Protein-Ligand Complex Generator & Drug Screening via Tiered Tensor Transform

The generation of small molecule candidate (ligand) binding poses in its target protein pocket is important for computer-aided drug discovery. Typical rigid-body docking methods ignore the pocket flexibility of protein, while the more accurate pose generation using molecular dynamics is hindered by slow protein dynamics. We develop a tiered tensor transform (3T) algorithm to rapidly generate diverse protein-ligand complex conformations for both pose and affinity estimation in drug screening, requiring neither machine learning training nor lengthy dynamics computation, while maintaining both coarse-grain-like coordinated protein dynamics and atomistic-level details of the complex pocket. The 3T conformation structures we generate achieve significantly higher accuracy in active ligand classification than traditional ensemble docking using hundreds of experimental protein conformations. Furthermore, we demonstrate that 3T can be used to explore distant protein-ligand binding poses within the protein pocket. 3T structure transformation is decoupled from the system physics, making future usage in other computational scientific domains possible

Towards Lightweight and Automated Representation Learning System for Networks

We propose LIGHTNE 2.0, a cost-effective, scalable, automated, and high-quality network embedding system that scales to graphs with hundreds of billions of edges on a single machine. In contrast to the mainstream belief that distributed architecture and GPUs are needed for large-scale network embedding with good quality, we prove that we can achieve higher quality, better scalability, lower cost, and faster runtime with shared-memory, CPU-only architecture. LIGHTNE 2.0 combines two theoretically grounded embedding methods NetSMF and ProNE. We introduce the following techniques to network embedding for the first time: (1) a newly proposed downsampling method to reduce the sample complexity of NetSMF while preserving its theoretical advantages; (2) a high-performance parallel graph processing stack GBBS to achieve high memory efficiency and scalability; (3) sparse parallel hash table to aggregate and maintain the matrix sparsifier in memory; (4) a fast randomized singular value decomposition (SVD) enhanced by power iteration and fast orthonormalization to improve vanilla randomized SVD in terms of both efficiency and effectiveness; (5) Intel MKL for proposed fast randomized SVD and spectral propagation; and (6) a fast and lightweight AutoML library FLAML for automated hyperparameter tuning. Experimental results show that LIGHTNE 2.0 can be up to 84X faster than GraphVite, 30X faster than PBG and 9X faster than NetSMF while delivering better performance. LIGHTNE 2.0 can embed very large graph with 1.7 billion nodes and 124 billion edges in half an hour on a CPU server, while other baselines cannot handle very large graphs of this scale

Fasudil in Combination With Bone Marrow Stromal Cells (BMSCs) Attenuates Alzheimer\u27s Disease-Related Changes Through the Regulation of the Peripheral Immune System.

Alzheimer\u27s disease (AD) is a chronic progressive neurodegenerative disease. Its mechanism is still not clear. Majority of research focused on the central nervous system (CNS) changes, while few studies emphasize on peripheral immune system modulation. Our study aimed to investigate the regulation of the peripheral immune system and its relationship to the severity of the disease after treatment in an AD model of APPswe/PSEN1dE9 transgenic (APP/PS1 Tg) mice. APP/PS1 Tg mice (8 months old) were treated with the ROCK-II inhibitor 1-(5-isoquinolinesulfonyl)-homo-piperazine (Fasudil) (intraperitoneal (i.p.) injections, 25 mg/kg/day), bone marrow stromal cells (BMSCs; caudal vein injections, 1 × 1

miR-1908 as a novel prognosis marker of glioma via promoting malignant phenotype and modulating SPRY4/RAF1 axis

