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.T ranslational regulation is a mechanism by which genetic expression can be modulated to cope with various biological conditions. In diseases such as cancer, dysregulation of protein synthesis is frequently observed; therefore, accurate translational control appears to be important for the maintenance of normal growth and proliferation (1, 2). Under stress conditions, global translational control mainly occurs at the point of translational initiation through modification of eukaryotic initiation factors (eIFs). A key regulatory mechanism of this process is phosphorylation of eIF2 subunit-α (eIF2α), which prevents formation of a ternary complex (TC) comprising eIF2, GTP, and Metcharged initiator tRNA (Met-tRNA i Met ), thereby inhibiting further rounds of translation initiation (3).Aminoacyl-tRNA synthetases (ARSs) are essential enzymes for protein synthesis, linking codons to their corresponding amino acids (4, 5). A key factor in translation initiation, methionyltRNA synthetase (MRS) produces Met-tRNA i Met , which is indispensable for TC formation. MRS has been also found in the nucleus, where it may play a role in the biogenesis of rRNA (6). Under oxidative stress, MRS charges Met to noncognate tRNAs at a high frequency, resulting in reduced translational fi...

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.

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Recent reports indicated that ROS is closely related with cancer metastasis. ROS targets major signaling molecules which are known to be involved in migration and invasion of cancer cells. Here we report that maclurin, a major phenolic component of ethanol extracted mulberry twigs, exerts anti-metastatic effect in A549 human non-small-cell lung cancer cells. Maclurin suppresses intracellular ROS level in A549 human non-small-cell lung cancer cells. Also, maclurin down-regulates Src and ERK, which are well known to be regulated with redox state. Suppressed Src/FAK and ERK signalings activate GSK3-β, thus inhibiting nuclear accumulation of β-catenin. As a result, transcriptional expressions of two major gelatinases (MMP-2 and MMP-9) were significantly down-regulated. Consequently, migration and invasion of A549 human non-small-cell lung cancer cells were attenuated. Anti-metastatic effect of maclurin on A549 human non-small-cell lung cancer cells were diminished by the treatment of hydrogen peroxide, thus further implicating that the effect of maclurin may be strongly related with its anti-oxidative activity. Thus, our data indicate that the anti-metastatic effect of maclurin is exerted by anti-oxidative activity and inhibition of Src/FAK-ERK-β-catenin signaling pathway.

Anatomical variations of the inferior mesenteric artery are extremely uncommon, since the inferior mesenteric artery is regularly diverged at the level of the third lumbar vertebra. We found a rare case in which the inferior mesenteric artery arose from the superior mesenteric artery. The findings were made during a routine dissection of the cadaver of an 82-yr-old Korean woman. This is the tenth report on this anomaly, the second female and the first Korean. The superior mesenteric artery normally arising from abdominal aorta sent the inferior mesenteric artery as the second branch. The longitudinal anastomosis vessels between the superior mesenteric artery and inferior mesenteric artery survived to form the common mesenteric artery. This anatomical variation concerning the common mesenteric artery is of clinical importance, performing procedures containing the superior mesenteric artery.

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SummaryBackground The danger hypothesis provides a new perspective of the mechanisms underlying drug allergy. In this study, we evaluated associations between variations in the genes involved in danger signal pathways and antibiotic-induced cutaneous allergic reactions (AICARs). Methods Two hundred cases with urticaria, angio-oedema, maculopapular rash, and erythema multiforme caused by antibiotics were extracted from the database of the Adverse Drug Reaction Research Group in Korea. All cases were confirmed by an allergy specialist. Causative antibiotics included penicillin, cephalosporin, quinolone, and others (approximately 40 different types). Ten single nucleotide polymorphisms (SNPs) in seven genes (À318C4T, 149A4G, and 16230G4A in CTLA4, IVS117T4C in CD28, À3479T4G and I170V in CD86, À1C4T in CD40, À3458A4G in CD40LG, À308G4A in TNF, and À31T4C in IL1B) were scored for cases and for healthy subjects without a history of AICARs. Results Our analysis failed to reveal differences in the distribution of the 10 SNPs between cases and controls. However, we could find a gene-gene interaction between À1C4T in CD40 and À3458A4G in CD40L using multifactor dimensionality reduction analysis. Subjects with minor alleles of both SNPs showed a significant risk for developing AICARs [P = 0.017, odds ratio (OR) (95% confidence interval) = 2.93 (1.20-7.97)]. Conclusion Our findings suggest that a genetic interaction between CD40 and CD40L favours the development of AICARs.