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Abstract Parkinson's disease (PD) is a neurodegenerative disease characterized by the degeneration of dopaminergic neurons in the substantia nigra (SN); the etiology and pathological mechanism of the disease are still unclear. Recent studies have shown that the activation of a neuroimmune response plays a key role in the development of PD. Alpha-synuclein (α-Syn), the primary pathological marker of PD, can gather in the SN and trigger a neuroinflammatory response by activating microglia which can further activate the dopaminergic neuron’s neuroimmune response mediated by reactive T cells through antigen presentation. It has been shown that adaptive immunity and antigen presentation processes are involved in the process of PD and further research on the neuroimmune response mechanism may open new methods for its prevention and therapy. While current therapeutic regimens are still focused on controlling clinical symptoms, applications such as immunoregulatory strategies can delay the symptoms and the process of neurodegeneration. In this review, we summarized the progression of the neuroimmune response in PD based on recent studies and focused on the use of mesenchymal stem cell (MSC) therapy and challenges as a strategy of disease-modifying therapy with multiple targets.

Abstract Lung adenocarcinoma (LUAD) is most common pathological type of lung cancer. LUAD with brain metastases (BMs) usually have poor prognosis. To identify the potential genetic factors associated with BM, a genomic comparison for BM cerebrospinal fluid (CSF) and primary lung tumor samples obtained from 1082 early- and late-stage LUAD patients was performed. We found that single nucleotide variation (SNV) of EGFR was highly enriched in CSF (87% of samples). Compared with the other primary lung tissues, copy number gain of EGFR (27%), CDK4 (11%), PMS2 (11%), MET (10%), IL7R (8%), RICTOR (7%), FLT4 (5%), and FGFR4 (4%), and copy number loss of CDKN2A (28%) and CDKN2B (18%) were remarkably more frequent in CSF samples. CSF had significantly lower tumor mutation burden (TMB) level but more abundant copy number variant. It was also found that the relationships among co-occurrent and mutually exclusive genes were dynamically changing with LUAD development. Additionally, CSF (97% of samples) harbored more abundant targeted drugs related driver and fusion genes. The signature 15 associated with defective DNA mismatch repair (dMMR) was only identified in the CSF group. Cancer associated pathway analysis further revealed that ErbB (95%) and cell cycle (84%) were unique pathways in CSF samples. The tumor evolution analysis showed that CSF carried significantly fewer clusters, but subclonal proportion of EGFR was remarkably increased with tumor progression. Collectively, CSF sequencing showed unique genomic characteristics and the intense copy number instability associated with cell cycle disorder and dMMR might be the crucial genetic factors in BM of LUAD.

Abstract Glioma is an extremely aggressive malignant neoplasm of the central nervous system. MicroRNA (miRNA) are known to bind to specific target mRNA to regulate post-transcriptional gene expression and are, therefore, currently regarded as promising biomarkers for glioma diagnosis and prognosis. The aim of the present study was to examine the pathogenesis and potential molecular markers of glioma by comparing the differential expression of miRNA and mRNA between glioma tissue and peritumor brain tissue. We explored the impact of screened core miRNA and mRNA on cell proliferation, invasion, and migration of glioma. An miRNA expression profile dataset (GSE90603) and a transcriptome profile dataset (GSE90598) were downloaded from combined miRNA-mRNA microarray chips in the Gene Expression Omnibus (GEO) database. Overall, 59 differentially expressed miRNAs (DEMs) and 419 differentially expressed genes (DEGs) were identified using the R limma software package. FunRich software was used to predict DEM target genes and miRNA-gene pairs, and Perl software was used to find overlapping genes between DEGs and DEM target genes. There were 129 overlapping genes regulated by nine miRNAs between target genes of the DEMs and DEGs. The Chinese Glioma Genome Atlas(CGGA) was analyzed in order to identify miRNAs with diagnostic and prognostic significance. MiR-139-5p, miR-137, and miR-338-3p were validated to be significantly linked to prognosis in glioma patients. Finally, we validated that miR-139-5p affected glioma malignant biological behavior via targeting gamma-aminobutyric acid A receptor alpha 1(GABRA1) through rescue experiments. Low miR-139-5p expression was correlated with survival probability and World Health Organization (WHO) grade. MiR-139-5p overexpression inhibited cell proliferation, migration, and invasion of glioma in vitro. GABRA1 was identified as a functional downstream target of miR-139-5p. Decreased GABRA1 expression was related to similar biological roles as miR-139-5p overexpression while upregulation of GABRA1 effectively reversed the inhibition effects of miR-139-5p. These results demonstrate a novel axis for miR-139-5p/GABRA1 in glioma progression and provide potential prognostic predictors and therapeutic target for glioma patients.

