Sungsoo S. Kim

The NIRSPEC Brown Dwarf Spectroscopic Survey. I. Low-Resolution Near-Infrared Spectra

We present the first results of a near-infrared (0.96-2.31 μm) spectroscopic survey of M, L, and T dwarfs obtained with NIRSPEC on the Keck II telescope. Our new survey has a resolving power of R = λ/Δλ ~ 2000 and is comprised of two major data sets: 53 J-band (1.14-1.36 μm) spectra covering all spectral types from M6 to T8 with at least two members in each spectral subclass (wherever possible), and 25 flux-calibrated spectra from 1.14 to 2.31 μm for most spectral classes between M6 and T8. Sixteen of these 25 objects have additional spectral coverage from 0.96 to 1.14 μm to provide overlap with optical spectra. Spectral flux ratio indexes for prominent molecular bands are derived, and equivalent widths (EWs) for several atomic lines are measured. We find that a combination of four H2O and two CH4 band strengths can be used for spectral classification of all these sources in the near-infrared and that the H2O indexes are almost linear with spectral type from M6 to T8. The H2O indexes near 1.79 and 1.96 μm should remain useful beyond T8. In the near-infrared a notable feature at the boundary between the M and L types is the disappearance of relatively weak (EW ~ 1-2 A) atomic lines of Al I and Ca I, followed by Fe I around L2. At the boundary between L and T dwarfs it is the appearance of CH4 in all near-infrared bands (J, H, and K) that provides a significant spectral change, although we find evidence of CH4 as early as L7 in the K band. The FeH strength and the equivalent width of the K I lines are not monotonic, but in combination with other factors provide useful constraints on spectral type. The K I lines are sensitive to surface gravity. The CO band strength near 2.30 μm is relatively insensitive to spectral class. The peak calibrated flux (Fλ) in the 0.96-2.31 μm region occurs near 1.10 μm at M6 but shifts to about 1.27 μm at T8. In addition, the relative peak flux in the J, H, and K bands is always in the sense J > H > K except around L6, where the differences are small. One object, 2MASS 2244+20 (L6.5), shows normal spectral behavior in the optical but has an infrared spectrum in which the peak flux in J band is less than at H and K.

AMP-activated Protein Kinase Activity Is Critical for Hypoxia-inducible Factor-1 Transcriptional Activity and Its Target Gene Expression under Hypoxic Conditions in DU145 Cells

AMP-activated protein kinase (AMPK) functions as an energy sensor to provide metabolic adaptations under the ATP-deprived conditions such as hypoxia. In the present study, we considered a role of AMPK in the adaptive response to hypoxia by examining whether AMPK is involved in the regulation of hypoxia-inducible factor-1 (HIF-1), a heterodimeric transcription factor that is critical for hypoxic induction of physiologically important genes. We demonstrate that hypoxia or CoCl2 rapidly activated AMPK in DU145 human prostate cancer cells, and its activation preceded the induction of HIF-1α expression. Under these conditions, blockade of AMPK activity by a pharmacological or molecular approach significantly attenuated hypoxia-induced responses such as HIF-1 target gene expression, secretion of vascular endothelial growth factor, glucose uptake, and HIF-1-dependent reporter gene expression, indicating that AMPK is critical for the HIF-1 transcriptional activity and its target gene expression. Its functional requirement for HIF-1 activity was also demonstrated in several different cancer cell lines, but AMPK activation alone was not sufficient to stimulate the HIF-1 transcriptional activity. We further present data showing that AMPK transmits a positive signal for HIF-1 activity via a signaling pathway that is independent of phosphatidylinositol 3-kinase/AKT and several mitogen-activated protein kinases. Taken together, our results suggest that AMPK is a novel and critical component of HIF-1 regulation, implying its new roles in oxygen-regulated cellular phenomena.

Resveratrol stimulates glucose transport in C2C12 myotubes by activating AMP-activated protein kinase

trans-Resveratrol (t-RVT), a naturally occurring polyphenol found in Polygonum cuspidatum, grape, and red wine, has been reported to have anti- inflammatory, cardioprotective, and cancer chemopreventive properties. However antidiabetic effect of t-RVT has not yet been reported. In this study, we show that t-RVT increases glucose uptake in C2C12 myotubes by activating AMP-activated protein kinase (AMPK), uncovering an antidiabetic potential of t-RVT for the first time. AMPK plays a central role in the regulation of glucose and lipid metabolism, and hence it is considered a novel therapeutic target for metabolic syndrome such as type 2 diabetes. t-RVT significantly induced glucose uptake in C2C12 cells, via AMPK activation, but not a phosphatidylinositol-3 kinase (PI-3 kinase) signal pathway. The induced glucose uptake was attenuated by pretreatment with a pharmacological inhibitor for AMPK, indicating that the effect of t-RVT primarily depends on AMPK activation. However, in the presence of insulin, t-RVT also potentiated the effect of insulin on glucose uptake via AMPK activation, which led to further activation of PI-3 kinase/Akt signal pathway.

