"Irregular" Verbs in Korean Revisited

A number of Korean verbs 1 do not follow the general phonological rules in their conjugation. However, the patternedness of their "irregularity" has long been noted by most grammarians. Thus even the earliest analyses set up different "classes" of "irregular" verbs (Choy 1937- 1971, Martin 1954, He 1965- 1972, C-W Kim 1967)2. Furthermore it was well known that many of the irregularities were due to some earlier historical processes. More recently in applying the generative theory, many linguists (C-W Kim 1970, Chag-yun Kim 1971, Lee 1973, Cook 1973) have come to believe that most, if not all, of these "anomalous" verbs are not really exceptions to some fixed rules but that they behave differently because they have different underlying forms. Thus superficially identical forms of "regular" and "irregular" verbs are thought to be a direct result of certain phonological rules which neutralize them in a well-defined environment. This paper purports to review some of the "regular" solutions thus far given and to present my own claim on the underlying representations of the "irregular" verbs and the phonlogical rules required to derive their phonetic representations. Choy(l937-71) gives twelve classes of verbs which show anomaly either in the shape of their stems or in the affixes that are attached to them. I shall group them into five sections in each of which related processes will be discussed

Should Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitor Be Continued beyond Progressive Disease?

Epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) is almost exclusively effective in patients with activating EGFR mutations, and median time to progression in such patients is generally up to 12 months. Usually, treatment with EGFR-TKI is terminated when disease progression is confirmed; however, acute exacerbation after the withdrawal of EGFR-TKI has been reported. In this paper, we report a case of a 35-year-old patient whose disease rapidly progressed after discontinuation of gefitinib and then rapidly regressed after reintroduction of gefitinib. In addition, we summarize the cases of 3 other patients who could be safely treated with continued erlotinib in combination with pemetrexed after disease progression. Currently, the mechanism of acquired resistance is intensively investigated and a number of new agents, such as irreversible EGFR inhibitors or MET inhibitors, are under development; however, they are still unavailable in clinical setting. We believe that continuing EGFR-TKI treatment after disease progression should be an option in patients who previously responded to EGFR-TKI under the present circumstances

Protein localization as a principal feature of the etiology and comorbidity of genetic diseases

Proteins localized within the same subcellular compartment tend to be functionally associated. This study shows that subcellular localization and network distance between disease-associated proteins provide complementary information explaining patterns of disease comorbidity

An mRNA-specific tRNAi carrier eIF2A plays a pivotal role in cell proliferation under stress conditions: Stress-resistant translation of c-Src mRNA is mediated by eIF2A

c-Src, a non-receptor protein tyrosine kinase, activates NF-��B and STAT3, which in turn triggers the transcription of anti-apoptosis- and cell cycle-related genes. c-Src protein regulates cell proliferation, cell motility and programmed cell death. And the elevated level of activated c-Src protein is related with solid tumor generation. Translation of c-Src mRNA is directed by an IRES element which mediates persistent translation under stress conditions when translation of most mRNAs is inhibited by a phosphorylation of the alpha subunit of eIF2 carrying the initiator tRNA (tRNAi) to 40S ribosomal subunit under normal conditions. The molecular basis of the stress-resistant translation of c-Src mRNA remained to be elucidated. Here, we report that eIF2A, an alternative tRNAi carrier, is responsible for the stress-resistant translation of c-Src mRNA. eIF2A facilitates tRNAi loading onto the 40S ribosomal subunit in a c-Src mRNAdependent manner. And a direct interaction between eIF2A and a stem-loop structure (SL I) in the c-Src IRES is required for the c-Src IRES-dependent translation under stress conditions but not under normal conditions. Finally, we showed that the eIF2Adependent translation of c-Src mRNA plays a pivotal role in cell proliferation under stress conditions. ? The Author(s) 2016.115sciescopu

eIF2A, an initiator tRNA carrier refractory to eIF2 kinases, functions synergistically with eIF5B

