Structural Dynamics of 1,2-Diiodoethane in Cyclohexane Probed by Picosecond X-ray Liquidography

Kim, Jeongho,Lee, Jae Hyuk,Kim, Joonghan,Jun, Sunhong,Kim, Kyung Hwan,Kim, Tae Wu,Wulff, Michael,Ihee, Hyotcherl American Chemical Society 2012 The journal of physical chemistry. A, Molecules, s Vol.116 No.11

<P>We investigate the structural dynamics of iodine elimination reaction of 1,2-diiodoethane (C<SUB>2</SUB>H<SUB>4</SUB>I<SUB>2</SUB>) in cyclohexane by applying time-resolved X-ray liquidography (TRXL). The TRXL technique combines structural sensitivity of X-ray diffraction and 100 ps time resolution of X-ray pulses from synchrotron and allows direct probing of transient structure of reacting molecules. From the analysis of time-dependent X-ray solution scattering patterns using global fitting based on DFT calculation and MD simulation, we elucidate the kinetics and structure of transient intermediates resulting from photodissociation of C<SUB>2</SUB>H<SUB>4</SUB>I<SUB>2</SUB>. In particular, the effect of solvent on the reaction kinetics and pathways is examined by comparison with an earlier TRXL study on the same reaction in methanol. In cyclohexane, the C<SUB>2</SUB>H<SUB>4</SUB>I radical intermediate undergoes two branched reaction pathways, formation of C<SUB>2</SUB>H<SUB>4</SUB>I–I isomer and direct dissociation into C<SUB>2</SUB>H<SUB>4</SUB> and I, while only isomer formation occurs in methanol. Also, the C<SUB>2</SUB>H<SUB>4</SUB>I–I isomer has a shorter lifetime in cyclohexane by an order of magnitude than in methanol. The difference in the reaction dynamics in the two solvents is accounted for by the difference in solvent polarity. In addition, we determine that the C<SUB>2</SUB>H<SUB>4</SUB>I radical has a bridged structure, not a classical structure, in cyclohexane.</P><P><B>Graphic Abstract</B> <IMG SRC='http://pubs.acs.org/appl/literatum/publisher/achs/journals/content/jpcafh/2012/jpcafh.2012.116.issue-11/jp2078314/production/images/medium/jp-2011-078314_0011.gif'></P><P><A href='http://pubs.acs.org/doi/suppl/10.1021/jp2078314'>ACS Electronic Supporting Info</A></P>

A novel cereblon modulator for targeted protein degradation

Kim, Sung Ah,Go, Ara,Jo, Seung-Hyun,Park, Sun Jun,Jeon, Young Uk,Kim, Ji Eun,Lee, Heung Kyoung,Park, Chi Hoon,Lee, Chong-Ock,Park, Sung Goo,Kim, Pilho,Park, Byoung Chul,Cho, Sung Yun,Kim, Sunhong,Ha, Elsevier 2019 European Journal of Medicinal Chemistry Vol.166 No.-

<P><B>Abstract</B></P> <P>Immunomodulatory drugs (IMiDs) exert anti-myeloma activity by binding to the protein cereblon (CRBN) and subsequently degrading IKZF1/3. Recently, their ability to recruit E3 ubiquitin ligase has been used in the proteolysis targeting chimera (PROTAC) technology. Herein, we design and synthesize a novel IMiD analog TD-106 that induces the degradation of IKZF1/3 and inhibits the proliferation of multiple myeloma cells <I>in vitro</I> as well as <I>in vivo</I>. Moreover, we demonstrate that TD-428, which comprises TD-106 linked to a BET inhibitor, JQ1 efficiently induce BET protein degradation in the prostate cancer cell line 22Rv1. Consequently, cell proliferation is inhibited due to suppressed C-MYC transcription. These results, therefore, firmly suggest that the newly synthesized IMiD analog, TD-106, is a novel CRBN modulator that can be used for targeted protein degradation.</P> <P><B>Highlights</B></P> <P> <UL> <LI> We design and synthesize a novel IMiD analog. </LI> <LI> TD-106 induces the degradation of IKZF1/3 and inhibits the proliferation of multiple myeloma cells. </LI> <LI> BET PROTAC with TD-106 efficiently induces the degradation of BET proteins. </LI> <LI> TD-106 as a novel CRBN modulator can be used for targeted protein degradation. </LI> </UL> </P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>

