Soft subdermal implant capable of wireless battery charging and programmable controls for applications in optogenetics.

Optogenetics is a powerful technique that allows target-specific spatiotemporal manipulation of neuronal activity for dissection of neural circuits and therapeutic interventions. Recent advances in wireless optogenetics technologies have enabled investigation of brain circuits in more natural conditions by releasing animals from tethered optical fibers. However, current wireless implants, which are largely based on battery-powered or battery-free designs, still limit the full potential of in vivo optogenetics in freely moving animals by requiring intermittent battery replacement or a special, bulky wireless power transfer system for continuous device operation, respectively. To address these limitations, here we present a wirelessly rechargeable, fully implantable, soft optoelectronic system that can be remotely and selectively controlled using a smartphone. Combining advantageous features of both battery-powered and battery-free designs, this device system enables seamless full implantation into animals, reliable ubiquitous operation, and intervention-free wireless charging, all of which are desired for chronic in vivo optogenetics. Successful demonstration of the unique capabilities of this device in freely behaving rats forecasts its broad and practical utilities in various neuroscience research and clinical applications.

A novel synthetic cathinone, α-pyrrolidinopentiothiophenone (PVT), produces locomotor sensitization in rat: Implications for GSK3ß connections in the nucleus accumbens core.

A novel psychoactive substance, α-pyrrolidinopentiothiophenone (α-PVT), is a structural analog to amphetamine. Recently, it has been shown that α-PVT has an abuse potential similar to psychomotor stimulants like cocaine or amphetamine. However, it has not been performed yet to determine whether α-PVT develops behavioral sensitization, a well-known phenomenon for psychomotor stimulants. In the present study, rats were first pre-exposed to either saline or α-PVT (20 mg/kg, IP) with a total of four injections in every 2-3 days of interval. Then, 2-weeks after withdrawal, locomotor activity was measured with a challenge dose (10 mg/kg, IP) of α-PVT and the nucleus accumbens core region was taken out. Similar to psychomotor stimulants, repeated administration of α-PVT produced locomotor sensitization. Further, the phosphorylation levels of GSK3ß in the nucleus accumbens core were found to be decreased only in rats with sensitization developed, but not in those with acute or non-sensitized. Correlation analysis revealed that the phosphorylation levels of GSK3ß have a strong negative correlation with locomotor activity only in rats with α-PVT pre-exposed, but not in those with its acute injection. These results suggest that a certain level of change in the phosphorylation levels of GSK3ß in the nucleus accumbens core may involve in mediating the expression of locomotor sensitization by repeated injection of α-PVT in rats.

CK2 inhibitor CX4945 induces sequential inactivation of proteins in the signaling pathways related with cell migration and suppresses metastasis of A549 human lung cancer cells.

Casein kinase 2 (CK2) is known to be involved in various cellular processes such as cell cycle, apoptosis and proliferation. It has been reported that the inhibition of CK2 induced by recently developed small molecule CX4945 shows anti-cancer effects including anti-proliferation and anti-angiogenesis in several different cancers including prostate cancer. Here we report that migration and invasion of A549 human lung cancer cells are suppressed by the inhibition of CK2 induced by CX4945. We found that CX4945 sequentially attenuates the proteins in PI3K/Akt and MAPK pathways, two signaling pathways related with cell migration. This sequential control of signal pathways inhibits the expression of membrane type 1-matrix metalloproteinase and this leads to the selective attenuation of one of the gelatinases, MMP-2, which can degrade components of extracellular matrix, and metastasis of A549 human lung cancer cell.

Anti-metastatic effect of cantharidin in A549 human lung cancer cells.

Cancer metastasis is represented by migration and invasion of cancer cells. Cancer cells invade into the blood or lymphatic vessels and this leads to the spread of cancer into the organs in distant sites. For cancer cells to migrate, extracellular matrix (ECM) must be degraded. Cantharidin, a compound derived from blister beetles, is known for its anti-cancer effect in several cancer cells. Here we report that cantharidin inhibits migration and invasion of A549 human lung cancer cell. We found that cantharidin inhibits activation of phosphatidylinositol 3-kinase/Akt signaling pathway. This leads to the selective attenuation of one of the gelatinases, matrix metalloproteinase 2, which can degrade components of ECM, and inhibits migration and invasion of A549 human lung cancer cell.

Contributions of aminoacyl-tRNA synthetase-interacting multifunctional protein-3 to mammalian translation initiation.

Aminoacyl-tRNA synthetase-interacting multifunctional protein-3 (AIMP3) stabilizes and protects mammalian methionyl-tRNA synthetase (MRS) and eukaryotic initiation factor 2 subunit gamma (eIF2γ), factors involved in the formation and the delivery of Met-tRNA(i)Met respectively, through the binding interactions. Due to the protections that MRS and eIF2γ are provided from the interactions with AIMP3, cellular levels of MRS and eIF2γ may be able to be maintained high enough for their canonical and/or non-canonical functions.

Dual role of methionyl-tRNA synthetase in the regulation of translation and tumor suppressor activity of aminoacyl-tRNA synthetase-interacting multifunctional protein-3.

Mammalian methionyl-tRNA synthetase (MRS) plays an essential role in initiating translation by transferring Met to initiator tRNA (tRNA(i)(Met)). MRS also provides a cytosolic anchoring site for aminoacyl-tRNA synthetase-interacting multifunctional protein-3 (AIMP3)/p18, a potent tumor suppressor that is translocated to the nucleus for DNA repair upon DNA damage. However, the mechanism by which this enzyme mediates these two seemingly unrelated functions is unknown. Here we demonstrate that AIMP3 is released from MRS by UV irradiation-induced stress. Dissociation was induced by phosphorylation of MRS at Ser662 by general control nonrepressed-2 (GCN2) following UV irradiation. Substitution of Ser662 to Asp (S662D) induced a conformational change in MRS and significantly reduced its interaction with AIMP3. This mutant possessed significantly reduced MRS catalytic activity because of loss of tRNA(Met) binding, resulting in down-regulation of global translation. According to the Met incorporation assay using stable HeLa cells expressing MRS S662A or eukaryotic initiation factor-2 subunit-α (eIF2α) S51A, inactivation of GCN2-induced phosphorylation at eIF2α or MRS augmented the role of the other, suggesting a cross-talk between MRS and eIF2α for efficient translational inhibition. This work reveals a unique mode of regulation of global translation as mediated by aminoacyl-tRNA synthetase, specifically MRS, which we herein identified as a previously unidentified GCN2 substrate. In addition, our research suggests a dual role for MRS: (i) as a coregulator with eIF2α for GCN2-mediated translational inhibition; and (ii) as a coupler of translational inhibition and DNA repair following DNA damage by releasing bound tumor suppressor AIMP3 for its nuclear translocation.