Increased Functional Connectivity Between Medulla and Inferior Parietal Cortex in Medication-Free Major Depressive Disorder

Emerging evidence has documented the abnormalities of primary brain functions in major depressive disorder (MDD). The brainstem has shown to play an important role in regulating basic functions of the human brain, but little is known about its role in MDD, especially the roles of its subregions. To uncover this, the present study adopted resting-state functional magnetic resonance imaging with fine-grained brainstem atlas in 23 medication-free MDD patients and 34 matched healthy controls (HC). The analysis revealed significantly increased functional connectivity of the medulla, one of the brainstem subregions, with the inferior parietal cortex (IPC) in MDD patients. A positive correlation was further identified between the increased medulla-IPC functional connectivity and Hamilton anxiety scores. Functional characterization of the medulla and IPC using a meta-analysis revealed that both regions primarily participated in action execution and inhibition. Our findings suggest that increased medulla-IPC functional connectivity may be related to over-activity or abnormal control of negative emotions in MDD, which provides a new insight for the neurobiology of MDD

Study of Xuanhuang Pill in protecting against alcohol liver disease using ultra-performance liquid chromatography/time-of-flight mass spectrometry and network pharmacology

IntroductionXuanhuang Pill (XHP) is a traditional Chinese medicine oral formula composed of 10 herbs. This study aims to verify the hepatoprotective activity of XHP and explain its possible mechanism.MethodsThe hepatoprotective activity of XHP was evaluated by constructing a mouse model of alcoholic liver disease, and the mechanism of XHP was preliminarily explained by utilizing ultra-performance liquid chromatography/time-of-flight mass spectrometry (UPLC-QTOF/MS), proteomics and network pharmacology.ResultsThe current study demonstrated that treatment with XHP ameliorated acute alcohol-induced liver injury in mice by significantly reducing alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels and triglycerides (TGs) and malondialdehyde (MDA) content. Remarkably, treatment also increased superoxide dismutase (SOD) activity and glutathione (GSH) content. UPLC-QTOF/MS, 199 compounds were identified as within the make-up of the XHP. Network pharmacology analysis showed that 103 targets regulated by 163 chemical components may play an important role in the protective liver effect mediated by XHP. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis suggest that the HIF-1, FoxO, PI3K-Akt, insulin, and thyroid hormone signaling pathways are key modulators of XHP’s effects. Finally, eight key targets including Mapk1, Mapk3, Akt1, Map2k1, Pik3ca, Pik3cg, Raf1, and Prkca were verified by molecular docking and proteomics analysis, which provide insight into the hepatoprotective effect observed with XHP treatment.ConclusionIn summary, these results improved upon knowledge of the chemical composition and the potential mechanisms of hepatoprotective action of oral XHP treatment, providing foundational support for this formulation as a viable therapeutic option for alcoholic liver disease

Proteomics and network pharmacology of Ganshu Nuodan capsules in the prevention of alcoholic liver disease

IntroductionGanshu Nuodan is a liver-protecting dietary supplement composed of Ganoderma lucidum (G. lucidum) spore powder, Pueraria montana (Lour.) Merr. (P. montana), Salvia miltiorrhiza Bunge (S. miltiorrhiza) and Astragalus membranaceus (Fisch.) Bunge. (A. membranaceus). However, its pharmacodynamic material basis and mechanism of action remain unknown.MethodsA mouse model of acute alcohol liver disease (ALD) induced by intragastric administration of 50% alcohol was used to evaluate the hepatoprotective effect of Ganshu Nuodan. The chemical constituents of Ganshu Nuodan were comprehensively identified by UPLC-QTOF/MS, and then its pharmacodynamic material basis and potential mechanism of action were explored by proteomics and network pharmacology.ResultsGanshu Nuodan could ameliorate acute ALD, which is mainly manifested in the significant reduction of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in serum and malondialdehyde (MDA) content in liver and the remarkably increase of glutathione (GSH) content and superoxide dismutase (SOD) activity in liver. Totally 76 chemical constituents were identified from Ganshu Nuodan by UPLC-QTOF/MS, including 21 quinones, 18 flavonoids, 11 organic acids, 7 terpenoids, 5 ketones, 4 sterols, 3 coumarins and 7 others. Three key signaling pathways were identified via proteomics studies, namely Arachidonic acid metabolism, Retinol metabolism, and HIF-1 signaling pathway respectively. Combined with network pharmacology and molecular docking, six key targets were subsequently obtained, including Ephx2, Lta4h, Map2k1, Stat3, Mtor and Dgat1. Finally, these six key targets and their related components were verified by molecular docking, which could explain the material basis of the hepatoprotective effect of Ganshu Nuodan.ConclusionGanshu Nuodan can protect acute alcohol-induced liver injury in mice by inhibiting oxidative stress, lipid accumulation and apoptosis. Our study provides a scientific basis for the hepatoprotective effect of Ganshu Nuodan in acute ALD mice and supports its traditional application

