Search

Glutamate is traditionally viewed as the first messenger to activate NMDAR (N-methyl-d-aspartate receptor)-dependent cell death pathways in stroke1,2, but unsuccessful clinical trials with NMDAR antagonists implicate the engagement of other mechanisms3–7. Here we show that glutamate and its structural analogues, including NMDAR antagonist l-AP5 (also known as APV), robustly potentiate currents mediated by acid-sensing ion channels (ASICs) associated with acidosis-induced neurotoxicity in stroke4. Glutamate increases the affinity of ASICs for protons and their open probability, aggravating ischaemic neurotoxicity in both in vitro and in vivo models. Site-directed mutagenesis, structure-based modelling and functional assays reveal a bona fide glutamate-binding cavity in the extracellular domain of ASIC1a. Computational drug screening identified a small molecule, LK-2, that binds to this cavity and abolishes glutamate-dependent potentiation of ASIC currents but spares NMDARs. LK-2 reduces the infarct volume and improves sensorimotor recovery in a mouse model of ischaemic stroke, reminiscent of that seen in mice with Asic1aknockout or knockout of other cation channels4–7. We conclude that glutamate functions as a positive allosteric modulator for ASICs to exacerbate neurotoxicity, and preferential targeting of the glutamate-binding site on ASICs over that on NMDARs may be strategized for developing stroke therapeutics lacking the psychotic side effects of NMDAR antagonists.

Hematopoietic stem/progenitor cells (HSPCs) are supported and regulated by niche cells in the bone marrow with an important characterization of physiological hypoxia. However, how hypoxia regulates HSPCs is still unclear. Here, we find that meteorin (Metrn) from hypoxic macrophages restrains HSPC mobilization. Hypoxia-induced factor 1α and Yin Yang 1 induce the high expression of Metrn in macrophages, and macrophage-specific Metrn knockout increases HSPC mobilization through modulating HSPC proliferation and migration. Mechanistically, Metrn interacts with its receptor 5-hydroxytryptamine receptor 2b (Htr2b) to regulate the reactive oxygen species levels in HSPCs through targeting phospholipase C signaling. The reactive oxygen species levels are reduced in HSPCs of macrophage-specific Metrn knockout mice with activated phospholipase C signaling. Targeting the Metrn/Htr2b axis could therefore be a potential strategy to improve HSPC mobilization for stem cell-based therapy.

Abstract: In this paper, the dynamic response of an infinite cylindrical hole embedded in a porous medium and subjected to an axisymmetric ring load is investigated. Two scalar potentials and two vector potentials are introduced to decouple the governing equations of Biot’s theory. By taking a Fourier transform with respect to time and the axial coordinate, we derive general solutions for the potentials, displacements, stresses and pore pressures in the frequency-wave-number domain. Using the general solutions and a set of boundary conditions applied at the hole surface, the frequency-wave-number domain solutions for the proposed problem are determined. Numerical inversion of the Fourier transform with respect to the axial wave number yields the frequency domain solutions, while a double inverse Fourier transform with respect to frequency as well as the axial wave number generates the time-space domain solution. The numerical results of this paper indicate that the dynamic response of a porous medium surrounding an infinite hole is dependant upon many factors including the parameters of the porous media, the location of receivers, the boundary conditions along the hole surface as well as the load characteristics.

Abstract: In this paper, the dynamic response of an infinite cylindrical hole embedded in a porous medium and subjected to an axisymmetric ring load is investigated. Two scalar potentials and two vector potentials are introduced to decouple the governing equations of Biot’s theory. By taking a Fourier transform with respect to time and the axial coordinate, we derive general solutions for the potentials, displacements, stresses and pore pressures in the frequency-wave-number domain. Using the general solutions and a set of boundary conditions applied at the hole surface, the frequency-wave-number domain solutions for the proposed problem are determined. Numerical inversion of the Fourier transform with respect to the axial wave number yields the frequency domain solutions, while a double inverse Fourier transform with respect to frequency as well as the axial wave number generates the time-space domain solution. The numerical results of this paper indicate that the dynamic response of a porous medium surrounding an infinite hole is dependant upon many factors including the parameters of the porous media, the location of receivers, the boundary conditions along the hole surface as well as the load characteristics.