Identification of N-Terminally Truncated Derivatives of Insulin Analogs Formed in Pharmaceutical Formulations.

PubMed

Zielińska, Joanna; Stadnik, Jacek; Bierczyńska-Krzysik, Anna; Stadnik, Dorota

2018-05-16

Isolation and identification of unknown impurities of recombinant insulin lispro (produced at IBA) formed during accelerated stability testing of pharmaceutical solutions. For comparative purposes also commercially available formulations of recombinant human insulin (Humulin S®; Lilly), recombinant insulin lispro (Humalog®; Lilly), recombinant insulin aspart (NovoRapid® Penfill®; Novo Nordisk), recombinant insulin detemir (Levemir®; Novo Nordisk) and recombinant insulin glargine (Lantus®; Sanofi-Aventis) were analyzed. The impurities of insulin analogs were isolated by RP-HPLC and identified with peptide mass fingerprinting using MALDI-TOF/TOF mass spectrometry. The identified derivatives were N-terminally truncated insulin analog impurities of decreased molecular mass of 119, 147 and 377 Da related to the original protein. The modifications resulting in a mass decrease were detected at the N-terminus of B chains of insulin lispro, insulin aspart, human insulin, insulin glargine, insulin detemir in all tested formulations. To our knowledge it is the first time that these impurities are reported. The following derivatives formed by truncation of the B chain in insulin analogs were identified in pharmaceutical formulations: desPhe B1 -N-formyl-Val B2 derivative, desPhe B1 derivative, pyroGlu B4 derivative.

Potent and selective oxytocin receptor agonists without disulfide bridges.

PubMed

Adachi, Yusuke; Sakimura, Katsuya; Shimizu, Yuji; Nakayama, Masaharu; Terao, Yasuko; Yano, Takahiko; Asami, Taiji

2017-06-01

Oxytocin (OT) is a neuropeptide involved in a wide variety of physiological actions, both peripherally and centrally. Many human studies have revealed the potential of OT to treat autism spectrum disorders and schizophrenia. OT interacts with the OT receptor (OTR) as well as vasopressin 1a and 1b receptors (V 1a R, V 1b R) as an agonist, and agonistic activity for V 1a R and V 1b R may have a negative impact on the therapeutic effects of OTR agonism in the CNS. An OTR-selective agonistic peptide, FE 202767, in which the structural differences from OT are a sulfide bond instead of a disulfide bond, and N-alkylglycine replacement for Pro at position 7, was reported. However, the effects of amino acid substitutions in OT have not been comprehensively investigated to compare OTR, V 1a R, and V 1b R activities. This led us to obtain a new OTR-selective analog by comprehensive amino acid substitutions of OT and replacement of the disulfide bond. A systematic amino acid scanning (Ala, Leu, Phe, Ser, Glu, or Arg) of desamino OT (dOT) at positions 2, 3, 4, 5, 7, and 8 revealed the tolerability for the substitution at positions 7 and 8. Further detailed study showed that trans-4-hydroxyproline (trans-Hyp) at position 7 and γ-methylleucine [Leu(Me)] at position 8 were markedly effective for improving receptor selectivity without decreasing the potency at the OTR. Subsequently, a combination of these amino acid substitutions with the replacement of the disulfide bond of dOT analogs with a sulfide bond (carba analog) or an amide bond (lactam analog) yielded several promising analogs, including carba-1-[trans-Hyp 7 ,Leu(Me) 8 ]dOT (14) with a higher potency (7.2pM) at OTR than that of OT and marked selectivity (>10,000-fold) over V 1a R and V 1b R. Hence, we investigated comprehensive modification of OT and obtained new OT analogs that exhibited high potency at OTR with marked selectivity. These OTR-selective agonists could be useful to investigate OTR-mediated effects on psychiatric disorders. Copyright © 2017 Elsevier Ltd. All rights reserved.

Function-Oriented Synthesis of Marine Phidianidine Derivatives as Potential PTP1B Inhibitors with Specific Selectivity.

PubMed

Liu, Jin; Chen, Yu; Li, Jing-Ya; Luo, Cheng; Li, Jia; Chen, Kai-Xian; Li, Xu-Wen; Guo, Yue-Wei

2018-03-20

Phidianidines A and B are two novel marine indole alkaloids bearing an uncommon 1,2,4-oxadiazole ring and exhibiting various biological activities. Our previous research showed that the synthesized phidianidine analogs had the potential to inhibit the activity of protein tyrosine phosphatase 1B (PTP1B), a validated target for Type II diabetes, which indicates that these analogs are worth further structural modification. Therefore, in this paper, a series of phidianidine derivatives were designed and rapidly synthesized with a function-oriented synthesis (FOS) strategy. Their inhibitory effects on PTP1B and T-cell protein tyrosine phosphatase (TCPTP) were evaluated, and several compounds displayed significant inhibitory potency and specific selectivity over PTP1B. The structure-activity relationship (SAR) and molecular docking analyses are also described.

Function-Oriented Synthesis of Marine Phidianidine Derivatives as Potential PTP1B Inhibitors with Specific Selectivity

PubMed Central

Liu, Jin; Chen, Yu; Li, Jing-Ya; Luo, Cheng; Li, Jia; Chen, Kai-Xian; Li, Xu-Wen

2018-01-01

Phidianidines A and B are two novel marine indole alkaloids bearing an uncommon 1,2,4-oxadiazole ring and exhibiting various biological activities. Our previous research showed that the synthesized phidianidine analogs had the potential to inhibit the activity of protein tyrosine phosphatase 1B (PTP1B), a validated target for Type II diabetes, which indicates that these analogs are worth further structural modification. Therefore, in this paper, a series of phidianidine derivatives were designed and rapidly synthesized with a function-oriented synthesis (FOS) strategy. Their inhibitory effects on PTP1B and T-cell protein tyrosine phosphatase (TCPTP) were evaluated, and several compounds displayed significant inhibitory potency and specific selectivity over PTP1B. The structure–activity relationship (SAR) and molecular docking analyses are also described. PMID:29558377

A low power, low noise Programmable Analog Front End (PAFE) for biopotential measurements.

PubMed

Adimulam, Mahesh Kumar; Divya, A; Tejaswi, K; Srinivas, M B

2017-07-01

A low power Programmable Analog Front End (PAFE) for biopotential measurements is presented in this paper. The PAFE circuit processes electrocardiogram (ECG), electromyography (EMG) and electroencephalogram (EEG) signals with higher accuracy. It consists mainly of improved transconductance programmable gain instrumentational amplifier (PGIA), programmable high pass filter (PHPF), and second order low pass filter (SLPF). A 15-bit programmable 5-stage successive approximation analog-to-digital converter (SAR-ADC) is implemented for improving the performance, whose power consumption is reduced due to multiple stages and by OTA/Comparator sharing technique between the stages. The power consumption is further reduced by operating the analog portion of PAFE on 0.5V supply voltage and digital portion on 0.3V supply voltage generated internally through a voltage regulator. The proposed low power PAFE has been fabricated in 180nm standard CMOS process. The performance parameters of PAFE in 15-bit mode are found to be, gain of 31-70 dB, input referred noise of 1.15 μVrms, CMRR of 110 dB, PSRR of 104 dB, and signal-to-noise distortion ratio (SNDR) of 83.5dB. The power consumption of the design is 1.1 μW @ 0.5 V supply voltage and it occupies a core silicon area of 1.2 mm 2 .

Inhibition of the NF-κB signaling pathway by the curcumin analog, 3,5-Bis(2-pyridinylmethylidene)-4-piperidone (EF31): anti-inflammatory and anti-cancer properties.

PubMed

Olivera, Anlys; Moore, Terry W; Hu, Fang; Brown, Andrew P; Sun, Aiming; Liotta, Dennis C; Snyder, James P; Yoon, Younghyoun; Shim, Hyunsuk; Marcus, Adam I; Miller, Andrew H; Pace, Thaddeus W W

2012-02-01

Nuclear factor kappa B (NF-κB) is a key signaling molecule in the elaboration of the inflammatory response. Data indicate that curcumin, a natural ingredient of the curry spice turmeric, acts as a NF-κB inhibitor and exhibits both anti-inflammatory and anti-cancer properties. Curcumin analogs with enhanced activity on NF-κB and other inflammatory signaling pathways have been developed including the synthetic monoketone compound 3,5-Bis(2-fluorobenzylidene)-4-piperidone (EF24). 3,5-Bis(2-pyridinylmethylidene)-4-piperidone (EF31) is a structurally-related curcumin analog whose potency for NF-κB inhibition has yet to be determined. To examine the activity of EF31 compared to EF24 and curcumin, mouse RAW264.7 macrophages were treated with EF31, EF24, curcumin (1-100 μM) or vehicle (DMSO 1%) for 1h. NF-κB pathway activity was assessed following treatment with lipopolysaccharide (LPS) (1 μg/mL). EF31 (IC(50)~5 μM) exhibited significantly more potent inhibition of LPS-induced NF-κB DNA binding compared to both EF24 (IC(50)~35 μM) and curcumin (IC(50) >50 μM). In addition, EF31 exhibited greater inhibition of NF-κB nuclear translocation as well as the induction of downstream inflammatory mediators including pro-inflammatory cytokine mRNA and protein (tumor necrosis factor-α, interleukin-1β, and interleukin-6). Regarding the mechanism of these effects on NF-κB, EF31 (IC(50)~1.92 μM) exhibited significantly greater inhibition of IκB kinase β compared to EF24 (IC(50)~131 μM). Finally, EF31 demonstrated potent toxicity in NF-κB-dependent cancer cell lines while having minimal and reversible toxicity in RAW264.7 macrophages. These data indicate that EF31 is a more potent inhibitor of NF-κB activity than either EF24 or curcumin while exhibiting both anti-inflammatory and anticancer activities. Thus, EF31 represents a promising curcumin analog for further therapeutic development. Copyright © 2011 Elsevier B.V. All rights reserved.

The impact of ethnicity, educational and economic status on the prescription of insulin therapeutic regimens and on glycemic control in patients with type 1 diabetes. A nationwide study in Brazil.

PubMed

Gomes, Marilia Brito; Rodacki, Melanie; Pavin, Elizabeth João; Cobas, Roberta Arnoldi; Felicio, João S; Zajdenverg, Lenita; Negrato, Carlos Antonio

2017-12-01

Establish the relationship between demographic, educational and economic status on insulin therapeutic regimens (ITRs) and on glycemic control in patients with type 1 diabetes. This was a cross-sectional, multicenter study with 1760 patients conducted between August 2011 and August 2014 in 10 Brazilian cities. Patients were stratified according to ITRs as follows: only NPH insulin (group 1, n=80(4.5%)); only long-acting insulin analogs (group 2, n=6(0.3%)); continuous subcutaneous insulin infusion (CSII) (group 3, n=62(3.5%)); NPH plus regular insulin (group 4, n=710(40.3%)); NPH plus ultra-rapid insulin analogs (group 5, n=259(14.8%)); long-acting insulin analogs plus regular insulin (group 6, n=25(4.4%)) and long-acting plus ultra-rapid insulin analogs (group 7, n=618 (35.1%)). As group A (provided free of charge by the government) we considered groups 1 and 4, and as group B (obtained through lawsuit or out-of-pocket) groups 2, 3 and 7. Multivariate logistic analysis showed that independent variables related to group B were older age, more years of school attendance, higher economic status and ethnicity (Caucasians). The independent variables related to better glycemic control were older age, higher adherence to diet, higher frequency of self-monitoring of blood glucose, more years of school attendance and belonging to group B. In Brazilian National Health Care System, prescriptions of insulin analogs or CSII are more frequent in Caucasian patients with type 1 diabetes, with higher economic status and more years ofschool attendance. Among these variables years of school attendance was the only one associated with better glycemic control. Copyright © 2017 Elsevier B.V. All rights reserved.

A 2,4-dichlorophenoxyacetic acid analog screened using a maize coleoptile system potentially inhibits indole-3-acetic acid influx in Arabidopsis thaliana

PubMed Central

Suzuki, Hiromi; Matano, Naoyuki; Nishimura, Takeshi; Koshiba, Tomokazu

2014-01-01

Studies using inhibitors of indole-3-acetic acid (IAA) transport, not only for efflux but influx carriers, provide many aspects of auxin physiology in plants. 1-Naphtoxyacetic acid (1-NOA), an analog of the synthetic auxin 1-N-naphtalene acetic acid (NAA), inhibits the IAA influx carrier AUX1. However, 1-NOA also shows auxin activity because of its structural similarity to NAA. In this study, we have identified another candidate inhibitor of the IAA influx carrier. The compound, “7-B3; ethyl 2-[(2-chloro-4-nitrophenyl)thio]acetate,” is a 2,4-dichlorophenoxyacetic acid (2,4-D) analog. At high concentrations (> 300 µM), 7-B3 slightly reduced IAA transport and tropic curvature of maize coleoptiles, whereas lower concentrations had almost no effect. We have analyzed the effects of 7-B3 on Arabidopsis thaliana seedlings. 7-B3 rescued the 2,4-D-inhibited root elongation, but not the NAA-inhibited root elongation. The effect of 7-B3 was weaker than that of 1-NOA. Both 1-NOA and 7-B3 inhibited DR5::GUS expression induced by IAA and 2,4-D, but not that induced by NAA. At high concentrations, 1-NOA exhibited auxin activity, but 7-B3 did not. Furthermore, 7-B3 inhibited apical hook formation in etiolated seedlings more effectively than 1-NOA did. These results indicate that 7-B3 is a potential inhibitor of IAA influx that has almost no effect on IAA efflux or auxin signaling. PMID:24800738

Thiamine Deficiency Induces Anorexia by Inhibiting Hypothalamic AMPK

PubMed Central

Liu, Mei; Alimov, Alexander; Wang, Haiping; Frank, Jacqueline A.; Katz, Wendy; Xu, Mei; Ke, Zun-Ji; Luo, Jia

2014-01-01

Obesity and eating disorders are prevailing health concerns worldwide. It is important to understand the regulation of food intake and energy metabolism. Thiamine (vitamin B1) is an essential nutrient. Thiamine deficiency (TD) can cause a number of disorders in humans, such as Beriberi and Wernicke-Korsakoff syndrome. We demonstrated here that TD caused anorexia in C57BL/6 mice. After feeding a TD diet for 16 days, the mice displayed a significant decrease in food intake and an increase in resting energy expenditure (REE), which resulted in a severe weight loss. At the 22nd day, the food intake was reduced by 69% and 74% for male and female mice, respectively in TD group. The REE increased by 9 folds in TD group. The loss of body weight (17–24%) was similar between male and female animals and mainly resulted from the reduction of fat mass (49% decrease). Re-supplementation of thiamine (benfotiamine) restored animal's appetite, leading to a total recovery of body weight. The hypothalamic AMPK is a critical regulator of food intake. TD inhibited the phosphorylation of AMPK in the arcuate nucleus (ARN) and paraventricular nucleus (PVN) of the hypothalamus without affecting its expression. TD-induced inhibition of AMPK phosphorylation was reversed once thiamine was re-supplemented. In contrast, TD increased AMPK phosphorylation in the skeletal muscle and upregulated the uncoupling protein (UCP)-1 in brown adipose tissues which was consistent with increased basal energy expenditure. Re-administration of thiamine stabilized AMPK phosphorylation in the skeletal muscle as well as energy expenditure. Taken together, TD may induce anorexia by inhibiting hypothalamic AMPK activity. With a simultaneous increase in energy expenditure, TD caused an overall body weight loss. The results suggest that the status of thiamine levels in the body may affect food intake and body weight. PMID:24607345

Estrogenic Effects of Several BPA Analogs in the Developing Zebrafish Brain

PubMed Central

Cano-Nicolau, Joel; Vaillant, Colette; Pellegrini, Elisabeth; Charlier, Thierry D.; Kah, Olivier; Coumailleau, Pascal

2016-01-01

Important set of studies have demonstrated the endocrine disrupting activity of Bisphenol A (BPA). The present work aimed at defining estrogenic-like activity of several BPA structural analogs, including BPS, BPF, BPAF, and BPAP, on 4- or 7-day post-fertilization (dpf) zebrafish larva as an in vivo model. We measured the induction level of the estrogen-sensitive marker cyp19a1b gene (Aromatase B), expressed in the brain, using three different in situ/in vivo strategies: (1) Quantification of cyp19a1b transcripts using RT-qPCR in wild type 7-dpf larva brains exposed to bisphenols; (2) Detection and distribution of cyp19a1b transcripts using in situ hybridization on 7-dpf brain sections (hypothalamus); and (3) Quantification of the cyp19a1b promoter activity in live cyp19a1b-GFP transgenic zebrafish (EASZY assay) at 4-dpf larval stage. These three different experimental approaches demonstrated that BPS, BPF, or BPAF exposure, similarly to BPA, significantly activates the expression of the estrogenic marker in the brain of developing zebrafish. In vitro experiments using both reporter gene assay in a glial cell context and competitive ligand binding assays strongly suggested that up-regulation of cyp19a1b is largely mediated by the zebrafish estrogen nuclear receptor alpha (zfERα). Importantly, and in contrast to other tested bisphenol A analogs, the bisphenol AP (BPAP) did not show estrogenic activity in our model. PMID:27047331

Experiments in Sound and Structural Vibrations Using an Air-Analog Model Ducted Propulsion System

DTIC Science & Technology

2007-08-01

Department of Aerospace S~and Mechanical Engineering I 20070904056 I EXPERIMENTS IN SOUND AND STRUCTURAL VIBRATIONS USING AN AIR -ANALOG MODEL DUCTED...SOUND AND STRUCTURAL * VIBRATIONS USING AN AIR -ANALOG MODEL DUCTED PROPULSION SYSTEM FINAL TECHNICAL REPORT Prepared by: Scott C. Morris Assistant...Vibration Using Air - 5b. GRANT NUMBER Analog Model Ducted Propulsion Systems N00014-1-0522 5C. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) 5d. PROJECT NUMBER

Investigation of 20S-hydroxyvitamin D3 analogs and their 1α-OH derivatives as potent vitamin D receptor agonists with anti-inflammatory activities.

PubMed

Lin, Zongtao; Marepally, Srinivasa R; Goh, Emily S Y; Cheng, Chloe Y S; Janjetovic, Zorica; Kim, Tae-Kang; Miller, Duane D; Postlethwaite, Arnold E; Slominski, Andrzej T; Tuckey, Robert C; Peluso-Iltis, Carole; Rochel, Natacha; Li, Wei

2018-01-24

20S-hydroxyvitamin D 3 [20S(OH)D 3 ] is anti-inflammatory and not hypercalcemic, suggesting its potential as a lead compound. In this study, side chain modified 20S(OH)D 3 analogs (4, 13, 23 and 33) together with their 1α-OH derivatives were synthesized and their metabolism and biological activities tested. 4, 13 and 23 are good substrates for CYP27B1, enabling enzymatic synthesis of their 1α-OH derivatives 5, 14 and 24. However, 33 could not be hydroxylated by CYP27B1 and acts as an inhibitor. All analogs were poorer substrates for CYP24A1 than calcitriol, indicating improved catabolic stability. While the parent analogs showed minimal VDR stimulating activity, their 1α-OH derivatives were potent VDR agonists. 4, 5, 14 and 24 significantly upregulated the expression of CYP24A1 at the mRNA level, consistent with their VDR activation abilities and indicating that 1α-hydroxylation is required to produce analogs with strong activity. These analogs have anti-inflammatory activities that are influenced by side chain composition and by 1α-hydroxylation. To understand their molecular interactions with the VDR, 20S(OH)D 3 , 4 and 33 were co-crystalized with the VDR ligand binding domain, which revealed subtle differences to the calcitriol-bound receptor. This study demonstrates the potential of the 20S(OH)D 3 scaffold for the development of novel anti-inflammatory agents.

Structure-activity relationship of indoloquinoline analogs anti-MRSA.

PubMed

Zhao, Min; Kamada, Tomonori; Takeuchi, Aya; Nishioka, Hiromi; Kuroda, Teruo; Takeuchi, Yasuo

2015-12-01

Indolo[3,2-b]quinoline analogs (3a-3s), 4-(acridin-9-ylamino) phenol hydrochloride (4), benzofuro[3,2-b]quinoline (3t), indeno[1,2-b]quinolines (3u and 3v) have been synthesized. Those compounds were found to exhibit anti-bacterial activity towards Methicillin-resistant Staphylococcus aureus (anti-MRSA activity). Structure-activity relationship studies were conducted that indoloquinoline ring, benzofuroquinoline ring and 4-aminophenol group are essential structure for anti-MRSA activity. Copyright © 2015 Elsevier Ltd. All rights reserved.

Considerations on Terrestrial Iron Depositing Analogs to Earliest Mars

NASA Technical Reports Server (NTRS)

Brown, Igor I.; Allen, Carlton C.; Sarkisova, S. A.; Garrison, D. H.; McKay, D. S.

2007-01-01

Iron oxide and hydroxide minerals, including hematite, can mineralize and preservemicrofossils and physical biomarkers (Allen at al., 2004). Preserved remnants of phototrophic microorganisms are recognized as biosignatures of past life on Earth (Schopf, 2006). To date, two types of surface iron depositing environments have been studied as analogs to possible habitable environments on earliest Mars: the highly acidified Rio Tinto River (Iberian Belt, Spain) [Gomez Ortis et al., 2007], and the nearneutral iron depositing Chocolate Pots Hot Spring (Yellowstone National Park, US) [Parenteau at al., 2005]. While phototrophs in the Rio Tinto are only represented by eukaryotic algae (Amaral Zettler et all., 2002), Chocolate Pots is mainly populated with cyanobacteria (Pierson et all., 2000; Brown et all., 2007). Which of these environments is the closer analog to a potentially habitable early Mars? Paleobiological data, combined with recent "tree of life" interpretations, suggest that phototrophic eukaryotes evolved not earlier than 2.5 - 2.8 b.y. after Earth s accretion (4.6 b.y.), while cyanobacteria and /or their iron-tolerant predecessors evolved between 1 - 1.5 b.y. after accretion (Brown et al., 2007). Lindsay and Brasier (2002) postulated that microbial life on Mars surface could have lasted no more than 1-1.5 b.y. after Mars accretion (also 4.6 b.y.). Recent multispectral mapping of Mars suggests that near-neutral wet environments prevailed at approximately this time (Bibring, et al., 2006). Thus, near-neutral iron depositing hot springs such as Chocolate Pots Hot Spring seem to be the more likely habitable analogs for earliest Mars.

A first-principles study on the B{sub 5}O{sub 5}{sup +/0} and B{sub 5}O{sub 5}{sup −} clusters: The boron oxide analogs of C{sub 6}H{sub 5}{sup +/0} and CH{sub 3}Cl

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tian, Wen-Juan; You, Xue-Rui; Ou, Ting

2015-08-14

The concept of boronyl (BO) and the BO/H isolobal analogy build an interesting structural link between boron oxide clusters and hydrocarbons. Based upon global-minimum searches and first-principles electronic structural calculations, we present here the perfectly planar C{sub 2v} B{sub 5}O{sub 5}{sup +} (1, {sup 1}A{sub 1}), C{sub 2v} B{sub 5}O{sub 5} (2, {sup 2}A{sub 1}), and tetrahedral C{sub s} B{sub 5}O{sub 5}{sup −} (3, {sup 1}A′) clusters, which are the global minima of the systems. Structural and molecular orbital analyses indicate that C{sub 2v} B{sub 5}O{sub 5}{sup +} (1) [B{sub 3}O{sub 3}(BO){sub 2}{sup +}] and C{sub 2v} B{sub 5}O{sub 5}more » (2) [B{sub 3}O{sub 3}(BO){sub 2}] feature an aromatic six-membered boroxol (B{sub 3}O{sub 3}) ring as the core with two equivalent boronyl terminals, similar to the recently reported boronyl boroxine D{sub 3h} B{sub 6}O{sub 6} [B{sub 3}O{sub 3}(BO){sub 3}]; whereas C{sub s} B{sub 5}O{sub 5}{sup −} (3) [B(BO){sub 3}(OBO){sup −}] is characterized with a tetrahedral B{sup −} center, terminated with three BO groups and one OBO unit, similar to the previously predicted boronyl methane T{sub d} B{sub 5}O{sub 4}{sup −} [B(BO){sub 4}{sup −}]. Alternatively, the 1–3 clusters can be viewed as the boron oxide analogs of phenyl cation C{sub 6}H{sub 5}{sup +}, phenyl radical C{sub 6}H{sub 5}, and chloromethane CH{sub 3}Cl, respectively. Chemical bonding analyses also reveal a dual three-center four-electron (3c-4e) π hyperbond in C{sub s} B{sub 5}O{sub 5}{sup −} (3). The infrared absorption spectra of B{sub 5}O{sub 5}{sup +} (1), B{sub 5}O{sub 5} (2), and B{sub 5}O{sub 5}{sup −} (3) and anion photoelectron spectrum of B{sub 5}O{sub 5}{sup −} (3) are predicted to facilitate their forthcoming experimental characterizations. The present work completes the B{sub n}O{sub n}{sup +/0/−} series for n = 1–6 and enriches the analogous relationship between boron oxides and hydrocarbons.« less

Ebselen and analogs as inhibitors of Bacillus anthracis thioredoxin reductase and bactericidal antibacterials targeting Bacillus species, Staphylococcus aureus and Mycobacterium tuberculosis.

PubMed

Gustafsson, Tomas N; Osman, Harer; Werngren, Jim; Hoffner, Sven; Engman, Lars; Holmgren, Arne

2016-06-01

Bacillus anthracis is the causative agent of anthrax, a disease associated with a very high mortality rate in its invasive forms. We studied a number of ebselen analogs as inhibitors of B. anthracis thioredoxin reductase and their antibacterial activity on Bacillus subtilis, Staphylococcus aureus, Bacillus cereus and Mycobacterium tuberculosis. The most potent compounds in the series gave IC(50) values down to 70 nM for the pure enzyme and minimal inhibitory concentrations (MICs) down to 0.4 μM (0.12 μg/ml) for B. subtilis, 1.5 μM (0.64 μg/ml) for S. aureus, 2 μM (0.86 μg/ml) for B. cereus and 10 μg/ml for M. tuberculosis. Minimal bactericidal concentrations (MBCs) were found at 1-1.5 times the MIC, indicating a general, class-dependent, bactericidal mode of action. The combined bacteriological and enzymological data were used to construct a preliminary structure-activity-relationship for the benzoisoselenazol class of compounds. When S. aureus and B. subtilis were exposed to ebselen, we were unable to isolate resistant mutants on both solid and in liquid medium suggesting a high resistance barrier. These results suggest that ebselen and analogs thereof could be developed into a novel antibiotic class, useful for the treatment of infections caused by B. anthracis, S. aureus, M. tuberculosis and other clinically important bacteria. Furthermore, the high barrier against resistance development is encouraging for further drug development. We have characterized the thioredoxin system from B. anthracis as a novel drug target and ebselen and analogs thereof as a potential new class of antibiotics targeting several important human pathogens. Copyright © 2016 Elsevier B.V. All rights reserved.

In vitro growth inhibition of human cancer cells by novel honokiol analogs.

PubMed

Lin, Jyh Ming; Prakasha Gowda, A S; Sharma, Arun K; Amin, Shantu

2012-05-15

Honokiol possesses many pharmacological activities including anti-cancer properties. Here in, we designed and synthesized honokiol analogs that block major honokiol metabolic pathway which may enhance their effectiveness. We studied their cytotoxicity in human cancer cells and evaluated possible mechanism of cell cycle arrest. Two analogs, namely 2 and 4, showed much higher growth inhibitory activity in A549 human lung cancer cells and significant increase of cell population in the G0-G1 phase. Further elucidation of the inhibition mechanism on cell cycle showed that analogs 2 and 4 inhibit both CDK1 and cyclin B1 protien levels in A549 cells. Copyright © 2012 Elsevier Ltd. All rights reserved.

Analysis of globotriaosylceramide (Gb3) isoforms/analogs in unfractionated leukocytes, B lymphocytes and monocytes from Fabry patients using ultra-high performance liquid chromatography/tandem mass spectrometry.

PubMed

Toupin, Amanda; Lavoie, Pamela; Arthus, Marie-Françoise; Abaoui, Mona; Boutin, Michel; Fortier, Carole; Ménard, Claudia; Bichet, Daniel G; Auray-Blais, Christiane

2018-07-26

Fabry disease is an X-linked lysosomal storage disorder with marked variability in the phenotype and genotype. Glycosphingolipids such as globotriaosylceramide (Gb 3 ) isoforms/analogs, globotriaosylsphingosine (lyso-Gb 3 ) and analogs, and galabiosylceramide (Ga 2 ) isoforms/analogs may accumulate in biological fluids and different organs. The aims of this study were to: 1) develop/validate a novel UHPLC-MS/MS method for relative quantitation of Gb 3 in leukocytes (unfractionated white blood cells), B lymphocytes and monocytes; 2) evaluate these biomarkers in a cohort of Fabry patients and healthy controls; and 3) assess correlations between these biomarkers, treatment and genotype. Whole blood, plasma and urine samples from 21 Fabry patients and 20 healthy controls were analyzed. Samples were purified by liquid-liquid extraction and analyzed by UHPLC-MS/MS in positive electrospray ionization. Methylated Gb 3 isoforms were detected, showing that a methylation process occurs at the cellular level. Our results show that there were no significant differences in the distribution of the different Gb 3 isoforms/analogs in blood cells between Fabry patients and healthy controls. In leukocyte, Gb 3 [(d18:1)(C14:0)], Gb 3 [(d18:1)(C16:0)], Gb 3 [(d18:1)(C16:0)]Me, Gb 3 [(d18:1)(C16:1)], Gb 3 [(d18:1)(C18:0)], Gb 3 [(d18:1)(C18:1)], Gb 3 [(d18:1)(C20:1)], Gb 3 [(d18:1)(C24:2)], Gb 3 [(d18:1)(C26:1)] and total Gb 3 allowed good discrimination between male Fabry patients and male controls, patients having higher biomarker levels than controls. Regarding B lymphocytes and monocytes, the same tendency was observed without reaching statistical significance. A positive concordance between mutation types and biomarker levels in white blood cells was established. Our results might provide a deeper mechanistic comprehension of the underlying biochemical processes of Gb 3 biomarkers in white blood cells of Fabry patients. Copyright © 2018 Elsevier B.V. All rights reserved.

Characterization of a novel curcumin analog P1 as potent inhibitor of the NF-κB signaling pathway with distinct mechanisms

PubMed Central

Peng, Yan-min; Zheng, Jian-bin; Zhou, Yu-bo; Li, Jia

2013-01-01

Aim: Curcumin has shown promising anticancer activity, which relies on its inhibition on NF-κB pathway. In this study, we characterized the pharmacological profile of a novel curcumin analog P1 and elucidate the related mechanisms. Methods: HEK293/NF-κB cells, stably transfected with an NF-κB-responsive luciferase reporter plasmid, were generated for high-throughput screen (HTS). Eight cancer cell lines, including PC3, COLO 205, HeLa cells etc. were tested. Cell viability was assessed using the sulforhodamine B (SRB) assays. Cell apoptosis was evaluated using FACS, immunocytochemistry, and Western blotting. H2-DCFDA and MitoSOX Red were used to detect cellular and mitochondrial reactive oxygen species (ROS). The mitochondrial function was evaluated using mitochondrial oxygen consumption assay. Results: P1, a tropinone curcumin, was found in HTS targeting the NF-κB pathway. Its IC50 value in inhibition of TNF-α-induced NF-κB activation was 0.8 μmol/L, whereas its IC50 values in inhibiting the growth of A549 and HeLa cells were 1.24 and 0.69 μmol/L, respectively, which was 20- to 30-fold more potent than curcumin. The inhibition of P1 on the NF-κB pathway was further addressed in HeLa cells. The compound up to 10 μmol/L did not affect the binding of NF-κB to DNA, but markedly inhibited NF-κB nuclear translocation, IκB degradation and IκB kinase phosphorylation. The compound (1 and 3 μmol/L) concentration-dependently induced ROS generation, whereas curcumin up to 20 μmol/L had no effect. P1-induced ROS generation was mainly localized in mitochondria, and reversed by NAC. Moreover, the compound significantly enhanced TNF-α-induced apoptosis. Conclusion: P1 is a novel curcumin analog with potent anticancer activities, which exerts a distinct inhibition on the NF-κB pathway. PMID:23603982

Magnetic properties of the mixed ferro-ferrimagnets composed of Prussian blue analogs with (AxB1 x)yC

NASA Astrophysics Data System (ADS)

Hu, Hongliang; Xin, Zihua; Liu, Weijie

2006-09-01

The phase diagrams of the mixed ferro-ferrimagnets composed of Prussian blue analogs with (AxB1 x)yC, consisting of spins S=1, S=5/2 and S=3/2, are investigated by the use of the effective-field theory with the correlations based on Ising model. The phase diagrams which are related to experimental work of molecule-based ferro-ferrimagnets (NiIIxMnII1 x)1.5[CrIII(CN)6] are obtained. The magnetic properties such as magnetization, the critical temperature, the compensation temperature, internal energy and specific heat are also calculated.

Design and synthesis of alkoxyindolyl-3-acetic acid analogs as peroxisome proliferator-activated receptor-γ/δ agonists.

PubMed

Gim, Hyo Jin; Li, Hua; Lee, Eun; Ryu, Jae-Ha; Jeon, Raok

2013-01-15

A series of carbazole or phenoxazine containing alkoxyindole-3-acetic acid analogs were prepared as PPARγ/δ agonists and their transactivation activities for PPAR receptor subtypes (α, γ and δ) were investigated. Structure-activity relationship studies disclosed the effect of the lipophilic tail, attaching position of the alkoxy group and N-benzyl substitution at indole. Compound 1b was the most potent for PPARδ and 3b for PPARγ. Molecular modeling suggested two different binding modes of our alkoxyindole-3-acetic acid analogs providing the insight into their PPAR activity. Copyright © 2012 Elsevier Ltd. All rights reserved.

Structure of the carboxypeptidase B complex with N-sulfamoyl-L-phenylalanine - a transition state analog of non-specific substrate.

PubMed

Akparov, Valery; Timofeev, Vladimir; Khaliullin, Ilyas; Švedas, Vytas; Kuranova, Inna

2018-03-01

Carboxypeptidase B (EC 3.4.17.2) (CPB) is commonly used in the industrial insulin production and as a template for drug design. However, its ability to discriminate substrates with hydrophobic, hydrophilic, and charged side chains is not well understood. We report structure of CPB complex with a transition state analog N-sulfamoyl-L-phenylalanine solved at 1.74Å. The study provided an insight into structural basis of CPB substrate specificity. Ligand binding is affected by structure-depended conformational changes of Asp255 in S1'-subsite, interactions with Asn144 and Arg145 in C-terminal binding subsite, and Glu270 in the catalytic center. Side chain of the non-specific substrate analog SPhe in comparison with that of specific substrate analog SArg (reported earlier) not only loses favorable electrostatic interactions and two hydrogen bonds with Asp255 and three fixed water molecules, but is forced to be in the unfavorable hydrophilic environment. Thus, Ser207, Gly253, Tyr248, and Asp255 residues play major role in the substrate recognition by S1'-subsite.

Comparison of Insect Kinin Analogs With cis-Peptide Bond Motif 4-Aminopyroglutamate Identifies Optimal Stereochemistry for Diuretic Activity

DTIC Science & Technology

2006-01-01

Amino acid side-chain-protecting groups were Pbf for Arg and Boc for Trp. The coupling of Fmoc-4-amino- pyroglutamic acids (Fmoc-aPy-OH, Fmoc-apy-OH...Inc. Biopolymers (Pept Sci) 88:1–7, 2007. Keywords: 4-aminopyroglutamic acid ; cis-peptide bond; b-turn mimetic; constrained insect kinin analog...analogs containing three stereochemical var- iants of the (2S, 4S)-4-aminopyroglutamic acid (APy) com- ponent (see Figure 1), a mimic of the cis-peptide

The influence of an intramolecular hydrogen bond in differential recognition of inhibitory acceptor analogs by human ABO(H) blood group A and B glycosyltransferases.

PubMed

Nguyen, Hoa P; Seto, Nina O L; Cai, Ye; Leinala, Eeva K; Borisova, Svetlana N; Palcic, Monica M; Evans, Stephen V

2003-12-05

Human ABO(H) blood group glycosyltransferases GTA and GTB catalyze the final monosaccharide addition in the biosynthesis of the human A and B blood group antigens. GTA and GTB utilize a common acceptor, the H antigen disaccharide alpha-l-Fucp-(1-->2)-beta-d-Galp-OR, but different donors, where GTA transfers GalNAc from UDP-GalNAc and GTB transfers Gal from UDP-Gal. GTA and GTB are two of the most homologous enzymes known to transfer different donors and differ in only 4 amino acid residues, but one in particular (Leu/Met-266) has been shown to dominate the selection between donor sugars. The structures of the A and B glycosyltransferases have been determined to high resolution in complex with two inhibitory acceptor analogs alpha-l-Fucp(1-->2)-beta-d-(3-deoxy)-Galp-OR and alpha-l-Fucp-(1-->2)-beta-d-(3-amino)-Galp-OR, in which the 3-hydroxyl moiety of the Gal ring has been replaced by hydrogen or an amino group, respectively. Remarkably, although the 3-deoxy inhibitor occupies the same conformation and position observed for the native H antigen in GTA and GTB, the 3-amino analog is recognized differently by the two enzymes. The 3-amino substitution introduces a novel intramolecular hydrogen bond between O2' on Fuc and N3' on Gal, which alters the minimum-energy conformation of the inhibitor. In the absence of UDP, the 3-amino analog can be accommodated by either GTA or GTB with the l-Fuc residue partially occupying the vacant UDP binding site. However, in the presence of UDP, the analog is forced to abandon the intramolecular hydrogen bond, and the l-Fuc residue is shifted to a less ordered conformation. Further, the residue Leu/Met-266 that was thought important only in distinguishing between donor substrates is observed to interact differently with the 3-amino acceptor analog in GTA and GTB. These observations explain why the 3-deoxy analog acts as a competitive inhibitor of the glycosyltransferase reaction, whereas the 3-amino analog displays complex modes of inhibition.

Design, Synthesis, and X-ray Crystal Structures of 2,4-Diaminofuro[2,3-d]pyrimidines as Multireceptor Tyrosine Kinase and Dihydrofolate Reductase Inhibitors

PubMed Central

Gangjee, Aleem; Li, Wei; Lin, Lu; Zeng, Yibin; Ihnat, Michael; Warnke, Linda A.; Green, Dixy W.; Cody, Vivian; Pace, Jim; Queener, Sherry F.

2009-01-01

To optimize dual receptor tyrosine kinase (RTK) and dihydrofolate reductase (DHFR) inhibition, the E- and Z-isomers of 5-[2-(2-methoxyphenyl)prop-1-en-1-yl]furo[2,3-d]pyrimidine-2,4-diamines (1a and 1b) were separated by HPLC and the X-ray crystal structures (2.0 Å and 1.4 Å respectively) with mouse DHFR and NADPH as well as 1b with human DHFR (1.5 Å) were determined. The E- and Z-isomers adopt different binding modes when bound to mouse DHFR. A series of 2,4-diaminofuro[2,3-d]pyrimidines 2–13 were designed and synthesized using the X-ray crystal structures of 1a and 1b with DHFR to increase their DHFR inhibitory activity. Wittig reactions of appropriate 2-methoxyphenyl ketones with 2,4-diamino-6-chloromethyl furo[2,3-d]pyrimidine afforded the C8–C9 unsaturated compounds 2–7 and catalytic reduction gave the saturated 8–13. Homologation of the C9-methyl analog maintains DHFR inhibitory activity. In addition, inhibition of EGFR and PDGFR-β were discovered for saturated C9-homologated analogs 9 and 10 that were absent in the saturated C9-methyl analogs. PMID:19748785

Differential half-maximal effects of human insulin and its analogs for in situ glucose transport and protein synthesis in rat soleus muscle

NASA Technical Reports Server (NTRS)

Weinstein, Randi B.; Eleid, Noura; LeCesne, Catherine; Durando, Bianca; Crawford, Julie T.; Heffner, Michelle; Layton, Christle; O'Keefe, Matthew; Robinson, Jennifer; Rudinsky, Suzy;

Quarter-Rate Superconducting Modulator for Improved High Resolution Analog-to-Digital Converter

DTIC Science & Technology

2006-08-01

third pulse to Output B2, and the fourth to Output C2. The fifth pulse goes to Output B1 and the pattern continues. The inductances LQA , LQB, LQC...inductance LQA . Junction JL1A is now biased with the loop phase being equal to – π. In the bottom left demultiplexer, junctions JR1B and JL2B are

Inhibition of mitogen activated protein kinases increases the sensitivity of A549 lung cancer cells to the cytotoxicity induced by a kava chalcone analog

PubMed Central

Warmka, Janel K.; Solberg, Eric L.; Zeliadt, Nicholette A.; Srinivasan, Balasubramanian; Charlson, Aaron T.; Xing, Chengguo; Wattenberg, Elizabeth V.

2012-01-01

We are interested in investigating the biological activity of chalcones, a major class of compounds found in the beverage kava, in order to develop potent and selective chemopreventive candidates. Consumption of kava in the South Pacific Islands is inversely correlated with cancer incidence, even among smokers. Accordingly, chalcones have anti-cancer activities in animal and cell culture models. To investigate signaling pathways that affect chalcone action we studied a potent analog, (E)-3-(3-hydroxy-4-methoxyphenyl)-1-(3,4,5-trimethoxyphenyl)prop-2-en-1-one (chalcone-24). Chalcone-24 was selected from a series of chalcone analogs that were synthesized based on the structures derived from flavokawain compounds found in kava, and screened in A549 lung cancer cells for induction of cytotoxicity and inhibition of NF-κB, a transcription factor associated with cell survival. Incubation of A549 cells with chalcone-24 resulted in a dose-dependent inhibition of cell viability, inhibition of NF-κB, activation of caspases, and activation of extracellular signal regulated kinase 1/2 (ERK1/2) and c-Jun N-terminal kinase (JNK); ERK1/2 and JNK are mitogen activated protein kinases that play central roles in regulating cell fate. Pharmacological inhibitors of ERK1/2 or JNK increased the sensitivity of A549 cells to chalcone-24-induced cytotoxicity, without affecting NF-κB or caspase activity. These results will help refine the synthesis of chalcone analogs to maximize the combination of actions required to prevent and treat cancer. PMID:22771807

A Search for Interstellar Monohydric Thiols

NASA Astrophysics Data System (ADS)

Gorai, Prasanta; Das, Ankan; Das, Amaresh; Sivaraman, Bhalamurugan; Etim, Emmanuel E.; Chakrabarti, Sandip K.

2017-02-01

It has been pointed out by various astronomers that a very interesting relationship exists between interstellar alcohols and the corresponding thiols (sulfur analog of alcohols) as far as the spectroscopic properties and chemical abundances are concerned. Monohydric alcohols such as methanol and ethanol are widely observed and 1-propanol was recently claimed to have been seen in Orion KL. Among the monohydric thiols, methanethiol (chemical analog of methanol) has been firmly detected in Orion KL and Sgr B2(N2) and ethanethiol (chemical analog of ethanol) has been observed in Sgr B2(N2), though the confirmation of this detection is yet to come. It is very likely that higher order thiols could be observed in these regions. In this paper, we study the formation of monohydric alcohols and their thiol analogs. Based on our quantum chemical calculation and chemical modeling, we find that the Tg conformer of 1-propanethiol is a good candidate of astronomical interest. We present various spectroscopically relevant parameters of this molecule to assist in its future detection in the interstellar medium.

Binding modes of dihydroquinoxalinones in a homology model of bradykinin receptor 1.

PubMed

Ha, Sookhee N; Hey, Pat J; Ransom, Rick W; Harrell, C Meacham; Murphy, Kathryn L; Chang, Ray; Chen, Tsing-Bau; Su, Dai-Shi; Markowitz, M Kristine; Bock, Mark G; Freidinger, Roger M; Hess, Fred J

2005-05-27

We report the first homology model of human bradykinin receptor B1 generated from the crystal structure of bovine rhodopsin as a template. Using an automated docking procedure, two B1 receptor antagonists of the dihydroquinoxalinone structural class were docked into the receptor model. Site-directed mutagenesis data of the amino acid residues in TM1, TM3, TM6, and TM7 were incorporated to place the compounds in the binding site of the homology model of the human B1 bradykinin receptor. The best pose in agreement with the mutation data was selected for detailed study of the receptor-antagonist interaction. To test the model, the calculated antagonist-receptor binding energy was correlated with the experimentally measured binding affinity (K(i)) for nine dihydroquinoxalinone analogs. The model was used to gain insight into the molecular mechanism for receptor function and to optimize the dihydroquinoxalinone analogs.

Synthesis, analgesic activity, and binding properties of some epibatidine analogs with a tropine skeleton.

PubMed

Rádl, S; Hafner, W; Budesínsky, M; Hejnová, L; Krejcí, I

2000-06-01

A series of epibatidine analogs and their positional isomers bearing an 8-azabicyclo[3.2.1]octane moiety is described. Also some of their simplified analogs bearing a 3-piperidine moiety are reported. Their receptor binding profiles (5-HT1A, 5-HT1B, M1, M2, neuronal nicotinic receptor) and analgesic activity (hot plate, acetic acid induced writhing) have been studied. Some of the compounds, especially those containing an 8-azabicyclo[3.2.1]oct-2-ene moiety possess high afinity for the nicotinic cholinergic receptor. The most analgesically active compounds are also highly toxic. Optimized structures (PM3-MOPAC, Alchemy 2000, Tripos Inc.) of compounds 1-9 were compared with that of epibatidine.

Resistance analysis and characterization of NITD008 as an adenosine analog inhibitor against hepatitis C virus.

PubMed

Qing, Jie; Luo, Rui; Wang, Yaxin; Nong, Junxiu; Wu, Ming; Shao, Yan; Tang, Ruoyi; Yu, Xi; Yin, Zheng; Sun, Yuna

2016-02-01

Hepatitis disease caused by hepatitis C virus (HCV) is a severe threat to global public health, affecting approximately 3% of the world's population. Sofosbuvir (PSI-7977), a uridine nucleotide analog inhibitor targeting the HCV NS5B polymerase, was approved by FDA at the end of 2013 and represents a key step towards a new era in the management of HCV infection. Previous study identified NITD008, an adenosine nucleoside analog, as the specific inhibitor against dengue virus and showed good antiviral effect on other flaviviruses or enteroviruses. In this report, we systematically analyzed the anti-HCV profile of NITD008, which was discovered to effectively suppress the replication of different strains of HCV in human hepatoma cells with a low nanomolar activity. On genotype 2a virus, or 2a, 1a, and 1b replicon cells, EC50 values were 8.7 nM, 93.3 nM, 60.0 nM and 67.2 nM, and selective index values were >2298.9, >214.4, >333.3, >298.5 respectively. We demonstrated that resistance to NITD008 was conferred by mutation in NS5B (S282T) in the HCV infectious virus genotype 2a (JFH-1). Then, we compared the resistant profiles of NITD008 and PSI-7977, and found that the folds change of EC50 of NITD008 to full replicon cells containing mutation S282T was much bigger than PSI-7977(folds 76.50 vs. 4.52). Analysis of NITD008 cross-resistance against previously reported NS5B drug-selected mutations showed that the resistance pattern of NITD008 was not completely similar to PSI-7977, and meanwhile, S282T resistant mutation to NITD008 emerge more easily in cell culture than PSI-7977. Interestingly, NITD008 displayed significant synergistic effects with the NS5B polymerase inhibitor PSI-7977, however, only additive effects with alpha interferon (IFNα-2b), ribavirin, and an NS3 protease inhibitor. These results verify that NITD008 is an effective analog inhibitor against hepatitis C virus and a good research tool as a supplement to other types of nucleoside analogs. Copyright © 2015 Elsevier B.V. All rights reserved.

Digitally Controlled Analog Signal Processing

DTIC Science & Technology

1988-04-01

each analog switch. The third is the parasiti - capacitance at the output (the capacitor side) of each analog switch. This last is of concern only when a...21) where fk (x) tf H(wk) -H(wk) for k = 1, 2,... n, and x denotes the vector containing n-+ I transfer function coefficients, a, a2 ,... am, and bl...b2, .... bt that are non-zero. We wish to solve this system of equations for x, the vector of unknown transfer function coefficients. The modified

In vitro characterization of DNA gyrase inhibition by microcin B17 analogs with altered bisheterocyclic sites

PubMed Central

Zamble, Deborah B.; Miller, Deborah A.; Heddle, Jonathan G.; Maxwell, Anthony; Walsh, Christopher T.; Hollfelder, Florian

2001-01-01

Microcin B17 (MccB17) is a 3.1-kDa Escherichia coli antibiotic that contains thiazole and oxazole heterocycles in a peptide backbone. MccB17 inhibits its cellular target, DNA gyrase, by trapping the enzyme in a complex that is covalently bound to double-strand cleaved DNA, in a manner similar to the well-known quinolone drugs. The identification of gyrase as the target of MccB17 provides an opportunity to analyze the relationship between the structure of this unusual antibiotic and its activity. In this report, steady-state parameters are used to describe the induction of the cleavable complex by MccB17 analogs containing modified bisheterocyclic sites. The relative potency of these analogs corresponds to the capacity of the compounds to prevent growth of sensitive cells. In contrast to previously reported experiments, inhibition of DNA gyrase supercoiling activity by wild-type MccB17 also was observed. These results suggest that DNA gyrase is the main intracellular target of MccB17. This study probes the structure-function relationship of a new class of gyrase inhibitors and demonstrates that these techniques could be used to analyze compounds in the search for clinically useful antibiotics that block DNA gyrase. PMID:11427730

VLBI2010 Receiver Back End Comparison

NASA Technical Reports Server (NTRS)

Petrachenko, Bill

2013-01-01

VLBI2010 requires a receiver back-end to convert analog RF signals from the receiver front end into channelized digital data streams to be recorded or transmitted electronically. The back end functions are typically performed in two steps: conversion of analog RF inputs into IF bands (see Table 2), and conversion of IF bands into channelized digital data streams (see Tables 1a, 1b and 1c). The latter IF systems are now completely digital and generically referred to as digital back ends (DBEs). In Table 2 two RF conversion systems are compared, and in Tables 1a, 1b, and 1c nine DBE systems are compared. Since DBE designs are advancing rapidly, the data in these tables are only guaranteed to be current near the update date of this document.

Inhibition of mitogen activated protein kinases increases the sensitivity of A549 lung cancer cells to the cytotoxicity induced by a kava chalcone analog.

PubMed

Warmka, Janel K; Solberg, Eric L; Zeliadt, Nicholette A; Srinivasan, Balasubramanian; Charlson, Aaron T; Xing, Chengguo; Wattenberg, Elizabeth V

2012-08-03

We are interested in investigating the biological activity of chalcones, a major class of compounds found in the beverage kava, in order to develop potent and selective chemopreventive candidates. Consumption of kava in the South Pacific Islands is inversely correlated with cancer incidence, even among smokers. Accordingly, chalcones have anti-cancer activities in animal and cell culture models. To investigate signaling pathways that affect chalcone action we studied a potent analog, (E)-3-(3-hydroxy-4-methoxyphenyl)-1-(3,4,5-trimethoxyphenyl)prop-2-en-1-one (chalcone-24). Chalcone-24 was selected from a series of chalcone analogs that were synthesized based on the structures derived from flavokawain compounds found in kava, and screened in A549 lung cancer cells for induction of cytotoxicity and inhibition of NF-κB, a transcription factor associated with cell survival. Incubation of A549 cells with chalcone-24 resulted in a dose-dependent inhibition of cell viability, inhibition of NF-κB, activation of caspases, and activation of extracellular signal regulated kinase 1/2 (ERK1/2) and c-Jun N-terminal kinase (JNK); ERK1/2 and JNK are mitogen activated protein kinases that play central roles in regulating cell fate. Pharmacological inhibitors of ERK1/2 or JNK increased the sensitivity of A549 cells to chalcone-24-induced cytotoxicity, without affecting NF-κB or caspase activity. These results will help refine the synthesis of chalcone analogs to maximize the combination of actions required to prevent and treat cancer. Copyright © 2012 Elsevier Inc. All rights reserved.

Pre-Steady State Kinetic Investigation of the Incorporation of Anti-Hepatitis B Nucleotide Analogs Catalyzed by Non-Canonical Human DNA Polymerases

PubMed Central

Brown, Jessica A.; Pack, Lindsey R.; Fowler, Jason D.; Suo, Zucai

2011-01-01

Antiviral nucleoside analogs have been developed to inhibit the enzymatic activities of the hepatitis B virus (HBV) polymerase, thereby preventing the replication and production of HBV. However, the usage of these analogs can be limited by drug toxicity because the 5′-triphosphates of these nucleoside analogs (nucleotide analogs) are potential substrates for human DNA polymerases to incorporate into host DNA. Although they are poor substrates for human replicative DNA polymerases, it remains to be established whether these nucleotide analogs are substrates for the recently discovered human X- and Y-family DNA polymerases. Using pre-steady state kinetic techniques, we have measured the substrate specificity values for human DNA polymerases β, λ, η, ι, κ, and Rev1 incorporating the active forms of the following anti-HBV nucleoside analogs approved for clinical use: adefovir, tenofovir, lamivudine, telbivudine, and entecavir. Compared to the incorporation of a natural nucleotide, most of the nucleotide analogs were incorporated less efficiently (2 to >122,000) by the six human DNA polymerases. In addition, the potential for entecavir and telbivudine, two drugs which possess a 3′-hydroxyl, to become embedded into human DNA was examined by primer extension and DNA ligation assays. These results suggested that telbivudine functions as a chain terminator while entecavir was efficiently extended by the six enzymes and was a substrate for human DNA ligase I. Our findings suggested that incorporation of anti-HBV nucleotide analogs catalyzed by human X- and Y-family polymerases may contribute to clinical toxicity. PMID:22132702

Far-infrared-induced magnetoresistance oscillations in GaAs/AlxGa1-xAs -based two-dimensional electron systems

NASA Astrophysics Data System (ADS)

Wirthmann, André; McCombe, Bruce D.; Heitmann, Detlef; Holland, Steffen; Friedland, Klaus-Jürgen; Hu, Can-Ming

2007-11-01

We report on photoresistance and magnetotransport measurements in a moderate mobility two-dimensional electron system subject to far-infrared (terahertz) radiation. The photoresistance shows radiation induced 1/B -periodic oscillations, which we identify as the terahertz analog of microwave-induced resistance oscillations (MIROs). The MIRO-analog oscillations show a sign reversal in the low-field, high current regime. We simultaneously observe magnetoplasmons and MIRO-analog oscillations with no apparent coupling between them. Using a meandering Hall-bar geometry allows us to greatly enhance sensitivity and detect these oscillations even at elevated temperatures and moderate mobilities.

Glucagon-Like Peptide-1 and Its Class B G Protein–Coupled Receptors: A Long March to Therapeutic Successes

PubMed Central

de Graaf, Chris; Donnelly, Dan; Wootten, Denise; Lau, Jesper; Sexton, Patrick M.; Miller, Laurence J.; Ahn, Jung-Mo; Liao, Jiayu; Fletcher, Madeleine M.; Brown, Alastair J. H.; Zhou, Caihong; Deng, Jiejie; Wang, Ming-Wei

2016-01-01

The glucagon-like peptide (GLP)-1 receptor (GLP-1R) is a class B G protein–coupled receptor (GPCR) that mediates the action of GLP-1, a peptide hormone secreted from three major tissues in humans, enteroendocrine L cells in the distal intestine, α cells in the pancreas, and the central nervous system, which exerts important actions useful in the management of type 2 diabetes mellitus and obesity, including glucose homeostasis and regulation of gastric motility and food intake. Peptidic analogs of GLP-1 have been successfully developed with enhanced bioavailability and pharmacological activity. Physiologic and biochemical studies with truncated, chimeric, and mutated peptides and GLP-1R variants, together with ligand-bound crystal structures of the extracellular domain and the first three-dimensional structures of the 7-helical transmembrane domain of class B GPCRs, have provided the basis for a two-domain–binding mechanism of GLP-1 with its cognate receptor. Although efforts in discovering therapeutically viable nonpeptidic GLP-1R agonists have been hampered, small-molecule modulators offer complementary chemical tools to peptide analogs to investigate ligand-directed biased cellular signaling of GLP-1R. The integrated pharmacological and structural information of different GLP-1 analogs and homologous receptors give new insights into the molecular determinants of GLP-1R ligand selectivity and functional activity, thereby providing novel opportunities in the design and development of more efficacious agents to treat metabolic disorders. PMID:27630114

Glucagon Like Peptide-1 (GLP-1) Modulates OVA-Induced Airway Inflammation and Mucus Secretion Involving a Protein Kinase A (PKA)-Dependent Nuclear Factor-κB (NF-κB) Signaling Pathway in Mice.

PubMed

Zhu, Tao; Wu, Xiao-Ling; Zhang, Wei; Xiao, Min

2015-08-26

Asthma is a common chronic pulmonary inflammatory disease, featured with mucus hyper-secretion in the airway. Recent studies found that glucagon like peptide-1 (GLP-1) analogs, including liraglutide and exenatide, possessed a potent anti-inflammatory property through a protein kinase A (PKA)-dependent signaling pathway. Therefore, the aim of current study was to investigate the value of GLP-1 analog therapy liraglutide in airway inflammation and mucus secretion in a murine model of ovalbumin (OVA)-induced asthma, and its underlying molecular mechanism. In our study, BALB/c mice were sensitized and challenged by OVA to induce chronic asthma. Pathological alterations, the number of cells and the content of inflammatory mediators in bronchoalveolar lavage fluid (BALF), and mucus secretion were observed and measured. In addition, the mRNA and protein expression of E-selectin and MUC5AC were analyzed by qPCR and Western blotting. Then, the phosphorylation of PKA and nuclear factor-κB (NF-κB) p65 were also measured by Western blotting. Further, NF-κB p65 DNA binding activity was detected by ELISA. OVA-induced airway inflammation, airway mucus hyper-secretion, the up-regulation of E-selectin and MUC5AC were remarkably inhibited by GLP-1 in mice (all p < 0.01). Then, we also found that OVA-reduced phosphorylation of PKA, and OVA-enhanced NF-κB p65 activation and NF-κB p65 DNA binding activity were markedly improved by GLP-1 (all p < 0.01). Furthermore, our data also figured out that these effects of GLP-1 were largely abrogated by the PKA inhibitor H-89 (all p < 0.01). Taken together, our results suggest that OVA-induced asthma were potently ameliorated by GLP-1 possibly through a PKA-dependent inactivation of NF-κB in mice, indicating that GLP-1 analogs may be considered an effective and safe drug for the potential treatment of asthma in the future.

Inhibitory activity of synthesized acetylated Procyanidin B1 analogs against HeLa S3 cells proliferation.

PubMed

Okamoto, Syuhei; Ishihara, Sayaka; Okamoto, Taisuke; Doi, Syoma; Harui, Kota; Higashino, Yusuke; Kawasaki, Takashi; Nakajima, Noriyuki; Saito, Akiko

2014-02-04

Proanthocyanidins, also known as condensed tannins and/or oligomeric flavonoids, occur in many edible plants and have various interesting biological activities. Previously, we reported a synthetic method for the preparation of various procyanidins in pure form and described their biological activities. Here, we describe the synthesis of procyanidin B1 acetylated analogs and discuss their inhibition activities against HeLa S3 cell proliferation. Surprisingly, the lower-unit acetylated procyanidin B1 strongly inhibited the proliferation of HeLa S3 cells. This molecule showed much stronger inhibitory activity than did epigallocatechin-3-O-gallate (EGCG), green tea polyphenol, and dimeric compounds that included EGCG as a unit. This result suggests that the phenolic hydroxyl groups of the upper-units in flavan-3-ols are important for their inhibitory activity against cancer cell proliferation and that a hydrophobic lower unit dimer enhances this activity.

Sulforaphane and its methylcarbonyl analogs inhibit the LPS-stimulated inflammatory response in human monocytes through modulating cytokine production, suppressing chemotactic migration and phagocytosis in a NF-κB- and MAPK-dependent manner.

PubMed

Reddy, Shridhivya A; Shelar, Sandeep B; Dang, Truong-Minh; Lee, Baxter Neng-Cun; Yang, Hong; Ong, Siew-Min; Ng, Hui-Li; Chui, Wai-Keung; Wong, Siew-Cheng; Chew, Eng-Hui

2015-02-01

Sulforaphane [SF; 1-isothiocyanato-4-(methylsulfinyl)-butane], an aliphatic isothiocyanate (ITC) naturally derived from cruciferous vegetables and largely known for its chemopreventive potential also appears to possess anti-inflammatory potential. In this study, structural analogs of SF {compound 1 [1-isothiocyanato-4-(methylcarbonyl)-butane] and 2 [1-isothiocyanato-3-(methylcarbonyl)-propane]} containing a carbonyl group in place of the sulfinyl group in SF, were evaluated for their anti-inflammatory activities. In RAW 264.7 cells, the ITCs at non-toxic concentrations caused an inhibition of NO and prostaglandin E2 (PGE2) release through suppressing expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), as well as a reduction in matrix metalloproteinase-9 (MMP-9) expression, secretion and gelatinolytic activity. Further work performed on human monocytes isolated from blood of healthy donors revealed that the ITCs not only suppressed the expression and release of pro-inflammatory mediators IL-1β, IL-6, TNF-α and MMP-9, but also suppressed their antibody-independent phagocytic and chemotactic migratory abilities. These anti-inflammatory activities were mediated through suppression of the NF-κB and MAPK signaling pathways. In addition, the ITCs were revealed to interact with the cysteines in inhibitor of nuclear factor-κB kinase β subunit (IKKβ), which could contribute at least partly to the suppression of NF-κB signaling. In conclusion, results obtained in this study provide deeper insights into the anti-inflammatory properties of SF and its methylcarbonyl analogs and the underlying mechanisms. These compounds thus serve as promising candidates for clinical applications in controlling inflammatory conditions. Copyright © 2015 Elsevier B.V. All rights reserved.

A CMOS image sensor with programmable pixel-level analog processing.

PubMed

Massari, Nicola; Gottardi, Massimo; Gonzo, Lorenzo; Stoppa, David; Simoni, Andrea

2005-11-01

A prototype of a 34 x 34 pixel image sensor, implementing real-time analog image processing, is presented. Edge detection, motion detection, image amplification, and dynamic-range boosting are executed at pixel level by means of a highly interconnected pixel architecture based on the absolute value of the difference among neighbor pixels. The analog operations are performed over a kernel of 3 x 3 pixels. The square pixel, consisting of 30 transistors, has a pitch of 35 microm with a fill-factor of 20%. The chip was fabricated in a 0.35 microm CMOS technology, and its power consumption is 6 mW with 3.3 V power supply. The device was fully characterized and achieves a dynamic range of 50 dB with a light power density of 150 nW/mm2 and a frame rate of 30 frame/s. The measured fixed pattern noise corresponds to 1.1% of the saturation level. The sensor's dynamic range can be extended up to 96 dB using the double-sampling technique.

Nucleoside Analog-treated Chronic Hepatitis B Patients showed Reduced Expression of PECAM-1 Gene in Peripheral Blood Mononuclear Cells in Bangladesh

PubMed Central

Tabassum, Shahina; Ullah Munshi, Saif; Hossain, Marufa; Imam, Akhter

2014-01-01

ABSTRACT Background and aim Assessment of therapeutic response is important for monitoring the prognosis and to take decision for cessation of nucleoside analogues therapy in chronic hepatitis B patients. In addition to serum alanine aminotransferase (ALT), hepatitis B virus (HBV) deoxyribonucleic acid (DNA) load and HBeAg status, identification of molecular markers associated with host immune response would be essential to assess therapeutic response. In this regard the current study was performed with the aim to detect expression of platelet endothelial cell adhesion molecule (PECAM)-I gene in peripheral blood monocytes (PBMCs) of treated chronic hepatitis B patients and also to correlate expression of this gene with serum HBV DNA load and serum ALT levels. Materials and methods The study analyzed 60 chronic hepatitis B (CHB) patients, including 30 untreated and 30 nucleoside analogs treated and 10 healthy controls. PECAM-1 gene expression/ transcripts were detected by conventional RT-PCR. Results The expression PECAM-1 mRNA in the PBMCs of CHB patients was significantly higher in untreated (3.17 ± 0.75) than the treated patients (1.64 ± 0.29) (p < 0.01). Expression of PECAM-1 was positively correlated with serum ALT levels of both untreated (r = 0.580) and treated (r = 0.566) CHB patients. Moreover, in both untreated and treated groups, these gene expressions were positively correlated to serum HBV DNA load with the correlation coefficient r = 0.545 and r = 0.591 respectively. Conclusion PECAM-1 may be used as a biomarker for assessment of inflammatory activity as well as therapeutic response in CHB patients. How to cite this article: Sultana N, Tabassum S, Munshi SU, Hossain M, Imam A. Nucleoside Analog-treated Chronic Hepatitis B Patients showed Reduced Expression of PECAM-1 Gene in Peripheral Blood Mononuclear Cells in Bangladesh. Euroasian J Hepato-Gastroenterol 2014;4(2):87-91. PMID:29699354

Synthesis, resolution and biological evaluation of cyclopropyl analogs of abscisic acid.

PubMed

Han, Xiaoqiang; Fan, Jinlong; Lu, Huizhe; Wan, Chuan; Li, Xiuyun; Li, Hong; Yang, Dongyan; Zhang, Yuanzhi; Xiao, Yumei; Qin, Zhaohai

2015-09-15

cis-2,3-Cyclopropanated abscisic acid (cis-CpABA) has high photostability and good ABA-like activity. To further investigate its activity and action mechanism, 2S,3S-2,3-cyclopropanated ABA (3a) and 2R,3R-2,3-cyclopropanated ABA (3b) were synthesized. Bioassay showed that 3a displayed higher inhibitory activity in germination than that of 3b and ABA at the concentration of 3.0 μM, but 3a and 3b had much weaker inhibitory activity in inhibition seedling growth compared to ABA. The study of photostability revealed that 3a and 3b showed high stability under UV light exposure, which were 4 times and 3 times greater than (±)-ABA, respectively. Action mechanism study showed that 3a presented higher inhibition on phosphatase activity of HAB1 than 3b, although they all inferior to ABA. Molecular docking studies of 3a, 3b and ABA receptor PYL10 were agreement with the bioassay data and confirmed the importance of the configuration of the 2,3-cyclopropyl ABA analogs for their bioactivity in somewhat. This study provides a new approach for the design of ABA analogs, and the results validated structure-based design for this target class. Copyright © 2015 Elsevier Ltd. All rights reserved.

Identification of potent maturation inhibitors against HIV-1 clade C.

PubMed

Timilsina, Uddhav; Ghimire, Dibya; Timalsina, Bivek; Nitz, Theodore J; Wild, Carl T; Freed, Eric O; Gaur, Ritu

2016-06-06

Antiretroviral therapy has led to a profound improvement in the clinical care of HIV-infected patients. However, drug tolerability and the evolution of drug resistance have limited treatment options for many patients. Maturation inhibitors are a new class of antiretroviral agents for treatment of HIV-1. They act by interfering with the maturation of the virus by blocking the last step in Gag processing: the cleavage of the capsid-spacer peptide 1 (CA-SP1) intermediate to mature CA by the viral protease (PR). The first-in-class maturation inhibitor bevirimat (BVM) failed against a subset of HIV-1 isolates in clinical trials due to polymorphisms present in the CA-SP1 region of the Gag protein. Sequence analysis indicated that these polymorphisms are more common in non-clade B strains of HIV-1 such as HIV-1 clade C. Indeed, BVM was found to be ineffective against HIV-1 clade C molecular clones tested in this study. A number of BVM analogs were synthesized by chemical modifications at the C-28 position to improve its activity. The new BVM analogs displayed potent activity against HIV-1 clade B and C and also reduced infectivity of the virus. This study identifies novel and broadly active BVM analogs that may ultimately demonstrate efficacy in the clinic.

New cytotoxic benzosuberene analogs. Synthesis, molecular modeling and biological evaluation.

PubMed

Chen, Zecheng; Maderna, Andreas; Sukuru, Sai Chetan K; Wagenaar, Melissa; O'Donnell, Christopher J; Lam, My-Hanh; Musto, Sylvia; Loganzo, Frank

2013-12-15

In this Letter we describe the synthesis and biological evaluation of new benzosuberene analogs with structural modifications on the B-ring. The focus was initially to probe the chemical space around the B-ring C-8 position. This position was readily available for derivatization chemistry using our recently developed new synthesis for this compound class. Furthermore, we describe two new B-ring analogs, one containing a diene and the other a cyclic ether group. Both new analogs show excellent potencies in tumor cell proliferation assays. In addition, we describe molecular modeling studies that provide a binding rationale for reference compound 8 in the colchicine binding site using the known colchicine crystal structure. We also examine whether the cell based potency data obtained with selected new analogs are supported by modeling results. Copyright © 2013 Elsevier Ltd. All rights reserved.

Effect of insulin analog initiation therapy on LDL/HDL subfraction profile and HDL associated enzymes in type 2 diabetic patients.

PubMed

Aslan, Ibrahim; Kucuksayan, Ertan; Aslan, Mutay

2013-04-24

Insulin treatment can lead to good glycemic control and result in improvement of lipid parameters in type 2 diabetic patients. This study was designed to evaluate the effect of insulin analog initiation therapy on low-density lipoprotein (LDL)/ high-density lipoprotein (HDL) sub-fractions and HDL associated enzymes in type 2 diabetic patients during early phase. Twenty four type 2 diabetic patients with glycosylated hemoglobin (HbA1c) levels above 10% despite ongoing combination therapy with sulphonylurea and metformin were selected. Former treatment regimen was continued for the first day followed by substitution of sulphonylurea therapy with different insulin analogs (0.4 U/kg/day) plus metformin. Glycemic profiles were determined over 72 hours by continuous glucose monitoring system (CGMS) and blood samples were obtained from all patients at 24 and 72 hours. Plasma levels of cholesteryl ester transfer protein (CETP), lecithin-cholesterol acyltransferase (LCAT), apolipoprotein B (apoB) and apolipoprotein A-1 (apoA-I) were determined by enzyme-linked immunosorbent assay (ELISA). Measurement of CETP and LCAT activity was performed via fluorometric analysis. Paraoxonase (PON1) enzyme activity was assessed from the rate of enzymatic hydrolysis of phenyl acetate to phenol formation. LDL and HDL subfraction analysis was done by continuous disc polyacrylamide gel electrophoresis. Mean blood glucose, total cholesterol (TC), triglyceride (TG) and very low-density lipoprotein cholesterol (VLDL-C) levels were significantly decreased while HDL-C levels were significantly increased after insulin treatment. Although LDL-C levels were not significantly different before and after insulin initiation therapy a significant increase in LDL-1 subgroup and a significant reduction in atherogenic LDL-3 and LDL-4 subgroups were observed. Insulin analog initiation therapy caused a significant increase in HDL-large, HDL- intermediate and a significant reduction in HDL-small subfractions. CETP protein level and activity was significantly increased while apoB levels were significantly decreased following insulin analog initiation therapy. No significant difference was found in LCAT mass, LCAT activity, apoA-I and PON-1 arylesterase levels following insulin initiation therapy. These findings indicate that insulin analog initiation therapy activates lipid metabolism via up-regulating CETP and shows anti-atherogenic effects by increasing HDL-large and decreasing LDL-3 and LDL-4 subfractions in a short time period.

Tight-Binding Inhibition of Human Monoamine Oxidase B by Chromone Analogs: A Kinetic, Crystallographic, and Biological Analysis.

PubMed

Reis, Joana; Manzella, Nicola; Cagide, Fernando; Mialet-Perez, Jeanne; Uriarte, Eugenio; Parini, Angelo; Borges, Fernanda; Binda, Claudia

2018-05-10

Monoamine oxidase B (MAO-B) is a validated drug target for Parkinson's disease. Chromone derivatives were identified as novel potent and reversible MAO-B inhibitors, and herewith we report on a crystallographic and biochemical analysis to investigate their inhibition mechanism. The crystal structures of human MAO-B in complex with three chromone analogs bearing different substituents on the exocyclic aromatic ring (determined at 1.6-1.8 Å resolution) showed that they all bind in the active site cavity of the protein with the chromone moiety located in front of the FAD cofactor. These inhibitors form two hydrogen bonds with Tyr435 and Cys172 and perfectly fit the hydrophobic flat active site of human MAO-B. This is reflected in their tight-binding mechanism of inhibition with K i values of 55, 17, and 31 nM for N-(3',4'-dimethylphenyl)-4-oxo-4 H-chromene-3-carboxamide (1), N-(3'-chlorophenyl)-4-oxo-4 H-chromene-3-carboxamide (2), and N-(3'-fluorophenyl)-4-oxo-4 H-chromene-3-carboxamide (3), respectively. These compounds were also 1000-fold more effective than l-deprenyl in reducing the cellular levels of reactive oxygen species (ROS).

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gentles, Robert G.; Sheriff, Steven; Beno, Brett R.

Structure based rationales for the activities of potent N-benzyl-4-heteroaryl-1-(phenylsulfonyl)piperazine-2-carboxamide inhibitors of the hepatitis C viral polymerase are described herein. These compounds bind to the hepatitis C virus non-structural protein 5B (NS5B), and co-crystal structures of select examples from this series with NS5B are reported. Comparison of co-crystal structures of a potent analog with both NS5B genotype 1a and genotype 1b provides a possible explanation for the genotype-selectivity observed with this compound class and suggests opportunities for the further optimization of the series.

Analogical processes in children's understanding of spatial representations.

