The Polarization States of Microglia in TBI: A New Paradigm for Pharmacological Intervention

Traumatic brain injury (TBI) is a serious medical and social problem worldwide. Because of the complex pathophysiological mechanisms of TBI, effective pharmacotherapy is still lacking. The microglial cells are resident tissue macrophages located in the brain and have two major polarization states, M1 phenotype and M2 phenotype, when activated. The M1 phenotype is related to the release of proinflammatory cytokines and secondary brain injury, while the M2 phenotype has been proved to be responsible for the release of anti-inflammation cytokines and for central nervous system (CNS) repair. In animal models, pharmacological strategies inhibiting the M1 phenotype and promoting the M2 phenotype of microglial cells could alleviate cerebral damage and improve neurological function recovery after TBI. In this review, we aimed to summarize the current knowledge about the pathological significance of microglial M1/M2 polarization in the pathophysiology of TBI. In addition, we reviewed several drugs that have provided neuroprotective effects against brain injury following TBI by altering the polarization states of the microglia. We emphasized that future investigation of the regulation mechanisms of microglial M1/M2 polarization in TBI is anticipated, which could contribute to the development of new targets of pharmacological intervention in TBI

Characterization of the complete chloroplast genome of Polygonatum sibiricum (Liliaceae), a well-known herb to China

Polygonatum sibiricum is a famous and well-known TCH (Traditional Chinese Herb) in China. In this paper, the complete chloroplast genome of P. sibiricum was studied and illustrated to add more genetic information and data. The chloroplast genome is 152,960 bp in length and a typical quadripartite structure, which exhibits a large single-copy region (LSC) of 81,471 bp, a small single-copy region (SSC) of 18,485 bp and a pair of inverted-repeat regions (IRs) of 26,502 bp in each. The overall nucleotide composition of chloroplast genome is: 30.7% A, 31.4% T, 19.3% C, 18.6% G and the total GC content 37.9%. A total of 136 genes were annotated that included 90 protein-coding genes (PCGs), 38 transfer RNA (tRNAs) and 8 ribosome RNA (rRNAs). The phylogenetic ML tree shown that P. sibiricum is closely related to P. cyrtonema on genetic position relationship by the Maximum-Likelihood (ML) method

Static charge is an ionic molecular fragment

Abstract What is static charge? Despite the long history of research, the identity of static charge and mechanism by which static is generated by contact electrification are still unknown. Investigations are challenging due to the complexity of surfaces. This study involves the molecular-scale analysis of contact electrification using highly well-defined surfaces functionalized with a self-assembled monolayer of alkylsilanes. Analyses show the elementary molecular steps of contact electrification: the exact location of heterolytic cleavage of covalent bonds (i.e., Si-C bond), exact charged species generated (i.e., alkyl carbocation), and transfer of molecular fragments. The strong correlation between charge generation and molecular fragments due to their signature odd-even effects further shows that contact electrification is based on cleavage of covalent bonds and transfer of ionic molecular fragments. Static charge is thus an alkyl carbocation; in general, it is an ionic molecular fragment. This mechanism based on cleavage of covalent bonds is applicable to general types of insulating materials, such as covalently bonded polymers. The odd-even effect of charging caused by the difference of only one atom explains the highly sensitive nature of contact electrification

Cryo-EM structure of the human concentrative nucleoside transporter CNT3.

Concentrative nucleoside transporters (CNTs), members of the solute carrier (SLC) 28 transporter family, facilitate the salvage of nucleosides and therapeutic nucleoside derivatives across the plasma membrane. Despite decades of investigation, the structures of human CNTs remain unknown. We determined the cryogenic electron microscopy (cryo-EM) structure of human CNT (hCNT) 3 at an overall resolution of 3.6 Å. As with its bacterial homologs, hCNT3 presents a trimeric architecture with additional N-terminal transmembrane helices to stabilize the conserved central domains. The conserved binding sites for the substrate and sodium ions unravel the selective nucleoside transport and distinct coupling mechanism. Structural comparison of hCNT3 with bacterial homologs indicates that hCNT3 is stabilized in an inward-facing conformation. This study provides the molecular determinants for the transport mechanism of hCNTs and potentially facilitates the design of nucleoside drugs

Phosphorylation of Ku dictates DNA double-strand break (DSB) repair pathway choice in S phase