Glucose deprivation increases mRNA stability of vascular endothelial growth factor through activation of AMP-activated protein kinase in DU145 prostate carcinoma

The induction of proangiogenic cytokines such as vascular endothelial growth factor (VEGF) is a critical feature of tumor angiogenesis. In the present study, we examined the mechanisms of VEGF gene expression induced by glucose deprivation in cancer cells, a role of AMP-activated protein kinase (AMPK) in the process, and the signal transduction pathway. AMPK functions as an energy sensor to provide metabolic adaptation under ATP-depleting conditions such as hypoxia and nutritional deprivation. Here, we show that glucose deprivation leads to a significant increase in the mRNA level of VEGF, GLUT1, and PFKFB3 genes in several cancer cells via a hypoxia-inducible factor-1-independent mechanism, and we demonstrate an essential role of AMPK in these gene expressions. Our data suggest that VEGF mRNA induction by glucose deprivation is due to an increase in mRNA stability, and the AMPK activity is necessary and sufficient to confer the stability to VEGF mRNA. We further show that reactive oxygen species is involved in glucose deprivation-induced AMPK activity in DU145 human prostate carcinomas, and c-Jun amino-terminal kinase acts as an upstream component in AMPK activation cascades under these conditions. LKB1, which was recently identified as a direct upstream kinase of AMPK, was not detected in DU145 cells. In conclusion, our results demonstrate a novel and major role of AMPK in the post-transcriptional regulation of VEGF, further implying its potential role in tumor angiogenesis.

An Extended Star Formation History for the Galactic Center from Hubble Space Telescope NICMOS Observations

We present Hubble Space Telescope (HST) Near-Infrared Camera and Multiobject Spectrometer (NICMOS) observations as evidence that continuous star formation has created much of the central stellar cusp of the Galaxy. The data are the deepest ever obtained for a Galactic center population, being more than 50% complete for mF205W < 19.3, or initial stellar masses 2 M☉. We use Geneva and Padova stellar evolution models to produce synthetic luminosity functions for burst and continuous star formation scenarios, finding that the observations are fitted best by continuous star formation at a rate that is consistent with the recent star formation activity that produced the three massive young clusters in the central 50 pc. Further, it is not possible to fit the observations with ancient burst models, such as would be appropriate for an old population like that in Baades window or NGC 6528.

Mesenchymal stem cells promote proliferation of endogenous neural stem cells and survival of newborn cells in a rat stroke model

Mesenchymal stem cells (MSCs) secrete bioactive factors that exert diverse responses in vivo. In the present study, we explored mechanism how MSCs may lead to higher functional recovery in the animal stroke model. Bone marrow-derived MSCs were transplanted into the brain parenchyma 3 days after induction of stroke by occluding middle cerebral artery for 2 h. Stoke induced proliferation of resident neural stem cells in subventricular zone. However, most of new born cells underwent cell death and had a limited impact on functional recovery after stroke. Transplantation of MSCs enhanced proliferation of endogenous neural stem cells while suppressing the cell death of newly generated cells. Thereby, newborn cells migrated toward ischemic territory and differentiated in ischemic boundaries into doublecortin+ neuroblasts at higher rates in animals with MSCs compared to control group. The present study indicates that therapeutic effects of MSCs are at least partly ascribed to dual functions of MSCs by enhancing endogenous neurogenesis and protecting newborn cells from deleterious environment. The results reinforce the prospects of clinical application using MSCs in the treatment of neurological disorders.

