Ai-Drugnet: a Network-Based Deep Learning Model For Drug Repurposing and Combination therapy in Neurological Disorders

Discovering effective therapies is difficult for neurological and developmental disorders in that disease progression is often associated with a complex and interactive mechanism. Over the past few decades, few drugs have been identified for treating Alzheimer\u27s disease (AD), especially for impacting the causes of cell death in AD. Although drug repurposing is gaining more success in developing therapeutic efficacy for complex diseases such as common cancer, the complications behind AD require further study. Here, we developed a novel prediction framework based on deep learning to identify potential repurposed drug therapies for AD, and more importantly, our framework is broadly applicable and may generalize to identifying potential drug combinations in other diseases. Our prediction framework is as follows: we first built a drug-target pair (DTP) network based on multiple drug features and target features, as well as the associations between DTP nodes where drug-target pairs are the DTP nodes and the associations between DTP nodes are represented as the edges in the AD disease network; furthermore, we incorporated the drug-target feature from the DTP network and the relationship information between drug-drug, target-target, drug-target within and outside of drug-target pairs, representing each drug-combination as a quartet to generate corresponding integrated features; finally, we developed an AI-based Drug discovery Network (AI-DrugNet), which exhibits robust predictive performance. The implementation of our network model help identify potential repurposed and combination drug options that may serve to treat AD and other diseases

Ad-Syn-Net: Systematic Identification of alzheimer\u27s Disease-Associated Mutation and Co-Mutation Vulnerabilities Via Deep Learning

Alzheimer\u27s disease (AD) is one of the most challenging neurodegenerative diseases because of its complicated and progressive mechanisms, and multiple risk factors. Increasing research evidence demonstrates that genetics may be a key factor responsible for the occurrence of the disease. Although previous reports identified quite a few AD-associated genes, they were mostly limited owing to patient sample size and selection bias. There is a lack of comprehensive research aimed to identify AD-associated risk mutations systematically. to address this challenge, we hereby construct a large-scale AD mutation and co-mutation framework (\u27AD-Syn-Net\u27), and propose deep learning models named Deep-SMCI and Deep-CMCI configured with fully connected layers that are capable of predicting cognitive impairment of subjects effectively based on genetic mutation and co-mutation profiles. Next, we apply the customized frameworks to data sets to evaluate the importance scores of the mutations and identified mutation effectors and co-mutation combination vulnerabilities contributing to cognitive impairment. Furthermore, we evaluate the influence of mutation pairs on the network architecture to dissect the genetic organization of AD and identify novel co-mutations that could be responsible for dementia, laying a solid foundation for proposing future targeted therapy for AD precision medicine. Our deep learning model codes are available open access here: https://github.com/Pan-Bio/AD-mutation-effectors

Differentiation of Bone Marrow Mesenchymal Stem Cells to Cardiomyocyte-Like Cells Is Regulated by the Combined Low Dose Treatment of Transforming Growth Factor- β

Bone marrow mesenchymal stem cells (BMMSCs) are used in cardiac tissue engineering for the regeneration of diseased hearts. We examined the differentiation of rat BMMSCs into cardiomyocyte-like cells when induced with a combined low dose treatment of transforming growth factor-β1 (TGF-β1) and 5-azacytidine (5-AZA). Results showed that cell proliferation in the combined low dose treatment group of TGF-β1 and 5-AZA was increased compared with the TGF-β1 group or the 5-AZA group. The cell apoptosis was relieved by combined TGF-β1 and 5-AZA treatment compared to 5-AZA treatment alone. The number of cells positive for myosin heavy chain, connexin-43, α-actin, and troponin I in the combined treatment group was higher than those observed in the TGF-β1 group or the 5-AZA group. Moreover, the combined low dose treatment group of TGF-β1 and 5-AZA reveals the strongest expression of troponin I, α-actin, and phosphorylated extracellular signal-regulated protein kinases 1 and 2 (p-ErK1/2) among the treatment groups. These results suggest that the combined low dose treatment of TGF-β1 and 5-AZA can improve the differentiation potential of rat BMMSCs into cardiomyocyte-like cells and alleviate cell damage effects in vitro. The mechanism that is involved in influencing differentiation may be associated with p-ErK1/2

Alternative Splicing of Gsdmb Modulates Killer Lymphocyte-Triggered Pyroptosis

Granzyme A from killer lymphocytes cleaves gasdermin B (GSDMB) and triggers pyroptosis in targeted human tumor cells, eliciting antitumor immunity. However, GSDMB has a controversial role in pyroptosis and has been linked to both anti- and protumor functions. Here, we found that GSDMB splicing variants are functionally distinct. Cleaved N-terminal (NT) fragments of GSDMB isoforms 3 and 4 caused pyroptosis, but isoforms 1, 2, and 5 did not. The nonfunctional isoforms have a deleted or modified exon 6 and therefore lack a stable belt motif. The belt likely contributes to the insertion of oligomeric GSDMB-NTs into the membrane. Consistently, noncytotoxic GSDMB-NTs blocked pyroptosis caused by cytotoxic GSDMB-NTs in a dominant-negative manner. Upon natural killer (NK) cell attack, GSDMB3-expressing cells died by pyroptosis, whereas GSDMB4-expressing cells died by mixed pyroptosis and apoptosis, and GSDMB1/2-expressing cells died only by apoptosis. GSDMB4 partially resisted NK cell-triggered cleavage, suggesting that only GSDMB3 is fully functional. GSDMB1-3 were the most abundant isoforms in the tested tumor cell lines and were similarly induced by interferon-γ and the chemotherapy drug methotrexate. Expression of cytotoxic GSDMB3/4 isoforms, but not GSDMB1/2 isoforms that are frequently up-regulated in tumors, was associated with better outcomes in bladder and cervical cancers, suggesting that GSDMB3/4-mediated pyroptosis was protective in those tumors. Our study indicates that tumors may block and evade killer cell-triggered pyroptosis by generating noncytotoxic GSDMB isoforms. Therefore, therapeutics that favor the production of cytotoxic GSDMB isoforms by alternative splicing may improve antitumor immunity

Concomitant Retrograde Coronary Venous Infusion of Basic Fibroblast Growth Factor Enhances Engraftment and Differentiation of Bone Marrow Mesenchymal Stem Cells for Cardiac Repair after Myocardial Infarction.