PubMed

Yuan, Lei; Uttal, David; Gentner, Dedre

2017-06-01

We propose that map reading can be construed as a form of analogical mapping. We tested 2 predictions that follow from this claim: First, young children's patterns of performance in map reading tasks should parallel those found in analogical mapping tasks; and, second, children will benefit from guided alignment instructions that help them see the relational correspondences between the map and the space. In 4 experiments, 3-year-olds completed a map reading task in which they were asked to find hidden objects in a miniature room, using a corresponding map. We manipulated the availability of guided alignment (showing children the analogical mapping between maps and spaces; Experiments 1, 2, and 3a), the format of guided alignment (gesture or relational language; Experiment 2), and the iconicity of maps (Experiments 3a and 3b). We found that (a) young children's difficulties in map reading follow from known patterns of analogical development-for example, focusing on object similarity over relational similarity; and (b) guided alignment based on analogical reasoning led to substantially better performance. Results also indicated that children's map reading performance was affected by the format of guided alignment, the iconicity of the maps, and the order of tasks. The results bear on the developmental mechanisms underlying young children's learning of spatial representations and also suggest ways to support this learning. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

Evidence for a Structure-Mapping Theory of Analogy and Metaphor

DTIC Science & Technology

1986-12-01

Results: Mean Number of Peiae B1 0~ T2 > B2 n~ Ti Bl n~ T2 = .038 B2 n~ TI .025 NS B > T B= .16 T=l. CA NS Bl >B2 BI .58 B2 =.58 NS T2 > Ti T2 .49 T1 .50...NS B > T B = .63 T = .59 F. B1 > B2 B1 = .37 B2 = .28 NS T2 > T1 T2 = .23 Ti = .39 NS I Bl > T1 B = .37 T1 = .39 NS T2 > B2 T2 =.23 B2 .28 NS a...iption Ti = N in top half of target description T2 = N in bottom half of target description B1 A3 T2 = N in both top half of base and I bcttom half

Exploring the anti-inflammatory activity of a novel 2-phenylquinazoline analog with protection against inflammatory injury

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chatterjee, Nabanita; Das, Subhadip; Bose, Dipayan

Inflammation is a protective immune response against harmful stimuli whose long time continuation results in host disease. Quinazolinones are nitrogen containing heterocyclic compounds with wide spectrum of biological activities. The anticancer effect of a 3-(arylideneamino)‐phenylquinazoline-4(3H)-one derivative was reported earlier. The anti-inflammatory effect of these quinazolinone derivatives has now been examined in endotoxin stimulated macrophages and in different in vivo models of inflammation by measuring the proinflammatory cytokines (TNF-α, IL-1β and IL-6), mediators NO and NF-κB (by ELISA and western blot), and translocation of the nuclear factor kB (by immunocytochemical analysis). To elucidate the in vivo effect, mice endotoxin model wasmore » and the various levels of edema, inflammatory pain and vascular permeability were studied. One of the quinazolinone derivatives showed significant anti-inflammatory activity in stimulated macrophage cells by inhibiting the expression of TNF-α, IL-1β, IL-6, iNOS, COX-2, p-IκB and NF-κBp65. Significant (P < 0.01) improvement was observed in the mortality of endotoxemic mice. The carrageenan and formalin-induced paw edema thicknesses were found to be reduced significantly (P < 0.01) along with the reduction of pain, vascular permeability and edema induced by complete Freund's adjuvant (P < 0.01). These findings indicate that 3-(arylideneamino)‐phenylquinazoline-4(3H)-one derivative as a potential anti-inflammatory agent. -- Highlights: ► 2-phenylquinazoline analog suppresses the cytokines in stimulated macrophages. ► 2-phenylquinazoline analog down regulated NF-kB P65 translocation. ► Role of 2-phenylquinazoline analog in endotoximia and peripheral inflammations.« less

Multi-parameter optimization of aza-follow-ups to BI 207524, a thumb pocket 1 HCV NS5B polymerase inhibitor. Part 2: Impact of lipophilicity on promiscuity and in vivo toxicity.

PubMed

Beaulieu, Pierre L; Bolger, Gordon; Deon, Dan; Duplessis, Martin; Fazal, Gulrez; Gagnon, Alexandre; Garneau, Michel; LaPlante, Steven; Stammers, Timothy; Kukolj, George; Duan, Jianmin

2015-03-01

We describe our efforts to identify analogs of thumb pocket 1 HCV NS5B inhibitor 1 (aza-analog of BI 207524) with improved plasma to liver partitioning and a predicted human half-life consistent with achieving a strong antiviral effect at a reasonable dose in HCV-infected patients. Compounds 3 and 7 were identified that met these criteria but exhibited off-target promiscuity in an in vitro pharmacology screen and in vivo toxicity in rats. High lipophilicity in this class was found to correlate with increased probability for promiscuous behavior and toxicity. The synthesis of an 8×11 matrix of analogs allowed the identification of C3, an inhibitor that displayed comparable potency to 1, improved partitioning to the liver and reduced lipophilicity. Although C3 displayed reduced propensity for in vitro off-target inhibition and the toxicity profile in rats was improved, the predicted human half-life of this compound was short, resulting in unacceptable dosing requirements to maintain a strong antiviral effect in patients. Copyright © 2015 Elsevier Ltd. All rights reserved.

Phenol-quinone tautomerism in (arylazo)naphthols and the analogous Schiff bases: benchmark calculations.

PubMed

Ali, S Tahir; Antonov, Liudmil; Fabian, Walter M F

2014-01-30

Tautomerization energies of a series of isomeric [(4-R-phenyl)azo]naphthols and the analogous Schiff bases (R = N(CH3)2, OCH3, H, CN, NO2) are calculated by LPNO-CEPA/1-CBS using the def2-TZVPP and def2-QZVPP basis sets for extrapolation. The performance of various density functionals (B3LYP, M06-2X, PW6B95, B2PLYP, mPW2PLYP, PWPB95) as well as MP2 and SCS-MP2 is evaluated against these results. M06-2X and SCS-MP2 yield results close to the LPNO-CEPA/1-CBS values. Solvent effects (CCl4, CHCl3, CH3CN, and CH3OH) are treated by a variety of bulk solvation models (SM8, IEFPCM, COSMO, PBF, and SMD) as well as explicit solvation (Monte Carlo free energy perturbation using the OPLSAA force field).

A 14-bit 40-MHz analog front end for CCD application

NASA Astrophysics Data System (ADS)

Jingyu, Wang; Zhangming, Zhu; Shubin, Liu

2016-06-01

A 14-bit, 40-MHz analog front end (AFE) for CCD scanners is analyzed and designed. The proposed system incorporates a digitally controlled wideband variable gain amplifier (VGA) with nearly 42 dB gain range, a correlated double sampler (CDS) with programmable gain functionality, a 14-bit analog-to-digital converter and a programmable timing core. To achieve the maximum dynamic range, the VGA proposed here can linearly amplify the input signal in a gain range from -1.08 to 41.06 dB in 6.02 dB step with a constant bandwidth. A novel CDS takes image information out of noise, and further amplifies the signal accurately in a gain range from 0 to 18 dB in 0.035 dB step. A 14-bit ADC is adopted to quantify the analog signal with optimization in power and linearity. An internal timing core can provide flexible timing for CCD arrays, CDS and ADC. The proposed AFE was fabricated in SMIC 0.18 μm CMOS process. The whole circuit occupied an active area of 2.8 × 4.8 mm2 and consumed 360 mW. When the frequency of input signal is 6.069 MHz, and the sampling frequency is 40 MHz, the signal to noise and distortion (SNDR) is 70.3 dB, the effective number of bits is 11.39 bit. Project supported by the National Natural Science Foundation of China (Nos. 61234002, 61322405, 61306044, 61376033), the National High-Tech Program of China (No. 2013AA014103), and the Opening Project of Science and Technology on Reliability Physics and Application Technology of Electronic Component Laboratory (No. ZHD201302).

Biochemical Characterization of the Active Anti-Hepatitis C Virus Metabolites of 2,6-Diaminopurine Ribonucleoside Prodrug Compared to Sofosbuvir and BMS-986094

PubMed Central

Ehteshami, Maryam; Tao, Sijia; Ozturk, Tugba; Zhou, Longhu; Cho, Jong Hyun; Zhang, Hongwang; Amiralaei, Sheida; Shelton, Jadd R.; Lu, Xiao; Khalil, Ahmed; Domaoal, Robert A.; Stanton, Richard A.; Suesserman, Justin E.; Lin, Biing; Lee, Sam S.; Amblard, Franck; Whitaker, Tony; Coats, Steven J.

2016-01-01

Ribonucleoside analog inhibitors (rNAI) target the hepatitis C virus (HCV) RNA-dependent RNA polymerase nonstructural protein 5B (NS5B) and cause RNA chain termination. Here, we expand our studies on β-d-2′-C-methyl-2,6-diaminopurine-ribonucleotide (DAPN) phosphoramidate prodrug 1 (PD1) as a novel investigational inhibitor of HCV. DAPN-PD1 is metabolized intracellularly into two distinct bioactive nucleoside triphosphate (TP) analogs. The first metabolite, 2′-C-methyl-GTP, is a well-characterized inhibitor of NS5B polymerase, whereas the second metabolite, 2′-C-methyl-DAPN-TP, behaves as an adenosine base analog. In vitro assays suggest that both metabolites are inhibitors of NS5B-mediated RNA polymerization. Additional factors, such as rNAI-TP incorporation efficiencies, intracellular rNAI-TP levels, and competition with natural ribonucleotides, were examined in order to further characterize the potential role of each nucleotide metabolite in vivo. Finally, we found that although both 2′-C-methyl-GTP and 2′-C-methyl-DAPN-TP were weak substrates for human mitochondrial RNA (mtRNA) polymerase (POLRMT) in vitro, DAPN-PD1 did not cause off-target inhibition of mtRNA transcription in Huh-7 cells. In contrast, administration of BMS-986094, which also generates 2′-C-methyl-GTP and previously has been associated with toxicity in humans, caused detectable inhibition of mtRNA transcription. Metabolism of BMS-986094 in Huh-7 cells leads to 87-fold higher levels of intracellular 2′-C-methyl-GTP than DAPN-PD1. Collectively, our data characterize DAPN-PD1 as a novel and potent antiviral agent that combines the delivery of two active metabolites. PMID:27216050

VMY-1-103, a dansylated analog of purvalanol B, induces caspase-3-dependent apoptosis in LNCaP prostate cancer cells

PubMed Central

Yenugonda, Venkata Mahidhar; Ghosh, Anup; Divito, Kyle; Trabosh, Valerie; Patel, Yesha; Brophy, Amanda; Grindrod, Scott; Lisanti, Michael P; Rosenthal, Dean; Brown, Milton L; Avantaggiati, Maria Laura; Rodriguez, Olga

2010-01-01

The 2,6,9-trisubstituted purine group of cyclin dependent kinase inhibitors have the potential to be clinically relevant inhibitors of cancer cell proliferation. We have recently designed and synthesized a novel dansylated analog of purvalanol B, termed VMY-1-103, that inhibited cell cycle progression in breast cancer cell lines more effectively than did purvalanol B and allowed for uptake analyses by fluorescence microscopy. ErbB-2 plays an important role in the regulation of signal transduction cascades in a number of epithelial tumors, including prostate cancer (PCa). Our previous studies demonstrated that transgenic expression of activated ErbB-2 in the mouse prostate initiated PCa and either the overexpression of ErbB-2 or the addition of the ErbB-2/ErbB-3 ligand, heregulin (HRG), induced cell cycle progression in the androgen-responsive prostate cancer cell line, LNCaP. In the present study, we tested the efficacy of VMY-1-103 in inhibiting HRG-induced cell proliferation in LNCaP prostate cancer cells. At concentrations as low as 1 µM, VMY-1-103 increased both the proportion of cells in G1 and p21CIP1 protein levels. At higher concentrations (5 µM or 10 µM), VMY-1-103 induced apoptosis via decreased mitochondrial membrane polarity and induction of p53 phosphorylation, caspase-3 activity and PARP cleavage. Treatment with 10 µM Purvalanol B failed to either influence proliferation or induce apoptosis. Our results demonstrate that VMY-1-103 was more effective in inducing apoptosis in PCa cells than its parent compound, purvalanol B, and support the testing of VMY-1-103 as a potential small molecule inhibitor of prostate cancer in vivo. PMID:20574155

The Anglo-Australian Planet Search. XXV. A Candidate Massive Saturn Analog Orbiting HD 30177

NASA Astrophysics Data System (ADS)

Wittenmyer, Robert A.; Horner, Jonathan; Mengel, M. W.; Butler, R. P.; Wright, D. J.; Tinney, C. G.; Carter, B. D.; Jones, H. R. A.; Anglada-Escudé, G.; Bailey, J.; O'Toole, Simon J.

2017-04-01

We report the discovery of a second long-period giant planet orbiting HD 30177, a star previously known to host a massive Jupiter analog (HD 30177b: a = 3.8 ± 0.1 au, m sin I = 9.7 ± 0.5 M Jup). HD 30177c can be regarded as a massive Saturn analog in this system, with a = 9.9 ± 1.0 au and m sin I = 7.6 ± 3.1 M Jup. The formal best-fit solution slightly favors a closer-in planet at a ˜ 7 au, but detailed n-body dynamical simulations show that configuration to be unstable. A shallow local minimum of longer period, lower eccentricity solutions was found to be dynamically stable, and hence we adopt the longer period in this work. The proposed ˜32 year orbit remains incomplete; further monitoring of this and other stars is necessary to reveal the population of distant gas giant planets with orbital separations a ˜ 10 au, analogous to that of Saturn.

Two analogy strategies: the cases of mind metaphors and introspection

NASA Astrophysics Data System (ADS)

Fischer, Eugen

2018-04-01

Analogical reasoning is often employed in problem-solving and metaphor interpretation. This paper submits that, as a default, analogical reasoning addressing these different tasks employs different mapping strategies. In problem-solving, it employs analogy-maximising strategies (like structure mapping, Gentner, D., & Markman, A. B. (1997). Structure mapping in analogy and similarity. American Psychologist, 52, 45-56); in metaphor interpretation, analogy-minimising strategies (like ATT-Meta, Barnden, J. A. (2015). Open-ended elaborations in creative metaphor. In T. R. Besold, M. Schorlemmer, & A. Smaill (Eds.), Computational creativity research: Towards creative machines (pp. 217-242). Berlin: Springer). The two strategies interact in analogical reasoning with conceptual metaphors. This interaction leads to predictable fallacies. The paper supports these hypotheses through case-studies on "mind" metaphors from ordinary discourse, and abstract problem-solving in the philosophy of mind, respectively. It shows that (1) default metaphorical interpretations for vision- and space-cognition metaphors can be derived with a variant of the analogy-minimising ATT-Meta approach, (2) philosophically influential introspective conceptions of the mind can be derived with conceptual metaphors only through an analogy-maximising strategy, and (3) the interaction of these strategies leads to hitherto unrecognised fallacies in analogical reasoning with metaphors. This yields a debunking explanation of introspective conceptions.

On the terminal homologation of physiologically active peptides as a means of increasing stability in human serum--neurotensin, opiorphin, B27-KK10 epitope, NPY.

PubMed

Seebach, Dieter; Lukaszuk, Aneta; Patora-Komisarska, Krystyna; Podwysocka, Dominika; Gardiner, James; Ebert, Marc-Olivier; Reubi, Jean Claude; Cescato, Renzo; Waser, Beatrice; Gmeiner, Peter; Hübner, Harald; Rougeot, Catherine

2011-05-01

The terminal homologation by CH(2) insertion into the peptides mentioned in the title is described. This involves replacement of the N-terminal amino acid residue by a β(2) - and of the C-terminal amino acid residue by a β(3) -homo-amino acid moiety (β(2) hXaa and β(3) hXaa, resp.; Fig. 1). In this way, the structure of the peptide chain from the N-terminal to the C-terminal stereogenic center is identical, and the modified peptide is protected against cleavage by exopeptidases (Figs. 2 and 3). Neurotensin (NT; 1) and its C-terminal fragment NT(8-13) are ligands of the G-protein-coupled receptors (GPCR) NT1, NT2, NT3, and NT analogs are promising tools to be used in cancer diagnostics and therapy. The affinities of homologated NT analogs, 2b-2e, for NT1 and NT2 receptors were determined by using cell homogenates and tumor tissues (Table 1); in the latter experiments, the affinities for the NT1 receptor are more or less the same as those of NT (0.5-1.3 vs. 0.6 nM). At the same time, one of the homologated NT analogs, 2c, survives in human plasma for 7 days at 37° (Fig. 6). An NMR analysis of NT(8-13) (Tables 2 and 4, and Fig. 8) reveals that this N-terminal NT fragment folds to a turn in CD(3) OH. - In the case of the human analgesic opiorphin (3a), a pentapeptide, and of the HIV-derived B27-KK10 (4a), a decapeptide, terminal homologation (→3b and 4b, resp.) led to a 7- and 70-fold half-life increase in plasma (Fig. 9). With N-terminally homologated NPY, 5c, we were not able to determine serum stability; the peptide consisting of 36 amino acid residues is subject to cleavage by endopetidases. Three of the homologated compounds, 2b, 2c, and 5c, were shown to be agonists (Fig. 7 and 11). A comparison of terminal homologation with other stability-increasing terminal modifications of peptides is performed (Fig. 5), and possible applications of the neurotensin analogs, described herein, are discussed. Copyright © 2011 Verlag Helvetica Chimica Acta AG, Zürich.

Analogical scaffolding: Making meaning in physics through representation and analogy

NASA Astrophysics Data System (ADS)

Podolefsky, Noah Solomon

This work reviews the literature on analogy, introduces a new model of analogy, and presents a series of experiments that test and confirm the utility of this model to describe and predict student learning in physics with analogy. Pilot studies demonstrate that representations (e.g., diagrams) can play a key role in students' use of analogy. A new model of analogy, Analogical Scaffolding, is developed to explain these initial empirical results. This model will be described in detail, and then applied to describe and predict the outcomes of further experiments. Two large-scale (N>100) studies will demonstrate that: (1) students taught with analogies, according to the Analogical Scaffolding model, outperform students taught without analogies on pre-post assessments focused on electromagnetic waves; (2) the representational forms used to teach with analogy can play a significant role in student learning, with students in one treatment group outperforming students in other treatment groups by factors of two or three. It will be demonstrated that Analogical Scaffolding can be used to predict these results, as well as finer-grained results such as the types of distracters students choose in different treatment groups, and to describe and analyze student reasoning in interviews. Abstraction in physics is reconsidered using Analogical Scaffolding. An operational definition of abstraction is developed within the Analogical Scaffolding framework and employed to explain (a) why physicists consider some ideas more abstract than others in physics, and (b) how students conceptions of these ideas can be modeled. This new approach to abstraction suggests novel approaches to curriculum design in physics using Analogical Scaffolding.

An integrated multichannel neural recording analog front-end ASIC with area-efficient driven right leg circuit.

PubMed

Tao Tang; Wang Ling Goh; Lei Yao; Jia Hao Cheong; Yuan Gao

2017-07-01

This paper describes an integrated multichannel neural recording analog front end (AFE) with a novel area-efficient driven right leg (DRL) circuit to improve the system common mode rejection ratio (CMRR). The proposed AFE consists of an AC-coupled low-noise programmable-gain amplifier, an area-efficient DRL block and a 10-bit SAR ADC. Compared to conventional DRL circuit, the proposed capacitor-less DRL design achieves 90% chip area reduction with enhanced CMRR performance, making it ideal for multichannel biomedical recording applications. The AFE circuit has been designed in a standard 0.18-μm CMOS process. Post-layout simulation results show that the AFE provides two gain settings of 54dB/60dB while consuming 1 μA per channel under a supply voltage of 1 V. The input-referred noise of the AFE integrated from 1 Hz to 10k Hz is only 4 μVrms and the CMRR is 110 dB.

Analog Building Blocks for Communications Modems.

DTIC Science & Technology

1977-01-01

x*—*- A0-A039 82b ELECTRONIC COMMUNICATIONS INC ST PETERSBURG FLA F/6 9/5 ANALOG BUILDING BLOCKS FOR COMMUNICATIONS MODEMS .(U) JAN 77 B BLACK...F33615-7<t-C-1120 UNCLASSIFIED AFAL-TR-76-29 NL ANALOG BUILDING BLOCKS FOR COMMUNICATIONS MODEMS ELECTRONIC COMMUNICATIONS INC. A SUBSIDIARY OF...Idantltr Or Mac* numb*,; Avionics Building-Block modules Frequency Synthesize* Costas Demodulator Amplifier Modem Frequency Multiplier ’ -^ « TRACT

Conformationally constrained farnesoid X receptor (FXR) agonists: heteroaryl replacements of the naphthalene.

PubMed

Bass, Jonathan Y; Caravella, Justin A; Chen, Lihong; Creech, Katrina L; Deaton, David N; Madauss, Kevin P; Marr, Harry B; McFadyen, Robert B; Miller, Aaron B; Mills, Wendy Y; Navas, Frank; Parks, Derek J; Smalley, Terrence L; Spearing, Paul K; Todd, Dan; Williams, Shawn P; Wisely, G Bruce

2011-02-15

To improve on the drug properties of GSK8062 1b, a series of heteroaryl bicyclic naphthalene replacements were prepared. The quinoline 1c was an equipotent FXR agonist with improved drug developability parameters relative to 1b. In addition, analog 1c lowered body weight gain and serum glucose in a DIO mouse model of diabetes. Copyright © 2010 Elsevier Ltd. All rights reserved.

Chiral mutagenesis of insulin. Contribution of the B20-B23 beta-turn to activity and stability.

PubMed

Nakagawa, Satoe H; Hua, Qing-xin; Hu, Shi-Quan; Jia, Wenhua; Wang, Shuhua; Katsoyannis, Panayotis G; Weiss, Michael A

2006-08-04

Insulin contains a beta-turn (residues B20-B23) interposed between two receptor-binding elements, the central alpha-helix of the B chain (B9-B19) and its C-terminal beta-strand (B24-B28). The turn contains conserved glycines at B20 and B23. Although insulin exhibits marked conformational variability among crystal forms, these glycines consistently maintain positive phi dihedral angles within a classic type-I beta-turn. Because the Ramachandran conformations of GlyB20 and GlyB23 are ordinarily forbidden to L-amino acids, turn architecture may contribute to structure or function. Here, we employ "chiral mutagenesis," comparison of corresponding D- and L-Ala substitutions, to investigate this turn. Control substitutions are introduced at GluB21, a neighboring residue exhibiting a conventional (negative) phi angle. The D- and L-Ala substitutions at B23 are associated with a marked stereospecific difference in activity. Whereas the D-AlaB23 analog retains native activity, the L analog exhibits a 20-fold decrease in receptor binding. By contrast, D- and L-AlaB20 analogs each exhibit high activity. Stereospecific differences between the thermodynamic stabilities of the analogs are nonetheless more pronounced at B20 (delta deltaG(u) 2.0 kcal/mole) than at B23 (delta deltaG(u) 0.7 kcal/mole). Control substitutions at B21 are well tolerated without significant stereospecificity. Chiral mutagenesis thus defines the complementary contributions of these conserved glycines to protein stability (GlyB20) or receptor recognition (GlyB23).

Acetyl analogs of combretastatin A-4: synthesis and biological studies.

PubMed

Babu, Balaji; Lee, Megan; Lee, Lauren; Strobel, Raymond; Brockway, Olivia; Nickols, Alexis; Sjoholm, Robert; Tzou, Samuel; Chavda, Sameer; Desta, Dereje; Fraley, Gregory; Siegfried, Adam; Pennington, William; Hartley, Rachel M; Westbrook, Cara; Mooberry, Susan L; Kiakos, Konstantinos; Hartley, John A; Lee, Moses

2011-04-01

The combretastatins have received significant attention because of their simple chemical structures, excellent antitumor efficacy and novel antivascular mechanisms of action. Herein, we report the synthesis of 20 novel acetyl analogs of CA-4 (1), synthesized from 3,4,5-trimethoxyphenylacetone that comprises the A ring of CA-4 with different aromatic aldehydes as the B ring. Molecular modeling studies indicate that these new compounds possess a 'twisted' conformation similar to CA-4. The new analogs effectively inhibit the growth of human and murine cancer cells. The most potent compounds 6k, 6s and 6t, have IC(50) values in the sub-μM range. Analog 6t has an IC(50) of 182 nM in MDA-MB-435 cells and has advantages over earlier analogs due to its enhanced water solubility (456 μM). This compound initiates microtubule depolymerization with an EC(50) value of 1.8 μM in A-10 cells. In a murine L1210 syngeneic tumor model 6t had antitumor activity and no apparent toxicity. Copyright © 2011 Elsevier Ltd. All rights reserved.

Biophysical Optimization of a Therapeutic Protein by Nonstandard Mutagenesis

PubMed Central

Pandyarajan, Vijay; Phillips, Nelson B.; Cox, Gabriela P.; Yang, Yanwu; Whittaker, Jonathan; Ismail-Beigi, Faramarz; Weiss, Michael A.

2014-01-01

Insulin provides a model for the therapeutic application of protein engineering. A paradigm in molecular pharmacology was defined by design of rapid-acting insulin analogs for the prandial control of glycemia. Such analogs, a cornerstone of current diabetes regimens, exhibit accelerated subcutaneous absorption due to more rapid disassembly of oligomeric species relative to wild-type insulin. This strategy is limited by a molecular trade-off between accelerated disassembly and enhanced susceptibility to degradation. Here, we demonstrate that this trade-off may be circumvented by nonstandard mutagenesis. Our studies employed LysB28, ProB29-insulin (“lispro”) as a model prandial analog that is less thermodynamically stable and more susceptible to fibrillation than is wild-type insulin. We have discovered that substitution of an invariant tyrosine adjoining the engineered sites in lispro (TyrB26) by 3-iodo-Tyr (i) augments its thermodynamic stability (ΔΔGu 0.5 ±0.2 kcal/mol), (ii) delays onset of fibrillation (lag time on gentle agitation at 37 °C was prolonged by 4-fold), (iii) enhances affinity for the insulin receptor (1.5 ± 0.1-fold), and (iv) preserves biological activity in a rat model of diabetes mellitus. 1H NMR studies suggest that the bulky iodo-substituent packs within a nonpolar interchain crevice. Remarkably, the 3-iodo-TyrB26 modification stabilizes an oligomeric form of insulin pertinent to pharmaceutical formulation (the R6 zinc hexamer) but preserves rapid disassembly of the oligomeric form pertinent to subcutaneous absorption (T6 hexamer). By exploiting this allosteric switch, 3-iodo-TyrB26-lispro thus illustrates how a nonstandard amino acid substitution can mitigate the unfavorable biophysical properties of an engineered protein while retaining its advantages. PMID:24993826

Genetic analysis of Bacillus stearothermophilus by protoplast fusion

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chen, Z.; Wojcik, S.F.; Welker, N.E.

1986-03-01

Efficient and reliable protoplasting, regeneration, and fusion techniques were established for the prototrophic strain Bacillus stearothermophilus NUB36. Auxotrophic mutants were isolated, and protoplast fusion was used to construct isogenic mutant strains and for chromosomal mapping. Markers were mapped using two-, three-, and four-factor crosses. The order of the markers was hom-1-thr-1-his-1-(gly-1 or gly-2)-pur-1-pur-2. These markers may be analogous to hom, thrA, hisA, glyC, and purA markers on the Bacillus subtilis chromosome. No analogous pur-1 marker has been reported in B. subtilis. The relative order of three of the markers (hom-1-thr-1-gly-1) was independently confirmed by transduction.

Design and synthesis of 2-nitroimidazoles with variable alkylating and acylating functionality.

PubMed

Winters, Thomas; Sercel, Anthony; Suto, Carla; Elliott, William; Leopold, Wilbur; Leopold, Judith; Showalter, Hollis

2014-01-01

The synthesis of a small series of 2-nitroimidazoles in which the β-amino alcohol side chain was amidated with a range of alkylating/acylating functionality is described. Synthetic methodologies were developed that generally provided for selective N-acyl versus N,O-bisacyl products. In vitro, target analogs showed minimal radiosensitization activity, with only a few exhibiting a sensitizer enhancement ratio (SER) >2.0 and C(1.6) values comparable to reference agents RB-6145 and RSU-1069. In an assay to determine potential to alkylate biomolecules, representative analogs showed <1% of the alkylating activity of RSU-1069. In vivo, one analog showed an enhancement ratio of 1.6 relative to vehicle control when tested in B6C3F1 mice with an implanted KHT sarcoma. The data reinforce prior findings that there is a correlation between alkylation potential and in vivo activity.

PSI-7851, a pronucleotide of beta-D-2'-deoxy-2'-fluoro-2'-C-methyluridine monophosphate, is a potent and pan-genotype inhibitor of hepatitis C virus replication.

PubMed

Lam, Angela M; Murakami, Eisuke; Espiritu, Christine; Steuer, Holly M Micolochick; Niu, Congrong; Keilman, Meg; Bao, Haiying; Zennou, Veronique; Bourne, Nigel; Julander, Justin G; Morrey, John D; Smee, Donald F; Frick, David N; Heck, Julie A; Wang, Peiyuan; Nagarathnam, Dhanapalan; Ross, Bruce S; Sofia, Michael J; Otto, Michael J; Furman, Phillip A

2010-08-01

The hepatitis C virus (HCV) NS5B RNA polymerase facilitates the RNA synthesis step during the HCV replication cycle. Nucleoside analogs targeting the NS5B provide an attractive approach to treating HCV infections because of their high barrier to resistance and pan-genotype activity. PSI-7851, a pronucleotide of beta-D-2'-deoxy-2'-fluoro-2'-C-methyluridine-5'-monophosphate, is a highly active nucleotide analog inhibitor of HCV for which a phase 1b multiple ascending dose study of genotype 1-infected individuals was recently completed (M. Rodriguez-Torres, E. Lawitz, S. Flach, J. M. Denning, E. Albanis, W. T. Symonds, and M. M. Berry, Abstr. 60th Annu. Meet. Am. Assoc. Study Liver Dis., abstr. LB17, 2009). The studies described here characterize the in vitro antiviral activity and cytotoxicity profile of PSI-7851. The 50% effective concentration for PSI-7851 against the genotype 1b replicon was determined to be 0.075+/-0.050 microM (mean+/-standard deviation). PSI-7851 was similarly effective against replicons derived from genotypes 1a, 1b, and 2a and the genotype 1a and 2a infectious virus systems. The active triphosphate, PSI-7409, inhibited recombinant NS5B polymerases from genotypes 1 to 4 with comparable 50% inhibitory concentrations. PSI-7851 is a specific HCV inhibitor, as it lacks antiviral activity against other closely related and unrelated viruses. PSI-7409 also lacked any significant activity against cellular DNA and RNA polymerases. No cytotoxicity, mitochondrial toxicity, or bone marrow toxicity was associated with PSI-7851 at the highest concentration tested (100 microM). Cross-resistance studies using replicon mutants conferring resistance to modified nucleoside analogs showed that PSI-7851 was less active against the S282T replicon mutant, whereas cells expressing a replicon containing the S96T/N142T mutation remained fully susceptible to PSI-7851. Clearance studies using replicon cells demonstrated that PSI-7851 was able to clear cells of HCV replicon RNA and prevent viral rebound.

Principles for Integrating Mars Analog Science, Operations, and Technology Research

NASA Technical Reports Server (NTRS)

Clancey, William J.

2003-01-01

During the Apollo program, the scientific community and NASA used terrestrial analog sites for understanding planetary features and for training astronauts to be scientists. Human factors studies (Harrison, Clearwater, & McKay 1991; Stuster 1996) have focused on the effects of isolation in extreme environments. More recently, with the advent of wireless computing, we have prototyped advanced EVA technologies for navigation, scheduling, and science data logging (Clancey 2002b; Clancey et al., in press). Combining these interests in a single expedition enables tremendous synergy and authenticity, as pioneered by Pascal Lee's Haughton-Mars Project (Lee 2001; Clancey 2000a) and the Mars Society s research stations on a crater rim on Devon Island in the High Canadian Arctic (Clancey 2000b; 2001b) and the Morrison Formation of southeast Utah (Clancey 2002a). Based on this experience, the following principles are proposed for conducting an integrated science, operations, and technology research program at analog sites: 1) Authentic work; 2) PI-based projects; 3) Unencumbered baseline studies; 4) Closed simulations; and 5) Observation and documentation. Following these principles, we have been integrating field science, operations research, and technology development at analog sites on Devon Island and in Utah over the past five years. Analytic methods include work practice simulation (Clancey 2002c; Sierhuis et a]., 2000a;b), by which the interaction of human behavior, facilities, geography, tools, and procedures are formalized in computer models. These models are then converted into the runtime EVA system we call mobile agents (Clancey 2002b; Clancey et al., in press). Furthermore, we have found that the Apollo Lunar Surface Journal (Jones, 1999) provides a vast repository or understanding astronaut and CapCom interactions, serving as a baseline for Mars operations and quickly highlighting opportunities for computer automation (Clancey, in press).

Asteroid (101955) 1999 RQ36: Spectroscopy from 0.4 to 2.4 Micrometer and Meteorite Analogs

NASA Technical Reports Server (NTRS)

Clark, Beth Ellen; Binzel, Richard P.; Howell, Ellen S.; Cloutis, Edward A.; Ockert-Bell, Maureen; Christensen, Phil; Barucci, Maria Antonietta; DeMeo, Francesca; Lauretta, Dante S.; Connolly, Harold, Jr.;

Synthesis and antimicrobial activity of new 1-[(tetrazol-5-yl)methyl] indole derivatives, their 1,2,4-triazole thioglycosides and acyclic analogs.

PubMed

El-Sayed, Weal A; Abdel Megeid, Randa E; Abbas, Hebat-Allah S

2011-07-01

New 1-[(tetrazol-5-yl)methyl]indole derivatives, their acyclic nucleoside analogs and the corresponding glycoside derivatives were synthesized. Furthermore, the [)(1,2,4-triazol-3-yl)methyl])-2H-tetrazole derivative as well as the corresponding thioglucoside were prepared. The synthesized compounds were tested for their antimicrobial activity against Aspergillus Niger, Penicillium sp, Candida albican, Bacillus subtilis, Streptococcus lacti, Escherichia coli, Pseudomonas sp., and streptomyces sp. Compounds 3, 5 and 19b exhibited potent antibacterial activity and compounds 4, 5 and 10 exhibited high activities against the tested fungi compared with fusidic acid.

CMOS analog baseband circuitry for an IEEE 802.11 b/g/n WLAN transceiver

NASA Astrophysics Data System (ADS)

Zheng, Gong; Xiaojie, Chu; Qianqian, Lei; Min, Lin; Yin, Shi

2012-11-01

An analog baseband circuit for a direct conversion wireless local area network (WLAN) transceiver in a standard 0.13-μm CMOS occupying 1.26 mm2 is presented. The circuit consists of active-RC receiver (RX) 4th order elliptic lowpass filters(LPFs), transmit (PGAs) with DC offset cancellation (DCOC) servo loops, and on-chip output buffers. The RX baseband gain can be programmed in the range of -11 to 49 dB in 2 dB steps with 50-30.2 nV/√Hz input referred noise (IRN) and a 21 to -41 dBm in-band 3rd order interception point (IIP3). The RX/TX LPF cutoff frequencies can be switched between 5 MHz, 10 MHz, and 20 MHz to fulfill the multimode 802.11b/g/n requirements. The TX baseband gain of the I/Q paths are tuned separately from -1.6 to 0.9 dB in 0.1 dB steps to calibrate TX I/Q gain mismatches. By using an identical integrator based elliptic filter synthesis method together with global compensation applied to the LPF capacitor array, the power consumption of the RX LPF is considerably reduced and the proposed chip draws 26.8 mA/8 mA by the RX/TX baseband paths from a 1.2 V supply.

International Symposium on Molecular Spectroscopy (46th) Held in Columbus, Ohio on 17-21 June 1991,

DTIC Science & Technology

1991-07-01

8217 in the X ’ B1 ground electronic state has suggested that this ion is quasilinear. Analogous conclusion is obtained from ab initio calculations () An...are also reported for C7 0 . The Dih rugby -ball shaped equilibrium geometry, obtained via analytic energy derivatives, is reminiscent of y.0 except...reference CISD calculations have been performed on the ground state (IA1) and the six lowest-energy excited states (I- B1 , ’-B2, and 1𔃽A2). The

Heterogeneous wireless/wireline optical access networks with the R-EAT as backend component

NASA Astrophysics Data System (ADS)

Hagedorn, Klaus; Gindera, Ralf; Stohr, Andreas; Jager, Dieter

2004-09-01

A heterogeneous wireless/wireline optical transmission link using a reflection type electroabsorption transceiver (R-EAT) is presented. Simultaneous transmission of full-duplex broadband wireless LAN (WLAN) channels and 1Gb/s base band data is experimentally demonstrated. The system link employs sub-carrier multiplexing (SCM) and two optical channels for full duplex transmission of various analog WLAN channels and downlink digital base band data. The developed link architecture is suitable for simultaneous transmission of broadband wireline and wireless signals, it enables the coexistence and interoperability between wireline and wireless access technologies. The developed R-EAT component employed in this wireline/wireless access system, features "single-chip-component" base stations in access networks with star type topology where only a single optical fiber is used for bidirectional optical transmission. The R-EAT can be used within the optical C-band (1530- 1560nm) and is suitable for (D)WDM networks. Bit error rate measurements demonstrate the capabilities of the R-EAT for 1Gb/s base band transmission. The analog performance for WLAN transmission is characterised by a spurious free dynamic range (SFDR) of more than 75dB and 90dB for uplink and downlink transmission, respectively. The link gain for uplink and downlink transmission is -42dB and -37dB, respectively. The demonstrates the analog performances of the R-EAT for being used in wireless access networks such as W-LAN.

Synthesis and coordinating ability of an anionic cobaltabisdicarbollide ligand geometrically analogous to BINAP.

PubMed

Rojo, Isabel; Teixidor, Francesc; Viñas, Clara; Kivekäs, Raikko; Sillanpää, Reijo

2004-10-25

The anionic chelating ligand [1,1'-(PPh2)2-3,3'-Co(1,2-C2B9H10)2]- has been synthesized from [3,3'-Co(1,2-C2B9H11)2]- in very good yield in a one-pot process with an easy work-up procedure. The coordinating ability of this ligand has been studied with Group 11 metal ions (Ag, Au) and with transition-metal ions (Pd, Rh). The two dicarbollide halves of the [1,1'-(PPh2)2-3,3'-Co(1,2-C2B9H10)2]- ligand can swing about one axis in a manner analogous to the constituent parts of BINAP and ferrocenyl phosphine derivatives. All these ligands function as hinges, with the most important property in relation to the coordination requirements of the metal being the PP distance. [1,1'-(PPh2)2-3,3'-Co(1,2-C2B9H10)2]-, BINAP, ferrocenyl phosphine derivatives, and other hinge ligands present a range of different PP separations, and consequently different coordination spheres and dispositions around metal cations. To account for these differences, the equation Dphi2 = D02 + 4 R2cos2(90-phi/2) has been developed. It relates the PP distance (Dphi) in a complex with the minimum PP distance (D0) that is characteristic of the hinge-type ligand.

Forecast of Remote Underwater Sensing Technology.

DTIC Science & Technology

1980-07-01

hr T. MAGNETICS (2 Replies) Q. What will be sensitivities of fluxgate , proton, optical pump, SQUID (superconducting) magnetometers ? A. Fluxgate 0.1...ft Oujtpuit Analog, digital and B3CD Cost $65.K 227 Manu factu rer EG&G Geometric Unit G-806M System Marine Search Proton Magnetometer Sensitivity...optional) Depth Range 0 to 100 m or 6000 m Precision +0.15% FS Time Constant 60 ms Output Digital display, analog and digital BCD output Cost $13.K 243

Inhibition of veratridine-induced delayed inactivation of the voltage-sensitive sodium channel by synthetic analogs of crambescin B.

PubMed

Tsukamoto, Tadaaki; Chiba, Yukie; Nakazaki, Atsuo; Ishikawa, Yuki; Nakane, Yoshiki; Cho, Yuko; Yotsu-Yamashita, Mari; Nishikawa, Toshio; Wakamori, Minoru; Konoki, Keiichi

2017-03-01

Crambescin B carboxylic acid, a synthetic analog of crambescin B, was recently found to inhibit the voltage-sensitive sodium channels (VSSC) in a cell-based assay using neuroblastoma Neuro 2A cells. In the present study, whole-cell patch-clamp recordings were conducted with three heterologously expressed VSSC subtypes, Na v 1.2, Na v 1.6 and Na v 1.7, in a human embryonic kidney cell line HEK293T to further characterize the inhibition of VSSC by crambescin B carboxylic acid. Contrary to the previous observation, crambescin B carboxylic acid did not inhibit peak current evoked by depolarization from the holding potential of -100mV to the test potential of -10mV in the absence or presence of veratridine (VTD). In the presence of VTD, however, crambescin B carboxylic acid diminished VTD-induced sustained and tail currents through the three VSSC subtypes in a dose-dependent manner, whereas TTX inhibited both the peak current and the VTD-induced sustained and tail currents through all subtypes of VSSC tested. We thus concluded that crambescin B carboxylic acid does not block VSSC in a similar manner to TTX but modulate the action of VTD, thereby causing an apparent block of VSSC in the cell-based assay. Copyright © 2017 Elsevier Ltd. All rights reserved.

All-digital 1.2-Gbit/s real-time HDTV VTR

NASA Astrophysics Data System (ADS)

Thorpe, Laurence J.; Yoshinaka, T.

1992-08-01

In 1984 the first real-time HDTV video tape recorder was introduced. The HDV-1000 was an analog VTR using one inch metal oxide tape and standard SMPTE open reels. It utilized basic Type-C recording principles although also incorporating a considerably higher FM carrier frequency, twice the deviation, and slightly more preemphasis, - all to achieve a 10 MHz baseband video recording bandwidth capability. Four such component analog recording channels were utilized in parallel to achieve a total recording capability of 40 MHz - made up of 20 MHz for the green video signal (or Luminance Y) and 10 MHz each for the red and blue signals (or R-Y and B-Y components in the case of Y, R-Y, B-Y recording). Almost 150 of these machines supported the early pioneering years of HDTV development - worldwide - over the period 1984 to the late 1980's. The HDTV video signal format to which this VTR was designed was based upon the preliminary 1 125/60/16:9/2: 1 system - having specified system bandwiths of 20 MHz for Luminance Y, and 7.0MHz R-Y, and 5.5 MHz B-Y. The HDV-1000 proved to be a remarkably robust, reliable HD VTR workhorse and it early and firmly established the viability of reliable RD real-time image capture. Nevertheless, it's technical shortcomings were soon exposed by a creative and demanding international program production community. The limitations of two channels of analog audio recording, and about four generations of liD video recording in post-production were inconsistent with the needs of high-end program production. The 45 db signal to noise limitation also imposed a boundary to the quality of the HDTV tape to 35 mm film transfers being made by both Electron Beam and Laser Recording techniques. The HDV-1000 had, however, pushed the state of the art in analog FM recording to the boundary. Head and tape technologies were not expected to advance sufficiently to warrant a new generation in analog recording design. Attention thus turned to digital recording techniques.

Representations of some quantum tori Lie subalgebras

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jiang, Jingjing; Wang, Song

2013-03-15

In this paper, we define the q-analog Virasoro-like Lie subalgebras in x{sub {infinity}}=a{sub {infinity}}(b{sub {infinity}}, c{sub {infinity}}, d{sub {infinity}}). The embedding formulas into x{sub {infinity}} are introduced. Irreducible highest weight representations of A(tilde sign){sub q}, B(tilde sign){sub q}, and C(tilde sign){sub q}-series of the q-analog Virasoro-like Lie algebras in terms of vertex operators are constructed. We also construct the polynomial representations of the A(tilde sign){sub q}, B(tilde sign){sub q}, C(tilde sign){sub q}, and D(tilde sign){sub q}-series of the q-analog Virasoro-like Lie algebras.

Is free halogen necessary for disinfection?

PubMed Central

Williams, D E; Elder, E D; Worley, S D

1988-01-01

The principle of Le Chatelier was used in demonstrating that 3-chloro-4,4-dimethyl-2-oxazolidinone (compound 1) itself kills Staphylococcus aureus rather than the very small amount of free chlorine in hydrolysis equilibrium with compound 1. On the other hand, when the N-bromo analog of compound 1 (compound 1B) was used as the disinfectant, the mixture of combined compound 1B and free bromine formed in the hydrolysis equilibrium provided disinfection. When the hydrolysis equilibrium for 1B was suppressed to the level at which a negligible amount of free bromine remained in solution, combined compound 1B was much more efficacious than combined compound 1 at killing S. aureus. PMID:3202636

Is free halogen necessary for disinfection?

PubMed

Williams, D E; Elder, E D; Worley, S D

1988-10-01

The principle of Le Chatelier was used in demonstrating that 3-chloro-4,4-dimethyl-2-oxazolidinone (compound 1) itself kills Staphylococcus aureus rather than the very small amount of free chlorine in hydrolysis equilibrium with compound 1. On the other hand, when the N-bromo analog of compound 1 (compound 1B) was used as the disinfectant, the mixture of combined compound 1B and free bromine formed in the hydrolysis equilibrium provided disinfection. When the hydrolysis equilibrium for 1B was suppressed to the level at which a negligible amount of free bromine remained in solution, combined compound 1B was much more efficacious than combined compound 1 at killing S. aureus.

Synthesis of Antidotes and Prophylactics for Organophosphorus Acetylcholinesterase Inhibitors

DTIC Science & Technology

1996-01-01

Choline A nalogs .............................................. 13 D . M iscellaneous Com pounds...27b 27c (PN-III-28) CH(CH3 )2 TsO 28a 28b 28c (PN-II-258) Ph I C. Carbamoyl enolates of Choline Analogs The enolates of 1-methyl-3-piperidone and 1...sodium bicarbonate solution. The crystalline solid obtained was filtered and dried to give 4.5 g (77%) of the amine. 6-Benzoyloxyimidazo[1,2-a]pyridine

Studies on Aculeines: Synthetic Strategy to the Fully Protected Protoaculeine B, the N-Terminal Amino Acid of Aculeine B.

PubMed

Shiozaki, Hiroki; Miyahara, Masayoshi; Otsuka, Kazunori; Miyako, Kei; Honda, Akito; Takasaki, Yuichi; Takamizawa, Satoshi; Tukada, Hideyuki; Ishikawa, Yuichi; Sakai, Ryuichi; Oikawa, Masato

2018-05-23

A synthetic strategy for accessing protoaculeine B (1), the N-terminal amino acid of the highly modified peptide toxin aculeine, was developed via the synthesis of the fully protected natural homologue of 1 with a 12-mer poly(propanediamine). The synthesis of mono(propanediamine) analog 2, as well as core amino acid 3, was demonstrated by this strategy. New amino acid 3 induced convulsions in mice; however, compound 2 showed no such activity.

Fluorescence 'turn-on' sensor for F- derived from vitamin B6 cofactor.

PubMed

Sharma, Darshna; Sahoo, Suban K; Chaudhary, Soma; Bera, Rati Kanta; Callan, John F

2013-07-07

A novel vitamin B6 Schiff base analog (L) was synthesized by combining vitamin B6 cofactor pyridoxal with 2-aminophenol. Receptor L displays a color change detectable by the naked-eye from yellow to red in the presence of fluoride and acetate due to the formation of hydrogen bonding host-guest complexes in 1 : 1 stoichiometry. Importantly, receptor L showed fluoride-selective 'turn-on' fluorescent response with a detection limit (3σ) of 7.39 × 10(-8) M.

Biotoxicity of Mars soils: 1. Dry deposition of analog soils on microbial colonies and survival under Martian conditions

NASA Astrophysics Data System (ADS)

Schuerger, Andrew C.; Golden, D. C.; Ming, Doug W.

2012-11-01

Six Mars analog soils were created to simulate a range of potentially biotoxic geochemistries relevant to the survival of terrestrial microorganisms on Mars, and included basalt-only (non-toxic control), salt, acidic, alkaline, aeolian, and perchlorate rich geochemistries. Experiments were designed to simulate the dry-deposition of Mars soils onto spacecraft surfaces during an active descent landing scenario with propellant engines. Six eubacteria were initially tested for tolerance to desiccation, and the spore-former Bacillus subtilis HA101 and non-spore former Enterococcus faecalis ATCC 29212 were identified to be strongly resistant (HA101) and moderately resistant (29212) to desiccation at 24 °C. Furthermore, tests with B. subtilis and E. faecalis demonstrated that at least 1 mm of Mars analog soil was required to fully attenuate the biocidal effects of a simulated Mars-normal equatorial UV flux. Biotoxicity experiments were conducted under simulated Martian conditions of 6.9 mbar, -10 °C, CO2-enriched anoxic atmosphere, and a simulated equatorial solar spectrum (200-1100 nm) with an optical depth of 0.1. For B. subtilis, the six analog soils were found, in general, to be of low biotoxicity with only the high salt and acidic soils exhibiting the capacity to inactivate a moderate number of spores (<1 log reductions) exposed 7 days to the soils under simulated Martian conditions. In contrast, the overall response of E. faecalis to the analog soils was more dramatic with between two and three orders of magnitude reductions in viable cells for most soils, and between six and seven orders of magnitude reductions observed for the high-salt soil. Results suggest that Mars soils are likely not to be overtly biotoxic to terrestrial microorganisms, and suggest that the soil geochemistries on Mars will not preclude the habitability of the Martian surface.

Incorporating a Nebulizer System Into High-Flow Nasal Cannula Improves Comfort in Infants With Bronchiolitis.

PubMed

Valencia-Ramos, Juan; Mirás, Alicia; Cilla, Amacia; Ochoa, Carlos; Arnaez, Juan

2018-07-01

High-flow nasal cannula (HFNC) is increasingly used to provide respiratory support in infants with bronchiolitis. The delivery of aerosol therapy through a jet nebulizer is widely indicated despite its controversial efficacy and poor tolerability. This randomized cross-over study aimed to evaluate the comfort and satisfaction of the delivery of aerosol therapy using a nebulization system integrated into HFNC compared with the standard practice of using a jet nebulizer with a face mask. The COMFORT-Behavior (COMFORT-B) scale, a visual analog scale, and a numeric rating scale were used by health professionals and caregivers to assess subjects' levels of comfort and satisfaction. A total of 113 nebulizations (64 via nebulizer with HFNC; 49 via jet nebulizer) were delivered to the 6 subjects included in the study. Use of the nebulizer with HFNC showed increased comfort and satisfaction during nebulization compared to use of the jet nebulizer, as measured by the COMFORT-B scale, the visual analog scale, and the numeric rating scale, with the following median (interquartile range) scores: 10.7 (7-16) versus 14.5 (10-20) ( P = .006), 8.5 (6-10) versus 7 (4-9) ( P = .02), and 3.84 (3.61-4.07) versus 1.83 (1.58-2.08) ( P < .001), respectively. Correlation between the COMFORT-B scale and the visual analog scale using Spearman's rho was -0.757 ( P < .001). The intraclass correlation coefficient for the COMFORT-B scale, visual analog scale, and numeric rating scale, as measured by 2 different nurses, was between 0.75 and 0.87. The use of a nebulizer incorporated into HFNC therapy results in an increased level of comfort and satisfaction compared to the use of a conventional jet nebulizer in subjects with bronchiolitis who required HFNC therapy. Further studies are needed to determine whether aerosol therapy delivered through HFNC improves the clinical course of this pathology. Copyright © 2018 by Daedalus Enterprises.

Stereoselective preparation of quaternary 2-vinyl sphingosines and ceramides and their effect on basal sphingolipid metabolism.

PubMed

Calderón, Raquel; Mercadal, Nerea; Abad, José Luis; Ariza, Xavier; Delgado, Antonio; Garcia, Jordi; Rodríguez, Aleix; Fabriàs, Gemma

2017-06-01

The dicyclohexylborane-mediated addition of allene 1 to (E)-2-tridecenal affords a quaternary protected 2-amino-2-vinyl-1,3-diol in good yield as a single diastereomer. This compound is readily transformed into the four stereoisomers of the quaternary (E)-2-vinyl analogs of sphingosine. The metabolic fate and the effect of these compounds on the basal sphingolipid metabolism in human A549 lung adenocarcinoma cells has been studied, together with the ceramide analog of the most relevant vinylsphingosine derivative. Copyright © 2017 Elsevier B.V. All rights reserved.

Hapten-antibody recognition studies in competitive immunoassay of α-zearalanol analogs by computational chemistry and Pearson Correlation analysis.

PubMed

Wang, Zhanhui; Luo, Pengjie; Cheng, Linli; Zhang, Suxia; Shen, Jianzhong

2011-01-01

The molecular recognition of hapten-antibody is a fundamental event in competitive immunoassay, which guarantees the sensitivity and specificity of immunoassay for the detection of haptens. The aim of this study is to investigate the correlation between binding ability of one monoclonal antibody, 1H9B4, recognizing and the molecular aspects of α-zearalanol analogs. The mouse-derived monoclonal antibody was produced by using α-zearalanol conjugated to bovine serum albumin as an immunogen. The antibody recognition abilities, expressed as IC(50) values, were determined by a competitive ELISA. All of the hapten molecules were optimized by Density Function Theory (DFT) at B3LYP/ 6-31G* level and the conformation and electrostatic molecular isosurface were employed to explain the molecular recognition between α-zearalanol analogs and antibody 1H9B4. Pearson Correlation analysis between molecular descriptors and IC(50) values was qualitatively undertaken and the results showed that one molecular descriptor, surface of the hapten molecule, clearly demonstrated linear relationship with antibody recognition ability, where the relationship coefficient was 0.88 and the correlation was significant at p < 0.05 level. The study shows that computational chemistry and Pearson Correlation analysis can be used as tool to help the immunochemistries better understand the processing of antibody recognition of hapten molecules in competitive immunoassay. Copyright © 2011 John Wiley & Sons, Ltd.

Automatic Generation of Analogy Questions for Student Assessment: An Ontology-Based Approach

ERIC Educational Resources Information Center

Alsubait, Tahani; Parsia, Bijan; Sattler, Uli

2012-01-01

Different computational models for generating analogies of the form "A is to B as C is to D" have been proposed over the past 35 years. However, analogy generation is a challenging problem that requires further research. In this article, we present a new approach for generating analogies in Multiple Choice Question (MCQ) format that can be used…

Structures of human monoamine oxidase B complexes with selective noncovalent inhibitors: safinamide and coumarin analogs.

PubMed

Binda, Claudia; Wang, Jin; Pisani, Leonardo; Caccia, Carla; Carotti, Angelo; Salvati, Patricia; Edmondson, Dale E; Mattevi, Andrea

2007-11-15

Structures of human monoamine oxidase B (MAO B) in complex with safinamide and two coumarin derivatives, all sharing a common benzyloxy substituent, were determined by X-ray crystallography. These compounds competitively inhibit MAO B with Ki values in the 0.1-0.5 microM range that are 30-700-fold lower than those observed with MAO A. The inhibitors bind noncovalently to MAO B, occupying both the entrance and the substrate cavities and showing a similarly oriented benzyloxy substituent.

Analogical Inference and Analogical Access.

DTIC Science & Technology

1987-08-04

Dedre Gentner 13a TYPE OF REPORT 13b TIME COVERED 14. DATE OF REPORT (Year, Month, Day) 15. PAGE COUNT Technical Report FROM 85-9-1 TO 88-8-3j 87-4-8 48...systems of relations, rather than isolated predicates. I will also use the term systeeaetcity at times to refer to the presence of a system of relations...agreement among the judgest they were within one point of each other 97% of the time . 10. These patterns were confirmed by an analysis of variance and by

2-acetylphenol analogs as potent reversible monoamine oxidase inhibitors.

PubMed

Legoabe, Lesetja J; Petzer, Anél; Petzer, Jacobus P

2015-01-01

Based on a previous report that substituted 2-acetylphenols may be promising leads for the design of novel monoamine oxidase (MAO) inhibitors, a series of C5-substituted 2-acetylphenol analogs (15) and related compounds (two) were synthesized and evaluated as inhibitors of human MAO-A and MAO-B. Generally, the study compounds exhibited inhibitory activities against both MAO-A and MAO-B, with selectivity for the B isoform. Among the compounds evaluated, seven compounds exhibited IC50 values <0.01 µM for MAO-B inhibition, with the most selective compound being 17,000-fold selective for MAO-B over the MAO-A isoform. Analyses of the structure-activity relationships for MAO inhibition show that substitution on the C5 position of the 2-acetylphenol moiety is a requirement for MAO-B inhibition, and the benzyloxy substituent is particularly favorable in this regard. This study concludes that C5-substituted 2-acetylphenol analogs are potent and selective MAO-B inhibitors, appropriate for the design of therapies for neurodegenerative disorders such as Parkinson's disease.

Human Health Countermeasures - Partial-Gravity Analogs Workshop

NASA Technical Reports Server (NTRS)

Barr, Yael; Clement, Gilles; Norsk, Peter

2016-01-01

The experimental conditions that were deemed the most interesting by the HHC Element lead scientists are those permitting studies of the long-term effects of exposure to (a) chronic rotation when supine or in head down tilt (ground-based); and (b) long-radius centrifugation (space based). It is interesting to note that chronic ground based slow rotation room studies have not been performed since the 1960's, when the USA and USSR were investigating the potential use of AG for long-duration space missions. On the other hand, the other partial gravity analogs, i.e., parabolic flight, HUT, suspension, and short-radius centrifugation, have been regularly used in the last three decades (see review in Clément et al. 2015). Based on the workshop evaluations and the scores by the HHC scientific disciplines indicated in tables 3 and 4, simulation of partial G between 0 and 1 should be prioritized as follows: Priority 1. Chronic space-based partial-G analogs: a. Chronic space-based long-radius centrifugation. The ideal scenario would be chronic long-radius centrifugation of cells, animals and humans in a translational research approach - ideally beyond low earth orbit under deep space environmental effects and at various rotations - to obtain different G-effects. In this scenario, all physiological systems could be evaluated and the relationship between physiological response and G level established. This would be the most integrative way of defining, for the first time ever, G-thresholds for each physiological system. b. Chronic space-based centrifugation of animals. Chronic centrifugation of rodents at various G levels in space would allow for determination of AG thresholds of protection for each physiological system. In this case, all physiological systems will be of interest. Intermittent centrifugation will be of secondary interest. c. Chronic space-based centrifugation of cell cultures (RWV). Bioreactor studies of cells and cell cultures of various tissues at various G levels would allow for intracellular investigations of the effects of partial-G. Priority 2. Acute, intermittent space based partial-G analogs: a. Acute, intermittent space-based short radius human centrifugation. Intermittent centrifugation of humans would allow determination of thresholds of AG for protection of astronaut health in space. Priority 3. Chronic ground-based partial-G analogs: a. Chronic centrifugation of supine or head-down tilted humans. b. Chronic head-up tilt in humans. c. Chronic head-out graded dry immersion in humans. d. Chronic partial suspension of rodents e. Chronic rotating bioreactor cell culture studies (RWV) Priority 4. Acute ground based partial-G analogs. a. Parabolic flights. Very acute and short term effects of G levels between 0 and 1 in humans for fast responding systems like cardiovascular and sensorimotor as well as for acute responses in cell cultures and animals. b. Other acute models as indicated in table 3.

Subtype specific internalization of P2Y1 and P2Y2 receptors induced by novel adenosine 5′-O-(1-boranotriphosphate) derivatives

PubMed Central

Tulapurkar, M E; Laubinger, W; Nahum, V; Fischer, B; Reiser, G

2004-01-01

P2Y-nucleotide receptors represent important targets for drug development. The lack of stable and receptor specific agonists, however, has prevented successful therapeutic applications. A novel series of P-boronated ATP derivatives (ATP-α-B) were synthesized by substitution of a nonbridging O at Pα with a BH3 group. This introduces a chiral center, thus resulting in diastereoisomers. In addition, at C2 of the adenine ring a further substitution was made (Cl- or methylthio-). The pairs of diastereoisomers were denoted here as A and B isomers. Here, we tested the receptor subtype specificity of these analogs on HEK 293 cells stably expressing rat P2Y1 and rat P2Y2 receptors, respectively, both attached to the fluorescent marker protein GFP (rP2Y1-GFP, rP2Y2-GFP). We investigated agonist-induced receptor endocytosis, [Ca2+]i rise and arachidonic acid (AA) release. Agonist-induced endocytosis of rP2Y1-GFP was more pronounced for the A isomers than the corresponding B counterparts for all ATP-α-B analogs. Both 2-MeS-substituted diastereoisomers induced a greater degree of agonist-induced receptor endocytosis as compared to the 2-Cl-substituted derivatives. Endocytosis results are in accordance with the potency to induce Ca2+ release by these compounds in HEK 293 cells stably transfected with rP2Y1. In case of rP2Y2-GFP, the borano-nucleotides were very weak agonists in comparison to UTP and ATP in terms of Ca2+ release, AA release and in inducing receptor endocytosis. The different ATP-α-B derivatives and also the diastereoisomers were equally ineffective. Thus, the new agonists may be considered as potent and highly specific agonist drug candidates for P2Y1 receptors. The difference in activity of the ATP analogs at P2Y receptors could be used as a tool to investigate structural differences between P2Y receptor subtypes. PMID:15197109

In vitro monoamine oxidase inhibition potential of alpha-methyltryptamine analog new psychoactive substances for assessing possible toxic risks.

PubMed

Wagmann, Lea; Brandt, Simon D; Kavanagh, Pierce V; Maurer, Hans H; Meyer, Markus R

2017-04-15

Tryptamines have emerged as new psychoactive substances (NPS), which are distributed and consumed recreationally without preclinical studies or safety tests. Within the alpha-methylated tryptamines, some of the psychoactive effects of the prototypical alpha-methyltryptamine (AMT) have been described decades ago and a contributing factor of its acute toxicity appears to involve the inhibition of monoamine oxidase (MAO). However, detailed information about analogs is scarce. Therefore, thirteen AMT analogs were investigated for their potential to inhibit MAO. An in vitro assay analyzed using hydrophilic interaction liquid chromatography-high resolution-tandem mass spectrometry was developed and validated. The AMT analogs were incubated with recombinant human MAO-A or B and kynuramine, a non-selective MAO substrate to determine the IC 50 values. The known MAO-A inhibitors 5-(2-aminopropyl)indole (5-IT), harmine, harmaline, yohimbine, and the MAO-B inhibitor selegiline were tested for comparison. AMT and all analogs showed MAO-A inhibition properties with IC 50 values between 0.049 and 166μM, whereas four analogs inhibited also MAO-B with IC 50 values between 82 and 376μM. 7-Me-AMT provided the lowest IC 50 value against MAO-A comparable to harmine and harmaline and was identified as a competitive MAO-A inhibitor. Furthermore, AMT, 7-Me-AMT, and nine further analogs inhibited MAO activity in human hepatic S9 fraction used as model for the human liver which expresses both isoforms. The obtained results suggested that MAO inhibition induced by alpha-methylated tryptamines might be clinically relevant concerning possible serotonergic and adrenergic effects and interactions with drugs (of abuse) particularly acting as monoamine reuptake inhibitors. However, as in vitro assays have only limited conclusiveness, further studies are needed. Copyright © 2017 Elsevier B.V. All rights reserved.

40 CFR 159.179 - Metabolites, degradates, contaminants, and impurities.

Code of Federal Regulations, 2010 CFR

2010-07-01

... chemical properties of the metabolite or degradate. (B) Data regarding structurally analogous chemicals. (C) Data regarding chemical reactivity of the metabolite or degradate and structurally analogous substances... any person described in § 159.158(a) that the metabolite or degradate, or analogous chemicals, may...

40 CFR 159.179 - Metabolites, degradates, contaminants, and impurities.

Code of Federal Regulations, 2011 CFR

2011-07-01

... chemical properties of the metabolite or degradate. (B) Data regarding structurally analogous chemicals. (C) Data regarding chemical reactivity of the metabolite or degradate and structurally analogous substances... any person described in § 159.158(a) that the metabolite or degradate, or analogous chemicals, may...

47 CFR 11.55 - EAS operation during a State or Local Area emergency.

Code of Federal Regulations, 2010 CFR

2010-10-01

... leaks or liquid spills, widespread power failures, industrial explosions, and civil disorders. (1) DBS...); analog cable systems, digital cable systems, and wireless cable systems must comply with § 11.54(b)(6... programming should comply with § 11.54(b)(8). (5) Upon completion of the State or Local Area EAS transmission...

28 CFR 2.21 - Reparole consideration guidelines.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 28 Judicial Administration 1 2010-07-01 2010-07-01 false Reparole consideration guidelines. 2.21....21 Reparole consideration guidelines. (a)(1) If revocation is based upon administrative violation(s... analogy with listed federal offense behaviors. (b) The guidelines for parole consideration specified at 28...

The optical analogy for vector fields

NASA Technical Reports Server (NTRS)

Parker, E. N. (Editor)

1991-01-01

This paper develops the optical analogy for a general vector field. The optical analogy allows the examination of certain aspects of a vector field that are not otherwise readily accessible. In particular, in the cases of a stationary Eulerian flow v of an ideal fluid and a magnetostatic field B, the vectors v and B have surface loci in common with their curls. The intrinsic discontinuities around local maxima in absolute values of v and B take the form of vortex sheets and current sheets, respectively, the former playing a fundamental role in the development of hydrodyamic turbulence and the latter playing a major role in heating the X-ray coronas of stars and galaxies.

Planar dicyclic B{sub 6}S{sub 6}, B{sub 6}S{sub 6}{sup −}, and B{sub 6}S{sub 6}{sup 2−} clusters: Boron sulfide analogues of naphthalene

DOE Office of Scientific and Technical Information (OSTI.GOV)

Li, Da-Zhi; Bai, Hui; Ou, Ting

2015-01-07

Inorganic analogues of hydrocarbons or polycyclic aromatic hydrocarbons (PAHs) are of current interest in chemistry. Based upon global structural searches and B3LYP and CCSD(T) calculations, we present herein the perfectly planar dicyclic boron sulfide clusters: D{sub 2h} B{sub 6}S{sub 6} (1, {sup 1}A{sub g}), D{sub 2h} B{sub 6}S{sub 6}{sup −} (2, {sup 2}B{sub 3u}), and D{sub 2h} B{sub 6}S{sub 6}{sup 2−} (3, {sup 1}A{sub g}). These are the global minima of the systems, being at least 0.73, 0.81, and 0.53 eV lower in energy, respectively, than their alternative isomers at the CCSD(T) level. The D{sub 2h} structures feature twin B{submore » 3}S{sub 2} five-membered rings, which are fused together via a B{sub 2} unit and terminated by two BS groups. Bonding analyses show that the closed-shell B{sub 6}S{sub 6}{sup 2−} (3) cluster possesses 10 delocalized π electrons, closely analogous to the bonding pattern of the aromatic naphthalene C{sub 10}H{sub 8}. The B{sub 6}S{sub 6}{sup −} (2) and B{sub 6}S{sub 6} (1) species are readily obtained upon removal of one or two π electrons from B{sub 6}S{sub 6}{sup 2−} (3). The results build a new analogous relationship between boron sulfide clusters and their PAH counterparts. The B{sub 6}S{sub 6}{sup −} (2) monoanion and B{sub 6}S{sub 6}{sup 2−} (3) dianion can be effectively stabilized in neutral LiB{sub 6}S{sub 6} and Li{sub 2}B{sub 6}S{sub 6} salts, respectively.« less

Synthesis of Improved Antileishmanial and Antitrypanosomal Drugs Treatment and Prophylaxis

DTIC Science & Technology

1986-11-01

for a diphenyl ether analog ((2) p. 44). 16 - -r , ü$$m&±ysc$c .<v£*^Ä VV’-Orfs aB9*>ratfe>^v CHART NO. 1 8-[(6-AMIDOXIMINOHEXYL)AMINO]-6-METHOXY...MALEATE (SNL-130) cico—(f)V-ci A1C1 CS 1 (58%) • Brü 1) »3PCH2CH2NMe2/n-BuLi 2) H30* 3) Oxalic Acid 4) OH 0 «CHCH,NMe 2ŕ,c2 2 (79%), Free base... diphenyl ether analog ((2) p. 44). A mixture of sodium amide (11.6 g, O.J mol), acetonitrile (15 mL, 11.8 g> 0.29 mol) and dry benzene (1 L) was heated

Sleep promotes analogical transfer in problem solving.

PubMed

Monaghan, Padraic; Sio, Ut Na; Lau, Sum Wai; Woo, Hoi Kei; Linkenauger, Sally A; Ormerod, Thomas C

2015-10-01

Analogical problem solving requires using a known solution from one problem to apply to a related problem. Sleep is known to have profound effects on memory and information restructuring, and so we tested whether sleep promoted such analogical transfer, determining whether improvement was due to subjective memory for problems, subjective recognition of similarity across related problems, or by abstract generalisation of structure. In Experiment 1, participants were exposed to a set of source problems. Then, after a 12-h period involving sleep or wake, they attempted target problems structurally related to the source problems but with different surface features. Experiment 2 controlled for time of day effects by testing participants either in the morning or the evening. Sleep improved analogical transfer, but effects were not due to improvements in subjective memory or similarity recognition, but rather effects of structural generalisation across problems. Copyright © 2015 Elsevier B.V. All rights reserved.

Two multichannel integrated circuits for neural recording and signal processing.

PubMed

Obeid, Iyad; Morizio, James C; Moxon, Karen A; Nicolelis, Miguel A L; Wolf, Patrick D

2003-02-01

We have developed, manufactured, and tested two analog CMOS integrated circuit "neurochips" for recording from arrays of densely packed neural electrodes. Device A is a 16-channel buffer consisting of parallel noninverting amplifiers with a gain of 2 V/V. Device B is a 16-channel two-stage analog signal processor with differential amplification and high-pass filtering. It features selectable gains of 250 and 500 V/V as well as reference channel selection. The resulting amplifiers on Device A had a mean gain of 1.99 V/V with an equivalent input noise of 10 microV(rms). Those on Device B had mean gains of 53.4 and 47.4 dB with a high-pass filter pole at 211 Hz and an equivalent input noise of 4.4 microV(rms). Both devices were tested in vivo with electrode arrays implanted in the somatosensory cortex.

New compounds, nanaomycin F and G, discovered by physicochemical screening from a culture broth of Streptomyces rosa subsp. notoensis OS-3966.

PubMed

Nakashima, Takuji; Boonsnongcheep, Panitch; Kimura, Toru; Iwatsuki, Masato; Sato, Noriko; Nonaka, Kenichi; Prathanturarug, Sompop; Takahashi, Yōko; Ōmura, Satoshi

2015-11-01

Two new compounds, nanaomycin F and G, were isolated by physicochemical screening method from cultured broth of Streptomyces rosa subsp. notoensis OS-3966, which is known to produce nanaomycin A, B, C, D, and E. Nanaomycin F is a new nanaomycin analog, a 4a-hydroxyl analog of nanaomycin B. Nanaomycin G has a unique skeleton with 1-indanone infused with a tetrahydropyran ring. Nanaomycin A possesses broad antimicrobial activity but nanaomycin F and G demonstrated no bioactivity against all bacteria and fungi tested in this study. In addition, in both nanaomycin F and G, the production of superoxide radicals was majorly decreased in comparison to nanaomycin A. It was considered that the antimicrobial properties were lost as a result of the decrease in production of the superoxide radicals. Copyright © 2015 The Society for Biotechnology, Japan. Published by Elsevier B.V. All rights reserved.

ALMA 1.3 Millimeter Map of the HD 95086 System -- A Young Analog of the HR 8799 System

NASA Astrophysics Data System (ADS)

Su, Kate; MacGregor, Meredith Ann; Booth, Mark; Wilner, David; Malhotra, Renu; Morrison, Sarah; OST STDT

2018-01-01

Planets and minor bodies such as asteroids, Kuiper-belt objects and comets are integral components of a planetary system. Interactions among them leave clues about the formation process of a planetary system. The signature of such interactions is best illustrated through resolved observations of its debris disk. Here we present ALMA 1.3 mm observations of HD 95086, a young analog of the HR 8799 system, that hosts a directly imaged giant planet b and a massive debris disk with both asteroid- and Kuiper-belt analogs. The location of the Kuiper-belt analog is resolved for the first time. Our deep ALMA map also reveals a bright source located near the edge of the ring. The properties of the source, based on limited data, are consistent with it being a luminous star-forming galaxy at high redshift. We will discuss future, resolved observations of debris disks, highlighting the potential of the Origins Space Telescope (OST), one of the four science and technology definition studies commissioned by NASA Headquarters for the 2020 Astronomy and Astrophysics Decadal survey.

Iterative Chemical Engineering of Vancomycin Leads to Novel Vancomycin Analogs With a High in Vitro Therapeutic Index.

PubMed

Mishra, Nigam M; Stolarzewicz, Izabela; Cannaerts, David; Schuermans, Joris; Lavigne, Rob; Looz, Yannick; Landuyt, Bart; Schoofs, Liliane; Schols, Dominique; Paeshuyse, Jan; Hickenbotham, Peter; Clokie, Martha; Luyten, Walter; Van der Eycken, Erik V; Briers, Yves

2018-01-01

Vancomycin is a glycopeptide antibiotic that inhibits transpeptidation during cell wall synthesis by binding to the D-Ala-D-Ala termini of lipid II. For long, it has been used as a last resort antibiotic. However, since the emergence of the first vancomycin-resistant enterococci in 1987, vancomycin resistance has become widespread, especially in hospitals. We have synthesized and evaluated 110 vancomycin analogs modified at the C-terminal carboxyl group of the heptapeptide moiety with R 2 NHR 1 NH 2 substituents. Through iterative optimizations of the substituents, we identified vancomycin analogs that fully restore (or even exceed) the original inhibitory activity against vancomycin-resistant enterococci (VRE), vancomycin-intermediate (VISA) and vancomycin-resistant Staphylococcus aureus (VRSA) strains. The best analogs have improved growth inhibitory activity and in vitro therapeutic indices against a broad set of VRE and methicillin-resistant S. aureus (MRSA) isolates. They also exceed the activity of vancomycin against Clostridium difficile ribotypes. Vanc-39 and Vanc-42 have a low probability to provoke antibiotic resistance, and overcome different vancomycin resistance mechanisms (VanA, VanB, and VanC1).

Exogenous Applications of Brassinosteroids Improve Color of Red Table Grape (Vitis vinifera L. Cv. "Redglobe") Berries.

PubMed

Vergara, Alexis E; Díaz, Katy; Carvajal, Rodrigo; Espinoza, Luis; Alcalde, José A; Pérez-Donoso, Alonso G

2018-01-01

Color and other quality parameters of "Redglobe" grape ( Vitis vinifera L.) berries were evaluated after treatment with brassinosteroid (BR) analogs. Three BRs analogs (24-epibrassinolide, Triol, or Lactone) were applied at three concentrations (0.0, 0.4, or 0.8 mg⋅L -1 ), at the onset of veraison. A commercial formulation (B-2000 ® ) was also applied, at a recommended rate of 0.06 mg⋅L -1 . The tested BR analogs were effective improving berry color (evaluated as color index for red grapes, CIRG), increasing the levels of soluble solids and anthocyanins, and changing the types of anthocyanins present without altering other quality and yield parameters. The effects of BR analogs on color enhancement could be explained by an increase in soluble solids content and/or anthocyanin content. Treatment with 24-epibrassinolide (at 0.4 mg⋅L -1 ) or the commercial formulation tended to favor the production of dihydroxylated anthocyanins, which are responsible for the red and pink colors of grape berries. Results indicate that the use of BRs constitutes a potential tool in the production of table grapes. This is the first report of this enhancement effect in a productive context.

Exogenous Applications of Brassinosteroids Improve Color of Red Table Grape (Vitis vinifera L. Cv. “Redglobe”) Berries

PubMed Central

Vergara, Alexis E.; Díaz, Katy; Carvajal, Rodrigo; Espinoza, Luis; Alcalde, José A.; Pérez-Donoso, Alonso G.

