Small Molecule-Induced Cytosolic Activation of Protein Kinase Akt Rescues Ischemia-Elicited Neuronal Death

Elevating Akt activation is an obvious clinical strategy to prevent progressive neuronal death in neurological diseases. However, this endeavor has been hindered because of the lack of specific Akt activators. Here, from a cell-based high-throughput chemical genetic screening, we identified a small molecule SC79 that inhibits Akt membrane translocation, but paradoxically activates Akt in the cytosol. SC79 specifically binds to the PH domain of Akt. SC79-bound Akt adopts a conformation favorable for phosphorylation by upstream protein kinases. In a hippocampal neuronal culture system and a mouse model for ischemic stroke, the cytosolic activation of Akt by SC79 is sufficient to recapitulate the primary cellular function of Akt signaling, resulting in augmented neuronal survival. Thus, SC79 is a unique specific Akt activator that may be used to enhance Akt activity in various physiological and pathological conditions

Precipitation Processes during Non-Isothermal Ageing of Fine-Grained 2024 Alloy

Mechanical alloying and powder metallurgy procedures were used to manufacture very fine-grained bulk material made from chips of the 2024 aluminum alloy. Studies of solution treatment and precipitation hardening of as-received material were based on differential scanning calorimetry (DSC) tests and TEM/STEM/EDX structural observations. Structural observations complemented by literature data lead to the conclusion that in the case of highly refined structure of commercial 2024 alloys prepared by severe plastic deformation, typical multi-step G-P-B →θ” →θ’ →θ precipitation mechanism accompanied with G-P-B →S” →S’ →S precipitation sequences result in skipping the formation of metastable phases and direct growth of the stable phases. Exothermic effects on DSC characteristics, which are reported for precipitation sequences in commercial materials, were found to be reduced with increased milling time. Moreover, prolonged milling of 2024 chips was found to shift the exothermic peak to lower temperature with respect to the material produced by means of common metallurgy methods. This effect was concluded to result from preferred heterogeneous nucleation of particles at subboundaries and grain boundaries, enhanced by the boundary diffusion in highly refined structures. Transmission electron microscopy and diffraction pattern analysis revealed the development of very fine Al4C3 particles that grow due to the chemical reaction between the Al matrix and graphite flakes introduced as a process control agent during the preliminary milling of chips. Al4C3 nano-particles are formed at high temperatures, i.e. during hot extrusion and the subsequent solution treatment of the samples. Highly refined insoluble particles such as aluminum carbide particles and aluminum oxides were found to retard recrystallization and reduce recovery processes during solution treatment of preliminarily milled materials. Therefore, the as-extruded material composed of a milled part and chip residuals retained its initial bimodal structure in spite of solution heat treatment procedures. This points to a high structural stability of the investigated materials, which is commonly required for new technologies of high-strength Al-based materials production