Dynamical Friction on Star Clusters near the Galactic Center

Numerical simulations of the dynamical friction suffered by a star cluster near the Galactic center have been performed with a parallelized tree code. Gerhard has suggested that dynamical friction, which causes a cluster to lose orbital energy and spiral in toward the Galactic center, may explain the presence of a cluster of very young stars in the central parsec, where star formation might be prohibitively difficult because of strong tidal forces. The clusters modeled in our simulations have an initial total mass of 105-106 M? and initial Galactocentric radii of 2.5-30 pc. We have identified a few simulations in which dynamical friction indeed brings a cluster to the central parsec, although this is only possible if the cluster either is very massive (~106 M?) or is formed near the central parsec (5 pc). In both cases, the cluster should have an initially very dense core (>106 M? pc-3). The initial core collapse and segregation of massive stars into the cluster core, which typically happens on a much shorter timescale than that characterizing the dynamical inspiral of the cluster toward the Galactic center, can provide the requisite high density. Furthermore, because it is the cluster core that is most likely to survive the cluster disintegration during its journey inward, this can help account for the observed distribution of presumably massive He I stars in the central parsec.

Inhibition of AMP-activated Protein Kinase Sensitizes Cancer Cells to Cisplatin-induced Apoptosis via Hyper-induction of p53

Cisplatin is one of the most effective and widely used chemotherapeutic agents. However, one of the most salient limitations to the clinical application of cisplatin is the acquired or intrinsic drug resistance exhibited by some tumors. In the present study, we have assessed the potential of an intracellular energy balancing system as a target for augmentation of cisplatin sensitivity in tumors. AMP-activated protein kinase (AMPK) regulates the energy balance system by monitoring intracellular energy status. Here we demonstrate that AMPK is rapidly activated by cisplatin in AGS and HCT116 cancer cells. The inhibition of AMPK in those cells and in xenografts of HCT116 resulted in a remarkable increase in cisplatin-induced apoptosis, which was associated with hyper-induction of the tumor suppressor p53. We further showed that ERK, but not ATM (ataxia telangiectasia mutated) and ATR (ATM- and Rad3-related) kinases, was involved in the hyper-induction of p53 by the inhibition of cisplatin-induced AMPK. By way of contrast, cisplatin did not induce AMPK activation in HeLa cells, which appear to have a relatively high sensitivity to cisplatin-induced cytotoxicity, but expression of the constitutive active form of AMPK in HeLa cells resulted in a significant increase of cell viability after cisplatin treatment. Collectively, our data suggest that AMPK performs a pivotal function for protection against the cytotoxic effect of cisplatin, thereby implying that AMPK is one of the cellular factors determining the cellular sensitivity to cisplatin. On the basis of these observations, we propose that a strategy combining cisplatin and AMPK inhibition could be developed into a novel chemotherapeutic modality.

Id proteins facilitate self-renewal and proliferation of neural stem cells.

Members of helix-loop-helix (HLH) protein family of Id (inhibitor of differentiation) dimerize with bHLH transcription factors and function as negative regulators of differentiation during development. Most of inhibitory roles of Id proteins have been demonstrated in non-neural tissues, and their roles in the developing nervous system are not clearly demonstrated. In this study, we show that Id1, Id2, and Id3 increase self-renewing and proliferation potential of cortical neural stem cells (NSCs) while inhibiting neuronal differentiation. In electrophoretic mobility gel shift and luciferase assays, Id proteins interfered with binding of NeuroD/E47 complexes to the E-box sequences and inhibited E-box-mediated gene expression. Overexpression of Id proteins in NSCs increased both the number and the size of neurospheres in colony-forming assays. Expression of Hes1 and Hes5 was not increased by overexpression of Id proteins under the condition in which Nestin expression was increased. In utero electroporation of Id yielded higher numbers of Ki67-positive and Sox2-positive cells in the mouse embryonic brain. The study suggests Id proteins play independent roles in the maintenance of neural stem properties.

The antioxidant effects of genistein are associated with AMP-activated protein kinase activation and PTEN induction in prostate cancer cells.

Epidemiological evidence suggests a lower incidence of prostate cancer in Asian countries, where soy products are more frequently consumed than in Western countries, indicating that isoflavones from soy have chemopreventive activities in prostate cells. Here, we tested the effects of the soy isoflavone genistein on antioxidant enzymes in DU145 prostate cancer cells. Genistein significantly decreased reactive oxygen species levels and induced the expression of the antioxidant enzymes manganese (Mn) superoxide dismutase (SOD) and catalase, which were associated with AMP-activated protein kinase (AMPK) and phosphatase and tensin homolog deleted from chromosome 10 (PTEN) pathways. The induced expression of catalase, MnSOD, and PTEN were attenuated by pretreatment with a pharmacological inhibitor for AMPK, indicating the effects of genistein primarily depend on AMPK. Furthermore, PTEN is essential for genistein activity, as shown by PTEN transfection in PTEN-deficient PC3 cells. Thus, genistein induces antioxidant enzymes through AMPK activation and increased PTEN expression.