A rationally designed small molecule for identifying an <i>in vivo</i> link between metal–amyloid-β complexes and the pathogenesis of Alzheimer's disease

Beck, Michael W.,Oh, Shin Bi,Kerr, Richard A.,Lee, Hyuck Jin,Kim, So Hee,Kim, Sujeong,Jang, Milim,Ruotolo, Brandon T.,Lee, Joo-Yong,Lim, Mi Hee Royal Society of Chemistry 2015 Chemical Science Vol.6 No.3

<▼1><P>An <I>in vivo</I> chemical tool designed to target metal–Aβ complexes and modulate their activity was applied to the 5XFAD mouse model of Alzheimer’s disease (AD) demonstrating the involvement of metal–Aβ in AD pathology.</P></▼1><▼2><P>Multiple factors, including amyloid-β (Aβ), metals, and reactive oxygen species (ROS), are involved in the development of Alzheimer's disease (AD). Metal ions can interact with Aβ species generating toxic oligomers and ROS <I>in vitro</I>; however, the involvement of metal–Aβ complexes in AD pathology <I>in vivo</I> remains unclear. To solve this uncertainty, we have developed a chemical tool (<B>L2-b</B>) that specifically targets metal–Aβ complexes and modulates their reactivity (<I>i.e.</I>, metal–Aβ aggregation, toxic oligomer formation, and ROS production). Through the studies presented herein, we demonstrate that <B>L2-b</B> is able to specifically interact with metal–Aβ complexes over metal-free Aβ analogues, redirect metal–Aβ aggregation into off-pathway, nontoxic less structured Aβ aggregates, and diminish metal–Aβ-induced ROS production, overall mitigating metal–Aβ-triggered toxicity, confirmed by multidisciplinary approaches. <B>L2-b</B> is also verified to enter the brain <I>in vivo</I> with relative metabolic stability. Most importantly, upon treatment of 5XFAD AD mice with <B>L2-b</B>, (i) metal–Aβ complexes are targeted and modulated in the brain; (ii) amyloid pathology is reduced; and (iii) cognition deficits are significantly improved. To the best of our knowledge, by employing an <I>in vivo</I> chemical tool specifically prepared for investigating metal–Aβ complexes, we report for the first time experimental evidence that metal–Aβ complexes are related directly to AD pathogenesis.</P></▼2>

Thermal and X-ray diffraction analysis studies during the decomposition of ammonium uranyl nitrate

Kim, B. H.,Lee, Y. B.,Prelas, M. A.,Ghosh, T. K. Springer Netherlands 2012 Journal of radioanalytical and nuclear chemistry Vol.292 No.3

