Mechanisms of PiT2-loop7 Missense Mutations Induced Pi Dyshomeostasis / 神经科学通报·英文版

PiT2 is an inorganic phosphate (Pi) transporter whose mutations are linked to primary familial brain calcification (PFBC). PiT2 mainly consists of two ProDom (PD) domains and a large intracellular loop region (loop7). The PD domains are crucial for the Pi transport, but the role of PiT2-loop7 remains unclear. In PFBC patients, mutations in PiT2-loop7 are mainly nonsense or frameshift mutations that probably cause PFBC due to C-PD1131 deletion. To date, six missense mutations have been identified in PiT2-loop7; however, the mechanisms by which these mutations cause PFBC are poorly understood. Here, we found that the p.T390A and p.S434W mutations in PiT2-loop7 decreased the Pi transport activity and cell surface levels of PiT2. Furthermore, we showed that these two mutations attenuated its membrane localization by affecting adenosine monophosphate-activated protein kinase (AMPK)- or protein kinase B (AKT)-mediated PiT2 phosphorylation. In contrast, the p.S121C and p.S601W mutations in the PD domains did not affect PiT2 phosphorylation but rather impaired its substrate-binding abilities. These results suggested that missense mutations in PiT2-loop7 can cause Pi dyshomeostasis by affecting the phosphorylation-regulated cell-surface localization of PiT2. This study helps understand the pathogenesis of PFBC caused by PiT2-loop7 missense mutations and indicates that increasing the phosphorylation levels of PiT2-loop7 could be a promising strategy for developing PFBC therapies.

The Pathology of Primary Familial Brain Calcification: Implications for Treatment / 神经科学通报·英文版

Primary familial brain calcification (PFBC) is an inherited neurodegenerative disorder mainly characterized by progressive calcium deposition bilaterally in the brain, accompanied by various symptoms, such as dystonia, ataxia, parkinsonism, dementia, depression, headaches, and epilepsy. Currently, the etiology of PFBC is largely unknown, and no specific prevention or treatment is available. During the past 10 years, six causative genes (SLC20A2, PDGFRB, PDGFB, XPR1, MYORG, and JAM2) have been identified in PFBC. In this review, considering mechanistic studies of these genes at the cellular level and in animals, we summarize the pathogenesis and potential preventive and therapeutic strategies for PFBC patients. Our systematic analysis suggests a classification for PFBC genetic etiology based on several characteristics, provides a summary of the known composition of brain calcification, and identifies some potential therapeutic targets for PFBC.

Integrating Network Pharmacology Based on UPLC-Q-Exactive/MS Technology to Explore the Mechanism of Chaihu Guizhi Decoction in the Treatment of Secondary Bacterial Pneumonia Caused by Influenza / 世界科学技术-中医药现代化

Objective To study the mechanism of Chaihu Guizhi Decoction(CGD)in the treatment of influenza and staphylococcus aureus co-infection.Methods The co-infection model of influenza and staphylococcus aureus was established and CGD was used to intervene.The chemical components of CGD were qualitatively analyzed by UPLC-Q-Exactive/MS technology.The potential action targets of chemical components in CGD and the related targets of influenza Staphylococcus aureus co-infection were mined by network pharmacology method.The"component target disease"network was constructed.Core targets were selected according to degree ranking.Core action pathways were enriched by KEGG analysis and GO annotation analysis.The core target was verified by RT-qPCR,and the interaction between the core component and the key target was verified by molecular docking.Results CGD could significantly improve the decrease of body weight and thymus index(P<0.05)caused by co-infection.The lung index(P<0.05),relative amount of MmRNA expression(P<0.05)and bacterial load(P<0.05)were decreased,and the survival rate was improved.51 chemical constituents were identified from CGD.Through network pharmacological analysis,107 related targets corresponding to CGD treatment of bacterial pneumonia secondary to influenza were excavated.TNF,AKT1,ALB,VEGFA,MAPK3,PTGS2,STAT3,EGFR and other targets with strong correlation,mainly involved Fc epsilon RI signal pathway,GnRH signal pathway,NF-κB signal path,etc.Molecular docking study showed that the main active component of CGD,including oroxyloside,baicalein and wogonin have strong affinity with TNF,PTGS2 and EGFR targets.Compared with co-infection model group,in CGD group TNF-α、EGFR and PTGS2 increased significantly(P<0.05).Conclusion The main active ingredient of CGD is oroxyloside,baicalein and wogonin.TNF-α,PTGS2,EGFR and other targets to played a role in the treatment of influenza staphylococcus aureus co-infection.

The application of computer network scoring system in national clinical skills competition / 中华医学教育探索杂志

The clinical skills competitions for national medical students in China have been well organized for five times.Experience has been accumulated,and much has been emphasized on the low assessment efficacy throughout the competitions.However,few solutions has been brought about to conquer such problem.This article mainly focused on introducing a computerized clinical skill assessment system based on current clinical skills competition assessment.The system realizes functions such as team management,online marking,score calculation,data analysis,and real-time result presentation.Such appliance of computer,internet and information technology on conventional clinical skills evaluation could hopefully replace the traditional manual calculating procedures,improving the efficiency of the future competitions,to ensure their openness,impartiality,and equitability,as well as to deliver observatory appeal among audience.