Combined probes of X-ray scattering and optical spectroscopy reveal how global conformational change is temporally and spatially linked to local structural perturbation in photoactive yellow protein

Kim, Tae Wu,Yang, Cheolhee,Kim, Youngmin,Kim, Jong Goo,Kim, Jeongho,Jung, Yang Ouk,Jun, Sunhong,Lee, Sang Jin,Park, Sungjun,Kosheleva, Irina,Henning, Robert,van Thor, Jasper J.,Ihee, Hyotcherl The Royal Society of Chemistry 2016 Physical chemistry chemical physics Vol.18 No.13

<P>Real-time probing of structural transitions of a photoactive protein is challenging owing to the lack of a universal time-resolved technique that can probe the changes in both global conformation and light-absorbing chromophores of the protein. In this work, we combine time-resolved X-ray solution scattering (TRXSS) and transient absorption (TA) spectroscopy to investigate how the global conformational changes involved in the photoinduced signal transduction of photoactive yellow protein (PYP) is temporally and spatially related to the local structural change around the light-absorbing chromophore. In particular, we examine the role of internal proton transfer in developing a signaling state of PYP by employing its E46Q mutant (E46Q-PYP), where the internal proton transfer is inhibited by the replacement of a proton donor. The comparison of TRXSS and TA spectroscopy data directly reveals that the global conformational change of the protein, which is probed by TRXSS, is temporally delayed by tens of microseconds from the local structural change of the chromophore, which is probed by TA spectroscopy. The molecular shape of the signaling state reconstructed from the TRXSS curves directly visualizes the three-dimensional conformations of protein intermediates and reveals that the smaller structural change in E46Q-PYP than in wild-type PYP suggested by previous studies is manifested in terms of much smaller protrusion, confirming that the signaling state of E46Q-PYP is only partially developed compared with that of wildtype PYP. This finding provides direct evidence of how the environmental change in the vicinity of the chromophore alters the conformational change of the entire protein matrix.</P>

Risk-informed Emergency Response Training for Backdraft in Nuclear Power Plants

Mihyun Kim,Wonkook Kim,Hongki Kim,Jungman Kim,Sunhong Yoon,Jangwon Choi,Heemoon Kim 한국화재소방학회 2023 International Journal of Fire Science and Engineer Vol.37 No.3

Research has been conducted for developing fire evacuation and response training programs for nuclear power plant (NPP) application. Among numerous fire scenarios that may occur in an NPP environment, three different points of origin for a fire were selected for the program based on a risk-informed approach: switchgear room, main control room, and safety injection pump room. Fire outcomes were predicted for these scenarios via numerical modeling and the results were incorporated into the newly developed fire evacuation and response training program for the APR1400, Korea’s next-generation NPP model. The switchgear room fire scenario was found to have the most potential for backdraft to occur during manual fire response following automatic gaseous fire suppression system activation. The emergency response manual does discuss this possible backdraft occurrence; however, the guidance to avoid injuries is qualitative, such as to be cautious of backdrafts and wait a sufficient amount of time after opening a door before entering the. In this study, backdraft phenomenon that may occur from a switchgear room fire was numerically examined using the recent version of the Fire Dynamics Simulator to develop an appropriate timeline to be implemented in the fire evacuation and response training program. Based on the findings, the following guidance is provided: (1) backdraft can only occur when the fire originates in the space near the door; (2) wait at least 10 minutes after opening the door before entering the room; (3) watch for rapid smoke production, as this may be an antecedent phenomenon of backdraft; and (4) when smoke production increases rapidly, leave the room as soon as possible to avoid being caught within the deflagrating flames from a backdraft.