The initiator tRNA (Met-tRNA(i)(Met)) at the P site of the small ribosomal subunit plays an important role in the recognition of an mRNA start codon. In bacteria, the initiator tRNA carrier, IF2, facilitates the positioning of Met-tRNAiMet on the small ribosomal subunit. Eukarya contain the Met-tRNAiMet carrier, eIF2 (unrelated to IF2), whose carrier activity is inhibited under stress conditions by the phosphorylation of its -subunit by stress-activated eIF2 kinases. The stress-resistant initiator tRNA carrier, eIF2A, was recently uncovered and shown to load Met-tRNAiMet on the 40S ribosomal subunit associated with a stress-resistant mRNA under stress conditions. Here, we report that eIF2A interacts and functionally cooperates with eIF5B (a homolog of IF2), and we describe the functional domains of eIF2A that are required for its binding of Met-tRNAiMet, eIF5B, and a stress-resistant mRNA. The results indicate that the eukaryotic eIF5B-eIF2A complex functionally mimics the bacterial IF2 containing ribosome-, GTP-, and initiator tRNA-binding domains in a single polypeptide.112Ysciescopu

The bent conformation of poly(A)-binding protein induced by RNA-binding is required for its translational activation function

A recent study revealed that poly(A)-binding protein (PABP) bound to poly(A) RNA exhibits a sharply bent configuration at the linker region between RNA-recognition motif 2 (RRM2) and RRM3, whereas free PABP exhibits a highly flexible linear configuration. However, the physiological role of the bent structure of mRNA-bound PABP remains unknown. We investigated a role of the bent structure of PABP by constructing a PABP variant that fails to form the poly(A)-dependent bent structure but maintains its poly (A)-binding activity. We found that the bent structure of PABP/poly(A) complex is required for PABP's efficient interaction with eIF4G and eIF4G/eIF4E complex. Moreover, the mutant PABP had compromised translation activation function and failed to augment the formation of 80S translation initiation complex in an in vitro translation system. These results suggest that the bent conformation of PABP, which is induced by the interaction with 30 poly(A) tail, mediates poly(A)-dependent translation by facilitating the interaction with eIF4G and the eIF4G/eIF4E complex. The preferential binding of the eIF4G/eIF4E complex to the bent PABP/poly(A) complex seems to be a mechanism discriminating the mRNA-bound PABPs participating in translation from the idling mRNA-unbound PABPs.111Ysciescopu

Cooperative protein structural dynamics of homodimeric hemoglobin linked to water cluster at subunit interface revealed by time-resolved X-ray solution scattering

Homodimeric hemoglobin (HbI) consisting of two subunits is a good model system for investigating the allosteric structural transition as it exhibits cooperativity in ligand binding. In this work, as an effort to extend our previous study on wild-type and F97Y mutant HbI, we investigate structural dynamics of a mutant HbI in solution to examine the role of well-organized interfacial water cluster, which has been known to mediate intersubunit communication in HbI. In the T72V mutant of HbI, the interfacial water cluster in the T state is perturbed due to the lack of Thr72, resulting in two less interfacial water molecules than in wild-type HbI. By performing picosecond time-resolved X-ray solution scattering experiment and kinetic analysis on the T72V mutant, we identify three structurally distinct intermediates (I1, I2, and I3) and show that the kinetics of the T72V mutant are well described by the same kinetic model used for wild-type and F97Y HbI, which involves biphasic kinetics, geminate recombination, and bimolecular CO recombination. The optimized kinetic model shows that the R-T transition and bimolecular CO recombination are faster in the T72V mutant than in the wild type. From structural analysis using species-associated difference scattering curves for the intermediates, we find that the T-like deoxy I3 intermediate in solution has a different structure from deoxy HbI in crystal. In addition, we extract detailed structural parameters of the intermediates such as E-F distance, intersubunit rotation angle, and heme-heme distance. By comparing the structures of protein intermediates in wild-type HbI and the T72V mutant, we reveal how the perturbation in the interfacial water cluster affects the kinetics and structures of reaction intermediates of HbI. © 2016 Author(s)1571sciescopu

Intercellular adhesion molecule-1 is upregulated in ischemic muscle, which mediates trafficking of endothelial progenitor cells

