Highlights d Purkinje cell-intrinsic plasticity is induced by TNF-a released from microglia d TNF-a and ATP following microglial activation facilitate synaptic transmission d Acute inflammation in the anterior cerebellum resulted in depression-like behaviors d Suppression of microglia rescued both hyperexcitability and behavioral modulation
BackgroundP.R4810K of RNF213 (mysterin: rs112735431), which is an AAA+ ATPase, is the susceptibility polymorphism for moyamoya disease (MMD) in East Asians. However, the role of RNF213 R4810K in the etiology of MMD is unknown.Methods and ResultsTo clarify the role of RNF213 in known angiogenic pathways, RNF213 expression was analyzed in endothelial cells (ECs) treated with several angiogenic and antiangiogenic factors, including interferons (IFNs). RNF213 was upregulated by IFN-β through signal transducer and activator of transcription x in the promoter and mediated antiangiogenic activity of IFN-β. RNF213 wild-type (WT) overexpression could not lower angiogenesis without IFN-β, but RNF213 R4810K overexpression could. To correlate biochemical function as ATPase and the role of RNF213 oligomer formation with antiangiogenic activity, we investigated the effects of mutations in the AAA+ module. A mutation of the Walker B motif (WEQ), which stabilizes oligomerization, inhibited angiogenesis, but AAA+ module deletion, which cannot initiate oligomerization, did not. Intriguingly, R4810K, similar to WEQ, decreased ATPase activity, suggesting its antiangiogenic activity through stabilizing oligomers. To confirm the antiangiogenic effect of RNF213 upregulation in vivo, vascular EC- or smooth muscle cell-specific Rnf213 R4757K (R4810K ortholog) or WT transgenic (Tg) mice were exposed to hypoxia. Cerebral angiogenesis by hypoxia was suppressed in EC-specific Rnf213 R4757K Tg mice, whereas it was not suppressed in other mice.ConclusionsThis study suggests the importance of inflammatory signals as environmental factors and R4810K carriers for susceptibility to cerebral hypoxia. A specific inhibitor of ATP binding to the first AAA+ could be a promising therapeutic candidate for MMD.
In the present study, a chemical shift saturation recovery method in hyperpolarized 129 Xe MR spectroscopy measurements was applied to two groups of spontaneously breathing mice, an elastase-induced emphysema model and a control group. Parameters detected were those related to lung structures and functions, such as alveolar septal thickness, h, the ratio of the alveolar septal volume relative to gas space volume, V s /V a , and the transit time of blood through the gas exchange region, t. To investigate the potential of these parameters as biomarkers, an attempt was made to detect physiologic changes in the lungs of elastase-treated mice. Our results showed that V s /V a was significantly reduced in elastase-treated mice, reflecting emphysema-like destruction of the alveolar wall. Compared with histologic results, this degree of reduction was shown to reflect the severity of wall destruction. On the other hand, significant changes in other parameters, h and t, were not shown. This study is the first application of hyperpolarized 129 Xe MR spectroscopy to a mouse model of emphysema and shows that the V s /V a volume ratio is an effective biomarker for emphysema that could become useful in drug research and development through noninvasive detection of pathologic changes in small rodents. Magn Reson Med 64:929-938,
ABSTRACT:The effect of reduced pressure on the polarization of 129 Xe has been examined in batch and continuous flow modes aiming at developing a simple and convenient hyperpolarizing system. The effect of foreign gases was found to show a different tendency at reduced pressure as low as 0.15 atm compared to that near atmospheric pressure. For example, 129 Xe polarization in binary mixtures of Xe and N 2 was larger than that observed in ternary mixtures of Xe, N 2 , and 4 He when compared with the same Xe content, and the highest polarization of 63.6% was given by the 5% Xe þ 95% N 2 mixture in the batch mode. The most noticeable result in the flow mode was that 129 Xe polarization reached a plateau at 0.15 atm when cell pressure was reduced from atmospheric pressure, being enhanced to about twice of that observed near atmospheric pressure. Also demonstrated is the use of isotopically enriched 129 Xe gas at reduced partial pressure. This will be devoid of the anesthetic side effects of Xe while making use of enhanced polarization at reduced pressure, leading to the development of a simple and convenient hyperpolarizing system for medical use.