<P>Two types of ammonium uranyl nitrate (NH<SUB>4</SUB>)<SUB>2</SUB>UO<SUB>2</SUB>(NO<SUB>3</SUB>)<SUB>4</SUB>·2H<SUB>2</SUB>O and NH<SUB>4</SUB>UO<SUB>2</SUB>(NO<SUB>3</SUB>)<SUB>3</SUB>, were thermally decomposed and reduced in a TG-DTA unit in nitrogen, air, and hydrogen atmospheres. Various intermediate phases produced by the thermal decomposition and reduction process were investigated by an X-ray diffraction analysis and a TG/DTA analysis. Both (NH<SUB>4</SUB>)<SUB>2</SUB>UO<SUB>2</SUB>(NO<SUB>3</SUB>)<SUB>4</SUB>·2H<SUB>2</SUB>O and NH<SUB>4</SUB>UO<SUB>2</SUB>(NO<SUB>3</SUB>)<SUB>3</SUB> decomposed to amorphous UO<SUB>3</SUB> regardless of the atmosphere used. The amorphous UO<SUB>3</SUB> from (NH<SUB>4</SUB>)<SUB>2</SUB>UO<SUB>2</SUB>(NO<SUB>3</SUB>)<SUB>4</SUB>·2H<SUB>2</SUB>O was crystallized to γ-UO<SUB>3</SUB> regardless of the atmosphere used without a change in weight. The amorphous UO<SUB>3</SUB> obtained from decomposition of NH<SUB>4</SUB>UO<SUB>2</SUB>(NO<SUB>3</SUB>)<SUB>3</SUB> was crystallized to α-UO<SUB>3</SUB> under a nitrogen and air atmosphere, and to β-UO<SUB>3</SUB> under a hydrogen atmosphere without a change in weight. Under each atmosphere, the reaction paths of (NH<SUB>4</SUB>)<SUB>2</SUB>UO<SUB>2</SUB>(NO<SUB>3</SUB>)<SUB>4</SUB>·2H<SUB>2</SUB>O and NH<SUB>4</SUB>UO<SUB>2</SUB>(NO<SUB>3</SUB>)<SUB>3</SUB> were as follows: under a nitrogen atmosphere: (NH<SUB>4</SUB>)<SUB>2</SUB>UO<SUB>2</SUB>(NO<SUB>3</SUB>)<SUB>4</SUB>·2H<SUB>2</SUB>O → (NH<SUB>4</SUB>)<SUB>2</SUB>UO<SUB>2</SUB>(NO<SUB>3</SUB>)<SUB>4</SUB>·H<SUB>2</SUB>O → (NH<SUB>4</SUB>)<SUB>2</SUB>UO<SUB>2</SUB>(NO<SUB>3</SUB>)<SUB>4</SUB> → NH<SUB>4</SUB>UO<SUB>2</SUB>(NO<SUB>3</SUB>)<SUB>3</SUB> → A-UO<SUB>3</SUB> → γ-UO<SUB>3</SUB> → U<SUB>3</SUB>O<SUB>8</SUB>, NH<SUB>4</SUB>UO<SUB>2</SUB>(NO<SUB>3</SUB>)<SUB>3</SUB> → A-UO<SUB>3</SUB> → α-UO<SUB>3</SUB> → U<SUB>3</SUB>O<SUB>8</SUB>; under an air atmosphere: (NH<SUB>4</SUB>)<SUB>2</SUB>UO<SUB>2</SUB>(NO<SUB>3</SUB>)<SUB>4</SUB>·2H<SUB>2</SUB>O → (NH<SUB>4</SUB>)<SUB>2</SUB>UO<SUB>2</SUB>(NO<SUB>3</SUB>)<SUB>4</SUB>·H<SUB>2</SUB>O → (NH<SUB>4</SUB>)<SUB>2</SUB>UO<SUB>2</SUB>(NO<SUB>3</SUB>)<SUB>4</SUB> → NH<SUB>4</SUB>UO<SUB>2</SUB>(NO<SUB>3</SUB>)<SUB>3</SUB> → A-UO<SUB>3</SUB> → γ-UO<SUB>3</SUB> → U<SUB>3</SUB>O<SUB>8</SUB>, NH<SUB>4</SUB>UO<SUB>2</SUB>(NO<SUB>3</SUB>)<SUB>3</SUB> → A-UO<SUB>3</SUB> → α-UO<SUB>3</SUB> → U<SUB>3</SUB>O<SUB>8</SUB>; and under a hydrogen atmosphere: (NH<SUB>4</SUB>)<SUB>2</SUB>UO<SUB>2</SUB>(NO<SUB>3</SUB>)<SUB>4</SUB>·2H<SUB>2</SUB>O → (NH<SUB>4</SUB>)<SUB>2</SUB>UO<SUB>2</SUB>(NO<SUB>3</SUB>)<SUB>4</SUB>·H<SUB>2</SUB>O → (NH<SUB>4</SUB>)<SUB>2</SUB>UO<SUB>2</SUB>(NO<SUB>3</SUB>)<SUB>4</SUB> → NH<SUB>4</SUB>UO<SUB>2</SUB>(NO<SUB>3</SUB>)<SUB>3</SUB> → A-UO<SUB>3</SUB> → γ-UO<SUB>3</SUB> → α-U<SUB>3</SUB>O<SUB>8</SUB> → UO<SUB>2</SUB>, NH<SUB>4</SUB> UO<SUB>2</SUB>(NO<SUB>3</SUB>)<SUB>3</SUB> → A-UO<SUB>3</SUB> → β-UO<SUB>3</SUB> → α-U<SUB>3</SUB>O<SUB>8</SUB> → UO<SUB>2</SUB>.</P>