AIM: Basic fibroblast growth factor (bFGF) increases the migration and viability of bone marrow mesenchymal stem cells (MSCs) in vitro. Retrograde coronary venous infusion can provide both increased regional bFGF concentrations and homogeneous cell dissemination. We determined whether retrograde delivery of bFGF enhances the potency of transplanted MSCs for cardiac repair in a canine infarct model. METHODS AND RESULTS: Under hypoxic conditions, cellular migration was significantly increased in MSCs co-cultured with bFGF compared to vascular endothelial growth factor or insulin-like growth factor, and bFGF promoted MSCs differentiation into a cardiomyocyte phenotype. A canine infarct model was employed by coronary ligation. One week later, animals were subjected to retrograde infusion of combination bFGF (200ng/mL) and MSCs (1×10(8) cells) (n=5), MSCs (1×10(8) cells, n=5), bFGF (200ng/mL, n=5), or placebo (phosphate-buffered saline, n=3). Four weeks after infusion, only the bFGF+MSCs therapy exhibited significantly increased left ventricular ejection fraction (LVEF) by echocardiography (p CONCLUSIONS: Retrograde coronary venous bFGF infusion augments engraftment and differentiation capacity of transplanted MSCs, recovering cardiac function and preventing adverse remodeling. This novel combined treatment and delivery method is a promising strategy for cardiac repair after ischemic injury

Impaired immunosuppressive role of myeloid-derived suppressor cells in acquired aplastic anemia

Myeloid-derived suppressor cells (MDSC) are a group of heterogeneous immature myeloid cells and display immunosuppressive function. In this study, MDSC populations were evaluated in acquired aplastic anemia (AA) (n=65) in which aberrant immune mechanisms contributed to bone marrow destruction. Our data demonstrate that both the proportion and immunosuppressive function of MDSC are impaired in AA patients. Decreased percentage of MDSC, especially monocytic MDSC, in the blood of AA patients (n=15) is positively correlated with the frequency of T-regulatory cells, bone marrow level of WT1 and decreased plasma level of arginase-1. RNA sequencing analyses reveal that multiple pathways including DNA damage, interleukin 4, apoptosis, and Jak kinase singnal transducer and activator of transcription are upregulated, whereas transcription, IL-6, IL-18, glycolysis, transforming growth factor and reactive oxygen species are downregulated in MDSC of AA (n=4), compared with that of healthy donors (n=3). These data suggest that AA MDSC are defective. Administration of rapamycin significantly increases the absolute number of MDSC and levels of intracellular enzymes, including arginase-1 and inducible nitric-oxide synthase. Moreover, rapamycin inhibits MDSC from differentiating into mature myeloid cells. These findings reveal that impaired MDSC are involved in the immunopathogenesis of AA. Pharmacologically targeting of MDSC by rapamycin might provide a promising therapeutic strategy for AA

Analytical Solution for One-Dimensional Transport of Particles considering Dispersion in Deposition Kinetics

The study of particle transport in porous media is of great significance for pollution mitigation, grouting reinforcement, municipal solid waste landfill management, and groundwater exploitation. We developed an analytical solution for a corrected convection-dispersion model that takes into account the effects of dispersion on deposition kinetics with regard to the particle concentration decay type. The rationality and correctness of the solution were verified using time, distance, deposition coefficient, diffusion coefficient, and decay coefficient. As the time increased, the particle concentration increased from zero to the peak value, then decreased to zero. However, as distance increased, the peak value of particle concentration gradually decreased. The deposition coefficient affected the magnitude of the peak value and the distance corresponding to the peak value. In addition, the greater the attenuation coefficient, the smaller the peak value. Overall, our method’s prediction results showed that considering the effect of dispersion on deposition kinetics produces better results than when this is not considered

Lightweight Chain-Typed Magnetic Fe₃O₄@rGO Composites with Enhanced Microwave-Absorption Properties

A lightweight microwave-absorbing material with a strong electromagnetic-absorption capability of practical significance in the field of electromagnetic compatibility was obtained by adjusting the ratio of Fe3O4 and rGO. A nanoparticle material with a chain-typed structure consisting of a combination of Fe3O4 and rGO was produced by a hydrothermal method under an applied magnetic field. The electromagnetic loss property of the Fe3O4@rGO composites is studied in the frequency range from 2 to 18 GHz. In addition, the reflection loss and the mechanism of microwave absorption are explored. By changing the amounts of rGO, the electromagnetic loss of the Fe3O4@rGO composites can be effectively regulated, which obtain better reflection loss. The minimum reflection loss of the Fe3O4@rGO composites is −49.4 dB at 16.2 GHz only with a thickness of 1.75 mm. Thus, the Fe3O4@rGO composites have an extremely thin thickness and a strong electromagnetic wave absorption capacity, which is a candidate for the development of lightweight magnetic absorbing materials