2018-01-01

Color and other quality parameters of “Redglobe” grape (Vitis vinifera L.) berries were evaluated after treatment with brassinosteroid (BR) analogs. Three BRs analogs (24-epibrassinolide, Triol, or Lactone) were applied at three concentrations (0.0, 0.4, or 0.8 mg⋅L-1), at the onset of veraison. A commercial formulation (B-2000®) was also applied, at a recommended rate of 0.06 mg⋅L-1. The tested BR analogs were effective improving berry color (evaluated as color index for red grapes, CIRG), increasing the levels of soluble solids and anthocyanins, and changing the types of anthocyanins present without altering other quality and yield parameters. The effects of BR analogs on color enhancement could be explained by an increase in soluble solids content and/or anthocyanin content. Treatment with 24-epibrassinolide (at 0.4 mg⋅L-1) or the commercial formulation tended to favor the production of dihydroxylated anthocyanins, which are responsible for the red and pink colors of grape berries. Results indicate that the use of BRs constitutes a potential tool in the production of table grapes. This is the first report of this enhancement effect in a productive context. PMID:29681907

All-optical analog comparator.

PubMed

Li, Pu; Yi, Xiaogang; Liu, Xianglian; Zhao, Dongliang; Zhao, Yongpeng; Wang, Yuncai

2016-08-23

An analog comparator is one of the core units in all-optical analog-to-digital conversion (AO-ADC) systems, which digitizes different amplitude levels into two levels of logical '1' or '0' by comparing with a defined decision threshold. Although various outstanding photonic ADC approaches have been reported, almost all of them necessitate an electrical comparator to carry out this binarization. The use of an electrical comparator is in contradiction to the aim of developing all-optical devices. In this work, we propose a new concept of an all-optical analog comparator and numerically demonstrate an implementation based on a quarter-wavelength-shifted distributed feedback laser diode (QWS DFB-LD) with multiple quantum well (MQW) structures. Our results show that the all-optical comparator is very well suited for true AO-ADCs, enabling the whole digital conversion from an analog optical signal (continuous-time signal or discrete pulse signal) to a binary representation totally in the optical domain. In particular, this all-optical analog comparator possesses a low threshold power (several mW), high extinction ratio (up to 40 dB), fast operation rate (of the order of tens of Gb/s) and a step-like transfer function.

All-optical analog comparator

PubMed Central

Li, Pu; Yi, Xiaogang; Liu, Xianglian; Zhao, Dongliang; Zhao, Yongpeng; Wang, Yuncai

2016-01-01

An analog comparator is one of the core units in all-optical analog-to-digital conversion (AO-ADC) systems, which digitizes different amplitude levels into two levels of logical ‘1’ or ‘0’ by comparing with a defined decision threshold. Although various outstanding photonic ADC approaches have been reported, almost all of them necessitate an electrical comparator to carry out this binarization. The use of an electrical comparator is in contradiction to the aim of developing all-optical devices. In this work, we propose a new concept of an all-optical analog comparator and numerically demonstrate an implementation based on a quarter-wavelength-shifted distributed feedback laser diode (QWS DFB-LD) with multiple quantum well (MQW) structures. Our results show that the all-optical comparator is very well suited for true AO-ADCs, enabling the whole digital conversion from an analog optical signal (continuous-time signal or discrete pulse signal) to a binary representation totally in the optical domain. In particular, this all-optical analog comparator possesses a low threshold power (several mW), high extinction ratio (up to 40 dB), fast operation rate (of the order of tens of Gb/s) and a step-like transfer function. PMID:27550874

All-optical analog comparator

NASA Astrophysics Data System (ADS)

Li, Pu; Yi, Xiaogang; Liu, Xianglian; Zhao, Dongliang; Zhao, Yongpeng; Wang, Yuncai

2016-08-01

An analog comparator is one of the core units in all-optical analog-to-digital conversion (AO-ADC) systems, which digitizes different amplitude levels into two levels of logical ‘1’ or ‘0’ by comparing with a defined decision threshold. Although various outstanding photonic ADC approaches have been reported, almost all of them necessitate an electrical comparator to carry out this binarization. The use of an electrical comparator is in contradiction to the aim of developing all-optical devices. In this work, we propose a new concept of an all-optical analog comparator and numerically demonstrate an implementation based on a quarter-wavelength-shifted distributed feedback laser diode (QWS DFB-LD) with multiple quantum well (MQW) structures. Our results show that the all-optical comparator is very well suited for true AO-ADCs, enabling the whole digital conversion from an analog optical signal (continuous-time signal or discrete pulse signal) to a binary representation totally in the optical domain. In particular, this all-optical analog comparator possesses a low threshold power (several mW), high extinction ratio (up to 40 dB), fast operation rate (of the order of tens of Gb/s) and a step-like transfer function.

Treatment of painful diabetic neuropathy

PubMed Central

Petropoulos, Ioannis N.; Alam, Uazman; Malik, Rayaz A.

2015-01-01

Painful diabetic neuropathy (PDN) is a debilitating consequence of diabetes that may be present in as many as one in five patients with diabetes. The objective assessment of PDN is difficult, making it challenging to diagnose and assess in both clinical practice and clinical trials. No single treatment exists to prevent or reverse neuropathic changes or to provide total pain relief. Treatment of PDN is based on three major approaches: intensive glycaemic control and risk factor management, treatments based on pathogenetic mechanisms, and symptomatic pain management. Clinical guidelines recommend pain relief in PDN through the use of antidepressants such as amitriptyline and duloxetine, the γ-aminobutyric acid analogues gabapentin and pregabalin, opioids and topical agents such as capsaicin. Of these medications, duloxetine and pregabalin were approved by the US Food and Drug Administration (FDA) in 2004 and tapentadol extended release was approved in 2012 for the treatment of PDN. Proposed pathogenetic treatments include α-lipoic acid (stems reactive oxygen species formation), benfotiamine (prevents vascular damage in diabetes) and aldose-reductase inhibitors (reduces flux through the polyol pathway). There is a growing need for studies to evaluate the most potent drugs or combinations for the management of PDN to maximize pain relief and improve quality of life. A number of agents are potential candidates for future use in PDN therapy, including Nav 1.7 antagonists, N-type calcium channel blockers, NGF antibodies and angiotensin II type 2 receptor antagonists. PMID:25553239

An Unusual Diterpene-Enhygromic Acid and Deoxyenhygrolides from a Marine Myxobacterium, Enhygromyxa sp.

PubMed

Tomura, Tomohiko; Nagashima, Shiori; Yamazaki, Satoshi; Iizuka, Takashi; Fudou, Ryosuke; Ojika, Makoto

2017-04-06

Three new compounds, enhygromic acid ( 1 ) and deoxyenhygrolides A ( 2 ) and B ( 3 ), were isolated from a marine myxobacterium, Enhygromyxa sp. Compound 1 was found to be an acrylic acid derivative with a rare polycyclic carbon skeleton, decahydroacenaphthylene, by spectroscopic analyses. Compounds 2 and 3 were deoxy analogs of the known γ-alkylidenebutenolides, enhygrolides. Compound 1 exhibited cytotoxicity against B16 melanoma cells and anti-bacterial activity against Bacillus subtilis , and enhanced the NGF-induced neurite outgrowth of PC12 cells.

Occurrence and estrogenic potency of eight bisphenol analogs in sewage sludge from the U.S. EPA targeted national sewage sludge survey.

PubMed

Yu, Xiaohua; Xue, Jingchuan; Yao, Hong; Wu, Qian; Venkatesan, Arjun K; Halden, Rolf U; Kannan, Kurunthachalam

2015-12-15

As health concerns over bisphenol A (BPA) in consumer products are mounting, this weak estrogen mimicking compound is gradually being replaced with structural analogs, whose environmental occurrence and estrogen risks are not well understood yet. We used high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) to determine the concentrations of eight bisphenol analogs in 76 sewage sludge samples collected by the U.S. Environmental Protection Agency (EPA) in 2006/2007 from 74 wastewater treatment plants (WWTPs) in 35 states. Bisphenols were detected at the following concentration ranges (ng/g dry weight) and detection frequencies: BPA (6.5-4700; 100%); bisphenol S (BPS; <1.79-1480; 84%); bisphenol F (BPF; <1.79-242; 68%); bisphenol AF (BPAF; <1.79-72.2; 46%); bisphenol P (BPP; <1.79-6.42; <5%), bisphenol B (BPB; <1.79-5.60; <5%), and bisphenol Z (BPZ; <1.79--66.7; <5%). Bisphenol AP (BPAP) was not detected in any of the samples (<1.79 ng/g dw). Concentrations of BPA in sewage sludge were an order of magnitude higher than those reported in China but similar to those in Germany. The calculated 17β-estradiol equivalents (E2EQ) of bisphenols present in sludge samples were 7.74 (0.26-90.5) pg/g dw, which were three orders of magnitude lower than the estrogenic activity contributed by natural estrogens present in the sludge. The calculated mass loading of bisphenols through the disposal of sludge and wastewater was <0.02% of the total U.S. production. As the usage of BPA is expected to decline further, environmental emissions of BPS, BPF, and BPAF are likely to increase in the future. This study establishes baseline levels and estrogenic activity of diverse bisphenol analogs in sewage sludge. Copyright © 2015 Elsevier B.V. All rights reserved.

Crystallographic studies of the complex of human HINT1 protein with a non-hydrolyzable analog of Ap4A.

PubMed

Dolot, Rafał; Kaczmarek, Renata; Sęda, Aleksandra; Krakowiak, Agnieszka; Baraniak, Janina; Nawrot, Barbara

2016-06-01

Histidine triad nucleotide-binding protein 1 (HINT1) represents the most ancient and widespread branch in the histidine triad proteins superfamily. HINT1 plays an important role in various biological processes, and it has been found in many species. Here, we report the first structure (at a 2.34Å resolution) of a complex of human HINT1 with a non-hydrolyzable analog of an Ap4A dinucleotide, containing bis-phosphorothioated glycerol mimicking a polyphosphate chain, obtained from a primitive monoclinic space group P21 crystal. In addition, the apo form of hHINT1 at the space group P21 refined to 1.92Å is reported for comparative studies. Copyright © 2016 Elsevier B.V. All rights reserved.

Boosting the pentose phosphate pathway restores cardiac progenitor cell availability in diabetes.

PubMed

Katare, Rajesh; Oikawa, Atsuhiko; Cesselli, Daniela; Beltrami, Antonio P; Avolio, Elisa; Muthukrishnan, Deepti; Munasinghe, Pujika Emani; Angelini, Gianni; Emanueli, Costanza; Madeddu, Paolo

2013-01-01

Diabetes impinges upon mechanisms of cardiovascular repair. However, the biochemical adaptation of cardiac stem cells to sustained hyperglycaemia remains largely unknown. Here, we investigate the molecular targets of high glucose-induced damage in cardiac progenitor cells (CPCs) from murine and human hearts and attempt safeguarding CPC viability and function through reactivation of the pentose phosphate pathway. Type-1 diabetes was induced by streptozotocin. CPC abundance was determined by flow cytometry. Proliferating CPCs were identified in situ by immunostaining for the proliferation marker Ki67. Diabetic hearts showed marked reduction in CPC abundance and proliferation when compared with controls. Moreover, Sca-1(pos) CPCs isolated from hearts of diabetic mice displayed reduced activity of key enzymes of the pentose phosphate pathway, glucose-6-phosphate dehydrogenase (G6PD), and transketolase, increased levels of superoxide and advanced glucose end-products (AGE), and inhibition of the Akt/Pim-1/Bcl-2 signalling pathway. Similarly, culture of murine CPCs or human CD105(pos) progenitor cells in high glucose inhibits the pentose phosphate and pro-survival signalling pathways, leading to the activation of apoptosis. In vivo and in vitro supplementation with benfotiamine reactivates the pentose phosphate pathway and rescues CPC availability and function. This benefit is abrogated by either G6PD silencing by small interfering RNA (siRNA) or Akt inhibition by dominant-negative Akt. We provide new evidence of the negative impact of diabetes and high glucose on mechanisms controlling CPC redox state and survival. Boosting the pentose phosphate pathway might represent a novel mechanistic target for protection of CPC integrity.

Boosting the pentose phosphate pathway restores cardiac progenitor cell availability in diabetes

PubMed Central

Katare, Rajesh; Oikawa, Atsuhiko; Cesselli, Daniela; Beltrami, Antonio P.; Avolio, Elisa; Muthukrishnan, Deepti; Munasinghe, Pujika Emani; Angelini, Gianni; Emanueli, Costanza; Madeddu, Paolo

2013-01-01

Aims Diabetes impinges upon mechanisms of cardiovascular repair. However, the biochemical adaptation of cardiac stem cells to sustained hyperglycaemia remains largely unknown. Here, we investigate the molecular targets of high glucose-induced damage in cardiac progenitor cells (CPCs) from murine and human hearts and attempt safeguarding CPC viability and function through reactivation of the pentose phosphate pathway. Methods and results Type-1 diabetes was induced by streptozotocin. CPC abundance was determined by flow cytometry. Proliferating CPCs were identified in situ by immunostaining for the proliferation marker Ki67. Diabetic hearts showed marked reduction in CPC abundance and proliferation when compared with controls. Moreover, Sca-1pos CPCs isolated from hearts of diabetic mice displayed reduced activity of key enzymes of the pentose phosphate pathway, glucose-6-phosphate dehydrogenase (G6PD), and transketolase, increased levels of superoxide and advanced glucose end-products (AGE), and inhibition of the Akt/Pim-1/Bcl-2 signalling pathway. Similarly, culture of murine CPCs or human CD105pos progenitor cells in high glucose inhibits the pentose phosphate and pro-survival signalling pathways, leading to the activation of apoptosis. In vivo and in vitro supplementation with benfotiamine reactivates the pentose phosphate pathway and rescues CPC availability and function. This benefit is abrogated by either G6PD silencing by small interfering RNA (siRNA) or Akt inhibition by dominant-negative Akt. Conclusion We provide new evidence of the negative impact of diabetes and high glucose on mechanisms controlling CPC redox state and survival. Boosting the pentose phosphate pathway might represent a novel mechanistic target for protection of CPC integrity. PMID:22997160

Indolyl-quinuclidinols inhibit ENOX activity and endothelial cell morphogenesis while enhancing radiation-mediated control of tumor vasculature

PubMed Central

Geng, Ling; Rachakonda, Girish; Morré, D. James; Morré, Dorothy M.; Crooks, Peter A.; Sonar, Vijayakumar N.; Roti, Joseph L. Roti; Rogers, Buck E.; Greco, Suellen; Ye, Fei; Salleng, Kenneth J.; Sasi, Soumya; Freeman, Michael L.; Sekhar, Konjeti R.

2009-01-01

There is a need for novel strategies that target tumor vasculature, specifically those that synergize with cytotoxic therapy, in order to overcome resistance that can develop with current therapeutics. A chemistry-driven drug discovery screen was employed to identify novel compounds that inhibit endothelial cell tubule formation. Cell-based phenotypic screening revealed that noncytotoxic concentrations of (Z)-(±)-2-(1-benzenesulfonylindol-3-ylmethylene)-1-azabicyclo[2. 2.2]octan-3-ol (analog I) and (Z)-(±)-2-(1-benzylindol-3-ylmethylene)-1-azabicyclo[2.2.2]octan-3-ol (analog II) inhibited endothelial cell migration and the ability to form capillary-like structures in Matrigel by ≥70%. The ability to undergo neoangiogenesis, as measured in a window-chamber model, was also inhibited by 70%. Screening of biochemical pathways revealed that analog II inhibited the enzyme ENOX1 (EC50 = 10 μM). Retroviral-mediated shRNA suppression of endothelial ENOX1 expression inhibited cell migration and tubule formation, recapitulating the effects observed with the small-molecule analogs. Genetic or chemical suppression of ENOX1 significantly increased radiation-mediated Caspase3-activated apoptosis, coincident with suppression of p70S6K1 phosphorylation. Administration of analog II prior to fractionated X-irradiation significantly diminished the number and density of tumor microvessels, as well as delayed syngeneic and xenograft tumor growth compared to results obtained with radiation alone. Analysis of necropsies suggests that the analog was well tolerated. These results suggest that targeting ENOX1 activity represents a novel therapeutic strategy for enhancing the radiation response of tumors.—Geng, L., Rachakonda, G., Morré, D. J., Morré, D. M., Crooks, P. A., Sonar, V. N., Roti Roti, J. L., Rogers, B. E., Greco, S., Ye, F., Salleng, K. J., Sasi, S., Freeman, M. L., Sekhar, K. R. Indolyl-quinuclidinols inhibit ENOX activity and endothelial cell morphogenesis while enhancing radiation-mediated control of tumor vasculature. PMID:19395476

Modulation of the human equilibrative nucleoside transporter1 (hENT1) activity by IL-4 and PMA in B cells from chronic lymphocytic leukemia.

PubMed

Fernández Calotti, Paula; Galmarini, Carlos María; Cañones, Cristian; Gamberale, Romina; Saénz, Daniel; Avalos, Julio Sánchez; Chianelli, Mónica; Rosenstein, Ruth; Giordano, Mirta

2008-02-15

Nucleoside transporters (NTs) are essential for the uptake of therapeutic nucleoside analogs, broadly used in cancer treatment. The mechanisms responsible for NT regulation are largely unknown. IL-4 is a pro-survival signal for chronic lymphocytic leukemia (CLL) cells and has been shown to confer resistance to nucleoside analogs. The aim of this study was to investigate whether IL-4 is able to modulate the expression and function of the human equilibrative NT1 (hENT1) in primary cultures of CLL cells and, consequently, to affect cytotoxicity induced by therapeutic nucleosides analogs. We found that treatment with IL-4 (20 ng/ml for 24 h) increased mRNA hENT1 expression in CLL cells without affecting that of normal B cells. Given that the enhanced mRNA levels of hENT1 in CLL cells did not result in increased transport activity, we examined the possibility that hENT1 induced by IL-4 may require post-translational modifications to become active. We found that the acute stimulation of PKC in IL-4-treated CLL cells by short-term incubation with PMA significantly increased hENT1 transport activity and favoured fludarabine-induced apoptosis. By contrast, and in line with previous reports, IL-4 plus PMA protected CLL cells from a variety of cytotoxic agents. Our findings indicate that the combined treatment with IL-4 and PMA enhances hENT1 activity and specifically sensitizes CLL cells to undergo apoptosis induced by fludarabine.

Visualizing Mixed Variable-Type Multidimensional Data Using Tree Distances

DTIC Science & Technology

2015-09-01

24 1. The Regression Method .................................................. 25 2. Maximum Deviance Ratio Method... Deviance Change as a Factor of the Amount of Correlation? ................................................... 50 B. A PROPOSED SOLUTION...Splice mapping using d1 ...................... 36 Figure 18. Reduction in 2R analog ( deviance ratio-DevRat) per variable for the Splice data

Developing Inhibitors of Translesion DNA Synthesis as Therapeutic Agents Against Lung Cancer

DTIC Science & Technology

2014-10-01

pol eta when replicating damaged DNA. 1S. SUBJECT TERMS: Mutagenesis, DNA polymerases, nucleoside analogs, chemotherapeutic agents 16. SECURITY ...such as polymerase eta, iota , and kappa that are involved in replicating damaged DNA. Our kinetic data obtained under Task 1B indicates that pol eta

A 160 μA biopotential acquisition IC with fully integrated IA and motion artifact suppression.

PubMed

Van Helleputte, Nick; Kim, Sunyoung; Kim, Hyejung; Kim, Jong Pal; Van Hoof, Chris; Yazicioglu, Refet Firat

2012-12-01

This paper proposes a 3-channel biopotential monitoring ASIC with simultaneous electrode-tissue impedance measurements which allows real-time estimation of motion artifacts on each channel using an an external μC. The ASIC features a high performance instrumentation amplifier with fully integrated sub-Hz HPF rejecting rail-to-rail electrode-offset voltages. Each readout channel further has a programmable gain amplifier and programmable 4th order low-pass filter. Time-multiplexed 12 b SAR-ADCs are used to convert all the analog data to digital. The ASIC achieves >; 115 dB of CMRR (at 50/60 Hz), a high input impedance of >; 1 GΩ and low noise (1.3 μVrms in 100 Hz). Unlike traditional methods, the ASIC is capable of actual motion artifact suppression in the analog domain before final amplification. The complete ASIC core operates from 1.2 V with 2 V digital IOs and consumes 200 μW when all 3 channels are active.

Asperentin B, a New Inhibitor of the Protein Tyrosine Phosphatase 1B.

PubMed

Wiese, Jutta; Aldemir, Hülya; Schmaljohann, Rolf; Gulder, Tobias A M; Imhoff, Johannes F

2017-06-21

In the frame of studies on secondary metabolites produced by fungi from deep-sea environments we have investigated inhibitors of enzymes playing key roles in signaling cascades of biochemical pathways relevant for the treatment of diseases. Here we report on a new inhibitor of the human protein tyrosine phosphatase 1B (PTP1B), a target in the signaling pathway of insulin. A new asperentin analog is produced by an Aspergillus sydowii strain isolated from the sediment of the deep Mediterranean Sea. Asperentin B ( 1 ) contains an additional phenolic hydroxy function at C-6 and exhibits an IC 50 value against PTP1B of 2 μM in vitro, which is six times stronger than the positive control, suramin. Interestingly, asperentin ( 2 ) did not show any inhibition of this enzymatic activity. Asperentin B ( 1 ) is discussed as possible therapeutic agents for type 2 diabetes and sleeping sickness.

Asperentin B, a New Inhibitor of the Protein Tyrosine Phosphatase 1B

PubMed Central

Wiese, Jutta; Aldemir, Hülya; Schmaljohann, Rolf; Gulder, Tobias A. M.; Imhoff, Johannes F.

2017-01-01

In the frame of studies on secondary metabolites produced by fungi from deep-sea environments we have investigated inhibitors of enzymes playing key roles in signaling cascades of biochemical pathways relevant for the treatment of diseases. Here we report on a new inhibitor of the human protein tyrosine phosphatase 1B (PTP1B), a target in the signaling pathway of insulin. A new asperentin analog is produced by an Aspergillus sydowii strain isolated from the sediment of the deep Mediterranean Sea. Asperentin B (1) contains an additional phenolic hydroxy function at C-6 and exhibits an IC50 value against PTP1B of 2 μM in vitro, which is six times stronger than the positive control, suramin. Interestingly, asperentin (2) did not show any inhibition of this enzymatic activity. Asperentin B (1) is discussed as possible therapeutic agents for type 2 diabetes and sleeping sickness. PMID:28635658

Alaskan Permafrost Analogs of Martian Small Valley Networks, Thermokarst, Terrain Softening, Terraces, and Volcanic Craters

NASA Technical Reports Server (NTRS)

Kargel, Jeffrey S.; Wessels, Rick; Beget, James E.; Eddy, Thomas; Lloyd, Sandra; Macaulay, Don; Proch, Mark; Skinner, Jim; Tanaka, Kenneth L.

2004-01-01

A geomorphic landscape analog in the Bering Land Bridge National Preserve (Alaska) offers a model for Mars where (1) fluvial and alluvial deposition, volcanism, and other processes first produced a layered ice-rich upper crust, and then (2) severe permafrost conditions (mild by today's Martian standards) and heterogeneous heat flow and volcanism have modified this terrain to produce a geomorphic areal mosaic that is alternately dominated by (a) geothermal meltwater and sublimation (bottom-up heat flow) and (b) surface-driven meltwater and sublimation (top-down heat flow).

A Bidirectional Neural Interface IC with Chopper Stabilized BioADC Array and Charge Balanced Stimulator

PubMed Central

Greenwald, Elliot; So, Ernest; Wang, Qihong; Mollazadeh, Mohsen; Maier, Christoph; Etienne-Cummings, Ralph; Cauwenberghs, Gert; Thakor, Nitish

2016-01-01

We present a bidirectional neural interface with a 4-channel biopotential analog-to-digital converter (bioADC) and a 4-channel current-mode stimulator in 180nm CMOS. The bioADC directly transduces microvolt biopotentials into a digital representation without a voltage-amplification stage. Each bioADC channel comprises a continuous-time first-order ΔΣ modulator with a chopper-stabilized OTA input and current feedback, followed by a second-order comb-filter decimator with programmable oversampling ratio. Each stimulator channel contains two independent digital-to-analog converters for anodic and cathodic current generation. A shared calibration circuit matches the amplitude of the anodic and cathodic currents for charge balancing. Powered from a 1.5V supply, the analog and digital circuits in each recording channel draw on average 1.54 μA and 2.13 μA of supply current, respectively. The bioADCs achieve an SNR of 58 dB and a SFDR of >70 dB, for better than 9-b ENOB. Intracranial EEG recordings from an anesthetized rat are shown and compared to simultaneous recordings from a commercial reference system to validate performance in-vivo. Additionally, we demonstrate bidirectional operation by recording cardiac modulation induced through vagus nerve stimulation, and closed-loop control of cardiac rhythm. The micropower operation, direct digital readout, and integration of electrical stimulation circuits make this interface ideally suited for closed-loop neuromodulation applications. PMID:27845676

Synthetic curcumin analog EF31 inhibits the growth of head and neck squamous cell carcinoma xenografts.

PubMed

Zhu, Shijun; Moore, Terry W; Lin, Xiaoqian; Morii, Nao; Mancini, Alessandra; Howard, Randy B; Culver, Deborah; Arrendale, Richard F; Reddy, Prabhakar; Evers, Taylor J; Zhang, Hongzheng; Sica, Gabriel; Chen, Zhuo G; Sun, Aiming; Fu, Haian; Khuri, Fadlo R; Shin, Dong M; Snyder, James P; Shoji, Mamoru

2012-06-01

Objectives are to examine the efficacy, pharmacokinetics, and toxicology of a synthetic curcumin analog EF31 in head and neck squamous cell carcinoma. The synthesis of EF31 was described for the first time. Solubility of EF24 and EF31 was compared using nephelometric analysis. Human head and neck squamous cell carcinoma Tu212 xenograft tumors were established in athymic nude mice and treated with EF31 i.p. once daily five days a week for about 5-6 weeks. The long term effect of EF31 on the NF-κB signaling system in the tumors was examined by Western blot analysis. EF31 at 25 mg kg(-1), i.p. inhibited tumor growth almost completely. Solubilities of EF24 and EF31 are <10 and 13 μg mL(-1) or <32 and 47 μM, respectively. The serum chemistry profiles of treated mice were within the limits of normal, they revealed a linear increase of C(max). EF31 decreased the level of phosphorylation of NF-κB p65. In conclusion, the novel synthetic curcumin analog EF31 is efficacious in inhibiting the growth of Tu212 xenograft tumors and may be useful for treating head and neck squamous cell carcinoma. The long term EF31 treatment inhibited NF-κB p65 phosphorylation in xenografts, implicating downregulation of cancer promoting transcription factors such as angiogenesis and metastasis.

Long Life MEM Switch Technology

DTIC Science & Technology

2006-05-23

Dussopt et al. on the two-level switched-capacitors [2], Peroulis et al. on the extended analog varactor [3], B- Kassem at el. on an extended range analog...Katehi, ”Highly reliable analog MEMS varactors,” 2004 IEEE MTT-S Int. Microwave Symp. Dig., vol. 2, pp. 869-872, June 2004. [4] M. Bakri- Kassem , R. R

Biostable beta-Amino Acid PK/PBAN Analogs: Agonist and Antagonist Properties

DTIC Science & Technology

2009-01-01

peptidases neprilysin and angiotensin converting enzyme that are shown to degrade the natural peptides . Despite the changes to the PK core, analog PK-bA-4...bound peptidase - resistant analogs of the insect allatostatins. Peptides 1999;20:23–9. [21] Nachman RJ, Holman GM, Cook BJ. Active fragments and...pheromonotropic activity of peptidase -resistant topical amphiphilic analogs of pyrokinin/PBAN insect neuropeptides. Peptides 2002;23:2035–43. [28] Nachman RJ

GABAA receptor activity modulating piperine analogs: In vitro metabolic stability, metabolite identification, CYP450 reaction phenotyping, and protein binding.

PubMed

Zabela, Volha; Hettich, Timm; Schlotterbeck, Götz; Wimmer, Laurin; Mihovilovic, Marko D; Guillet, Fabrice; Bouaita, Belkacem; Shevchenko, Bénédicte; Hamburger, Matthias; Oufir, Mouhssin

2018-01-01

In a screening of natural products for allosteric modulators of GABA A receptors (γ-aminobutyric acid type A receptor), piperine was identified as a compound targeting a benzodiazepine-independent binding site. Given that piperine is also an activator of TRPV1 (transient receptor potential vanilloid type 1) receptors involved in pain signaling and thermoregulation, a series of piperine analogs were prepared in several cycles of structural optimization, with the aim of separating GABA A and TRPV1 activating properties. We here investigated the metabolism of piperine and selected analogs in view of further cycles of lead optimization. Metabolic stability of the compounds was evaluated by incubation with pooled human liver microsomes, and metabolites were analyzed by UHPLC-Q-TOF-MS. CYP450 isoenzymes involved in metabolism of compounds were identified by reaction phenotyping with Silensomes™. Unbound fraction in whole blood was determined by rapid equilibrium dialysis. Piperine was the metabolically most stable compound. Aliphatic hydroxylation, and N- and O-dealkylation were the major routes of oxidative metabolism. Piperine was exclusively metabolized by CYP1A2, whereas CYP2C9 contributed significantly in the oxidative metabolism of all analogs. Extensive binding to blood constituents was observed for all compounds. Copyright © 2017 Elsevier B.V. All rights reserved.

Design, synthesis, and evaluation of A/C/D-ring analogs of the fungal metabolite K-76 as potential complement inhibitors.

PubMed

Kaufman, T S; Srivastava, R P; Sindelar, R D; Scesney, S M; Marsh, H C

1995-04-28

The terpenoid 6,7-diformyl-3',4',4a',5',6',7',8',8a'-octahydro-4,6',7'-trihydrox y-2',5',5', 8a'-tetramethylspiro[1'(2'H)-naphthalene-2(3H)-benzofuran] (1a; K-76), a natural product of fungal origin, and its monocarboxylate sodium salt 1c (R = COONa; K-76COONa) inhibit the classical and alternative pathways of complement, and 1c was shown to inhibit the classical pathway at the C5 activation step. In an attempt to elucidate the essential pharmacophore of 1a,c, the natural product was used as a "topographical model" for the design of partial analogs retaining the desired complement inhibiting potency. Therefore, A/C/D-ring analogs have been synthesized, as shown in Scheme 1 using 3-methoxyphenol (3) and limonene chloride (5) as starting materials, which contain functional groups similar to those found on the natural product. The use of (4R)-(+)- and (4S)(-)-limonene chloride (5a,b, respectively) provided two series of compounds differing in the stereochemistry of the C-4 chiral center (limonene moiety numbering). The in vitro assay results of the inhibition of anaphylatoxin production and classical complement-mediated hemolysis revealed that 7-carboxy-2-(R,S)-methyl-2-(1'-methylcyclohexen-(4'R)-yl)-4-met hoxybenzofuran (13a) and 7-carboxy-2-(R,S)-methyl-2-(1'-methylcyclohexen-(4'S)-yl)-4-met hoxybenzofuran (13b) were active in the same range of concentrations as the natural product.

Reconfigurable Multiparameter Biosignal Acquisition SoC for Low Power Wearable Platform

PubMed Central

Kim, Jongpal; Ko, Hyoungho

2016-01-01

A low power and low noise reconfigurable analog front-end (AFE) system on a chip (SoC) for biosignal acquisition is presented. The presented AFE can be reconfigured for use in electropotential, bioimpedance, electrochemical, and photoelectrical modes. The advanced healthcare services based on multiparameter physiological biosignals can be easily implemented with these multimodal and highly reconfigurable features of the proposed system. The reconfigurable gain and input referred noise of the core instrumentation amplifier block are 25 dB to 52 dB, and 1 μVRMS, respectively. The power consumption of the analog blocks in one readout channel is less than 52 μW. The reconfigurable capability among various modes of applications including electrocardiogram, blood glucose concentration, respiration, and photoplethysmography are shown experimentally. PMID:27898004

Novel Pactamycin Analogs Induce p53 Dependent Cell-Cycle Arrest at S-Phase in Human Head and Neck Squamous Cell Carcinoma (HNSCC) Cells

PubMed Central

Guha, Gunjan; Liang, Xiaobo; Kulesz-Martin, Molly F.; Mahmud, Taifo; Indra, Arup Kumar; Ganguli-Indra, Gitali

2015-01-01

Pactamycin, although putatively touted as a potent antitumor agent, has never been used as an anticancer drug due to its high cytotoxicity. In this study, we characterized the effects of two novel biosynthetically engineered analogs of pactamycin, de-6MSA-7-demethyl-7-deoxypactamycin (TM-025) and 7-demethyl-7-deoxypactamycin (TM-026), in head and neck squamous cell carcinoma (HNSCC) cell lines SCC25 and SCC104. Both TM-025 and TM-026 exert growth inhibitory effects on HNSCC cells by inhibiting cell proliferation. Interestingly, unlike their parent compound pactamycin, the analogs do not inhibit synthesis of nascent protein in a cell-based assay. Furthermore, they do not induce apoptosis or autophagy in a dose- or a time-dependent manner, but induce mild senescence in the tested cell lines. Cell cycle analysis demonstrated that both analogs significantly induce cell cycle arrest of the HNSCC cells at S-phase resulting in reduced accumulation of G2/M-phase cells. The pactamycin analogs induce expression of cell cycle regulatory proteins including master regulator p53, its downstream target p21Cip1/WAF1, p27kip21, p19, cyclin E, total and phospho Cdc2 (Tyr15) and Cdc25C. Besides, the analogs mildly reduce cyclin D1 expression without affecting expression of cyclin B, Cdk2 and Cdk4. Specific inhibition of p53 by pifithrin-α reduces the percentage of cells accumulated in S-phase, suggesting contribution of p53 to S-phase increase. Altogether, our results demonstrate that Pactamycin analogs TM-025 and TM-026 induce senescence and inhibit proliferation of HNSCC cells via accumulation in S-phase through possible contribution of p53. The two PCT analogs can be widely used as research tools for cell cycle inhibition studies in proliferating cancer cells with specific mechanisms of action. PMID:25938491

Wideband LTE power amplifier with integrated novel analog pre-distorter linearizer for mobile wireless communications.

PubMed

Uthirajoo, Eswaran; Ramiah, Harikrishnan; Kanesan, Jeevan; Reza, Ahmed Wasif

2014-01-01

For the first time, a new circuit to extend the linear operation bandwidth of a LTE (Long Term Evolution) power amplifier, while delivering a high efficiency is implemented in less than 1 mm2 chip area. The 950 µm × 900 µm monolithic microwave integrated circuit (MMIC) power amplifier (PA) is fabricated in a 2 µm InGaP/GaAs process. An on-chip analog pre-distorter (APD) is designed to improve the linearity of the PA, up to 20 MHz channel bandwidth. Intended for 1.95 GHz Band 1 LTE application, the PA satisfies adjacent channel leakage ratio (ACLR) and error vector magnitude (EVM) specifications for a wide LTE channel bandwidth of 20 MHz at a linear output power of 28 dBm with corresponding power added efficiency (PAE) of 52.3%. With a respective input and output return loss of 30 dB and 14 dB, the PA's power gain is measured to be 32.5 dB while exhibiting an unconditional stability characteristic from DC up to 5 GHz. The proposed APD technique serves to be a good solution to improve linearity of a PA without sacrificing other critical performance metrics.

Wideband LTE Power Amplifier with Integrated Novel Analog Pre-Distorter Linearizer for Mobile Wireless Communications

PubMed Central

Uthirajoo, Eswaran; Ramiah, Harikrishnan; Kanesan, Jeevan; Reza, Ahmed Wasif

2014-01-01

For the first time, a new circuit to extend the linear operation bandwidth of a LTE (Long Term Evolution) power amplifier, while delivering a high efficiency is implemented in less than 1 mm2 chip area. The 950 µm × 900 µm monolithic microwave integrated circuit (MMIC) power amplifier (PA) is fabricated in a 2 µm InGaP/GaAs process. An on-chip analog pre-distorter (APD) is designed to improve the linearity of the PA, up to 20 MHz channel bandwidth. Intended for 1.95 GHz Band 1 LTE application, the PA satisfies adjacent channel leakage ratio (ACLR) and error vector magnitude (EVM) specifications for a wide LTE channel bandwidth of 20 MHz at a linear output power of 28 dBm with corresponding power added efficiency (PAE) of 52.3%. With a respective input and output return loss of 30 dB and 14 dB, the PA’s power gain is measured to be 32.5 dB while exhibiting an unconditional stability characteristic from DC up to 5 GHz. The proposed APD technique serves to be a good solution to improve linearity of a PA without sacrificing other critical performance metrics. PMID:25033049

Synthesis, biophysical and functional studies of two BP100 analogues modified by a hydrophobic chain and a cyclic peptide.

PubMed

Carretero, Gustavo P B; Saraiva, Greice K V; Cauz, Ana C G; Rodrigues, Magali A; Kiyota, Sumika; Riske, Karin A; Dos Santos, Alcindo A; Pinatto-Botelho, Marcos F; Bemquerer, Marcelo P; Gueiros-Filho, Frederico J; Chaimovich, Hernan; Schreier, Shirley; Cuccovia, Iolanda M

2018-05-09

Antimicrobial peptides (AMPs) work as a primary defense against pathogenic microorganisms. BP100, (KKLFKKILKYL-NH 2 ), a rationally designed short, highly cationic AMP, acts against many bacteria, displaying low toxicity to eukaryotic cells. Previously we found that its mechanism of action depends on membrane surface charge and on peptide-to-lipid ratio. Here we present the synthesis of two BP100 analogs: BP100‑alanyl‑hexadecyl‑1‑amine (BP100-Ala-NH-C 16 H 33 ) and cyclo(1‑4)‑d‑Cys 1 , Ile 2 , Leu 3 , Cys 4 -BP100 (Cyclo(1‑4)‑cILC-BP100). We examined their binding to large unilamellar vesicles (LUV), conformational and functional properties, and compared with those of BP100. The analogs bound to membranes with higher affinity and a lesser dependence on electrostatic forces than BP100. In the presence of LUV, BP100 and BP100-Ala-NH-C 16 H 33 acquired α-helical conformation, while Cyclo(1‑4)‑cILC-BP100) was partly α-helical and partly β-turn. Taking in conjunction: 1. particle sizes and zeta potential, 2. effects on lipid flip-flop, 3. leakage of LUVs internal contents, and 4. optical microscopy of giant unilamellar vesicles, we concluded that at high concentrations, all three peptides acted by a carpet mechanism, while at low concentrations the peptides acted by disorganizing the lipid bilayer, probably causing membrane thinning. The higher activity and lesser membrane surface charge dependence of the analogs was probably due to their greater hydrophobicity. The MIC values of both analogs towards Gram-positive and Gram-negative bacteria were similar to those of BP100 but both analogues were more hemolytic. Confocal microscopy showed Gram-positive B. subtilis killing with concomitant extensive membrane damage suggestive of lipid clustering, or peptide-lipid aggregation. These results were in agreement with those found in model membranes. Copyright © 2018. Published by Elsevier B.V.

Synthesis, biological evaluation, and live cell imaging of novel fluorescent duocarmycin analogs.

PubMed

Tietze, Lutz F; Behrendt, Frank; Pestel, Galina F; Schuberth, Ingrid; Mitkovski, Mišo

2012-11-01

For a better understanding of the mode of action of duocarmycin and its analogs, the novel fluorescent duocarmycin derivatives 13-15 and 17b-19b were synthesized, and their bioactivity as well as their cellular uptake investigated using confocal laser scanning microscopy (CLSM) in live-cell imaging experiments. Copyright © 2012 Verlag Helvetica Chimica Acta AG, Zürich.

Coordination chemistry and catalytic activity of N-heterocyclic carbene iridium(I) complexes.

PubMed

Fu, Ching-Feng; Chang, Yung-Hung; Liu, Yi-Hong; Peng, Shei-Ming; Elsevier, Cornelis J; Chen, Jwu-Ting; Liu, Shiuh-Tzung

2009-09-21

Iridium complexes [(CO)2Ir(NHC-R)Cl] (R = Et-, 3a; PhCH2-, 3b; CH3OCH2CH2-, 3c; o-CH3OC6H4CH2-, 3d; NHC: N-heterocyclic carbene) are prepared via the carbene transfer from [(NHC-R)W(CO)5] to [Ir(COD)Cl]2. By using substitution with 13CO, we are able to estimate the activation energy (G) of the CO-exchange in 3a-d, which are in the range of 12-13 kcal mol-1, significantly higher than those for the phosphine analog [(CO)2Ir(PCy3)Cl]. Reactions of 3b and 3d with an equimolar amount of PPh3 result in the formation of the corresponding [(NHC-R)Ir(CO)(PPh3)Cl] with the phosphine and NHC in trans arrangement. In contrast, the analogous reaction of 3a or 3c with phosphine undergoes substitution followed by the anion metathesis to yield the corresponding di-substituted [(NHC-R)Ir(CO)(PPh3)2]BF4 (5) directly. Treatment of 3b or 3d with excess of PPh3 leads to the similar product of disubstitution 5b and 5d. The analysis for the IR data of carbonyliridium complexes provides the estimation of electron-donating power of NHCs versus phosphines. The NHC moiety on the iridium center cannot be replaced by phosphines, even 1,2-bis(diphenylphohino)ethane (dppe). All the carbene moieties on the iridium complexes are inert toward sulfur treatment, indicating a strong interaction between NHC and the iridium centers. Complexes 3a-c are active on the catalysis of the oxidative cyclization of 2-(o-aminophenyl)ethanol to yield the indole compound. The phosphine substituted complexes or analogs are less active.

Picoradio: Communication/Computation Piconodes for Sensor Networks

DTIC Science & Technology

2003-01-02

diagram of PicoNode III, or Quark node. It is made from two custom chips, Strange RF and Charm digital processor , and is complemented by a set of...the chipset comprising of Strange (analog OOK transceiver) and Charm (digital processor ) chips. 44 Figure 33: System block diagram of the Quark node...19 2.B PICONODE II - TWO-CHIP PICONODE IMPLEMENTATION ......................................... 21 2.B.1 Baseband processor (BBP

In vitro anti-proliferative and anti-angiogenic activities of thalidomide dithiocarbamate analogs.

PubMed

El-Aarag, Bishoy Y A; Kasai, Tomonari; Zahran, Magdy A H; Zakhary, Nadia I; Shigehiro, Tsukasa; Sekhar, Sreeja C; Agwa, Hussein S; Mizutani, Akifumi; Murakami, Hiroshi; Kakuta, Hiroki; Seno, Masaharu

2014-08-01

Inhibition of angiogenesis is currently perceived as a promising strategy in the treatment of cancer. The anti-angiogenicity of thalidomide has inspired a second wave of research on this teratogenic drug. The present study aimed to investigate the anti-proliferative and anti-angiogenic activities of two thalidomide dithiocarbamate analogs by studying their anti-proliferative effects on human umbilical vein endothelial cells (HUVECs) and MDA-MB-231 human breast cancer cell lines. Their action on the expression levels of IL-6, IL-8, TNF-α, VEGF165, and MMP-2 was also assessed. Furthermore, their effect on angiogenesis was evaluated through wound healing, migration, tube formation, and nitric oxide (NO) assays. Results illustrated that the proliferation of HUVECs and MDA-MB-231 cells was not significantly affected by thalidomide at 6.25-100μM. Thalidomide failed to block angiogenesis at similar concentrations. By contrast, thalidomide dithiocarbamate analogs exhibited significant anti-proliferative action on HUVECs and MDA-MB-231 cells without causing cytotoxicity and also showed powerful anti-angiogenicity in wound healing, migration, tube formation, and NO assays. Thalidomide analogs 1 and 2 demonstrated more potent activity to suppress expression levels of IL-6, IL-8, TNF-α, VEGF165, and MMP-2 than thalidomide. Analog 1 consistently, showed the highest potency and efficacy in all the assays. Taken together, our results support further development and evaluation of novel thalidomide analogs as anti-tumor and anti-angiogenic agents. Copyright © 2014. Published by Elsevier B.V.

Structural and Epimeric Isomers of HPPH [3-Devinyl 3-{1-(1-hexyloxy) ethyl}pyropheophorbide-a]: Effects on Uptake and Photodynamic Therapy of Cancer.

PubMed

Saenz, Courtney; Cheruku, Ravindra R; Ohulchanskyy, Tymish Y; Joshi, Penny; Tabaczynski, Walter A; Missert, Joseph R; Chen, Yihui; Pera, Paula; Tracy, Erin; Marko, Aimee; Rohrbach, Daniel; Sunar, Ulas; Baumann, Heinz; Pandey, Ravindra K

2017-04-21

The tetrapyrrole structure of porphyrins used as photosentizing agents is thought to determine uptake and retention by malignant epithelial cancer cells. To assess the contribution of the oxidized state of individual rings to these cellular processes, bacteriochlorophyll a was converted into the ring "D" reduced 3-devinyl-3-[1-(1-hexyloxy)ethyl]pyropheophorbide-a (HPPH) and the corresponding ring "B" reduced isomer (iso-HPPH). The carboxylic acid analogs of both ring "B" and ring "D" reduced isomers showed several-fold higher accumulation into the mitochondria and endoplasmic reticulum by primary culture of human lung and head and neck cancer cells than the corresponding methyl ester analogs that localize primarily to granular vesicles and to a lesser extent to mitochondria. However, long-term cellular retention of these compounds exhibited an inverse relationship with tumor cells generally retaining better the methyl-ester derivatives. In vivo distribution and tumor uptake was evaluated in the isogenic model of BALB/c mice bearing Colon26 tumors using the respective 14 C-labeled analogs. Both carboxylic acid derivatives demonstrated similar intracellular localization and long-term tumor cure with no significant skin phototoxicity. PDT-mediated tumor action involved vascular damage, which was confirmed by a reduction in blood flow and immunohistochemical assessment of damage to the vascular endothelium. The HPPH stereoisomers (epimers) showed identical uptake (in vitro & in vivo), intracellular retention and photoreaction.

Menaquinone analogs inhibit growth of bacterial pathogens.

PubMed

Schlievert, Patrick M; Merriman, Joseph A; Salgado-Pabón, Wilmara; Mueller, Elizabeth A; Spaulding, Adam R; Vu, Bao G; Chuang-Smith, Olivia N; Kohler, Petra L; Kirby, John R

2013-11-01

Gram-positive bacteria cause serious human illnesses through combinations of cell surface and secreted virulence factors. We initiated studies with four of these organisms to develop novel topical antibacterial agents that interfere with growth and exotoxin production, focusing on menaquinone analogs. Menadione, 1,4-naphthoquinone, and coenzymes Q1 to Q3 but not menaquinone, phylloquinone, or coenzyme Q10 inhibited the growth and to a greater extent exotoxin production of Staphylococcus aureus, Bacillus anthracis, Streptococcus pyogenes, and Streptococcus agalactiae at concentrations of 10 to 200 μg/ml. Coenzyme Q1 reduced the ability of S. aureus to cause toxic shock syndrome in a rabbit model, inhibited the growth of four Gram-negative bacteria, and synergized with another antimicrobial agent, glycerol monolaurate, to inhibit S. aureus growth. The staphylococcal two-component system SrrA/B was shown to be an antibacterial target of coenzyme Q1. We hypothesize that menaquinone analogs both induce toxic reactive oxygen species and affect bacterial plasma membranes and biosynthetic machinery to interfere with two-component systems, respiration, and macromolecular synthesis. These compounds represent a novel class of potential topical therapeutic agents.

9 CFR 102.3 - License applications.

Code of Federal Regulations, 2013 CFR

2013-01-01

... AGRICULTURE VIRUSES, SERUMS, TOXINS, AND ANALOGOUS PRODUCTS; ORGANISMS AND VECTORS LICENSES FOR BIOLOGICAL... License shall be accompanied by an application for one or more U.S. Veterinary Biological Product Licenses... time. (b) U.S. Veterinary Biological Product License. (1) The licensee of each establishment or...

9 CFR 121.4 - Overlap select agents and toxins.

Code of Federal Regulations, 2010 CFR

2010-01-01

... in paragraph (b) of this section that have been genetically modified. (d) Overlap select agents or... OF AGRICULTURE VIRUSES, SERUMS, TOXINS, AND ANALOGOUS PRODUCTS; ORGANISMS AND VECTORS POSSESSION, USE... elements, recombinant nucleic acids, and recombinant organisms: (1) Nucleic acids that can produce...

Design and Synthesis of Tight Pitch FLCs for Analog Voltage-Limited Electro-Optic Modulators

DTIC Science & Technology

1994-05-27

or decision, unless so designated b other documentation. 12a. DISTRIBUTION/AVAILABILITY STATEMENT 𔃼b, DISTRIBUTION CODE Approved for public release...other end, a wide variety of cores can be synthesized. This is the preferred method for making about 40% of the cores shown in Figure 1. [PGO(Ar) -- B ...methanol, and finally dehydration to the nitrile 51 using phosphorus pentoxide. 0 OHO %%’QL X1) Bu2 BOTf A). 482 ) CH3CHO 49 it N •N O =Xc DEAD, TPP C8H17 O H

Molecular modeling of retinoschisin with functional analysis of pathogenic mutations from human X-linked retinoschisis

PubMed Central

Sergeev, Y.V.; Caruso, R.C.; Meltzer, M.R.; Smaoui, N.; MacDonald, I.M.; Sieving, P.A.

2010-01-01

Gene mutations that encode retinoschisin (RS1) cause X-linked retinoschisis (XLRS), a form of juvenile macular and retinal degeneration that affects males. RS1 is an adhesive protein which is proposed to preserve the structural and functional integrity of the retina, but there is very little evidence of the mechanism by which protein changes are related to XLRS disease. Here, we report molecular modeling of the RS1 protein and consider perturbations caused by mutations found in human XLRS subjects. In 60 XLRS patients who share 27 missense mutations, we then evaluated possible correlations of the molecular modeling with retinal function as determined by the electroretinogram (ERG) a- and b-waves. The b/a-wave ratio reflects visual-signal transfer in retina. We sorted the ERG b/a-ratios by patient age and by the mutation impact on protein structure. The majority of RS1 mutations caused minimal structure perturbation and targeted the protein surface. These patients' b/a-ratios were similar across younger and older subjects. Maximum structural perturbations from either the removal or insertion of cysteine residues or changes in the hydrophobic core were associated with greater difference in the b/a-ratio with age, with a significantly smaller ratio at younger ages, analogous to the ERG changes with age observed in mice with no RS1-protein expression due to a recombinant RS1-knockout gene. The molecular modeling suggests an association between the predicted structural alteration and/or damage to retinoschisin and the severity of XLRS as measured by the ERG analogous to the RS1-knockout mouse. PMID:20061330

Tricycloalternarene Analogs from a Symbiotic Fungus Aspergillus sp. D and Their Antimicrobial and Cytotoxic Effects.

PubMed

Zhang, Huawei; Zhao, Ziping; Chen, Jianwei; Bai, Xuelian; Wang, Hong

2018-04-09

Bioassay-guided fractionation of the crude extract of fermentation broth of one symbiotic strain Aspergillus sp. D from the coastal plant Edgeworthia chrysantha Lindl. led to isolation of one new meroterpenoid, tricycloalternarene 14b ( 1 ), together with four known analogs ( 2 - 5 ), tricycloalternarenes 2b ( 2 ), 3a ( 3 ), 3b ( 4 ), and ACTG-toxin F ( 5 ). Their chemical structures were unambiguously established on the basis of NMR, mass spectrometry, and optical rotation data analysis, as well as by comparison with literature data. Biological assays indicated that compound 2 exhibited potent in vitro cytotoxicity against human lung adenocarcinoma A549 cell line with an IC 50 value of 2.91 μM, and compound 5 had a moderate inhibitory effect on Candida albicans , with an MIC value of 15.63 μM. The results indicated that this symbiotic strain D is an important producer of tricycloalternarene derivatives, with potential therapeutic application in treatment of cancer and pathogen infection.

Fish SAMHD1 performs as an activator for IFN expression.

PubMed

Li, Meifeng; Xu, Xiaowen; Jiang, Zeyin; Liu, Changxin; Shi, Xiao; Qi, Guoqin; Li, Yinping; Chen, Xin; Huang, Qingli; Mao, Huiling; Hu, Chengyu

2018-09-01

As a host limiting factor, Sterile Alpha Motif and Histidine-Aspartate Domain 1 protein (SAMHD1) is associated with IRF3-mediated antiviral and apoptotic responses in mammals. However, the antiviral mechanism of SAMHD1 remains indistinct in fish. In this study, we found the expression of Ctenopharyngodon idella SAMHD1 (MF326081) was up-regulated after transfection with poly I:C (dsRNA analog), B-DNA or Z-DNA into C. idella kidney cells (CIKs), but these expression profiles had no obvious change when the cells were incubated with these nucleic acids. These data may indicate that CiSAMHD1 participates in the intracellular PRR-mediated signaling pathway rather than extracellular PRR-mediated signaling pathway. Subcellular localization assay suggested that a part of over-expressed CiSAMHD1 were translocated from nuclear to cytoplasm when C. idella ovary cells (COs) were transfected with poly I:C, B-DNA or Z-DNA. Nucleic acid pulldown assays were performed to investigate the reason for nuclear-cytoplasm translocation of CiSAMHD1. The results showed that CiSAMHD1 had a high affinity with B-DNA, Z-DNA and ISD-PS (dsRNA analog). In addition, co-IP assays revealed the interaction of CiSAMHD1 with CiSTING (KF494194). Taken together, all these results suggest that grass carp SAMHD1 performs as an activator for innate immune response through STING-mediated signaling pathway. Copyright © 2018 Elsevier Ltd. All rights reserved.

Transition metal carbides, nitrides and borides, and their oxygen containing analogs useful as water gas shift catalysts

DOEpatents

Thompson, Levi T.; Patt, Jeremy; Moon, Dong Ju; Phillips, Cory

2003-09-23

Mono- and bimetallic transition metal carbides, nitrides and borides, and their oxygen containing analogs (e.g. oxycarbides) for use as water gas shift catalysts are described. In a preferred embodiment, the catalysts have the general formula of M1.sub.A M2.sub.B Z.sub.C O.sub.D, wherein M1 is selected from the group consisting of Mo, W, and combinations thereof; M2 is selected from the group consisting of Fe, Ni, Cu, Co, and combinations thereof; Z is selected from the group consisting of carbon, nitrogen, boron, and combinations thereof; A is an integer; B is 0 or an integer greater than 0; C is an integer; O is oxygen; and D is 0 or an integer greater than 0. The catalysts exhibit good reactivity, stability, and sulfur tolerance, as compared to conventional water shift gas catalysts. These catalysts hold promise for use in conjunction with proton exchange membrane fuel cell powered systems.

Legubicin, a Tumor-Activated Prodrug for Breast Cancer Therapy

DTIC Science & Technology

2007-04-01

carcinomas, leukemias, lymphomas, melanomas, fibrosarcomas , neuroblastoma, and the like. The cancer can, for example, be autoimmune deficiency syndrome...their analogs. (a) 4-Nitrophenyl chloroformate, Py, CH2Cl2, 0°C; (b) (i) OsO4 ( cat ), NMO, citric acid, CH2Cl2-H2O (10:1), RT, (ii) NaIO4, THF- H2O (1:1

Synthesis of Mismatched Heterojunction/Substrate Interfaces

DTIC Science & Technology

1991-10-11

and advantages of strained layers. DD IZ JAN7 1473 EDITION OF INOV 65 IS OBSOLETE *’~~s.*. ~ ~.-A ~’ SECURITY CLASSIFICATIO14 Ol THIS PAGE (When Dsea...cross-section is shown ini 1-ig. 1.14(a), is analogous to the polysilicon -gate FET in Si-MOS devices. From the band diagam in Fig 1.14(b), it can be seen

Isolation and characterization of anti-adenoviral secondary metabolites from marine actinobacteria.

PubMed

Strand, Mårten; Carlsson, Marcus; Uvell, Hanna; Islam, Koushikul; Edlund, Karin; Cullman, Inger; Altermark, Björn; Mei, Ya-Fang; Elofsson, Mikael; Willassen, Nils-Peder; Wadell, Göran; Almqvist, Fredrik

2014-01-28

Adenovirus infections in immunocompromised patients are associated with high mortality rates. Currently, there are no effective anti-adenoviral therapies available. It is well known that actinobacteria can produce secondary metabolites that are attractive in drug discovery due to their structural diversity and their evolved interaction with biomolecules. Here, we have established an extract library derived from actinobacteria isolated from Vestfjorden, Norway, and performed a screening campaign to discover anti-adenoviral compounds. One extract with anti-adenoviral activity was found to contain a diastereomeric 1:1 mixture of the butenolide secondary alcohols 1a and 1b. By further cultivation and analysis, we could isolate 1a and 1b in different diastereomeric ratio. In addition, three more anti-adenoviral butenolides 2, 3 and 4 with differences in their side-chains were isolated. In this study, the anti-adenoviral activity of these compounds was characterized and substantial differences in the cytotoxic potential between the butenolide analogs were observed. The most potent butenolide analog 3 displayed an EC50 value of 91 μM and no prominent cytotoxicity at 2 mM. Furthermore, we propose a biosynthetic pathway for these compounds based on their relative time of appearance and structure.

Externally-Modulated Electro-Optically Coupled Detector Architecture for Nuclear Physics Instrumentation

NASA Astrophysics Data System (ADS)

Xi, Wenze; McKisson, J. E.; Weisenberger, Andrew G.; Zhang, Shukui; Zorn, Carl

2014-06-01

A new laser-based externally-modulated electro-optically coupled detector (EOCD) architecture is being developed to enable high-density readout for radiation detectors with accurate analog radiation pulse shape and timing preservation. Unlike digital conversion before electro-optical modulation, the EOCD implements complete analog optical signal modulation and multiplexing in its detector front-end. The result is a compact, high performance detector readout that can be both radiation tolerant and immune to magnetic fields. In this work, the feasibility of EOCD was explored by constructing a two-wavelength laser-based externally-modulated EOCD, and testing analog pulse shape preservation and wavelength-division multiplexing (WDM) crosstalk. Comparisons were first made between the corresponding initial pulses and the electro-optically coupled analog pulses. This confirmed an excellent analog pulse preservation over 29% of the modulator's switching voltage range. Optical spectrum analysis revealed less than -14 dB crosstalk with 1.2 nm WDM wavelength bandgap, and provided insight on experimental conditions that could lead to increased inter-wavelength crosstalk. Further discussions and previous research on the radiation tolerance and magnetic field immunity of the candidate materials were also given, and quantitative device testing is proposed in the future.

A design method for high performance seismic data acquisition based on oversampling delta-sigma modulation

NASA Astrophysics Data System (ADS)

Gao, Shanghua; Xue, Bing

2017-04-01

The dynamic range of the currently most widely used 24-bit seismic data acquisition devices is 10-20 dB lower than that of broadband seismometers, and this can affect the completeness of seismic waveform recordings under certain conditions. However, this problem is not easy to solve because of the lack of analog to digital converter (ADC) chips with more than 24 bits in the market. So the key difficulties for higher-resolution data acquisition devices lie in achieving more than 24-bit ADC circuit. In the paper, we propose a method in which an adder, an integrator, a digital to analog converter chip, a field-programmable gate array, and an existing low-resolution ADC chip are used to build a third-order 16-bit oversampling delta-sigma modulator. This modulator is equipped with a digital decimation filter, thus forming a complete analog to digital converting circuit. Experimental results show that, within the 0.1-40 Hz frequency range, the circuit board's dynamic range reaches 158.2 dB, its resolution reaches 25.99 dB, and its linearity error is below 2.5 ppm, which is better than what is achieved by the commercial 24-bit ADC chips ADS1281 and CS5371. This demonstrates that the proposed method may alleviate or even solve the amplitude-limitation problem that broadband observation systems so commonly have to face during strong earthquakes.

The design of CMOS general-purpose analog front-end circuit with tunable gain and bandwidth for biopotential signal recording systems.

PubMed

Chen, Wei-Ming; Yang, Wen-Chia; Tsai, Tzung-Yun; Chiueh, Herming; Wu, Chung-Yu

2011-01-01

In this paper an 8-channel CMOS general-purpose analog front-end (AFE) circuit with tunable gain and bandwidth for biopotential signal recording systems is presented. The proposed AFE consists of eight chopper stabilized pre-amplifiers, an 8-to-1 analog multiplexer, and a programmable gain amplifier. It can be used to sense and amplify different kinds of biopotential signals, such as electrocorticogram (ECoG), electrocardiogram (ECG) and electromyogram (EMG). The AFE chip is designed and fabricated in 0.18-μm CMOS technology. The measured maximum gain of AFE is 60.8 dB. The low cutoff frequency can achieve as low as 0.8 Hz and high cutoff frequency can be adjusted from 200 Hz to 10 kHz to suit for different kinds of biopotential signals. The measured input-referred noise is 0.9 μV(rms), with the power consumption of 18μW per channel at 1.8-V power supply. And the noise efficiency factor (NEF) is only 1.3 for pre-amplifier.

Synthesis and functional survey of new Tacrine analogs modified with nitroxides or their precursors

PubMed Central

Kálai, Tamás; Altman, Robin; Maezawa, Izumi; Balog, Mária; Morisseau, Christophe; Petrlova, Jitka; Hammock, Bruce D.; Jin, Lee-Way; Trudell, James; Voss, John C.; Hideg, Kálmán

2014-01-01

A series of new Tacrine analogs modified with nitroxides or pre-nitroxides on 9-amino group via methylene or piperazine spacers were synthesized; the nitroxide or its precursors were incorporated into the Tacrine scaffold. The new compounds were tested for their hydroxyl radical and peroxyl radical scavenging ability, acetyl cholinesterase inhibitor activity and protection against Aβ-induced cytotoxicity. Based on these assays, we conclude that Tacrine analogs connected to five and six-membered nitroxides via piperazine spacers (9b, 9b/HCl and 12) exhibited the best activity, providing direction for further development of additional candidates with dual functionality (anti Alzheimer’s and antioxidant). PMID:24657571

Sulfur mustard analog induces oxidative stress and activates signaling cascades in the skin of SKH-1 hairless mice.

PubMed

Pal, Arttatrana; Tewari-Singh, Neera; Gu, Mallikarjuna; Agarwal, Chapla; Huang, Jie; Day, Brian J; White, Carl W; Agarwal, Rajesh

2009-12-01

A monofunctional analog of the chemical warfare agent sulfur mustard (HD), 2-chloroethyl ethyl sulfide (CEES), induces tissue damage similar to HD. Herein we studied the molecular mechanisms associated with CEES-induced skin inflammation and toxicity in SKH-1 hairless mice. Topical CEES exposure caused an increase in oxidative stress as observed by enhanced 4-hydroxynonenal and 5,5-dimethyl-2-(8-octanoic acid)-1-pyrroline N-oxide protein adduct formation and an increase in protein oxidation. The CEES-induced increase in the formation of 8-oxo-2-deoxyguanosine indicated DNA oxidation. CEES exposure instigated an increase in the phosphorylation of mitogen-activated protein kinases (MAPKs; ERK1/2, JNK, and p38). After CEES exposure, a significant increase in the phosphorylation of Akt at Ser473 and Thr308 was observed as well as upregulation of its upstream effector, PDK1, in mouse skin tissue. Subsequently, CEES exposure caused activation of AP-1 family proteins and the NF-kappaB pathway, including phosphorylation and degradation of IkappaBalpha in addition to phosphorylation of the NF-kappaB essential modulator. Collectively, our results indicate that CEES induces oxidative stress and the activation of the transcription factors AP-1 and NF-kappaB via upstream signaling pathways including MAPKs and Akt in SKH-1 hairless mouse skin. These novel molecular targets could be supportive in the development of prophylactic and therapeutic interventions against HD-related skin injury.

Glucagon-like peptide-1 receptor expression on human eosinophils and its regulation of eosinophil activation.

PubMed

Mitchell, P D; Salter, B M; Oliveria, J P; El-Gammal, A; Tworek, D; Smith, S G; Sehmi, R; Gauvreau, G M; Butler, M; O'Byrne, P M

2017-03-01

Glucagon-like peptide-1 (GLP-1) and its receptor are part of the incretin family of hormones that regulate glucose metabolism. GLP-1 also has immune modulatory roles. To measure the expression of the GLP-1 receptor (GLP-1R) on eosinophils and neutrophils in normal and asthmatic subjects and evaluate effects of a GLP-1 analog on eosinophil function. Peripheral blood samples were taken from 10 normal and 10 allergic asthmatic subjects. GLP-1R expression was measured on eosinophils and neutrophils. Subsequently, the asthmatic subjects underwent allergen and diluent inhalation challenges, and GLP-1R expression was measured. Purified eosinophils, collected from mild asthmatic subjects, were stimulated with lipopolysaccharide (LPS) and a GLP-1 analog to evaluate eosinophil cell activation markers CD11b and CD69 and cytokine (IL-4, IL-5, IL-8 and IL-13) production. Glucagon-like peptide-1 receptor is expressed on human eosinophils and neutrophils. Eosinophil, but not neutrophil, expression of GLP-1R is significantly higher in normal controls compared to allergic asthmatics. The expression of GLP-1R did not change on either eosinophils or neutrophils following allergen challenge. A GLP-1 analog significantly decreased the expression of eosinophil-surface activation markers following LPS stimulation and decreased eosinophil production of IL-4, IL-8 and IL-13, but not IL-5. Glucagon-like peptide-1 receptor is expressed on human eosinophils and neutrophils. A GLP-1 analog attenuates LPS-stimulated eosinophil activation. GLP-1 agonists may have additional adjunctive indications in treating persons with concomitant type 2 diabetes mellitus and asthma. © 2016 John Wiley & Sons Ltd.

Survival of Bacillus subtilis endospores on ultraviolet-irradiated rover wheels and Mars regolith under simulated Martian conditions.

PubMed

Kerney, Krystal R; Schuerger, Andrew C

2011-06-01

Endospores of Bacillus subtilis HA101 were applied to a simulated Mars Exploration Rover (MER) wheel and exposed to Mars-normal UV irradiation for 1, 3, or 6 h. The experiment was designed to simulate a contaminated rover wheel sitting on its landing platform before rolling off onto the martian terrain, as was encountered during the Spirit and Opportunity missions. When exposed to 1 h of Mars UV, a reduction of 81% of viable endospores was observed compared to the non-UV irradiated controls. When exposed for 3 or 6 h, reductions of 94.6% and 96.6%, respectively, were observed compared to controls. In a second experiment, the contaminated rover wheel was rolled over a bed of heat-sterilized Mars analog soil; then the analog soil was exposed to full martian conditions of UV irradiation, low pressure (6.9 mbar), low temperature (-10°C), and an anaerobic CO(2) martian atmosphere for 24 h to determine whether endospores of B. subtilis on the contaminated rover wheel could be transferred to the surface of the analog soil and survive martian conditions. The experiment simulated conditions in which a rover wheel might come into contact with martian regolith immediately after landing, such as is designed for the upcoming Mars Science Laboratory (MSL) rover. The contaminated rover wheel transferred viable endospores of B. subtilis to the Mars analog soil, as demonstrated by 31.7% of samples showing positive growth. However, when contaminated soil samples were exposed to full martian conditions for 24 h, only 16.7% of samples exhibited positive growth-a 50% reduction in the number of soil samples positive for the transferred viable endospores.

76 FR 27294 - Proposed Revocation of the Significant New Use Rule on a Certain Chemical Substance

Federal Register 2010, 2011, 2012, 2013, 2014

2011-05-11

...)(ii) for analogous polyanionic monomers. EPA has received and reviewed aquatic toxicity test data for... environmental effect criteria at Sec. 721.170(b)(4)(ii) for analogous polyanionic monomers. Subsequently, the...

Silicon optical modulators for optical digital and analog communications (Conference Presentation)

NASA Astrophysics Data System (ADS)

Yang, Lin; Ding, Jianfeng; Zhang, Lei; Shao, Sizu

2017-02-01

Silicon photonics is considered as a promising technology to overcome the difficulties of the existing digital and analog optical communication systems, such as low integration, high cost, and high power consumption. Silicon optical modulator, as a component to transfer data from electronic domain to optical one, has attracted extensive attentions in the past decade. In this paper, we review the statuses of the silicon optical modulators for digital and analog optical communications and introduce our efforts on these topics. We analyze the relationship between the performance and the structural parameters of the silicon optical modulator and present how to optimize its performance including electro-optical bandwidth, modulation efficiency, optical bandwidth and insertion loss. The fabricated silicon optical modulator has an electro-optical bandwidth of 30 GHz. Its extinction ratios are 14.0 dB, 11.2 dB and 9.0 dB at the speeds of 40 Gbps, 50 Gbps and 64 Gbps for OOK modulation. The high extinction ratio of the silicon optical modulator at the high speed makes it very appropriate for the application of optical coherent modulation, such as QPSK and 16-QAM. The fabricated silicon optical modulator also can be utilized for analog optical communication. With respect to a noise floor of -165 dBc, the dynamic ranges for the second-order harmonic and the third-order intermodulation distortion are 90.8 dB and 110.5 dB respectively. By adopting a differential driving structure, the dynamic range for the second-order harmonic can be further improved to 100.0 dB while the third-order intermodulation distortion remains the same level.

Synthesis, Cytotoxic and Contraceptive Activity of 6,8,9-Trihydroxy-2-methyl-2H-naphtho[2,3-b]pyran-5,10-dione, a Pigment of Echinothrix diadema, and its Analogs.

PubMed

Pokhilo, Natalia D; Melman, Galina I; Kiseleva, Marina I; Denisenko, Vladimir A; Anufriev, Victor Ph

2015-07-01

6,8,9-Trihydroxy-2-methyl-2H-naphtho[2,3-b]pyran-5,10-dion, a pigment of the sea urchin Echinothrix diadema, and six analogs were synthesized. The cytotoxic activity and contraceptive properties of the synthesized pyranonaphthazarins have been investigated using the sperm and eggs of the sea urchin Strongylocentrotus intermedius.

Adaptive Hybrid Picture Coding. Volume 2.

DTIC Science & Technology

1985-02-01

ooo5 V.a Measurement Vector ..eho..............57 V.b Size Variable o .entroi* Vector .......... .- 59 V * c Shape Vector .Ř 0-60o oe 6 I V~d...the Program for the Adaptive Line of Sight Method .i.. 18.. o ... .... .... 1 B Details of the Feature Vector FormationProgram .. o ...oo..-....- .122 C ...shape recognition is analogous to recognition of curves in space. Therefore, well known concepts and theorems from differential geometry can be 34 . o

Thermodynamics of the GTP-GDP-operated Conformational Switch of Selenocysteine-specific Translation Factor SelB*

PubMed Central

Paleskava, Alena; Konevega, Andrey L.; Rodnina, Marina V.

2012-01-01

SelB is a specialized translation factor that binds GTP and GDP and delivers selenocysteyl-tRNA (Sec-tRNASec) to the ribosome. By analogy to elongation factor Tu (EF-Tu), SelB is expected to control the delivery and release of Sec-tRNASec to the ribosome by the structural switch between GTP- and GDP-bound conformations. However, crystal structures of SelB suggested a similar domain arrangement in the apo form and GDP- and GTP-bound forms of the factor, raising the question of how SelB can fulfill its delivery function. Here, we studied the thermodynamics of guanine nucleotide binding to SelB by isothermal titration calorimetry in the temperature range between 10 and 25 °C using GTP, GDP, and two nonhydrolyzable GTP analogs, guanosine 5′-O-(γ-thio)triphosphate (GTPγS) and guanosine 5′-(β,γ-imido)-triphosphate (GDPNP). The binding of SelB to either guanine nucleotide is characterized by a large heat capacity change (−621, −467, −235, and −275 cal × mol−1 × K−1, with GTP, GTPγS, GDPNP, and GDP, respectively), associated with compensatory changes in binding entropy and enthalpy. Changes in heat capacity indicate a large decrease of the solvent-accessible surface area in SelB, amounting to 43 or 32 amino acids buried upon binding of GTP or GTPγS, respectively, and 15–19 amino acids upon binding GDP or GDPNP. The similarity of the GTP and GDP forms in the crystal structures can be attributed to the use of GDPNP, which appears to induce a structure of SelB that is more similar to the GDP than to the GTP-bound form. PMID:22740700

Thermodynamics of the GTP-GDP-operated conformational switch of selenocysteine-specific translation factor SelB.

PubMed

Paleskava, Alena; Konevega, Andrey L; Rodnina, Marina V

2012-08-10

SelB is a specialized translation factor that binds GTP and GDP and delivers selenocysteyl-tRNA (Sec-tRNA(Sec)) to the ribosome. By analogy to elongation factor Tu (EF-Tu), SelB is expected to control the delivery and release of Sec-tRNA(Sec) to the ribosome by the structural switch between GTP- and GDP-bound conformations. However, crystal structures of SelB suggested a similar domain arrangement in the apo form and GDP- and GTP-bound forms of the factor, raising the question of how SelB can fulfill its delivery function. Here, we studied the thermodynamics of guanine nucleotide binding to SelB by isothermal titration calorimetry in the temperature range between 10 and 25 °C using GTP, GDP, and two nonhydrolyzable GTP analogs, guanosine 5'-O-(γ-thio)triphosphate (GTPγS) and guanosine 5'-(β,γ-imido)-triphosphate (GDPNP). The binding of SelB to either guanine nucleotide is characterized by a large heat capacity change (-621, -467, -235, and -275 cal × mol(-1) × K(-1), with GTP, GTPγS, GDPNP, and GDP, respectively), associated with compensatory changes in binding entropy and enthalpy. Changes in heat capacity indicate a large decrease of the solvent-accessible surface area in SelB, amounting to 43 or 32 amino acids buried upon binding of GTP or GTPγS, respectively, and 15-19 amino acids upon binding GDP or GDPNP. The similarity of the GTP and GDP forms in the crystal structures can be attributed to the use of GDPNP, which appears to induce a structure of SelB that is more similar to the GDP than to the GTP-bound form.

Chemoprevention of Leishmaniasis: In vitro antiparasitic activity of dibenzalacetone, a synthetic curcumin analog leads to apoptotic cell death in Leishmania donovani.

PubMed

Chauhan, Indira Singh; SubbaRao, G; Shankar, Jai; Chauhan, Lalit Kumar Singh; Kapadia, Govind J; Singh, Neeloo

2018-06-15

Curcumin is the major phenolic compound found in turmeric, a dry powder of rhizomes and roots of the plant, Curcuma longa L., which is widely used as spice and food colorant around the world, and in herbal medicinal practice in Asian countries. The present study reports the leishmanicidal activity of trans-dibenzalacetone (DBA), a synthetic monoketone analog of curcumin, against Leishmania donovani parasites. We for the first time report the antiproliferative effect of a curcumin analog (DBA) on the intracellular amastigotes of L. donovani, the clinically more relevant stage of the parasite than its promastigotes stage. The leishmanicidal effect of DBA was further confirmed by scanning and transmission electron microscopies. Cell growth was arrested in G0/G1 phase with increased concentration of cytosolic calcium and dissipation of mitochondrial membrane potential. Further, the unique trypanothione/trypanothione reductase (TR) system of Leishmania cells was significantly inhibited by DBA. This economically synthesizable simple monoketone analog of curcumin has the potential for field use against visceral leishmaniasis which is currently widespread in tropical and subtropical developing countries of the world. In conclusion, we have identified an analog of curcumin for potential applications against leishmaniasis, based on its strong antiparasitic activity and low toxicity. This curcumin analog compares favorably, at least in vitro, with the existing medication miltefosine. Copyright © 2017. Published by Elsevier B.V.