MicroRNAs (miRNAs) are reported to be involved in the development of glioma. However, study on miRNAs in glioma is limited. The present study aimed to identify miRNAs which can act as potential novel prognostic markers for glioma and analyze its possible mechanism. We show that miR-1908 correlates with shorter survival time of glioma patients via promoting cell proliferation, invasion, anti-apoptosis and regulating SPRY4/RAF1 axis. Analysis of GEO and TCGA database found that miR-1908 was significantly upregulated in glioma tissues, and strongly associated with shorter survival time of glioma patients. Further Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis revealed that miR-1908 is mainly involved in regulating cell proliferation, invasion and apoptosis. To further confirm the above results, in vitro, glioma U251 cells were transfected with miR-1908 mimics or inhibitor, and upregulated miR-1908 promoted U251 cell proliferation, and enhanced the ability of invasion by transwell assay. In addition, upregulated miR-1908 also enhanced anti-apoptosis ability of U251 cells through decreasing pro-apoptosis protein Bax expression. Since miRNAs regulate numerous biological processes by targeting broad set of messenger RNAs, validated target genes of miR-1908 in glioma were analyzed by Targetscan and miRTarBase databases. Among them SPRY4 was significantly decreased in glioma tissues and associated with short survival time, which was selected as the key target gene of miR-1908. Moreover, protein-protein interaction (PPI) showed that SPRY4 could interacted with pro-oncogene RAF1 and negatively correlated with RAF1 expression. Consistent with above analysis, in vitro, western blot analysis identified that miR-1908 upregulated significantly decreased SPRY4 expression and increased RAF1 expression. Hence, miR-1908 was correlated with poor prognosis of glioma via promoting cell proliferation, invasion, anti-apoptosis and regulating SPRF4/RAF1 axis. Our results elucidated the tumor promoting role of miR-1908 and established miR-1908 as a potential novel prognostic marker for glioma

Fasudil in Combination With Bone Marrow Stromal Cells (BMSCs) Attenuates Alzheimer’s Disease-Related Changes Through the Regulation of the Peripheral Immune System

Alzheimer’s disease (AD) is a chronic progressive neurodegenerative disease. Its mechanism is still not clear. Majority of research focused on the central nervous system (CNS) changes, while few studies emphasize on peripheral immune system modulation. Our study aimed to investigate the regulation of the peripheral immune system and its relationship to the severity of the disease after treatment in an AD model of APPswe/PSEN1dE9 transgenic (APP/PS1 Tg) mice. APP/PS1 Tg mice (8 months old) were treated with the ROCK-II inhibitor 1-(5-isoquinolinesulfonyl)-homo-piperazine (Fasudil) (intraperitoneal (i.p.) injections, 25 mg/kg/day), bone marrow stromal cells (BMSCs; caudal vein injections, 1 × 106 BMSCs /time/mouse), Fasudil combined with BMSCs, or saline (i.p., control) for 2 months. Morris water maze (MWM) test was used to evaluate learning and memory. The mononuclear cells (MNCs) of spleens of APP/PS1 Tg mice were analyzed using flow cytometry for CD4+ T-cells, macrophages, and the pro-inflammatory and anti-inflammatory molecules of the macrophages. Immunohistochemical staining was used to examine the expression of ROCK-II in the spleens of APP/PS1 Tg mice. The MWM test showed improved spatial learning ability in APP/PS1 Tg mice treated with Fasudil or BMSCs alone or in combination, compared to untreated APP/PS1 Tg mice. Fasudil combined with BMSCs intervention significantly promoted the proliferation of CD4+/CD25+ and CD4+/ IL-10 lymphocytes, induced the release of cytokine factors, and regulated the balance of the immune system to work functionally. It also shifted M1 (MHC-II, CD86) to M2 (IL-10, CD206) phenotype of macrophages of CD11b and significantly enhanced the anti-inflammatory and phagocytic abilities (CD16/32) of macrophages of CD11b. Immunohistochemical staining showed significantly decreased expression of ROCK-II in mice treated with combination of Fasudil with BMSCs as compared to saline control. Fasudil in combination of BMSCs improved cognition of APP/PS1 Tg mice through the regulation of the peripheral immune system, including reduction of ROCK-II expression and increased proportion of anti-inflammatory M2 mononuclear phenotype and phagocytic macrophages in the spleen of the peripheral immune system. The latter was achieved through the communication between brain and spleen to improve the immunoregulation of CNS and AD disease conditions

Fasudil in Combination With Bone Marrow Stromal Cells (BMSCs) Attenuates Alzheimer’s Disease-Related Changes Through the Regulation of the Peripheral Immune System