Background. Accumulating evidence has demonstrated the role of differentially expressed miRNAs in glioma progression. Our previous bioinformatics analyses revealed a role of miR-138-5p in glioma. miR-138-5p was decreased in various tumors, and He et al. found that miR-138-5p had an inhibitory effect on glioma cells in 2021. However, the role of miR-138-5p in the development of glioma and the underlying mechanism is unknown. In this study, we explored whether miR-138-5p affects the biology of glioma by regulating WEE1 expression. Methods. miR-138-5p and WEE1 G2 checkpoint kinase (WEE1) RNA and protein expression levels in glioma tissues were detected with qRT-PCR and western blotting, respectively. The effects of miR-138-5p and WEE1 on glioma cell migration and invasion were investigated using Transwell assays. CCK-8 assay was used to measure the effects of miR-138-5p and WEE1 on glioma cell proliferation. The mortality of glioma cells transfected with miR-138-5p and WEE1 was measured with flow cytometry. The relationship between miR-138-5p and WEE1 was explored using a luciferase reporter analysis. Results. Functional studies indicated that overexpression of miR-138-5p suppressed cell proliferation, migration, and invasion and promoted death in glioma cell lines. WEE1 was identified as a target of miR-138-5p, and overexpression of miR-138-5p significantly suppressed the levels of WEE1. Moreover, reintroduction of WEE1 partially abrogated miR-138-5p-induced suppression of motility and invasion in glioma cells. Conclusion. The low expression of miR-138-5p in glioma suggests a tumor suppressor role for this miRNA. miR-138-5p suppresses glioma progression by regulating WEE1. These data provide new insights into the molecular mechanism of glioma.

This paper investigates the problem of how to achieve a positive cash flow balance by multimode multiproject scheduling, in which a contractor must implement multiple projects concurrently, and activities can be performed with one of several alternative modes. First, based on formulating cash flows for the projects, we construct an optimization model that can minimize the maximum gap between accumulative cash outflow and cash inflow, thus balancing cash flow positively by arranging optimal execution modes and start times for activities. Then, we prove the NP-hardness of the studied problem and design two metaheuristic algorithms, namely, tabu search (TS) and simulated annealing (SA), which search the desirable solutions in nested and mixed ways, respectively. Finally, taking the multistart iterative improvement (MSII) as comparison algorithm, the performance of the two algorithms developed is evaluated through a computational experiment performed on a data set generated randomly. From the research results, the following conclusions are drawn. The TS and SA are more suitable for solving the smaller and larger problems, respectively, while the nested searching structure could enhance the algorithm's efficiency. With increases in the advance payment proportion, the number of milestone activities, the client's payment proportion, or the project deadline, the contractor's maximal cash flow gap decreases.

This paper investigates the project scheduling problem to minimize the maximum cash flow gap of contractors under random activity duration. A comprehensive optimization model with time buffers added to the baseline schedule by project proactive scheduling and the schedule adjustment cost determined by project reactive scheduling is constructed to manage disruptions caused by the randomness of activity durations. Due to the problem's intractability, two hybrid metaheuristic algorithms, namely, tabu simulated annealing (tabu-SA) and variable neighborhood tabu search (VNTS), are developed, and several improvement measures are proposed to enhance the algorithms' performance. Based on a randomly generated data set, a computational experiment is performed to evaluate the algorithms, with the effects on results of certain key parameters also analyzed. The conclusions are as follows: tabu-SA outperforms VNTS for large-scale problems, however, the reverse holds for small-scale problems. The key parameters, including the project deadline, the cost per time buffer, the activity instability weight, the activity duration variability, the number of payments, and the payment proportion can exert important effects on the contractor's maximum cash flow gap.

Rheumatoid arthritis (RA) is a complex and not fully understood autoimmune disease associated with multijoint damage. The main effector cells, the synovial fibroblasts, are apoptosis resistant and hyperplastic which indicate that autophagy level is high in synovial tissue. Real-time PCR, immunocytochemistry, and western blotting were used in this paper to study the autophagy status of the synovial tissues obtained from RA and OA patients at the time of joint replacement surgery. We further evaluated the correlation between autophagy levels with RA activity-associated serum markers with SPSS. The results showed that the expression levels (both in mRNA and in protein level) of autophagy-related proteins (belcin1, Atg5, and LC3) in the synovial tissue of patients with active rheumatoid arthritis (n=20) were significantly higher than those in OA patients (n=16). We further showed that the LC3-II/β-actin relative gray value was strongly correlated with the serum levels of several RA activity-related markers: CRP, ESR, CCP, and RF. Our results indicate that evaluating the autophagy level of synovial biopsies might be a useful way to diagnose RA and to estimate the disease activity. Reducing the expression level of autophagy-related genes might become a new therapeutic target for active rheumatoid arthritis.

We study a new problem of location-inventory-routing in forward and reverse logistic (LIRP-FRL) network design, which simultaneously integrates the location decisions of distribution centers (DCs), the inventory policies of opened DCs, and the vehicle routing decision in serving customers, in which new goods are produced and damaged goods are repaired by a manufacturer and then returned to the market to satisfy customers’ demands as new ones. Our objective is to minimize the total costs of manufacturing and remanufacturing goods, building DCs, shipping goods (new or recovered) between the manufacturer and opened DCs, and distributing new or recovered goods to customers and ordering and storage costs of goods. A nonlinear integer programming model is proposed to formulate the LIRP-FRL. A new tabu search (NTS) algorithm is developed to achieve near optimal solution of the problem. Numerical experiments on the benchmark instances of a simplified version of the LIRP-FRL, the capacitated location routing problem, and the randomly generated LIRP-FRL instances demonstrate the effectiveness and efficiency of the proposed NTS algorithm in problem resolution.