The Lindstrom-Madden Method for Series Systems with Repeated Components

DTIC Science & Technology

1984-08-01

Further, numerical evidence indicates (Harris and Soms (1983)) that for a levels of practical significance b() a( (4.4) (4.4) was incorrectly...candidate is the one for which .,1 4 j 4 k, is a maximum. we might expect, by analogy, that for a levels of practical interest

Retinoids, retinoid analogs, and lactoferrin interact and differentially affect cell viability of 2 bovine mammary cell types in vitro.

PubMed

Wang, Y; Baumrucker, C R

2010-07-01

Two bovine mammary cell types (BME-UV1 and MeBo cells) were used to evaluate the effect of natural retinoids, retinoid analogs, and bovine lactoferrin (bLf) on cell viability in vitro. Experiments with Alamar Blue showed a linear relationship between fluorescence and cell viability index. The BME-UV1 cells exhibited twice the metabolic activity but required half the doubling time of the MeBo cells. The BME-UV1 cells were very sensitive to all-trans retinoic acid (atRA) inhibition of cell viability (P<0.05) and exhibited a dose-dependent inhibition with 9-cisRA (9cRA; P<0.05). The MeBo cells exhibited some inhibition with these natural ligands (P<0.05), but they were not as sensitive. The addition of bLf had similar inhibitory effects (P<0.05) on cell viability of the 2 mammary cell types. Applications of RA receptor (RAR) agonist indicated that the stimulation of the RAR in both mammary cell types was highly effective in inhibition of cell viability (P<0.05), whereas the application of an RAR antagonist stimulated MeBo cell viability (P<0.05) and inhibited BME-UV1 cell viability (P<0.05). Finally, the use of the RAR antagonist in conjunction with bLf indicated a rescue of the bLf effect in the MeBo cells, suggesting that bLf is acting through the RAR receptor. Conversely, bLf reverted inhibition of cell viability by 9cRA in the BME-UV1 cell type (P<0.05). We conclude that RAR interaction in bovine mammary cell types regulates cell viability in vitro; we hypothesize that the natural ligands mediate regulation of bovine mammary cell viability in vivo and that bLf can either enhance or reverse the retinoid-induced inhibition of cell viability, depending on the type of bovine mammary cell studied.

Nonparametric Estimation of Distribution and Density Functions with Applications.

DTIC Science & Technology

1982-05-01

8 > Z C.. o i, ,- 4 8 ...S C[ 17 : - j 46 0- IA ~ IL ar’ D rn B- - 4 -4A B- 8 ~a *~jai 188 the jackknife may be found in Gray, et al., and Cressie (Refs 15,28). Analogous to...convergence. 21 =7w; Ul I 0083 q C/) 22S , WJ 8 , J035 224 43 UC I a- 04 14 Q) ’I 4 -4a-Q 23z Let R1 be the real line, the borel field on R 1 and P,

Theory of one-dimensional hopping motion of a heavy particle interacting with phonons by different couplings

NASA Astrophysics Data System (ADS)

Itai, K.

1987-02-01

Two models which describe one-dimensional hopping motion of a heavy particle interacting with phonons are discussed. Model A corresponds to hopping in 1D metals or to the polaron problem. In model B the momentum dependence of the particle-phonon coupling is proportional to k-1/2. The scaling equations show that only in model B does localization occur for a coupling larger than a critical value. In the localization region this model shows close analogy to the Caldeira-Leggett model for macroscopic quantum tunneling.

Prophylaxis of murine candidiasis via application of liposome-encapsulated amphotericin B and a muramyl dipeptide analog, alone and in combination.

PubMed Central

Mehta, R T; Lopez-Berestein, G; Hopfer, R L; Mehta, K; White, R A; Juliano, R L

1985-01-01

The present study was conducted to examine the effect of a lipophilic analog of muramyl dipeptide, 6-O-stearoyl-N-acetylmuramyl-L-alpha-aminobutyryl-D-isoglutamine (6-O-S-Abu-MDP), a macrophage activator, on the prophylactic activity of liposomal amphotericin B (L-AmpB) against disseminated candidiasis in mice. Multilamellar vesicles containing AmpB and (6-O-S-Abu)-MDP were prepared by using dimyristoyl phosphatidylcholine and dimyristoyl phosphatidylglycerol (7:3 molar ratio). Hale-Stoner mice (6 to 8 weeks old) were injected with 7 X 10(5) CFU of Candida albicans 336 isolated from a patient. Groups of mice were injected intravenously with different doses of L-AmpB and L-(6-O-S-Abu)-MDP, individually or in combination, 2 days before challenge with C. albicans. The mice were injected with a fixed dose of L-AmpB (1.2 mg/kg in 400 mg of lipid per kg) and various doses of L-(6-O-S-Abu)-MDP (0.6, 1.2, 2, and 4 mg/kg in 400 mg of lipid per kg) or vice versa. Other control groups included untreated mice and those receiving empty liposomes (400 mg of lipid per kg), free AmpB (0.6 mg/kg), or free (6-O-S-Abu)-MDP (4 mg/kg). The mice receiving L-AmpB (1.2 mg/kg) plus L-(6-O-S-Abu)-MDP (0.6 to 4.0 mg/kg) survived up to 25 to 30 days as compared with those injected with L-AmpB alone (15 days) or with L-(6-O-S-Abu)-MDP alone (10 to 15 days). All the mice in other control groups died within 7 to 11 days. The kidney cultures of the mice that received L-AmpB (4 mg/kg) plus L-(6-O-S-Abu)-MDP (1.2 mg/kg) were free of C. albicans infection, unlike those injected with L-AmpB. Variance analysis of these findings indicates a synergistic activity between L-AmpB and L-(6-O-S-Abu)-MDP in the prophylaxis of candidiasis. PMID:4073873

SEMICONDUCTOR INTEGRATED CIRCUITS: A reconfigurable analog baseband circuit for WLAN, WCDMA, and Bluetooth

NASA Astrophysics Data System (ADS)

Tao, Tong; Baoyong, Chi; Ziqiang, Wang; Ying, Zhang; Hanjun, Jiang; Zhihua, Wang

2010-05-01

A reconfigurable analog baseband circuit for WLAN, WCDMA, and Bluetooth in 0.35 μm CMOS is presented. The circuit consists of two variable gain amplifiers (VGA) in cascade and a Gm-C elliptic low-pass filter (LPF). The filter-order and the cut-off frequency of the LPF can be reconfigured to satisfy the requirements of various applications. In order to achieve the optimum power consumption, the bandwidth of the VGAs can also be dynamically reconfigured and some Gm cells can be cut off in the given application. Simulation results show that the analog baseband circuit consumes 16.8 mW for WLAN, 8.9 mW for WCDMA and only 6.5 mW for Bluetooth, all with a 3 V power supply. The analog baseband circuit could provide -10 to +40 dB variable gain, third-order low pass filtering with 1 MHz cut-off frequency for Bluetooth, fourth-order low pass filtering with 2.2 MHz cut-off frequency for WCDMA, and fifth-order low pass filtering with 11 MHz cut-off frequency for WLAN, respectively.

Synthesis of 2'-deoxy-2'-[.sup.18F]fluoro-5-methyl-1-B-D-arabinofuranosyluracil (.sup.18F-FMAU)

DOEpatents

Li, Zibo; Cai, Hancheng; Conti, Peter S

2014-12-16

The present invention relates to methods of synthesizing .sup.18F-FMAU. In particular, .sup.18F-FMAU is synthesized using one-pot reaction conditions in the presence of Friedel-Crafts catalysts. The one-pot reaction conditions are incorporated into a fully automated cGMP-compliant radiosynthesis module, which results in a reduction in synthesis time and simplifies reaction conditions. The one-pot reaction conditions are also suitable for the production of 5-substituted thymidine or cytidine analogs. The products from the one-pot reaction (e.g. the labeled thymidine or cytidine analogs) can be used as probes for imaging tumor proliferative activity. More specifically, these [.sup.18F]-labeled thymidine or cytidine analogs can be used as a PET tracer for certain medical conditions, including, but not limited to, cancer disease, autoimmunity inflammation, and bone marrow transplant.

QPPM receiver for free-space laser communications

NASA Technical Reports Server (NTRS)

Budinger, J. M.; Mohamed, J. H.; Nagy, L. A.; Lizanich, P. J.; Mortensen, D. J.

1994-01-01

A prototype receiver developed at NASA Lewis Research Center for direct detection and demodulation of quaternary pulse position modulated (QPPM) optical carriers is described. The receiver enables dual-channel communications at 325-Megabits per second (Mbps) per channel. The optical components of the prototype receiver are briefly described. The electronic components, comprising the analog signal conditioning, slot clock recovery, matched filter and maximum likelihood data recovery circuits are described in more detail. A novel digital symbol clock recovery technique is presented as an alternative to conventional analog methods. Simulated link degradations including noise and pointing-error induced amplitude variations are applied. The bit-error-rate performance of the electronic portion of the prototype receiver under varying optical signal-to-noise power ratios is found to be within 1.5-dB of theory. Implementation of the receiver as a hybrid of analog and digital application specific integrated circuits is planned.

Craters of the Moon National Monument as a Terrestrial Mars Analog: Examination of Mars Analog Phosphate Minerals, Phosphate Mineral Shock-Recovery Experiments, and Phosphate Minerals in Martian Meteorites

NASA Astrophysics Data System (ADS)

Adcock, C. T.; Hausrath, E.; Tschauner, O. D.; Udry, A.

2015-12-01

Martian analogs, meteorites, and data from unmanned missions have greatly advanced our understanding of martian surface and near-surface processes. In particular, terrestrial analogs allow us to investigate Mars-relevant geomorphic, geochemical, petrogenetic, and hydrologic processes, as well as potential habitability. Craters of the Moon National Monument (COTM), located on the Snake River Plain of Idaho in the United States, represents a valuable phosphate-rich Mars analog, allowing us to examine phosphate minerals, important as volatile indicators and potential nutrient providers, under Mars-relevant conditions. COTM is in an arid to semi-arid environment with sub-freezing lows much of the year. Though wetter than present day Mars (24 - 38 cm MAP) [1], COTM may be analogous to a warmer and wetter past Mars. The area is also the locale of numerous lava flows, a number of which have been dated (2,000 to >18,000 y.b.p.) [2]. The flows have experienced weathering over time and thus represent a chronosequence with application to weathering on Mars. The flows have unusual chemistries, including high average phosphate contents (P2O5 1.75 wt% n=23 flows) [2], close to those in rocks analyzed at Gusev Crater, Mars (P2O5 1.79 wt% n=18 rocks) [3]. The Mars-like high phosphorus contents indicate a potential petrogenetic link and are also of astrobiological interest. Further, current samples of Mars phosphate minerals are limited to meteorites which have been heavily shocked - COTM represents a potential pre-shock and geochemical analog to Mars. We investigated weathering on COTM basalts and shock effects on Mars-relevant phosphate minerals. We used scanning electron microscopy, backscattered electron imagery, and X-Ray analysis/mapping to investigate COTM thin sections. Synchrotron diffraction was used to investigate martian meteorites and laboratory shocked Mars/COTM-relevant minerals for comparison. Results of our investigations indicate porosity development correlates with flow age, and shock alteration of phosphate minerals obscures the original phosphate mineralogy in martian meteorites. Thus COTM represents an important chronosequence and pre-shock mineralogy analog for Mars. [1] Vaughan et al. (2008) SSSAJ 75, [2] Kuntz, et al. (1992) GSA Mem. 179, [3] Adcock et al. (2013) Nat. Geos. 6.

FPGA-based digital signal processing for the next generation radio astronomy instruments: ultra-pure sideband separation and polarization detection

NASA Astrophysics Data System (ADS)

Alvear, Andrés.; Finger, Ricardo; Fuentes, Roberto; Sapunar, Raúl; Geelen, Tom; Curotto, Franco; Rodríguez, Rafael; Monasterio, David; Reyes, Nicolás.; Mena, Patricio; Bronfman, Leonardo

2016-07-01

Field Programmable Gate Arrays (FPGAs) capacity and Analog to Digital Converters (ADCs) speed have largely increased in the last decade. Nowadays we can find one million or more logic blocks (slices) as well as several thousand arithmetic units (ALUs/DSP) available on a single FPGA chip. We can also commercially procure ADC chips reaching 10 GSPS, with 8 bits resolution or more. This unprecedented power of computing hardware has allowed the digitalization of signal processes traditionally performed by analog components. In radio astronomy, the clearest example has been the development of digital sideband separating receivers which, by replacing the IF hybrid and calibrating the system imbalances, have exhibited a sideband rejection above 40dB; this is 20 to 30dB higher than traditional analog sideband separating (2SB) receivers. In Rodriguez et al.,1 and Finger et al.,2 we have demonstrated very high digital sideband separation at 3mm and 1mm wavelengths, using laboratory setups. We here show the first implementation of such technique with a 3mm receiver integrated into a telescope, where the calibration was performed by quasi-optical injection of the test tone in front of the Cassegrain antenna. We also reported progress in digital polarization synthesis, particularly in the implementation of a calibrated Digital Ortho-Mode Transducer (DOMT) based on the Morgan et al. proof of concept.3 They showed off- line synthesis of polarization with isolation higher than 40dB. We plan to implement a digital polarimeter in a real-time FPGA-based (ROACH-2) platform, to show ultra-pure polarization isolation in a non-stop integrating spectrometer.

HEK. VI. On the Dearth of Galilean Analogs in Kepler, and the Exomoon Candidate Kepler-1625b I

NASA Astrophysics Data System (ADS)

Teachey, A.; Kipping, D. M.; Schmitt, A. R.

2018-01-01

Exomoons represent an outstanding challenge in modern astronomy, with the potential to provide rich insights into planet formation theory and habitability. In this work, we stack the phase-folded transits of 284 viable moon hosting Kepler planetary candidates, in order to search for satellites. These planets range from Earth- to Jupiter-sized and from ∼0.1 to 1.0 au in separation—so-called “warm” planets. Our data processing includes two-pass harmonic detrending, transit timing variations, model selection, and careful data quality vetting to produce a grand light curve with an rms of 5.1 ppm. We find that the occurrence rate of Galilean analog moon systems for planets orbiting between ∼0.1 and 1.0 au can be constrained to be η < 0.38 to 95% confidence for the 284 KOIs considered, with a 68.3% confidence interval of η ={0.16}-0.10+0.13. A single-moon model of variable size and separation locates a slight preference for a population of short-period moons with radii ∼0.5 R ⊕ orbiting at 5–10 planetary radii. However, we stress that the low Bayes factor of just 2 in this region means it should be treated as no more than a hint at this time. Splitting our data into various physically motivated subsets reveals no strong signal. The dearth of Galilean analogs around warm planets places the first strong constraint on exomoon formation models to date. Finally, we report evidence for an exomoon candidate Kepler-1625b I, which we briefly describe ahead of scheduled observations of the target with the Hubble Space Telescope.

Tea Catechin Auto-oxidation Dimers are Accumulated and Retained by Caco-2 Human Intestinal Cells

PubMed Central

Neilson, Andrew P.; Song, Brian J.; Sapper, Teryn N.; Bomser, Joshua A.; Ferruzzi, Mario G.

2010-01-01

Despite the presence of bioactive catechin B-ring auto-oxidation dimers in tea, little is known regarding their absorption in humans. Our hypothesis for this research is that catechin auto-oxidation dimers are present in teas and are absorbable by human intestinal epithelial cells. Dimers [theasinensins (THSNs) and P-2 analogs) were quantified in commercial teas by HPLC-MS. (−)-Epigallocatechin (EGC) and (−)-epigallocatechin gallate (EGCG) homodimers were present at 10–43 and 0–62 µmol/g leaf, respectively. EGC-EGCG heterodimers were present at 0–79 µmol/g. The potential intestinal absorption of these dimers was assessed using Caco-2 intestinal cells. Catechin monomers and dimers were detected in cells exposed to media containing monomers and preformed dimers. Accumulation of dimers was significantly greater than monomers from test media. Three h accumulation of EGC and EGCG was 0.19– 0.55% and 1.24–1.35% respectively. Comparatively, 3h accumulation of the EGC P-2 analog, and THSNs C/E was 0.89 ± 0.28% and 1.53 ± 0.36%. Accumulation of P-2, and THSNs A/D was 6.93 ± 2.1%, and 10.1 ± 3.6%. EGCG-EGC heterodimer P-2 analog, and THSN B 3h accumulation was 4.87 ± 2.2%, and 4.65 ± 2.8% respectively. One h retention of P-2, and THSNs A/D was 171 ± 22%, and 29.6 ± 9.3% of accumulated amount suggesting intracellular oxidative conversion of THSNs to P-2. These data suggest that catechin dimers present in the gut lumen may be readily absorbed by intestinal epithelium. PMID:20579525

Determination of the complex refractive indices of Titan haze analogs using photothermal deflection spectroscopy

NASA Astrophysics Data System (ADS)

Vuitton, Véronique; Tran, Buu N.; Persans, Peter D.; Ferris, James P.

2009-10-01

The spectrometers of the Cassini mission to the Saturn system have detected haze layers reaching up to 800 km in Titan's atmosphere. Knowledge of the complex refractive index ( k) of the haze is important for modeling the surface and atmosphere of Titan and retrieving some information about the functional groups present in the aerosols. Plasma discharges or ultraviolet radiation are commonly used to drive the formation of solid organics assumed to be good analogs of the Titan aerosols. [Tran, B.N., Ferris, J.P., Chera, J.J., 2003a. The photochemical formation of a Titan haze analog. Structural analysis by X-ray photoelectron and infrared spectroscopy. Icarus 162, 114-124; Tran, B.N., Force, M., Briggs, R., Ferris J.P., Persans, P., Chera, J.J., 2008. Photochemical processes on Titan: Irradiation of mixtures of gases that simulate Titan's atmosphere. Icarus 177, 106-115] reported the index of refraction of analogs synthesized by far ultraviolet irradiation of various gas mixtures. k was determined in the 200-800 nm wavelength range from transmission and reflection spectroscopy. However, this technique is limited by (i) uncertainties in the absorption values because of the small amounts of organics available, (ii) light scattering by the surface roughness and particulates in the sample. These limitations prompted us to perform new measurements using photothermal deflection spectroscopy (PDS), a technique based on the conversion of absorbed light into heat in the material of interest. By combining traditional spectroscopy ( λ < 500 nm) and PDS ( λ > 500 nm), we determined values of k over the 375-1550 nm range. k values as low as 10 -4 above 1000 nm were determined. This is one order of magnitude lower than the measurements generally used as a reference for Titan's aerosols analogs [Khare, B.N., Sagan, C., Arakawa, E.T., Suits, F., Callicott, T.A., Williams, M.W., 1984. Optical-constants of organic Tholins produced in a simulated Titanian atmosphere—from soft-X-ray to microwave-frequencies. Icarus 60(1), 127-137]. We recommend that these results were used in models to describe the optical properties of the aerosols produced in Titan's stratosphere.

Proton transfer in the K-channel analog of B-type Cytochrome c oxidase from Thermus thermophilus.

PubMed

Woelke, Anna Lena; Wagner, Anke; Galstyan, Gegham; Meyer, Tim; Knapp, Ernst-Walter

2014-11-04

A key enzyme in aerobic metabolism is cytochrome c oxidase (CcO), which catalyzes the reduction of molecular oxygen to water in the mitochondrial and bacterial membranes. Substrate electrons and protons are taken up from different sides of the membrane and protons are pumped across the membrane, thereby generating an electrochemical gradient. The well-studied A-type CcO uses two different entry channels for protons: the D-channel for all pumped and two consumed protons, and the K-channel for the other two consumed protons. In contrast, the B-type CcO uses only a single proton input channel for all consumed and pumped protons. It has the same location as the A-type K-channel (and thus is named the K-channel analog) without sharing any significant sequence homology. In this study, we performed molecular-dynamics simulations and electrostatic calculations to characterize the K-channel analog in terms of its energetic requirements and functionalities. The function of Glu-15B as a proton sink at the channel entrance is demonstrated by its rotational movement out of the channel when it is deprotonated and by its high pKA value when it points inside the channel. Tyr-244 in the middle of the channel is identified as the valve that ensures unidirectional proton transfer, as it moves inside the hydrogen-bond gap of the K-channel analog only while being deprotonated. The electrostatic energy landscape was calculated for all proton-transfer steps in the K-channel analog, which functions via proton-hole transfer. Overall, the K-channel analog has a very stable geometry without large energy barriers.

Proton Transfer in the K-Channel Analog of B-Type Cytochrome c Oxidase from Thermus thermophilus

PubMed Central

Woelke, Anna Lena; Wagner, Anke; Galstyan, Gegham; Meyer, Tim; Knapp, Ernst-Walter

2014-01-01

A key enzyme in aerobic metabolism is cytochrome c oxidase (CcO), which catalyzes the reduction of molecular oxygen to water in the mitochondrial and bacterial membranes. Substrate electrons and protons are taken up from different sides of the membrane and protons are pumped across the membrane, thereby generating an electrochemical gradient. The well-studied A-type CcO uses two different entry channels for protons: the D-channel for all pumped and two consumed protons, and the K-channel for the other two consumed protons. In contrast, the B-type CcO uses only a single proton input channel for all consumed and pumped protons. It has the same location as the A-type K-channel (and thus is named the K-channel analog) without sharing any significant sequence homology. In this study, we performed molecular-dynamics simulations and electrostatic calculations to characterize the K-channel analog in terms of its energetic requirements and functionalities. The function of Glu-15B as a proton sink at the channel entrance is demonstrated by its rotational movement out of the channel when it is deprotonated and by its high pKA value when it points inside the channel. Tyr-244 in the middle of the channel is identified as the valve that ensures unidirectional proton transfer, as it moves inside the hydrogen-bond gap of the K-channel analog only while being deprotonated. The electrostatic energy landscape was calculated for all proton-transfer steps in the K-channel analog, which functions via proton-hole transfer. Overall, the K-channel analog has a very stable geometry without large energy barriers. PMID:25418102

Evaluation of tricine and EDDA as Co-ligands for 99mTc-labeled HYNIC-MSH analogs for melanoma imaging.

PubMed

Garcia, Maria Fernanda; Zhang, Xiuli; Gallazzi, Fabio; Fernandez, Marcelo; Moreno, Maria; Gambini, Juan Pablo; Porcal, Williams; Cabral, Pablo; Quinn, Thomas P

2015-01-01

Several radiolabeled alpha-melanocyte stimulating hormone (α-MSH) analogs have been studied for their abilities to target melanoma tumor cells through specific recognition and binding to the melanocortin receptor 1 (MCR1). In this work, a lactam bridgecyclized α-MSH analog was labeled with (99m) via the hydrazinonicotinamide (HYNIC) chelator and characterized for its melanoma tumor targeting properties. The bifunctional chelating agent HYNIC-Boc was attached to the N-terminus of the MSH peptide followed by the lactam cyclization, resulting in the HYNIC-cyc-MSH analog. The lactam cyclized peptide displayed high affinity and specificity for MC1-receptors present on B16/F1 melanoma tumor cells, exhibiting an IC50 of 6.48 nM. HYNIC-cyc-MSH was radiolabeled with (99m)Tc using two common co-ligands, tricine and EDDA. In vitro, the radiochemical stability, cell binding and efflux properties were similar between the peptides radiolabeled with tricine and EDDA as co-ligands. In vivo, biodistribution studies (n=4) demonstrated that (99m)Tc- HYNIC-cyc-MSH/tricine had superior tumor to muscle and tumor to blood ratios than (99m)Tc-HYNIC-cyc-MSH/EDDA at early time points. Planar gamma imaging of melanoma bearing mice showed that 99mTc-HYNIC-cyc-MSH/tricine was able to clearly visualize tumors, underscoring the potential utility of (99m)Tc labeled lactam cyclized MSH molecules as melanoma imaging agents.

Using Voice Recognition Equipment to Run the Warfare Environmental Simulator (WES),

DTIC Science & Technology

1981-03-01

simulations and models are often used. War games are a type of simulation frequently used by the military to evaluate C3 effectiveness. Through the use of a...to 162 words or short phrases (Appendix B). B. EQUIPMENT USED 1. Hardware Description [13] For the experiment a Threshold Model T600 discrete... Model T600 terminal used in this experiment con- sists of an analog speech preprocessor, microcomputer, CRT/keyboard unit, magnetic tape cartridge unit

Determination of nucleoside analog mono-, di-, and tri-phosphates in cellular matrix by solid phase extraction and ultra-sensitive LC-MS/MS detection.

PubMed

Bushman, Lane R; Kiser, Jennifer J; Rower, Joseph E; Klein, Brandon; Zheng, Jia-Hua; Ray, Michelle L; Anderson, Peter L

2011-09-10

An ultra-sensitive liquid chromatography tandem mass spectrometry (LC-MS/MS) assay was developed and validated to facilitate the assessment of clinical pharmacokinetics of nucleotide analogs from lysed intracellular matrix. The method utilized a strong anion exchange isolation of mono-(MP), di-(DP), and tri-phosphates (TP) from intracellular matrix. Each fraction was then dephosphorylated to the parent moiety yielding a molar equivalent to the original nucleotide analog intracellular concentration. The analytical portion of the methodology was optimized in specific nucleoside analog centric modes (i.e. tenofovir (TFV) centric, zidovudine (ZDV) centric), which included desalting/concentration by solid phase extraction and detection by LC-MS/MS. Nucleotide analog MP-, DP-, and TP-determined on the TFV centric mode of analysis include TFV, lamivudine (3TC), and emtricitibine (FTC). The quantifiable linear range for TFV was 2.5-2000 fmol/sample, and that for 3TC/FTC was 0.1 200 pmol/sample. Nucleoside analog MP-, DP-, and TP-determined on the ZDV centric mode of analysis included 3TC and ZDV. The quantifiable linear range for 3TC was 0.1 100 pmol/sample, and 5-2000 fmol/sample for ZDV. Stable labeled isotopic internal standards facilitated accuracy and precision in alternative cell matrices, which supported the intended use of the method for MP, DP, and TP determinations in various cell types. The method was successfully applied to clinical research samples generating novel intracellular information for TFV, FTC, ZDV, and 3TC nucleotides. This document outlines method development, validation, and application to clinical research. Copyright © 2011 Elsevier B.V. All rights reserved.

The roles of the analogy with natural selection in B.F. Skinner's philosophy.

PubMed

Smith, Terry L

2018-02-17

Beginning in the 1950s, B.F. Skinner made increasing reference to an analogy between operant conditioning and natural selection. This analogy is the basis of an argument that, in contrast to Skinner's other critiques of cognitive science, is neither epistemological nor pragmatic. Instead, it is based on the claim that ontogenetic adaptation is due to a special mode of causation he called "selection by consequences." He argued that this mode of causation conflicts with explanations that attribute action to an autonomous agent with reasons for acting. This argument dismisses ordinary explanations of action, and has implications not only for cognitive science but also for morals. Skinner cited the latter implications to counter objections to the application of behavior analysis to the reform of society and its institutions. Skinner's critique, however, rests upon empirical assumptions that have been criticized by other behavior analysts. Although for Skinner the major role of the analogy was to propose an empirical thesis, it also can play a metaphysical role-namely, to demonstrate the possibility of ontogenetic adaptation without reference to agents who have reasons for acting. These two roles, empirical and metaphysical, are the mirror image of the empirical and metaphysical roles of the computer analogy for cognitive science. That analogy also can be (and has been) interpreted as an empirical thesis. Its empirical implications, however, have been difficult to confirm. It also, however, has played a metaphysical role-namely, to demonstrate the possibility that a physical process could perform logical operations on states having propositional content. Neither analogy provides a well-confirmed, general answer to the question of how to explain the process of ontogenetic adaptation. But together they show there are two metaphysically coherent, but conflicting, answers to this question. Depending upon one's epistemology, the analogy with natural selection may provide a useful point of departure for a strategy of research. Such a pragmatic grounding for a research strategy does not, however, provide sufficient reason to abandon for purposes of ethics the concept of persons as autonomous agents. Copyright © 2018 Elsevier B.V. All rights reserved.

Potencies of vitamin D analogs, 1α-hydroxyvitamin D3 , 1α-hydroxyvitamin D2 and 25-hydroxyvitamin D3 , in lowering cholesterol in hypercholesterolemic mice in vivo.

PubMed

Quach, Holly P; Dzekic, Tamara; Bukuroshi, Paola; Pang, K Sandy

2018-04-01

Vitamin D 3 and the synthetic vitamin D analogs, 1α-hydroxyvitamin D 3 [1α(OH)D 3 ], 1α-hydroxyvitamin D 2 [1α(OH)D 2 ] and 25-hydroxyvitamin D 3 [25(OH)D 3 ] were appraised for their vitamin D receptor (VDR) associated-potencies as cholesterol lowering agents in mice in vivo. These precursors are activated in vivo: 1α(OH)D 3 and 1α(OH)D 2 are transformed by liver CYP2R1 and CYP27A1 to active VDR ligands, 1α,25-dihydroxyvitamin D 3 [1,25(OH) 2 D 3 ] and 1α,25-dihydroxyvitamin D 2 [1,25(OH) 2 D 2 ] , respectively. 1α(OH)D 2 may also be activated by CYP24A1 to 1α,24-dihydroxyvitamin D 2 [1,24(OH) 2 D 2 ], another active VDR ligand. 25(OH)D 3 , the metabolite formed via CYP2R1 and or CYP27A1 in liver from vitamin D 3 , is activated by CYP27B1 in the kidney to 1,25(OH) 2 D 3 . In C57BL/6 mice fed the high fat/high cholesterol Western diet for 3 weeks, vitamin D analogs were administered every other day intraperitoneally during the last week of the diet. The rank order for cholesterol lowering, achieved via mouse liver small heterodimer partner (Shp) inhibition and increased cholesterol 7α-hydroxylase (Cyp7a1) expression, was: 1.75 nmol/kg 1α(OH)D 3  > 1248 nmol/kg 25(OH)D 3 (dose ratio of 0.0014) > > 1625 nmol/kg vitamin D 3 . Except for 1.21 nmol/kg 1α(OH)D 2 that failed to lower liver and plasma cholesterol contents, a significant negative correlation was observed between the liver concentration of 1,25(OH) 2 D 3 formed from the precursors and liver cholesterol levels. The composite results show that vitamin D analogs 1α(OH)D 3 and 25(OH)D 3 exhibit cholesterol lowering properties upon activation to 1,25(OH) 2 D 3 : 1α(OH)D 3 is rapidly activated by liver enzymes and 25(OH)D 3 is slowly activated by renal Cyp27b1 in mouse. Copyright © 2018 John Wiley & Sons, Ltd.

Magnetic properties of the ternary alloy with a structure of Prussian blue analogs

NASA Astrophysics Data System (ADS)

Dely, J.; Bobák, A.

2007-01-01

The magnetic properties (phase diagram, compensation temperature, magnetic susceptibility, and magnetization) of the ABpC1-p ternary alloy in the presence of a single-ion anisotropy on the B ions only are investigated by the use of a mean-field theory. Depending on the values of the parameters in the model Hamiltonian, the present system may exhibit one, two or even three compensation temperatures Tk. It is shown that the total magnetic susceptibility of the ferrimagnetic system can generally take a finite value at transition temperature Tc only if the relation Tc=Tk is exactly satisfied. Also, by using this model, some characteristics observed in the Prussian blue analog of the type (FepIIMn1-pII)1.5[CrIII(CN)6]·nH2O are quantitatively or qualitatively well reproduced.

Contribution of TyrB26 to the Function and Stability of Insulin

PubMed Central

Pandyarajan, Vijay; Phillips, Nelson B.; Rege, Nischay; Lawrence, Michael C.; Whittaker, Jonathan; Weiss, Michael A.

2016-01-01

Crystallographic studies of insulin bound to receptor domains have defined the primary hormone-receptor interface. We investigated the role of TyrB26, a conserved aromatic residue at this interface. To probe the evolutionary basis for such conservation, we constructed 18 variants at B26. Surprisingly, non-aromatic polar or charged side chains (such as Glu, Ser, or ornithine (Orn)) conferred high activity, whereas the weakest-binding analogs contained Val, Ile, and Leu substitutions. Modeling of variant complexes suggested that the B26 side chains pack within a shallow depression at the solvent-exposed periphery of the interface. This interface would disfavor large aliphatic side chains. The analogs with highest activity exhibited reduced thermodynamic stability and heightened susceptibility to fibrillation. Perturbed self-assembly was also demonstrated in studies of the charged variants (Orn and Glu); indeed, the GluB26 analog exhibited aberrant aggregation in either the presence or absence of zinc ions. Thus, although TyrB26 is part of insulin's receptor-binding surface, our results suggest that its conservation has been enjoined by the aromatic ring's contributions to native stability and self-assembly. We envisage that such classical structural relationships reflect the implicit threat of toxic misfolding (rather than hormonal function at the receptor level) as a general evolutionary determinant of extant protein sequences. PMID:27129279

A novel cantharidin analog N-Benzylcantharidinamide reduces the expression of MMP-9 and invasive potentials of Hep3B via inhibiting cytosolic translocation of HuR

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lee, Ji-Yeon; Chung, Tae-Wook; Choi, Hee-Jung

2014-05-02

Highlights: • We examined the inhibition of N-Benzylcantharidinamide on MMP-9-mediated invasion. • Unlike cantharidin, N-Benzylcantharidinamide has very low toxicity on Hep3B cells. • The reduced MMP-9 expression was due to HuR-mediated decrease of mRNA stability. • We suggest N-Benzylcantharidinamide as a novel inhibitor of MMP-9-related invasion. - Abstract: Invasion and metastasis are major causes of malignant tumor-associated mortality. The present study aimed to investigate the molecular events underlying inhibitory effect of N-Benzylcantharidinamide, a novel synthetic analog of cantharidin, on matrix metalloproteinase-9 (MMP-9)-mediated invasion in highly metastatic hepatocellular carcinoma Hep3B cells. In this investigation, among six analogs of cantharidin, only N-Benzylcantharidinamidemore » has the inhibitory action on MMP-9 expression at non-toxic dose. The MMP-9 expression and invasion of Hep3B cells were significantly suppressed by treatment of N-Benzylcantharidinamide in a dose-dependent manner. On the other hand, the transcriptional activity of MMP-9 promoter and nuclear levels of NF-κB and AP-1 as the main transcriptional factors inducing MMP-9 expression were not affected by it although the level of MMP-9 mRNA was reduced by treatment of N-Benzylcantharidinamide. Interestingly, the stability of MMP-9 mRNA was significantly reduced by N-Benzylcantharidinamide-treatment. In addition, the cytosolic translocation of human antigen R (HuR), which results in the increase of MMP-9 mRNA stability through interaction of HuR with 3′-untranslated region of MMP-9 mRNA, was suppressed by treatment of N-Benzylcantharidinamide, in a dose-dependent manner. Taken together, it was demonstrated, for the first time, that N-Benzylcantharidinamide suppresses MMP-9 expression by reducing HuR-mediated MMP-9 mRNA stability for the inhibition of invasive potential in highly metastatic Hep3B cells.« less

47 CFR 73.403 - Digital audio broadcasting service requirements.

Code of Federal Regulations, 2010 CFR

2010-10-01

... programming stream at no direct charge to listeners. In addition, a broadcast radio station must simulcast its analog audio programming on one of its digital audio programming streams. The DAB audio programming... analog programming service currently provided to listeners. (b) Emergency information. The emergency...

The use of UV, FT-IR and Raman spectra for the identification of the newest penem analogs: solutions based on mathematic procedure and the density functional theory.

PubMed

Cielecka-Piontek, J; Lewandowska, K; Barszcz, B; Paczkowska, M

2013-02-15

The application of ultraviolet, FT-IR and Raman spectra was proposed for identification studies of the newest penem analogs (doripenem, biapenem and faropenem). An identification of the newest penem analogs based on their separation from related substances was achieved after the application of first derivative of direct spectra in ultraviolet which permitted elimination of overlapping effects. A combination of experimental and theoretical studies was performed for analyzing the structure and vibrational spectra (FT-IR and Raman spectra) of doripenem, biapenem and faropenem. The calculations were conducted using the density functional theory with the B3LYP hybrid functional and 6-31G(d,p) basis set. The confirmation of the applicability of the DFT methodology for interpretation of vibrational IR and Raman spectra of the newest penem analogs contributed to determination of changes of vibrations in the area of the most labile bonds. By employing the theoretical approach it was possible to eliminate necessity of using reference standards which - considering the instability of penem analogs - require that correction coefficients are factored in. Copyright © 2012 Elsevier B.V. All rights reserved.

PG&E's Seismic Network Goes Digital With Strong Motion: Successes and Challenges

NASA Astrophysics Data System (ADS)

Stanton, M. A.; Cullen, J.; McLaren, M. K.

2008-12-01

Pacific Gas and Electric Company (PG&E) is in year 3 of a 5-year project to upgrade the Central Coast Seismic Network (CCSN) from analog to digital. Located along the south-central California coast, the CCSN began operation in 1987, with 20 analog stations; 15 vertical component and 5 dual gain 3-component S-13 sensors. The analog signals travel over FM radio telemetry links and voice channels via PG&E's microwave network to our facility in San Francisco (SF), where the A/D conversion is performed on a computer running Earthworm v7.1, which also transmits the data to the USGS in Menlo Park. At the conversion point the dynamic ranges of the vertical and dual-gain sensors are 40-50dB and 60-70dB, respectively. Dynamic range exceedance (data clipping) generally occurs for a M2.5 or greater event within about 40 km of a station. The motivations to upgrade the seismic network were the need for higher dynamic range and to retire obsolete analog transmission equipment. The upgraded digital stations consist of the existing velocity sensors, a 131A-02/3 accelerometer and a Reftek 130-01 Broadband Seismic Recorder for digital data recording and transmission to SF. Vertical only stations have one component of velocity and 3 components of acceleration. Dual gain sites have 3 components of velocity and 3 of acceleration. To date we have successfully upgraded 6 sites; 3 more will be installed by the end of 2008. Some of the advantages of going digital are 1) data is recorded at each site and in SF, 2) substantially increased dynamic range of the velocity sensors to 120dB, as observed by on scale, close-by recordings from a M3.9 San Simeon aftershock on 04/29/2008, 3) accelerometers for on scale recording of large earthquakes, and 4) ability to contribute our strong motion data to USGS ShakeMaps. A significant challenge has been consistent radio communications. To resolve this issue we are installing point-to-multipoint Motorola Canopy spread spectrum radios at the stations and communication towers.

Drug Development of the Antimalarial Agent Artemisinin: Total Synthesis, Analog Synthesis, and Structure-Activity Relationship Studies

DTIC Science & Technology

1990-08-15

16. SUPPLEMENTARY NOTATION 17 COSATi CODES FiELD 07 06 CROUP 03 01 SUB-GROUP IB SUBJECT TERMS (Cont/nu* on rtvtnt if ntctiwy *ne identity b ...number of requisite substituents resulted in the synthesis of ring cleaved analogs and partial structures of artemisinin: (+)-C/D, (+)-A/ B /C, (+)-A/C...in the preparation of the unstable aldehyde 2, and in commendable fashion others have employed an enol ether photo-oxygenation as entry to that

64Cu-labeled alpha-melanocyte-stimulating hormone analog for microPET imaging of melanocortin 1 receptor expression.

PubMed

Cheng, Zhen; Xiong, Zhengming; Subbarayan, Murugesan; Chen, Xiaoyuan; Gambhir, Sanjiv Sam

2007-01-01

The alpha-melanocyte-stimulating hormone (alpha-MSH) receptor (melanocortin type 1 receptor, or MC1R) plays an important role in the development and growth of melanoma cells. It was found that MC1R was overexpressed on most murine and human melanoma, making it a promising molecular target for melanoma imaging and therapy. Radiolabeled alpha-MSH peptide and its analogs that can specifically bind with MC1R have been extensively explored for developing novel agents for melanoma detection and radionuclide therapy. The goal of this study was to evaluate a 64Cu-labeled alpha-MSH analog, Ac-Nle-Asp-His-D-Phe-Arg-Trp-Gly-Lys(DOTA)-NH2 (DOTA-NAPamide), as a potential molecular probe for microPET imaging of melanoma and MC1R expression in melanoma xenografted mouse models. 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) conjugated NAPamide was synthesized and radiolabeled with 64Cu (t1/2=12 h) in NH4OAc (0.1 M; pH 5.5) buffered solution for 60 min at 50 degrees C. Cell culture studies reveal rapid and high uptake and internalization of 64Cu-DOTA-NAPamide in B16F10 cells. Over 90% of receptor-bound tracer is internalized at 3 h incubation. A cellular retention study demonstrates that the receptor-bound 64Cu-DOTA-NAPamide is slowly released from the B16F10 cells into the medium; 66% of the radioactivity is still associated with the cells even after 3 h incubation. The biodistribution of 64Cu-DOTA-NAPamide was then investigated in C57BL/6 mice bearing subcutaneous murine B16F10 melanoma tumors with high capacity of MC1R and Fox Chase Scid mice bearing human A375M melanoma with a relatively low number of MC1R receptors. Tumor uptake values of 64Cu-DOTA-NAPamide are found to be 4.63 +/- 0.45% and 2.49 +/- 0.31% ID/g in B16F10 and A375M xenografted melanoma at 2 h postinjection (pi), respectively. The B16F10 tumor uptake at 2 h pi is further inhibited to 2.29 +/- 0.24% ID/g, while A375M tumor uptake at 2 h pi remains 2.20 +/- 0.41% ID/g with a coinjection of excess alpha-MSH peptide. MicroPET imaging of 64Cu-DOTA-NAPamide in B16F10 tumor mice clearly shows good tumor localization. However, low A375M tumor uptake and poor tumor to normal tissue contrast were observed. This study demonstrates that 64Cu-DOTA-NAPamide is a promising molecular probe for alpha-MSH receptor positive melanoma PET imaging as well as MC1R expression imaging in living mice.

14 CFR 121.346 - Flight data recorders: filtered data.

Code of Federal Regulations, 2013 CFR

2013-01-01

... sensor signal has been changed in any way, other than changes necessary to: (1) Accomplish analog to... high frequency component of a signal that is outside the operational bandwidth of the sensor. (b) An original sensor signal for any flight recorder parameter required to be recorded under § 121.344 may be...

14 CFR 121.346 - Flight data recorders: filtered data.

Code of Federal Regulations, 2014 CFR

2014-01-01

... sensor signal has been changed in any way, other than changes necessary to: (1) Accomplish analog to... high frequency component of a signal that is outside the operational bandwidth of the sensor. (b) An original sensor signal for any flight recorder parameter required to be recorded under § 121.344 may be...

14 CFR 121.346 - Flight data recorders: filtered data.

Code of Federal Regulations, 2012 CFR

2012-01-01

... sensor signal has been changed in any way, other than changes necessary to: (1) Accomplish analog to... high frequency component of a signal that is outside the operational bandwidth of the sensor. (b) An original sensor signal for any flight recorder parameter required to be recorded under § 121.344 may be...

Unfolded-protein response-associated stabilization of p27(Cdkn1b) interferes with lens fiber cell denucleation, leading to cataract

USDA-ARS?s Scientific Manuscript database

Failure of lens fiber cell denucleation (LFCD) is associated with congenital cataracts, but the pathobiology awaits elucidation. Recent work has suggested that mechanisms that direct the unidirectional process of LFCD are analogous to the cyclic processes associated with mitosis. We found that lens-...

Analogies between Vanadoborates and Planar Aromatic Hydrocarbons: A High-Spin Analogue of Aromaticity.

PubMed

King, R Bruce

2017-12-23

The vanadium-vanadium interactions in the polygonal aggregates of d¹ vanadium(IV) atoms, with a total of 4 k + 2 vanadium electrons ( k an integer) imbedded in an electronically inactive borate matrix in certain vanadoborate structures are analogous to the ring carbon-carbon interactions in diamagnetic planar cyclic hydrocarbons. They thus represent a high-spin analogue of aromaticity. Thus, the vanadoborate anion [V₆B 20 O 50 H₈] 8- with six V(IV) electrons (i.e., 4 k + 2 for k = 1) contains a macrohexagon of d¹ V(IV) atoms with four unpaired electrons. This high-spin system is related to the low-spin aromaticity in the diamagnetic benzene having six π electrons. Similarly, the vanadoborate anion [V 10 B 28 O 74 H₈] 16- with ten V(IV) electrons (i.e., 4 k + 2 for k = 2) contains a macrodecagon of d¹ V(IV) atoms with eight unpaired electrons. Again, this high-spin system is related to the aromaticity in the diamagnetic 1,6-methanol[10]annulene, having ten π electrons.

The Quest for the Ultimate Anisotropic Banach Space

NASA Astrophysics Data System (ADS)

Baladi, Viviane

2017-02-01

We present a new scale U^{t,s}_p (s<-t<0 and 1≤p <∞) of anisotropic Banach spaces, defined via Paley-Littlewood, on which the transfer operator L_g φ = (g \\cdot φ) circ T^{-1} associated to a hyperbolic dynamical system T has good spectral properties. When p=1 and t is an integer, the spaces are analogous to the "geometric" spaces B^{t,|s+t|} considered by Gouëzel and Liverani (Ergod Theory Dyn Syst 26:189-217, 2006). When p>1 and -1+1/p

Alternative [SU(3)]4 model of leptonic color and dark matter

NASA Astrophysics Data System (ADS)

Kownacki, Corey; Ma, Ernest; Pollard, Nicholas; Popov, Oleg; Zakeri, Mohammadreza

2018-03-01

The alternative [ SU (3) ] 4 model of leptonic color and dark matter is discussed. It unifies at MU ∼1014 GeV and has the low-energy subgroup SU(3)q × SU(2)l × SU(2)L × SU(2)R × U(1)X with (u , h) R instead of (u , d) R as doublets under SU(2)R. It has the built-in global U (1) dark symmetry which is generalized B- L. In analogy to SU(3)q quark triplets, it has SU(2)l hemion doublets which have half-integral charges and are confined by SU(2)l gauge bosons (stickons). In analogy to quarkonia, their vector bound states (hemionia) are uniquely suited for exploration at a future e-e+ collider.

A Better Understanding of Protein Structure and Function by the Synthesis and Incorporation of Selenium- and Tellurium Containing Tryptophan Analogs

DOE Office of Scientific and Technical Information (OSTI.GOV)

Helmey, Sherif Samir; Rice, Ambrose Eugene; Hatch, Duane Michael

Unnatural heavy metal-containing amino acid analogs have shown to be very important in the analysis of protein structure, using methods such as X-ray crystallography, mass spectroscopy, and NMR spectroscopy. Synthesis and incorporation of selenium-containing methionine analogs has already been shown in the literature however with some drawbacks due to toxicity to host organisms. Thus synthesis of heavy metal tryptophan analogs should prove to be more effective since the amino acid tryptophan is naturally less abundant in many proteins. For example, bioincorporation of β-seleno[3,2-b]pyrrolyl-L-alanine ([4,5]SeTrp) and β-selenolo[2,3-b]pyrrolyl-L-alanine ([6,7]SeTrp) has been shown in the following proteins without structural or catalytic perturbations: humanmore » annexin V, barstar, and dihydrofolate reductase. The reported synthesis of these Se-containing analogs is currently not efficient for commercial purposes. Thus a more efficient, concise, high-yield synthesis of selenotryptophan, as well as the corresponding, tellurotryptophan, will be necessary for wide spread use of these unnatural amino acid analogs. This research will highlight our progress towards a synthetic route of both [6,7]SeTrp and [6,7]TeTrp, which ultimately will be used to study the effect on the catalytic activity of Lignin Peroxidase (LiP).« less

Categorizing entities by common role.

PubMed

Goldwater, Micah B; Markman, Arthur B

2011-04-01

Many categories group together entities that play a common role across situations. For example, guest and host refer to complementary roles in visiting situations and, thus, are role-governed categories (A. B. Markman & Stilwell, Journal of Experiment & Theoretical Artificial Intelligence, 13, 329-358, 2001). However, categorizing an entity by role is one of many possible classification strategies. This article examines factors that promote role-governed categorization over thematic-relation-based categorization (Lin & Murphy, Journal of Experimental Psychology: General, 130, 3-28, 2001). In Experiments 1a and 1b, we demonstrate that the use of novel category labels facilitates role-governed categorization. In Experiments 2a and 2b, we demonstrate that analogical comparison facilitates role-governed categorization. In Experiments 1b and 2b, we show that these facilitatory factors induce a general sensitivity to role information, as opposed to only promoting role-governed categorization on an item-by-item basis.

An analog of camptothecin inactive against Topoisomerase I is broadly neutralizing of HIV-1 through inhibition of Vif-dependent APOBEC3G degradation.

PubMed

Bennett, Ryan P; Stewart, Ryan A; Hogan, Priscilla A; Ptak, Roger G; Mankowski, Marie K; Hartman, Tracy L; Buckheit, Robert W; Snyder, Beth A; Salter, Jason D; Morales, Guillermo A; Smith, Harold C

2016-12-01

Camptothecin (CPT) is a natural product discovered to be active against various cancers through its ability to inhibit Topoisomerase I (TOP1). CPT analogs also have anti-HIV-1 (HIV) activity that was previously shown to be independent of TOP1 inhibition. We show that a cancer inactive CPT analog (O2-16) inhibits HIV infection by disrupting multimerization of the HIV protein Vif. Antiviral activity depended on the expression of the cellular viral restriction factor APOBEC3G (A3G) that, in the absence of functional Vif, has the ability to hypermutate HIV proviral DNA during reverse transcription. Our studies demonstrate that O2-16 has low cytotoxicity and inhibits Vif-dependent A3G degradation, enabling A3G packaging into HIV viral particles that results in A3G signature hypermutations in viral genomes. This antiviral activity was A3G-dependent and broadly neutralizing against sixteen HIV clinical isolates from groups M (subtypes A-G), N, and O as well as seven single and multi-drug resistant strains of HIV. Molecular modeling predicted binding near the PPLP motif crucial for Vif multimerization and activity. O2-16 also was active in blocking Vif degradation of APOBEC3F (A3F). We propose that CPT analogs not active against TOP1 have novel therapeutic potential as Vif antagonists that enable A3G-dependent hypermutation of HIV. Copyright © 2016 Elsevier B.V. All rights reserved.

THE UBV(RI){sub C} COLORS OF THE SUN

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ramirez, I.; Michel, R.; Schuster, W. J.

2012-06-10

Photometric data in the UBV(RI){sub C} system have been acquired for 80 solar analog stars for which we have previously derived highly precise atmospheric parameters T{sub eff}, log g, and [Fe/H] using high-resolution, high signal-to-noise ratio spectra. UBV and (RI){sub C} data for 46 and 76 of these stars, respectively, are published for the first time. Combining our data with those from the literature, colors in the UBV(RI){sub C} system, with {approx_equal} 0.01 mag precision, are now available for 112 solar analogs. Multiple linear regression is used to derive the solar colors from these photometric data and the spectroscopically derivedmore » T{sub eff}, log g, and [Fe/H] values. To minimize the impact of systematic errors in the model-dependent atmospheric parameters, we use only the data for the 10 stars that most closely resemble our Sun, i.e., the solar twins, and derive the following solar colors: (B - V){sub Sun} = 0.653 {+-} 0.005, (U - B){sub Sun} = 0.166 {+-} 0.022, (V - R){sub Sun} = 0.352 {+-} 0.007, and (V - I){sub Sun} = 0.702 {+-} 0.010. These colors are consistent, within the 1{sigma} errors, with those derived using the entire sample of 112 solar analogs. We also derive the solar colors using the relation between spectral-line-depth ratios and observed stellar colors, i.e., with a completely model-independent approach, and without restricting the analysis to solar twins. We find (B - V){sub Sun} = 0.653 {+-} 0.003, (U - B){sub Sun} = 0.158 {+-} 0.009, (V - R){sub Sun} = 0.356 {+-} 0.003, and (V - I){sub Sun} = 0.701 {+-} 0.003, in excellent agreement with the model-dependent analysis.« less

SCY-635, a Novel Nonimmunosuppressive Analog of Cyclosporine That Exhibits Potent Inhibition of Hepatitis C Virus RNA Replication In Vitro ▿ †

PubMed Central

Hopkins, Sam; Scorneaux, Bernard; Huang, Zhuhui; Murray, Michael G.; Wring, Stephen; Smitley, Craig; Harris, Richard; Erdmann, Frank; Fischer, Gunter; Ribeill, Yves

2010-01-01

SCY-635 is a novel nonimmunosuppressive cyclosporine-based analog that exhibits potent suppression of hepatitis C virus (HCV) replication in vitro. SCY-635 inhibited the peptidyl prolyl isomerase activity of cyclophilin A at nanomolar concentrations but showed no detectable inhibition of calcineurin phosphatase activity at concentrations up to 2 μM. Metabolic studies indicated that SCY-635 did not induce the major cytochrome P450 enzymes 1A2, 2B6, and 3A4. SCY-635 was a weak inhibitor and a poor substrate for P-glycoprotein. Functional assays with stimulated Jurkat cells and stimulated human peripheral blood mononuclear cells indicated that SCY-635 is a weaker inhibitor of interleukin-2 secretion than cyclosporine. A series of two-drug combination studies was performed in vitro. SCY-635 exhibited synergistic antiviral activity with alpha interferon 2b and additive antiviral activity with ribavirin. SCY-635 was shown to be orally bioavailable in multiple animal species and produced blood and liver concentrations of parent drug that exceeded the 50% effective dose determined in the bicistronic con1b-derived replicon assay. These results suggest that SCY-635 warrants further investigation as a novel therapeutic agent for the treatment of individuals who are chronically infected with HCV. PMID:19933795

Biological properties of prolactin-releasing peptide analogs with a modified aromatic ring of a C-terminal phenylalanine amide.

PubMed

Maletínská, Lenka; Spolcová, Andrea; Maixnerová, Jana; Blechová, Miroslava; Zelezná, Blanka

2011-09-01

Prolactin-releasing peptide (PrRP)-induced secretion of prolactin is not currently considered a primary function of PrRP, but the development of late-onset obesity in both PrRP and PrRP receptor knock-out mice indicates the unique anorexigenic properties of PrRP. In our recent study, we showed comparable potencies of peptides PrRP31 and PrRP20 in binding, intracellular signaling and prolactin release in pituitary RC-4B/C cells, and anorexigenic effect after central administration in fasted mice. In the present study, eight analogs of PrRP20 with C-terminal Phe amide modified with a bulky side chain or a halogenated aromatic ring revealed high binding potency, activation of mitogen-activated protein kinase/extracellular-regulated kinase (MAPK/ERK1/2) and cAMP response element-binding protein (CREB) and prolactin release in RC-4B/C cells. In particular, [PheNO(2)(31)]PrRP20, [1-Nal(31)]PrRP20, [2-Nal(31)]PrRP20 and [Tyr(31)]PrRP20 showed not only in vitro effects comparable or higher than those of PrRP20, but also a very significant and long-lasting anorexigenic effect after central administration in fasted mice. The design of potent and long-lasting PrRP analogs with selective anorexigenic properties promises to contribute to the study of food intake disorders. Copyright © 2011 Elsevier Inc. All rights reserved.

Species differences in unlocking B-side electron transfer in bacterial reaction centers

DOE PAGES

Dylla, Nicholas P.; Faries, Kaitlyn M.; Wyllie, Ryan M.; ...

2016-06-21

The structure of the bacterial photosynthetic reaction center (RC) reveals symmetry-related electron transfer (ET) pathways, but only one path is used in native RCs. Analogous mutations have been made in two Rhodobacter (R.) species. A glutamic acid at position 133 in the M subunit increases transmembrane charge separation via the naturally inactive (B-side) path through impacts on primary ET in mutant R. sphaeroidesRCs. Prior work showed that the analogous substitution in the R. capsulatusRC also increases B-side activity, but mainly affects secondary ET. Finally, the overall yields of transmembrane ET are similar, but enabled in fundamentally different ways.

Species differences in unlocking B-side electron transfer in bacterial reaction centers

DOE Office of Scientific and Technical Information (OSTI.GOV)

Dylla, Nicholas P.; Faries, Kaitlyn M.; Wyllie, Ryan M.

The structure of the bacterial photosynthetic reaction center (RC) reveals symmetry-related electron transfer (ET) pathways, but only one path is used in native RCs. Analogous mutations have been made in two Rhodobacter (R.) species. A glutamic acid at position 133 in the M subunit increases transmembrane charge separation via the naturally inactive (B-side) path through impacts on primary ET in mutant R. sphaeroidesRCs. Prior work showed that the analogous substitution in the R. capsulatusRC also increases B-side activity, but mainly affects secondary ET. Finally, the overall yields of transmembrane ET are similar, but enabled in fundamentally different ways.

Salt-sparing diuretic action of a water-soluble urea analog inhibitor of urea transporters UT-A and UT-B in rats

PubMed Central

Cil, Onur; Esteva-Font, Cristina; Tas, Sadik Taskin; Su, Tao; Lee, Sujin; Anderson, Marc O.; Ertunc, Mert; Verkman, A. S.

2015-01-01

Inhibitors of kidney urea transporter (UT) proteins have potential use as salt-sparing diuretics (‘urearetics’) with a different mechanism of action than diuretics that target salt transporters. To study UT inhibition in rats, we screened about 10,000 drugs, natural products and urea analogs for inhibition of rat UT-A1. Drug and natural product screening found nicotine, sanguinarine and an indolcarbonylchromenone with IC50 of 10–20 μM. Urea analog screening found methylacetamide and dimethylthiourea (DMTU). DMTU fully and reversibly inhibited rat UT-A1 and UT-B by a noncompetitive mechanism with IC50 of 2–3 mM. Homology modeling and docking computations suggested DMTU binding sites on rat UT-A1. Following a single intraperitoneal injection of 500 mg/kg DMTU, peak plasma concentration was 9 mM with t1/2 of about 10 hours, and a urine concentration of 20–40 mM. Rats chronically treated with DMTU had a sustained, reversible reduction in urine osmolality from 1800 to 600 mOsm, a 3-fold increase in urine output, and mild hypokalemia. DMTU did not impair urinary concentrating function in rats on a low protein diet. Compared to furosemide-treated rats, the DMTU-treated rats had greater diuresis and reduced urinary salt loss. In a model of Syndrome of Inappropriate Antidiuretic Hormone secretion, DMTU treatment prevented hyponatremia and water retention produced by water-loading in dDAVP-treated rats. Thus, our results establish a rat model of UT inhibition and demonstrate the diuretic efficacy of UT inhibition. PMID:25993324

Salt-sparing diuretic action of a water-soluble urea analog inhibitor of urea transporters UT-A and UT-B in rats.

PubMed

Cil, Onur; Esteva-Font, Cristina; Tas, Sadik Taskin; Su, Tao; Lee, Sujin; Anderson, Marc O; Ertunc, Mert; Verkman, Alan S

2015-08-01

Inhibitors of kidney urea transporter (UT) proteins have potential use as salt-sparing diuretics ('urearetics') with a different mechanism of action than diuretics that target salt transporters. To study UT inhibition in rats, we screened about 10,000 drugs, natural products and urea analogs for inhibition of rat UT-A1. Drug and natural product screening found nicotine, sanguinarine and an indolcarbonylchromenone with IC50 of 10-20 μM. Urea analog screening found methylacetamide and dimethylthiourea (DMTU). DMTU fully and reversibly inhibited rat UT-A1 and UT-B by a noncompetitive mechanism with IC50 of 2-3 mM. Homology modeling and docking computations suggested DMTU binding sites on rat UT-A1. Following a single intraperitoneal injection of 500 mg/kg DMTU, peak plasma concentration was 9 mM with t1/2 of about 10 h, and a urine concentration of 20-40 mM. Rats chronically treated with DMTU had a sustained, reversible reduction in urine osmolality from 1800 to 600 mOsm, a 3-fold increase in urine output, and mild hypokalemia. DMTU did not impair urinary concentrating function in rats on a low protein diet. Compared to furosemide-treated rats, the DMTU-treated rats had greater diuresis and reduced urinary salt loss. In a model of syndrome of inappropriate antidiuretic hormone secretion, DMTU treatment prevented hyponatremia and water retention produced by water-loading in dDAVP-treated rats. Thus, our results establish a rat model of UT inhibition and demonstrate the diuretic efficacy of UT inhibition.

Angiotensin I-converting enzyme inhibitors potentiate bradykinin's inotropic effects independently of blocking its inactivation.

PubMed

Minshall, R D; Erdös, E G; Vogel, S M

1997-08-04

The positive inotropic effects of bradykinin (BK) and 2 analogs resistant to angiotensin I-converting enzyme (ACE) were potentiated on isolated guinea pig atrial preparations by enalaprilat. The stable BK analogs, dextran-BK and [Hyp3-Tyr(Me)8]-BK, were as active as BK. Pretreatment for 5 min with enalaprilat augmented the maximal positive inotropic effect of [Hyp3-Tyr(Me)8]-BK 2.8-fold, from 19% to 53% and that of BK from 28% to 42% over baseline; inotropic responses to dextran-BK (1 microM) were similarly increased. The activity of atrial ACE, a zinc-requiring enzyme, was completely inhibited by 8-hydroxyquinoline-5-sulfonic acid (QSA, 10 mM), which raised the maximal inotropic effect of BK to 39% above baseline. This value rose to 67% when in addition to QSA, 1 microM enalaprilat was added; enalaprilat thus, potentiated the effects of BK independently of enzyme inhibition. The positive inotropic effects to BK and its analogs decline with time in the presence of these agonists. After 10 min of exposure, the response to 1 microM [Hyp3-Tyr(Me)8]-BK decreased to about half, and after 20 min, to 0. Enalaprilat, when present in the tissue bath, prevented the decline in inotropy; even after tachyphylaxis occurred, it reversed this decrease in activity when added. The effects of 1 microM [Hyp3-Tyr(Me)8]-BK, in the absence or presence of enalaprilat, were abolished by the BK B2 receptor antagonist icatibant (0.75 microM). The results indicate that ACE inhibitors, by potentiating the BK effects and blocking BK B2-receptor desensitization, may contribute to the beneficial cardiac effects of BK independently of blocking its inactivation.

Subsite specificity of trypanosomal cathepsin L-like cysteine proteases. Probing the S2 pocket with phenylalanine-derived amino acids.

PubMed

Lecaille, F; Authié, E; Moreau, T; Serveau, C; Gauthier, F; Lalmanach, G

2001-05-01

The S2 subsite of mammalian cysteine proteinases of the papain family is essential for specificity. Among natural amino acids, all these enzymes prefer bulky hydrophobic residues such as phenylalanine at P2. This holds true for their trypanosomal counterparts: cruzain from Trypanosoma cruzi and congopain from T. congolense. A detailed analysis of the S2 specificity of parasitic proteases was performed to gain information that might be of interest for the design of more selective pseudopeptidyl inhibitors. Nonproteogenic phenylalanyl analogs (Xaa) have been introduced into position P2 of fluorogenic substrates dansyl-Xaa-Arg-Ala-Pro-Trp, and their kinetic constants (Km, kcat/Km) have been determined with congopain and cruzain, and related host cathepsins B and L. Trypanosomal cysteine proteases are poorly stereoselective towards D/L-Phe, the inversion of chirality modifying the efficiency of the reaction but not the Km. Congopain binds cyclohexylalanine better than aromatic Phe derivatives. Another characteristic feature of congopain compared to cruzain and cathepsins B and L was that it could accomodate a phenylglycyl residue (kcat/Km = 1300 mM-1.s-1), while lengthening of the side chain by a methylene group only slightly impaired the specificity constant towards trypanosomal cysteine proteases. Mono- and di-halogenation or nitration of Phe did not affect Km for cathepsin L-like enzymes, but the presence of constrained Phe derivatives prevented a correct fitting into the S2 subsite. A model of congopain has been built to study the fit of Phe analogs within the S2 pocket. Phe analogs adopted a positioning within the S2 pocket similar to that of the Tyr of the cruzain/Z-Tyr-Ala-fluoromethylketone complex. However, cyclohexylalanine has an energetically favorable chair-like conformation and can penetrate deeper into the subsite. Fitting of modeled Phe analogs were in good agreement with kinetic parameters. Furthermore, a linear relationship could be established with logP, supporting the suggestion that fitting into the S2 pocket of trypanosomal cysteine proteases depends on the hydrophobicity of Phe analogs.

An ultra low-power front-end IC for wearable health monitoring system.

PubMed

Yu-Pin Hsu; Zemin Liu; Hella, Mona M

2016-08-01

This paper presents a low-power front-end IC for wearable health monitoring systems. The IC, designed in a standard 0.13μm CMOS technology, fully integrates a low-noise analog front-end (AFE) to process the weak bio-signals, followed by an analog-to-digital converter (ADC) to digitize the extracted signals. An AC-coupled driving buffer, that interfaces between the AFE and the ADC is introduced to scale down the power supply of the ADC. The power consumption decreases by 50% compared to the case without power supply scaling. The AFE passes signals from 0.5Hz to 280Hz and from 0.7Hz to 160Hz with a simulated input referred noise of 1.6μVrms and achieves a maximum gain of 35dB/41dB respectively, with a noise-efficiency factor (NEF) of the AFE is 1. The 8-bit ADC achieves a simulated 7.96-bit resolution at 10KS/s sampling rate under 0.5V supply voltage. The overall system consumes only 0.86μW at dual supply voltages of 1V (AFE) and 0.5 V (ADC).

A New Ergosterol Analog, a New Bis-Anthraquinone and Anti-Obesity Activity of Anthraquinones from the Marine Sponge-Associated Fungus Talaromyces stipitatus KUFA 0207

PubMed Central

Noinart, Jidapa; Buttachon, Suradet; Dethoup, Tida; Gales, Luís; Pereira, José A.; Urbatzka, Ralph; Freitas, Sara; Lee, Michael; Silva, Artur M. S.; Pinto, Madalena M. M.; Vasconcelos, Vítor; Kijjoa, Anake

2017-01-01

A new ergosterol analog, talarosterone (1) and a new bis-anthraquinone derivative (3) were isolated, together with ten known compounds including palmitic acid, ergosta-4,6,8(14),22-tetraen-3-one, ergosterol-5,8-endoperoxide, cyathisterone (2), emodin (4a), questinol (4b), citreorosein (4c), fallacinol (4d), rheoemodin (4e) and secalonic acid A (5), from the ethyl acetate extract of the culture of the marine sponge-associated fungus Talaromyces stipitatus KUFA 0207. The structures of the new compounds were established based on extensive 1D and 2D spectral analysis, and in the case of talarosterone (1), the absolute configurations of its stereogenic carbons were determined by X-ray crystallographic analysis. The structure and stereochemistry of cyathisterone (2) was also confirmed by X-ray analysis. The anthraquinones 4a–e and secalonic acid A (5) were tested for their anti-obesity activity using the zebrafish Nile red assay. Only citreorosein (4c) and questinol (4b) exhibited significant anti-obesity activity, while emodin (4a) and secalonic acid A (5) caused toxicity (death) for all exposed zebrafish larvae after 24 h. PMID:28509846

The initial characterization of a revised 10-Gsps analog-to-digital converter board for radio telescopes

NASA Astrophysics Data System (ADS)

Jiango, Homin; Liuo, Howard; Guzzino, Kim

2016-07-01

In this study, the design of a 4 bit, 10-gigasamples-per-second analog-to-digital converter (ADC) printed circuit board assembly (PCBA) was revised, manufactured, and tested. It is used for digitizing radio telescopes. An Adsantec ANST7120-KMA flash ADC chip was used, as in the original design. Associated with the field-programmable gate array platform developed by the Collaboration for Astronomy Signal Processing and Electronics Research community, the developed PCBA provides data acquisition systems with a wider bandwidth and simplifies the intermediate frequency section. The current version of the PCBA exhibits an analog bandwidth of up to 10 GHz (3 dB loss), and the chip exhibits an analog bandwidth of up to 18 GHz. This facilitates second and third Nyquist sampling. The following worstcase performance parameters were obtained from the revised PCBA at over 5 GHz: spurious-free dynamic range of 12 dB, signal-to-noise and distortion ratio of 2 dB, and effective number of bits of 0.7. The design bugs in the ADC chip caused the poor performance. The vendor created a new batch run and confirmed that the ADC chips of the new batch will meet the specifications addressed in its data sheet.

Modernization of B-2 Data, Video, and Control Systems Infrastructure

NASA Technical Reports Server (NTRS)

Cmar, Mark D.; Maloney, Christian T.; Butala, Vishal D.

2012-01-01

The National Aeronautics and Space Administration (NASA) Glenn Research Center (GRC) Plum Brook Station (PBS) Spacecraft Propulsion Research Facility, commonly referred to as B-2, is NASA s third largest thermal-vacuum facility with propellant systems capability. B-2 has completed a modernization effort of its facility legacy data, video and control systems infrastructure to accommodate modern integrated testing and Information Technology (IT) Security requirements. Integrated systems tests have been conducted to demonstrate the new data, video and control systems functionality and capability. Discrete analog signal conditioners have been replaced by new programmable, signal processing hardware that is integrated with the data system. This integration supports automated calibration and verification of the analog subsystem. Modern measurement systems analysis (MSA) tools are being developed to help verify system health and measurement integrity. Legacy hard wired digital data systems have been replaced by distributed Fibre Channel (FC) network connected digitizers where high speed sampling rates have increased to 256,000 samples per second. Several analog video cameras have been replaced by digital image and storage systems. Hard-wired analog control systems have been replaced by Programmable Logic Controllers (PLC), fiber optic networks (FON) infrastructure and human machine interface (HMI) operator screens. New modern IT Security procedures and schemes have been employed to control data access and process control flows. Due to the nature of testing possible at B-2, flexibility and configurability of systems has been central to the architecture during modernization.

Modernization of B-2 Data, Video, and Control Systems Infrastructure

NASA Technical Reports Server (NTRS)

Cmar, Mark D.; Maloney, Christian T.; Butala, Vishal D.

2012-01-01

The National Aeronautics and Space Administration (NASA) Glenn Research Center (GRC) Plum Brook Station (PBS) Spacecraft Propulsion Research Facility, commonly referred to as B-2, is NASA's third largest thermal-vacuum facility with propellant systems capability. B-2 has completed a modernization effort of its facility legacy data, video and control systems infrastructure to accommodate modern integrated testing and Information Technology (IT) Security requirements. Integrated systems tests have been conducted to demonstrate the new data, video and control systems functionality and capability. Discrete analog signal conditioners have been replaced by new programmable, signal processing hardware that is integrated with the data system. This integration supports automated calibration and verification of the analog subsystem. Modern measurement systems analysis (MSA) tools are being developed to help verify system health and measurement integrity. Legacy hard wired digital data systems have been replaced by distributed Fibre Channel (FC) network connected digitizers where high speed sampling rates have increased to 256,000 samples per second. Several analog video cameras have been replaced by digital image and storage systems. Hard-wired analog control systems have been replaced by Programmable Logic Controllers (PLC), fiber optic networks (FON) infrastructure and human machine interface (HMI) operator screens. New modern IT Security procedures and schemes have been employed to control data access and process control flows. Due to the nature of testing possible at B-2, flexibility and configurability of systems has been central to the architecture during modernization.

Microwave analog fiber-optic link for use in the deep space network

NASA Technical Reports Server (NTRS)

Logan, R. T., Jr.; Lutes, G. F.; Maleki, L.

1990-01-01

A novel fiber-optic system with dynamic range of up to 150 dB-Hz for transmission of microwave analog signals is described. The design, analysis, and laboratory evaluations of this system are reported, and potential applications in the NASA/JPL Deep Space Network are discussed.

Bandwidth tunable microwave photonic filter based on digital and analog modulation

NASA Astrophysics Data System (ADS)

Zhang, Qi; Zhang, Jie; Li, Qiang; Wang, Yubing; Sun, Xian; Dong, Wei; Zhang, Xindong

2018-05-01

A bandwidth tunable microwave photonic filter based on digital and analog modulation is proposed and experimentally demonstrated. The digital modulation is used to broaden the effective gain spectrum and the analog modulation is to get optical lines. By changing the symbol rate of data pattern, the bandwidth is tunable from 50 MHz to 700 MHz. The interval of optical lines is set according to the bandwidth of gain spectrum which is related to the symbol rate. Several times of bandwidth increase are achieved compared to a single analog modulation and the selectivity of the response is increased by 3.7 dB compared to a single digital modulation.

Synthesis, analytical analysis, and medicinal aspect of novel benzimidazoles and their metal complexes.

PubMed

Agrawal, Sangeeta; Bhatnagar, Rishi Raj; Tiwari, Anjani; Srivastava, Rakesh; Sharma, Upasana

2013-11-01

Benzimidazole and their metal analogs that can act as multimodal agent and have non-peptidic CCK-B receptor antagonist were synthesized and characterized on the basis of spectroscopic techniques such as FT-IR, NMR, FAB-MS and also evaluated for biologic efficacy. The ligands showed binding to most of the organs, known to express CCK receptors in biodistribution studies. Cholecystokinin (CCK1 and CCK2) receptor binding affinities of these analogs (IC50) are 0.802 ± 0.007 for compound C and 0.326 ± 0.012 for compound D in rat pancreatic acini. These studies have provided a new template for further development of novel agents for various related diseases.

Pressure driven topological semi metallic phase in SrTe

NASA Astrophysics Data System (ADS)

Kunduru, Lavanya; Roshan, S. C. Rakesh; Yedukondalu, N.; Sainath, M.

2018-05-01

We have investigated the structural, electronic properties and Fermi surface topology of SrTe under high pressure up to 50 GPa based on density functional theory calculations. We predict that SrTe undergoes a structural phase transition from NaCl (B1) to CsCl (B2)-type structure at 14.7 GPa which is consistent with the experimental observations as well as with previous theoretical studies. The ambient (B1) and high pressure (B2) phases are found to be indirect band gap semiconductors and upon further compression B2 phase turns into a nontrivial topological semimetal. Interestingly, we have observed that B2 phase of SrTe has band inversion at Γ and M symmetry directions which lead to formation of 3D topological nodal line semimetal at high pressure which is analogous to CaTe and Cu3PdN due to nontrivial band topology.

NF-κB dynamics show digital activation and analog information processing in cells

NASA Astrophysics Data System (ADS)

Tay, Savas; Hughey, Jake; Lee, Timothy; Lipniacki, Tomasz; Covert, Markus; Quake, Stephen

2010-03-01

Cells operate in ever changing environments using extraordinary communication capabilities. Cell-to-cell communication is mediated by signaling molecules that form spatiotemporal concentration gradients, which requires cells to respond to a wide range of signal intensities. We used high-throughput microfluidic cell culture, quantitative gene expression analysis and mathematical modeling to investigate how single mammalian cells respond to different concentrations of the signaling molecule TNF-α via the transcription factor NF-κB. We measured NF-κB activity in thousands of live cells under TNF-α doses covering four orders of magnitude. In contrast to population studies, the activation is a stochastic, switch-like process at the single cell level with fewer cells responding at lower doses. The activated cells respond fully and express early genes independent of the TNF-α concentration, while only high dose stimulation results in the expression of late genes. Cells also encode a set of analog parameters such as the NF-κB peak intensity, response time and number of oscillations to modulate the outcome. We developed a stochastic model that reproduces both the digital and analog dynamics as well as the gene expression profiles at all measured conditions, constituting a broadly applicable model for TNF-α induced NF-κB signaling in various types of cells.

