Adaptive transmission in heterogeneous networks

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/166243/1/cmu2bf00018.pd

Senolytic therapy is neuroprotective and improves functional outcome long-term after traumatic brain injury in mice

IntroductionChronic neuroinflammation can exist for months to years following traumatic brain injury (TBI), although the underlying mechanisms remain poorly understood.MethodsIn the current study, we used a controlled cortical impact mouse model of TBI to examine whether proinflammatory senescent cells are present in the brain long-term (months) after TBI and whether ablation of these cells via administration of senolytic drugs can improve long-term functional outcome after TBI. The results revealed that astrocytes and microglia in the cerebral cortex, hippocampus, corpus callosum and lateral posterior thalamus colocalized the senescent cell markers, p16Ink4a or p21Cip1/Waf1 at 5 weeks post injury (5wpi) and 4 months post injury (4mpi) in a controlled cortical impact (CCI) model. Intermittent administration of the senolytic drugs, dasatinib and quercetin (D + Q) beginning 1-month after TBI for 13 weeks significantly ablated p16Ink4a-positive- and p21Cip1/Waf1-positive-cells in the brain of TBI animals, and significantly reduced expression of the major senescence-associated secretory phenotype (SASP) pro-inflammatory factors, interleukin-1β and interleukin-6. Senolytic treatment also significantly attenuated neurodegeneration and enhanced neuron number at 18 weeks after TBI in the ipsilateral cortex, hippocampus, and lateral posterior thalamus. Behavioral testing at 18 weeks after TBI further revealed that senolytic therapy significantly rescued defects in spatial reference memory and recognition memory, as well as depression-like behavior in TBI mice.DiscussionTaken as a whole, these findings indicate there is robust and widespread induction of senescent cells in the brain long-term after TBI, and that senolytic drug treatment begun 1-month after TBI can efficiently ablate the senescent cells, reduce expression of proinflammatory SASP factors, reduce neurodegeneration, and rescue defects in reference memory, recognition memory, and depressive behavior

Near-death high-frequency hyper-synchronization in the rat hippocampus

Near-death experiences (NDE) are episodes of enhanced perception with impending death, which have been associated with increased high-frequency (13–100 Hz) synchronization of neuronal activity, which is implicated in cognitive processes like perception, attention and memory. To test whether the NDE-associated high-frequency oscillations surge is related to cardiac arrest, recordings were made from the hippocampus of anesthetized rats dying from an overdose of the sedative chloral hydrate (CH). At a lethal dose, CH caused a surge in beta band power in CA3 and CA1 and a surge in gamma band power in CA1. CH increased the inter-regional coherence of high-frequency oscillations within and between hippocampi. Whereas the surge in beta power developed at non-lethal chloral hydrate doses, the surge in gamma power was specific for impending death. In contrast, CH strongly suppressed theta band power in both CA1 and CA3 and reduced inter-regional coherence in the theta band. The simultaneously recorded electrocardiogram showed a small decrease in heart rate but no change in waveform during the high-frequency oscillation surge, with cardiac arrest only developing after the cessation of breathing and collapse of all oscillatory activity. These results demonstrate that the high-frequency oscillation surge just before death is not limited to cardiac arrest and that especially the increase in gamma synchronization in CA1 may contribute to NDE observed both with and without cardiac arrest

m7GHub: deciphering the location, regulation and pathogenesis of internal mRNA N7-methylguanosine (m7G) sites in human

Motivation Recent progress in N7-methylguanosine (m7G) RNA methylation studies has focused on its internal (rather than capped) presence within mRNAs. Tens of thousands of internal mRNA m7G sites have been identified within mammalian transcriptomes, and a single resource to best share, annotate and analyze the massive m7G data generated recently are sorely needed. Results We report here m7GHub, a comprehensive online platform for deciphering the location, regulation and pathogenesis of internal mRNA m7G. The m7GHub consists of four main components, including: the first internal mRNA m7G database containing 44 058 experimentally validated internal mRNA m7G sites, a sequence-based high-accuracy predictor, the first web server for assessing the impact of mutations on m7G status, and the first database recording 1218 disease-associated genetic mutations that may function through regulation of m7G methylation. Together, m7GHub will serve as a useful resource for research on internal mRNA m7G modification

Sodium Fluoride Arrests Renal G2/M Phase Cell-Cycle Progression by Activating ATM-Chk2-P53/Cdc25C Signaling Pathway in Mice

Background/Aims: Excessive fluoride intake can induce cytotoxicity, DNA damage and cell-cycle changes in many tissues and organs, including the kidney. However, the underlying molecular mechanisms of fluoride-induced renal cell-cycle changes are not well understood at present. In this study, we used a mouse model to investigate how sodium fluoride (NaF) induces cell-cycle changes in renal cells. Methods: Two hundred forty ICR mice were randomly assigned to four equal groups for intragastric administration of NaF (0, 12, 24 and 48 mg/kg body weight/day) for 42 days. Kidneys were taken to measure changes of the cell-cycle at 21 and 42 days of the experiment, using flow cytometry, quantitative real-time polymerase chain reaction (qRT-PCR) and western blot methods. Results: NaF, at more than 12 mg/kg body weight, induced G2/M phase cell-cycle arrest in the renal cells, which was supported by the finding of significantly increased percentages of renal cells in the G2/M phase. We found also that G2/M phase cell-cycle arrest was accompanied by up-regulation of p-ATM, p-Chk2, p-p53, p-Cdc25C, p-CDK1, p21, and Gadd45a protein expression levels; up-regulation of ATM, Chk2, p53, p21, and Gadd45a mRNA expression levels; down-regulation of CyclinB1, mdm2, PCNA protein expression levels; and down-regulation of CyclinB1, CDK1, Cdc25C, mdm2, and PCNA mRNA expression levels. Conclusion: In this mouse model, NaF, at more than 12 mg/ kg, induced G2/M phase cell-cycle arrest by activating the ATM-Chk2-p53/Cdc25C signaling pathway, which inhibits the proliferation of renal cells and development of the kidney. Activation of the ATM-Chk2-p53/Cdc25C signaling pathway is the mechanism of NaF-induced renal G2/M phase cell-cycle arrest in this model

Effects of Extrusion and Rolling Processes on the Microstructure and Mechanical Properties of Zn-Li-Ag Alloys

In this work, a novel Zn-0.5%Li-0.1%Ag alloy was cast and extruded into rods, which were rolled into a plate, and the effects of extrusion and rolling on the microstructure and mechanical properties of the Zn-0.5%Li-0.1%Ag alloy were evaluated. The results show that grain strengthening occurs in all of the alloys because of the presence of nano-LiZn4 precipitates. The extrusion and rolling processes promote grain size refinement and orientation order, and the microstructure and mechanical properties of the Zn-0.5%Li-0.1%Ag alloy can be significantly improved by secondary processing. The elastic modulus and tensile strength of the processed alloy increased to 83.1 GPa and 251.6 MPa, respectively, compared to 75.6 GPa and 185.8 MPa, respectively, for the as-cast Zn-0.5%Li-0.1%Ag alloy. More importantly, elongation was greatly improved, from 16.9% to 92.6%, which is an increase of up to 448%, and there were transgranular cleavage planes and intergranular cleavage planes in the fracture surfaces. The intergranular cleavage planes were dominant, and they showed ductile fracture characteristics