Method for persistent topological features extraction of schizophrenia patients' electroencephalography signal based on persistent homology.

With the development of network science and graph theory, brain network research has unique advantages in explaining those mental diseases, the neural mechanism of which is unclear. Additionally, it can provide a new perspective in revealing the pathophysiological mechanism of brain diseases from the system level. The selection of threshold plays an important role in brain networks construction. There are no generally accepted criteria for determining the proper threshold. Therefore, based on the topological data analysis of persistent homology theory, this study developed a multi-scale brain network modeling analysis method, which enables us to quantify various persistent topological features at different scales in a coherent manner. In this method, the Vietoris-Rips filtering algorithm is used to extract dynamic persistent topological features by gradually increasing the threshold in the range of full-scale distances. Subsequently, the persistent topological features are visualized using barcodes and persistence diagrams. Finally, the stability of persistent topological features is analyzed by calculating the Bottleneck distances and Wasserstein distances between the persistence diagrams. Experimental results show that compared with the existing methods, this method can extract the topological features of brain networks more accurately and improves the accuracy of diagnostic and classification. This work not only lays a foundation for exploring the higher-order topology of brain functional networks in schizophrenia patients, but also enhances the modeling ability of complex brain systems to better understand, analyze, and predict their dynamic behaviors.

A tumour microenvironment-responsive polymeric complex for targeted depletion of tumour-associated macrophages (TAMs).

Tumour-associated macrophages (TAMs) play pivotal roles in promoting cancer progression. Systemic delivery of therapeutic agents to efficiently eliminate these cells remains challenging. Here, we report the development of a bio-responsive polymeric complex (P3AB) that can be systemically administrated to target and eliminate TAMs in tumours. This complex comprises a polymeric 'shell' and 'core'. The shell (PPP) consists of poly(ethylene glycol) (PEG), poly(lactic-co-glycolic acid) (PLGA), and a peptide that can be cleaved by matrix metalloproteases (MMPs) in the tumour microenvironment; and the 'core' (AB) is a bisphosphonate-glucomannan conjugate that has affinity for macrophage mannose receptors and selectively eliminates TAMs. Our data show that the P3AB complex can be accumulated in the tumour site thanks to its appropriate size and its PPP shell is sensitively cleaved by MMPs, efficiently releasing the AB core that can potently reduce TAM viability. The systemically delivered P3AB complex demonstrates favourable responses to the physiological features of the tumour microenvironment (e.g. underdeveloped vasculature and high MMP levels), and effectively inhibits tumour growth and restores local immunosurveillance in vivo, without exerting hepatotoxicity. Taken together, our findings suggest that P3AB has the potential to be an effective and safe tool for TAM-targeting cancer immunotherapy.

Re-polarizing Myeloid-derived Suppressor Cells (MDSCs) with Cationic Polymers for Cancer Immunotherapy.

Our evolving understandings of cell-material interactions provide insights for using polymers to modulate cell behaviour that may lead to therapeutic applications. It is known that in certain cancers, myeloid-derived suppressor cells (MDSCs) play vital roles in promoting tumour progression, chiefly because of their 'alternatively activated' (or M2) phenotype that orchestrates immunosuppression. In this study, we demonstrated that two cationic polymers - cationic dextran (C-dextran) and polyethyleneimine (PEI) - could directly remodel these cells into an anti-tumour, 'classically activated' (or M1) phenotype, thereby stimulating these cells to express tumouricidal cytokines, reactivating the T cell functions, and prolonging the lifespan of the mice model. Our investigations with knock-out mice further indicate that the functions of these cationic polymers require the involvement of toll-like receptor 4-mediated signalling. Taken together, our study suggests that these cationic polymers can effectively and directly re-polarize MDSCs from an immunosuppressive characteristic to an anti-tumour phenotype, leading to successful restoration of immune surveillance in the tumour microenvironment and elimination of tumour cells. Our findings may have immediate impact on further development of polymer-based therapeutics for cancer immunotherapy.

Targeted delivery of let-7b to reprogramme tumor-associated macrophages and tumor infiltrating dendritic cells for tumor rejection.

Both tumor associated macrophages (TAMs) and tumor infiltrating dendritic cells (TIDCs) are important components in the tumor microenvironment that mediate tumor immunosuppression and promote cancer progression. Targeting these cells and altering their phenotypes may become a new strategy to recover their anti-tumor activities and thereby restore the local immune surveillance against tumor. In this study, we constructed a nucleic acid delivery system for the delivery of let-7b, a synthetic microRNA mimic. Our carrier has an affinity for the mannose receptors on TAMs/TIDCs and is responsive to the low-pH tumor microenvironment. The delivery of let-7b could reactivate TAMs/TIDCs by acting as a TLR-7 agonist and suppressing IL-10 production in vitro. In a breast cancer mouse model, let-7b delivered by this system efficiently reprogrammed the functions of TAMs/TIDCs, reversed the suppressive tumor microenvironment, and inhibited tumor growth. Taken together, this strategy, designed based upon TAMs/TIDCs-targeting delivery and the dual biological functions of let-7b (TLR-7 ligand and IL-10 inhibitor), may provide a new approach for cancer immunotherapy.

A Naturally Derived, Growth Factor-Binding Polysaccharide for Therapeutic Angiogenesis.

We herein report the discovery of a naturally derived carbohydrate with binding affinities for two pro-angiogenic growth factors-fibroblast growth factor-2 (FGF-2) and platelet-derived growth factor-BB (PDGF-BB). This galacturonic acid-containing polysaccharide (EUP3) sequestered endogenous FGF-2 and PDGF-BB in vivo and promoted in situ formation and maturation of new blood vessels. Our findings suggest EUP3 as the first nonglycosaminoglycan, nonanimal-originated carbohydrate molecule that binds two pro-angiogenic growth factors to stimulate angiogenesis. Further investigations into this carbohydrate may lead to the development of new tools for therapeutic angiogenesis.

An orally administrated nucleotide-delivery vehicle targeting colonic macrophages for the treatment of inflammatory bowel disease.

Tumor necrosis factor-alpha (TNF-α) plays a central role in the pathogenesis of inflammatory bowel disease (IBD). Anti-TNF-α therapies have shown protective effects against colitis, but an efficient tool for target suppression of its secretion - ideally via oral administration - remains in urgent demand. In the colon tissue, TNF-α is mainly secreted by the colonic macrophages. Here, we report an orally-administrated microspheric vehicle that can target the colonic macrophages and suppress the local expression of TNF-α for IBD treatment. This vehicle is formed by cationic konjac glucomannan (cKGM), phytagel and an antisense oligonucleotide against TNF-α. It was given to dextran sodium sulfate (DSS) colitic mice via gastric perfusion. The unique swelling properties of cKGM enabled the spontaneous release of cKGM& antisense nucleotide (ASO) nano-complex from the phytagel scaffold into the colon lumen, where the ASO was transferred into colonic macrophages via receptor-mediated phagocytosis. The treatment significantly decreased the local level of TNF-α and alleviated the symptoms of colitis in the mice. In summary, our study demonstrates a convenient, orally-administrated drug delivery system that effectively targets colonic macrophages for suppression of TNF-α expression. It may represent a promising therapeutic approach in the treatment of IBD.