BACKGROUND: Trafficking of transplanted endothelial progenitor cells (EPCs) to an ischemic organ is a critical step in neovascularization. This study was performed to elucidate the molecular mechanism of EPC trafficking in terms of adhesion molecules. METHODS AND RESULTS: Using murine hindlimb ischemia model, we examined expressions of E-selectin, intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and platelet-endothelial cell adhesion molecule-1 (PECAM-1) in ischemic muscle by immunofluorescence. ICAM-1 was overexpressed in ischemic muscle compared with nonischemic muscle, whereas expressions of E-selectin, VCAM-1, and PECAM-1 did not show that much difference. ICAM-1 was also upregulated by hypoxia in murine endothelial cells (ECs) as assessed by immunoblot and flow cytometry. EPCs were attached to ECs specifically through ICAM-1/beta-2 integrin interaction in vitro. When EPCs were labeled with fluorescent dye or radioisotope (Tc-99m-HMPAO) and systemically administrated in vivo, EPCs preferentially homed to ischemic muscle. By blocking ICAM-1, EPCs entrapment to ischemic limb in vivo was significantly reduced and neovascularization induced by EPC transplantation was attenuated. CONCLUSIONS: ICAM-1 is upregulated by ischemia, and this is closely associated with EPCs entrapment to ischemic limb. Our findings suggest that ICAM-1 expression might be important in regulating the process of neovascularization through its ability to recruit EPCs

Radiolabeling of NOTA and DOTA with Positron Emitting 68Ga and

Purpose: We established radiolabeling conditions of NOTA and DOTA with a generator-produced PET radionuclide 68Ga and studied in vitro characteristics such as stability, serum protein binding, octanol/water distribution, and interference with other metal ions. Materials and Methods: Various concentrations of NOTA․3HCl and DOTA․ 4HCl were labeled with 1 mL 68GaCl3 (0.18～5.75 mCi in 0.1 M HCl) in various pH. NOTA․3HCl (0.373 mM) was labeled with 68GaCl3 (0.183～0.232 mCi/0.1 M HCl 1.0 mL) in the presense of CuCl2, FeCl2, InCl3, FeCl3, GaCl3, MgCl2 or CaCl2 (0～6.07 mM) at room temperature. The labeling efficiencies of 68Ga-NOTA and 68Ga-DOTA were checked by ITLC-SG using acetone or saline as mobile phase. Stabilities, protein bindings, and octanol distribution coefficients of the labeled compounds also were investigated. Results: 68Ga-NOTA and 68Ga-DOTA were labeled optimally at pH 6.5 and pH 3.5, respectively, and the chelates were stable for 4 hr either in the reaction mixture at room temperature or in the human serum at 37°C. NOTA was labeled at room temperature while DOTA required heating for labeling. 68Ga-NOTA labeling efficiency was reduced by CuCl2, FeCl2, InCl2, FeCl3 or GaCl3, however, was not influenced by MgCl2 or CaCl2. The protein binding was low (2.04~3.32%). Log P value of 68Ga-NOTA was -3.07 indicating high hydrophilicity. Conclusion: We found that NOTA is a better bifunctional chelating agent than DOTA for 68Ga labeling. Although, 68Ga-NOTA labeling is interfered by various metal ions, it shows high stability and low serum protein binding.한국과학재단 국가지정연구실사업 (R0A-2008-000- 20116-0) 및 원자력연구개발사업 (2007-01238

Translation-competent 48S complex formation on HCV IRES requires the RNA-binding protein NSAP1

Translation of many cellular and viral mRNAs is directed by internal ribosomal entry sites (IRESs). Several proteins that enhance IRES activity through interactions with IRES elements have been discovered. However, the molecular basis for the IRES-activating function of the IRES-binding proteins remains unknown. Here, we report that NS1-associated protein 1 (NSAP1), which augments several cellular and viral IRES activities, enhances hepatitis C viral (HCV) IRES function by facilitating the formation of translation-competent 48S ribosome–mRNA complex. NSAP1, which is associated with the solvent side of the 40S ribosomal subunit, enhances 80S complex formation through correct positioning of HCV mRNA on the 40S ribosomal subunit. NSAP1 seems to accomplish this positioning function by directly binding to both a specific site in the mRNA downstream of the initiation codon and a 40S ribosomal protein (or proteins)