Field Trapping Bactrocera latifrons (Diptera: Tephritidae) with Select Eugenol Analogs That Have Been Found to Attract Other 'Non-Responsive' Fruit Fly Species.

PubMed

McQuate, Grant T; Royer, Jane E; Sylva, Charmaine D

2018-05-01

Bactrocera latifrons (Hendel) (Diptera: Tephritidae) is a pest fruit fly species native to Oriental Asia which has invaded and established in Hawaii and Tanzania and has been recovered in detection trapping in California. It is largely non-responsive to the male lures cuelure and methyl eugenol. Alpha-ionol + cade oil is a moderately effective male B. latifrons attractant, but is not as attractive as cuelure or methyl eugenol are to other fruit fly species. An improved attractant is therefore desired. With the recent success in finding other non-responsive fruit fly species attracted to isoeugenol, methyl-isoeugenol, or dihydroeugenol in Australia and other countries, we wanted to assess whether B. latifrons might also respond to these “eugenol analogs.” Working with wild B. latifrons populations in Hawaii, we assessed the relative catch of B. latifrons in traps baited with the eugenol analogs with catch in traps baited with alpha-ionol, alpha-ionol + cade oil, or alpha-ionol + eugenol. Catch was significantly higher in traps baited with alpha-ionol + cade oil relative to traps with any of the other baits. There was, though, some male B. latifrons catch in traps baited with dihydroeugenol or isoeugenol but none in traps baited with methyl-isoeugenol.

High Resolution Crystal Structure of the Methylcobalamin Analogs Ethylcobalamin and Butylcobalamin by X-ray Synchrotron Diffraction

PubMed Central

Hannibal, Luciana; Smith, Clyde A; Smith, Jessica A.; Axhemi, Armend; Miller, Abby; Wang, Sihe; Brasch, Nicola E.; Jacobsen, Donald W.

2009-01-01

The X-ray crystal structures of the methylcobalamin (MeCbl) analogs ethylcobalamin (EtCbl) and butylcobalamin (BuCbl) are reported. The X-ray crystal structures of EtCbl and BuCbl were obtained with some of the lowest crystallographic residuals ever achieved for cobalamins (R = 0.0468 and 0.0438, respectively). The Co-C bond distances for EtCbl and BuCbl are 2.023(2) and 2.028(4) Å, whereas the Co-α-5,6-dimethylbenzimidazole (Co-N3B) bond distances were 2.232(1) and 2.244(1) Å, respectively. Although EtCbl and BuCbl displayed a longer Co-N3B bond than that observed in the naturally occurring methylcobalamin, the orientation of the α-5,6-dimethylbenzimidazole moiety with respect to the corrin ring did not vary substantially amongst the structures. The lengthening of both Co-C and Co-N3B bonds in EtCbl and BuCbl can be attributed to the “inverse” trans influence exerted by the σ-donating alkyl groups, typically observed in alkylcobalamins. Analysis of the molecular surface maps showed that the alkyl ligands in EtCbl and BuCbl are directed towards the hydrophobic side of the corrin ring. The corrin fold angles in EtCbl and BuCbl were determined to be 14.7° and 13.1°, respectively. A rough correlation exists between the corrin fold angle and the length of the Co-N3B bond, and both alkylcobalamins follow the same trend. PMID:19545130

Structural basis for 18-β-glycyrrhetinic acid as a novel non-GSH analog glyoxalase I inhibitor.

PubMed

Zhang, Hong; Huang, Qiang; Zhai, Jing; Zhao, Yi-ning; Zhang, Li-ping; Chen, Yun-yun; Zhang, Ren-wei; Li, Qing; Hu, Xiao-peng

2015-09-01

Glyoxalase I (GLOI), a glutathione (GSH)-dependent enzyme, is overexpressed in tumor cells and related to multi-drug resistance in chemotherapy, making GLOI inhibitors as potential anti-tumor agents. But the most studied GSH analogs exhibit poor pharmacokinetic properties. The aim of this study was to discover novel non-GSH analog GLOI inhibitors and analyze their binding mechanisms. Mouse GLOI (mGLOI) was expressed in BL21 (DE3) pLysS after induction with isopropyl-β-D-1-thiogalactopyranoside and purified using AKTA FPLC system. An in vitro mGLOI enzyme assay was used to screen a small pool of compounds containing carboxyl groups. Crystal structure of the mGLOI-inhibitor complex was determined at 2.3 Å resolution. Molecular docking study was performed using Discovery Studio 2.5 software package. A natural compound 18-β-glycyrrhetinic acid (GA) and its derivative carbenoxolone were identified as potent competitive non-GSH analog mGLOI inhibitors with Ki values of 0.29 μmol/L and 0.93 μmol/L, respectively. Four pentacyclic triterpenes (ursolic acid, oleanolic acid, betulic acid and tripterine) showed weak activities (mGLOI inhibition ratio <25% at 10 μmol/L) and other three (maslinic acid, corosolic acid and madecassic acid) were inactive. The crystal structure of the mGLOI-GA complex showed that the carboxyl group of GA mimicked the γ-glutamyl residue of GSH by hydrogen bonding to the glutamyl sites (residues Arg38B, Asn104B and Arg123A) in the GSH binding site of mGLOI. The extensive van der Waals interactions between GA and the surrounding residues also contributed greatly to the binding of GA and mGLOI. This work demonstrates a carboxyl group to be an important functional feature of non-GSH analog GLOI inhibitors.

Automated Performance Monitoring and Assessment for DCS Digital Systems.

DTIC Science & Technology

1977-10-01

5.2 Analog Radio Systems 439 A.6 Group Data Modem (AN/USC-26) 453 A.6.1 Data Rates 453 vii ^II^^^IH^^^H^^^ HH ^ HH ^MflH^MBHBIEiiH^B^B&99S&_ 7...in U. 03 ÜJ 03 1 is «r V X V 1 ts ro O O M O 1 rs CM ^r 1- 1 rs TI o _i ! is o *•* OI- hh -Hhh- «c o> s Ci ÜJ li’ UJ UJ ÜJ u i •o o IS H d Ci Ci...j 0) tOOOOQiklkHH 03 03 UI0)BfiSSAAHI> HH ttaaAuuuuoocccs s E z xi 03 o^i a a i- 2: x x x x cß<:ffi<:ä<i:ä<:a«iB<c« s- 1- > r> z r: z z u u M M x

Extending Halogen-based Medicinal Chemistry to Proteins

PubMed Central

El Hage, Krystel; Pandyarajan, Vijay; Phillips, Nelson B.; Smith, Brian J.; Menting, John G.; Whittaker, Jonathan; Lawrence, Michael C.; Meuwly, Markus; Weiss, Michael A.

2016-01-01

Insulin, a protein critical for metabolic homeostasis, provides a classical model for protein design with application to human health. Recent efforts to improve its pharmaceutical formulation demonstrated that iodination of a conserved tyrosine (TyrB26) enhances key properties of a rapid-acting clinical analog. Moreover, the broad utility of halogens in medicinal chemistry has motivated the use of hybrid quantum- and molecular-mechanical methods to study proteins. Here, we (i) undertook quantitative atomistic simulations of 3-[iodo-TyrB26]insulin to predict its structural features, and (ii) tested these predictions by X-ray crystallography. Using an electrostatic model of the modified aromatic ring based on quantum chemistry, the calculations suggested that the analog, as a dimer and hexamer, exhibits subtle differences in aromatic-aromatic interactions at the dimer interface. Aromatic rings (TyrB16, PheB24, PheB25, 3-I-TyrB26, and their symmetry-related mates) at this interface adjust to enable packing of the hydrophobic iodine atoms within the core of each monomer. Strikingly, these features were observed in the crystal structure of a 3-[iodo-TyrB26]insulin analog (determined as an R6 zinc hexamer). Given that residues B24–B30 detach from the core on receptor binding, the environment of 3-I-TyrB26 in a receptor complex must differ from that in the free hormone. Based on the recent structure of a “micro-receptor” complex, we predict that 3-I-TyrB26 engages the receptor via directional halogen bonding and halogen-directed hydrogen bonding as follows: favorable electrostatic interactions exploiting, respectively, the halogen's electron-deficient σ-hole and electronegative equatorial band. Inspired by quantum chemistry and molecular dynamics, such “halogen engineering” promises to extend principles of medicinal chemistry to proteins. PMID:27875310

Over-the-air in-band full-duplex system with hybrid RF optical and baseband digital self-interference cancellation

NASA Astrophysics Data System (ADS)

Zhang, Yunhao; Li, Longsheng; Bi, Meihua; Xiao, Shilin

2017-12-01

In this paper, we propose a hybrid analog optical self-interference cancellation (OSIC) and baseband digital SIC (DSIC) system for over-the-air in-band full-duplex (IBFD) wireless communication. Analog OSIC system is based on optical delay line, electro-absorption modulation lasers (EMLs) and balanced photodetector (BPD), which has the properties of high adjusting precision and broad processing bandwidth. With the help of baseband DSIC, the cancellation depth limitation of OSIC can be mitigated so as to achieve deeper total SIC depth. Experimental results show about 20-dB depth by OSIC and 10-dB more depth by DSIC over 1GHz broad baseband, so that the signal of interest (SOI) overlapped by wideband self-interference (SI) signal is better recovered compared to the IBFD system with OSIC or DSIC only. The hybrid of OSIC and DSIC takes advantages of the merits of optical devices and digital processors to achieve deep cancellation depth over broad bandwidth.

Lessons Learned from Preparing OSIRIS-REx Spectral Analog Samples for Bennu

NASA Technical Reports Server (NTRS)

Schrader, D. L.; McCoy, T. J.; Cody, G. D.; King, A. J.; Schofield, P. F.; Russell, S. S.; Connolly, H. C., Jr.; Keller, L. P.; Donaldson Hanna, K.; Bowles, N.;

Multi-octave analog photonic link with improved second- and third-order SFDRs

NASA Astrophysics Data System (ADS)

Tan, Qinggui; Gao, Yongsheng; Fan, Yangyu; He, You

2018-03-01

The second- and third-order spurious free dynamic ranges (SFDRs) are two key performance indicators for a multi-octave analogy photonic link (APL). The linearization methods for either second- or third-order intermodulation distortion (IMD2 or IMD3) have been intensively studied, but the simultaneous suppression for the both were merely reported. In this paper, we propose an APL with improved second- and third-order SFDRs for multi-octave applications based on two parallel DPMZM-based sub-APLs. The IMD3 in each sub-APL is suppressed by properly biasing the DPMZM, and the IMD2 is suppressed by balanced detecting the two sub-APLs. The experiment demonstrates significant suppression ratios for both the IMD2 and IMD3 after linearization in the proposed link, and the measured second- and third-order SFDRs with the operating frequency from 6 to 40 GHz are above 91 dB ṡHz 1 / 2 and 116 dB ṡHz 2 / 3, respectively.

Low-temperature neutron structure determinations of a series of scorpionate complexes of molybdenum containing B sbnd H sbnd Mo agostic bonds

NASA Astrophysics Data System (ADS)

Piccoli, Paula M. B.; Cowan, John A.; Schultz, Arthur J.; Koetzle, Thomas F.; Yap, Glenn P. A.; Trofimenko, Swiatoslaw

2008-11-01

The structures of four dihydrobis(pyrazol-1-yl)borate (Bp) complexes of molybdenum have been determined at low temperature by single crystal neutron diffraction in order to accurately characterize the three-center B sbnd H sbnd Mo agostic bonding. The B sbnd H1A (agostic) distance is found to be elongated by about 0.05-0.08 Å compared to the B sbnd H1B distance (not agostically bound to the metal center). This systematic study of a series of molecules with different substituents on the Bp ligand permits us to examine the effects of electronic and steric factors on the overall structure and bonding, and particularly on the agostic bond. It is observed that a closer approach of H1A to Mo leads to a longer trans-Mo sbnd CO bond distance, analogous to the trans hydride structural effect in hydride complexes. In addition Fenske-Hall calculations were performed on these complexes, and the results are reported herein.

Inhibition of TNF-{alpha}-mediated inflammatory responses by a benzodioxolylacetylamino-linked benzothiazole analog in human fibroblast-like synoviocytes

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lee, Young-Rae; Jin, Guo Hua; Lee, Sang-Myeong

Highlights: {yields} We synthesized SPA0537, a benzothiazole analog. {yields} SPA0537 is a potent NF-{kappa}B inhibitor. {yields} SPA0537 suppresses the production of proinflammatory mediators in human rheumatoid fibroblast-like synoviocytes. {yields} SPA0537 is effective at suppressing osteoclast differentiation. -- Abstract: The pathologic processes of rheumatoid arthritis are mediated by a number of cytokines, chemokines, and matrix metalloproteinases, the expressions of which are controlled by NF-{kappa}B. This study was performed to explore the effects of a benzothiazole analog, SPA0537, on the control of the NF-{kappa}B activation pathway. We also investigated whether SPA0537 had any anti-inflammatory effects in human rheumatoid fibroblast-like synoviocytes (FLS). SPA0537more » inhibited the nuclear translocation and the DNA binding of NF-{kappa}B subunits, which correlated with the inhibitory effects on IKK phosphorylation and I{kappa}B{alpha} degradation in TNF-{alpha}-stimulated rheumatoid FLS. These events further suppressed chemokine production, matrix metalloproteinase secretion, and TNF-{alpha}-induced cell proliferation. In addition, SPA0537 inhibited the osteoclast differentiation induced by macrophage colony-stimulating factor (MCSF) and receptor activator of the NF-{kappa}B ligand (RANKL) in bone marrow macrophages. These findings suggest that SPA0537 exerts anti-inflammatory effects in rheumatoid FLS through the inhibition of the NF-{kappa}B pathway. Therefore, it may have therapeutic value for the treatment of rheumatoid arthritis.« less

Molecular characterization of the receptor binding structure-activity relationships of influenza B virus hemagglutinin.

PubMed

Carbone, V; Kim, H; Huang, J X; Baker, M A; Ong, C; Cooper, M A; Li, J; Rockman, S; Velkov, T

2013-01-01

Selectivity of α2,6-linked human-like receptors by B hemagglutinin (HA) is yet to be fully understood. This study integrates binding data with structure-recognition models to examine the impact of regional-specific sequence variations within the receptor-binding pocket on selectivity and structure activity relationships (SAR). The receptor-binding selectivity of influenza B HAs corresponding to either B/Victoria/2/1987 or the B/Yamagata/16/88 lineages was examined using surface plasmon resonance, solid-phase ELISA and gel-capture assays. Our SAR data showed that the presence of asialyl sugar units is the main determinant of receptor preference of α2,6 versus α2,3 receptor binding. Changes to the type of sialyl-glycan linkage present on receptors exhibit only a minor effect upon binding affinity. Homology-based structural models revealed that structural properties within the HA pocket, such as a glyco-conjugate at Asn194 on the 190-helix, sterically interfere with binding to avian receptor analogs by blocking the exit path of the asialyl sugars. Similarly, naturally occurring substitutions in the C-terminal region of the 190-helix and near the N-terminal end of the 140-loop narrows the horizontal borders of the binding pocket, which restricts access of the avian receptor analog LSTa. This study helps bridge the gap between ligand structure and receptor recognition for influenza B HA; and provides a consensus SAR model for the binding of human and avian receptor analogs to influenza B HA.

A New Titanium-Bearing Calcium Aluminosilicate Phase. 1; Meteoritic Occurrences and Formation in Synthetic Systems

NASA Technical Reports Server (NTRS)

Paque, Julie M.; Beckett, John R.; Barber, David J.; Stolper, Edward M.

1994-01-01

A new titanium-bearing calcium aluminosilicate mineral has been identified in coarse-grained calcium-aluminum-rich inclusions (CAIs) from carbonaceous chondrites. The formula for this phase, which we have temporarily termed "UNK," is Ca3Ti(AlTi)2(Si,Al)3O14, and it is present in at least 8 of the 20 coarse-grained CAIs from the Allende CV3 chondrite examined as part of this project. The phase occurs in Types A and B1 inclusions as small tabular crystals oriented along two mutually perpendicular planes in melilite. UNK crystallizes from melts in dynamic crystallization experiments conducted in air from four bulk compositions modeled after Types A, B1, B2 and C inclusions. Cooling rates resulting in crystallization of UNK ranged from 0.5 to 200 C/h from maximum (initial) temperatures of 1375 to 1580 C. Only below 1190 C does UNK itself begin to crystallize. To first order, the presence or absence of UNK from individual experiments can be understood in terms of the compositions of residual melts and nucleation probabilities. Compositions of synthetic and meteoritic LINK are very similar in terms of major oxides, differing only in the small amounts of trivalent Ti (7-13% of total Ti) in meteoritic samples. UNK crystallized from the Type A analog is similar texturally to that found in CAls, although glass, which is typically associated with synthetic UN& is not observed in meteoritic occurrences. A low Ti end-member of UNK ("Si-UNK") with a composition new that of Ca3Al2Si4O14 was produced in a few samples from the Type B1 analog. This phase has not been found in the meteoritic inclusions.

A new titanium-bearing calcium aluminosilicate phase. 1: Meteoritic occurrences and formation in synthetic systems

NASA Technical Reports Server (NTRS)

Paque, Julie M.; Beckett, John R.; Barber, David J.; Stolper, Edward M.

1994-01-01

A new titanium-bearing calcium aluminosilicate mineral has been identified in coarse-grained calcium-aluminum-rich inclusions (CAIs) from carbonaceous chondrites. The formula for this phase, which we have temporarily termed 'UNK,' is Ca3Ti(Al,Ti)2(Si,Al)3O14, and it is present in at least 8 of the 20 coarse-grained CAIs from the Allende CV3 chondrite examined as part of this project. The phase occurs in Types A and B1 inclusions as small tabular crystal oriented along two mutually perpendicular planes in melilite. UNK crystallizes from melts in dynamic crystallization experiments conducted in air from four bulk compositions modeled after Types A, B1, B2 and C inclusions. Cooling rates resulting in crystallization of UNK ranged from 0.5 to 200 C/h from maximum (initial) temperatures of 1375 to 1580 C. Only below 1190 C does UNK itself begin to crystallize. To first order, the presence or absence of UNK from individual experiments can be understood in terms of the compositions of residual melts and nucleation probabilities. Compositions of synthetic and meteoritic UNK are very similar in terms of major oxides, differing only in the small amounts of trivalent Ti(7-13% of total Ti) in meteoritic samples. UNK crystallized from the Type A analog is similar texturally to that found in CAIs, although glass, which is typically associated with synthetic UNK, is not observed in the meteoritic occurrences. A low Ti end-member of UNK ('Si-UNK') with a composition near that of Ca3Al2Si4O14 was produced in a few samples from the Type B1 analog. This phase has not been found in the meteoritic inclusions.

Time-dependent slowly-reversible inhibition of monoamine oxidase A by N-substituted 1,2,3,6-tetrahydropyridines.

PubMed

Wichitnithad, Wisut; O'Callaghan, James P; Miller, Diane B; Train, Brian C; Callery, Patrick S

2011-12-15

A novel class of N-substituted tetrahydropyridine derivatives was found to have multiple kinetic mechanisms of monoamine oxidase A inhibition. Eleven structurally similar tetrahydropyridine derivatives were synthesized and evaluated as inhibitors of MAO-A and MAO-B. The most potent MAO-A inhibitor in the series, 2,4-dichlorophenoxypropyl analog 12, displayed time-dependent mixed noncompetitive inhibition. The inhibition was reversed by dialysis, indicating reversible enzyme inhibition. Evidence that the slow-binding inhibition of MAO-A with 12 involves a covalent bond was gained from stabilizing a covalent reversible intermediate product by reduction with sodium borohydride. The reduced enzyme complex was not reversible by dialysis. The results are consistent with slowly reversible, mechanism-based inhibition. Two tetrahydropyridine analogs that selectively inhibited MAO-A were characterized by kinetic mechanisms differing from the kinetic mechanism of 12. As reversible inhibitors of MAO-A, tetrahydropyridine analogs are at low risk of having an adverse effect of tyramine-induced hypertension. Copyright © 2011 Elsevier Ltd. All rights reserved.

Skin autofluorescence as a measure of advanced glycation endproduct deposition: a novel risk marker in chronic kidney disease.

PubMed

Smit, Andries J; Gerrits, Esther G

2010-11-01

Skin autofluorescence (SAF) is a new method to noninvasively assess accumulation of advanced glycation endproducts (AGEs) in a tissue with low turnover. Recent progress in the clinical application of SAF as a risk marker for diabetic nephropathy as well as cardiovascular disease in nondiabetic end-stage kidney disease, less advanced chronic kidney disease, and renal transplant recipients is reviewed. Experimental studies highlight the fundamental role of the interaction of AGEs with the receptor for AGEs (RAGEs), also called the AGE-RAGE axis, in the pathogenesis of vascular and chronic kidney disease. SAF predicts (cardiovascular) mortality in renal failure and also chronic renal transplant dysfunction. Long-term follow-up results from the Diabetes Control and Complications Trial and UK Prospective Diabetes Study suggest that AGE accumulation is a key carrier of metabolic memory and oxidative stress. Short-term intervention studies in diabetic nephropathy with thiamine, benfotiamine and angiotensin-receptor blockers aimed at reducing AGE formation have reported mixed results. SAF is a noninvasive marker of AGE accumulation in a tissue with low turnover, and thereby of metabolic memory and oxidative stress. SAF independently predicts cardiovascular and renal risk in diabetes, as well as in chronic kidney disease. Further long-term studies are required to assess the potential benefits of interventions to reduce AGE accumulation.

Potent and selective agonists of alpha-melanotropin (alphaMSH) action at human melanocortin receptor 5; linear analogs of alpha-melanotropin.

PubMed

Bednarek, Maria A; MacNeil, Tanya; Tang, Rui; Fong, Tung M; Cabello, M Angeles; Maroto, Marta; Teran, Ana

2007-05-01

Alpha-melanotropin, Ac-Ser(1)-Tyr-Ser-Met-Glu-His(6)-Phe(7)-Arg(8)-Trp(9)-Gly-Lys-Pro-Val(13)-NH(2)(1), is a non-selective endogenous agonist for the melanocortin receptor 5; the receptor present in various peripheral tissues and in the brain, cortex and cerebellum. Most of the synthetic analogs of alphaMSH, including a broadly used and more potent the NDP-alphaMSH peptide, Ac-Ser(1)-Tyr-Ser-Nle(4)-Glu-His(6)-D-Phe(7)-Arg(8)-Trp(9)-Gly-Lys-Pro-Val(13)-NH(2), are also not particularly selective for MC5R. To elucidate physiological functions of the melanocortin receptor 5 in rodents and humans, the receptor subtype selective research tools are needed. We report herein syntheses and pharmacological evaluation in vitro of several analogs of NDP-alphaMSH which are highly potent and specific agonists for the human MC5R. The new linear peptides, of structures and solubility properties similar to those of the endogenous ligand alphaMSH, are exemplified by compound 7, Ac-Ser(1)-Tyr-Ser-Met-Glu-Oic(6)-D-4,4'-Bip(7)-Pip(8)-Trp(9)-Gly-Lys-Pro-Val(13)-NH(2) (Oic: octahydroindole-2-COOH, 4,4'-Bip: 4,4'-biphenylalanine, Pip: pipecolic acid), shortly NODBP-alphaMSH, which has an IC(50)=0.74 nM (binding assay) and EC(50)=0.41 (cAMP production assay) at hMC5R nM and greater than 3500-fold selectivity with respect to the melanocortin receptors 1b, 3 and 4. A shorter peptide derived from NODBP-alphaMSH: Ac-Nle-Glu-Oic(6)-D-4,4'-Bip(7)-Pip(8)-Trp(9) -NH(2) (17) was measured to be an agonist only 10-fold less potent at hMC5R than the full length parent peptide. In the structure of this smaller analog, the Nle-Glu-Oic(6)-D-4,4'-Bip(7)-Pip(8) segment was found to be critical for high agonist potency, while the C-terminal Trp(9) residue was shown to be required for high hMC5R selectivity versus hMC1b,3,4R.

Charge-Coupled Devices for Analog Signal Processing -- A Circuit Study

DTIC Science & Technology

1976-03-01

FNG( T+H/2) ) /H (X2»Y3»Z2) 1*2*K2-^2*K3*’ɜ) /o.3 ECK TO SEE IF IT’S TIME TO PRINT OUT. SGN(L)*1.’.5E-9>=i^«𔃽 THEN 1120 80 ^^^^ LEI rt=b 113^ LEI a...DISTRIBUTION LIST No. Copies 1. Defense Docmnentation Center 2 Cameron Station Alexandria, Virginia 22314 2. Library, Code 0212 2 Naval Postgraduate School

New Gastrin Releasing Peptide Receptor-Directed [99mTc]Demobesin 1 Mimics: Synthesis and Comparative Evaluation.

PubMed

Nock, Berthold A; Charalambidis, David; Sallegger, Werner; Waser, Beatrice; Mansi, Rosalba; Nicolas, Guillaume P; Ketani, Eleni; Nikolopoulou, Anastasia; Fani, Melpomeni; Reubi, Jean-Claude; Maina, Theodosia

2018-04-12

We have previously reported on the gastrin releasing peptide receptor (GRPR) antagonist [ 99m Tc]1, ([ 99m Tc]demobesin 1, 99m Tc-[N 4 '-diglycolate-dPhe 6 ,Leu-NHEt 13 ]BBN(6-13)). [ 99m Tc]1 has shown superior biological profile compared to analogous agonist-based 99m Tc-radioligands. We herein present a small library of [ 99m Tc]1 mimics generated after structural modifications in (a) the linker ([ 99m Tc]2, [ 99m Tc]3, [ 99m Tc]4), (b) the peptide chain ([ 99m Tc]5, [ 99m Tc]6), and (c) the C-terminus ([ 99m Tc]7 or [ 99m Tc]8). The effects of above modifications on the biological properties of analogs were studied in PC-3 cells and tumor-bearing SCID mice. All analogs showed subnanomolar affinity for the human GRPR, while most receptor-affine 4 and 8 behaved as potent GRPR antagonists in a functional internalization assay. In mice bearing PC-3 tumors, [ 99m Tc]1-[ 99m Tc]6 exhibited GRPR-specific tumor uptake, rapidly clearing from normal tissues. [ 99m Tc]4 displayed the highest tumor uptake (28.8 ± 4.1%ID/g at 1 h pi), which remained high even after 24 h pi (16.3 ± 1.8%ID/g), well surpassing that of [ 99m Tc]1 (5.4 ± 0.7%ID/g at 24 h pi).

Adefovir

MedlinePlus

Adefovir is used to treat chronic (long-term) hepatitis B infection (swelling of the liver caused by a ... analogs. It works by decreasing the amount of hepatitis B virus (HBV) in the body. Adefovir will not ...

Entecavir

MedlinePlus

Entecavir is used to treat chronic (long-term) hepatitis B infection (swelling of the liver caused by a ... analogs. It works by decreasing the amount of hepatitis B virus (HBV) in the body. Entecavir does not ...

Generation of reactive oxygen species by a novel berberine–bile acid analog mediates apoptosis in hepatocarcinoma SMMC-7721 cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Li, Qingyong, E-mail: li_qingyong@126.com; Zhang, Li; Zu, Yuangang

2013-04-19

Graphical abstract: - Highlights: • Anticancer effects of B4, a novel berberine–bile acid analog, were tested. • B4 inhibited cell proliferation in hepatocellular carcinoma cells. • It also stimulated mitochondrial ROS production and membrane depolarization. • Effects of B4 were inhibited by a non-specific ROS scavenger. • Regulation of ROS generation may be a strategy for treating hepatic carcinoma. - Abstract: 2,3-Methenedioxy-9-O-(3′α,7′α-dihydroxy-5′β-cholan-24′-propy-lester) berberine (B4) is a novel berberine–bile acid analog synthesized in our laboratory. Previously, we showed that B4 exerted greater cytotoxicity than berberine in several human cancer cell lines. Therefore, we further evaluated the mechanism governing its anticancer actionsmore » in hepatocellular carcinoma SMMC-7721 cells. B4 inhibited the proliferation of SMMC-7721 cells, and stimulated reactive oxygen species (ROS) production and mitochondrial membrane depolarization; anti-oxidant capacity was reduced. B4 also induced the release of cytochrome c from the mitochondria to the cytosol and an increase in poly ADP-ribose polymerase (PARP) cleavage products, reflective of caspase-3 activation. Moreover, B4 induced the nuclear translocation of apoptosis-inducing factor (AIF) and a rise in DNA fragmentation. Pretreatment with the anti-oxidant N-acetylcysteine (NAC) inhibited B4-mediated effects, including cytotoxicity, ROS production, mitochondrial membrane depolarization increase in intracellular Ca{sup 2+}, cytochrome c release, PARP cleavage, and AIF translocation. Our data suggest that B4 induces ROS-triggered caspase-dependent and caspase-independent apoptosis pathways in SMMC-7721 cells and that ROS production may be a specific potential strategy for treating hepatic carcinoma.« less

Insulin glulisine: an evaluation of its pharmacodynamic properties and clinical application.

PubMed

Helms, Kristen L; Kelley, Kristi W

2009-04-01

To evaluate the pharmacodynamic properties, efficacy, safety, and clinical application of insulin glulisine, a rapid-acting insulin analog, in the treatment of diabetes mellitus in ambulatory and hospitalized patients. Searches were performed with the headings glulisine, insulin analog, [LysB3, GluB29] insulin, insulin glulisine, rDNA insulin, rapid-acting insulin, SoloStar, safety, efficacy, pharmacodynamics, and cost analysis within MEDLINE and PubMed, American Diabetes Association (ADA), the Food and Drug Administration (FDA), and Sanofi-aventis Pharmaceuticals (1990-August 2008). Phase 1, Phase 2, Phase 3, and postmarketing trials examining the efficacy and safety of glulisine in type 1 or type 2 diabetes were reviewed. Studies published as abstracts and the manufacturer's product information supplemented data absent from clinical trials. Insulin glulisine is a rapid-acting insulin with relative equivalence in efficacy and safety to other short- and rapid-acting insulins. Glulisine's onset of action of 20 minutes and 4-hour duration of action allow for bolus administration 15-20 minutes prior to or up to 20 minutes after meals. Clinical trials have demonstrated the safety and efficacy in adults with type 1 or type 2 diabetes. Several studies indicated a statistically significant decrease of hemoglobin A1C (A1C) with glulisine compared with regular insulin (0.10 decrease); however, no difference in A1C control was found compared with insulin aspart or lispro. Significant adverse effects appear to be limited to localized and systemic allergic reactions and hypoglycemia. Insulin glulisine is a safe and effective rapid-acting insulin analog for the treatment of adults with diabetes. Clinical benefit over other short- and rapid-acting insulin products is not established. Addition of insulin glulisine to a formulary should be based on institution-specific availability and cost differences between glulisine, lispro, and aspart in the absence of superiority of clinical efficacy or safety and data beyond 26 weeks.

Endomorphin-2 analogs with C-terminal esterification produce potent systemic antinociception with reduced tolerance and gastrointestinal side effects.

PubMed

Wang, Chang-Lin; Qiu, Ting-Ting; Yang, Dai-Jun; Yuan, Bi-Yu; Han, Feng-Tong; Li, Li; Gu, Ning

2017-04-01

C-terminal esterification of opioid peptides may change their opioid activities due to the modified physicochemical properties. In the present study, the pharmacological activities of C-terminal esterified endomorphin-2 (EM-2) analogs 1-3 were characterized by in vitro metabolic stability and octanol/buffer distribution assays. Also, the antinociceptive profiles in the radiant heat paw withdrawal test and related side effects of these analogs were determined. Our results showed that all three analogs significantly increased the metabolic stability and lipophilicity. Moreover, analogs 1-3 displayed potent antinociceptive activities after intracerebroventricular (i.c.v.) administration. Analogs 1 and 3 exhibited about 2-fold higher antinociception than EM-2, and differential opioid mechanisms were involved. In addition, EM-2 at 50 μmol/kg failed to produce any significant antinociceptive activity after subcutaneous (s.c.) administration, whereas equimolar dose of analogs 1-3 produced significant analgesic effects. Analog 3 showed the highest antinociceptive activity after systemic administration, which was consistent with its in vitro stability and lipophilicity. We further evaluated the antinociceptive tolerance of analogs 1-3. In acute tolerance test, analogs 1-3 shifted the dose-response curves rightward by only 1.4-3.2 fold as determined by tolerance ratio, whereas EM-2 by 5.6-fold, demonstrating reduced antinociceptive tolerance. Also, analogs 1 and 2 decreased chronic antinociceptive tolerance by central and peripheral administration of drugs. In particular, analogs 3 displayed insignificant chronic antinociceptive tolerance. Furthermore, analogs 1-3 were less prone to induce gastrointestinal side effects at analgesic doses. The present investigation gave the evidence that C-terminal esterified modifications of EM-2 will facilitate the development of novel opioid analgesics with reduced side effects. Copyright © 2016 Elsevier Ltd. All rights reserved.

Structural design of intrinsically fluorescent oxysterols.

PubMed

Nåbo, Lina J; Modzel, Maciej; Krishnan, Kathiresan; Covey, Douglas F; Fujiwara, Hideji; Ory, Daniel S; Szomek, Maria; Khandelia, Himanshu; Wüstner, Daniel; Kongsted, Jacob

2018-05-01

Oxysterols are oxidized derivatives of cholesterol with many important biological functions. Trafficking of oxysterols in and between cells is not well studied, largely due to the lack of appropriate oxysterol analogs. Intrinsically fluorescent oxysterols present a new route towards direct observation of intracellular oxysterol trafficking by fluorescence microscopy. We characterize the fluorescence properties of the existing fluorescent 25-hydroxycholesterol analog 25-hydroxycholestatrienol, and propose a new probe with an extended conjugated system. The location of both probes inside a membrane is analyzed and compared with that of 25-hydroxycholesterol using molecular dynamics simulations. The analogs' one- and two-photon absorption properties inside the membrane are evaluated using electronic structure calculations with polarizable embedding. Due to predicted keto-enol tautomerisation of the new oxysterol analog, we also evaluate the keto form. Both analogs are found to be good probe candidates for 25-hydroxycholesterol, provided that the new analog remains in the enol-form. Only the new analog with extended conjugated system shows significant two-photon absorption, which is strongly enhanced by the presence of the membrane. Copyright © 2018 Elsevier B.V. All rights reserved.

The interplay of conflict and analogy in multidisciplinary teams.

PubMed

Paletz, Susannah B F; Schunn, Christian D; Kim, Kevin H

2013-01-01

Creative teamwork in multidisciplinary teams is a topic of interest to cognitive psychologists on the one hand, and to both social and organizational psychologists on the other. However, the interconnections between cognitive and social layers have been rarely explored. Drawing on mental models and dissonance theories, the current study takes a central variable studied by cognitive psychologists-analogy-and examines its relationship to a central variable examined by social psychologists-conflict. In an observational, field study, over 11h of audio-video data from conversations of the Mars Exploration Rover scientists were coded for different types of analogy and micro-conflicts that reveal the character of underlying psychological mechanisms. Two different types of time-lagged logistic models applied to these data revealed asymmetric patterns of associations between analogy and conflict. Within-domain analogies, but not within-discipline or outside-discipline analogies, preceded science and work process conflicts, suggesting that in multidisciplinary teams, representational gaps in very close domains will be more likely to spark conflict. But analogies also occurred in reaction to conflict: Process and negative conflicts, but not task conflicts, preceded within-discipline analogies, but not to within-domain or outside-discipline analogies. This study demonstrates ways in which cognition can be bidirectionally tied to social processes and discourse. Copyright © 2012 Elsevier B.V. All rights reserved.

From Quasi-Planar B56 to Penta-Ring Tubular Ca©B56: Prediction of Metal-Stabilized Ca©B56 as the Embryo of Metal-Doped Boron α-Nanotubes

NASA Astrophysics Data System (ADS)

Tian, Wen-Juan; Chen, Qiang; Tian, Xin-Xin; Mu, Yue-Wen; Lu, Hai-Gang; Li, Si-Dian

2016-11-01

Motifs of planar metalloborophenes, cage-like metalloborospherenes, and metal-centered double-ring tubular boron species have been reported. Based on extensive first-principles theory calculations, we present herein the possibility of doping the quasi-planar C2v B56 (A-1) with an alkaline-earth metal to produce the penta-ring tubular Ca©B56 (B-1) which is the most stable isomer of the system obtained and can be viewed as the embryo of metal-doped (4,0) boron α-nanotube Ca©BNT(4,0) (C-1). Ca©BNT(4,0) (C-1) can be constructed by rolling up the most stable boron α-sheet and is predicted to be metallic in nature. Detailed bonding analyses show that the highly stable planar C2v B56 (A-1) is the boron analog of circumbiphenyl (C38H16) in π-bonding, while the 3D aromatic C4v Ca©B56 (B-1) possesses a perfect delocalized π system over the σ-skeleton on the tube surface. The IR and Raman spectra of C4v Ca©B56 (B-1) and photoelectron spectrum of its monoanion C4v Ca©B56- are computationally simulated to facilitate their spectroscopic characterizations.

A Low-cost 4 Bit, 10 Giga-samples-per-second Analog-to-digital Converter Printed Circuit Board Assembly for FPGA-based Backends

NASA Astrophysics Data System (ADS)

Jiang, Homin; Yu, Chen-Yu; Kubo, Derek; Chen, Ming-Tang; Guzzino, Kim

2016-11-01

In this study, a 4 bit, 10 giga-samples-per-second analog-to-digital converter (ADC) printed circuit board assembly (PCBA) was designed, manufactured, and characterized for digitizing radio telescopes. For this purpose, an Adsantec ANST7120A-KMA flash ADC chip was used. Together with the field-programmable gate array platform, developed by the Collaboration for Astronomy Signal Processing and Electronics Research community, the PCBA enables data acquisition with a wide bandwidth and simplifies the intermediate frequency section. In the current version, the PCBA and the chip exhibit an analog bandwidth of 10 GHz (3 dB loss) and 20 GHz, respectively, which facilitates second, third, and even fourth Nyquist sampling. The following average performance parameters were obtained from the first and second Nyquist zones of the three boards: a spurious-free dynamic range of 31.35/30.45 dB, a signal-to-noise and distortion ratio of 22.95/21.83 dB, and an effective number of bits of 3.65/3.43, respectively.

Rubrolides as model for the development of new lactones and their aza analogs as potential photosynthesis inhibitors.

PubMed

Pereira, Ulisses A; Barbosa, Luiz C A; Demuner, Antônio J; Silva, Antônio A; Bertazzini, Michele; Forlani, Giuseppe

2015-07-01

Natural phytotoxins and their synthetic analogs are a potential source of new bioactive compounds for agriculture. Analogs of rubrolides, a class of γ-alkylidene-γ-lactones isolated from different ascidians, have been shown to interfere with the photosynthetic electron-transport chain, yet their activity needs to be improved. With this aim, ten 5-aryl-6-benzyl-4-bromopyridazin-3(2H)-ones were prepared in yields ranging from 44 to 88% by reaction of their correspondent γ-alkylidene-γ-lactones with NH2 NH2 . The structures of these rubrolide analogs were determined by (1) H- and (13) C-NMR, 2D-NMR (COSY and HETCOR), NOE difference, and MS techniques. These compounds were evaluated for their abilities of interfering with the light-driven reduction of ferricyanide by isolated spinach chloroplasts. Lactones with electron-withdrawing substituents in the para-position of the benzylidene ring were the most effective inhibitors. Characterization of the activity of 11b/11b' suggested a mechanism based on the interaction with the plastoquinone binding site of photosystem II. Addition of several compounds to the culture medium of a cyanobacterial model strain was found to inhibit algal growth. However, the relative effectiveness was not consistent with their activity in vitro, suggesting the occurrence of multiple targets and/or detoxyfication mechanisms. Indeed, the compounds showed differential effects on the heterotrophic growth of some crop species, Cucumis sativus and Sorghum bicolor. Pyridazin-3(2H)-ones 12e, 12i, and 12j, which have been found poorly active against the photosynthetic electron transport, were the most effective in inhibiting the growth of some weeds, Ipomoea grandifolia and Brachiaria decumbens, under greenhouse conditions. Copyright © 2015 Verlag Helvetica Chimica Acta AG, Zürich.

Anaerobic humus and Fe(III) reduction and electron transport pathway by a novel humus-reducing bacterium, Thauera humireducens SgZ-1.

PubMed

Ma, Chen; Yu, Zhen; Lu, Qin; Zhuang, Li; Zhou, Shun-Gui

2015-04-01

In this study, an anaerobic batch experiment was conducted to investigate the humus- and Fe(III)-reducing ability of a novel humus-reducing bacterium, Thauera humireducens SgZ-1. Inhibition tests were also performed to explore the electron transport pathways with various electron acceptors. The results indicate that in anaerobic conditions, strain SgZ-1 possesses the ability to reduce a humus analog, humic acids, soluble Fe(III), and Fe(III) oxides. Acetate, propionate, lactate, and pyruvate were suitable electron donors for humus and Fe(III) reduction by strain SgZ-1, while fermentable sugars (glucose and sucrose) were not. UV-visible spectra obtained from intact cells of strain SgZ-1 showed absorption peaks at 420, 522, and 553 nm, characteristic of c-type cytochromes (cyt c). Dithionite-reduced cyt c was reoxidized by Fe-EDTA and HFO (hydrous ferric oxide), which suggests that cyt c within intact cells of strain SgZ-1 has the ability to donate electrons to extracellular Fe(III) species. Inhibition tests revealed that dehydrogenases, quinones, and cytochromes b/c (cyt b/c) were involved in reduction of AQS (9, 10-anthraquinone-2-sulfonic acid, humus analog) and oxygen. In contrast, only NADH dehydrogenase was linked to electron transport to HFO, while dehydrogenases and cyt b/c were found to participate in the reduction of Fe-EDTA. Thus, various different electron transport pathways are employed by strain SgZ-1 for different electron acceptors. The results from this study help in understanding the electron transport processes and environmental responses of the genus Thauera.

New treatment option for second-stage African sleeping sickness: in vitro and in vivo efficacy of aza analogs of DB289.

PubMed

Wenzler, Tanja; Boykin, David W; Ismail, Mohamed A; Hall, James Edwin; Tidwell, Richard R; Brun, Reto

2009-10-01

African sleeping sickness is a fatal parasitic disease, and all drugs currently in use for treatment have strong liabilities. It is essential to find new, effective, and less toxic drugs, ideally with oral application, to control the disease. In this study, the aromatic diamidine DB75 (furamidine) and two aza analogs, DB820 and DB829 (CPD-0801), as well as their methoxyamidine prodrugs and amidoxime metabolites, were evaluated against African trypanosomes. The active parent diamidines showed similar in vitro profiles against different Trypanosoma brucei strains, melarsoprol- and pentamidine-resistant lines, and a P2 transporter knockout strain (AT1KO), with DB75 as the most trypanocidal molecule. In the T. b. rhodesiense strain STIB900 acute mouse model, the aza analogs DB820 and DB829 demonstrated activities superior to that of DB75. The aza prodrugs DB844 and DB868, as well as two metabolites of DB844, were orally more potent in the T. b. brucei strain GVR35 mouse central nervous system (CNS) model than DB289 (pafuramidine maleate). Unexpectedly, the parent diamidine DB829 showed high activity in the mouse CNS model by the intraperitoneal route. In conclusion, DB868 with oral and DB829 with parenteral application are potential candidates for further development of a second-stage African sleeping sickness drug.

New carbocyclic N(6)-substituted adenine and pyrimidine nucleoside analogues with a bicyclo[2.2.1]heptane fragment as sugar moiety; synthesis, antiviral, anticancer activity and X-ray crystallography.

PubMed

Tănase, Constantin I; Drăghici, Constantin; Cojocaru, Ana; Galochkina, Anastasia V; Orshanskaya, Jana R; Zarubaev, Vladimir V; Shova, Sergiu; Enache, Cristian; Maganu, Maria

2015-10-01

New nucleoside analogues with an optically active bicyclo[2.2.1]heptane skeleton as sugar moiety and 6-substituted adenine were synthesized by alkylation of 6-chloropurine intermediate. Thymine and uracil analogs were synthesized by building the pyrimidine ring on amine 1. X-ray crystallography confirmed an exo-coupling of the thymine to the ring and an L configuration of the nucleoside analogue. The library of compounds was tested for their inhibitory activity against influenza virus A∖California/07/09 (H1N1)pdm09 and coxsackievirus B4 in cell culture. Compounds 13a and 13d are the most promising for their antiviral activity against influenza, and compound 3c against coxsackievirus B4. Compounds 3b and 3g were tested for anticancer activity. Copyright © 2015 Elsevier Ltd. All rights reserved.

A Test of the Paired-Associate Analogy to RI in Free Recall.

ERIC Educational Resources Information Center

Perlmutter, Jane; Royer, James M.

To provide a further test of the paired-associate analogy to retroactive inhibition in free recall, this experiment investigated the effect of presenting both original learning (OL) and interpolated learning (IL) in either blocked category (B) or random (R) fashion. IL-OL Similar (S), IL-OL Different (D), and control (C) conditions were included.…

Cathepsin B inhibitory activities of three new phthalate derivatives isolated from seahorse, Hippocampus Kuda Bleeler.

PubMed

Li, Yong; Qian, Zhong-Ji; Kim, Se-Kwon

2008-12-01

Three new phthalate acid derivatives, 2,12-diethyl-11-methylhexadecyl 2-ethyl-11-methylhexadecyl phthalate (1), 2-ethyldecyl 2-ethylundecyl phthalate (2), and bis(2-ethyldodecyl) phthalate (3), were isolated from seahorse, Hippocampus Kuda Bleeler, together with a known natural analog bis(2-ethylheptyl) phthalate (4). The structures of these compounds were elucidated mainly by means of the comprehensive analysis of their NMR spectroscopic data. The four phthalate derivatives showed dose-dependent cathepsin B inhibitions activities with IC(50) values of 0.13 mM (1), 0.21 mM (2), 0.18 mM (3), and 0.29 mM (4), respectively.

Synthesis and preliminary biological evaluation of new derivatives of the marine alkaloid leucettamine B as kinase inhibitors.

PubMed

Debdab, Mansour; Renault, Stéven; Lozach, Olivier; Meijer, Laurent; Paquin, Ludovic; Carreaux, François; Bazureau, Jean-Pierre

2010-02-01

New derivatives of the marine alkaloid leucettamine B were prepared in five steps with overall yields ranging from 23 to 30%. The key step of our strategy has been the sulfur/nitrogen displacement under solvent-free microwave irradiation of (5Z) 5-benzo[1,3]-dioxo-5-ylmethylene-2-ethylsulfanyl-3,5-dihydroimidazol-4-one 3 with a mono-protected ethylenediamine 2. After deprotection of the N-Boc group, the amino derivative of leucettamine B 5 was subjected to reductive amination in two steps with retention of configuration of the double bond, to lead to eight new analogs of leucettamine B. The effect of these compounds on CK1alpha/beta, CDK5/p25, and GSK-3alpha/beta were investigated. Copyright 2009 Elsevier Masson SAS. All rights reserved.

Development of digital sideband separating down-conversion for Yuan-Tseh Lee Array

NASA Astrophysics Data System (ADS)

Li, Chao-Te; Kubo, Derek; Cheng, Jen-Chieh; Kuroda, John; Srinivasan, Ranjani; Ho, Solomon; Guzzino, Kim; Chen, Ming-Tang

2016-07-01

This report presents a down-conversion method involving digital sideband separation for the Yuan-Tseh Lee Array (YTLA) to double the processing bandwidth. The receiver consists of a MMIC HEMT LNA front end operating at a wavelength of 3 mm, and sub-harmonic mixers that output signals at intermediate frequencies (IFs) of 2-18 GHz. The sideband separation scheme involves an analog 90° hybrid followed by two mixers that provide down-conversion of the IF signal to a pair of in-phase (I) and quadrature (Q) signals in baseband. The I and Q baseband signals are digitized using 5 Giga sample per second (Gsps) analog-to-digital converters (ADCs). A second hybrid is digitally implemented using field-programmable gate arrays (FPGAs) to produce two sidebands, each with a bandwidth of 1.6 GHz. The 2 x 1.6 GHz band can be tuned to cover any 3.6 GHz window within the aforementioned IF range of the array. Sideband rejection ratios (SRRs) above 20 dB can be obtained across the 3.6 GHz bandwidth by equalizing the power and delay between the I and Q baseband signals. Furthermore, SRRs above 30 dB can be achieved when calibration is applied.

The emerging role of Rab GTPases in the pathogenesis of Parkinson's disease.

PubMed

Gao, Yujing; Wilson, Gabrielle R; Stephenson, Sarah E M; Bozaoglu, Kiymet; Farrer, Matthew J; Lockhart, Paul J

2018-02-01

The identification of pathogenic mutations in Ras analog in brain 39B (RAB39B) and Ras analog in brain 32 (RAB32) that cause Parkinson's disease (PD) has highlighted the emerging role of protein trafficking in disease pathogenesis. Ras analog in brain (Rab) Guanosine triphosphatase (GTPase) function as master regulators of membrane trafficking, including vesicle formation, movement along cytoskeletal networks, and membrane fusion. Recent studies have linked Rab GTPases with α-synuclein, Leucine-rich repeat kinase 2, and Vacuolar protein sorting 35, 3 key proteins in PD pathogenesis. In this review, we discuss the various RAB GTPases associated with PD, current progress in the research, and potential future directions. Investigations into the function of RAB GTPases will likely provide significant insight into the etiology of PD and identify novel therapeutic targets for a currently incurable disease. © 2018 International Parkinson and Movement Disorder Society. © 2018 International Parkinson and Movement Disorder Society.

A novel methodology for radiative transfer in a planetary atmosphere. I - The functions a exponent m and b exponent m of anisotropic scattering

NASA Technical Reports Server (NTRS)

Fymat, A. L.; Kalaba, R. E.

1977-01-01

The original problem of anisotropic scattering in an atmosphere illuminated by a unidirectional source is replaced by an analogous formulation where the incident light is omnidirectional. A radiative-transfer equation for the omnidirectional case is obtained in which the direction of illumination plays no role and the source-function analog, Sobolev's (1972) source function Phi exponent m, contains only a single integral term. For radiation incident on the top or the bottom of the atmosphere, this equation involves the functions b exponent m and h exponent m, respectively, with m corresponding to the order of the harmonic component of the scattered radiation field; these two functions are shown to be only one through some simple reciprocity relations. The transfer problem is then reformulated for the function a exponent m, in which case the source-function analog (Sobolev's function D exponent m) involves incident direction.

Design and characterization of α-melanotropin peptide analogs cyclized through rhenium and technetium metal coordination

PubMed Central

Giblin, Michael F.; Wang, Nannan; Hoffman, Timothy J.; Jurisson, Silvia S.; Quinn, Thomas P.

1998-01-01

α-Melanocyte stimulating hormone (α-MSH) analogs, cyclized through site-specific rhenium (Re) and technetium (Tc) metal coordination, were structurally characterized and analyzed for their abilities to bind α-MSH receptors present on melanoma cells and in tumor-bearing mice. Results from receptor-binding assays conducted with B16 F1 murine melanoma cells indicated that receptor-binding affinity was reduced to approximately 1% of its original levels after Re incorporation into the cyclic Cys4,10, d-Phe7–α-MSH4-13 analog. Structural analysis of the Re–peptide complex showed that the disulfide bond of the original peptide was replaced by thiolate–metal–thiolate cyclization. A comparison of the metal-bound and metal-free structures indicated that metal complexation dramatically altered the structure of the receptor-binding core sequence. Redesign of the metal binding site resulted in a second-generation Re–peptide complex (ReCCMSH) that displayed a receptor-binding affinity of 2.9 nM, 25-fold higher than the initial Re–α-MSH analog. Characterization of the second-generation Re–peptide complex indicated that the peptide was still cyclized through Re coordination, but the structure of the receptor-binding sequence was no longer constrained. The corresponding 99mTc- and 188ReCCMSH complexes were synthesized and shown to be stable in phosphate-buffered saline and to challenges from diethylenetriaminepentaacetic acid (DTPA) and free cysteine. In vivo, the 99mTcCCMSH complex exhibited significant tumor uptake and retention and was effective in imaging melanoma in a murine-tumor model system. Cyclization of α-MSH analogs via 99mTc and 188Re yields chemically stable and biologically active molecules with potential melanoma-imaging and therapeutic properties. PMID:9788997

“Ba{sub 6}Nb{sub 4}RuO{sub 18}” and “LaBa{sub 4}Nb{sub 3}RuO{sub 15}” – The structural consequences of substituting paramagnetic cations into A{sub n}B{sub n−1}O{sub 3n} cation-deficient perovskite oxides

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kamil, Elynor L.; Morgan, Harry W.T.; Hayward, Michael A., E-mail: michael.hayward@chem.ox.ac.uk

The B-cation deficient perovskite phases Ba{sub 6}Nb{sub 4}RuO{sub 18} and LaBa{sub 4}Nb{sub 3}RuO{sub 15} were prepared by ceramic synthesis. Neutron powder diffraction analysis indicates that rather than the 6-layer and 5-layer cation-deficient perovskite structures expected for these phases (by analogy to the known structures of Ba{sub 6}Nb{sub 4}TiO{sub 18} and LaBa{sub 4}Nb{sub 3}TiO{sub 15}) they adopt 5-layer and 4-layer B-cation deficient perovskite structures respectively, and are better described as Ba{sub 5}Nb{sub 3.33}Ru{sub 0.81}O{sub 15} and Ba{sub 3.16}La{sub 0.84}Nb{sub 2.36}Ru{sub 0.72}O{sub 12}. The factors that lead to the compositionally analogous Nb/Ru and Nb/Ti phases adopting different structures are discussed on themore » basis of the difference between d{sup 0} and non-d{sup 0} transition metal cations. - Graphical abstract: The ruthenium-containing B-cation deficient perovskite phases, Ba{sub 5}Nb{sub 3.33}Ru{sub 0.81}O{sub 15} and Ba{sub 3.16}La{sub 0.84}Nb{sub 2.36}Ru{sub 0.72}O{sub 12}, adopt 5-layer and 4-layer structures respectively, rather than the 6-layer and 5-layer cation-deficient structures adopted by the analogous titanium-containing phases Ba{sub 6}Nb{sub 4}TiO{sub 18} and LaBa{sub 4}Nb{sub 3}TiO{sub 15}. Display Omitted - Highlights: • B-cation deficient perovskite containing paramagnetic cations. • B-cation deficient structure determined by neutron powder diffraction. • Low ‘solubility’ of BaRuO{sub 3} in Ba{sub 5}Nb{sub 4}O{sub 15} leads to novel structure.« less

A merged pipe organ binary-analog correlator

NASA Astrophysics Data System (ADS)

Miller, R. S.; Berry, M. B.

1982-02-01

The design of a 96-stage, programmable binary-analog correlator is described. An array of charge coupled device (CCD) delay lines of differing lengths perform the delay and sum functions. Merging of several CCD channels is employed to reduce the active area. This device architecture allows simplified output detection while maintaining good device performance at higher speeds (5-10 MHz). Experimental results indicate a 50 dB broadband dynamic range and excellent agreement with the theoretical processing gain (19.8 dB) when operated at a 6 MHz sampling frequency as a p-n sequence matched filter.

Comparative acid-base properties of the surface of components of the CdTe-ZnS system in series of substitutional solid solutions and their analogs

NASA Astrophysics Data System (ADS)

Kirovskaya, I. A.; Kasatova, I. Yu.

2011-07-01

The acid-base properties of the surface of solid solutions and binary components of the CdTe-ZnS system are studied by hydrolytic adsorption, nonaqueous conductometric titration, mechanochemistry, IR spectroscopy, and Raman scattering spectroscopy. The strength, nature, and concentration of acid centers on the original surface and that exposed to CO are determined. The changes in acid-base properties in dependence on the composition of the system under investigation in the series of CdB6, ZnB6 analogs are studied.

Three-dimensional modeling of n+-nu-n+ and p+-pi-p+ semiconducting devices for analog ULSI microelectronics

NASA Astrophysics Data System (ADS)

Gillet, Jean-Numa; Degorce, Jean-Yves; Belisle, Jonathan; Meunier, Michel

2004-03-01

Three-dimensional modeling of n^+-ν -n^+ and p^+-π -p^+ semiconducting devices for analog ULSI microelectronics Jean-Numa Gillet,^a,b Jean-Yves Degorce,^a Jonathan Bélisle^a and Michel Meunier.^a,c ^a École Polytechnique de Montréal, Dept. of Engineering Physics, CP 6079, Succ. Centre-vile, Montréal, Québec H3C 3A7, Canada. ^b Corresponding author. Email: Jean-Numa.Gillet@polymtl.ca ^c Also with LTRIM Technologies, 140-440, boul. A.-Frappier, Laval, Québec H7V 4B4, Canada. We present for the first time three-dimensional (3-D) modeling of n^+-ν -n^+ and p^+-π -p^+ semiconducting resistors, which are fabricated by laser-induced doping in a gateless MOSFET and present significant applications for analog ULSI microelectronics. Our modeling software is made up of three steps. The two first concerns modeling of a new laser-trimming fabrication process. With the molten-silicon temperature distribution obtained from the first, we compute in the second the 3-D dopant distribution, which creates the electrical link through the device gap. In this paper the emphasis is on the third step, which concerns 3-D modeling of the resistor electronic behavior with a new tube multiplexing algorithm (TMA). The device current-voltage (I-V) curve is usually obtained by solving three coupled partial differential equations with a finite-element method. A 3-D device as our resistor cannot be modeled with this classical method owing to its prohibitive computational cost in three dimensions. This problem is however avoided by our TMA, which divides the 3-D device into one-dimensional (1-D) multiplexed tubes. In our TMA 1-D systems of three ordinary differential equations are solved to determine the 3-D device I-V curve, which substantially increases computation speed compared with the classical method. Numerical results show a good agreement with experiments.

Relationship between structure and antiproliferative activity of 1-azaflavanones.

PubMed

Kawaii, Satoru; Endo, Kotaro; Tokiwano, Tetsuo; Yoshizawa, Yuko

2012-07-01

The synthesis of 19 derivatives of 2-phenyl-3,4-dihydroquinolin-4(1H)-one, as aza analogs of flavanones, was carried out and these compounds were further screened for their antiproliferative activity toward HL60 promyelocytic leukemia cells. In comparison with flavanone the replacement of C-ring ether oxygen atom with a nitrogen atom potentiated activity by more than 100-fold. It was suggested that the aromaticity of the B-ring contributes greatly to the activity of 1-azaflavanones.

Chimeric analogs of human β-defensin 1 and θ-defensin disrupt pre-established bacterial biofilms.

PubMed

Mathew, Basil; Olli, Sudar; Guru, Ankeeta; Nagaraj, Ramakrishanan

2017-08-01

Antibiofilm activity of several human defensin analogs that have the ability to kill planktonic bacteria, against pre-established biofilms of Escherichia coli MG1655 and Staphylococcus aureus NCTC 8530 were examined. Linear and linear fatty acylated analogs did not show any activity while disulfide constrained analogs disrupted pre-established S. aureus biofilms. Chimeric analogs of human β-defensin 1 and θ-defensin, hBTD-1 and [d]hBTD-1 were highly active against S. aureus biofilms. Among the analogs tested, only the d-enantiomer [d]hBTD-1 showed activity against E. coli biofilm. Our study provides insights into the structural requirements for the eradication of pre-established biofilms in defensin analogs. Copyright © 2017 Elsevier Ltd. All rights reserved.

New size-expanded RNA nucleobase analogs: a detailed theoretical study.

PubMed

Zhang, Laibin; Zhang, Zhenwei; Ren, Tingqi; Tian, Jianxiang; Wang, Mei

2015-04-05

Fluorescent nucleobase analogs have attracted much attention in recent years due to their potential applications in nucleic acids research. In this work, four new size-expanded RNA base analogs were computationally designed and their structural, electronic, and optical properties are investigated by means of DFT calculations. The results indicate that these analogs can form stable Watson-Crick base pairs with natural counterparts and they have smaller ionization potentials and HOMO-LUMO gaps than natural ones. Particularly, the electronic absorption spectra and fluorescent emission spectra are calculated. The calculated excitation maxima are greatly red-shifted compared with their parental and natural bases, allowing them to be selectively excited. In gas phase, the fluorescence from them would be expected to occur around 526, 489, 510, and 462 nm, respectively. The influences of water solution and base pairing on the relevant absorption spectra of these base analogs are also examined. Copyright © 2015 Elsevier B.V. All rights reserved.

Metabolically inactive insulin analog prevents type I diabetes in prediabetic NOD mice.

PubMed Central

Karounos, D G; Bryson, J S; Cohen, D A

1997-01-01

The purpose of this study was to determine the relative importance of the metabolic effects of insulin for diabetes prevention by administering insulin or an inactive insulin analog by daily subcutaneous injections to prediabetic mice. A recombinant monomeric human insulin analog, which does not bind to the insulin receptor as a consequence of an alteration of a single amino acid at position 25 of the B chain, was shown to be equally effective at diabetes prevention as was intact insulin. In contrast to native insulin, the insulin analog did not cause hypoglycemia after subcutaneous injection. The insulin analog, however, protected young adult mice from diabetes, even when it was initiated after the onset of extensive lymphocytic infiltration of the islets. Thus, preventative therapy by daily subcutaneous injections of insulin does not require the hypoglycemic response, or binding to the insulin receptor to prevent the onset of type I diabetes. PMID:9294099

Novel 4-Substituted-N,N-dimethyltetrahydronaphthalen-2-amines: Synthesis, Affinity, and In Silico Docking Studies at Serotonin 5-HT2-type and Histamine H1 G Protein-Coupled Receptors

PubMed Central

Sakhuja, Rajeev; Kondabolu, Krishnakanth; Córdova-Sintjago, Tania; Travers, Sean; Vincek, Adam S.; Kim, Myong Sang; Abboud, Khalil A.; Fang, Lijuan; Sun, Zhuming; Canal, Clinton E.; Booth, Raymond G.

2015-01-01

Syntheses were undertaken of derivatives of (2S, 4R)-(−)-trans-4-phenyl-N,N-dimethyl-1,2,3,4-tetrahydronaphthalen-2-amine (4-phenyl-2-dimethylaminotetralin, PAT), a stereospecific agonist at the serotonin 5-HT2C G protein-coupled receptor (GPCR), with inverse agonist activity at 5-HT2A and 5-HT2B GPCRs. Molecular changes were made at the PAT C(4)-position, while preserving N, N-dimethyl substitution at the 2-position as well as trans-stereochemistry, structural features previously shown to be optimal for 5-HT2 binding. Affinities of analogs were determined at recombinant human 5-HT2 GPCRs in comparison to the phylogenetically closely-related histamine H1 GPCR, and in silico ligand docking studies were conducted at receptor molecular models to help interpret pharmacological results and guide future ligand design. In most cases, C(4)-substituted PAT analogs exhibited the same stereoselectivity ([−]-trans > [+]-trans) as the parent PAT across 5-HT2 and H1 GPCRs, albeit, with variable receptor selectivity. 4-(4′-substituted)-PAT analogs, however, demonstrated reversed stereoselectivity ([2S, 4R]-[+]-trans > [2S, 4R]-[−]-trans), with absolute configuration confirmed by single X-ray crystallographic data for the 4-(4′-Cl)-PAT analog. Pharmacological affinity results and computational results herein support further PAT drug development studies and provide a basis for predicting and interpreting translational results, including, for (+)-trans-4-(4′-Cl)-PAT and (−)-trans-4-(3′-Br)-PAT that were previously shown to be more potent and efficacious than their corresponding enantiomers in rodent models of psychoses, psychostimulant-induced behaviors, and compulsive feeding (‘binge-eating’). PMID:25703249

The active analog approach applied to the pharmacophore identification of benzodiazepine receptor ligands

NASA Astrophysics Data System (ADS)

Tebib, Souhail; Bourguignon, Jean-Jacques; Wermuth, Camille-Georges

1987-07-01

Applied to seven potent benzodiazepine-receptor ligands belonging to chemically different classes, the active analog approach allowed the stepwise identification of the pharmacophoric pattern associated with the recognition by the benzodiazepine receptor. A unique pharmacophore model was derived which involves six critical zones: (a) a π-electron rich aromatic (PAR) zone; (b) two electron-rich zones δ1 and δ2 placed at 5.0 and 4.5 Å respectively from the reference centroid in the PAR zone; (c) a freely rotating aromatic ring (FRA) region; (d) an out-of-plane region (OPR), strongly associated with agonist properties; and (e) an additional hydrophobic region (AHR). The model accommodates all presently known ligands of the benzodiazepine receptor, identifies sensitivity to steric hindrance close to the δ1 zone, accounts for R and S differential affinities and distinguishes requirements for agonist versus non-agonist activity profiles.

Pseudo-differential CMOS analog front-end circuit for wide-bandwidth optical probe current sensor

NASA Astrophysics Data System (ADS)

Uekura, Takaharu; Oyanagi, Kousuke; Sonehara, Makoto; Sato, Toshiro; Miyaji, Kousuke

2018-04-01

In this paper, we present a pseudo-differential analog front-end (AFE) circuit for a novel optical probe current sensor (OPCS) aimed for high-frequency power electronics. It employs a regulated cascode transimpedance amplifier (RGC-TIA) to achieve a high gain and a large bandwidth without using an extremely high performance operational amplifier. The AFE circuit is designed in a 0.18 µm standard CMOS technology achieving a high transimpedance gain of 120 dB Ω and high cut off frequency of 16 MHz. The measured slew rate is 70 V/µs and the input referred current noise is 1.02 pA/\\sqrt{\\text{Hz}} . The magnetic resolution and bandwidth of OPCS are estimated to be 1.29 mTrms and 16 MHz, respectively; the bandwidth is higher than that of the reported Hall effect current sensor.

Measurement of the B 0 s lifetime in the flavor-specific decay channel B 0 s → D - sμ +νX

DOE PAGES

Abazov, Victor Mukhamedovich

2015-02-09

We present an updated measurement of the B 0 s lifetime using the semileptonic decays B 0 s → D - sμ +νX, with D – s → π – and Φ → K +K – (and the charge conjugate process). This measurement uses the full Tevatron Run II sample of proton-antiproton collisions at √s = 1.96 TeV, comprising an integrated luminosity of 10.4 fb –1. We find a flavor-specific lifetime τ fs(B 0 s) = 1.479 ± 0.010(stat) ± 0.021(syst) ps. This technique is also used to determine the B 0 lifetime using the analogous B 0 → Dmore » –μ +νX decay with D – → Φπ – and Φ → K +K –, yielding τ(B 0) = 1.534 ± 0.019(stat) ± 0.021(syst) ps. Both measurements are consistent with the current world averages, and the B 0 s lifetime measurement is one of the most precise to date. As a result, taking advantage of the cancellation of systematic uncertainties, we determine the lifetime ratio τ fs(B 0 s)/τ(B 0) = 0.964 ± 0.013(stat) ± 0.007(syst).« less

A potent, selective, and orally bioavailable inhibitor of the protein-tyrosine phosphatase PTP1B improves insulin and leptin signaling in animal models.

PubMed

Krishnan, Navasona; Konidaris, Konstantis F; Gasser, Gilles; Tonks, Nicholas K

2018-02-02

The protein-tyrosine phosphatase PTP1B is a negative regulator of insulin and leptin signaling and a highly validated therapeutic target for diabetes and obesity. Conventional approaches to drug development have produced potent and specific PTP1B inhibitors, but these inhibitors lack oral bioavailability, which limits their potential for drug development. Here, we report that DPM-1001, an analog of the specific PTP1B inhibitor trodusquemine (MSI-1436), is a potent, specific, and orally bioavailable inhibitor of PTP1B. DPM-1001 also chelates copper, which enhanced its potency as a PTP1B inhibitor. DPM-1001 displayed anti-diabetic properties that were associated with enhanced signaling through insulin and leptin receptors in animal models of diet-induced obesity. Therefore, DPM-1001 represents a proof of concept for a new approach to therapeutic intervention in diabetes and obesity. Although the PTPs have been considered undruggable, the findings of this study suggest that allosteric PTP inhibitors may help reinvigorate drug development efforts that focus on this important family of signal-transducing enzymes. © 2018 by The American Society for Biochemistry and Molecular Biology, Inc.

Benzylmorpholine Analogs as Selective Inhibitors of Lung Cytochrome P450 2A13 for the Chemoprevention of Lung Cancer in Tobacco Users

PubMed Central

Blake, Linda C.; Roy, Anuradha; Neul, David; Schoenen, Frank J.; Aubé, Jeffrey; Scott, Emily E.

2013-01-01

Purpose 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), one of the most prevalent and procarcinogenic compounds in tobacco, is bioactivated by respiratory cytochrome P450 (CYP) 2A13, forming DNA adducts and initiating lung cancer. CYP2A13 inhibition offers a novel strategy for chemoprevention of tobacco-associated lung cancer. Methods Twenty-four analogs of a 4-benzylmorpholine scaffold identified by high throughput screening were evaluated for binding and inhibition of both functional human CYP2A enzymes, CYP2A13 and the 94%-identical hepatic CYP2A6, whose inhibition is undesirable. Thus, selectivity is the major challenge in compound design. Results A key feature resulting in CYP2A13-selective binding and inhibition was substitution at the benzyl ortho position, with three analogs being >25-fold selective for CYP2A13 over CYP2A6. Conclusions Two such analogs were negative for genetic and hERG toxicities and metabolically stable in human lung microsomes, but displayed rapid metabolism in human liver and in mouse and rat lung and liver microsomes, likely due to CYP2B-mediated degradation. A specialized knockout mouse mimicking the human lung demonstrates compound persistence in lung and provides an appropriate test model. Compound delivered by inhalation may be effective in the lung but rapidly cleared otherwise, limiting systemic exposure. PMID:23756756

Does the usage of digital chest drainage systems reduce pleural inflammation and volume of pleural effusion following oncologic pulmonary resection?-A prospective randomized trial.

PubMed

De Waele, Michèle; Agzarian, John; Hanna, Waël C; Schieman, Colin; Finley, Christian J; Macri, Joseph; Schneider, Laura; Schnurr, Terri; Farrokhyar, Forough; Radford, Katherine; Nair, Parameswaran; Shargall, Yaron

2017-06-01

Prolonged air leak and high-volume pleural drainage are the most common causes for delays in chest tube removal following lung resection. While digital pleural drainage systems have been successfully used in the management of post-operative air leak, their effect on pleural drainage and inflammation has not been studied before. We hypothesized that digital drainage systems (as compared to traditional analog continuous suction), using intermittent balanced suction, are associated with decreased pleural inflammation and postoperative drainage volumes, thus leading to earlier chest tube removal. One hundred and three [103] patients were enrolled and randomized to either analog (n=50) or digital (n=53) drainage systems following oncologic lung resection. Chest tubes were removed according to standardized, pre-defined protocol. Inflammatory mediators [interleukin-1B (IL-1B), 6, 8, tumour necrosis factor-alpha (TNF-α)] in pleural fluid and serum were measured and analysed. The primary outcome of interest was the difference in total volume of postoperative fluid drainage. Secondary outcome measures included duration of chest tube in-situ, prolonged air-leak incidence, length of hospital stay and the correlation between pleural effusion formation, degree of inflammation and type of drainage system used. There was no significant difference in total amount of fluid drained or length of hospital stay between the two groups. A trend for shorter chest tube duration was found with the digital system when compared to the analog (P=0.055). Comparison of inflammatory mediator levels revealed no significant differences between digital and analog drainage systems. The incidence of prolonged post-operative air leak was significantly higher when using the analog system (9 versus 2 patients; P=0.025). Lobectomy was associated with longer chest tube duration (P=0.001) and increased fluid drainage when compared to sub-lobar resection (P<0.001), regardless of drainage system. Use of post-lung resection digital drainage does not appear to decrease pleural fluid formation, but is associated with decreased prolonged air leaks. Total pleural effusion volumes did not differ with the type of drainage system used. These findings support previously established benefits of the digital system in decreasing prolonged air leaks, but the advantages do not appear to extend to decreased pleural fluid formation.

Relative potency for altered humoral immunity induced by polybrominated and polychlorinated dioxins/furans in female B6C3F1/N mice.

PubMed

Frawley, Rachel; DeVito, Michael; Walker, Nigel J; Birnbaum, Linda; White, Kimber; Smith, Matthew; Maynor, Timothy; Recio, Leslie; Germolec, Dori

2014-06-01

The use of brominated flame retardants and incineration of bromine-containing materials has lead to an increase in polybrominated dibenzo-p-dioxins and dibenzofurans (PBDD/Fs) in the environment. Measurable amounts of PBDD/Fs have been detected in soil, seafood, and human breast milk and serum. Studies indicate that the relative potencies of some PBDD/Fs based on enzyme induction are equivalent to those of some polychlorinated dibenzo-p-dioxins and dibenzofurans. To assess the humoral immunity relative potencies of PBDD/Fs and compare them to their chlorinated analogs, female B6C3F1/N mice received a single oral exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), 2,3,7,8-tetrabromodibenzofuran (TBDF), 2,3,7,8-tetrachlorodibenzofuran (TCDF), 1,2,3,7,8-pentabromodibenzofuran (1PeBDF), 1,2,3,7,8-pentachlorodibenzofuran (1PeCDF), 2,3,4,7,8-pentabromodibenzofuran (4PeBDF), 2,3,4,7,8-pentachlorodibenzofuran (4PeCDF), 2,3-dibromo-7,8-dichlorodibenzo-p-dioxin (DBDCDD), or 2,3,7-tribromodibenzo-p-dioxin (TriBDD). Inhibition of the immunoglobulin M (IgM) antibody forming cell response was measured 4 days following immunization with sheep red blood cells. The data were fit to a Hill model to estimate the ED50 for inhibition. Expression of xenobiotic metabolizing enzyme (XME) and thyroxine transport protein (Ttr) genes in liver was measured by PCR to assess aryl hydrocarbon-mediated responses. TCDD, TBDF, TCDF, 1PeBDF, 4PeBDF, 4PeCDF, and DBDCDD suppressed the IgM antibody response and Ttr gene expression, and upregulated phase I XME genes. 1PeCDF suppressed the IgM antibody response but only upregulated phase I XME genes; TriBDD had no effect on antibody response. The rank order of potency (ED50) for these chemicals was TCDD>TBDF>4PeBDF>TCDF/4PeCDF/1PeBDF>1PeCDF. Whereas TCDD was the most potent compound tested, the brominated analogs were more potent than their chlorinated analogs, suggesting that these compounds should be considered in toxic equivalency factor evaluation and risk assessment.

47 CFR 27.1233 - Reimbursement costs of transitioning.

Code of Federal Regulations, 2014 CFR

2014-10-01

... nanoseconds for analog operations over any individual six megahertz MBS channel. (b) Migration of Video... migration, a program track must contain EBS programming that complies with § 27.1203 (b) and (c). (ii) The...