Photochemistry of HgBr₂ in methanol investigated using time-resolved X-ray liquidography

Jun, Sunhong,Lee, Jae Hyuk,Kim, Jeongho,Kim, Joonghan,Kim, Kyung Hwan,Kong, Qingyu,Kim, Tae Kyu,Lo Russo, Manuela,Wulff, Michael,Ihee, Hyotcherl Royal Society of Chemistry 2010 Physical chemistry chemical physics Vol.12 No.37

<P>We investigate the photoinduced dissociation of HgBr<SUB>2</SUB> in methanol and the ensuring structural dynamics of the photo-products over a time span from 100 ps to 1 μs after photolysis at 267 nm by using time-resolved X-ray liquidography (TRXL). By making use of the atomic-level structural sensitivity of X-ray scattering and the superb 100 ps time resolution of X-ray pulses from a 3rd-generation synchrotron, the structural dynamics of a chemical reaction in solution can be directly monitored. The measured time-dependent X-ray solution scattering signals, analyzed using global-fitting based on DFT calculations and MD simulations, show that photoexcited HgBr<SUB>2</SUB> dissociates <I>via</I> both two-body (HgBr + Br) and three-body (Hg + Br + Br) dissociation pathways with a ∼2 : 1 branching ratio. Following dissociation, the photoproducts recombine <I>via</I> three reactions involving Br species: (1) Hg + Br, (2) HgBr + Br, and (3) Br + Br. The associated rate constants and branching ratios are determined from the global-fitting analysis. Also, we examine the energy dissipation from reacting solute molecules and relaxation of excited molecules to solvent bath accompanying the temperature rise of 0.54 K. Compared to a previous TRXL study of the photodissociation of HgI<SUB>2</SUB>, the results of this work suggest that the photodissociation pathway of HgBr<SUB>2</SUB> is different from that of HgI<SUB>2</SUB>, which dissociates predominantly <I>via</I> two-body dissociation, at least to within the currently available time resolution of ∼100 ps. In addition, the error analysis of the fit parameters used in the global-fitting are discussed in detail with a comparison of various error estimation algorithms.</P> <P>Graphic Abstract</P><P>The photo-dissociation of HgBr<SUB>2</SUB> in methanol and the structural dynamics of the photo-products were investigated by time-resolved X-ray liquidography. <IMG SRC='http://pubs.rsc.org/services/images/RSCpubs.ePlatform.Service.FreeContent.ImageService.svc/ImageService/image/GA?id=c002004d'> </P>

The Tumor Suppressor, p53, Negatively Regulates Non-Canonical NF-κB Signaling through miRNA-Induced Silencing of NF-κB-Inducing Kinase

Jang, Hanbit,Park, Seulki,Kim, Jaehoon,Kim, Jong Hwan,Kim, Seon-Young,Cho, Sayeon,Park, Sung Goo,Park, Byoung Chul,Kim, Sunhong,Kim, Jeong-Hoon Korean Society for Molecular and Cellular Biology 2020 Molecules and cells Vol.43 No.1

NF-κB signaling through both canonical and non-canonical pathways plays a central role in immune responses and inflammation. NF-κB-inducing kinase (NIK) stabilization is a key step in activation of the non-canonical pathway and its dysregulation implicated in various hematologic malignancies. The tumor suppressor, p53, is an established cellular gatekeeper of proliferation. Abnormalities of the TP53 gene have been detected in more than half of all human cancers. While the non-canonical NF-κB and p53 pathways have been explored for several decades, no studies to date have documented potential cross-talk between these two cancer-related mechanisms. Here, we demonstrate that p53 negatively regulates NIK in an miRNA-dependent manner. Overexpression of p53 decreased the levels of NIK, leading to inhibition of the non-canonical NF-κB pathway. Conversely, its knockdown led to increased levels of NIK, IKKα phosphorylation, and p100 processing. Additionally, miR-34b induced by nutlin-3 directly targeted the coding sequences (CDS) of NIK. Treatment with anti-miR-34b-5p augmented NIK levels and subsequent non-canonical NF-κB signaling. Our collective findings support a novel cross-talk mechanism between non-canonical NF-κB and p53.