Modeling Rett Syndrome Using TALEN-Edited MECP2 Mutant Cynomolgus Monkeys

Gene-editing technologies have made it feasible to create nonhuman primate models for human genetic disorders. Here, we report detailed genotypes and phenotypes of TALEN-edited MECP2 mutant cynomolgus monkeys serving as a model for a neurodevelopmental disorder, Rett syndrome (RTT), which is caused by loss-of-function mutations in the human MECP2 gene. Male mutant monkeys were embryonic lethal, reiterating that RTT is a disease of females. Through a battery of behavioral analyses, including primate-unique eye-tracking tests, in combination with brain imaging via MRI, we found a series of physiological, behavioral, and structural abnormalities resembling clinical manifestations of RTT. Moreover, blood transcriptome profiling revealed that mutant monkeys resembled RTT patients in immune gene dysregulation. Taken together, the stark similarity in phenotype and/or endophenotype between monkeys and patients suggested that gene-edited RTT founder monkeys would be of value for disease mechanistic studies as well as development of potential therapeutic interventions for RTT

Active Aberration Correction with Adaptive Coefficient SPGD Algorithm for Laser Scanning Confocal Microscope

A laser scanning confocal microscope (LSCM) is an effective scientific instrument for studying sub-micron structures, and it has been widely used in the field of biological detection. However, the illumination depth of LSCMs is limited due to the optical aberrations introduced by living biological tissue, which acts as an optical medium with a non-uniform refractive index, resulting in a significant dispersion of the focus of LSCM illumination light and, hence, a loss in the resolution of the image. In this study, to minimize the effect of optical aberrations, an image-based adaptive optics technology using an optimized stochastic parallel gradient descent (SPGD) algorithm with an adaptive coefficient is applied to the optical path of an LSCM system. The effectiveness of the proposed aberration correction approach is experimentally evaluated in the LSCM system. The results illustrate that the proposed adaptive optics system with an adaptive coefficient SPGD algorithm can effectively reduce the interference caused by aberrations during depth imaging

Island division and multi-objective network reconstruction considering power flow entropy

Modern power system can identify component faults, isolate faults and resume operation quickly. In view of the problem that the distribution of line load in distribution network is not reasonable and it is easy to fall into the self-organized critical state, this paper introduces power flow entropy as an evaluation index to measure the robustness of power network reconstruction. Based on the power supply capability and node load level of distributed power supply in the process of network reconstruction, a strategy of island division is proposed. Then, a mathematical model is set up to minimize power flow entropy, network loss and node voltage drop, and the problem of network reconstruction after fault is solved by the improved chaos theory and binary particle swarm optimization algorithm. Finally, an example of IEEE-33 node distribution system is given to verify the feasibility of the proposed strategy and the effectiveness of the algorithm

Island division and multi-objective network reconstruction considering power flow entropy

Modern power system can identify component faults, isolate faults and resume operation quickly. In view of the problem that the distribution of line load in distribution network is not reasonable and it is easy to fall into the self-organized critical state, this paper introduces power flow entropy as an evaluation index to measure the robustness of power network reconstruction. Based on the power supply capability and node load level of distributed power supply in the process of network reconstruction, a strategy of island division is proposed. Then, a mathematical model is set up to minimize power flow entropy, network loss and node voltage drop, and the problem of network reconstruction after fault is solved by the improved chaos theory and binary particle swarm optimization algorithm. Finally, an example of IEEE-33 node distribution system is given to verify the feasibility of the proposed strategy and the effectiveness of the algorithm

Proteomics analysis and proteogenomic characterization of different physiopathological human lenses

Abstract Background The aim of the present study was to identify the proteomic differences among human lenses in different physiopathological states and to screen for susceptibility genes/proteins via proteogenomic characterization. Methods The total proteomes identified across the regenerative lens with secondary cataract (RLSC), congenital cataract (CC) and age-related cataract (ARC) groups were compared to those of normal lenses using isobaric tagging for relative and absolute protein quantification (iTRAQ). The up-regulated proteins between the groups were subjected to biological analysis. Whole exome sequencing (WES) was performed to detect genetic variations. Results The most complete human lens proteome to date, which consisted of 1251 proteins, including 55.2% previously unreported proteins, was identified across the experimental groups. Bioinformatics functional annotation revealed the common involvement of cellular metabolic processes, immune responses and protein folding disturbances among the groups. RLSC-over-expressed proteins were characteristically enriched in the intracellular immunological signal transduction pathways. The CC groups featured biological processes relating to gene expression and vascular endothelial growth factor (VEGF) signaling transduction, whereas the molecular functions corresponding to external stress were specific to the ARC groups. Combined with WES, the proteogenomic characterization narrowed the list to 16 candidate causal molecules. Conclusions These findings revealed common final pathways with diverse upstream regulation of cataractogenesis in different physiopathological states. This proteogenomic characterization shows translational potential for detecting susceptibility genes/proteins in precision medicine