Multiple DNA double-strand break (DSB) repair pathways are active in S phase of the cell cycle; however, DSBs are primarily repaired by homologous recombination (HR) in this cell cycle phase. As the non-homologous end-joining (NHEJ) factor, Ku70/80 (Ku), is quickly recruited to DSBs in S phase, we hypothesized that an orchestrated mechanism modulates pathway choice between HR and NHEJ via displacement of the Ku heterodimer from DSBs to allow HR. Here, we provide evidence that phosphorylation at a cluster of sites in the junction of the pillar and bridge regions of Ku70 mediates the dissociation of Ku from DSBs. Mimicking phosphorylation at these sites reduces Ku's affinity for DSB ends, suggesting that phosphorylation of Ku70 induces a conformational change responsible for the dissociation of the Ku heterodimer from DNA ends. Ablating phosphorylation of Ku70 leads to the sustained retention of Ku at DSBs, resulting in a significant decrease in DNA end resection and HR, specifically in S phase. This decrease in HR is specific as these phosphorylation sites are not required for NHEJ. Our results demonstrate that the phosphorylation-mediated dissociation of Ku70/80 from DSBs frees DNA ends, allowing the initiation of HR in S phase and providing a mechanism of DSB repair pathway choice in mammalian cells

The Polarization States of Microglia in TBI: A New Paradigm for Pharmacological Intervention

Traumatic brain injury (TBI) is a serious medical and social problem worldwide. Because of the complex pathophysiological mechanisms of TBI, effective pharmacotherapy is still lacking. The microglial cells are resident tissue macrophages located in the brain and have two major polarization states, M1 phenotype and M2 phenotype, when activated. The M1 phenotype is related to the release of proinflammatory cytokines and secondary brain injury, while the M2 phenotype has been proved to be responsible for the release of anti-inflammation cytokines and for central nervous system (CNS) repair. In animal models, pharmacological strategies inhibiting the M1 phenotype and promoting the M2 phenotype of microglial cells could alleviate cerebral damage and improve neurological function recovery after TBI. In this review, we aimed to summarize the current knowledge about the pathological significance of microglial M1/M2 polarization in the pathophysiology of TBI. In addition, we reviewed several drugs that have provided neuroprotective effects against brain injury following TBI by altering the polarization states of the microglia. We emphasized that future investigation of the regulation mechanisms of microglial M1/M2 polarization in TBI is anticipated, which could contribute to the development of new targets of pharmacological intervention in TBI

Paraspeckle protein 1 (PSPC1) is involved in the cisplatin induced DNA damage response--role in G1/S checkpoint.

Paraspeckle protein 1 (PSPC1) was first identified as a structural protein of the subnuclear structure termed paraspeckle. However, the exact physiological functions of PSPC1 are still largely unknown. Previously, using a proteomic approach, we have shown that exposure to cisplatin can induce PSPC1 expression in HeLa cells, indicating the possible involvement for PSPC1 in the DNA damage response (DDR). In the current study, the role of PSPC1 in DDR was examined. First, it was found that cisplatin treatment could indeed induce the expression of PSPC1 protein. Abolishing PSPC1 expression by siRNA significantly inhibited cell growth, caused spontaneous cell death, and increased DNA damage. However, PSPC1 did not co-localize with γH2AX, 53BP1, or Rad51, indicating no direct involvement in DNA repair pathways mediated by these molecules. Interestingly, knockdown of PSPC1 disrupted the normal cell cycle distribution, with more cells entering the G2/M phase. Furthermore, while cisplatin induced G1/S arrest in HeLa cells, knockdown of PSPC1 caused cells to escape the G1/S checkpoint and enter mitosis, and resulted in more cell death. Taken together, these observations indicate a new role for PSPC1 in maintaining genome integrity during the DDR, particularly in the G1/S checkpoint

Numerical and theoretical research on flexural behaviour of steel-precast UHPC composite beams

In order to promote the utilization of high strength materials and application of prefabricated structures, flexural behaviour of section steel-precast UHPC (Ultra-High performance concrete) slab composite beams prefabricated with bolt shear connectors are numerically simulated by the finite element (FE) software ABAQUS. The model is verified by three prefabricated steel-concrete composite beams tested. Numerical analysis results are in good accordance with experimental results. Furthermore, parametric studies are conducted to investigate the effects of strength of section steel and concrete of precast slab, thickness of section steel, width and height of precast concrete slab, diameters of steel bars and bolt shear connectors. The flexural behaviour of composite beams, in terms of bearing capacity, deflection, ductility and energy dissipation, are compared. The numerical results indicate that the improvement of strength of section steel results in a decrease of ductility, but a significant increase of the ultimate load and energy dissipation. Compared with composite beam made of section steel with thickness of 10 mm, the ultimate load of beams made of section steel with thickness of 14 and 18 mm improve by 29.0% and 58.8%, respectively, the ductility enhance by 2.8% and 8.3%, respectively, and the energy dissipation improve by 8.0% and 12.3%, respectively. With the increase of concrete strength, the ultimate load, deflection and energy dissipation gradually increase. The ductility of steel-UHPC composite beam is the highest, that of steel-HSC composite beam is the lowest. The effect of reinforcement ratio of concrete slab and diameter of shear bolts on the ultimate load of composite beam is limited. Simplified formulae for two different sectional types of proper-reinforced section steel-precast UHPC slab composite beams occurred bending failure are proposed, and the predicted results fit well with the simulated results. The results can be taken as a reference for the design and construction of section steel-precast UHPC slab composite beams