The Short-Chain Fatty Acid Receptor GPR43 Modulates YAP/TAZ via RhoA

Park, Bi-Oh,Kim, Seong Heon,Kim, Jong Hwan,Kim, Seon-Young,Park, Byoung Chul,Han, Sang-Bae,Park, Sung Goo,Kim, Jeong-Hoon,Kim, Sunhong Korean Society for Molecular and Cellular Biology 2021 Molecules and cells Vol.44 No.7

GPR43 (also known as FFAR2 or FFA2) is a G-protein-coupled receptor primarily expressed in immune cells, enteroendocrine cells and adipocytes that recognizes short-chain fatty acids, such as acetate, propionate, and butyrate, likely to be implicated in innate immunity and host energy homeostasis. Activated GPR43 suppresses the cAMP level and induces Ca²⁺ flux via coupling to Gα_i and Gα_q families, respectively. Additionally, GPR43 is reported to facilitate phosphorylation of ERK through G-protein-dependent pathways and interacts with β-arrestin 2 to inhibit NF-κB signaling. However, other G-protein-dependent and independent signaling pathways involving GPR43 remain to be established. Here, we have demonstrated that GPR43 augments Rho GTPase signaling. Acetate and a synthetic agonist effectively activated RhoA and stabilized YAP/TAZ transcriptional coactivators through interactions of GPR43 with Gα_q/11 and Gα_12/13. Acetate-induced nuclear accumulation of YAP was blocked by a GPR43-specific inverse agonist. The target genes induced by YAP/TAZ were further regulated by GPR43. Moreover, in THP-1-derived M1-like macrophage cells, the Rho-YAP/TAZ pathway was activated by acetate and a synthetic agonist. Our collective findings suggest that GPR43 acts as a mediator of the Rho-YAP/TAZ pathway.

Allele-Specific Suppressors of <i>lin-1(R175Opal)</i> Identify Functions of MOC-3 and DPH-3 in tRNA Modification Complexes in <i>Caenorhabditis elegans</i>

Kim, Sunhong,Johnson, Wade,Chen, Changchun,Sewell, Aileen K.,Byströ,m, Anders S.,Han, Min The Genetics Society of America 2010 Genetics Vol.185 No.4

Characteristics and health effects of PM_2.5 emissions from various sources in Gwangju, South Korea

Kim, Injeong,Lee, Kwangyul,Lee, Sunhong,Kim, Sang Don Elsevier 2019 The Science of the total environment Vol.696 No.-