Couette-Taylor crystallizer: Effective control of crystal size distribution and recovery of l-lysine in cooling crystallization

Nguyen, A.T.,Yu, T.,Kim, W.S. North-Holland Pub. Co 2017 Journal of crystal growth Vol.469 No.-

A Couette-Taylor crystallizer is developed to enhance the l-Lysine crystal size distribution and recovery in the case of continuous cooling crystallization. When using the proposed Couette-Taylor (CT) crystallizer, the size distribution and crystal product recovery were much narrower and higher, respectively, than those from a conventional stirred tank (ST) crystallizer. Here, the coefficient of the size distribution for the crystal product from the CT crystallizer was only 0.45, while it was 0.78 in the case of the conventional ST crystallizer at an agitation speed of 700rpm, mean residence time of 20min, and feed concentration of 900(g/L). Furthermore, when using the CT crystallizer, the crystal product recovery was remarkably enhanced up to 100%wt with a mean residence time of only 20min, while it required a mean residence time of at least 60min when using the conventional ST crystallizer. This result indicates that the CT crystallizer was much more effective than the conventional ST crystallizer in terms of controlling a narrower size distribution and achieving a 100%wt l-lysine crystal product recovery from continuous cooling crystallization. The advantage of the CT crystallizer over the conventional ST crystallizer was explained based on the higher energy dissipation of the Taylor vortex flow and larger surface area for heat transfer of the CT crystallizer. Here, the energy dissipation of the Taylor vortex flow in the CT crystallizer was 13.6 times higher than that of the random fluid motion in the conventional ST crystallizer, while the surface area per unit volume for heat transfer of the CT crystallizer was 8.0 times higher than that of the conventional ST crystallizer. As a result, the mixing condition and heat transfer of the CT crystallizer were much more effective than those of the conventional ST crystallizer for the cooling crystallization of l-lysine, thereby enhancing the l-lysine crystal size distribution and product recovery.

Reconstitution of ST2 (IL-1R4) specific for IL-33 activity; no suppression by IL-1Ra though a common chain IL-1R3 (IL-1RAcP) shared with IL-1

Jo, S.,Kim, E.,Kwak, A.,Lee, J.,Hong, J.,Lee, J.,Youn, S.,Bae, S.,Kim, B.,Ryoo, S.,Kang, T.B.,Her, E.,Choi, D.K.,Kim, Y.S.,Lee, Y.,Jhun, H.,Kim, S. Saunders Scientific Publications, W.B. Saunders ; 2016 Cytokine Vol.83 No.-

Interleukin-33 (IL-33) receptors are composed of ST2 (also known as IL-1R4), a ligand binding chain, and IL-1 receptor accessory protein (IL-1RAcP, also known as IL-1R3), a signal transducing chain. IL-1R3 is a common receptor for IL-1α, and IL-1β, IL-33, and three IL-36 isoforms. A549 human lung epithelial cells are highly sensitive to IL-1α and IL-1β but not respond to IL-33. The lack of responsiveness to IL-33 is due to ST2 expression. ST2 was stably transfected into A549 cells to reconstitute its activity. RT-PCR and FACS analysis confirmed ST2 expression on the cell surface of A549/ST2 cells. Upon IL-33 stimulation, A549/ST2 cells induced IL-8 and IL-6 production in a dose dependent manner while A549/mock cells remained unresponsive. There was no difference in IL-1α and IL-1β activity in A549/ST2 cells compared to A549/mock cells despite the fact that IL-33 shares IL-1R3 with IL-1α/β. IL-33 activated inflammatory signaling molecules in a time- and dose-dependent manner. Anti-ST2 antibody and soluble recombinant ST2-Fc abolished IL-33-induced IL-6 and IL-8 production in A549/ST2 cells but the IL-1 receptor antagonist failed to block IL-33-induced cytokines. This result demonstrates for the first time the reconstitution of ST2 in A549 human lung epithelial cell line and verified its function in IL-33-mediated cytokine production and signal transduction.

Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase ½ dose escalation and expansion trial

El-Khoueiry, A.B.,Sangro, B.,Yau, T.,Crocenzi, T.S.,Kudo, M.,Hsu, C.,Kim, T.Y.,Choo, S.P.,Trojan, J.,Welling, T.H.,Meyer, T.,Kang, Y.K.,Yeo, W.,Chopra, A.,Anderson, J.,dela Cruz, C.,Lang, L.,Neely, J. J. Onwhyn ; Elsevier Science Ltd 2017 The Lancet Vol.389 No.10088

Background: For patients with advanced hepatocellular carcinoma, sorafenib is the only approved drug worldwide, and outcomes remain poor. We aimed to assess the safety and efficacy of nivolumab, a programmed cell death protein-1 (PD-1) immune checkpoint inhibitor, in patients with advanced hepatocellular carcinoma with or without chronic viral hepatitis. Methods: We did a phase ½, open-label, non-comparative, dose escalation and expansion trial (CheckMate 040) of nivolumab in adults (≥18 years) with histologically confirmed advanced hepatocellular carcinoma with or without hepatitis C or B (HCV or HBV) infection. Previous sorafenib treatment was allowed. A dose-escalation phase was conducted at seven hospitals or academic centres in four countries or territories (USA, Spain, Hong Kong, and Singapore) and a dose-expansion phase was conducted at an additional 39 sites in 11 countries (Canada, UK, Germany, Italy, Japan, South Korea, Taiwan). At screening, eligible patients had Child-Pugh scores of 7 or less (Child-Pugh A or B7) for the dose-escalation phase and 6 or less (Child-Pugh A) for the dose-expansion phase, and an Eastern Cooperative Oncology Group performance status of 1 or less. Patients with HBV infection had to be receiving effective antiviral therapy (viral load <100 IU/mL); antiviral therapy was not required for patients with HCV infection. We excluded patients previously treated with an agent targeting T-cell costimulation or checkpoint pathways. Patients received intravenous nivolumab 0.1-10 mg/kg every 2 weeks in the dose-escalation phase (3+3 design). Nivolumab 3 mg/kg was given every 2 weeks in the dose-expansion phase to patients in four cohorts: sorafenib untreated or intolerant without viral hepatitis, sorafenib progressor without viral hepatitis, HCV infected, and HBV infected. Primary endpoints were safety and tolerability for the escalation phase and objective response rate (Response Evaluation Criteria In Solid Tumors version 1.1) for the expansion phase. This study is registered with ClinicalTrials.gov, number NCT01658878. Findings: Between Nov 26, 2012, and Aug 8, 2016, 262 eligible patients were treated (48 patients in the dose-escalation phase and 214 in the dose-expansion phase). 202 (77%) of 262 patients have completed treatment and follow-up is ongoing. During dose escalation, nivolumab showed a manageable safety profile, including acceptable tolerability. In this phase, 46 (96%) of 48 patients discontinued treatment, 42 (88%) due to disease progression. Incidence of treatment-related adverse events did not seem to be associated with dose and no maximum tolerated dose was reached. 12 (25%) of 48 patients had grade ¾ treatment-related adverse events. Three (6%) patients had treatment-related serious adverse events (pemphigoid, adrenal insufficiency, liver disorder). 30 (63%) of 48 patients in the dose-escalation phase died (not determined to be related to nivolumab therapy). Nivolumab 3 mg/kg was chosen for dose expansion. The objective response rate was 20% (95% CI 15-26) in patients treated with nivolumab 3 mg/kg in the dose-expansion phase and 15% (95% CI 6-28) in the dose-escalation phase. Interpretation: Nivolumab had a manageable safety profile and no new signals were observed in patients with advanced hepatocellular carcinoma. Durable objective responses show the potential of nivolumab for treatment of advanced hepatocellular carcinoma. Funding: Bristol-Myers Squibb.