47 CFR 27.1233 - Reimbursement costs of transitioning.

Code of Federal Regulations, 2013 CFR

2013-10-01

... nanoseconds for analog operations over any individual six megahertz MBS channel. (b) Migration of Video... migration, a program track must contain EBS programming that complies with § 27.1203 (b) and (c). (ii) The...

Facile synthesis of cyclopentenone B1- and L1-type Phytoprostanes

NASA Astrophysics Data System (ADS)

Guy, Alexandre; Flanagan, Seamus; Durand, Thierry; Oger, Camille; Galano, Jean-Marie

2015-07-01

Phytoprostanes (PhytoPs) represent non-enzymatic metabolites of α-linolenic acid (ALA), the essential omega-3 polyunsaturated fatty acid (PUFA) derived from plants. PhytoPs are present in the plant kingdom and represent endogenous mediators capable of protecting cells from oxidative stress damages in plants. Recently, it was found that such metabolites are present in cooking oil in high quantities, and also that B1-PhytoPs protect immature neurons from oxidant injury and promote differentiation of oligodendrocyte progenitors through PPAR-γ activation. We report a novel and facile synthesis of natural 2,3-substituted cyclopentenone PhytoPs, 16-B1-PhytoP and 9-L1-PhytoP. Our strategy is based on reductive alkylation at the 2-position of 1,3-cyclopentanedione using a recent protocol developed by Ramachary et al., and on a cross-coupling metathesis to access conjugate dienone system. In conclusion, this strategy permitted access to B1- and L1-PhytoPs in a relative short sequence process, and afford the possibility to easily develop analogs of PhytoPs.

Facile synthesis of cyclopentenone B1- and L1-type phytoprostanes

PubMed Central

Guy, Alexandre; Flanagan, Séamus; Durand, Thierry; Oger, Camille; Galano, Jean-Marie

2015-01-01

Phytoprostanes (PhytoPs) represent non-enzymatic metabolites of α-linolenic acid (ALA), the essential omega-3 polyunsaturated fatty acid (PUFA) derived from plants. PhytoPs are present in the plant kingdom and represent endogenous mediators capable of protecting cells from oxidative stress damages in plants. Recently, it was found that such metabolites are present in cooking oil in high quantities, and also that B1-PhytoPs protect immature neurons from oxidant injury and promote differentiation of oligodendrocyte progenitors through PPAR-γ activation. We report a novel and facile synthesis of natural 2,3-substituted cyclopentenone PhytoPs, 16-B1-PhytoP, and 9-L1-PhytoP. Our strategy is based on reductive alkylation at the 2-position of 1,3-cyclopentanedione using a recent protocol developed by Ramachary et al. and on a cross-coupling metathesis to access conjugate dienone system. In conclusion, this strategy permitted access to B1- and L1-PhytoPs in a relative short sequence process, and afford the possibility to easily develop analogs of PhytoPs. PMID:26217659

Evaluation of a PK/PBAN analog with an (E)-alkene, trans-Pro isostere identifies the Pro orientation for activity in four diverse PK/PBAN bioassays

USDA-ARS?s Scientific Manuscript database

The pyrokinin/pheromone biosynthesis activating neuropeptide (PK/PBAN) family plays a multifunctional role in an array of important physiological processes in a variety of insects. An active core analog containing an (E)-alkene, transPro isosteric component was evaluated in four disparate PK/PBAN b...

19-nor vitamin-D analogs: a new class of potent inhibitors of proliferation and inducers of differentiation of human myeloid leukemia cell lines.

PubMed

Asou, H; Koike, M; Elstner, E; Cambell, M; Le, J; Uskokovic, M R; Kamada, N; Koeffler, H P

1998-10-01

We have studied the in vitro biological activities and mechanisms of action of 1,25-dihydroxyvitamin D3 (1,25D3) and nine potent 1,25D3 analogs on proliferation and differentiation of myeloid leukemia cell lines (HL-60, retinoic acid-resistant HL-60 [RA-res HL-60], NB4 and Kasumi-1). The common novel structural motiff for almost all the analogs included removal of C-19 (19-nor); each also had unsaturation of the side chain. All the compounds were potent; for example, the concentration of analogs producing a 50% clonal inhibition (ED50) ranged between 1 x 10(-9) to 4 x 10(-11) mol/L when using the HL-60 cell line. The most active compound [1, 25(OH)2-16,23E-diene-26-trifluoro-19-nor-cholecalciferol (Ro 25-9716)] had an ED50 of 4 x 10(-11) mol/L; in contrast, the 1,25D3 produced an ED50 of 10(-9) mol/L with the HL-60 target cells. Ro 25-9716 (10(-9) mol/L, 3 days) was a strong inducer of myeloid differentiation because it caused 92% of the HL-60 cells to express CD11b and 75% of these cells to reduce nitroblue tetrazolium (NBT). This compound (10(-8) mol/L, 4 days) also caused HL-60 cells to arrest in the G1 phase of the cell cycle (88% cells in G1 v 48% of the untreated control cells). The p27(kip-1), a cyclin-dependent kinase inhibitor which is important in blocking the cell cycle, was induced more quickly and potently by Ro 25-9716 (10(-7) mol/L, 0 to 5 days) than by 1,25D3, suggesting a possible mechanism by which these analogs inhibit proliferation of leukemic growth. The NB4 promyelocytic leukemia cells cultured with the Ro 25-9716 were also inhibited in their clonal proliferation (ED50, 5 x 10(-11) mol/L) and their expression of CD11b was enhanced (80% positive [10(-9) mol/L, 4 days] v 27% untreated NB4 cells). Moreover, the combination of Ro 25-9716 (10(-9) mol/L) and all-trans retinoic acid (ATRA, 10(-7) mol/L) induced 92% of the NB4 cells to reduce NBT, whereas only 26% of the cells became NBT positive after a similar exposure to the combination of 1,25D3 and ATRA. Surprisingly, Ro 25-9716 also inhibited the clonal growth of poorly differentiated leukemia cell lines (RA-res HL-60 [ED50, 4 x 10(-9) mol/L] and Kasumi-1 [ED50, 5 x 10(-10) mol/L]). For HL-60 cells, Ro 25-9716 markedly decreased the percent of the cells in S phase of the cell cycle and increased the expression of the cyclin-dependent kinase inhibitor, p27(kip-1). In summary, 19-nor vitamin D3 compounds strongly induced differentiation and inhibited clonal proliferation of various myeloid leukemia cell lines, suggesting a therapeutic niche for their use in myeloid leukemia.

Experimental evidence for curcumin and its analogs for management of diabetes mellitus and its associated complications.

PubMed

Rivera-Mancía, Susana; Lozada-García, María Concepción; Pedraza-Chaverri, José

2015-06-05

Diabetes mellitus is a serious world health problem and one of the most studied diseases; a major concern about its treatment is that β-cell mass and functionality is hard to restore. In addition, it is frequently associated with severe complications, such as diabetic nephropathy and cardiomyopathy. The anti-inflammatory, anti-oxidative and anti-apoptotic properties of curcumin have made it a promising molecule for the treatment of this pathology; however, its solubility and bioavailability problems are still the subject of multiple studies. To cope with those difficulties, several approaches have been evaluated, such as the development of pharmaceutical formulations and curcumin analogs. This review discusses some of the studied therapeutic targets for curcumin in diabetes as well as the structural characteristics and targets of its analogs. The shortening of the central seven-carbon chain of curcumin has given rise to compounds without glucose-lowering effects but potentially useful for the treatment of diabetes complications; whereas preserving this chain retains the glucose-lowering properties. Most of the analogs discussed here have been recently synthesized and tested in animal models of type 1 diabetes; more studies in models of type 2 diabetes are needed. Copyright © 2015 Elsevier B.V. All rights reserved.

Discovery and evaluation of asymmetrical monocarbonyl analogs of curcumin as anti-inflammatory agents

PubMed Central

Zhang, Yali; Zhao, Chengguang; He, Wenfei; Wang, Zhe; Fang, Qilu; Xiao, Bing; Liu, Zhiguo; Liang, Guang; Yang, Shulin

2014-01-01

Sepsis is a systemic inflammatory response syndrome and is mainly caused by lipopolysaccharides (LPS) – a component of the cell walls of gram-negative bacteria, via toll-like receptor 4–mitogen-activated protein kinases/nuclear factor-kappa B-dependent proinflammatory signaling pathway. Here, we synthesized 26 asymmetric monocarbonyl analogs of curcumin and evaluated their anti-inflammatory activity by inhibiting the LPS-induced secretion of tumor necrosis factor-α and interleukin-6 in mouse RAW264.7 macrophages. Five active compounds (3a, 3c, 3d, 3j, and 3l) exhibited dose-dependent inhibition against the release of tumor necrosis factor-α and interleukin-6, and they also showed much higher chemical stability than curcumin in vitro. The anti-inflammatory activity of analogs 3a and 3c may be associated with their inhibition of the phosphorylation of extracellular signal-regulated kinase and the activation of nuclear factor-kappa B. In addition, 3c exhibited significant protection against LPS-induced septic death in vivo. These results indicate that asymmetrical monocarbonyl curcumin analogs may be utilized as candidates for the treatment of acute inflammatory diseases. PMID:24741294

Crystal structure of the unactivated ribulose 1,5-bisphosphate carboxylase/oxygenase complexed with a transition state analog, 2-carboxy-D-arabinitol 1,5-bisphosphate.

PubMed Central

Zhang, K. Y.; Cascio, D.; Eisenberg, D.

1994-01-01

The crystal structure of unactivated ribulose 1,5-bisphosphate carboxylase/oxygenase from Nicotiana tabacum complexed with a transition state analog, 2-carboxy-D-arabinitol 1,5-bisphosphate, was determined to 2.7 A resolution by X-ray crystallography. The transition state analog binds at the active site in an extended conformation. As compared to the binding of the same analog in the activated enzyme, the analog binds in a reverse orientation. The active site Lys 201 is within hydrogen bonding distance of the carboxyl oxygen of the analog. Loop 6 (residues 330-339) remains open and flexible upon binding of the analog in the unactivated enzyme, in contrast to the closed and ordered loop 6 in the activated enzyme complex. The transition state analog is exposed to solvent due to the open conformation of loop 6. PMID:8142899

Eye movements provide insight into individual differences in children's analogical reasoning strategies.

PubMed

Starr, Ariel; Vendetti, Michael S; Bunge, Silvia A

2018-05-01

Analogical reasoning is considered a key driver of cognitive development and is a strong predictor of academic achievement. However, it is difficult for young children, who are prone to focusing on perceptual and semantic similarities among items rather than relational commonalities. For example, in a classic A:B::C:? propositional analogy task, children must inhibit attention towards items that are visually or semantically similar to C, and instead focus on finding a relational match to the A:B pair. Competing theories of reasoning development attribute improvements in children's performance to gains in either executive functioning or semantic knowledge. Here, we sought to identify key drivers of the development of analogical reasoning ability by using eye gaze patterns to infer problem-solving strategies used by six-year-old children and adults. Children had a greater tendency than adults to focus on the immediate task goal and constrain their search based on the C item. However, large individual differences existed within children, and more successful reasoners were able to maintain the broader goal in mind and constrain their search by initially focusing on the A:B pair before turning to C and the response choices. When children adopted this strategy, their attention was drawn more readily to the correct response option. Individual differences in children's reasoning ability were also related to rule-guided behavior but not to semantic knowledge. These findings suggest that both developmental improvements and individual differences in performance are driven by the use of more efficient reasoning strategies regarding which information is prioritized from the start, rather than the ability to disengage from attractive lure items. Copyright © 2018 Elsevier B.V. All rights reserved.

Synthesis and analgesic activity of some quinazoline analogs of anpirtoline.

PubMed

Rádl, S; Hezky, P; Proska, J; Krejcí, I

2000-11-01

New condensed derivatives of anpirtoline, in which the pyridine ring is replaced with quinoline, quinazoline, 7-chloroquinoline, and 7-chloroquinazoline nuclei, have been synthesized. Their receptor binding profiles (5-HT1A, 5-HT1B) and analgesic activity (hot plate, acetic acid induced writhing) have been studied. The analgesic activity of compounds 4e-4g, and 4l are at least comparable to that of clinically used drugs flupirtine and tramadol under the same conditions.

A Stability-Indicating HPLC Method for the Determination of Nitrosylcobalamin (NO-Cbl), a Novel Vitamin B12 Analog.

PubMed

Dunphy, Michael J; Sysel, Annette M; Lupica, Joseph A; Griffith, Kristie; Sherrod, Taylor; Bauer, Joseph A

2014-04-01

Nitrosylcobalamin (NO-Cbl), a novel vitamin B 12 analog and anti-tumor agent, functions as a biologic 'Trojan horse', utilizing the vitamin B 12 transcobalamin II transport protein and cell surface receptor to specifically target cancer cells. a stability-indicating HPLC method was developed for the detection of NO-Cbl during forced degradation studies. This method utilized an ascentis ® RP-amide (150 mm × 4.6 mm, 5 μm) column at 35 °C with a mobile phase (1.0 mL min -1 ) combining a gradient of methanol and an acetate buffer at pH 6.0. Detection wavelengths of 450 and 254 nm were used to detect corrin and non-corrin-based products, respectively. NO-Cbl, synthesized from hydroxocobalamin and pure nitric oxide gas, was subjected to degradative stress conditions including oxidation, hydrolysis and thermal and radiant energy challenge. The method was validated by assessing linearity, accuracy, precision, detection and quantitation limits and robustness. The method was applied successfully for purity assessment of synthesized NO-Cbl and for the determination of NO-Cbl during kinetic studies in aqueous solution and in solid-state degradation assessments. This HPLC method is suitable for the separation of cobalamins in aqueous and methanolic solutions, for routine detection of NO-Cbl and for purity assessment of synthesized NO-Cbl. additionally, this method has potential application in identification and monitoring of diseases involving altered nitric oxide homeostasis where vitamin B 12 therapy is utilized to scavenge excess nitric oxide, subsequently resulting in the in vivo production of NO-Cbl.

A Stability-Indicating HPLC Method for the Determination of Nitrosylcobalamin (NO-Cbl), a Novel Vitamin B12 Analog

PubMed Central

Dunphy, Michael J.; Sysel, Annette M.; Lupica, Joseph A.; Griffith, Kristie; Sherrod, Taylor

2014-01-01

Nitrosylcobalamin (NO-Cbl), a novel vitamin B12 analog and anti-tumor agent, functions as a biologic ‘Trojan horse’, utilizing the vitamin B12 transcobalamin II transport protein and cell surface receptor to specifically target cancer cells. a stability-indicating HPLC method was developed for the detection of NO-Cbl during forced degradation studies. This method utilized an ascentis® RP-amide (150 mm × 4.6 mm, 5 μm) column at 35 °C with a mobile phase (1.0 mL min−1) combining a gradient of methanol and an acetate buffer at pH 6.0. Detection wavelengths of 450 and 254 nm were used to detect corrin and non-corrin-based products, respectively. NO-Cbl, synthesized from hydroxocobalamin and pure nitric oxide gas, was subjected to degradative stress conditions including oxidation, hydrolysis and thermal and radiant energy challenge. The method was validated by assessing linearity, accuracy, precision, detection and quantitation limits and robustness. The method was applied successfully for purity assessment of synthesized NO-Cbl and for the determination of NO-Cbl during kinetic studies in aqueous solution and in solid-state degradation assessments. This HPLC method is suitable for the separation of cobalamins in aqueous and methanolic solutions, for routine detection of NO-Cbl and for purity assessment of synthesized NO-Cbl. additionally, this method has potential application in identification and monitoring of diseases involving altered nitric oxide homeostasis where vitamin B12 therapy is utilized to scavenge excess nitric oxide, subsequently resulting in the in vivo production of NO-Cbl. PMID:24855323

Two New Long-period Giant Planets from the McDonald Observatory Planet Search and Two Stars with Long-period Radial Velocity Signals Related to Stellar Activity Cycles

NASA Astrophysics Data System (ADS)

Endl, Michael; Brugamyer, Erik J.; Cochran, William D.; MacQueen, Phillip J.; Robertson, Paul; Meschiari, Stefano; Ramirez, Ivan; Shetrone, Matthew; Gullikson, Kevin; Johnson, Marshall C.; Wittenmyer, Robert; Horner, Jonathan; Ciardi, David R.; Horch, Elliott; Simon, Attila E.; Howell, Steve B.; Everett, Mark; Caldwell, Caroline; Castanheira, Barbara G.

2016-02-01

We report the detection of two new long-period giant planets orbiting the stars HD 95872 and HD 162004 (ψ1 Dra B) by the McDonald Observatory planet search. The planet HD 95872b has a minimum mass of 4.6 {M}{{Jup}} and an orbital semimajor axis of 5.2 AU. The giant planet ψ1 Dra Bb has a minimum mass of 1.5 {M}{{Jup}} and an orbital semimajor axis of 4.4 AU. Both of these planets qualify as Jupiter analogs. These results are based on over one and a half decades of precise radial velocity (RV) measurements collected by our program using the McDonald Observatory Tull Coude spectrograph at the 2.7 m Harlan J. Smith Telescope. In the case of ψ1 Dra B we also detect a long-term nonlinear trend in our data that indicates the presence of an additional giant planet, similar to the Jupiter-Saturn pair. The primary of the binary star system, ψ1 Dra A, exhibits a very large amplitude RV variation due to another stellar companion. We detect this additional member using speckle imaging. We also report two cases—HD 10086 and HD 102870 (β Virginis)—of significant RV variation consistent with the presence of a planet, but that are probably caused by stellar activity, rather than reflexive Keplerian motion. These two cases stress the importance of monitoring the magnetic activity level of a target star, as long-term activity cycles can mimic the presence of a Jupiter-analog planet.

Pharmacological lineage analysis revealed the binding affinity of broad-spectrum substance P antagonists to receptors for gonadotropin-releasing peptide.

PubMed

Arai, Kazune; Kashiwazaki, Aki; Fujiwara, Yoko; Tsuchiya, Hiroyoshi; Sakai, Nobuya; Shibata, Katsushi; Koshimizu, Taka-aki

2015-02-15

A group of synthetic substance P (SP) antagonists, such as [Arg(6),D-Trp(7,9),N(Me)Phe(8)]-substance P(6-11) and [D-Arg(1),D-Phe(5),D-Trp(7,9),Leu(11)]-substance P, bind to a range of distinct G-protein-coupled receptor (GPCR) family members, including V1a vasopressin receptors, and they competitively inhibit agonist binding. This extended accessibility enabled us to identify a GPCR subset with a partially conserved binding site structure. By combining pharmacological data and amino acid sequence homology matrices, a pharmacological lineage of GPCRs that are sensitive to these two SP antagonists was constructed. We found that sensitivity to the SP antagonists was not limited to the Gq-protein-coupled V1a and V1b receptors; Gs-coupled V2 receptors and oxytocin receptors, which couple with both Gq and Gi, also demonstrated sensitivity. Unexpectedly, a dendrogram based on the amino acid sequences of 222 known GPCRs showed that a group of receptors sensitive to the SP antagonists are located in close proximity to vasopressin/oxytocin receptors. Gonadotropin-releasing peptide receptors, located near the vasopressin receptors in the dendrogram, were also sensitive to the SP analogs, whereas α1B adrenergic receptors, located more distantly from the vasopressin receptors, were not sensitive. Our finding suggests that pharmacological lineage analysis is useful in selecting subsets of candidate receptors that contain a conserved binding site for a ligand with broad-spectrum binding abilities. The knowledge that the binding site of the two broad-spectrum SP analogs partially overlaps with that of distinct peptide agonists is valuable for understanding the specificity/broadness of peptide ligands. Copyright © 2015 Elsevier B.V. All rights reserved.

Melanoma targeting with alpha-melanocyte stimulating hormone analogs labeled with fac-[99mTc(CO)3]+: effect of cyclization on tumor-seeking properties.

PubMed

Raposinho, Paula D; Xavier, Catarina; Correia, João D G; Falcão, Soraia; Gomes, Paula; Santos, Isabel

2008-03-01

Early detection of primary melanoma tumors is essential because there is no effective treatment for metastatic melanoma. Several linear and cyclic radiolabeled alpha-melanocyte stimulating hormone (alpha-MSH) analogs have been proposed to target the melanocortin type 1 receptor (MC1R) overexpressed in melanoma. The compact structure of a rhenium-cyclized alpha-MSH analog (Re-CCMSH) significantly enhanced its in vivo tumor uptake and retention. Melanotan II (MT-II), a cyclic lactam analog of alpha-MSH (Ac-Nle-cyclo[Asp-His-DPhe-Arg-Trp-Lys]-NH2]), is a very potent and stable agonist peptide largely used in the characterization of melanocortin receptors. Taking advantage of the superior biological features associated with the MT-II cyclic peptide, we assessed the effect of lactam-based cyclization on the tumor-seeking properties of alpha-MSH analogs by comparing the pharmacokinetics profile of the 99mTc-labeled cyclic peptide betaAla-Nle-cyclo[Asp-His-D-Phe-Arg-Trp-Lys]-NH2 with that of the linear analog betaAla-Nle-Asp-His-DPhe-Arg-Trp-Lys-NH2 in melanoma-bearing mice. We have synthesized and coupled the linear and cyclic peptides to a bifunctional chelator containing a pyrazolyl-diamine backbone (pz) through the amino group of betaAla, and the resulting pz-peptide conjugates were reacted with the fac-[99mTc(CO)3]+ moiety. The 99mTc(CO)3-labeled conjugates were obtained in high yield, high specific activity, and high radiochemical purity. The cyclic 99mTc(CO)3-labeled conjugate presents a remarkable internalization (87.1% of receptor-bound tracer and 50.5% of total applied activity, after 6 h at 37 degrees C) and cellular retention (only 24.7% released from the cells after 5 h) in murine melanoma B16F1 cells. A significant tumor uptake and retention was obtained in melanoma-bearing C57BL6 mice for the cyclic radioconjugate [9.26 +/- 0.83 and 11.31 +/- 1.83% ID/g at 1 and 4 h after injection, respectively]. The linear 99mTc(CO)3-pz-peptide presented lower values for both cellular internalization and tumor uptake. Receptor blocking studies with the potent (Nle4,DPhe7)-alphaMSH agonist demonstrated the specificity of the radioconjugates to MC1R (74.8 and 44.5% reduction of tumor uptake at 4 h after injection for cyclic and linear radioconjugates, respectively).

A Systematic Evaluation of Analogs and Automated Read ...

EPA Pesticide Factsheets

Read-across is a data gap filling technique widely used within category and analog approaches to predict a biological property for a data-poor (target) chemical using known information from similar (source analog) chemical(s). Potential source analogs are typically identified based on structural similarity. Although much guidance has been published for read-across, practical principles for the identification and evaluation of the scientific validity of source analogs remains lacking. This case study explores how well 3 structure descriptor sets (Pubchem, Chemotyper and MoSS) are able to identify analogs for read-across and predict Estrogen Receptor (ER) binding activity for a specific class of chemicals: hindered phenols. For each target chemical, analogs were selected using each descriptor set with two cut-offs: (1) Minimum Tanimoto similarity (range 0.1 - 0.9), and (2) Closest N analogs (range 1 - 10). Each target-analog pair was then evaluated for its agreement with measured ER binding and agonism. The analogs were subsequently filtered using: (1) physchem properties (LogKow & Molecular Volume), and (2) number of literature sources as a marker for the quality of the experimental data. A majority vote prediction was made for each target phenol by reading-across from the closest N analogs. The data set comprised 462 hindered phenols and 257 non-hindered phenols. The results demonstrate that: (1) The concordance in ER activity rises with increasing similarity,

Inhibition of RANKL- and LPS-induced osteoclast differentiations by novel NF-κB inhibitor DTCM-glutarimide.

PubMed

Koide, Naoki; Kaneda, Ayumi; Yokochi, Takashi; Umezawa, Kazuo

2015-03-01

We have isolated 9-methylstreptimidone from microorganism as a new NF-κB inhibitor. Later, we designed 3-[(dodecylthiocarbonyl) methyl]-glutarimide (DTCM-glutarimide) as an analog of this compound, which shows anti-inflammatory activity in vivo. In the present research, we found that DTCM-glutarimide inhibited receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclast differentiation of mouse bone marrow-derived macrophages and RANKL- or lipopolysaccharide (LPS)-induced osteoclast differentiation of RAW 264.7 cells without any toxicity. It also inhibited the RANKL-induced NFATc1 expression. Upstream signaling involving phosphorylation of Akt and GSK-3β was induced by RANKL, of which the signaling was inhibited by DTCM-glutarimide. Then DTCM-glutarimide was confirmed to inhibit RANKL-induced NF-κB activity, possibly by inhibiting the Akt-mediated activation of IKK. Thus, DTCM-glutarimide inhibited osteoclastogenesis by blocking both the Akt-GSK3β-NFATc1 and NF-κB-NFATc1 pathways. DTCM-glutarimide may be a candidate as a chemotherapeutic agent for severe bone resorption diseases. Copyright © 2015 Elsevier B.V. All rights reserved.

Isoform selectivity of harmine-conjugated 1,2,3-triazoles against human monoamine oxidase.

PubMed

Haider, Saqlain; Alhusban, Manal; Chaurasiya, Narayan D; Tekwani, Babu L; Chittiboyina, Amar G; Khan, Ikhlas A

2018-05-23

There is little information available on the monoamine oxidase isoform selectivity of N-alkyl harmine analogs, which exhibit a myriad of activities including monoamine oxidase isoform A (MAO-A), tyrosine-phosphorylation-regulated kinase (DYRK1A) and cytotoxicity to several select cancer cell lines. Compounds 3e and 4c exhibited an IC 50 of 0.83 ± 0.03 and 0.43 ± 0.002 μM against MAO-A and an IC 50 of 0.26 ± 0.04 and 0.36 ± 0.001 μM against MAO-B, respectively. Molecular docking studies revealed π-π interactions between the synthesized molecules and aromatic amino acid residues. Conclusion & future perspective: The current study delineates the structural requirements for MAO-A selectivity and such information may be helpful in designing selective analogs for kinase, DYRK1A and harmine-based cytotoxics without apparent MAO enzyme inhibition.

Extending Halogen-based Medicinal Chemistry to Proteins: IODO-INSULIN AS A CASE STUDY.

PubMed

El Hage, Krystel; Pandyarajan, Vijay; Phillips, Nelson B; Smith, Brian J; Menting, John G; Whittaker, Jonathan; Lawrence, Michael C; Meuwly, Markus; Weiss, Michael A

2016-12-30

Insulin, a protein critical for metabolic homeostasis, provides a classical model for protein design with application to human health. Recent efforts to improve its pharmaceutical formulation demonstrated that iodination of a conserved tyrosine (Tyr B26 ) enhances key properties of a rapid-acting clinical analog. Moreover, the broad utility of halogens in medicinal chemistry has motivated the use of hybrid quantum- and molecular-mechanical methods to study proteins. Here, we (i) undertook quantitative atomistic simulations of 3-[iodo-Tyr B26 ]insulin to predict its structural features, and (ii) tested these predictions by X-ray crystallography. Using an electrostatic model of the modified aromatic ring based on quantum chemistry, the calculations suggested that the analog, as a dimer and hexamer, exhibits subtle differences in aromatic-aromatic interactions at the dimer interface. Aromatic rings (Tyr B16 , Phe B24 , Phe B25 , 3-I-Tyr B26 , and their symmetry-related mates) at this interface adjust to enable packing of the hydrophobic iodine atoms within the core of each monomer. Strikingly, these features were observed in the crystal structure of a 3-[iodo-Tyr B26 ]insulin analog (determined as an R 6 zinc hexamer). Given that residues B24-B30 detach from the core on receptor binding, the environment of 3-I-Tyr B26 in a receptor complex must differ from that in the free hormone. Based on the recent structure of a "micro-receptor" complex, we predict that 3-I-Tyr B26 engages the receptor via directional halogen bonding and halogen-directed hydrogen bonding as follows: favorable electrostatic interactions exploiting, respectively, the halogen's electron-deficient σ-hole and electronegative equatorial band. Inspired by quantum chemistry and molecular dynamics, such "halogen engineering" promises to extend principles of medicinal chemistry to proteins. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

Why is the antipodal effect in closo-1-SB9H9 so large? A possible explanation based on the geometry from the concerted use of gas electron diffraction and computational methods.

PubMed

Hnyk, Drahomír; Wann, Derek A; Holub, Josef; Samdal, Svein; Rankin, David W H

2011-06-07

The molecular structure of 1-thia-closo-decaborane(9), 1-SB(9)H(9), has been determined by the concerted use of gas electron diffraction and quantum-chemical calculations. Assuming C(4v) symmetry, the cage structure was distorted from a symmetrically bicapped square antiprism (D(4d) symmetry) mainly through substantial expansion of the tetragonal belt of boron atoms adjacent to sulfur. The S-B and (B-B)(mean) distances are well determined with r(h1) = 193.86(14) and 182.14(8) pm, respectively. Geometrical parameters calculated using the MP2(full)/6-311++G** method and at levels reported earlier [MP2(full)/6-311G**, B3LYP/6-311G** and B3LYP/cc-pVQZ], as well as calculated vibrational amplitudes and (11)B NMR chemical shifts, are in good agreement with the experimental findings. In particular, the so-called antipodal chemical shift of apical B(10) (71.8 ppm) is reproduced well by the GIAO-MP2 calculations and its large magnitude is schematically accounted for, as is the analogous antipodal chemical shift of B(12) in the twelve-vertex closo-1-SB(11)H(11).

Determination of bisphenols in beverages by mixed-mode solid-phase extraction and liquid chromatography coupled to tandem mass spectrometry.

PubMed

Regueiro, Jorge; Wenzl, Thomas

2015-11-27

Facing growing restrictions on the use of bisphenol A in food contact materials, several bisphenol analogs are arising as major alternatives to replace this chemical in most of its applications. This work reports a simple and robust method based on mixed-mode solid-phase extraction and stable-isotope dilution liquid chromatography-tandem mass spectrometry for the analysis of bisphenol A and its main analogs - bisphenol S, 4,4'-sulfonylbis(2-methylphenol), bisphenol F, bisphenol E, bisphenol B, bisphenol Z, bisphenol AF, bisphenol AP, tetrabromobisphenol A and bisphenol P - in alcoholic and non-alcoholic beverages. Mixed-mode solid-phase extraction, combining cationic exchange and reversed-phase mechanisms, was optimized to provide a selective extraction and purification of the target analytes. Derivatization of bisphenols with pyridine-3-sulfonyl chloride allowed increasing their ionization efficiency by electrospray ionization. Validation of the proposed method was performed in terms of selectivity, matrix effects, linearity, precision, measurement uncertainty, trueness and limits of detection. Satisfactory repeatability and intermediate precision were obtained; the related relative standard deviations were ≤9% and ≤12%, respectively. The relative expanded uncertainty (k=2) was below 20% for all bisphenol analogs and the trueness of the method was demonstrated by recovery experiments. Limits of detection (LOD) ranged from 1.6ngL(-1) to 27.9ngL(-1) for all compounds. Finally, several canned and non-canned beverages were analyzed to demonstrate the applicability of the method. Only bisphenol A and three bisphenol F isomers were detected in any of the samples. Bisphenol A concentration ranged from

Generation of a novel artificial TrkB agonist, BM17d99, using T7 phage-displayed random peptide libraries.

PubMed

Ohnishi, Toshiyuki; Sakamoto, Kotaro; Asami-Odaka, Asano; Nakamura, Kimie; Shimizu, Ayako; Ito, Takashi; Asami, Taiji; Ohtaki, Tetsuya; Inooka, Hiroshi

2017-01-29

Tropomyosin receptor kinase B (TrkB) is a known receptor of brain-derived neurotrophic factor (BDNF). Because it plays a critical role in the regulation of neuronal development, maturation, survival, etc., TrkB is a good target for drugs against central nervous system diseases. In this study, we aimed to generate peptidic TrkB agonists by applying random peptide phage display technology. After the phage panning against recombinant Fc-fused TrkB (TrkB-Fc), agonistic phages were directly screened against TrkB-expressing HEK293 cells. Through subsequent screening of the first-hit BM17 peptide-derived focus library, we successfully obtained the BM17d99 peptide, which had no sequence similarity with BDNF but had TrkB-binding capacity. We then synthesized a dimeric BM17d99 analog peptide that could phosphorylate or activate TrkB by facilitating receptor homodimerization. Treatment of TrkB-expressing HEK293 cells with the dimeric BM17d99 analog peptide significantly induced the phosphorylation of TrkB, suggesting that homodimerization of TrkB was enhanced by the dimeric peptide. This report demonstrates that our approach is useful for the generation of artificial peptidic agonists of cell surface receptors. Copyright © 2016 Elsevier Inc. All rights reserved.

Organization of fluorescent cholesterol analogs in lipid bilayers - lessons from cyclodextrin extraction.

PubMed

Milles, Sigrid; Meyer, Thomas; Scheidt, Holger A; Schwarzer, Roland; Thomas, Lars; Marek, Magdalena; Szente, Lajos; Bittman, Robert; Herrmann, Andreas; Günther Pomorski, Thomas; Huster, Daniel; Müller, Peter

2013-08-01

To characterize the structure and dynamics of cholesterol in membranes, fluorescent analogs of the native molecule have widely been employed. The cholesterol content in membranes is in general manipulated by using water-soluble cyclodextrins. Since the interactions between cyclodextrins and fluorescent-labeled cholesterol have not been investigated in detail so far, we have compared the cyclodextrin-mediated membrane extraction of three different fluorescent cholesterol analogs (one bearing a NBD and two bearing BODIPY moieties). Extraction of these analogs was followed by measuring the Förster resonance energy transfer between a rhodamine moiety linked to phosphatidylethanolamine and the labeled cholesterol. The extraction kinetics revealed that the analogs are differently extracted from membranes. We examined the orientation of the analogs within the membrane and their influence on lipid condensation using NMR and EPR spectroscopies. Our data indicate that the extraction of fluorescent sterols from membranes is determined by several parameters, including their impact on lipid order, their hydrophobicity, their intermolecular interactions with surrounding lipids, their orientation within the bilayer, and their affinity with the exogenous acceptor. Copyright © 2013 Elsevier B.V. All rights reserved.

Neural underpinnings of divergent production of rules in numerical analogical reasoning.

PubMed

Wu, Xiaofei; Jung, Rex E; Zhang, Hao

2016-05-01

Creativity plays an important role in numerical problem solving. Although the neural underpinnings of creativity have been studied over decades, very little is known about neural mechanisms of the creative process that relates to numerical problem solving. In the present study, we employed a numerical analogical reasoning task with functional Magnetic Resonance Imaging (fMRI) to investigate the neural correlates of divergent production of rules in numerical analogical reasoning. Participants performed two tasks: a multiple solution analogical reasoning task and a single solution analogical reasoning task. Results revealed that divergent production of rules involves significant activations at Brodmann area (BA) 10 in the right middle frontal cortex, BA 40 in the left inferior parietal lobule, and BA 8 in the superior frontal cortex. The results suggest that right BA 10 and left BA 40 are involved in the generation of novel rules, and BA 8 is associated with the inhibition of initial rules in numerical analogical reasoning. The findings shed light on the neural mechanisms of creativity in numerical processing. Copyright © 2016 Elsevier B.V. All rights reserved.

Purine Analog-Like Properties of Bendamustine Underlie Rapid Activation of DNA Damage Response and Synergistic Effects with Pyrimidine Analogues in Lymphoid Malignancies

PubMed Central

Hiraoka, Nobuya; Kikuchi, Jiro; Yamauchi, Takahiro; Koyama, Daisuke; Wada, Taeko; Uesawa, Mitsuyo; Akutsu, Miyuki; Mori, Shigehisa; Nakamura, Yuichi; Ueda, Takanori; Kano, Yasuhiko; Furukawa, Yusuke

2014-01-01

Bendamustine has shown considerable clinical activity against indolent lymphoid malignancies as a single agent or in combination with rituximab, but combination with additional anti-cancer drugs may be required for refractory and/or relapsed cases as well as other intractable tumors. In this study, we attempted to determine suitable anti-cancer drugs to be combined with bendamustine for the treatment of mantle cell lymphoma, diffuse large B-cell lymphoma, aggressive lymphomas and multiple myeloma, all of which are relatively resistant to this drug, and investigated the mechanisms underlying synergism. Isobologram analysis revealed that bendamustine had synergistic effects with alkylating agents (4-hydroperoxy-cyclophosphamide, chlorambucil and melphalan) and pyrimidine analogues (cytosine arabinoside, gemcitabine and decitabine) in HBL-2, B104, Namalwa and U266 cell lines, which represent the above entities respectively. In cell cycle analysis, bendamustine induced late S-phase arrest, which was enhanced by 4-hydroperoxy-cyclophosphamide, and potentiated early S-phase arrest by cytosine arabinoside (Ara-C), followed by a robust increase in the size of sub-G1 fractions. Bendamustine was able to elicit DNA damage response and subsequent apoptosis faster and with shorter exposure than other alkylating agents due to rapid intracellular incorporation via equilibrative nucleoside transporters (ENTs). Furthermore, bendamustine increased the expression of ENT1 at both mRNA and protein levels and enhanced the uptake of Ara-C and subsequent increase in Ara-C triphosphate (Ara-CTP) in HBL-2 cells to an extent comparable with the purine analog fludarabine. These purine analog-like properties of bendamustine may underlie favorable combinations with other alkylators and pyrimidine analogues. Our findings may provide a theoretical basis for the development of more effective bendamustine-based combination therapies. PMID:24626203

Diverse Effects of Cyclosporine on Hepatitis C Virus Strain Replication

PubMed Central

Ishii, Naoto; Watashi, Koichi; Hishiki, Takayuki; Goto, Kaku; Inoue, Daisuke; Hijikata, Makoto; Wakita, Takaji; Kato, Nobuyuki; Shimotohno, Kunitada

2006-01-01

Recently, a production system for infectious particles of hepatitis C virus (HCV) utilizing the genotype 2a JFH1 strain has been developed. This strain has a high capacity for replication in the cells. Cyclosporine (CsA) has a suppressive effect on HCV replication. In this report, we characterize the anti-HCV effect of CsA. We observe that the presence of viral structural proteins does not influence the anti-HCV activity of CsA. Among HCV strains, the replication of genotype 1b replicons was strongly suppressed by treatment with CsA. In contrast, JFH1 replication was less sensitive to CsA and its analog, NIM811. Replication of JFH1 did not require the cellular replication cofactor, cyclophilin B (CyPB). CyPB stimulated the RNA binding activity of NS5B in the genotype 1b replicon but not the genotype 2a JFH1 strain. These findings provide an insight into the mechanisms of diversity governing virus-cell interactions and in the sensitivity of these strains to antiviral agents. PMID:16611911

Search for isobar-analog states of superheavy hydrogen isotopes5-7He

NASA Astrophysics Data System (ADS)

Chernyshev, B. A.; Gurov, Yu B.; Korotkova, L. Yu; Kuznetsov, D. S.; Lapushkin, S. V.; Tel'kushev, M. V.; Schurenkova, T. D.

2016-02-01

Search for isobar-analog states (IAS) of superheavy hydrogen isotopes 5-7H was performed among the high-excited states of helium isotopes 5-7He. The excited spectra were measured in stopped pion absorption by light nuclei. The experiment was performed at low energy pion channel of LANL with two-arm multilayer semiconductor spectrometer. Excited states of 5-7He were observed in three-body reaction channels on 10,11B nuclei. Several excited levels were observed for the first time. 6He excited state with Ex = 27.0(8) MeV observed in 10B(π-,pt)X channel is an IAS candidate for 6H with Er ∼ 5.5 MeV. 7He excited state with Ex = 24.8(4) MeV observed in 10B(π-,pd)X, nB(π-,pt)X and nB(π-,dd)X channels is an IAS candidate for 7H with Er ∼ 3 MeV.

RF Photonic Technology in Optical Fiber Links

NASA Astrophysics Data System (ADS)

Chang, William S. C.

2007-06-01

List of contributors; Introduction and preface; 1. Figures of merit and performance analysis of photonic microwave links Charles Cox and William S. C. Chang; 2. RF subcarrier links in local access networks Xiaolin Lu; 3. Analog modulation of semiconductor lasers Joachim Piprek and John E. Bowers; 4. LiNbO3 external modulators and their use in high performance analog links Gary E. Betts; 5. Broadband traveling wave modulators in LiNbO3 Marta M. Howerton and William K. Burns; 6. Multiple quantum well electroabsorption modulators for RF photonic links William S. C. Chang; 7. Polymer modulators for RF photonics Timothy Van Eck; 8. Photodiodes for high performance analog links P. K. L. Yu and Ming C. Wu; 9. Opto-electronic oscillators X. Steve Yao; 10. Photonic link techniques for microwave frequency conversion Stephen A. Pappert, Roger Helkey and Ronald T. Logan Jr; 11. Antenna-coupled millimeter-wave electro-optical modulators William B. Bridges; 12. System design and performance of wideband photonic phased array antennas Greg L. Tangonan, Willie Ng, Daniel Yap and Ron Stephens; Acknowledgements; References; Index.

Highly linear ring modulator from hybrid silicon and lithium niobate.

PubMed

Chen, Li; Chen, Jiahong; Nagy, Jonathan; Reano, Ronald M

2015-05-18

We present a highly linear ring modulator from the bonding of ion-sliced x-cut lithium niobate onto a silicon ring resonator. The third order intermodulation distortion spurious free dynamic range is measured to be 98.1 dB Hz(2/3) and 87.6 dB Hz(2/3) at 1 GHz and 10 GHz, respectively. The linearity is comparable to a reference lithium niobate Mach-Zehnder interferometer modulator operating at quadrature and over an order of magnitude greater than silicon ring modulators based on plasma dispersion effect. Compact modulators for analog optical links that exploit the second order susceptibility of lithium niobate on the silicon platform are envisioned.

Silicon photonic dynamic optical channel leveler with external feedback loop.

PubMed

Doylend, J K; Jessop, P E; Knights, A P

2010-06-21

We demonstrate a dynamic optical channel leveler composed of a variable optical attenuator (VOA) integrated monolithically with a defect-mediated photodiode in a silicon photonic waveguide device. An external feedback loop mimics an analog circuit such that the photodiode directly controls the VOA to provide blind channel leveling within +/-1 dB across a 7-10 dB dynamic range for wavelengths from 1530 nm to 1570 nm. The device consumes approximately 50 mW electrical power and occupies a 6 mm x 0.1 mm footprint per channel. Dynamic leveling is accomplished without tapping optical power from the output path to the photodiode and thus the loss penalty is minimized.

Snow survey and vegetation growth in the Swiss Alps

NASA Technical Reports Server (NTRS)

Haefner, H. (Principal Investigator)

1975-01-01

The author has identified the following significant results. Analog processing of S190A and B color and infrared color transparencies showed that it is possible to evaluate the courses of the temporary snow line and the upper limit of vegetation growth over large areas. By transferring the results from S190A onto a topo-map 1:200,000, an accuracy of + or - 50 m could be achieved. With S190B transferred onto a map 1:100,000, an accuracy of + or - 20 m was reached. Digital processing of S192 multispectral data allowed a separation of snow and clouds by combining the information from channels 9, 15, and 18.

Role of preoperative air-bone gap in tinnitus outcome after tympanoplasty for chronic otitis media with tinnitus.

PubMed

Kim, Hong Chan; Jang, Chul Ho; Kim, Young Yoon; Seong, Jong Yuap; Kang, Sung Hoon; Cho, Yong Beom

Previous reports indicated that middle ear surgery might partially improve tinnitus after surgery. However, until now, no influencing factor has been determined for tinnitus outcome after middle ear surgery. The purpose of this study was to investigate the association between preoperative air-bone gap and tinnitus outcome after tympanoplasty type I. Seventy-five patients with tinnitus who had more than 6 months of symptoms of chronic otitis media on the ipsilateral side that were refractory to medical treatment were included in this study. All patients were evaluated through otoendoscopy, pure tone/speech audiometer, questionnaire survey using the visual analog scale and the tinnitus handicap inventory for tinnitus symptoms before and 6 months after tympanoplasty. The influence of preoperative bone conduction, preoperative air-bone-gap, and postoperative air-bone-gap on tinnitus outcome after the operation was investigated. The patients were divided into two groups based on preoperative bone conduction of less than 25dB (n=50) or more than 25dB (n=25). The postoperative improvement of tinnitus in both groups showed statistical significance. Patients whose preoperative air-bone-gap was less than 15dB showed no improvement in postoperative tinnitus using the visual analog scale (p=0.889) and the tinnitus handicap inventory (p=0.802). However, patients whose preoperative air-bone-gap was more than 15dB showed statistically significant improvement in postoperative tinnitus using the visual analog scale (p<0.01) and the tinnitus handicap inventory (p=0.016). Postoperative change in tinnitus showed significance compared with preoperative tinnitus using visual analog scale (p=0.006). However, the correlation between reduction in the visual analog scale score and air-bone-gap (p=0.202) or between reduction in tinnitus handicap inventory score and air-bone-gap (p=0.290) was not significant. We suggest that the preoperative air-bone-gap can be a predictor of tinnitus outcome after tympanoplasty in chronic otitis media with tinnitus. Copyright © 2017 Associação Brasileira de Otorrinolaringologia e Cirurgia Cérvico-Facial. Published by Elsevier Editora Ltda. All rights reserved.

Glucagon-like peptide-1 exerts anti-inflammatory effects on mouse colon smooth muscle cells through the cyclic adenosine monophosphate/nuclear factor-κB pathway in vitro.

PubMed

Al-Dwairi, Ahmed; Alqudah, Tamara E; Al-Shboul, Othman; Alqudah, Mohammad; Mustafa, Ayman G; Alfaqih, Mahmoud A

2018-01-01

Intestinal smooth muscle cells (SMCs) undergo substantial morphological, phenotypic, and contractile changes during inflammatory bowel disease (IBD). SMCs act as a source and target for different inflammatory mediators, however their role in IBD pathogenesis is usually overlooked. Glucagon-like peptide-1 (GLP-1) is an incretin hormone reported to exert multiple anti-inflammatory effects in different tissues including the gastrointestinal tract through various mechanisms. The aim of this research is to explore the effect of GLP-1 analog exendin-4 on the expression and secretion of inflammatory markers from mouse colon smooth muscle cells (CSMCs) after stimulation with lipopolysaccharide (LPS). Freshly isolated CSMCs from male BALB/c mice were cultured in DMEM and treated with vehicle, LPS (1 μg/mL), LPS+exendin-4 (50 nM), or LPS+exendin-4 (100 nM) for 24 h. Expression of inflammatory cytokines was then evaluated by antibody array membrane. CSMCs showed basal expression of several cytokines which was enhanced with the induction of inflammation by LPS. However, exendin-4 (50 and 100 nM) significantly ( p <0.05) reduced the expression of multiple cytokines including tumor necrosis factor-α (TNF-α), interleukin-1α (IL-1α), T cell activation gene-3 (TCA-3), stromal cell-derived factor-1 (SDF-1), and macrophage colony stimulating factor (M-CSF). To confirm these results, expression of these cytokines was further assessed by enzyme-linked immunosorbent assay and real-time polymerase chain reaction and similar results were also observed. Moreover, secretion of TNF-α and IL1-α into the conditioned media was significantly downregulated by exendin-4 when compared to LPS-treated cells. Furthermore, LPS increased NF-κB phosphorylation, while exendin-4 significantly reduced levels of NF-κB phosphorylation. These data indicate that GLP-1 analogs can exert significant anti-inflammatory effects on CSMCs and can potentially be used as an adjunct treatment for inflammatory bowel conditions.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Michael, Alicia K.; Fribourgh, Jennifer L.; Chelliah, Yogarany

The basic helix-loop-helix PAS domain (bHLH-PAS) transcription factor CLOCK:BMAL1 (brain and muscle Arnt-like protein 1) sits at the core of the mammalian circadian transcription/translation feedback loop. Precise control of CLOCK:BMAL1 activity by coactivators and repressors establishes the ~24-h periodicity of gene expression. Formation of a repressive complex, defined by the core clock proteins cryptochrome 1 (CRY1):CLOCK:BMAL1, plays an important role controlling the switch from repression to activation each day. Here in this paper, we show that CRY1 binds directly to the PAS domain core of CLOCK: BMAL1, driven primarily by interaction with the CLOCK PAS-B domain. Integrative modeling and solutionmore » X-ray scattering studies unambiguously position a key loop of the CLOCK PAS-B domain in the secondary pocket of CRY1, analogous to the antenna chromophore-binding pocket of photolyase. CRY1 docks onto the transcription factor alongside the PAS domains, extending above the DNA-binding bHLH domain. Single point mutations at the interface on either CRY1 or CLOCK disrupt formation of the ternary complex, highlighting the importance of this interface for direct regulation of CLOCK:BMAL1 activity by CRY1.« less

Structural and functional similarities between a ribulose-1,5-bisphosphate carboxylase/oxygenase (RuBisCO)-like protein from Bacillus subtilis and photosynthetic RuBisCO.

PubMed

Saito, Yohtaro; Ashida, Hiroki; Sakiyama, Tomoko; de Marsac, Nicole Tandeau; Danchin, Antoine; Sekowska, Agnieszka; Yokota, Akiho

2009-05-08

The sequences classified as genes for various ribulose-1,5-bisphosphate (RuBP) carboxylase/oxygenase (RuBisCO)-like proteins (RLPs) are widely distributed among bacteria, archaea, and eukaryota. In the phylogenic tree constructed with these sequences, RuBisCOs and RLPs are grouped into four separate clades, forms I-IV. In RuBisCO enzymes encoded by form I, II, and III sequences, 19 conserved amino acid residues are essential for CO(2) fixation; however, 1-11 of these 19 residues are substituted with other amino acids in form IV RLPs. Among form IV RLPs, the only enzymatic activity detected to date is a 2,3-diketo-5-methylthiopentyl 1-phosphate (DK-MTP-1-P) enolase reaction catalyzed by Bacillus subtilis, Microcystis aeruginosa, and Geobacillus kaustophilus form IV RLPs. RLPs from Rhodospirillum rubrum, Rhodopseudomonas palustris, Chlorobium tepidum, and Bordetella bronchiseptica were inactive in the enolase reaction. DK-MTP-1-P enolase activity of B. subtilis RLP required Mg(2+) for catalysis and, like RuBisCO, was stimulated by CO(2). Four residues that are essential for the enolization reaction of RuBisCO, Lys(175), Lys(201), Asp(203), and Glu(204), were conserved in RLPs and were essential for DK-MTP-1-P enolase catalysis. Lys(123), the residue conserved in DK-MTP-1-P enolases, was also essential for B. subtilis RLP enolase activity. Similarities between the active site structures of RuBisCO and B. subtilis RLP were examined by analyzing the effects of structural analogs of RuBP on DK-MTP-1-P enolase activity. A transition state analog for the RuBP carboxylation of RuBisCO was a competitive inhibitor in the DK-MTP-1-P enolase reaction with a K(i) value of 103 mum. RuBP and d-phosphoglyceric acid, the substrate and product, respectively, of RuBisCO, were weaker competitive inhibitors. These results suggest that the amino acid residues utilized in the B. subtilis RLP enolase reaction are the same as those utilized in the RuBisCO RuBP enolization reaction.

Correlational approach to turbulent saturated film boiling

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chu, T.Y.

A correlation method for saturated film boiling is proposed. The correlation is based on the analogy between film boiling and natural convection. As in the case of natural convection, the turbulent film boiling correlation takes the form of a Nusselt number versus the Raleigh number power law, Nu[sub B] [proportional to] Ra[sub B][sup 1.3]. The proposed correlation shows very good agreement with current data for film boiling of water from vertical surfaces. The general applicability of the correlation is established by comparisons with film boiling data from R-113 and cryogenic fluids. 25 refs., 8 figs.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kuvin, S. A.; Wuosmaa, A. H.; Lister, C. J.

Here, the rate of the T=1, 2+ to T=1, 0 + transition in 10B ( T=1, T z=0) is compared to the analog transitions in 10Be ( T=1, T z=–1) and 10C ( T=1, T z=+1) to provide constraints on ab initio calculations using realistic nuclear forces. The relevant state in 10B, at E x=5.164 MeV, is particle unbound. Therefore, a determination of the B( E2) electromagnetic transition rate requires a precise and accurate determination of the width of the state, as well as the α-particle and γ-ray branching ratios. Previous measurements of the α-particle branching ratio are just barelymore » in agreement. We report on a new study of the α-particle branch by studying the 10B(p,p') 10B* reaction in inverse kinematics with the HELIOS spectrometer. The α-particle branching ratio that we observe, 0.144±0.027, is in good agreement with the evaluated value and improves the associated uncertainty. The resulting experimental B( E2) value is 7.0±2.2 e 2fm 4 and is more consistent with a flat trend across the A=10 triplet than previously reported. This is inconsistent with Green's function Monte Carlo predictions using realistic three-nucleon Hamiltonians, which overpredict the B(E2) value in 10C and 10B.« less

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kuvin, S. A.; Wuosmaa, A. H.; Lister, C. J.

The rate of the T = 1, 2(+) to T = 1, 0(+) transition in B-10 (T = 1, T-z = 0) is compared to the analog transitions in Be-10 (T = 1, T-z = -1) and C-10 (T = 1, T-z = +1) to provide constraints on ab initio calculations using realistic nuclear forces. The relevant state in B-10, at E-x = 5.164 MeV, is particle unbound. Therefore, a determination of the B(E2) electromagnetic transition rate requires a precise and accurate determination of the width of the state, as well as the alpha-particle and gamma-ray branching ratios. Previous measurementsmore » of the a-particle branching ratio are just barely in agreement. We report on a new study of the alpha-particle branch by studying the B-10(p, p') B-10* reaction in inverse kinematics with the HELIOS spectrometer. The alpha-particle branching ratio that we observe, 0.144 +/- 0.027, is in good agreement with the evaluated value and improves the associated uncertainty. The resulting experimental B(E2) value is 7.0 +/- 2.2 e(2)fm(4) and is more consistent with a flat trend across the A = 10 triplet than previously reported. This is inconsistent with Green's functionMonte Carlo predictions using realistic three-nucleon Hamiltonians, which overpredict the B(E2) value in C-10 and B-10.« less

A structure-function study of PACAP using conformationally-restricted analogs: identification of PAC1 receptor-selective PACAP agonists

PubMed Central

Ramos-Álvarez, Irene; Mantey, Samuel A.; Nakamura, Taichi; Nuche-Berenguer, Bernardo; Moreno, Paola; Moody, Terry W.; Maderdrut, Jerome L.; Coy, David H.; Jensen, Robert T.

2015-01-01

Pituitary adenylate-cyclase-activating polypeptide (PACAP) has widespread physiological/pathophysiological actions and there is increased interest for its use therapeutically, especially in the CNS (neuroprotection). Unfortunately, no selective PACAP-analogs exist for PACAP-preferring PAC1-receptors, primarily because of its high sequence identity to VIP and particularly, because of the inability of structure-function studies to separate the pharmacophore of PAC1-R from VPAC1-R, which has high affinity for PACAP and VIP. The present study attempted to develop PAC1-R-selective agonists primarily by making conformationally-restricted PACAP -analogs in positions important for receptor-selectivity/affinity. Forty-six PACAP-related-analogs were synthesized with substitutions in positions 1–4, 14–17, 20–22 ,28,34,38 and receptor-selectivity determined in PAC1-R,VPAC1-R,VPAC2-R-transfected or native cells from binding or cAMP-generation experiments. Fifteen PACAP-analogs had 6–78-fold higher affinities for PAC1-R than VPAC1-R and 13 were agonists. Although binding-affinities correlated significantly with agonist potency, the degree of receptor-spareness varied markedly for the different PACAP-analogs, resulting in selective potencies for activating the PAC1 receptor over the VPAC1 receptor from 0- to-103-fold. In addition, a number of PACAP-analogs were identified that had high selectivity for PAC1-R over VPAC2-R as well as PACAP-analogs that could prove more useful therapeutically because of substitutions known to extend their half-lives (substitutions at potential sites of proteolysis and attachment of long-chain fatty acids). This study provides for the first time a separation of the pharmacophores for PAC1-R and VPAC1-R, resulting in PACAP-related analogs that are PAC1-R-preferring. Some of these analogs, or their modifications, could prove useful as therapeutic agents for various diseases. PMID:25698233

Soviet Defense Spending: The Spartan Analogy

DTIC Science & Technology

1989-10-01

with Plutarch , Life of Lycurgus, xii, 5. Xenophon, The Lacedwncnian Constitution, xiv, 4, is the source for the ban on foreigners and the illegality...result of the I1 Plutarch (Lyc. viii, 3; cf. xvi, 1) claims that in the initial land distribution, 9,000 plots were set aside for the honoioi, although...715 B.C.) by Sparta, which enslaved them and occupied their land. 16 141n Moralia (239de), Plutarch mentioned the "rent" (apophora) that the helots had

Two new compounds from the fruits of Arctium lappa.

PubMed

He, Jun; Huang, Xiao-Ying; Yang, Ya-Nan; Feng, Zi-Ming; Jiang, Jian-Shuang; Zhang, Pei-Cheng

2016-05-01

Phytochemical investigation of the extract of Arctii Fructus led to the isolation and characterization of two new compounds, named arctiisesquineolignan B (1) and arctiiphenolglycoside A (2). Their structures were elucidated by means of spectroscopic methods (UV, IR, HR-ESI-MS, 1D and 2D NMR) and chemical evidence, as well as by comparison with known analogs in the literature. Compound 2 exhibited stronger antioxidant activity than the positive control ascorbic acid at a concentration of 10 μM.

New inhibitors of colony spreading in Bacillus subtilis and Bacillus anthracis.

PubMed

Hao, Xin; Nguyen, Tam; Kearns, Daniel B; Arpin, Carolynn C; Fall, Ray; Sammakia, Tarek

2011-09-15

We have recently characterized sliding motility in Bacillus subtilis strains that lack functional flagella, and here describe the discovery of inhibitors of colony spreading in these strains as well as the aflagellate pathogen, Bacillus anthracis. Aflagellate B. subtilis strains were used to screen for new types of antibacterials that might inhibit colony spreading on semi-solid media. From a diverse set of organic structures, p-nitrophenylglycerol (NPG), an agent used primarily in clinical laboratories to control Proteus swarming, was found to inhibit colony spreading. The four stereoisomers of NPG were synthesized and tested, and only the 1R,2S-(1R-anti) and 1R,2R-(1R-syn) NPG isomers had significant activity in a quantitative colony-spreading assay. Twenty-six NPG analogs and related structures were synthesized and tested to identify more active inhibitors. p-Methylsulfonylphenylglycerol (p-SPG), but not its ortho or meta analogs, was found to be the most effective of these compounds, and synthesis and testing of all four p-SPG stereoisomers showed that the 1R-anti-isomer was the most active with an average IC(50) of 16 μM (3-5 μg mL(-1)). For B. anthracis, the colony-spreading IC(50) values for 1R-anti-SPG and 1R-anti-NPG are 12 μM (2-4 μg mL(-1)) and >150 μM, respectively. For both Bacillus species tested, 1R-anti-SPG inhibits colony spreading of surface cultures on agar plates, but is not bacteriostatic or bacteriocidal in liquid cultures. Work is in progress to find the cellular target(s) of the NPG/SPG class of compounds, since this could lead to an understanding of the mechanism(s) of colony spreading as well as design and development of more potent inhibitors for the control of B. anthracis surface cultures. Copyright © 2011 Elsevier Ltd. All rights reserved.

Corticotropin-releasing factor peptide antagonists: design, characterization and potential clinical relevance.

PubMed

Rivier, Jean E; Rivier, Catherine L

2014-04-01

Elusive for more than half a century, corticotropin-releasing factor (CRF) was finally isolated and characterized in 1981 from ovine hypothalami and shortly thereafter, from rat brains. Thirty years later, much has been learned about the function and localization of CRF and related family members (Urocortins 1, 2 and 3) and their 2 receptors, CRF receptor type 1 (CRFR1) and CRF receptor type 2 (CRFR2). Here, we report the stepwise development of peptide CRF agonists and antagonists, which led to the CRFR1 agonist Stressin1; the long-acting antagonists Astressin2-B which is specific for CRFR2; and Astressin B, which binds to both CRFR1 and CRFR2.This analog has potential for the treatment of CRF-dependent diseases in the periphery, such as irritable bowel syndrome. Copyright © 2013 Elsevier Inc. All rights reserved.

Impacts of the N-terminal fragment analog of human parathyroid hormone on structure, composition and biomechanics of bone.

PubMed

Chunxiao, Wang; Yu, Zhang; Wentao, Liu; Jingjing, Liu; Jiahui, Ye; Qingmei, Chen

2012-12-18

Osteoporosis is a skeletal disease characterized by low bone mass and microarchitectural deterioration of bone tissue, and it is a serious threat to human lives. We previously showed that the N-terminal peptide analog of human parathyroid hormone (Pro-Pro-PTH(1-34)) enhanced plasma calcium concentration. In this paper, we study the impact of PTH N-terminal fragment analog on the structure, component, and mechanical properties of the rat bones. Daily subcutaneous injections of Pro-Pro-hPTH (1-34) induces 26.5-32.8% increase in femur bone mineral density (BMD), 23.0-34.2% decrease the marrow cavity or increase in trabecular bone area. The peptide also increases 16.0-59.5%, 28.8-48.2% and 14.0-17.8% of bone components of calcium, phosphorus and collagen, respectively. In terms of mechanic properties, administration of the peptide elevates the bone rigidity by 45.4-76.6%, decreases the flexibility by 23.0-31.6%, and improves modulus of elasticity by 32.8-63.4%. The results suggest that Pro-Pro-hPTH (1-34) has a positive effect on bone growth and strength, and possesses anti-fracture capability, thus a potential candidate for the application for the treatment of osteoporosis. Copyright © 2012 Elsevier B.V. All rights reserved.

A Systematic Evaluation of Analogs for the Read-across ...

EPA Pesticide Factsheets

Read-across is a data gap filling technique widely used within category and analog approaches to predict a biological property for a target data-poor chemical using known information from similar (source analog) chemical(s). Potential source analogs are typically identified based on structural similarity. Although much guidance has been published for read-across, practical guiding principles for the identification and evaluation of the scientific validity of source analogs, which is a critical step in deriving a robust read-across prediction, remains largely lacking.This case study explores the extent to which 3 structure descriptor sets (Pubchem, Chemotyper and MoSS) and their combinations are able to identify valid analogs for reading across Estrogen Receptor (ER) activity for a specific class of chemicals: hindered phenols. For each target chemical, two sets of analogs (hindered and non-hindered phenols) were selected using each descriptor set with two cut-offs: (1). Minimum Tanimoto similarity (range 0.1 - 0.9), and (2). Closest N analogs (range 1 - 10). Each target-analog pair was then evaluated for its agreement with measured ER binding and agonism. Subsequently, the analogs were filtered using physchem properties (LogKow & Molecular Volume) and the resultant agreement between each target-analog pair was evaluated. The data set comprised 462 hindered phenols and 296 non-hindered phenols. The results demonstrate that: (1). The concordance in ER activity r

Formation of [b3 - 1 + cat]+ ions from metal-cationized tetrapeptides containing beta-alanine, gamma-aminobutyric acid or epsilon-aminocaproic acid residues.

PubMed

Osburn, Sandra M; Ochola, Sila O; Talaty, Erach R; Van Stipdonk, Michael J

2008-11-01

The presence and position of a single beta-alanine (betaA), gamma-aminobutyric acid (gammaABu) or epsilon-aminocaproic acid (Cap) residue has been shown to have a significant influence on the formation of b(n)+ and y(n)+ product ions from a series of model, protonated peptides. In this study, we examined the effect of the same residues on the formation of analogous [b3 - 1 + cat]+ products from metal (Li+, Na+ and Ag+)-cationized peptides. The larger amino acids suppress formation of b3+ from protonated peptides with general sequence AAXG (where X = beta-alanine, gamma-aminobutyric acid or epsilon-aminocaproic acid), presumably because of the prohibitive effect of larger cyclic intermediates in the 'oxazolone' pathway. However, abundant [b3 - 1 + cat]+ products are generated from metal-cationized versions of AAXG. Using a group of deuterium-labeled and exchanged peptides, we found that formation of [b3 - 1 + cat]+ involves transfer of either amide or alpha-carbon position H atoms, and the tendency to transfer the atom from the alpha-carbon position increases with the size of the amino acid in position X. To account for the transfer of the H atom, a mechanism involving formation of a ketene product as [b3 - 1 + cat]+ is proposed.

Structure of ThiM from Vitamin B1 biosynthetic pathway of Staphylococcus aureus - Insights into a novel pro-drug approach addressing MRSA infections

NASA Astrophysics Data System (ADS)

Drebes, Julia; Künz, Madeleine; Windshügel, Björn; Kikhney, Alexey G.; Müller, Ingrid B.; Eberle, Raphael J.; Oberthür, Dominik; Cang, Huaixing; Svergun, Dmitri I.; Perbandt, Markus; Betzel, Christian; Wrenger, Carsten

2016-03-01

Infections caused by the methicillin-resistant Staphylococcus aureus (MRSA) are today known to be a substantial threat for global health. Emerging multi-drug resistant bacteria have created a substantial need to identify and discover new drug targets and to develop novel strategies to treat bacterial infections. A promising and so far untapped antibiotic target is the biosynthesis of vitamin B1 (thiamin). Thiamin in its activated form, thiamin pyrophosphate, is an essential co-factor for all organisms. Therefore, thiamin analogous compounds, when introduced into the vitamin B1 biosynthetic pathway and further converted into non-functional co-factors by the bacterium can function as pro-drugs which thus block various co-factor dependent pathways. We characterized one of the key enzymes within the S. aureus vitamin B1 biosynthetic pathway, 5-(hydroxyethyl)-4-methylthiazole kinase (SaThiM; EC 2.7.1.50), a potential target for pro-drug compounds and analyzed the native structure of SaThiM and complexes with the natural substrate 5-(hydroxyethyl)-4-methylthiazole (THZ) and two selected substrate analogues.

A Proposal of B to B Collaboration Process Model based on a Concept of Service and its Application to Energy Saving Service Business

NASA Astrophysics Data System (ADS)

Zhang, Qi; Kosaka, Michitaka; Shirahada, Kunio; Yabutani, Takashi

This paper proposes a new framework for B to B collaboration process based on a concept of service. Service value, which gives users satisfaction for provided services, depends on the situation, user characteristics, and user objectives in seeking the service. Vargo proposed Service Dominant Logic (SDL), which determines service value according to “value in use”. This concept illustrates the importance of the relationship between the service itself and its situation. This relationship is analogous to electro-magnetic field theory in physics. We developed the concept of service fields to create service value based on an analogy of the electro-magnetic field. By applying this concept to B to B collaboration, a model of service value co-creation in the collaboration can be formulated. Then, the collaboration can be described by 4 steps of KIKI model (Knowledge sharing related to service system, Identification of service field, Knowledge creation for new service idea, Implementation of service idea). As its application to B to B collaboration, the energy saving service business is reported to demonstrate the validity of the proposed collaboration model. This concept can be applied to make a collaboration process effective.

Artifacts in Radar Imaging of Moving Targets

DTIC Science & Technology

2012-09-01

CA, USA, 2007. [11] B. Borden, Radar imaging of airborne targets: A primer for Applied mathematicians and Physicists . New York, NY: Taylor and... Project (0704–0188) Washington DC 20503. 1. AGENCY USE ONLY (Leave blank) 2. REPORT DATE 21 September 2012 3. REPORT TYPE AND DATES COVERED...CW Continuous Wave DAC Digital to Analog Convertor DFT Discrete Fourier Transform FBP Filtered Back Projection FFT Fast Fourier Transform GPS

Evaluation of DCS III Transmission Alternatives, Phase 1B.

DTIC Science & Technology

1980-09-30

Most commonly used measure are straight and precision tubing, dielectric lining, and helix construction. These measures make the millimeter waveguide...channel tran- sistorized and microprocessor-controlled L5E. The broadband signal, either analog or digital, can be transmitted over a coaxial cable...kilowatts. One kind of mm source is travelling wave tubes ( TWT ) which are currently under development in the frequency range from 20 to 50 GHz with

On Wave-Ice Interaction in the Arctic Marginal Ice Zone: Dispersion, Attenuation, and Ice Response

DTIC Science & Technology

2016-06-01

PROJECT NUMBER 5e. TASK NUMBER 5f. WORK UNIT NUMBER 2. REPORT TYPE1. REPORT DATE (DD-MM-YYYY) 4. TITLE AND SUBTITLE 6. AUTHOR(S) 8. PERFORMING...schemes and contributes to a change of wave height (and direction) analogous to shoaling and refraction. A method for jointly measuring dispersion and...46 APPENDEX B: WAVE HEIGHTS MEASURED IN ARTIC ICE

Pneumatically Modulated Liquid Delivery System for Nebulizers

DTIC Science & Technology

2011-12-02

VII. Acknowledgements 18 APPENDIX A: Complete Parts List 19 APPENDIX B: Source code for the Arduino Uno microcontroller (CD) 23 1 I...implemented. The Arduino Uno is a well-established hobbyist microcontroller, focused on ease-of-use and teaching non-computer programmers about embedded...circuits. The Arduino Uno uses an Atmega328 microcontroller with thirteen digital TTL control lines, six 10-bit resolution 0-5 V analog inputs, TTL

An Over 90 dB Intra-Scene Single-Exposure Dynamic Range CMOS Image Sensor Using a 3.0 μm Triple-Gain Pixel Fabricated in a Standard BSI Process.

PubMed

Takayanagi, Isao; Yoshimura, Norio; Mori, Kazuya; Matsuo, Shinichiro; Tanaka, Shunsuke; Abe, Hirofumi; Yasuda, Naoto; Ishikawa, Kenichiro; Okura, Shunsuke; Ohsawa, Shinji; Otaka, Toshinori

2018-01-12

To respond to the high demand for high dynamic range imaging suitable for moving objects with few artifacts, we have developed a single-exposure dynamic range image sensor by introducing a triple-gain pixel and a low noise dual-gain readout circuit. The developed 3 μm pixel is capable of having three conversion gains. Introducing a new split-pinned photodiode structure, linear full well reaches 40 ke - . Readout noise under the highest pixel gain condition is 1 e - with a low noise readout circuit. Merging two signals, one with high pixel gain and high analog gain, and the other with low pixel gain and low analog gain, a single exposure dynamic rage (SEHDR) signal is obtained. Using this technology, a 1/2.7", 2M-pixel CMOS image sensor has been developed and characterized. The image sensor also employs an on-chip linearization function, yielding a 16-bit linear signal at 60 fps, and an intra-scene dynamic range of higher than 90 dB was successfully demonstrated. This SEHDR approach inherently mitigates the artifacts from moving objects or time-varying light sources that can appear in the multiple exposure high dynamic range (MEHDR) approach.

A Fast Multiple Sampling Method for Low-Noise CMOS Image Sensors With Column-Parallel 12-bit SAR ADCs.

PubMed

Kim, Min-Kyu; Hong, Seong-Kwan; Kwon, Oh-Kyong

2015-12-26

This paper presents a fast multiple sampling method for low-noise CMOS image sensor (CIS) applications with column-parallel successive approximation register analog-to-digital converters (SAR ADCs). The 12-bit SAR ADC using the proposed multiple sampling method decreases the A/D conversion time by repeatedly converting a pixel output to 4-bit after the first 12-bit A/D conversion, reducing noise of the CIS by one over the square root of the number of samplings. The area of the 12-bit SAR ADC is reduced by using a 10-bit capacitor digital-to-analog converter (DAC) with four scaled reference voltages. In addition, a simple up/down counter-based digital processing logic is proposed to perform complex calculations for multiple sampling and digital correlated double sampling. To verify the proposed multiple sampling method, a 256 × 128 pixel array CIS with 12-bit SAR ADCs was fabricated using 0.18 μm CMOS process. The measurement results shows that the proposed multiple sampling method reduces each A/D conversion time from 1.2 μs to 0.45 μs and random noise from 848.3 μV to 270.4 μV, achieving a dynamic range of 68.1 dB and an SNR of 39.2 dB.

Nine color eleven parameter immunophenotyping using three laser flow cytometry.

PubMed

Bigos, M; Baumgarth, N; Jager, G C; Herman, O C; Nozaki, T; Stovel, R T; Parks, D R; Herzenberg, L A

1999-05-01

This study describes a three laser flow cytometer, reagents, and software used to simultaneously evaluate nine distinct fluorescent parameters on one cell sample. We compare the quality of data obtained with (1) full software compensation and (2) the use of partial spectral compensation of selected pairs of parameters in analog hardware, in combination with final software compensation. An application characterizing low frequency murine B cell subpopulations is given. The fluorochromes used are: fluorescein (FITC), phycoerythrin (PE), Cy5PE and Cy7PE, excited at 488 nm by an argon laser; Texas Red (TR), allophycocyanin (APC), and Cy7APC excited at 595 nm by a pumped dye laser; and cascade blue (CB) and cascade yellow (CY) excited at 407 nm by a violet-enhanced krypton laser. Custom additions to commercial electronics and an extended optical bench allow the measurement of these nine parameters plus forward and side scatter light signals. We find the use of partial analog compensation reduces the variation in the background staining levels introduced by the compensation process. Novel B cell populations with frequencies below 1% are characterized. Nine color flow cytometry is capable of providing measurements with high information content. The choice of reagent-dye combinations and the ability to compensate in multi-parameter measurement space are crucial to obtaining satisfactory results.

An Over 90 dB Intra-Scene Single-Exposure Dynamic Range CMOS Image Sensor Using a 3.0 μm Triple-Gain Pixel Fabricated in a Standard BSI Process †

PubMed Central

Takayanagi, Isao; Yoshimura, Norio; Mori, Kazuya; Matsuo, Shinichiro; Tanaka, Shunsuke; Abe, Hirofumi; Yasuda, Naoto; Ishikawa, Kenichiro; Okura, Shunsuke; Ohsawa, Shinji; Otaka, Toshinori

2018-01-01

To respond to the high demand for high dynamic range imaging suitable for moving objects with few artifacts, we have developed a single-exposure dynamic range image sensor by introducing a triple-gain pixel and a low noise dual-gain readout circuit. The developed 3 μm pixel is capable of having three conversion gains. Introducing a new split-pinned photodiode structure, linear full well reaches 40 ke−. Readout noise under the highest pixel gain condition is 1 e− with a low noise readout circuit. Merging two signals, one with high pixel gain and high analog gain, and the other with low pixel gain and low analog gain, a single exposure dynamic rage (SEHDR) signal is obtained. Using this technology, a 1/2.7”, 2M-pixel CMOS image sensor has been developed and characterized. The image sensor also employs an on-chip linearization function, yielding a 16-bit linear signal at 60 fps, and an intra-scene dynamic range of higher than 90 dB was successfully demonstrated. This SEHDR approach inherently mitigates the artifacts from moving objects or time-varying light sources that can appear in the multiple exposure high dynamic range (MEHDR) approach. PMID:29329210

Crystal structure of botulinum neurotoxin type A in complex with the cell surface co-receptor GT1b-insight into the toxin-neuron interaction.