Alzheimer’s disease (AD) is a chronic progressive neurodegenerative disease. Its mechanism is still not clear. Majority of research focused on the central nervous system (CNS) changes, while few studies emphasize on peripheral immune system modulation. Our study aimed to investigate the regulation of the peripheral immune system and its relationship to the severity of the disease after treatment in an AD model of APPswe/PSEN1dE9 transgenic (APP/PS1 Tg) mice. APP/PS1 Tg mice (8 months old) were treated with the ROCK-II inhibitor 1-(5-isoquinolinesulfonyl)- homo-piperazine (Fasudil) (intraperitoneal (i.p.) injections, 25 mg/kg/day), bone marrow stromal cells (BMSCs; caudal vein injections, 1 × 106 BMSCs /time/mouse), Fasudil combined with BMSCs, or saline (i.p., control) for 2 months. Morris water maze (MWM) test was used to evaluate learning and memory. The mononuclear cells (MNCs) of spleens of APP/PS1 Tg mice were analyzed using flow cytometry for CD4+ T-cells, macrophages, and the pro-inflammatory and anti-inflammatory molecules of the macrophages. Immunohistochemical staining was used to examine the expression of ROCK-II in the spleens of APP/PS1 Tg mice. The MWM test showed improved spatial learning ability in APP/PS1 Tg mice treated with Fasudil or BMSCs alone or in combination, compared to untreated APP/PS1 Tg mice. Fasudil combined with BMSCs intervention significantly promoted the proliferation of CD4+/CD25+ and CD4+/ IL-10 lymphocytes, induced the release of cytokine factors, and regulated the balance of the immune system to work functionally. It also shifted M1 (MHC-II, CD86) to M2 (IL-10, CD206) phenotype of macrophages of CD11b and significantly enhanced the anti-inflammatory and phagocytic abilities (CD16/32) of macrophages of CD11b. Immunohistochemical staining showed significantly decreased expression of ROCK-II in mice treated with combination of Fasudil with BMSCs as compared to saline control. Fasudil in combination of BMSCs improved cognition of APP/PS1 Tg mice through the regulation of the peripheral immune system, including reduction of ROCK-II expression and increased proportion of anti-inflammatory M2 mononuclear phenotype and phagocytic macrophages in the spleen of the peripheral immune system. The latter was achieved through the communication between brain and spleen to improve the immunoregulation of CNS and AD disease conditions

Chronic salmon calcitonin exerts an antidepressant effect via modulating the p38 MAPK signaling pathway

Depression is a common recurrent psychiatric disorder with a high lifetime prevalence and suicide rate. At present, although several traditional clinical drugs such as fluoxetine and ketamine, are widely used, medications with a high efficiency and reduced side effects are of urgent need. Our group has recently reported that a single administration of salmon calcitonin (sCT) could ameliorate a depressive-like phenotype via the amylin signaling pathway in a mouse model established by chronic restraint stress (CRS). However, the molecular mechanism underlying the antidepressant effect needs to be addressed. In this study, we investigated the antidepressant potential of sCT applied chronically and its underlying mechanism. In addition, using transcriptomics, we found the MAPK signaling pathway was upregulated in the hippocampus of CRS-treated mice. Further phosphorylation levels of ERK/p38/JNK kinases were also enhanced, and sCT treatment was able only to downregulate the phosphorylation level of p38/JNK, with phosphorylated ERK level unaffected. Finally, we found that the antidepressant effect of sCT was blocked by p38 agonists rather than JNK agonists. These results provide a mechanistic explanation of the antidepressant effect of sCT, suggesting its potential for treating the depressive disorder in the clinic

Salmon Calcitonin Exerts an Antidepressant Effect by Activating Amylin Receptors

Depressive disorder is defined as a psychiatric disease characterized by the core symptoms of anhedonia and learned helplessness. Currently, the treatment of depression still calls for medications with high effectiveness, rapid action, and few side effects, although many drugs, including fluoxetine and ketamine, have been approved for clinical usage by the Food and Drug Administration (FDA). In this study, we focused on calcitonin as an amylin receptor polypeptide, of which the antidepressant effect has not been reported, even if calcitonin gene-related peptides have been previously demonstrated to improve depressive-like behaviors in rodents. Here, the antidepressant potential of salmon calcitonin (sCT) was first evaluated in a chronic restraint stress (CRS) mouse model of depression. We observed that the immobility duration in CRS mice was significantly increased during the tail suspension test and forced swimming test. Furthermore, a single administration of sCT was found to successfully rescue depressive-like behaviors in CRS mice. Lastly, AC187 as a potent amylin receptor antagonist was applied to investigate the roles of amylin receptors in depression. We found that AC187 significantly eliminated the antidepressant effects of sCT. Taken together, our data revealed that sCT could ameliorate a depressive-like phenotype probably via the amylin signaling pathway. sCT should be considered as a potential therapeutic candidate for depressive disorder in the future