Effects of Resveratrol and Essential Oils on Growth Performance, Immunity, Digestibility and Fecal Microbial Shedding in Challenged Piglets

Ahmed, S.T.,Hossain, M.E.,Kim, G.M.,Hwang, J.A.,Ji, H.,Yang, C.J. Asian Australasian Association of Animal Productio 2013 Animal Bioscience Vol.26 No.5

A study was conducted to evaluate the effects of resveratrol and essential oils from medicinal plants on the growth performance, immunity, digestibility, and fecal microbial shedding of weaned piglets. A total of 48 weaned piglets (8 kg initial weight, 28-d-old) were randomly allotted to four dietary treatments with 3 replications of 4 piglets each. The dietary treatments were NC (negative control; basal diet), PC (positive control; basal diet+0.002% apramycin), T1 (basal diet+0.2% resveratrol), and T2 (basal diet+0.0125% essential oil blend). All piglets were orally challenged with 5 ml culture fluid containing $2.3{\times}10^8$ cfu/ml of Escherichia coli KCTC 2571 and $5.9{\times}10^8$ cfu/ml Salmonella enterica serover Typhimurium. The PC group (p<0.05) showed the highest average daily gain (ADG) and average daily feed intake (ADFI) throughout the experimental period, although feed conversion ratio (FCR) was improved in the T1 group (p>0.05). Serum IgG level was increased in the T1 group, whereas TNF-${\alpha}$ levels was reduced in the supplemented groups compared to control (p<0.05). The PC diet improved the dry matter (DM) digestibility, whereas PC and T2 diets improved nitrogen (N) digestibility compared to NC and T1 diets (p<0.05). Fecal Salmonella and E. coli counts were reduced in all treatment groups compared to control (p<0.05). Fecal Lactobacillus spp. count was increased in the T2 group compared to others (p<0.05). Dietary treatments had no significant effect on fecal Bacillus spp. count throughout the entire experimental period. Based on these results, resveratrol showed strong potential as antibiotic alternatives for reversing the adverse effects of weaning stress on growth performance, immunity and microbial environment in E. coli and Salmonella-challenged piglets.

Calcium nitrate (Ca(NO₃)₂)-based inorganic salt electrode for supercapacitor with long-cycle life performance

Cho, S.,Han, J.,Kim, J.,Jo, Y.,Woo, H.,Lee, S.,Aqueel Ahmed, A.T.,Chavan, H.C.,Pawar, S.M.,Gunjakar, J.L.,Kwak, J.,Park, Y.,Inamdar, A.I.,Kim, H.,Kim, H.,Im, H. ELSEVIER 2017 CURRENT APPLIED PHYSICS Vol.17 No.9

<P>A novel water-soluble inorganic Ca(NO3)(2) salt electrode is investigated for its pseudocapacitance in an aqueous KOH electrolyte. Commercially available Ca(NO3)(2) salt is directly used as the key electrode material. The supercapacitor electrode contains Ca(NO3)(2) salt, carbon black, and polyvinylidene fluoride (PVDF) in a ratio of 80:10:10. The Ca(NO3)(2)-based electrode demonstrates an exceptionally long life cycling stability, and a reasonably sound specific capacitance of 234 F/g is obtained at a current density of 3 A/g. Via chemical and electrochemical reactions, the in-situ activation of the Ca(NO3)(2) forms an intermediate CaO which contributes to the pseudocapacitance of the electrode. The electrode undergoes a reversible redox reaction between Cu2+ <-> Cu+ during the charge-discharge process. Superior rate capability and excellent specific capacitance retention of similar to 120% over 2000 cycles are achieved compared with other inorganic salt electrodes. (C) 2017 Elsevier B.V. All rights reserved.</P>

Detection of the T - DNA in Chromosome a of Haplopappus gracilis by in Situ Hybridization

Kim, Sang Gu,T J A Quayle,C I Kado 한국유전학회 1988 Genes & Genomics Vol.10 No.4

The T-DNA of the pTi plasmid of Agrobacterium tumefaciens has been analyzed by in situ hybridization and Southern analysis in cloned transformed plant cell lines of Haplopappus gracilis, a plant with two distinctive chromosomes. Southern analyses performed on these tumor cell lines indicated that transformation in plants of H. gracilis by A. tumefaciens strain C58 can result in T-DNA integration at different positions within the plant genome, and of varying size and copy number. A cell line with one full length copy of T-DNA was selected for in situ hybridization analysis. Protoplasts isolated in metaphase provided relatively planar target chromosomes free of interfering cell walls. In situ hybridization analysis has mapped this T-DNA insertion to a region near the centromere in the long arm of chromosome A of H. gracilis. Similarly (using the ribosomal RNA genes of wheat as probe) the position of ribosomal RNA genes of H. gracilis have been mapped by in situ hybridization to a position near the subterminal centromere of chromosome B.