Specific turn-on detection of enzyme activities is of fundamental importance in drug discovery research, as well as medical diagnostics. Although magnetic resonance imaging (MRI) is one of the most powerful techniques for noninvasive visualization of enzyme activity, both in vivo and ex vivo, promising strategies for imaging specific enzymes with high contrast have been very limited to date. We report herein a novel signal-amplifiable self-assembling (19) F NMR/MRI probe for turn-on detection and imaging of specific enzymatic activity. In NMR spectroscopy, these designed probes are "silent" when aggregated, but exhibit a disassembly driven turn-on signal change upon cleavage of the substrate part by the catalytic enzyme. Using these (19) F probes, nanomolar levels of two different target enzymes, nitroreductase (NTR) and matrix metalloproteinase (MMP), could be detected and visualized by (19) F NMR spectroscopy and MRI. Furthermore, we have succeeded in imaging the activity of endogenously secreted MMP in cultured media of tumor cells by (19) F MRI, depending on the cell lines and the cellular conditions. These results clearly demonstrate that our turn-on (19) F probes may serve as a screening platform for the activity of MMPs.
This study examined the external morphology and morphometry of the human embryonic inner ear membranous labyrinth and documented its three-dimensional position in the developing embryo using phasecontrast X-ray computed tomography and magnetic resonance imaging. A total of 27 samples between Carnegie stage (CS) 17 and the postembryonic phase during trimester 1 (approximately 6-10 weeks after fertilization) were included. The otic vesicle elongated along the dorsoventral axis and differentiated into the end lymphatic appendage and cochlear duct (CD) at CS 17. The spiral course of the CD began at CS18, with anterior and posterior semicircular ducts (SDs) forming prominent circles with a common crus. The spiral course of the CD comprised more than two turns at the postembryonic phase, at which time the height of the CD was evident. A linear increase was observed in the length of anterior, posterior, and lateral SDs, in that order, and the length of the CD increased exponentially over the course of development. Bending in the medial direction was observed between the cochlear and vestibular parts from the latero-caudal view, with the angle decreasing during development. The position of the inner ear was stable throughout the period of observation on the lateral to ventral side of the rhombencephalon, caudal to the pontine flexure, and adjacent to the auditory ganglia. The plane of the lateral semicircular canal was approximately 8.08-14.68 with respect to the cranial caudal (z-)axis, indicating that the orientation of the inner ear changes during growth to adulthood. Anat Rec, 298:2081Rec, 298: -2090Rec, 298: , 2015. V C 2015 Wiley Periodicals, Inc.Abbreviations used: CD 5 cochlear duct; CS 5 Carnegie stage; IEL 5 Inner ear length; MRI 5 magnetic resonance imaging; PCXT 5 phase-contrast X-ray computed tomography; PE 5 postembryonic phase
In the present study, a balanced steady-state free precession pulse sequence combined with compressed sensing was applied to hyperpolarized (129) Xe lung imaging in spontaneously breathing mice. With the aid of fast imaging techniques, the temporal resolution was markedly improved in the resulting images. Using these protocols and respiratory gating, (129) Xe lung images in end-inspiratory and end-expiratory phases were obtained successfully. The application of these techniques for pulmonary functional imaging made it possible to simultaneously evaluate regional ventilation and gas exchange in the same animal. A comparative study between healthy and elastase-induced mouse models of emphysema showed abnormal ventilation as well as gas exchange in elastase-treated mice.
Purpose: To apply a continuous flow-type hyperpolarizing (CF-HP) system to lung imaging and investigate the feasibility of hyperpolarized 129 Xe MRI at a low xenon concentration. Materials and Methods:Under two conditions where a 3% or 70% xenon gas mixture was constantly supplied, gasand dissolved-phase 129 Xe images and diffusion-weighted 129 Xe-gas images were obtained from the mouse lung. Signal-to-noise ratio (SNR) of the 129 Xe images and the apparent diffusion coefficient (ADC) of xenon were compared between the two gas mixtures. Results:The SNR of gas-and dissolved-phase images were 28.9 Ϯ 5.2 and 12.0 Ϯ 2.0, respectively, using the 70% xenon gas mixture, while they were 22.9 Ϯ 4.8 and 6.8 Ϯ 0.6, using the 3% mixture. The ADC of xenon using the 3% xenon gas mixture was approximately 1.5 times higher than that using the 70% one. These results indicated that the high ADC increases the apparent replenishment rate of gas-phase magnetization, thus resulting in a reduction of the SNR loss induced by diluting xenon with quenching gases. Conclusion:The CF-HP system is useful for lung imaging at an extremely low concentration of xenon, which enables one to fully restrain an anesthetic effect of xenon and to reduce consumption of xenon in a measurement.
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