<P><B>Abstract</B></P> <P>Increasing evidence suggests that the toxicity of fine dust particles (PM<SUB>2.5</SUB>) is linked to specific components rather than their mass. However, research on the chemical composition and health risk of PM<SUB>2.5</SUB> is insufficient. This study analyzed the metals, polycyclic aromatic hydrocarbon (PAHs), organochlorine pesticides (OCPs), and polychlorinated biphenyls (PCBs) present in PM<SUB>2.5</SUB> and evaluated their risk to health during outdoor activities. The concentration of metals was one order of magnitude higher than that of PAHs and the concentration and detection frequency of OCPs and PCBs were considerably lower than those of metals and PAHs. The lifetime excess cancer risk (LECR) for carcinogens in PM<SUB>2.5</SUB> exceeded <I>de minimis</I> risk (1 × 10<SUP>−6</SUP>) as 1.33–3.44 × 10<SUP>−6</SUP> (at 5th–95th percentile) as Cr(VI), As, and Cd showed high contributions. Children in the 2 < years <18 age group had a high risk of cancer due to early-life susceptibility. The proportion of ∑Metals to LECR was approximately 95%, while ∑PAHs attributed to 5% of total LECR. The effects of ∑OCPs and 2,3′,4,4′,5′-Pentachlorobiphenyl (PCB-123) on LECR were negligible. The hazard quotient (HQ) for non-carcinogens was <1, and non-carcinogenic effects were not expected. Mn, BaP, Pb, As, and Cd were the key determinants of the HQ values and among the identified PM<SUB>2.5</SUB> sources they are closely related to industrial activities, oil combustion, and gasoline exhaust. Therefore, control strategies for these sources can effectively reduce PM<SUB>2.5</SUB> risk. This study measured the concentrations of toxic compounds in ambient PM<SUB>2.5</SUB> and considered only PM<SUB>2.5</SUB> exposure during outdoor activities. PM<SUB>2.5</SUB> health risk during the entire day would be higher than the PM<SUB>2.5</SUB> risk determined in this study, and further research is required for this evaluating this risk.</P> <P><B>Highlights</B></P> <P> <UL> <LI> LECR was 1.33–3.44 × 10<SUP>−6</SUP> (5th–95th percentile); this cannot be ignored. </LI> <LI> Non-carcinogenic effects are not expected by acute exposure of PM2.5 (HQ < 1). </LI> <LI> The major contributors to PM<SUB>2.5</SUB> risk were As, Cr(VI), Cd, Mn, BaP, and Pb. </LI> <LI> Related sources were industrial activities, combustion of oil, and vehicle exhaust. </LI> </UL> </P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>

Determination of toxic organic pollutants in fine particulate matter using selective pressurized liquid extraction and gas chromatography–tandem mass spectrometry

Kim, Injeong,Lee, Sunhong,Kim, Sang Don Elsevier 2019 Journal of chromatography A Vol.1590 No.-

<P><B>Abstract</B></P> <P>Studies investigating toxic organic pollutants in fine dust (PM2.5), such as polycyclic aromatic hydrocarbons (PAHs), organochlorine pesticides (OCPs) and polychlorinated biphenyls (PCBs), are insufficient, despite the pollutants’ potent toxicity. The objective of this study is to develop an analytical method for determining PAHs, OCPs and PCBs in ambient PM2.5 using selective pressurized liquid extraction (SPLE). To maximize the extraction efficiency of target analytes, the extraction parameters of SPLE, particularly solvent type, temperature, static time, and cycle number, were optimized. The highest recoveries were observed under the conditions of dichloromethane:acetone (9:1), 100℃, 5 min of static time, and 1 cycle extraction, which is selected as the optimal method of SPLE. In the method validation, the results showed that the suggested method can quantify 17 PAHs, 20 OCPs, and 63 PCBs in PM2.5. Using urban dust SRM (1648a) and ambient PM2.5 samples, the applicability of the method was also confirmed. Total concentration of PAHs was the highest (2639.42–7377.75 pg/m<SUP>3</SUP>) followed by OCPs (80.57–674.69 pg/m<SUP>3</SUP>) and PCBs (1.39–9.34 pg/m<SUP>3</SUP>). Most of the PAHs were detected, whereas 2–7 compounds among 20 OCPs and 2–6 compounds among 63 PCBs were determined. The developed analytical method is highly efficient in terms of process (a one-step extraction process), time (15 min extraction time per one sample) and solvent usage (less than 30 mL per one sample), showing good performance. This method can be applied to investigate the organic toxicants in PM2.5, and it can contribute to monitoring and risk assessment, leading to an effective risk management policy for PM2.5 in Korea.</P> <P><B>Highlights</B></P> <P> <UL> <LI> One-step SPLE extraction method for PAHs, OCPs and PCBs in PM2.5 was developed. </LI> <LI> Seventeen PAHs, 20 OCPs, and 63 PCBs showed a low LOQ and good recoveries. </LI> <LI> Dozens of PAHs and several OCPs and PCBs were detected from ambient PM2.5 in Korea. </LI> <LI> Newly developed method is cost-effective to analyze massive PM2.5 samples. </LI> </UL> </P>