Functional roles of mannose-binding protein in the adhesion, cytotoxicity and phagocytosis of Acanthamoeba castellanii

Kim, J.H.,Matin, A.,Shin, H.J.,Park, H.,Yoo, K.T.,Yuan, X.Z.,Kim, K.S.,Jung, S.Y. Academic Press 2012 Experimental parasitology Vol.132 No.2

Acanthamoeba castellanii is a single-celled protozoan that is widely distributed in the environment and is a well-known of causing human keratitis, a vision-threatening infection. In this study, an ethyl methane sulfonate (EMS) and a selection of saccharide were applied to A. castellanii by chemical mutagenesis. To understand the functional roles of a mannose-binding protein (MBP). A. castellanii were treated with methyl-alpha-d-mannopyranoside abbreviated Man, with and without the EMS pre-treatment, and their adhesion and cytotoxicity were analyzed, using a human brain microvascular endothelial cell (HBMEC) as the target cell. Both EMS and Man mutants exhibited significantly decreased levels of MBP expression and cytotoxicity to HBMEC, but showed similar levels of binding to HBMEC, as compared with the wild type. Of interest was that the exogenous mannose inhibited amoebae (i.e., Man mutant) binding to the HBMEC by <20%. Only the mutant Man exhibited a significant decrease in bacterial uptake, as compared to the wild type, 0.020 vs 0.032 (p<0.05) and proteolytic activity. The results showed that MBP should be clearly provided as the pathogenic target candidate, to further target-based therapy, but EMS mutation should not be associated with initial adhesion and phagocytosis of A. castellanii.

Detection of SFTS Virus in Ixodes nipponensis and Amblyomma testudinarium (Ixodida: Ixodidae) Collected From Reptiles in the Republic of Korea

Suh, J. H.,Kim, H. C.,Yun, S. M.,Lim, J. W.,Kim, J. H.,Chong, S. T.,Kim, D. H.,Kim, H. T.,Kim, H.,Klein, T. A. ESA ENTOMOLOGICAL SOCIETY OF AMERICA 2016 Journal of medical entomology Vol.53 No.3

<P>A survey of reptile-associated ticks and their infection status with severe fever with thrombocytopenia syndrome (SFTS) virus was conducted to determine the relative abundance and distribution among lizards, skinks, and snakes in the Republic of Korea (ROK). In total, 132 reptiles, including 49 lizards (two species), 15 skinks (one species), and 68 snakes (eight species) were collected. In total, 84 ixodid ticks belonging to two genera (Ixodes and Amblyomma) were collected from 28/132 (21.2%) lizards, skinks, and snakes. Ixodes nipponensis Kitaoka & Saito was only collected from lizards and skinks, while Amblyomma testudinarium Koch was only collected from snakes. Takydromus wolteri had the highest tick index (0.7; total number ticks/total number collected hosts) among lizards and skinks, while Rhabdophis tigrinus had the highest tick index (2.2) among the snakes. Ixodes nipponensis larvae and nymphs accounted for 11.1% and 88.9%, respectively, of all ticks collected from lizards and skinks, while only A. testudinarium nymphs were collected from snakes. Nymphs of both species of ticks were collected from lizards and skinks from April to October, while I. nipponensis larvae were collected only from September to October. Ixodes nipponensis larvae and nymphs were preferentially attached to the lateral trunk (83.3%) and the foreleg axillae (16.7%) of lizards and skinks. SFTS virus was detected in both I. nipponensis and A. testudinarium collected from lizards and snakes. Phylogenetic analysis of SFTS viruses of ticks collected from two lizards and one snake demonstrated close relationships with SFTS virus strains observed from humans and ticks in the ROK, China, and Japan. These results implicate lizards and snakes as potential hosts of SFTS virus.</P>