PubMed

Stenmark, Pål; Dupuy, Jérôme; Imamura, Akihiro; Kiso, Makoto; Stevens, Raymond C

2008-08-15

Botulinum neurotoxins have a very high affinity and specificity for their target cells requiring two different co-receptors located on the neuronal cell surface. Different toxin serotypes have different protein receptors; yet, most share a common ganglioside co-receptor, GT1b. We determined the crystal structure of the botulinum neurotoxin serotype A binding domain (residues 873-1297) alone and in complex with a GT1b analog at 1.7 A and 1.6 A, respectively. The ganglioside GT1b forms several key hydrogen bonds to conserved residues and binds in a shallow groove lined by Tryptophan 1266. GT1b binding does not induce any large structural changes in the toxin; therefore, it is unlikely that allosteric effects play a major role in the dual receptor recognition. Together with the previously published structures of botulinum neurotoxin serotype B in complex with its protein co-receptor, we can now generate a detailed model of botulinum neurotoxin's interaction with the neuronal cell surface. The two branches of the GT1b polysaccharide, together with the protein receptor site, impose strict geometric constraints on the mode of interaction with the membrane surface and strongly support a model where one end of the 100 A long translocation domain helix bundle swing into contact with the membrane, initiating the membrane anchoring event.

Enterovirus inhibitory activity of C-8-tert-butyl substituted 4-aryl-6,7,8,9-tetrahydrobenzo[4,5]thieno[3,2-e][1,2,4]triazolo[4,3-a]pyrimidin-5(4H)-ones.

PubMed

Kumar Biswas, Bishyajit; Malpani, Yashwardhan R; Ha, Neul; Kwon, Do-Hyun; Soo Shin, Jin; Kim, Hae-Soo; Kim, Chonsaeng; Bong Han, Soo; Lee, Chong-Kyo; Jung, Young-Sik

2017-08-01

Members of a series of 4-aryl-6,7,8,9-tetrahydrobenzo[4,5]thieno[3,2-e][1,2,4]triazolo[4,3-a]pyrimidin-5(4H)-ones (1, Fig. 2) were prepared and tested against representative enteroviruses including Human Coxsackievirus B1 (Cox B1), Human Coxsackievirus B3 (Cox B3), human Poliovirus 3 (PV3), human Rhinovirus 14 (HRV14), human Rhinovirus 21 (HRV 21) and human Rhinovirus 71 (HRV 71). The C-8-tert-butyl group on the tetrahydrobenzene ring in these substances was found to be crucial for their enterovirus activity. One member of this group, 1e, showed single digit micromolar activities (1.6-8.85μM) against a spectrum of viruses screened, and the highest selectivity index (SI) values for Cox B1 (>11.2), for Cox B3 (>11.5), and for PV3 (>51.2), respectively. In contrast, 1p, was the most active analog against the selected HRVs (1.8-2.6μM), and showed the highest selectivity indices among the group of compounds tested. The SI values for 1p were 11.5 for HRV14, 8.4 for HRV21, and 12.1 for HRV71, respectively. Copyright © 2017 Elsevier Ltd. All rights reserved.

Clinical and pharmacogenomic data mining: 1. Generalized theory of expected information and application to the development of tools.

PubMed

Robson, Barry

2003-01-01

New scientific problems, arising from the human genome project, are challenging the classical means of using statistics. Yet quantified knowledge in the form of rules and rule strengths based on real relationships in data, as opposed to expert opinion, is urgently required for researcher and physician decision support. The problem is that with many parameters, the space to be analyzed is highly dimensional. That is, the combinations of data to examine are subject to a combinatorial explosion as the number of possible events (entries, items, sub-records) (a),(b),(c),... per record (a,b,c,..) increases, and hence much of the space is sparsely populated. These combinatorial considerations are particularly problematic for identifying those associations called "Unicorn Events" which occur significantly less than expected to the extent that they are never seen to be counted. To cope with the combinatorial explosion, a novel numerical "book keeping" approach is taken to generate information terms relating to the combinatorial subsets of events (a,b,c,..), and, most importantly, the zeta (Zeta) function is employed. The incomplete Zeta function zeta(s,n) with s = 1, in which frequencies of occurrence such as n = n(a,b,c,...) determine the range of summation n, is argued to be the natural choice of information function. It emerges from Bayesian integration, taken over the distribution of possible values of information measures for sparse and ample data alike. Expected mutual information l(a;b;c) in nats (i.e., natural units analogous to bits but based on the natural logarithm), such as is available to the observer, is measured as e.g., the difference zeta(s,o(a,b,c..)) - zeta(s,e(a,b,c..)) where o(a,b,c,..) and e(a,b,c,..) are, or relate to, the observed and expected frequencies of occurrence, respectively. For real values of s > 1 the qualitative impact of strongly (positively or negatively) ranked data is preserved despite several numerical approximations. As real s increases, and the output of the information functions converge into three values +1, 0, and -1 nats representing a trinary logic system. For quantitative data, a useful ad hoc method, to report sigma-normalized covariations in an analogous manner to mutual information for significance comparison purposes, is demonstrated. Finally, the potential ability to make use of mutual information in a complex biomedical study, and to include Bayesian prior information derived from statistical, tabular, anecdotal, and expert opinion is briefly illustrated.

Structure-activity relationship of ibogaine analogs interacting with nicotinic acetylcholine receptors in different conformational states.

PubMed

Arias, Hugo R; Feuerbach, Dominik; Targowska-Duda, Katarzyna M; Jozwiak, Krzysztof

2011-09-01

The interaction of ibogaine analogs with nicotinic acetylcholine receptors (AChRs) in different conformational states was studied by functional and structural approaches. The results established that ibogaine analogs: (a) inhibit (±)-epibatidine-induced Ca²⁺ influx in human embryonic muscle AChRs with the following potency sequence (IC(50) in μM): (±)-18-methylaminocoronaridine (5.9±0.3)∼(±)-18-methoxycoronaridine (18-MC) (6.8±0.8)>(-)-ibogaine (17±3)∼(+)-catharanthine (20±1)>(±)-albifloranine (46±13), (b) bind to the [³H]TCP binding site with higher affinity when the Torpedo AChR is in the desensitized state compared to that in the resting state. Similar results were obtained using [³H]18-MC. These and docking results suggest a steric interaction between TCP and ibogaine analogs for the same site, (c) enhance [³H]cytisine binding to resting but not to desensitized AChRs, with desensitizing potencies (apparent EC₅₀) that correlate very well with the pK(i) values in the desensitized state, and (d) there are good bilinear correlations between the ligand molecular volumes and their affinities in the desensitized and resting states, with an optimal volume of ∼345 ų for the ibogaine site. These results indicate that the size of the binding sites for ibogaine analogs, located between the serine and nonpolar rings and shared with TCP, is an important structural feature for binding and for inducing desensitization. Copyright © 2011 Elsevier Ltd. All rights reserved.

α decay of the T = 1 ,   2 + state in B 10 and isospin symmetry breaking in the A = 10 triplet

DOE PAGES

Kuvin, S. A.; Wuosmaa, A. H.; Lister, C. J.; ...

2017-10-03

Here, the rate of the T=1, 2+ to T=1, 0 + transition in 10B ( T=1, T z=0) is compared to the analog transitions in 10Be ( T=1, T z=–1) and 10C ( T=1, T z=+1) to provide constraints on ab initio calculations using realistic nuclear forces. The relevant state in 10B, at E x=5.164 MeV, is particle unbound. Therefore, a determination of the B( E2) electromagnetic transition rate requires a precise and accurate determination of the width of the state, as well as the α-particle and γ-ray branching ratios. Previous measurements of the α-particle branching ratio are just barelymore » in agreement. We report on a new study of the α-particle branch by studying the 10B(p,p') 10B* reaction in inverse kinematics with the HELIOS spectrometer. The α-particle branching ratio that we observe, 0.144±0.027, is in good agreement with the evaluated value and improves the associated uncertainty. The resulting experimental B( E2) value is 7.0±2.2 e 2fm 4 and is more consistent with a flat trend across the A=10 triplet than previously reported. This is inconsistent with Green's function Monte Carlo predictions using realistic three-nucleon Hamiltonians, which overpredict the B(E2) value in 10C and 10B.« less

Comparison of topical capsaicin and topical turpentine Oil for treatment of painful diabetic neuropathy.

PubMed

Musharraf, Muhammad Usman; Ahmad, Zaheer; Yaqub, Zernab

2017-01-01

Diabetes Mellitus is a pandemic of the modern era owing to our rapidly deteriorating lifestyle. Painful diabetic neuropathy is one of the costliest and disabling complications of diabetes mellitus. No single treatment exists to prevent or reverse neuropathic changes or to provide total pain relief. Topical Capsaicin and Turpentine Oil are found to be effective in treatment of painful diabetic neuropathy. Patients of either gender with ages between 18 and 70 years having painful diabetic neuropathy already taking one oral drug for painful neuropathy and treatment for diabetes mellitus and an HbA1C less than 8.5% were included while Pregnant or lactating mothers, patients with chronic liver disease and patients with renal insufficiency (creatinine >3.0 mg/dl) and peripheral arterial disease were excluded from study. Patients were randomly divided into two groups (A & B) using computer generated random number table. Group A was given topical application of capsaicin while Group B was given topical application of commercially available turpentine oil over painful site on feet. 300 patients were equally divided in two groups. The patients in group A had a Visual Analog Pain Score of 7.91±5.10 at baseline and 5.10±1.343 after 3 months of treatment (p-value 0.0001). The patients in group B had a Visual Analog Pain Score of 7.83±1.012 at baseline and 5.20±1.187 after 3 months of treatment (p-value 0.0001). Chi Square test was applied to compare efficacy of both groups. It was noted that 71 (53%) had efficacy in group A and 63 (47%) had efficacy in the group B but the difference was not statistically significant. (p-value=0.399). It has been concluded that turpentine oil is effective in managing diabetic neuropathic pain similar to capsaicin cream.

Demonstration of Nondeclarative Sequence Learning in Mice: Development of an Animal Analog of the Human Serial Reaction Time Task

ERIC Educational Resources Information Center

Christie, Michael A.; Hersch, Steven M.

2004-01-01

In this paper, we demonstrate nondeclarative sequence learning in mice using an animal analog of the human serial reaction time task (SRT) that uses a within-group comparison of behavior in response to a repeating sequence versus a random sequence. Ten female B6CBA mice performed eleven 96-trial sessions containing 24 repetitions of a 4-trial…

Combinations of Adefovir with Nucleoside Analogs Produce Additive Antiviral Effects against Hepatitis B Virus In Vitro

PubMed Central

Delaney, William E.; Yang, Huiling; Miller, Michael D.; Gibbs, Craig S.; Xiong, Shelly

2004-01-01

Combination therapies may be required for long-term management of some patients chronically infected with hepatitis B virus (HBV). Adefovir is a nucleotide analog that has similar activity against wild-type and lamivudine-resistant HBV. In contrast to lamivudine, clinical resistance to the prodrug adefovir dipivoxil emerges infrequently. Based on its clinical efficacy and low frequency of resistance, adefovir dipivoxil may form an important component of combination regimens. We therefore investigated the in vitro antiviral efficacy of combinations of adefovir with other nucleoside analogs (lamivudine, entecavir, emtricitabine [FTC],and telbivudine [L-dT]) and the nucleotide analog tenofovir. Using a novel stable cell line that expresses high levels of wild-type HBV, we assayed the antiviral activity of each drug alone and in combination with adefovir. All two-drug combinations resulted in greater antiviral effects than treatments with single agents and could be characterized as additive by the Bliss independence model. Analysis using the Loewe additivity model indicated that adefovir exerted additive antiviral effects when combined with lamivudine, FTC, or L-dT and moderately synergistic effects when combined with entecavir or tenofovir. There was no evidence of cytotoxicity with any of the drugs when used alone or in combination at the tested doses. PMID:15388423

Synthesis and anti-cancer activity evaluation of novel prenylated and geranylated chalcone natural products and their analogs.

PubMed

Wang, Hao-Meng; Zhang, Li; Liu, Jiang; Yang, Zhao-Liang; Zhao, Hong-Ye; Yang, Yao; Shen, Di; Lu, Kui; Fan, Zhen-Chuan; Yao, Qing-Wei; Zhang, Yong-Min; Teng, Yu-Ou; Peng, Yu

2015-03-06

Four natural chalcones bearing prenyl or geranyl groups, i.e., bavachalcone (1a), xanthoangelol (1b), isobavachalcone (1c), and isoxanthoangelol (1d) were synthesized by using a regio-selective iodination and the Suzuki coupling reaction as key steps. The first total synthesis of isoxanthoangelol (1d) was achieved in 36% overall yield. A series of diprenylated and digeranylated chalcone analogs were also synthesized by alkylation, regio-selective iodination, aldol condensation, Suzuki coupling and [1,3]-sigmatropic rearrangement. The structures of the 11 new derivatives were confirmed by (1)H NMR, (13)C NMR and HRMS. The anticancer activity of these new chalcone derivatives against human tumor cell line K562 were evaluated by MTT assay in vitro. SAR studies suggested that the 5'-prenylation/geranylation of the chalcones significantly enhance their cytotoxic activity. Among them, Bavachalcone (1a) displayed the most potent cytotoxic activity against K562 with IC50 value of 2.7 μM. The morphology changes and annexin-V/PI staining studies suggested that those chalcone derivatives inhibited the proliferation of K562 cells by inducing apoptosis. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

55-mW, 1.2-V, 12-bit, 100-MSPS Pipeline ADCs for Wireless Receivers

NASA Astrophysics Data System (ADS)

Ito, Tomohiko; Kurose, Daisuke; Ueno, Takeshi; Yamaji, Takafumi; Itakura, Tetsuro

For wireless receivers, low-power 1.2-V 12-bit 100-MSPS pipeline ADCs are fabricated in 90-nm CMOS technology. To achieve low-power dissipation at 1.2V without the degradation of SNR, the configuration of 2.5bit/stage is employed with an I/Q amplifier sharing technique. Furthermore, single-stage pseudo-differential amplifiers are used in a Sample-and-Hold (S/H) circuit and a 1st Multiplying Digital-to-Analog Converter (MDAC). The pseudo-differential amplifier with two-gain-stage transimpedance gain-boosting amplifiers realizes high DC gain of more than 90dB with low power. The measured SNR of the 100-MSPS ADC is 66.7dB at 1.2-V supply. Under that condition, each ADC dissipates only 55mW.

Comparative study of substrate and product binding to the human ABO(H) blood group glycosyltransferases.

PubMed

Soya, Naoto; Shoemaker, Glen K; Palcic, Monica M; Klassen, John S

2009-11-01

The first comparative thermodynamic study of the human blood group glycosyltransferases, alpha-(1-->3)-N-acetylgalactosaminyltransferase (GTA) and alpha-(1-->3)-galactosyltransferase (GTB), interacting with donor substrates, donor and acceptor analogs, and trisaccharide products in vitro is reported. The binding constants, measured at 24 degrees C with the direct electrospray ionization mass spectrometry (ES-MS) assay, provide new insights into these model GTs and their interactions with substrate and product. Notably, the recombinant forms of GTA and GTB used in this study are shown to exist as homodimers, stabilized by noncovalent interactions at neutral pH. In the absence of divalent metal ion, neither GTA nor GTB exhibits any appreciable affinity for its native donors (UDP-GalNAc, UDP-Gal). Upon introduction of Mn(2+), both donors undergo enzyme-catalyzed hydrolysis in the presence of either GTA or GTB. Hydrolysis of UDP-GalNAc in the presence of GTA proceeds very rapidly under the solution conditions investigated and a binding constant could not be directly measured. In contrast, the rate of hydrolysis of UDP-Gal in the presence of GTB is significantly slower and, utilizing a modified approach to analyze the ES-MS data, a binding constant of 2 x 10(4) M(-1) was established. GTA and GTB bind the donor analogs UDP-GlcNAc, UDP-Glc with affinities similar to those measured for UDP-Gal and UDP-GalNAc (GTB only), suggesting that the native donors and donor analogs bind to the GTA and GTB through similar interactions. The binding constant determined for GTA and UDP-GlcNAc (approximately 1 x 10(4) M(-1)), therefore, provides an estimate for the binding constant for GTA and UDP-GalNAc. Binding of GTA and GTB with the A and B trisaccharide products was also investigated for the first time. In the absence of UDP and Mn(2+), both GTA and GTB recognize their respective trisaccharide products but with a low affinity approximately 10(3) M(-1); the presence of UDP and Mn(2+) has no effect on A trisaccharide binding but precludes B-trisaccharide binding.

L-Band Transmit/Receive Module for Phase-Stable Array Antennas

NASA Technical Reports Server (NTRS)

Andricos, Constantine; Edelstein, Wendy; Krimskiy, Vladimir

2008-01-01

Interferometric synthetic aperture radar (InSAR) has been shown to provide very sensitive measurements of surface deformation and displacement on the order of 1 cm. Future systematic measurements of surface deformation will require this capability over very large areas (300 km) from space. To achieve these required accuracies, these spaceborne sensors must exhibit low temporal decorrelation and be temporally stable systems. An L-band (24-cmwavelength) InSAR instrument using an electronically steerable radar antenna is suited to meet these needs. In order to achieve the 1-cm displacement accuracy, the phased array antenna requires phase-stable transmit/receive (T/R) modules. The T/R module operates at L-band (1.24 GHz) and has less than 1- deg absolute phase stability and less than 0.1-dB absolute amplitude stability over temperature. The T/R module is also high power (30 W) and power efficient (60-percent overall efficiency). The design is currently implemented using discrete components and surface mount technology. The basic T/R module architecture is augmented with a calibration loop to compensate for temperature variations, component variations, and path loss variations as a function of beam settings. The calibration circuit consists of an amplitude and phase detector, and other control circuitry, to compare the measured gain and phase to a reference signal and uses this signal to control a precision analog phase shifter and analog attenuator. An architecture was developed to allow for the module to be bidirectional, to operate in both transmit and receive mode. The architecture also includes a power detector used to maintain a transmitter power output constant within 0.1 dB. The use of a simple, stable, low-cost, and high-accuracy gain and phase detector made by Analog Devices (AD8302), combined with a very-high efficiency T/R module, is novel. While a self-calibrating T/R module capability has been sought for years, a practical and cost-effective solution has never been demonstrated. By adding the calibration loop to an existing high-efficiency T/R module, there is a demonstrated order-of-magnitude improvement in the amplitude and phase stability.

Towards a category theory approach to analogy: Analyzing re-representation and acquisition of numerical knowledge.

PubMed

Navarrete, Jairo A; Dartnell, Pablo

2017-08-01

Category Theory, a branch of mathematics, has shown promise as a modeling framework for higher-level cognition. We introduce an algebraic model for analogy that uses the language of category theory to explore analogy-related cognitive phenomena. To illustrate the potential of this approach, we use this model to explore three objects of study in cognitive literature. First, (a) we use commutative diagrams to analyze an effect of playing particular educational board games on the learning of numbers. Second, (b) we employ a notion called coequalizer as a formal model of re-representation that explains a property of computational models of analogy called "flexibility" whereby non-similar representational elements are considered matches and placed in structural correspondence. Finally, (c) we build a formal learning model which shows that re-representation, language processing and analogy making can explain the acquisition of knowledge of rational numbers. These objects of study provide a picture of acquisition of numerical knowledge that is compatible with empirical evidence and offers insights on possible connections between notions such as relational knowledge, analogy, learning, conceptual knowledge, re-representation and procedural knowledge. This suggests that the approach presented here facilitates mathematical modeling of cognition and provides novel ways to think about analogy-related cognitive phenomena.

Towards a category theory approach to analogy: Analyzing re-representation and acquisition of numerical knowledge

PubMed Central

2017-01-01

Category Theory, a branch of mathematics, has shown promise as a modeling framework for higher-level cognition. We introduce an algebraic model for analogy that uses the language of category theory to explore analogy-related cognitive phenomena. To illustrate the potential of this approach, we use this model to explore three objects of study in cognitive literature. First, (a) we use commutative diagrams to analyze an effect of playing particular educational board games on the learning of numbers. Second, (b) we employ a notion called coequalizer as a formal model of re-representation that explains a property of computational models of analogy called “flexibility” whereby non-similar representational elements are considered matches and placed in structural correspondence. Finally, (c) we build a formal learning model which shows that re-representation, language processing and analogy making can explain the acquisition of knowledge of rational numbers. These objects of study provide a picture of acquisition of numerical knowledge that is compatible with empirical evidence and offers insights on possible connections between notions such as relational knowledge, analogy, learning, conceptual knowledge, re-representation and procedural knowledge. This suggests that the approach presented here facilitates mathematical modeling of cognition and provides novel ways to think about analogy-related cognitive phenomena. PMID:28841643

Cyclopentanoid analogs of phosphatidylcholine: susceptibility to phospholipase A2.

PubMed

Lister, M D; Hancock, A J

1988-10-01

Six isomers of dipalmitoylcyclopentanetriol phosphocholine (cyclopentano-lecithin) were tested as potential substrates for phospholipase A2. Since each of these analogs possesses a configuration that mimics a narrow range of conformations of a glycerophospholipid molecule, the analogs were used to assess the enzyme's conformational requirements. Studies showed that all of the analogs containing the phosphocholine at the C-1 (or C-3) position could be hydrolyzed, while only one of the three analogs that contains the polar head group at the C-2 position was susceptible. Kinetic studies, however, revealed that only the all-trans-(1,3/2-1P)-cyclopentano-lecithin gave initial rates of hydrolysis that were measurable by pH-stat. Acyl group specificity of the enzyme towards the all-trans isomer was determined with an analog was acyl groups were distinguishable. The synthesis of this mixed-acid-cyclopentano-PC is described herein. When this analog was enzymatically assayed, results unequivocally showed the enzyme to be specific for C-2 acyl hydrolysis. This specificity, and data showing that the all-trans analog is stereospecifically hydrolyzed, indicate that it is acted on in an analogous manner to dipalmitoylphosphatidylcholine. These studies indicate that although the configuration of the analog is not necessarily a prerequisite for hydrolysis, there does appear to be an optimal spatial orientation for enzymatic activity. The analogy between the susceptibilities of all-trans-(1,3/2-1P)-cyclopentano-lecithin and glycero-lecithin suggests that the conformation of the glycero-lecithin during phospholipase A2-mediated hydrolysis may be best simulated by the all-trans orientation of C-O bonds in the artificial substrate.

Effect of long-term administration of an analog of growth hormone-releasing factor on the GH response in rats.

PubMed

Karashima, T; Olsen, D; Schally, A V

1987-06-22

The effect of the repeated or continuous administration of an analog of GH releasing factor (GH-RF), D-Tyr-1, D-Ala-2, Nle-27, GH-RF(1-29)-NH2 (DBO-29), on the subsequent response to this peptide was investigated in pentobarbital-anesthetized male rats. A sc administration of this analog induced a greater and more prolonged GH release than doses 10 times larger of GH-RF(1-29). The GH increase after sc injection of 10 micrograms/kg bw of the analog was greater than that induced by iv administration of 2 micrograms/kg bw of GH-RF(1-44). Pretreatment with 10 micrograms/kg bw of the analog did not affect the pituitary response to a strong stimulus (20 micrograms/kg bw) of GH-RF(1-44), 24 h later. Pretreatment with the analog in doses of 10 micrograms/kg bw, sc twice a day, 5 days per week for 4 weeks, significantly diminished the GH release in response to a sc injection of the analog (10 micrograms/kg bw), as compared to vehicle-pretreated controls (P less than 0.01). On the other hand, a continuous sc administration of 0.4 micrograms/h of the analog to intact rats for 7 days did not result in a decrease in GH response to a sc injection of the analog (10 micrograms/kg bw). Since the rats injected repeatedly with the analog for 4 weeks still showed a marked, although somewhat reduced response, analogs of this type may be useful clinically.

Sorption of lead by settling pond soils after reclamation treatments

NASA Astrophysics Data System (ADS)

Asensio, Verónica; Forján, Rubén; Vega, Flora A.; Andrade, Luisa; Covelo, Emma F.

2013-04-01

The reclamation of degraded soils adding waste amendments can add significant concentrations of Pb. Because of this, it is important to know the sorption capacity of Pb by the soils where wastes with high concentrations of this metal are applied. To determine the sorption capacity of Pb by mine soils, before and after reclamation treatments, four different sites were selected at a settling pond mine zone: an untreated one as the control sample (B1), a vegetated one with pines for 21 years (B2v), a vegetated with eucalyptus for 6 years (B3v) and an amended with sewage sludges and paper mill residues for 5 months (B4w). All soils had one horizon except B4w, where twice were sampled (B4Aw and B4Bw). The B4Bw is considered analogous of the control soil. To evaluate the sorption capacity by the soils, sorption isotherms were constructed using single-metal solutions of Pb2+ nitrates (0.03, 0.05, 0.08, 0.1 and 0.5 mmol L-1) containing 0.01 M NaNO3 as background electrolyte (Vega et al., 2009). The overall capacity of the soil to sorb Pb was evaluated as the slope Kr (Vega et al., 2008). The obtained results show that the sorption isotherm of Pb by control soil (B1) and its analogous (B4Bw) are of L-type curve, whereas the sorption isotherms of the treated soils (B2v, B3v and B4Aw) are of H-type curve (Giles et al., 1974). The most of the obtained isotherms do not fit with the models of Langmuir or Freundlich, therefore sorption capacity was evaluated by Kr parameter. According to the obtained Kr parameter, B1 and B4Bw have the lowest Pb sorption capacity (Kr = 0.480 and 0.556, respectively), which increased two times after recently waste amending (B4Aw; Kr = 0.998). The vegetated sites (B2v and B3v) also have higher sorption capacity than B1, but lower than B4Aw (Kr = 0.692 and 0.725, respectively). The highest sorption capacity of Pb by the amended soil is due to its characteristics such as high pH and organic carbon content. This is corroborated by the significantly positive correlation of Kr for Pb and the soil pH, effective cation exchange capacity (CECe), the different forms of C (inorganic, humin, fulvic and humic acids), the percentage of clay fraction and the percentage of crystalline minerals in that fraction (P < 0.01). Therefore, the best treatment to increase the sorption capacity of Pb by mine soils is the amendment with organic wastes. References Giles, C.H.; Smith, D.; Huitson, A. 1974. J. Colloid. Interface Sci. 47: 755-756. Vega, F.A.; Covelo, E.F.; Andrade, M.L. 2009. J. Hazard. Mater. 169: 36-45. Vega, F.A.; Covelo, E.F.; Andrade, M.L. 2008. J. Colloid. Interface Sci. 327: 275-286.

Theoretical tuning of the firefly bioluminescence spectra by the modification of oxyluciferin

NASA Astrophysics Data System (ADS)

Cheng, Yuan-Yuan; Zhu, Jia; Liu, Ya-Jun

2014-01-01

Extending the firefly bioluminescence is of practical significance for the improved visualization of living cells and the development of a multicolor reporter. Tuning the color of bioluminescence in fireflies mainly involves the modification of luciferase and luciferin. In this Letter, we theoretically studied the emission spectra of 9 firefly oxyluciferin analogs in the gas phase and in solutions. Three density functionals, including B3LYP, CAM-B3LYP and M06-2X, were employed to theoretically predict the efficiently luminescent analogs. The reliable functionals for calculating the targeted systems were suggested. The luminescence efficiency, solvent effects, and substituent effects are discussed based on the calculated results.

Practical application of a bidirectional microwave photonic filter: simultaneous transmission of analog TV signals

NASA Astrophysics Data System (ADS)

Correa-Mena, Ana Gabriela; Zaldívar-Huerta, Ignacio E.; Abril García, Jose Humberto; García-Juárez, Alejandro; Vera-Marquina, Alicia

2016-10-01

A practical application of a bidirectional microwave photonic filter (MPF) to transmit simultaneous analog TV signals coded on microwave carriers is experimentally demonstrated. The frequency response of the bidirectional MPF is obtained by the interaction of an externally modulated multimode laser diode emitting at 1.55 μm associated to the free-spectral range of the optical source, the chromatic dispersion parameter of the optical fiber, as well as the length of the optical link. The filtered microwave bandpass window generated around 2 GHz is used as electrical carrier in order to simultaneously transmit TV signals of 67.25 and 61.25 MHz in both directions. The obtained signal-to-noise ratios for the transmitted signals of 67.25 and 61.25 MHz are 37.62 and 44.77 dB, respectively.

ALMA 1.3 mm Map of the HD 95086 System

NASA Astrophysics Data System (ADS)

Su, Kate Y. L.; MacGregor, Meredith A.; Booth, Mark; Wilner, David J.; Flaherty, Kevin; Hughes, A. Meredith; Phillips, Neil M.; Malhotra, Renu; Hales, Antonio S.; Morrison, Sarah; Ertel, Steve; Matthews, Brenda C.; Dent, William R. F.; Casassus, Simon

2017-12-01

Planets and minor bodies such as asteroids, Kuiper-Belt objects, and comets are integral components of a planetary system. Interactions among them leave clues about the formation process of a planetary system. The signature of such interactions is most prominent through observations of its debris disk at millimeter wavelengths where emission is dominated by the population of large grains that stay close to their parent bodies. Here we present ALMA 1.3 mm observations of HD 95086, a young early-type star that hosts a directly imaged giant planet b and a massive debris disk with both asteroid- and Kuiper-Belt analogs. The location of the Kuiper-Belt analog is resolved for the first time. The system can be depicted as a broad (ΔR/R ˜ 0.84), inclined (30° ± 3°) ring with millimeter emission peaked at 200 ± 6 au from the star. The 1.3 mm disk emission is consistent with a broad disk with sharp boundaries from 106 ± 6 to 320 ± 20 au with a surface density distribution described by a power law with an index of -0.5 ± 0.2. Our deep ALMA map also reveals a bright source located near the edge of the ring, whose brightness at 1.3 mm and potential spectral energy distribution are consistent with it being a luminous star-forming galaxy at high redshift. We set constraints on the orbital properties of planet b assuming coplanarity with the observed disk.

Single Amino Acid Substitutions at Specific Positions of the Heptad Repeat Sequence of Piscidin-1 Yielded Novel Analogs That Show Low Cytotoxicity and In Vitro and In Vivo Antiendotoxin Activity

PubMed Central

Kumar, Amit; Tripathi, Amit Kumar; Kathuria, Manoj; Shree, Sonal; Tripathi, Jitendra Kumar; Purshottam, R. K.; Ramachandran, Ravishankar; Mitra, Kalyan

2016-01-01

Piscidin-1 possesses significant antimicrobial and cytotoxic activities. To recognize the primary amino acid sequence(s) in piscidin-1 that could be important for its biological activity, a long heptad repeat sequence located in the region from amino acids 2 to 19 was identified. To comprehend the possible role of this motif, six analogs of piscidin-1 were designed by selectively replacing a single isoleucine residue at a d (5th) position or at an a (9th or 16th) position with either an alanine or a valine residue. Two more analogs, namely, I5F,F6A-piscidin-1 and V12I-piscidin-1, were designed for investigating the effect of interchanging an alanine residue at a d position with an adjacent phenylalanine residue and replacing a valine residue with an isoleucine residue at another d position of the heptad repeat of piscidin-1, respectively. Single alanine-substituted analogs exhibited significantly reduced cytotoxicity against mammalian cells compared with that of piscidin-1 but appreciably retained the antibacterial and antiendotoxin activities of piscidin-1. All the single valine-substituted piscidin-1 analogs and I5F,F6A-piscidin-1 showed cytotoxicity greater than that of the corresponding alanine-substituted analogs, antibacterial activity marginally greater than or similar to that of the corresponding alanine-substituted analogs, and also antiendotoxin activity superior to that of the corresponding alanine-substituted analogs. Interestingly, among these peptides, V12I-piscidin-1 showed the highest cytotoxicity and antibacterial and antiendotoxin activities. Lipopolysaccharide (12 mg/kg of body weight)-treated mice, further treated with I16A-piscidin-1, the piscidin-1 analog with the highest therapeutic index, at a single dose of 1 or 2 mg/kg of body weight, showed 80 and 100% survival, respectively. Structural and functional characterization of these peptides revealed the basis of their biological activity and demonstrated that nontoxic piscidin-1 analogs with significant antimicrobial and antiendotoxin activities can be designed by incorporating single alanine substitutions in the piscidin-1 heptad repeat. PMID:27067326

Forward Behavioral Modeling of a Three-Way Amplitude Modulator-Based Transmitter Using an Augmented Memory Polynomial

PubMed Central

Chatrath, Jatin; Aziz, Mohsin; Helaoui, Mohamed

2018-01-01

Reconfigurable and multi-standard RF front-ends for wireless communication and sensor networks have gained importance as building blocks for the Internet of Things. Simpler and highly-efficient transmitter architectures, which can transmit better quality signals with reduced impairments, are an important step in this direction. In this regard, mixer-less transmitter architecture, namely, the three-way amplitude modulator-based transmitter, avoids the use of imperfect mixers and frequency up-converters, and their resulting distortions, leading to an improved signal quality. In this work, an augmented memory polynomial-based model for the behavioral modeling of such mixer-less transmitter architecture is proposed. Extensive simulations and measurements have been carried out in order to validate the accuracy of the proposed modeling strategy. The performance of the proposed model is evaluated using normalized mean square error (NMSE) for long-term evolution (LTE) signals. NMSE for a LTE signal of 1.4 MHz bandwidth with 100,000 samples for digital combining and analog combining are recorded as −36.41 dB and −36.9 dB, respectively. Similarly, for a 5 MHz signal the proposed models achieves −31.93 dB and −32.08 dB NMSE using digital and analog combining, respectively. For further validation of the proposed model, amplitude-to-amplitude (AM-AM), amplitude-to-phase (AM-PM), and the spectral response of the modeled and measured data are plotted, reasonably meeting the desired modeling criteria. PMID:29510501

Syntheses, receptor bindings, in vitro and in vivo stabilities and biodistributions of DOTA-neurotensin(8-13) derivatives containing β-amino acid residues - a lesson about the importance of animal experiments.

PubMed

Sparr, Christof; Purkayastha, Nirupam; Yoshinari, Tomohiro; Seebach, Dieter; Maschauer, Simone; Prante, Olaf; Hübner, Harald; Gmeiner, Peter; Kolesinska, Beata; Cescato, Renzo; Waser, Beatrice; Reubi, Jean Claude

2013-12-01

Neurotensin(8-13) (NTS(8-13)) analogs with C- and/or N-terminal β-amino acid residues and three DOTA derivatives thereof have been synthesized (i.e., 1-6). A virtual docking experiment showed almost perfect fit of one of the 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) derivatives, 6a, into a crystallographically identified receptor NTSR1 (Fig.1). The affinities for the receptors of the NTS analogs and derivatives are low, when determined with cell-membrane homogenates, while, with NTSR1-exhibiting cancer tissues, affinities in the single-digit nanomolar range can be observed (Table 2). Most of the β-amino acid-containing NTS(8-13) analogs (Table 1 and Fig.2), including the (68) Ga complexes of the DOTA-substituted ones (6; Figs.2 and 5), are stable for ca. 1 h in human serum and plasma, and in murine plasma. The biodistributions of two (68) Ga complexes (of 6a and 6b) in HT29 tumor-bearing nude mice, in the absence and in the presence of a blocking compound, after 10, 30, and 60 min (Figs. 3 and 4) lead to the conclusion that the amount of specifically bound radioligand is rather low. This was confirmed by PET-imaging experiments with the tumor-bearing mice (Fig.6). Comparison of the in vitro plasma stability (after 1 h) with the ex vivo blood content (after 10-15 min) of the two (68) Ga complexes shows that they are rapidly cleaved in the animals (Fig.5). Copyright © 2013 Verlag Helvetica Chimica Acta AG, Zürich.

A new model for the origin of Type-B and Fluffy Type-A CAIs: Analogies to remelted compound chondrules

NASA Astrophysics Data System (ADS)

Rubin, Alan E.

2012-06-01

In the scenario developed here, most types of calcium-aluminum-rich inclusions (CAIs) formed near the Sun where they developed Wark-Lovering rims before being transported by aerodynamic forces throughout the nebula. The amount of ambient dust in the nebula varied with heliocentric distance, peaking in the CV-CK formation location. Literature data show that accretionary rims (which occur outside the Wark-Lovering rims) around CAIs contain substantial 16O-rich forsterite, suggesting that, at this time, the ambient dust in the nebula consisted largely of 16O-rich forsterite. Individual sub-millimeter-size Compact Type-A CAIs (each surrounded by a Wark-Lovering rim) collided in the CV-CK region and stuck together (in a manner similar to that of sibling compound chondrules); the CTAs were mixed with small amounts of 16O-rich mafic dust and formed centimeter-size compound objects (large Fluffy Type-A CAIs) after experiencing minor melting. In contrast to other types of CAIs, centimeter-size Type-B CAIs formed directly in the CV-CK region after gehlenite-rich Compact Type-A CAIs collided and stuck together, incorporated significant amounts of 16O-rich forsteritic dust (on the order of 10-15%) and probably some anorthite, and experienced extensive melting and partial evaporation. (Enveloping compound chondrules formed in an analogous manner.) In those cases where appreciably higher amounts of 16O-rich forsterite (on the order of 25%) (and perhaps minor anorthite and pyroxene) were incorporated into compound Type-A objects prior to melting, centimeter-size forsterite-bearing Type-B CAIs (B3 inclusions) were produced. Type-B1 inclusions formed from B2 inclusions that collided with and stuck to melilite-rich Compact Type-A CAIs and experienced high-temperature processing.

Room temperature 1040fps, 1 megapixel photon-counting image sensor with 1.1um pixel pitch

NASA Astrophysics Data System (ADS)

Masoodian, S.; Ma, J.; Starkey, D.; Wang, T. J.; Yamashita, Y.; Fossum, E. R.

2017-05-01

A 1Mjot single-bit quanta image sensor (QIS) implemented in a stacked backside-illuminated (BSI) process is presented. This is the first work to report a megapixel photon-counting CMOS-type image sensor to the best of our knowledge. A QIS with 1.1μm pitch tapered-pump-gate jots is implemented with cluster-parallel readout, where each cluster of jots is associated with its own dedicated readout electronics stacked under the cluster. Power dissipation is reduced with this cluster readout because of the reduced column bus parasitic capacitance, which is important for the development of 1Gjot arrays. The QIS functions at 1040fps with binary readout and dissipates only 17.6mW, including I/O pads. The readout signal chain uses a fully differential charge-transfer amplifier (CTA) gain stage before a 1b-ADC to achieve an energy/bit FOM of 16.1pJ/b and 6.9pJ/b for the whole sensor and gain stage+ADC, respectively. Analog outputs with on-chip gain are implemented for pixel characterization purposes.

Cyclic Disilylated and Digermylated Germylenes

PubMed Central

2013-01-01

The preparation of triethylphosphine adducts of cyclic disilylated or digermylated germylenes was achieved by reaction of 1,4-dipotassio-1,1,4,4-tetrakis(trimethylsilyl)tetramethyltetrasilane with GeBr2·(dioxane) and PEt3. Phosphine abstraction with B(C6F5)3 allowed formation of the base-free germylenes, which undergo 1,2-trimethylsilyl shifts to the germylene atom to form the respective silagermene or digermene, which further dimerize in [2 + 2] cycloadditions to tricyclic compounds. The reasons responsible for the germylenes’ completely different reactivities in comparison to the previously studied analogous stannylenes and plumbylenes were elucidated in a theoretical study. PMID:23874054

Comparison of the Defense Meteorological Satellite Program (DMSP) and the NOAA Polar-Orbiting Operational Environmental Satellite (POES) Program,

DTIC Science & Technology

1985-10-01

grid points on 1 /20 lat /long meshI 4 c. SST global scale analysis ( 1 or 100 km lat /long grid) .. d. SST climatic scale analysis (50 or 500 km lat ...long grid) e. SST monthly means (2 1 /20 or 250 km lat /long grid) 3. Analog Sea Surface Temperature Product Set ’-%". V" " a. GOSSTCOMP charts - weekly...Mercator contour charts, each a ., 500 by 500 lat /long segment, 1 °C contour interval b. Regional charts - set of three charts covering the U.S

Binding of (/sup 3/H)Forskolin to rat brain membranes

DOE Office of Scientific and Technical Information (OSTI.GOV)

Seamon, K.B.; Vaillancourt, R.; Edwards, M.

1984-08-01

(12-/sup 3/H)Forskolin (27 Ci/mmol) has been used to study binding sites in rat brain tissue by using both centrifugation and filtration assays. The binding isotherm measured in the presence of 5 mM MgCl/sub 2/ by using the centrifugation assay is described best by a two-site model: K/sub d1/ = 15 nM, B/sub max/sub 1// (maximal binding) = 270 fmol/mg of protein; K/sub d2/ = 1.1 ..mu..M; B/sub max/sub 2// = 4.2 pmol/mg of protein. Only the high-affinity binding sites are detected when the binding is determined by using a filtration assay; K/sub d/ = 26 nM, B/sub max/ = 400more » fmol/mg of protein. Analogs of forskolin that do not activate adenylate cyclase (EC 4.6.1.1) do not compete effectively for (/sup 3/H)forskolin binding sites. Analogs of forskolin that are less potent than forskolin in activating adenylate cyclase are also less potent in competing for forskolin binding sites. The presence of 5 mM MgCl/sub 2/ or MnCl/sub 2/ was found to enhance binding. In the presence of 1 mM EDTA the amount of high-affinity binding is reduced to 110 fmol/mg of protein with no change in K/sub d/. There is no effect of CaCl/sub 2/ (20 mM) or NaCl (100 mM) on the binding. No high-affinity binding can be detected in membranes from ram sperm, which contains an adenylate cyclase that is not activated by forskolin. It is proposed that the high-affinity binding sites for forskolin are associated with the activated complex of catalytic subunit and stimulatory guanine nucleotide binding protein. 23 references, 5 figures, 2 tables.« less

High-resolution study of Gamow-Teller excitations in the 42Ca(3He,t )42Sc reaction and the observation of a "low-energy super-Gamow-Teller state"

NASA Astrophysics Data System (ADS)

Fujita, Y.; Fujita, H.; Adachi, T.; Susoy, G.; Algora, A.; Bai, C. L.; Colò, G.; Csatlós, M.; Deaven, J. M.; Estevez-Aguado, E.; Guess, C. J.; Gulyás, J.; Hatanaka, K.; Hirota, K.; Honma, M.; Ishikawa, D.; Krasznahorkay, A.; Matsubara, H.; Meharchand, R.; Molina, F.; Nakada, H.; Okamura, H.; Ong, H. J.; Otsuka, T.; Perdikakis, G.; Rubio, B.; Sagawa, H.; Sarriguren, P.; Scholl, C.; Shimbara, Y.; Stephenson, E. J.; Suzuki, T.; Tamii, A.; Thies, J. H.; Yoshida, K.; Zegers, R. G. T.; Zenihiro, J.

2015-06-01

To study the Gamow-Teller (GT) transitions from the Tz=+1 nucleus 42Ca to the Tz=0 nucleus 42Sc, where Tz is the z component of isospin T , we performed a (p ,n )-type (3He,t ) charge-exchange reaction at 140 MeV/nucleon and scattering angles around 0∘. With an energy resolution of 29 keV, states excited by GT transitions (GT states) could be studied accurately. The reduced GT transition strengths B (GT) were derived up to the excitation energy of 13 MeV, assuming the proportionality between the cross sections at 0∘ and B (GT) values. The main part of the observed GT transition strength is concentrated in the lowest 0.611-MeV, Jπ=1+ GT state. All the other states at higher energies are weakly excited. Shell-model calculations could reproduce the gross feature of the experimental B (GT) distribution, and random-phase-approximation calculations including an attractive isoscalar interaction showed that the 0.611-MeV state has a collective nature. It was found that this state has all of the properties of a "low-energy super-Gamow-Teller state." It is expected that low-lying Jπ=1+ GT states have T =0 in the Tz=0 nucleus 42Sc. However, T =1 states are situated in a higher energy region. Assuming an isospin-analogous structure in A =42 isobars, analogous T =1 , 1+ states are also expected in 42Ca. Comparing the (3He 42,tCa) 42Sc and 42Ca(p ,p') spectra measured at 0∘, candidates for T =1 GT states could be found in the 10 -12 -MeV region of 42Sc. They were all weakly excited. The mass dependence of the GT strength distributions in Sc isotopes is also discussed.

Targeting the NF-κB and mTOR pathways with a quinoxaline urea analog that inhibits IKKβ for pancreas cancer therapy.

PubMed

Radhakrishnan, Prakash; Bryant, Vashti C; Blowers, Elizabeth C; Rajule, Rajkumar N; Gautam, Nagsen; Anwar, Muhammad M; Mohr, Ashley M; Grandgenett, Paul M; Bunt, Stephanie K; Arnst, Jamie L; Lele, Subodh M; Alnouti, Yazen; Hollingsworth, Michael A; Natarajan, Amarnath

2013-04-15

The presence of TNF-α in approximately 50% of surgically resected tumors suggests that the canonical NF-κB and the mTOR pathways are activated. Inhibitor of IκB kinase β (IKKβ) acts as the signaling node that regulates transcription via the p-IκBα/NF-κB axis and regulates translation via the mTOR/p-S6K/p-eIF4EBP axis. A kinome screen identified a quinoxaline urea analog 13-197 as an IKKβ inhibitor. We hypothesized that targeting the NF-κB and mTOR pathways with 13-197 will be effective in malignancies driven by these pathways. Retrospective clinical and preclinical studies in pancreas cancers have implicated NF-κB. We examined the effects of 13-197 on the downstream targets of the NF-κB and mTOR pathways in pancreatic cancer cells, pharmacokinetics, toxicity and tumor growth, and metastases in vivo. 13-197 inhibited the kinase activity of IKKβ in vitro and TNF-α-mediated NF-κB transcription in cells with low-μmol/L potency. 13-197 inhibited the phosphorylation of IκBα, S6K, and eIF4EBP, induced G1 arrest, and downregulated the expression of antiapoptotic proteins in pancreatic cancer cells. Prolonged administration of 13-197 did not induce granulocytosis and protected mice from lipopolysaccharide (LPS)-induced death. Results also show that 13-197 is orally available with extensive distribution to peripheral tissues and inhibited tumor growth and metastasis in an orthotopic pancreatic cancer model without any detectable toxicity. These results suggest that 13-197 targets IKKβ and thereby inhibits mTOR and NF-κB pathways. Oral availability along with in vivo efficacy without obvious toxicities makes this quinoxaline urea chemotype a viable cancer therapeutic.

Inhibition of Isolated Mycobacterium tuberculosis Fatty Acid Synthase I by Pyrazinamide Analogs▿

PubMed Central

Ngo, Silvana C.; Zimhony, Oren; Chung, Woo Jin; Sayahi, Halimah; Jacobs, William R.; Welch, John T.

2007-01-01

An analog of pyrazinamide (PZA), 5-chloropyrazinamide (5-Cl-PZA), has previously been shown to inhibit mycobacterial fatty acid synthase I (FASI). FASI has been purified from a recombinant strain of M. smegmatis (M. smegmatis Δfas1 attB::M. tuberculosis fas1). Following purification, FASI activity and inhibition were assessed spectrophotometrically by monitoring NADPH oxidation. The observed inhibition was both concentration and structure dependent, being affected by both substitution at the 5 position of the pyrazine nucleus and the nature of the ester or N-alkyl group. Under the conditions studied, both 5-Cl-PZA and PZA exhibited concentration and substrate dependence consistent with competitive inhibition of FASI with Kis of 55 to 59 μM and 2,567 to 2,627 μM, respectively. The results were validated utilizing a radiolabeled fatty acid synthesis assay. This assay showed that FASI was inhibited by PZA and pyrazinoic acid as well as by a series of PZA analogs. PMID:17485499

Activating mutations in the NT5C2 nucleotidase gene drive chemotherapy resistance in relapsed ALL

PubMed Central

Tzoneva, Gannie; Garcia, Arianne Perez; Carpenter, Zachary; Khiabanian, Hossein; Tosello, Valeria; Allegretta, Maddalena; Paietta, Elisabeth; Racevskis, Janis; Rowe, Jacob M.; Tallman, Martin S.; Paganin, Maddalena; Basso, Giuseppe; Hof, Jana; Kirschner-Schwabe, Renate; Palomero, Teresa; Rabadan, Raul; Ferrando, Adolfo

2013-01-01

Acute lymphoblastic leukemia (ALL) is an aggressive hematological tumor resulting from the malignant transformation of lymphoid progenitors. Despite intensive chemotherapy, 20% of pediatric and over 50% of adult ALL patients fail to achieve a complete remission or relapse after intensified chemotherapy, making disease relapse and resistance to therapy the most significant challenge in the treatment of this disease1,2. Using whole exome sequencing, here we identify mutations in the cytosolic 5'-nucleotidase II gene (NT5C2), which encodes a 5'-nucleotidase enzyme responsible for inactivation of nucleoside analog chemotherapy drugs, in 20/103 (19%) relapse T-ALLs and in 1/35 (3%) relapse B-precursor ALLs analyzed. NT5C2 mutant proteins show increased nucleotidase activity in vitro and conferred resistance to chemotherapy with 6-mercaptopurine and 6-thioguanine when expressed in ALL lymphoblasts. These results support a prominent role for activating mutations in NT5C2 and increased nucleoside analog metabolism in disease progression and chemotherapy resistance in ALL. PMID:23377281

Synthesis and optimization of novel allylated mono-carbonyl analogs of curcumin (MACs) act as potent anti-inflammatory agents against LPS-induced acute lung injury (ALI) in rats.

PubMed

Zhu, Heping; Xu, Tingting; Qiu, Chenyu; Wu, Beibei; Zhang, Yali; Chen, Lingfeng; Xia, Qinqin; Li, Chenglong; Zhou, Bin; Liu, Zhiguo; Liang, Guang

2016-10-04

A series of novel symmetric and asymmetric allylated mono-carbonyl analogs of curcumin (MACs) were synthesized using an appropriate synthetic route and evaluated experimentally thru the LPS-induced expression of TNF-α and IL-6. Most of the obtained compounds exhibited improved water solubility as a hydrochloride salt compared to lead molecule 8f. The most active compound 7a was effective in reducing the Wet/Dry ratio in the lungs and protein concentration in bronchoalveolar lavage fluid. Meanwhile, 7a also inhibited mRNA expression of several inflammatory cytokines, including TNF-α, IL-6, IL-1β, and VCAM-1, in Beas-2B cells after Lipopolysaccharide (LPS) challenge. These results suggest that 7a could be therapeutically beneficial for use as an anti-inflammatory agent in the clinical treatment of acute lung injury (ALI). Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Structural studies of the nudix hydrolase DR1025 from deinococcus radiodurans and its ligand complexes

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ranatunga, Wasantha; Hill, Emma E.; Mooster, Jana L.

We have determined the crystal structure, at 1.4, of the Nudix hydrolase DR1025 from the extremely radiation resistant bacterium Deinococcus radiodurans. The protein forms an intertwined homodimer by exchanging N-terminal segments between chains. We have identified additional conserved elements of the Nudix fold, including the metal-binding motif, a kinked b-strand characterized by a proline two positions upstream of the Nudix consensus sequence, and participation of the N-terminal extension in the formation of the substrate-binding pocket. Crystal structures were also solved of DR1025 crystallized in the presence of magnesium and either a GTP analog or Ap4A (both at 1.6 resolution). Inmore » the Ap4Aco-crystal, the electron density indicated that the product of asymmetric hydrolysis, ATP, was bound to the enzyme. The GTP analog bound structure showed that GTP was bound almost identically as ATP. Neither nucleoside triphosphate was further cleaved.« less

A comparative interregional analysis of selected data from LANDSAT-1 and EREP for the inventory and monitoring of natural ecosystems

NASA Technical Reports Server (NTRS)

Poulton, C. E.

1975-01-01

Comparative statistics were presented on the capability of LANDSAT-1 and three of the Skylab remote sensing systems (S-190A, S-190B, S-192) for the recognition and inventory of analogous natural vegetations and landscape features important in resource allocation and management. Two analogous regions presenting vegetational zonation from salt desert to alpine conditions above the timberline were observed, emphasizing the visual interpretation mode in the investigation. An hierarchical legend system was used as the basic classification of all land surface features. Comparative tests were run on image identifiability with the different sensor systems, and mapping and interpretation tests were made both in monocular and stereo interpretation with all systems except the S-192. Significant advantage was found in the use of stereo from space when image analysis is by visual or visual-machine-aided interactive systems. Some cost factors in mapping from space are identified. The various image types are compared and an operational system is postulated.

Pharmacologic Calcitriol Inhibits Osteoclast Lineage Commitment via the BMP-Smad1 and IκB-NF-κB Pathways.

PubMed

Li, Anna; Cong, Qian; Xia, Xuechun; Leong, Wai Fook; Yeh, James; Miao, Dengshun; Mishina, Yuji; Liu, Huijuan; Li, Baojie

2017-07-01

Vitamin D is involved in a range of physiological processes and its active form and analogs have been used to treat diseases such as osteoporosis. Yet how vitamin D executes its function remains unsolved. Here we show that the active form of vitamin D calcitriol increases the peak bone mass in mice by inhibiting osteoclastogenesis and bone resorption. Although calcitriol modestly promoted osteoclast maturation, it strongly inhibited osteoclast lineage commitment from its progenitor monocyte by increasing Smad1 transcription via the vitamin D receptor and enhancing BMP-Smad1 activation, which in turn led to increased IκBα expression and decreased NF-κB activation and NFATc1 expression, with IκBα being a Smad1 target gene. Inhibition of BMP type I receptor or ablation of Bmpr1a in monocytes alleviated the inhibitory effects of calcitriol on osteoclast commitment, bone resorption, and bone mass augmentation. These findings uncover crosstalk between the BMP-Smad1 and RANKL-NF-κB pathways during osteoclastogenesis that underlies the action of active vitamin D on bone health. © 2017 American Society for Bone and Mineral Research. © 2017 American Society for Bone and Mineral Research.

Physalin B inhibits Rhodnius prolixus hemocyte phagocytosis and microaggregation by the activation of endogenous PAF-acetyl hydrolase activities.

PubMed

Castro, D P; Figueiredo, M B; Genta, F A; Ribeiro, I M; Tomassini, T C B; Azambuja, P; Garcia, E S

2009-06-01

The effects of physalin B (a natural secosteroidal chemical from Physalis angulata, Solanaceae) on phagocytosis and microaggregation by hemocytes of 5th-instar larvae of Rhodnius prolixus were investigated. In this insect, hemocyte phagocytosis and microaggregation are known to be induced by the platelet-activating factor (PAF) or arachidonic acid (AA) and regulated by phospholipase A(2) (PLA(2)) and PAF-acetyl hydrolase (PAF-AH) activities. Phagocytic activity and formation of hemocyte microaggregates by Rhodnius hemocytes were strongly blocked by oral treatment of this insect with physalin B (1mug/mL of blood meal). The inhibition induced by physalin B was reversed for both phagocytosis and microaggregation by exogenous arachidonic acid (10microg/insect) or PAF (1microg/insect) applied by hemocelic injection. Following treatment with physalin B there were no significant alterations in PLA(2) activities, but a significant enhancement of PAF-AH was observed. These results show that physalin B inhibits hemocytic activity by depressing insect PAF analogous (iPAF) levels in hemolymph and confirm the role of PAF-AH in the cellular immune reactions in R. prolixus.

Hepatitis C Virus Nucleotide Inhibitors PSI-352938 and PSI-353661 Exhibit a Novel Mechanism of Resistance Requiring Multiple Mutations within Replicon RNA▿†

PubMed Central

Lam, Angela M.; Espiritu, Christine; Bansal, Shalini; Micolochick Steuer, Holly M.; Zennou, Veronique; Otto, Michael J.; Furman, Phillip A.

2011-01-01

PSI-352938, a cyclic phosphate nucleotide, and PSI-353661, a phosphoramidate nucleotide, are prodrugs of β-d-2′-deoxy-2′-α-fluoro-2′-β-C-methylguanosine-5′-monophosphate. Both compounds are metabolized to the same active 5′-triphosphate, PSI-352666, which serves as an alternative substrate inhibitor of the NS5B RNA-dependent RNA polymerase during HCV replication. PSI-352938 and PSI-353661 retained full activity against replicons containing the S282T substitution, which confers resistance to certain 2′-substituted nucleoside/nucleotide analogs. PSI-352666 was also similarly active against both wild-type and S282T NS5B polymerases. In order to identify mutations that confer resistance to these compounds, in vitro selection studies were performed using HCV replicon cells. While no resistant genotype 1a or 1b replicons could be selected, cells containing genotype 2a JFH-1 replicons cultured in the presence of PSI-352938 or PSI-353661 developed resistance to both compounds. Sequencing of the NS5B region identified a number of amino acid changes, including S15G, R222Q, C223Y/H, L320I, and V321I. Phenotypic evaluation of these mutations indicated that single amino acid changes were not sufficient to significantly reduce the activity of PSI-352938 and PSI-353661. Instead, a combination of three amino acid changes, S15G/C223H/V321I, was required to confer a high level of resistance. No cross-resistance exists between the 2′-F-2′-C-methylguanosine prodrugs and other classes of HCV inhibitors, including 2′-modified nucleoside/-tide analogs such as PSI-6130, PSI-7977, INX-08189, and IDX-184. Finally, we determined that in genotype 1b replicons, the C223Y/H mutation failed to support replication, and although the A15G/C223H/V321I triple mutation did confer resistance to PSI-352938 and PSI-353661, this mutant replicated at only about 10% efficiency compared to the wild type. PMID:21957306

Grassystatins A–C from Marine Cyanobacteria, Potent Cathepsin E Inhibitors that Reduce Antigen Presentation

PubMed Central

Kwan, Jason C.; Eksioglu, Erika A.; Liu, Chen; Paul, Valerie J.; Luesch, Hendrik

2009-01-01

In our efforts to explore marine cyanobacteria as a source of novel bioactive compounds we discovered a statine unit-containing linear decadepsipeptide, grassystatin A (1), which we screened against a diverse set of 59 proteases. We describe the structure determination of 1 and two natural analogs, grassystatins B (2) and C (3), using NMR, MS, and chiral HPLC techniques. Compound 1 selectively inhibited cathepsins D and E with IC50s of 26.5 nM and 886 pM, respectively. Compound 2 showed similar potency and selectivity against cathepsins D and E (IC50s 7.27 nM and 354 pM, respectively), whereas the truncated peptide analog grassystatin C (3), which consists of two fewer residues than 1 and 2, was less potent against both but still selective for cathepsin E. The selectivity of compounds 1–3 for cathepsin E over D (20- to 38-fold) suggests that these natural products may be useful tools to probe cathepsin E function. We investigated the structural basis of this selectivity using molecular docking. We also show that 1 can reduce antigen presentation by dendritic cells, a process thought to rely on cathepsin E. PMID:19715320

A digitally controlled AGC loop circuitry for GNSS receiver chip with a binary weighted accurate dB-linear PGA

NASA Astrophysics Data System (ADS)

Gang, Jin; Yiqi, Zhuang; Yue, Yin; Miao, Cui

2015-03-01

A novel digitally controlled automatic gain control (AGC) loop circuitry for the global navigation satellite system (GNSS) receiver chip is presented. The entire AGC loop contains a programmable gain amplifier (PGA), an AGC circuit and an analog-to-digital converter (ADC), which is implemented in a 0.18 μm complementary metal-oxide-semiconductor (CMOS) process and measured. A binary-weighted approach is proposed in the PGA to achieve wide dB-linear gain control with small gain error. With binary-weighted cascaded amplifiers for coarse gain control, and parallel binary-weighted trans-conductance amplifier array for fine gain control, the PGA can provide a 64 dB dynamic range from -4 to 60 dB in 1.14 dB gain steps with a less than 0.15 dB gain error. Based on the Gaussian noise statistic characteristic of the GNSS signal, a digital AGC circuit is also proposed with low area and fast settling. The feed-backward AGC loop occupies an area of 0.27 mm2 and settles within less than 165 μs while consuming an average current of 1.92 mA at 1.8 V.

The crystal structure of synthetic simmonsite, Na 2LiAlF 6

NASA Astrophysics Data System (ADS)

Ross, Kirk C.; Mitchell, Roger H.; Chakhmouradian, Anton R.

2003-04-01

The structure of the synthetic fluoroperovskite, Na 2LiAlF 6 (simmonsite), has been determined by powder X-ray diffraction using the Rietveld method of structure refinement. The compound adopts space group P2 1/ n [#14; a=5.2842(1); b=5.3698(1); c=7.5063(2) Å; β=89.98(1)°; Z=4), and is a member of the cryolite (Na 2NaAlF 6) structural group characterized by ordering of the B-site cations (Li, Al) and tilting of the BF 6 octahedra according to the tilt scheme a-b-c+. Rotations of the B-site polyhedra are less ( ΦLi=14.9°; ΦAl=17.0°) than those found in cryolite ( ΦNa=18.6; ΦAl=23.5°) because of the larger difference in the ionic radii of the B-site cations in cryolite as compared to those in simmonsite. Na at the A-site is displaced from the special position resulting in 10- and 8-fold coordination in simmonsite and cryolite, respectively. By analogy with the synthetic compound, naturally occurring simmonsite is considered to adopt space group P2 1/ n (#14) and not the P2 1(#4) or P2 1/ m(#11) space groups.

Synthesis and activity of a novel diether phosphonoglycerol in phospholipase-resistant synthetic lipid:peptide lung surfactants†

PubMed Central

Schwan, Adrian L.; Singh, Suneel P.; Davy, Jason A.; Waring, Alan J.; Gordon, Larry M.; Walther, Frans J.; Wang, Zhengdong; Notter, Robert H.

2012-01-01

This paper reports the chemical synthesis and purification of a novel phospholipase-resistant C16:0, C16:1 diether phosphonoglycerol with structural analogy to ester-linked anionic phosphatidylglycerol (PG) in endogenous pulmonary surfactant. This diether phosphonoglycerol (PG 1) is studied for phospholipase A2 (PLA2) resistance and for surface activity in synthetic exogenous surfactants combined with Super Mini-B (S-MB) peptide and DEPN-8, a previously-reported diether phosphonolipid analog of dipalmitoyl phosphatidylcholine (DPPC, the major zwitterionic phospholipid in native lung surfactant). Activity experiments measured both adsorption and dynamic surface tension lowering due to the known importance of these surface behaviors in lung surfactant function in vivo. Synthetic surfactants containing 9 : 1 DEPN-8:PG 1 + 3% S-MB were resistant to degradation by PLA2 in chromatographic studies, while calf lung surfactant extract (CLSE, the substance of the bovine clinical surfactant Infasurf®) was significantly degraded by PLA2. The 9 : 1 DEPN-8:PG 1 + 3% S-MB mixture also had small but consistent increases in both adsorption and dynamic surface tension lowering ability compared to DEPN-8 + 3% S-MB. Consistent with these surface activity increases, molecular dynamics simulations using Protein Modeller, GROMACS force-field, and PyMOL showed that bilayers containing DPPC and palmitoyl-oleoyl-PC (POPC) as surrogates of DEPN-8 and PG 1 were penetrated to a greater extent by S-MB peptide than bilayers of DPPC alone. These results suggest that PG 1 or related anionic phosphono-PG analogs may have functional utility in phospholipase-resistant synthetic surfactants targeting forms of acute pulmonary injury where endogenous surfactant becomes dysfunctional due to phospholipase activity in the innate inflammatory response. PMID:22530092

Relative Potency for Altered Humoral Immunity Induced by Polybrominated and Polychlorinated Dioxins/Furans in Female B6C3F1/N Mice

PubMed Central

Frawley, Rachel; DeVito, Michael; Walker, Nigel J.; Birnbaum, Linda; White, Kimber; Smith, Matthew; Maynor, Timothy; Recio, Leslie; Germolec, Dori

2014-01-01

The use of brominated flame retardants and incineration of bromine-containing materials has lead to an increase in polybrominated dibenzo-p-dioxins and dibenzofurans (PBDD/Fs) in the environment. Measurable amounts of PBDD/Fs have been detected in soil, seafood, and human breast milk and serum. Studies indicate that the relative potencies of some PBDD/Fs based on enzyme induction are equivalent to those of some polychlorinated dibenzo-p-dioxins and dibenzofurans. To assess the humoral immunity relative potencies of PBDD/Fs and compare them to their chlorinated analogs, female B6C3F1/N mice received a single oral exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), 2,3,7,8-tetrabromodibenzofuran (TBDF), 2,3,7,8-tetrachlorodibenzofuran (TCDF), 1,2,3,7,8-pentabromodibenzofuran (1PeBDF), 1,2,3,7,8-pentachlorodibenzofuran (1PeCDF), 2,3,4,7,8-pentabromodibenzofuran (4PeBDF), 2,3,4,7,8-pentachlorodibenzofuran (4PeCDF), 2,3-dibromo-7,8-dichlorodibenzo-p-dioxin (DBDCDD), or 2,3,7-tribromodibenzo-p-dioxin (TriBDD). Inhibition of the immunoglobulin M (IgM) antibody forming cell response was measured 4 days following immunization with sheep red blood cells. The data were fit to a Hill model to estimate the ED50 for inhibition. Expression of xenobiotic metabolizing enzyme (XME) and thyroxine transport protein (Ttr) genes in liver was measured by PCR to assess aryl hydrocarbon-mediated responses. TCDD, TBDF, TCDF, 1PeBDF, 4PeBDF, 4PeCDF, and DBDCDD suppressed the IgM antibody response and Ttr gene expression, and upregulated phase I XME genes. 1PeCDF suppressed the IgM antibody response but only upregulated phase I XME genes; TriBDD had no effect on antibody response. The rank order of potency (ED50) for these chemicals was TCDD>TBDF>4PeBDF>TCDF/4PeCDF/1PeBDF>1PeCDF. Whereas TCDD was the most potent compound tested, the brominated analogs were more potent than their chlorinated analogs, suggesting that these compounds should be considered in toxic equivalency factor evaluation and risk assessment. PMID:24713691

Da0324, an inhibitor of nuclear factor-κB activation, demonstrates selective antitumor activity on human gastric cancer cells

PubMed Central

Jin, Rong; Xia, Yiqun; Chen, Qiuxiang; Li, Wulan; Chen, Dahui; Ye, Hui; Zhao, Chengguang; Du, Xiaojing; Shi, Dengjian; Wu, Jianzhang; Liang, Guang

2016-01-01

Background The transcription factor nuclear factor-κB (NF-κB) is constitutively activated in a variety of human cancers, including gastric cancer. NF-κB inhibitors that selectively kill cancer cells are urgently needed for cancer treatment. Curcumin is a potent inhibitor of NF-κB activation. Unfortunately, the therapeutic potential of curcumin is limited by its relatively low potency and poor cellular bioavailability. In this study, we presented a novel NF-κB inhibitor named Da0324, a synthetic asymmetric mono-carbonyl analog of curcumin. The purpose of this study is to research the expression of NF-κB in gastric cancer and the antitumor activity and mechanism of Da0324 on human gastric cancer cells. Methods The expressions between gastric cancer tissues/cells and normal gastric tissues/cells of NF-κB were evaluated by Western blot. The inhibition viability of compounds on human gastric cancer cell lines SGC-7901, BGC-823, MGC-803, and normal gastric mucosa epithelial cell line GES-1 was assessed with the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide assay. Absorption spectrum method and high-performance liquid chromatography method detected the stability of the compound in vitro. The compound-induced changes of inducible NF-κB activation in the SGC-7901 and BGC-823 cells were examined by Western blot analysis and immunofluorescence methods. The antitumor activity of compound was performed by clonogenic assay, matrigel invasion assay, flow cytometric analysis, Western blot analysis, and Hoechst 33258 staining assay. Results High levels of p65 were found in gastric cancer tissues and cells. Da0324 displayed higher growth inhibition against several types of gastric cancer cell lines and showed relatively low toxicity to GES-1. Moreover, Da0324 was more stable than curcumin in vitro. Western blot analysis and immunofluorescence methods showed that Da0324 blocked NF-κB activation. In addition, Da0324 significantly inhibited tumor proliferation and invasion, arrested the cell cycle, and induced apoptosis in vitro. Conclusion The asymmetric mono-carbonyl analog of curcumin Da0324 exhibited significantly improved antigastric cancer activity. Da0324 may be a promising NF-κB inhibitor for the selective targeting of cancer cells. However, further studies are needed in animals to validate these findings for the therapeutic use of Da0324. PMID:27042000

Formation of a repressive complex in the mammalian circadian clock is mediated by the secondary pocket of CRY1

DOE PAGES

Michael, Alicia K.; Fribourgh, Jennifer L.; Chelliah, Yogarany; ...

2017-01-31

The basic helix-loop-helix PAS domain (bHLH-PAS) transcription factor CLOCK:BMAL1 (brain and muscle Arnt-like protein 1) sits at the core of the mammalian circadian transcription/translation feedback loop. Precise control of CLOCK:BMAL1 activity by coactivators and repressors establishes the ~24-h periodicity of gene expression. Formation of a repressive complex, defined by the core clock proteins cryptochrome 1 (CRY1):CLOCK:BMAL1, plays an important role controlling the switch from repression to activation each day. Here in this paper, we show that CRY1 binds directly to the PAS domain core of CLOCK: BMAL1, driven primarily by interaction with the CLOCK PAS-B domain. Integrative modeling and solutionmore » X-ray scattering studies unambiguously position a key loop of the CLOCK PAS-B domain in the secondary pocket of CRY1, analogous to the antenna chromophore-binding pocket of photolyase. CRY1 docks onto the transcription factor alongside the PAS domains, extending above the DNA-binding bHLH domain. Single point mutations at the interface on either CRY1 or CLOCK disrupt formation of the ternary complex, highlighting the importance of this interface for direct regulation of CLOCK:BMAL1 activity by CRY1.« less

Strigolactone analogs derived from ketones using a working model for germination stimulants as a blueprint.

PubMed

Mwakaboko, Alinanuswe S; Zwanenburg, Binne

2011-04-01

Strigolactones are important signaling compounds in the plant kingdom. Here we focus on their germination stimulatory effect on seeds of the parasitic weeds Striga and Orobanche spp. and more particularly on the design and synthesis of new active strigolactone analogs derived from simple cyclic ketones. New analogs derived from 1-indanone, 1-tetralone, cyclopentanone, cyclohexanone and a series of substituted cyclohexanones (including carvone and pulegone) are prepared by formylation of the ketones with ethyl formate followed by coupling with a halo butenolide. Both enantiomers of the analog derived from 1-tetralone have been prepared by employing a homochiral synthon for the coupling reaction. For three other strigolactone analogs the antipodes have been obtained by chromatography on a chiral column. All analogs have an appreciable germinating activity towards seeds of Striga hermomonthica and Orobanche crenata and O. cernua. Stereoisomers having the same configuration at the D-ring as in naturally occurring strigol have a higher stimulatory effect than the corresponding antipodes. The analogs obtained from 1-indanone and 1-tetralone have an activity comparable with that of the well known stimulant GR 24. Analogs derived from 2-phenyl-cylohexanone, carvone and pulegone also have a good germinating response. The results show that the working model for designing new bioactive strigolactones is applicable.

A novel synthetic analog of militarin, MA-1 induces mitochondrial dependent apoptosis by ROS generation in human lung cancer cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yoon, Deok Hyo; Lim, Mi-Hee; Lee, Yu Ran

A synthetic Militarin analog-1[(2R,3R,4R,5R)-1,6-bis(4-(2,4,4-trimethylpentan-2-yl)phenoxy) hexane-2,3,4,5-tetraol] is a novel derivative of constituents from Cordyceps militaris, which has been used to treat a variety of chronic diseases including inflammation, diabetes, hyperglycemia and cancers. Here, we report for the first time the synthesis of Militarin analog-1 (MA-1) and the apoptotic mechanism of MA-1 against human lung cancer cell lines. Treatment with MA-1 significantly inhibited the viability of 3 human lung cancer cell lines. The inhibition of viability and growth in MA-1-treated A549 cells with an IC{sub 50} of 5 μM were mediated through apoptosis induction, as demonstrated by an increase in DNA fragmentation,more » sub-G{sub 0}/G{sub 1}-DNA fraction, nuclear condensation, and phosphatidylserine exposure. The apoptotic cell death caused mitochondrial membrane permeabilization through regulation of expression of the Bcl-2 family proteins, leading to cytochrome c release in a time-dependent manner. Subsequently, the final stage of apoptosis, activation of caspase-9/-3 and cleavage of poly (ADP ribose) polymerase, was induced. Furthermore, A549 lung cancer cells were more responsive to MA-1 than a bronchial epithelial cell line (BEAS-2B), involving the rapid generation of reactive oxygen species (ROS), c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK) activation. The pharmacological inhibition of ROS generation and JNK/p38 MAPK exhibited attenuated DNA fragmentation in MA-1-induced apoptosis. Oral administration of MA-1 also retarded growth of A549 orthotopic xenografts. In conclusion, the present study indicates that the new synthetic derivative MA-1 triggers mitochondrial apoptosis through ROS generation and regulation of MAPKs and may be a potent therapeutic agent against human lung cancer. - Highlights: • We report a novel synthesized derivative, militarin analog-1 (MA-1). • MA-1-induced cancer cell death was triggered by the ROS generation through MAPKs. • The MA-1-induced cell death was also modulated by the mitochondria-mediated pathway. • The apoptotic cancer cell death by MA-1 was also exhibited in orthotopic xenografts. • Our findings suggest MA-1 as a clinically useful agent for human lung cancer.« less

f-electron dependence of the physical properties of REAlB4; an AlB2-type analogous "tiling" compound

NASA Astrophysics Data System (ADS)

Mori, T.; Kudou, K.; Shishido, T.; Okada, S.

2011-04-01

α-HoAlB4 and α-ErAlB4 were synthesized, and their magnetic properties and specific heat investigated in comparison with other known rare-earth analogs. Recent developments in rare-earth aluminoboride compounds with two-dimensional boron layers have attracted interest due to the heavy fermion superconductivity in β-YbAlB4, multiple anomalies manifesting below the Néel temperatures in α-TmAlB4 attributed to intrinsic building defects, and field stable state in Tm2 AlB6. Strikingly, α-HoAlB4 and α-ErAlB4 were discovered to exhibit superparamagnetic or spin glass behavior in contrast to the magnetic ordering or nonordering observed for the other rare-earth element compounds. The magnetic field dependence of the irreversibility was consistent with the de Almeida Thouless (AT) line versus the quadratic suppression typically observed for antiferromagnetic systems. The specific heat exhibited behavior indicative of a multilevel Schottky anomaly and four states of the 5 I8 Hund's rule multiplet of Ho3+ are indicated to lie below 20 K. While building defects are not evident, it is indicated that disorder is strong in α-HoAlB4 and α-ErAlB4 and possible ferromagnetic interactions can be giving rise to frustration.

Isobar analog states (IAS), double isobar analog states (DIAS), configuration states (CS), and double configuration states (DCS) in halo nuclei. Halo isomers

NASA Astrophysics Data System (ADS)

Izosimov, I. N.

