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.

Human speech production obeys the same acoustic principles as vocal production in other animals but has distinctive features: A stable vocal source is filtered by rapidly changing formant frequencies. To understand speech evolution, we examined a wide range of primates, combining observations of phonation with mathematical modeling. We found that source stability relies upon simplifications in laryngeal anatomy, specifically the loss of air sacs and vocal membranes. We conclude that the evolutionary loss of vocal membranes allows human speech to mostly avoid the spontaneous nonlinear phenomena and acoustic chaos common in other primate vocalizations. This loss allows our larynx to produce stable, harmonic-rich phonation, ideally highlighting formant changes that convey most phonetic information. Paradoxically, the increased complexity of human spoken language thus followed simplification of our laryngeal anatomy.