neck lymph nodes metastasis, and was none-significant relation with age, gender, clinical stage and pathological classification. The expression of LMP1 showed a significant positive correlation with that of COX2. LMP1 could enhance NPC neck lymph nodes metastasis by up-regulating the expression of COX2.