2015-10-01

It has been shown that IAS, DIAS, CS, and DCS can simultaneously have n-n, n-p, and p-p halo components in their wave functions. Differences in halo structure of the excited and ground states can result in the formation of isomers (halo-isomers). Both the Borromean and tango halo types can be observed for n-p configurations of atomic nuclei. The structure of the ground and excited states with different isospin quantum number in halo like nuclei is discussed. B(Mλ) and B(Eλ) for γ-transitions in 6,7,8Li, 8,9,10Be, 8,10,11B, 10,11,12,13,14C, 13,14,15,16,17N, 15,16,17,19O, and 17F are analyzed. Special attention is given to nuclei whose ground state does not exhibit halo structure but the excited state may have one.

Organics-bearing Clays from the Rio Tinto (spain): A Novel Analog for the Phyllosilicates Outcrops Seen By Omega-mex

NASA Astrophysics Data System (ADS)

Bonaccorsi, Rosalba

2007-12-01

The Rio Tinto (RT) is considered an important analog of Sinus Meridiani on Mars and an ideal model analog for a subsurface Martian setting [1]. The RT system comprises the upper sequence of an acid rock drainage system where weathered iron -rich rocks, overlain a massive-pyrite deposit. The RT analog site is ideal for testing on the preservation of organics in hematite-rich vs. phyllosilicates-rich environments [3]. It is suggested here that RT near-surface rocks, which embed pockets of Clays, represent also a potential new model analog for the phyllosilicates-rich outcrops seen by OMEGA-MEx on the surface of Mars [5]. Results from the analysis of cores drilled under the 2005 Robotic experiment of the MARTE project (Borehole#7 Site 607cm) [2-3] are presented in this paper. Primary mineral assemblages include hematite, goethite, and Phyllosilicates e.g.,smectite, kaolinite, as quantified by X-ray diffraction [4]. Organic carbon is at low concentration (<0.05%) beneath the soil horizon in most cores dominated by iron minerals but is considerably higher in Phyllosilicate-rich levels i.e., 0.2-0.3Wt% at 385 -550 cm-depth [2-3]. Phyllosilicate-rich terrains have been identified OMEGA/MEx in the Nili Fossae, Mawrth Valles and Candor Chasma regions [e.g., 5]. These outcrops are surrounded by hematite-rich deposits, which are potentially barren in organics [6]. The potential of phyllosilicates to preserve higher amounts of organics/ biosignatures is well known for several Earth environments as well as the RT near subsurface. This potential brings a relevant element for the selection of candidate sites for the MSL mission [e.g., 1]. References: [1]Fernandez-Remolar et al.,2005 EPSL, 240,149-167; [2]Stoker et al., 2007; [3] Bonaccorsi et al., 2007; [4] Sutter et al., 2007 in Astrobiology,MARTE Spec. Issue; [5] Bibring et al., 2006, Science 312, 400-404; [6] Sumner, 2004, JGR 109. Anknowlegments: NASA-Postdoctoral-Program/C.Stoker, B.Sutter, A.F Davila and the MARTE team for valuable suggestions.

[Comparative immunophenotypic characterization of human and monkey permanent lymphoid culture cells].

PubMed

Agrba, V Z; Lapin, B A; Medvedeva, N M; Ignatova, I E; Karal-Ogly, D D

2007-01-01

The aim of the study was to define the comparative immunophenotypic characteristics ofwidely spread lymphoid cell cultures, derived from Burkett's lymphoma named as Raji and P3HR-1 in comparison with analogous monkey cultures. It has been shown that P3HR-1 culture consists of similar type cells - activated B-lymphocytes CD23 with k phenotype, which demonstrates its monoclonality. Raji culture includes cells with markers of immature B-lymphocytes CD10 and CD24, as well as elements expressing CD10 antigens. T-cell markers were found in none of the cultures. In contrast to human cells, monkey lymphoid culture expressed both B- and T-cell markers. Moreover, in one of them, obtained from a green monkey, T-cells of suppressor type (CD8) prevailed. The immunophenotypic characteristics of primate lymphoid cell cultures, revealed by the study, are of great importance for their proper application to medical and biological studies.

Abstracts of the International Symposium on Gas Kinetics (9th) Held in Talence (France) on 20-25 July 1986.

DTIC Science & Technology

1986-07-25

1 - chloropropane is much higher than unity. We were interested In the alternative radical chain process which is strongly inhibited by the products...AD-A174 474 flj? s 1 /JUL UNCLASSIFIED I/- ~-~J4-S..g1F/C 7/4 PL NW100 2- o use 1315 1112-2. -U- 1 *18 I11I 1 - I11I15 11-61 UNIVERSITY OF BORDEAUX...10.20 A2 Study of the H + H2 (V = 1 ) reaction and its isotopic analogs. V.B. Rozenshtein, Y.M. Gershenzon, A.V. Ivanov, S.D. Ilin, S.I. Kucheryavii

Quinoxaline-substituted chalcones as new inhibitors of breast cancer resistance protein ABCG2: polyspecificity at B-ring position

PubMed Central

Winter, Evelyn; Gozzi, Gustavo Jabor; Chiaradia-Delatorre, Louise Domeneghini; Daflon-Yunes, Nathalia; Terreux, Raphael; Gauthier, Charlotte; Mascarello, Alessandra; Leal, Paulo César; Cadena, Silvia M; Yunes, Rosendo Augusto; Nunes, Ricardo José; Creczynski-Pasa, Tania Beatriz; Di Pietro, Attilio

2014-01-01

A series of chalcones substituted by a quinoxaline unit at the B-ring were synthesized and tested as inhibitors of breast cancer resistance protein-mediated mitoxantrone efflux. These compounds appeared more efficient than analogs containing other B-ring substituents such as 2-naphthyl or 3,4-methylenedioxyphenyl while an intermediate inhibitory activity was obtained with a 1-naphthyl group. In all cases, two or three methoxy groups had to be present on the phenyl A-ring to produce a maximal inhibition. Molecular modeling indicated both electrostatic and steric positive contributions. A higher potency was observed when the 2-naphthyl or 3,4-methylenedioxyphenyl group was shifted to the A-ring and methoxy substituents were shifted to the phenyl B-ring, indicating preferences among polyspecificity of inhibition. PMID:24920885

Anti-tumorigenic effects of a novel digitoxin derivative on both estrogen receptor-positive and triple-negative breast cancer cells.

PubMed

Kulkarni, Yogesh M; Yakisich, Juan S; Azad, Neelam; Venkatadri, Rajkumar; Kaushik, Vivek; O'Doherty, George; Iyer, Anand Krishnan V

2017-06-01

While there are targeted treatments for triple positive breast cancers, lack of specific biomarkers for triple-negative breast cancers (TNBC) has hindered the development of therapies for this subset of cancers. In this study, we evaluated the anticancer properties of cardiac glycoside Digitoxin (Dtx) and its synthetic analog MonoD on breast cancer cell lines MCF-7 (estrogen receptor-positive breast cancer) and MDA-MB-468 (triple-negative breast cancer). Both cardiac glycosides, at concentrations within the therapeutic range, increased the fraction of cells in the G 0 /G 1 phase of the cell cycle, decreased viability, and inhibited the migration of MCF-7 and MDA-MB-468 cells. Both cardiac glycosides increased production of superoxide and induced apoptosis in both cell types. Reduced protein levels of nuclear factor kappa B and IkappaB kinase-beta were found in cardiac glycoside-treated cells, indicating that the cellular effects of these compounds are mediated via nuclear factor kappa B pathway. This study demonstrates the cytotoxic potential of digitoxin, and more importantly its synthetic analog MonoD, in the treatment of triple-positive breast cancer and more importantly the aggressive triple-negative breast cancer. Collectively, this study provides a basis for the reevaluation of cardiac glycosides in the treatment of breast cancer and more importantly reveals their potential in the treatment of triple-negative breast cancers.

Fully Integrated Biopotential Acquisition Analog Front-End IC

PubMed Central

Song, Haryong; Park, Yunjong; Kim, Hyungseup; Ko, Hyoungho

2015-01-01

A biopotential acquisition analog front-end (AFE) integrated circuit (IC) is presented. The biopotential AFE includes a capacitively coupled chopper instrumentation amplifier (CCIA) to achieve low input referred noise (IRN) and to block unwanted DC potential signals. A DC servo loop (DSL) is designed to minimize the offset voltage in the chopper amplifier and low frequency respiration artifacts. An AC coupled ripple rejection loop (RRL) is employed to reduce ripple due to chopper stabilization. A capacitive impedance boosting loop (CIBL) is designed to enhance the input impedance and common mode rejection ratio (CMRR) without additional power consumption, even under an external electrode mismatch. The AFE IC consists of two-stage CCIA that include three compensation loops (DSL, RRL, and CIBL) at each CCIA stage. The biopotential AFE is fabricated using a 0.18 µm one polysilicon and six metal layers (1P6M) complementary metal oxide semiconductor (CMOS) process. The core chip size of the AFE without input/output (I/O) pads is 10.5 mm2. A fourth-order band-pass filter (BPF) with a pass-band in the band-width from 1 Hz to 100 Hz was integrated to attenuate unwanted signal and noise. The overall gain and band-width are reconfigurable by using programmable capacitors. The IRN is measured to be 0.94 µVRMS in the pass band. The maximum amplifying gain of the pass-band was measured as 71.9 dB. The CIBL enhances the CMRR from 57.9 dB to 67 dB at 60 Hz under electrode mismatch conditions. PMID:26437404

Effects of bisphenol A and its analogs bisphenol F and S on life parameters, antioxidant system, and response of defensome in the marine rotifer Brachionus koreanus.

PubMed

Park, Jun Chul; Lee, Min-Chul; Yoon, Deok-Seo; Han, Jeonghoon; Kim, Moonkoo; Hwang, Un-Ki; Jung, Jee-Hyun; Lee, Jae-Seong

2018-06-01

To understand the adverse outcome in response to bisphenol A and its analogs bisphenol F and S (BPA, BPF, and BPS), we examined acute toxicity, life parameter, and defensome in the marine rotifer Brachionus koreanus. Among the bisphenol analogs, BPA showed the highest acute toxicity and then BPF and BPS, accordingly in the view of descending magnitude of toxicity. In life parameters including life span and reproduction, BPA, BPF, and BPS were found to cause adverse effect. Both intracellular ROS level and GST activity were significantly increased (P < 0.05) in response to each dosage of bisphenol analogs exposures. In response to bisphenol analogs, defensomes of phase I, II, and III detoxification mechanism demonstrated inverse relationship between the lipophilicity of bisphenol analogs and the expression patterns of defensomes. BPA and BPF were found to have significant modulation (P < 0.05) in the expression of cytochrome P450 (CYP) and GST genes. In phase III, BPS with comparatively lower lipophilicity demonstrated highly diversified expressional pattern, suggesting that BPS is likely caused less toxicity compared to BPA and BPF. In this study, via phase I, II, and III detoxification mechanism, bisphenol A and its analogs F and S demonstrated specific detoxification mechanism in rotifer. Copyright © 2018 Elsevier B.V. All rights reserved.

A New N-methoxypyridone from the Co-Cultivation of Hawaiian Endophytic Fungi Camporesia sambuci FT1061 and Epicoccum sorghinum FT1062.

PubMed

Li, Chunshun; Sarotti, Ariel M; Yang, Baojun; Turkson, James; Cao, Shugeng

2017-07-12

A new N -methoxypyridone analog ( 1 ), together with four known compounds, was isolated from the co-culture of Hawaiian endophytic fungi Camporesia sambuci FT1061 and Epicoccum sorghinum FT1062. The structure of the new compound was elucidated as 11 S -hydroxy-1-methoxyfusaricide ( 1 ) by extensive spectroscopic analysis and comparison with the literature. The absolute configuration of 1 was determined by comparison with the experimental and calculated ECD spectra. The absolute configuration of compound 3 was investigated and renamed as (+)-epipyridone by comparison of the optical rotation and CD spectrum with those of 1 . The other known compounds were identified as epicoccarine B ( 2 ), D8646-2-6 ( 4 ), and iso-D8646-2-6 ( 5 ). Compounds 4 and 5 showed modest inhibitory activity towards pathogenic fungi. Epicoccarine B ( 2 ) inhibited A2780 and TK-10 with an IC 50 value of 22 μM.

Performance analysis of InGaAs/GaAsP heterojunction double gate tunnel field effect transistor

NASA Astrophysics Data System (ADS)

Ahish, S.; Sharma, Dheeraj; Vasantha, M. H.; Kumar, Y. B. N.

2017-03-01

In this paper, analog/RF performance of InGaAs/GaAsP heterojunction double gate tunnel field effect transistor (HJTFET) has been explored. A highly doped n+ layer is placed at the Source-Channel junction in order to improve the horizontal electric field component and thus, improve the realiability of the device. The analog performance of the device is analysed by extracting current-voltage characteristics, transcondutance (gm), gate-to-drain capacitance (Cgd) and gate-to-source capacitance (Cgs). Further, RF performance of the device is evaluated by obtaining cut-off frequency (fT) and Gain Bandwidth (GBW) product. ION /IOFF ratio equal to ≈ 109, subthreshold slope of 27 mV/dec, maximum fT of 2.1 THz and maximum GBW of 484 GHz were achieved. Also, the impact of temperature variation on the linearity performance of the device has been investigated. Furthermore, the circuit level performance of the device is performed by implementing a Common Source (CS) amplifier; maximum gain of 31.11 dB and 3-dB cut-off frequency equal to 91.2 GHz were achieved for load resistance (RL) = 17.5 KΩ.

Ensemble Atmospheric Properties of Small Planets around M Dwarfs

NASA Astrophysics Data System (ADS)

Guo, Xueying; Ballard, Sarah; Dragomir, Diana

2018-01-01

With the growing number of planets discovered by the Kepler mission and ground-base surveys, people start to try to understand the atmospheric features of those uncovered new worlds. While it has been found that hot Jupiters exhibit diverse atmosphere composition with both clear and cloudy/hazy atmosphere possible, similar studies on ensembles of smaller planets (Earth analogs) have been held up due to the faintness of most of their host stars. In this work, a sample of 20 Earth analogs of similar periods around M dwarfs with existing Kepler transit information and Spitzer observations is composed, complemented with previously studies GJ1214b and GJ1132b, as well as the recently announced 7 small planets in the TRAPPIST-1 system. We evaluate their transit depths with uncertainties on the Spitzer 4.5 micron band using the “pixel-level decorrelation” method, and together with their well analyzed Kepler data and Hubble data, we put constraints on their atmosphere haze slopes and cloud levels. Aside from improving the understanding of ensemble properties of small planets, this study will also provide clues of potential targets for detailed atmospheric studies using the upcoming James Webb Telescope.

In vitro remineralization of hybrid layers using biomimetic analogs*

PubMed Central

Lin, Hui-ping; Lin, Jun; Li, Juan; Xu, Jing-hong; Mehl, Christian

2016-01-01

Resin-dentin bond degradation is a major cause of restoration failures. The major aim of the current study was to evaluate the impact of a remineralization medium on collagen matrices of hybrid layers of three different adhesive resins using nanotechnology methods. Coronal dentin surfaces were prepared from freshly extracted premolars and bonded to composite resin using three adhesive resins (FluoroBond II, Xeno-III-Bond, and iBond). From each tooth, two central slabs were selected for the study. The slabs used as controls were immersed in a simulated body fluid (SBF). The experimental slabs were immersed in a Portland cement-based remineralization medium that contained two biomimetic analogs (biomineralization medium (BRM)). Eight slabs per group were retrieved after 1, 2, 3, and 4 months, respectively and immersed in Rhodamine B for 24 h. Confocal laser scanning microscopy was used to evaluate the permeability of hybrid layers to Rhodamine B. Data were analyzed by analysis of variance (ANOVA) and Tukey’s honest significant difference (HSD) tests. After four months, all BRM specimens exhibited a significantly smaller fluorescent area than SBF specimens, indicating a remineralization of the hybrid layer (P≤0.05). A clinically applicable biomimetic remineralization delivery system could potentially slow down bond degradation. PMID:27819133

In vitro remineralization of hybrid layers using biomimetic analogs.

PubMed

Lin, Hui-Ping; Lin, Jun; Li, Juan; Xu, Jing-Hong; Mehl, Christian

Resin-dentin bond degradation is a major cause of restoration failures. The major aim of the current study was to evaluate the impact of a remineralization medium on collagen matrices of hybrid layers of three different adhesive resins using nanotechnology methods. Coronal dentin surfaces were prepared from freshly extracted premolars and bonded to composite resin using three adhesive resins (FluoroBond II, Xeno-III-Bond, and iBond). From each tooth, two central slabs were selected for the study. The slabs used as controls were immersed in a simulated body fluid (SBF). The experimental slabs were immersed in a Portland cement-based remineralization medium that contained two biomimetic analogs (biomineralization medium (BRM)). Eight slabs per group were retrieved after 1, 2, 3, and 4 months, respectively and immersed in Rhodamine B for 24 h. Confocal laser scanning microscopy was used to evaluate the permeability of hybrid layers to Rhodamine B. Data were analyzed by analysis of variance (ANOVA) and Tukey's honest significant difference (HSD) tests. After four months, all BRM specimens exhibited a significantly smaller fluorescent area than SBF specimens, indicating a remineralization of the hybrid layer (P≤0.05). A clinically applicable biomimetic remineralization delivery system could potentially slow down bond degradation.

Lunar Analog

NASA Technical Reports Server (NTRS)

Cromwell, Ronita L.

2009-01-01

In this viewgraph presentation, a ground-based lunar analog is developed for the return of manned space flight to the Moon. The contents include: 1) Digital Astronaut; 2) Bed Design; 3) Lunar Analog Feasibility Study; 4) Preliminary Data; 5) Pre-pilot Study; 6) Selection of Stockings; 7) Lunar Analog Pilot Study; 8) Bed Design for Lunar Analog Pilot.

Study of temperature effect on junctionless Si nanotube FET concerning analog/RF performance

NASA Astrophysics Data System (ADS)

Tayal, Shubham; Nandi, Ashutosh

2018-06-01

This paper for the first time investigates the effect of temperature variation on analog/RF performance of SiO2 as well as high-K gate dielectric based junctionless silicon nanotube FET (JL-SiNTFET). It is observed that the change in temperature does not variate the analog/RF performance of junctionless silicon nanotube FET by substantial amount. By increasing the temperature from 77 K to 400 K, the deterioration in intrinsic dc gain (AV) is marginal that is only ∼3 dB. Furthermore, the variation in cut-off frequency (fT), maximum oscillation frequency (fMAX), and gain-frequency product (GFP) with temperature is also minimal in JLSiNT-FET. More so, the same trend is observed even at scaled gate length (Lg = 15 nm). Furthermore, we have observed that the use of high-K gate dielectric deteriorates the analog/RF performance of JLSiNT-FET. However, the use of high-K gate dielectric negligibly changes the effect of temperature variation on analog/RF performance of JLSINT-FET device.

Noise-Enhanced Measurement of Weak Doublet Spectra with a Fourier-Transform Spectrometer and a 1-Bit Analog-to-Digital Converter.

PubMed

Lim, M; Saloma, C

2001-04-10

We demonstrate an efficient noise dithering procedure for measuring the power spectrum of a weak spectral doublet with a Fourier-transform spectrometer in which the subthreshold interferogram is measured by a 1-bit analog-to-digital converter without oversampling. In the absence of noise, no information is obtained regarding the doublet spectrum because the modulation term s(x) of its interferogram is below the instrumental detection limit B, i.e., |s(x)| < B, for all path difference x values. Extensive numerical experiments are carried out concerning the recovery of the doublet power spectrum that is represented by s(x) = (s(0)/2)exp(-pi(2)x(2)/beta)[cos(2pif(1)x) + cos(2pif(2)x)], where s(0) is a constant, beta is the linewidth factor, and ?f? = (f(1) + f(2))/2. Different values of ?f?, s(0), and beta are considered to evaluate thoroughly the accuracy of the procedure to determine the unknown values of f(1) and f(2), the spectral linewidth, and the peak values of the spectral profiles. Our experiments show that, even for short observation times, the resonant frequencies of s(x) could be located with high accuracy over a wide range of ?f? and beta values. Signal-to-noise ratios as high as 50 are also gained for the recovered power spectra. The performance of the procedure is also analyzed with respect to another method that recovers the amplitude values of s(x) directly.

Neurobehavioral Effects of Carbon Monoxide (CO) Exposure in Humans: Elevated Carboxyhemoglobin (COHb) and Cerebrovascular Responses

DTIC Science & Technology

1989-05-19

were (a) the dicrotic notch (see Figure 1) had to be present (b) no truncation or clipping could be present (c) the falling portion after the dichrotic... dicrotic notch or closing of the aortic valve (see Figure 1). The analog signal is fed to a delta z rebalancing circuit which has a maximum D.C. limit in... notch had to be relatively linear and (d) there could be only moderate baseline drift (maximum of approximately 30 degree baseline angle with respect

Analogy Just Looks Like High Level Perception: Why a Domain-General Approach to Analogical Mapping is Right

DTIC Science & Technology

1998-01-01

rerepresentation processes) will be able to use analogy better than those who have not. There is some psychological evidence for this gentrification of knowledge... useful as a technical proposal. We focus on five issues: (1) how perception relates to analogy, (2) how flexibility arises in analogical processing, (3...whether analogy is a domain-general process, (4) how should micro-worlds be used in the study of analogy, and (5) how best to assess the psychological

A Combination of Short and Simple Surfactant Protein B and C Analogues as a New Synthetic Surfactant: In Vitro and Animal Experiments.

PubMed

Choi, Yong Sung; Chung, Sung Hoon; Bae, Chong Woo

2017-07-01

Pulmonary surfactants for preterm infants contain mostly animal-derived surfactant proteins (SPs), which are essential for lowering surface tension. We prepared artificial pulmonary surfactants using synthetic human SP analogs and performed in vitro and in vivo experiments. We synthesized peptide analogues that resemble human SP-B (RMLPQLVCRLVLRCSMD) and SP-C (CPVHLKRLLLLLLLLLLLLLLLL). Dipalmitoylphosphatidylcholine (DPPC), phosphatidylglycerol (PG), and palmitic acid (PA) were added and mixed in lyophilized to render powdered surfactant. Synsurf-1 was composed of DPPC:PG:PA:SP-B (75:25:10:3, w/w); Synsurf-2 was composed of DPPC:PG:PA:SP-C (75:25:10:3, w/w); and Synsurf-3 was composed of DPPC:PG:PA:SP-B:SP-C (75:25:10:3:3, w/w). We performed in vitro study to compare the physical characteristics using pulsating bubble surfactometer and modified Wilhelmy balance test. Surface spreading and adsorption test of the surfactant preparations were measured. In vivo test was performed using term and preterm rabbit pups. Pressure-volume curves were generated during the deflation phase. Histologic findings were examined. Pulsating bubble surfactometer readings revealed following minimum and maximum surface tension (mN/m) at 5 minutes: Surfacten® (5.5±0.4, 32.8±1.6), Synsurf-1 (16.7±0.6, 28.7±1.5), Synsurf-2 (7.9±1.0, 33.1±1.6), and Synsurf-3 (7.1±0.8, 34.5±1.0). Surface spreading rates were as follows: Surfacten® (27 mN/m), Synsurf-1 (43 mN/m), Synsurf-2 (27 mN/m), and Synsurf-3 (27 mN/m). Surface adsorption rate results were as follows: Surfacten® (28 mN/m), Synsurf-1 (35 mN/m), Synsurf-2 (29 mN/m), and Synsurf-3 (27 mN/m). The deflation curves were best for Synsurf-3; those for Synsurf-2 were better than those for Surfacten®. Synsurf-1 was the worst surfactant preparation. Microscopic examination showed the largest aerated area of the alveoli in the Synsurf-3 group, followed by Synsurf-1 and Surfacten®; Synsurf-2 was the smallest. Synsurf-3 containing both SP-B and SP-C synthetic analogs showed comparable and better efficacy than commercially used Surfacten® in lowering surface tension, pressure-volume curves, and tissue aerated area of the alveoli. © Copyright: Yonsei University College of Medicine 2017

Synthesis and anti-H5N1 activity of chiral gossypol derivatives and its analogs implicated by a viral entry blocking mechanism.

PubMed

Yang, Jian; Chen, Gang; Li, Long Long; Pan, Wei; Zhang, Fang; Yang, Jingxiang; Wu, Shuwen; Tien, Po

2013-05-01

A series of chiral gossypol derivatives and its analogs were synthesized and tested in vitro for their anti-H5N1 activity. Interestingly, (+)-gossypol derivatives and its analogs were more active against H5N1 than the corresponding (-)-gossypol derivatives and its analogs. Through a simple chemical modification with amino acids, less active chiral gossypol could be converted into more active derivatives, and most of chiral gossypol derivatives were more potent against H5N1 than 1-adamantylamine. With regard to the mechanism of action, chiral gossypol derivatives and its analogs might impair the virus entry step of cell infection, likely targeting to HA2 protein. Copyright © 2013 Elsevier Ltd. All rights reserved.

Crystal Structure of Botulinum Neurotoxin Type a in Complex With the Cell Surface Co-Receptor GT1b-Insight Into the Toxin-Neuron Interaction

DOE Office of Scientific and Technical Information (OSTI.GOV)

Stenmark, P.; Dupuy, J.; Inamura, A.

2009-05-26

Botulinum neurotoxins have a very high affinity and specificity for their target cells requiring two different co-receptors located on the neuronal cell surface. Different toxin serotypes have different protein receptors; yet, most share a common ganglioside co-receptor, GT1b. We determined the crystal structure of the botulinum neurotoxin serotype A binding domain (residues 873-1297) alone and in complex with a GT1b analog at 1.7 A and 1.6 A, respectively. The ganglioside GT1b forms several key hydrogen bonds to conserved residues and binds in a shallow groove lined by Tryptophan 1266. GT1b binding does not induce any large structural changes in themore » toxin; therefore, it is unlikely that allosteric effects play a major role in the dual receptor recognition. Together with the previously published structures of botulinum neurotoxin serotype B in complex with its protein co-receptor, we can now generate a detailed model of botulinum neurotoxin's interaction with the neuronal cell surface. The two branches of the GT1b polysaccharide, together with the protein receptor site, impose strict geometric constraints on the mode of interaction with the membrane surface and strongly support a model where one end of the 100 A long translocation domain helix bundle swing into contact with the membrane, initiating the membrane anchoring event.« less

High-Threshold Fault-Tolerant Quantum Computation with Analog Quantum Error Correction

NASA Astrophysics Data System (ADS)

Fukui, Kosuke; Tomita, Akihisa; Okamoto, Atsushi; Fujii, Keisuke

2018-04-01

To implement fault-tolerant quantum computation with continuous variables, the Gottesman-Kitaev-Preskill (GKP) qubit has been recognized as an important technological element. However, it is still challenging to experimentally generate the GKP qubit with the required squeezing level, 14.8 dB, of the existing fault-tolerant quantum computation. To reduce this requirement, we propose a high-threshold fault-tolerant quantum computation with GKP qubits using topologically protected measurement-based quantum computation with the surface code. By harnessing analog information contained in the GKP qubits, we apply analog quantum error correction to the surface code. Furthermore, we develop a method to prevent the squeezing level from decreasing during the construction of the large-scale cluster states for the topologically protected, measurement-based, quantum computation. We numerically show that the required squeezing level can be relaxed to less than 10 dB, which is within the reach of the current experimental technology. Hence, this work can considerably alleviate this experimental requirement and take a step closer to the realization of large-scale quantum computation.

Isolation of the antibiotic pseudopyronine B and SAR evaluation of C3/C6 alkyl analogs.

PubMed

Bouthillette, Leah M; Darcey, Catherine A; Handy, Tess E; Seaton, Sarah C; Wolfe, Amanda L

2017-06-15

Natural products are an abundant source of structurally diverse compounds with antibacterial activity that can be used to develop new and potent antibiotics. One such class of natural products is the pseudopyronines. Here we present the isolation of pseudopyronine B (2) from a Pseudomonas species found in garden soil in Western North Carolina, and SAR evaluation of C3 and C6 alkyl analogs of the natural product for antibacterial activity against Gram-positive and Gram-negative bacteria. We found a direct relationship between antibacterial activity and C3/C6 alkyl chain length. For inhibition of Gram-positive bacteria, alkyl chain lengths between 6 and 7 carbons were found to be the most active (IC 50 =0.04-3.8µg/mL) whereas short alkyl chain analogs showed modest activity against Gram-negative bacteria (IC 50 =223-304µg/mL). This demonstrates the potential for this class of natural products to be optimized for selective activity against either Gram-positive or Gram-negative bacteria. Copyright © 2017 Elsevier Ltd. All rights reserved.

Assessment of pepper spray product potency in Asian and Caucasian forearm skin using transepidermal water loss, skin temperature and reflectance colorimetry.

PubMed

Pershing, Lynn K; Reilly, Christopher A; Corlett, Judy L; Crouch, Dennis J

2006-01-01

Historically, pepper spray product potency has been established using a taste test evaluation. A taste test is subjective and may not be appropriate for assessing pepper potency in skin. The current study evaluated chemically diverse pepper sprays in human forearm skin using three objective, noninvasive parameters: transepidermal water loss, skin surface temperature and erythema, as a means for assessing dermal pharmacology, toxicology and product potency. Five commercial pepper spray products containing various capsaicinoid analogs at various concentrations were evaluated in duplicate on volar forearms of six Caucasians and six Asians using a 10 min exposure. Mean surface skin temperature, transepidermal water loss results were highly variable and therefore did not demonstrate dose responsive behavior to increasing capsaicinoid concentrations. Erythema, as measured by increases in a* (reflected light in the red-to-green color spectrum) of the L*a*b* uniform color scale, was superior among parameters evaluated in discriminating pepper spray potency and correlated well with the relative and total capsaicinoid concentration in the products. Products containing greater than 16 mg ml(-1) capsaicinoid concentration produced greater erythema responses in Caucasians than Asians. Asians responded greater to the synthetic analog, nonivamide, than to mixtures of capsaicinoids, while Caucasians responded equally to both capsaicinoid analogs. Thus, pepper spray product potency in human skin reflects the total capsaicinoid concentration, the specific capsaicin analog(s) present, and the race of the individual exposed. The finding that the reflectance colorimeter a* scale can differentiate these parameters in skin will have a significant impact on evaluating the use and efficacy of pepper spray products in humans. 2005 John Wiley & Sons, Ltd.

Thiamin diphosphate-dependent enzymes: from enzymology to metabolic regulation, drug design and disease models.

PubMed

Bunik, Victoria I; Tylicki, Adam; Lukashev, Nikolay V

2013-12-01

Bringing a knowledge of enzymology into research in vivo and in situ is of great importance in understanding systems biology and metabolic regulation. The central metabolic significance of thiamin (vitamin B1 ) and its diphosphorylated derivative (thiamin diphosphate; ThDP), and the fundamental differences in the ThDP-dependent enzymes of metabolic networks in mammals versus plants, fungi and bacteria, or in health versus disease, suggest that these enzymes are promising targets for biotechnological and medical applications. Here, the in vivo action of known regulators of ThDP-dependent enzymes, such as synthetic structural analogs of the enzyme substrates and thiamin, is analyzed in light of the enzymological data accumulated during half a century of research. Mimicking the enzyme-specific catalytic intermediates, the phosphonate analogs of 2-oxo acids selectively inhibit particular ThDP-dependent enzymes. Because of their selectivity, use of these compounds in cellular and animal models of ThDP-dependent enzyme malfunctions improves the validity of the model and its predictive power when compared with the nonselective and enzymatically less characterized oxythiamin and pyrithiamin. In vitro studies of the interaction of thiamin analogs and their biological derivatives with potential in vivo targets are necessary to identify and attenuate the analog selectivity. For both the substrate and thiamin synthetic analogs, in vitro reactivities with potential targets are highly relevant in vivo. However, effective concentrations in vivo are often higher than in vitro studies would suggest. The significance of specific inihibition of the ThDP-dependent enzymes for the development of herbicides, antibiotics, anticancer and neuroprotective strategies is discussed. © 2013 FEBS.

Cdc25B Dual-Specificity Phosphatase Inhibitors Identified in a High-Throughput Screen of the NIH Compound Library

PubMed Central

Foster, Caleb A.; Tierno, Marni Brisson; Shun, Tong Ying; Shinde, Sunita N.; Paquette, William D.; Brummond, Kay M.; Wipf, Peter; Lazo, John S.

2009-01-01

Abstract The University of Pittsburgh Molecular Library Screening Center (Pittsburgh, PA) conducted a screen with the National Institutes of Health compound library for inhibitors of in vitro cell division cycle 25 protein (Cdc25) B activity during the pilot phase of the Molecular Library Screening Center Network. Seventy-nine (0.12%) of the 65,239 compounds screened at 10 μM met the active criterion of ≥50% inhibition of Cdc25B activity, and 25 (31.6%) of these were confirmed as Cdc25B inhibitors with 50% inhibitory concentration (IC50) values <50 μM. Thirteen of the Cdc25B inhibitors were represented by singleton chemical structures, and 12 were divided among four clusters of related structures. Thirteen (52%) of the Cdc25B inhibitor hits were quinone-based structures. The Cdc25B inhibitors were further characterized in a series of in vitro secondary assays to confirm their activity, to determine their phosphatase selectivity against two other dual-specificity phosphatases, mitogen-activated protein kinase phosphatase (MKP)-1 and MKP-3, and to examine if the mechanism of Cdc25B inhibition involved oxidation and inactivation. Nine Cdc25B inhibitors did not appear to affect Cdc25B through a mechanism involving oxidation because they did not generate detectable amounts of H2O2 in the presence of dithiothreitol, and their Cdc25B IC50 values were not significantly affected by exchanging the dithiothreitol for β-mercaptoethanol or reduced glutathione or by adding catalase to the assay. Six of the nonoxidative hits were selective for Cdc25B inhibition versus MKP-1 and MKP-3, but only the two bisfuran-containing hits, PubChem substance identifiers 4258795 and 4260465, significantly inhibited the growth of human MBA-MD-435 breast and PC-3 prostate cancer cell lines. To confirm the structure and biological activity of 4260465, the compound was resynthesized along with two analogs. Neither of the substitutions to the two analogs was tolerated, and only the resynthesized hit 26683752 inhibited Cdc25B activity in vitro (IC50 = 13.83 ± 1.0 μM) and significantly inhibited the growth of the MBA-MD-435 breast and PC-3 prostate cancer cell lines (IC50 = 20.16 ± 2.0 μM and 24.87 ± 2.25 μM, respectively). The two bis-furan-containing hits identified in the screen represent novel nonoxidative Cdc25B inhibitor chemotypes that block tumor cell proliferation. The availability of non-redox active Cdc25B inhibitors should provide valuable tools to explore the inhibition of the Cdc25 phosphatases as potential mono- or combination therapies for cancer. PMID:19530895

Using thermodynamic integration MD simulation to compute relative protein-ligand binding free energy of a GSK3β kinase inhibitor and its analogs.

PubMed

Lee, Hsing-Chou; Hsu, Wen-Chi; Liu, An-Lun; Hsu, Chia-Jen; Sun, Ying-Chieh

2014-06-01

Thermodynamic integration molecular dynamics simulation was used to investigate how TI-MD simulation preforms in reproducing relative protein-ligand binding free energy of a pair of analogous GSK3β kinase inhibitors of available experimental data (see Fig. 1), and to predict the affinity for other analogs. The computation for the pair gave a ΔΔG of 1.0 kcal/mol, which was in reasonably good agreement with the experimental value of -0.1 kcal/mol. The error bar was estimated at 0.5 kcal/mol. Subsequently, we employed the same protocol to proceed with simulations to find analogous inhibitors with a stronger affinity. Four analogs with a substitution at one site inside the binding pocket were the first to be tried, but no significant enhancement in affinity was found. Subsequent simulations for another 7 analogs was focused on substitutions at the benzene ring of another site, which gave two analogs (analogs 9 and 10) with ΔΔG values of -0.6 and -0.8 kcal/mol, respectively. Both analogs had a OH group at the meta position and another OH group at the ortho position at the other side of the benzene ring, as shown in Table 3. To explore further, another 4 analogs with this characteristic were investigated. Three analogs with ΔΔG values of -2.2, -1.7 and -1.2 kcal/mol, respectively, were found. Hydrogen bond analysis suggested that the additional hydrogen bonds of the added OH groups with Gln185 and/or Asn64, which did not appear in the reference inhibitor or as an analog with one substitution only in the examined cases, were the main contributors to an enhanced affinity. A prediction for better inhibitors should interest experimentalists of enzyme and/or cell assays. Analysis of the interactions between GSK3β kinase and the investigated analogs will be useful in the design of GSK3β kinase inhibitors for compounds of this class. Copyright © 2014 Elsevier Inc. All rights reserved.

Synthesis of Amide and Ester Derivatives of Cinnamic Acid and Its Analogs: Evaluation of Their Free Radical Scavenging and Monoamine Oxidase and Cholinesterase Inhibitory Activities.

PubMed

Takao, Koichi; Toda, Kazuhiro; Saito, Takayuki; Sugita, Yoshiaki

2017-01-01

A series of cinnamic acid derivatives, amides (1-12) and esters (13-22), were synthesized, and structure-activity relationships for antioxidant activity, and monoamine oxidases (MAO) A and B, acetylcholinesterase, and butyrylcholinesterase (BChE) inhibitory activities were analyzed. Among the synthesized compounds, compounds 1-10, 12-18, and rosmarinic acid (23), which contained catechol, o-methoxyphenol or 5-hydroxyindole moieties, showed potent 1,1-diphenyl-2-picrylhydrazyl (DPPH) free radical scavenging activity. Compounds 9-11, 15, 17-22 showed potent and selective MAO-B inhibitory activity. Compound 20 was the most potent inhibitor of MAO-B. Compounds 18 and 21 showed moderate BChE inhibitory activity. In addition, compound 18 showed potent antioxidant activity and MAO-B inhibitory activity. In a comparison of the cinnamic acid amides and esters, the amides exhibited more potent DPPH free radical scavenging activity, while the esters showed stronger inhibitory activities against MAO-B and BChE. These results suggested that cinnamic acid derivatives such as compound 18, p-coumaric acid 3,4-dihydroxyphenethyl ester, and compound 20, p-coumaric acid phenethyl ester, may serve as lead compounds for the development of novel MAO-B inhibitors and candidate lead compounds for the prevention or treatment of Alzheimer's disease.

Activation of the p38- pathway by a novel monoketone curcumin analog, EF24, suggests a potential combination strategy

PubMed Central

Thomas, Shala L.; Zhao, Jing; Li, Zijian; Lou, Bin; Du, Yuhong; Purcell, Jamie; Snyder, James P.; Khuri, Fadlo R.; Liotta, Dennis; Fu, Haian

2010-01-01

Increasing attention has been given to the anti-cancer effects of curcumin and the ability of this natural product to inhibit cancer cell proliferation. New curcumin analogs have been developed to optimize the in vitro and in vivo activity of the parent compound yet retain the same safety profile. EF24, a fluorinated synthetic analog, surpasses curcumin in its ability to inhibit cancer cell viability and down-regulate TNFα-induced NF-κB activation. Here we report a critical role of the p38-mediated signaling pathway in the determination of lung cancer cell’s sensitivity to EF24. We have found that EF24-induced decease of lung cancer cell viability was accompanied by upregulated mitogen-activated protein kinases (MAPK) as evidenced by increased phosphorylation of ERK1/2, JNK, and p38. Pharmacological investigation led to our suggestion that EF24 triggers a negative feedback loop through p38 activation. In support of this model, inhibition of p38, either by small molecule inhibitors or through an RNAi-mediated knockdown approach, enhanced the EF24 induced apoptotic death of A549 cells. Thus, inhibition of p38 may boost the EF24 anticancer effect. Indeed, a combination of EF24 and SB203580, a p38 inhibitor, synergistically inhibited clonogenic activity of A549 lung cancer cells and induced their apoptosis as reflected by poly(ADP-ribose) polymerase cleavage, the accumulation of the sub-G1 fraction of cells, and apoptotic cell staining. These studies offer a novel strategy that combines the curcumin analog EF24 with a p38 inhibitor for potentially enhanced therapy in the treatment of lung cancer. PMID:20615389

Activation of the p38 pathway by a novel monoketone curcumin analog, EF24, suggests a potential combination strategy.

PubMed

Thomas, Shala L; Zhao, Jing; Li, Zijian; Lou, Bin; Du, Yuhong; Purcell, Jamie; Snyder, James P; Khuri, Fadlo R; Liotta, Dennis; Fu, Haian

2010-11-01

Increasing attention has been given to the anticancer effects of curcumin and the ability of this natural product to inhibit cancer cell proliferation. New curcumin analogs have been developed to optimize the in vitro and in vivo activity of the parent compound yet retain the same safety profile. EF24, a fluorinated synthetic analog, surpasses curcumin in its ability to inhibit cancer cell viability and down-regulate TNFα-induced NF-κB activation. Here we report a critical role of the p38-mediated signaling pathway in the determination of lung cancer cell's sensitivity to EF24. We have found that EF24-induced decease of lung cancer cell viability was accompanied by upregulated mitogen-activated protein kinases (MAPK) as evidenced by increased phosphorylation of ERK1/2, JNK, and p38. Pharmacological investigation led to our suggestion that EF24 triggers a negative feedback loop through p38 activation. In support of this model, inhibition of p38, either by small molecule inhibitors or through an RNAi-mediated knockdown approach, enhanced the EF24-induced apoptotic death of A549 cells. Thus, inhibition of p38 may boost the EF24 anticancer effect. Indeed, a combination of EF24 and SB203580, a p38 inhibitor, synergistically inhibited clonogenic activity of A549 lung cancer cells and induced their apoptosis as reflected by poly(ADP-ribose) polymerase cleavage, the accumulation of the sub-G(1) fraction of cells, and apoptotic cell staining. These studies offer a novel strategy that combines the curcumin analog EF24 with a p38 inhibitor for potentially enhanced therapy in the treatment of lung cancer. Copyright © 2010 Elsevier Inc. All rights reserved.

Comparative Positron-Emission Tomography (PET) Imaging and Phototherapeutic Potential of 124I- Labeled Methyl- 3-(1′-iodobenzyloxyethyl) pyropheophorbide-a vs. the Corresponding Glucose- and Galactose-Conjugates

PubMed Central

Pandey, Suresh K.; Sajjad, Munawwar; Chen, Yihui; Zheng, Xiang; Yao, Rutao; Missert, Joseph R.; Batt, Carrie; Nabi, Hani A.; Oseroff, Allan R.; Pandey, Ravindra K.

2009-01-01

In our present study, 3-(1′-m-iodobenzyloxyethyl) pyropheophorbide-a methyl ester 1, 3-(1′-m-iodobenzyloxyethyl)-172-{(2-deoxy)glucose} pyropheophorbide-a 2, and 3-(1′-m-iodo benzyloxyethyl)-172-{(1-deoxy)galactose} pyropheophorbide-a 3 were synthesized and converted into the corresponding 124I- labeled analogs by reacting the intermediate trimethyltin analogs with Na124I. Photosensitizers 1–3 were evaluated for the PDT efficacy in C3H mice bearing RIF tumors at variable doses and showed a significant long-term tumor cure. Among the compounds investigated, the non-carbohydrate analog 1 was most effective. These results were in contrast to the in vitro data, where compared to the parent analog the corresponding galactose-and glucose derivatives showed enhanced cell kill. Among the corresponding 124I-labeled in analogs, excellent tumor images were obtained from compound 1 both tumor models (RIF and Colon-26) and the best tumor contrast was observed at 72 h post injection. Conjugating a glucose moiety to photosensitizer 1 diminished its tumor uptake, whereas with time the corresponding galactose analog showed improved tumor contrast. PMID:19090663

Turbulent cascades in foreign exchange markets

NASA Astrophysics Data System (ADS)

Ghashghaie, S.; Breymann, W.; Peinke, J.; Talkner, P.; Dodge, Y.

1996-06-01

THE availability of high-frequency data for financial markets has made it possible to study market dynamics on timescales of less than a day1. For foreign exchange (FX) rates Müller et al.2 have shown that there is a net flow of information from long to short timescales: the behaviour of long-term traders (who watch the markets only from time to time) influences the behaviour of short-term traders (who watch the markets continuously). Motivated by this hierarchical feature, we have studied FX market dynamics in more detail, and report here an analogy between these dynamics and hydrodynamic turbulence3-8. Specifically, the relationship between the probability density of FX price changes (δx) and the time delay (δt) (Fig. la) is much the same as the relationship between the probability density of the velocity differences (δv) of two points in a turbulent flow and their spatial separation δr (Fig. 1b). Guided by this similarity we claim that there is an information cascade in FX market dynamics that corresponds to the energy cascade in hydrodynamic turbulence. On the basis of this analogy we can now rationalize the statistics of FX price differences at different time delays, which is important for, for example, option pricing. The analogy also provides a conceptual framework for understanding the short-term dynamics of speculative markets.

Effect of experimental analogs of contingency management treatment on cocaine seeking behavior.

PubMed

Greenwald, Mark K; Ledgerwood, David M; Lundahl, Leslie H; Steinmiller, Caren L

2014-06-01

Contingency management (CM) treatment is effective for treating cocaine dependence but further mechanistic studies of its efficacy are warranted. This study aimed to determine whether: (a) higher vs. lower predictable money amounts ($3 vs. $1; analogs of standard voucher-based CM) increase cocaine demand elasticity; and (b) probabilistic amounts matched for expected value with the $3-predictable amount (50% chance of $6; 25% chance of $12; and 12.5% chance of $24; analogs of prize CM) similarly affect cocaine choice. Each of 15 cocaine-dependent participants first completed a qualifying session to ensure that intranasal cocaine functioned as a reinforcer, then completed a 10-session, within-subject, randomized crossover study. During each of the 10 sessions, the participant responded on a progressive ratio schedule to earn units of cocaine (5-mg or 10-mg) and/or money (five monetary conditions above). During the reinforcement qualifying session (10-mg vs. 0-mg units; no money alternative), cocaine choice was high. The $3-predictable amount significantly decreased cocaine choice relative to both the $1-predictable amount and the qualifying session. Cocaine-choices in the probabilistic conditions were similar to the $3 predictable condition. These findings indicate that CM interventions targeted at reducing cocaine self-administration are more likely to succeed with higher value non-drug reinforcement. Copyright © 2014. Published by Elsevier Ireland Ltd.

A serendipitous discovery of antifreeze protein-specific activity in C-linked antifreeze glycoprotein analogs.

PubMed

Eniade, Adewale; Purushotham, Madhusudhan; Ben, Robert N; Wang, J B; Horwath, Kathleen

2003-01-01

Structurally diverse carbon-linked (C-linked) analogs of antifreeze glycoprotein (AFGP) have been prepared via linear or convergent solid phase synthesis. These analogs range in molecular weight from approx 1.5-4.1 KDa and do not possess the beta-D-galactose-1,3-alpha-D-N-acetylgalactosamine carbohydrate moiety or the L-threonine-L-alanine-L-alanine polypeptide backbone native to the AFGP wild-type. Despite these dramatic structural modifications, the 2.7-KDa and 4.1-KDa analogs possess antifreeze protein-specific activity as determined by recrystallization-inhibition (RI) and thermal hysteresis (TH) assays. These analogs are weaker than the wild-type in their activity, but nanoliter osmometry indicates that these compounds are binding to ice and affecting a localized freezing point depression. This is the first example of a C-linked AFGP analog that possesses TH and RI activity and suggests that the rational design and synthesis of chemically and biologically stable AFGP analogs is a feasible and worthwhile endeavor. Given the low degree of TH activity, these compounds may prove useful for the protection of cells during freezing and thawing cycles.

Temporal alteration of spreading depression by the glycine transporter type-1 inhibitors NFPS and Org-24461 in chicken retina.

PubMed

Kertesz, Szabolcs; Szabo, Geza; Udvari, Szabolcs; Levay, Gyorgy; Matyus, Peter; Harsing, Laszlo G

2013-01-25

We used isolated chicken retina to induce spreading depression by the glutamate receptor agonist N-methyl-d-aspartate. The N-methyl-d-aspartate-induced latency time of spreading depression was extended by the glycine(B) binding site competitive antagonist 7-chlorokynurenic acid. Addition of the glycine transporter type-1 inhibitors NFPS and Org-24461 reversed the inhibitory effect of 7-chlorokynurenic acid on N-methyl-d-aspartate-evoked spreading depression. The glycine uptake inhibitory activity of Org-24461, NFPS, and some newly synthesized analogs of NFPS was determined in CHO cells stably expressing human glycine transporter type-1b isoform. Compounds, which failed to inhibit glycine transporter type-1, also did not have effect on retinal spreading depression. These experiments indicate that the spreading depression model in chicken retina is a useful in vitro test to determine activity of glycine transporter type-1 inhibitors. In addition, our data serve further evidence for the role of glycine transporter type-1 in retinal neurotransmission and light processing. Copyright © 2012 Elsevier B.V. All rights reserved.

Anthraquinones from a Marine-Derived Streptomyces spinoverrucosus

PubMed Central

Hu, Youcai; Martinez, Elisabeth D.; MacMillan, John B.

2012-01-01

Four new anthraquinone analogs including galvaquinones A-C (1–3) and an isolation artifact 5,8-dihydroxy-2,2,4-trimethyl-6-(3-methylbutyl)anthra[9,1-de][1,3]oxazin-7(2H)-one (4) were isolated from a marine-derived Streptomyces spinoverrucosus based on activity in an image-based assay to identify epigenetic modifying compounds. The structures of 1–4 were elucidated by comprehensive NMR and MS spectroscopic analysis. Galvaquinone B (2) was found to show epigenetic modulatory activity at 1.0 μM, and exhibited moderate cytotoxicity against non-small cell lung cancer (NSCLC) cell lines Calu-3 and H2887. PMID:23057874

Impact of novel palmitoylated prolactin-releasing peptide analogs on metabolic changes in mice with diet-induced obesity

PubMed Central

Pelantová, Helena; Bugáňová, Martina; Pirník, Zdenko; Mikulášková, Barbora; Popelová, Andrea; Blechová, Miroslava; Haluzík, Martin; Železná, Blanka; Kuzma, Marek; Kuneš, Jaroslav; Maletínská, Lenka

2017-01-01

Analogs of anorexigenic neuropeptides, such as prolactin-releasing peptide (PrRP), have a potential as new anti-obesity drugs. In our previous study, palmitic acid attached to the N-terminus of PrRP enabled its central anorexigenic effects after peripheral administration. In this study, two linkers, γ-glutamic acid at Lys11 and a short, modified polyethylene glycol at the N-terminal Ser and/or Lys11, were applied for the palmitoylation of PrRP31 to improve its bioavailability. These analogs had a high affinity and activation ability to the PrRP receptor GPR10 and the neuropeptide FF2 receptor, as well as short-term anorexigenic effect similar to PrRP palmitoylated at the N-terminus. Two-week treatment with analogs that were palmitoylated through linkers to Lys11 (analogs 1 and 2), but not with analog modified both at the N-terminus and Lys11 (analog 3) decreased body and liver weights, insulin, leptin, triglyceride, cholesterol and free fatty acid plasma levels in a mouse model of diet-induced obesity. Moreover, the expression of uncoupling protein-1 was increased in brown fat suggesting an increase in energy expenditure. In addition, treatment with analogs 1 and 2 but not analog 3 significantly decreased urinary concentrations of 1-methylnicotinamide and its oxidation products N-methyl-2-pyridone-5-carboxamide and N-methyl-4-pyridone-3-carboxamide, as shown by NMR-based metabolomics. This observation confirmed the previously reported increase in nicotinamide derivatives in obesity and type 2 diabetes mellitus and the effectiveness of analogs 1 and 2 in the treatment of these disorders. PMID:28820912

Design of a wideband CMOS impedance spectroscopy ASIC analog front-end for multichannel biosensor interfaces.

PubMed

Valente, Virgilio; Dai Jiang; Demosthenous, Andreas

2015-08-01

This paper presents the preliminary design and simulation of a flexible and programmable analog front-end (AFE) circuit with current and voltage readout capabilities for electric impedance spectroscopy (EIS). The AFE is part of a fully integrated multifrequency EIS platform. The current readout comprises of a transimpedance stage and an automatic gain control (AGC) unit designed to accommodate impedance changes larger than 3 order of magnitude. The AGC is based on a dynamic peak detector that tracks changes in the input current over time and regulates the gain of a programmable gain amplifier in order to optimise the signal-to-noise ratio. The system works up to 1 MHz. The voltage readout consists of a 2 stages of fully differential current-feedback instrumentation amplifier which provide 100 dB of CMRR and a programmable gain up to 20 V/V per stage with a bandwidth in excess of 10MHz.

Using signal amplification by reversible exchange (SABRE) to hyperpolarise 119Sn and 29Si NMR nuclei.

PubMed

Olaru, Alexandra M; Burt, Alister; Rayner, Peter J; Hart, Sam J; Whitwood, Adrian C; Green, Gary G R; Duckett, Simon B

2016-12-13

The hyperpolarisation of the 119 Sn and 29 Si nuclei in 5-(tributylstannyl)pyrimidine (A Sn ) and 5-(trimethylsilyl)pyrimidine (B Si ) is achieved through their reaction with [IrCl(COD)(IMes)] (1a) or [IrCl(COD)(SIMes)] (1b) and parahydrogen via the SABRE process. 1a exhibits superior activity in both cases. The two inequivalent pyrimidine proton environments of A Sn readily yielded signal enhancements totalling ∼2300-fold in its 1 H NMR spectrum at a field strength of 9.4 T, with the corresponding 119 Sn signal being 700 times stronger than normal. In contrast, B Si produced analogous 1 H signal gains of ∼2400-fold and a 29 Si signal that could be detected with a signal to noise ratio of 200 in a single scan. These sensitivity improvements allow NMR detection within seconds using micromole amounts of substrate and illustrate the analytical potential of this approach for high-sensitivity screening. Furthermore, after extended reaction times, a series of novel iridium trimers of general form [Ir(H) 2 Cl(NHC)(μ-pyrimidine-κN:κN')] 3 precipitate from these solutions whose identity was confirmed crystallographically for B Si .

A Computer-Based Visual Analog Scale,

DTIC Science & Technology

1992-06-01

34 keys on the computer keyboard or other input device. The initial position of the arrow is always in the center of the scale to prevent biasing the...3 REFERENCES 1. Gift, A.G., "Visual Analogue Scales: Measurement of Subjective Phenomena." Nursing Research, Vol. 38, pp. 286-288, 1989. 2. Ltmdberg...3. Menkes, D.B., Howard, R.C., Spears, G.F., and Cairns, E.R., "Salivary THC Following Cannabis Smoking Correlates With Subjective Intoxication and

A Fast Multiple Sampling Method for Low-Noise CMOS Image Sensors With Column-Parallel 12-bit SAR ADCs

PubMed Central

Kim, Min-Kyu; Hong, Seong-Kwan; Kwon, Oh-Kyong

2015-01-01

This paper presents a fast multiple sampling method for low-noise CMOS image sensor (CIS) applications with column-parallel successive approximation register analog-to-digital converters (SAR ADCs). The 12-bit SAR ADC using the proposed multiple sampling method decreases the A/D conversion time by repeatedly converting a pixel output to 4-bit after the first 12-bit A/D conversion, reducing noise of the CIS by one over the square root of the number of samplings. The area of the 12-bit SAR ADC is reduced by using a 10-bit capacitor digital-to-analog converter (DAC) with four scaled reference voltages. In addition, a simple up/down counter-based digital processing logic is proposed to perform complex calculations for multiple sampling and digital correlated double sampling. To verify the proposed multiple sampling method, a 256 × 128 pixel array CIS with 12-bit SAR ADCs was fabricated using 0.18 μm CMOS process. The measurement results shows that the proposed multiple sampling method reduces each A/D conversion time from 1.2 μs to 0.45 μs and random noise from 848.3 μV to 270.4 μV, achieving a dynamic range of 68.1 dB and an SNR of 39.2 dB. PMID:26712765

Chlorination of Side Chains: A Strategy for Achieving a High Open Circuit Voltage Over 1.0 V in Benzo[1,2-b:4,5-b']dithiophene-Based Non-Fullerene Solar Cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chao, Pengjie; Mu, Zhao; Wang, Huan

Here, a benzo[1,2-b:4,5-b']dithiophene-based donor material with chlorine atoms substituted on its side chains, named PBClT, was designed and developed for application in non-fullerene solar cells to enhance the open-circuit voltage ( V oc) without decreasing charge carrier transfer in the corresponding blend films. The results demonstrated that the chlorinated PBClT polymer was an efficient donor in non-fullerene polymer solar cells (PSCs) and exhibited a blue-shifted absorbance, resulting in more complementary light absorption with non-fullerene acceptors, such as ITIC. In addition, the chlorine substitution decreased the HOMO level of PBClT, and as a result, the V oc of the corresponding solarmore » cell increased dramatically to 1.01 V, which is much higher than that of the non-chlorine analog, PTB7-Th, with a V oc of approximately 0.82 V. The 2D-GIWAX results illustrated that the PBClT/ITIC blend film exhibited a “face-on” orientation, which suggested that the chlorine substituents on the side chains favored π-π stacking in the direction perpendicular to the electron flow in photovoltaic devices. Furthermore, the PBClT/ITIC blend film showed a π-π stacking distance of 3.85 Å, which was very close to that of its non-chlorine analog blend film with a distance of approximately 3.74 Å. Based on this result, the introduction of multiple chlorine atoms on the conjugated side chains not only adjusted the energy level of the low-band-gap polymer through the electron withdrawing ability of the chlorine atoms but also subtly avoided obvious morphological changes that could result from strong steric hindrance in the main chain of the polymers. The PBClT/ITIC-based PSCs exhibited a maximum PCE of 8.46% with a V oc of 1.01 V, which is an increase in the PCE of approximately 22% compared to the PTB7-Th-based device based on our parallel experiments.« less

Chlorination of Side Chains: A Strategy for Achieving a High Open Circuit Voltage Over 1.0 V in Benzo[1,2-b:4,5-b']dithiophene-Based Non-Fullerene Solar Cells

DOE PAGES

Chao, Pengjie; Mu, Zhao; Wang, Huan; ...

2018-04-23

Here, a benzo[1,2-b:4,5-b']dithiophene-based donor material with chlorine atoms substituted on its side chains, named PBClT, was designed and developed for application in non-fullerene solar cells to enhance the open-circuit voltage ( V oc) without decreasing charge carrier transfer in the corresponding blend films. The results demonstrated that the chlorinated PBClT polymer was an efficient donor in non-fullerene polymer solar cells (PSCs) and exhibited a blue-shifted absorbance, resulting in more complementary light absorption with non-fullerene acceptors, such as ITIC. In addition, the chlorine substitution decreased the HOMO level of PBClT, and as a result, the V oc of the corresponding solarmore » cell increased dramatically to 1.01 V, which is much higher than that of the non-chlorine analog, PTB7-Th, with a V oc of approximately 0.82 V. The 2D-GIWAX results illustrated that the PBClT/ITIC blend film exhibited a “face-on” orientation, which suggested that the chlorine substituents on the side chains favored π-π stacking in the direction perpendicular to the electron flow in photovoltaic devices. Furthermore, the PBClT/ITIC blend film showed a π-π stacking distance of 3.85 Å, which was very close to that of its non-chlorine analog blend film with a distance of approximately 3.74 Å. Based on this result, the introduction of multiple chlorine atoms on the conjugated side chains not only adjusted the energy level of the low-band-gap polymer through the electron withdrawing ability of the chlorine atoms but also subtly avoided obvious morphological changes that could result from strong steric hindrance in the main chain of the polymers. The PBClT/ITIC-based PSCs exhibited a maximum PCE of 8.46% with a V oc of 1.01 V, which is an increase in the PCE of approximately 22% compared to the PTB7-Th-based device based on our parallel experiments.« less

Optimal Order of Successive Office Hysteroscopy and Endometrial Biopsy for the Evaluation of Abnormal Uterine Bleeding: A Randomized Controlled Trial.

PubMed

Sarkar, Papri; Mikhail, Emad; Schickler, Robyn; Plosker, Shayne; Imudia, Anthony N

2017-09-01

To estimate the optimal order of office hysteroscopy and endometrial biopsy when performed successively for evaluation of abnormal uterine bleeding. Patients undergoing successive office hysteroscopy and endometrial biopsy were included in a single-blind, prospective, randomized trial. The primary outcome was to evaluate the effect of order of procedures on patients' pain score. Prespecified secondary outcomes include procedure duration, hysteroscopic visualization of the uterine cavity, endometrial sample adequacy, and number of attempts at biopsy. Pain scores were assessed using a visual analog scale from 0 to 10 and endometrial sample adequacy was determined from the histopathology report. Hysteroscopy images were recorded. Sample size of 34 per group (n=68) was determined to be adequate to detect a difference of 20% in visual analog scale score between hysteroscopy first (group A) and biopsy first (group B) at α of 0.05 and 80% power. Between October 2015 and January 2017, 78 women were randomized to group A (n=40) and group B (n=38). There was no difference in global pain perception [7 (0-10) vs 7 (0-10); P=.57, 95% CI 5.8-7.1]. Procedure duration [3 (1-9) vs 3 (2-10), P=.32, 95% CI 3.3-4.1] and endometrial sample adequacy (78.9% vs 75.7%, P=.74) were similar in both groups. Group A patients had better endometrial visualization (P<.001) than group B based on the hysteroscopic images: excellent (50% vs 7.9%), good (20% vs 34.2%), and fair (22.5% vs 44.7%); group B participants required fewer endometrial biopsy attempts at obtaining adequate tissue sample (two vs one; P<.001, 1.6-1.9). Patients having successive office hysteroscopy and endometrial biopsy for evaluation of abnormal uterine bleeding, the global pain perception, and time required are independent of the order in which procedures are performed. Performing hysteroscopy first ensures better image, whereas biopsy first yields adequate tissue sample with fewer attempts. ClinicalTrials.gov, NCT02472184.

Chloroquine Analog Interaction with C2- and Iota-Toxin in Vitro and in Living Cells.

PubMed

Kronhardt, Angelika; Beitzinger, Christoph; Barth, Holger; Benz, Roland

2016-08-10

C2-toxin from Clostridium botulinum and Iota-toxin from Clostridium perfringens belong both to the binary A-B-type of toxins consisting of two separately secreted components, an enzymatic subunit A and a binding component B that facilitates the entry of the corresponding enzymatic subunit into the target cells. The enzymatic subunits are in both cases actin ADP-ribosyltransferases that modify R177 of globular actin finally leading to cell death. Following their binding to host cells' receptors and internalization, the two binding components form heptameric channels in endosomal membranes which mediate the translocation of the enzymatic components Iota a and C2I from endosomes into the cytosol of the target cells. The binding components form ion-permeable channels in artificial and biological membranes. Chloroquine and related 4-aminoquinolines were able to block channel formation in vitro and intoxication of living cells. In this study, we extended our previous work to the use of different chloroquine analogs and demonstrate that positively charged aminoquinolinium salts are able to block channels formed in lipid bilayer membranes by the binding components of C2- and Iota-toxin. Similarly, these molecules protect cultured mammalian cells from intoxication with C2- and Iota-toxin. The aminoquinolinium salts did presumably not interfere with actin ADP-ribosylation or receptor binding but blocked the pores formed by C2IIa and Iota b in living cells and in vitro. The blocking efficiency of pores formed by Iota b and C2IIa by the chloroquine analogs showed interesting differences indicating structural variations between the types of protein-conducting nanochannels formed by Iota b and C2IIa.

Chloroquine Analog Interaction with C2- and Iota-Toxin in Vitro and in Living Cells

PubMed Central

Kronhardt, Angelika; Beitzinger, Christoph; Barth, Holger; Benz, Roland

2016-01-01

C2-toxin from Clostridium botulinum and Iota-toxin from Clostridium perfringens belong both to the binary A-B-type of toxins consisting of two separately secreted components, an enzymatic subunit A and a binding component B that facilitates the entry of the corresponding enzymatic subunit into the target cells. The enzymatic subunits are in both cases actin ADP-ribosyltransferases that modify R177 of globular actin finally leading to cell death. Following their binding to host cells’ receptors and internalization, the two binding components form heptameric channels in endosomal membranes which mediate the translocation of the enzymatic components Iota a and C2I from endosomes into the cytosol of the target cells. The binding components form ion-permeable channels in artificial and biological membranes. Chloroquine and related 4-aminoquinolines were able to block channel formation in vitro and intoxication of living cells. In this study, we extended our previous work to the use of different chloroquine analogs and demonstrate that positively charged aminoquinolinium salts are able to block channels formed in lipid bilayer membranes by the binding components of C2- and Iota-toxin. Similarly, these molecules protect cultured mammalian cells from intoxication with C2- and Iota-toxin. The aminoquinolinium salts did presumably not interfere with actin ADP-ribosylation or receptor binding but blocked the pores formed by C2IIa and Iota b in living cells and in vitro. The blocking efficiency of pores formed by Iota b and C2IIa by the chloroquine analogs showed interesting differences indicating structural variations between the types of protein-conducting nanochannels formed by Iota b and C2IIa. PMID:27517960

Localization in human interleukin 2 of the binding site to the alpha chain (p55) of the interleukin 2 receptor.

PubMed Central

Sauvé, K; Nachman, M; Spence, C; Bailon, P; Campbell, E; Tsien, W H; Kondas, J A; Hakimi, J; Ju, G

1991-01-01

Human interleukin 2 (IL-2) analogs with defined amino acid substitutions were used to identify specific residues that interact with the 55-kDa subunit (p55) or alpha chain of the human IL-2 receptor. Analog proteins containing specific substitutions for Lys-35, Arg-38, Phe-42, or Lys-43 were inactive in competitive binding assays for p55. All of these analogs retained substantial competitive binding to the intermediate-affinity p70 subunit (beta chain) of the receptor complex. The analogs varied in ability to interact with the high-affinity p55/p70 receptor. Despite the lack of binding to p55, all analogs exhibited significant biological activity, as assayed on the murine CTLL cell line. The dissociation constants of Arg-38 and Phe-42 analogs for p70 were consistent with intermediate-affinity binding; the Kd values were not significantly affected by the presence of p55 in binding to the high-affinity IL-2 receptor complex. These results confirm the importance of the B alpha-helix in IL-2 as the locus for p55-receptor binding and support a revised model of IL-2-IL-2 receptor interaction. PMID:2052547

An amino acid depleted cell-free protein synthesis system for the incorporation of non-canonical amino acid analogs into proteins.

PubMed

Singh-Blom, Amrita; Hughes, Randall A; Ellington, Andrew D

2014-05-20

Residue-specific incorporation of non-canonical amino acids into proteins is usually performed in vivo using amino acid auxotrophic strains and replacing the natural amino acid with an unnatural amino acid analog. Herein, we present an efficient amino acid depleted cell-free protein synthesis system that can be used to study residue-specific replacement of a natural amino acid by an unnatural amino acid analog. This system combines a simple methodology and high protein expression titers with a high-efficiency analog substitution into a target protein. To demonstrate the productivity and efficacy of a cell-free synthesis system for residue-specific incorporation of unnatural amino acids in vitro, we use this system to show that 5-fluorotryptophan and 6-fluorotryptophan substituted streptavidin retain the ability to bind biotin despite protein-wide replacement of a natural amino acid for the amino acid analog. We envisage this amino acid depleted cell-free synthesis system being an economical and convenient format for the high-throughput screening of a myriad of amino acid analogs with a variety of protein targets for the study and functional characterization of proteins substituted with unnatural amino acids when compared to the currently employed in vivo methodologies. Copyright © 2014 Elsevier B.V. All rights reserved.

Stand-alone front-end system for high- frequency, high-frame-rate coded excitation ultrasonic imaging.

PubMed

Park, Jinhyoung; Hu, Changhong; Shung, K Kirk

2011-12-01

A stand-alone front-end system for high-frequency coded excitation imaging was implemented to achieve a wider dynamic range. The system included an arbitrary waveform amplifier, an arbitrary waveform generator, an analog receiver, a motor position interpreter, a motor controller and power supplies. The digitized arbitrary waveforms at a sampling rate of 150 MHz could be programmed and converted to an analog signal. The pulse was subsequently amplified to excite an ultrasound transducer, and the maximum output voltage level achieved was 120 V(pp). The bandwidth of the arbitrary waveform amplifier was from 1 to 70 MHz. The noise figure of the preamplifier was less than 7.7 dB and the bandwidth was 95 MHz. Phantoms and biological tissues were imaged at a frame rate as high as 68 frames per second (fps) to evaluate the performance of the system. During the measurement, 40-MHz lithium niobate (LiNbO(3)) single-element lightweight (<;0.28 g) transducers were utilized. The wire target measure- ment showed that the -6-dB axial resolution of a chirp-coded excitation was 50 μm and lateral resolution was 120 μm. The echo signal-to-noise ratios were found to be 54 and 65 dB for the short burst and coded excitation, respectively. The contrast resolution in a sphere phantom study was estimated to be 24 dB for the chirp-coded excitation and 15 dB for the short burst modes. In an in vivo study, zebrafish and mouse hearts were imaged. Boundaries of the zebrafish heart in the image could be differentiated because of the low-noise operation of the implemented system. In mouse heart images, valves and chambers could be readily visualized with the coded excitation.

The curcumin analog EF24 targets NF-κB and miRNA-21, and has potent anticancer activity in vitro and in vivo.

PubMed

Yang, Chuan He; Yue, Junming; Sims, Michelle; Pfeffer, Lawrence M

2013-01-01

EF24 is a curcumin analog that has improved anticancer activity over curcumin, but its therapeutic potential and mechanism of action is unknown, which is important to address as curcumin targets multiple signaling pathways. EF24 inhibits the NF-κB but not the JAK-STAT signaling pathway in DU145 human prostate cancer cells and B16 murine melanoma cells. EF24 induces apoptosis in these cells apparently by inhibiting miR-21 expression, and also enhances the expression of several miR-21 target genes, PTEN and PDCD4. EF24 treatment significantly suppressed the growth of DU145 prostate cancer xenografts in immunocompromised mice and resulted in tumor regression. EF24 enhanced the expression of the miR-21 target PTEN in DU145 tumor tissue, but suppressed the expression of markers of proliferating cells (cyclin D1 and Ki67). In syngeneic mice injected with B16 cells, EF24 treatment inhibited the formation of lung metastasis, prolonged animal survival, inhibited miR-21 expression and increased the expression of miR-21 target genes. Expression profiling of miRNAs regulated by EF24 in vitro and in vivo showed that the antitumor activity of EF24 reflected the enhanced expression of potential tumor suppressor miRNAs as well as the suppressed expression of oncogenic miRNAs, including miR-21. Taken together, our data suggest that EF24 is a potent anticancer agent and selectively targets NF-κB signaling and miRNA expression, indicating that EF24 has significant potential as a therapeutic agent in various cancers.

The Curcumin Analog EF24 Targets NF-κB and miRNA-21, and Has Potent Anticancer Activity In Vitro and In Vivo

PubMed Central

Yang, Chuan He; Yue, Junming; Sims, Michelle; Pfeffer, Lawrence M.

2013-01-01

EF24 is a curcumin analog that has improved anticancer activity over curcumin, but its therapeutic potential and mechanism of action is unknown, which is important to address as curcumin targets multiple signaling pathways. EF24 inhibits the NF-κB but not the JAK-STAT signaling pathway in DU145 human prostate cancer cells and B16 murine melanoma cells. EF24 induces apoptosis in these cells apparently by inhibiting miR-21 expression, and also enhances the expression of several miR-21 target genes, PTEN and PDCD4. EF24 treatment significantly suppressed the growth of DU145 prostate cancer xenografts in immunocompromised mice and resulted in tumor regression. EF24 enhanced the expression of the miR-21 target PTEN in DU145 tumor tissue, but suppressed the expression of markers of proliferating cells (cyclin D1 and Ki67). In syngeneic mice injected with B16 cells, EF24 treatment inhibited the formation of lung metastasis, prolonged animal survival, inhibited miR-21 expression and increased the expression of miR-21 target genes. Expression profiling of miRNAs regulated by EF24 in vitro and in vivo showed that the antitumor activity of EF24 reflected the enhanced expression of potential tumor suppressor miRNAs as well as the suppressed expression of oncogenic miRNAs, including miR-21. Taken together, our data suggest that EF24 is a potent anticancer agent and selectively targets NF-κB signaling and miRNA expression, indicating that EF24 has significant potential as a therapeutic agent in various cancers. PMID:23940701

Phosphodiesterase 4 regulates the migration of B16-F10 melanoma cells.

PubMed

Watanabe, Yoshihiro; Murata, Taku; Shimizu, Kasumi; Morita, Hiroshi; Inui, Madoka; Tagawa, Toshiro

2012-08-01

Phosphodiesterases (PDEs) are important regulators of signal transduction processes. Eleven PDE gene families (PDE1-11) have been identified and several PDE isoforms are selectively expressed in various cell types. PDE4 family members specifically hydrolyze cyclic AMP (cAMP). Four genes (PDE4A-D) are known to encode PDE4 enzymes, with additional diversity generated by the use of alternative mRNA splicing and the use of different promoters. While PDE4 selective inhibitors show therapeutic potential for treating major diseases such as asthma and chronic obstructive pulmonary disease, little is known concerning the role of PDE4 in malignant melanoma. In this study, we examined the role of PDE4 in mouse B16-F10 melanoma cells. In these cells, PDE4 activity was found to be ∼60% of total PDE activity. RT-PCR detected only PDE4B and PDE4D mRNA. Cell growth was inhibited by the cAMP analog, 8-bromo-cAMP, but not by the specific PDE4 inhibitors, rolipram and denbufylline, which increased intracellular cAMP concentrations. Finally, migration of the B16-F10 cells was inhibited by the PDE4 inhibitors and 8-bromo-cAMP, while migration was increased by a protein kinase A (PKA) inhibitor, PKI(14-22), and was not affected by 8-pCPT-2'-O-Me-cAMP, which is an analog of exchange protein activated by cAMP (Epac). The inhibitory effect of rolipram on migration was reversed by PKI(14-22). Based on these results, PDE4 appears to play an important role in the migration of B16-F10 cells, and therefore may be a novel target for the treatment of malignant melanoma.

Hepatitis B Virus Capsid Assembly Modulators, but Not Nucleoside Analogs, Inhibit the Production of Extracellular Pregenomic RNA and Spliced RNA Variants

PubMed Central

Ren, Suping; Espiritu, Christine; Kelly, Mollie; Lau, Vincent; Zheng, Lingjie; Hartman, George D.; Flores, Osvaldo A.; Klumpp, Klaus

2017-01-01

ABSTRACT The hepatitis B virus (HBV) core protein serves multiple essential functions in the viral life cycle, and antiviral agents that target the core protein are being developed. Capsid assembly modulators (CAMs) are compounds that target core and misdirect capsid assembly, resulting in the suppression of HBV replication and virion production. Besides HBV DNA, circulating HBV RNA has been detected in patient serum and can be associated with the treatment response. Here we studied the effect of HBV CAMs on the production of extracellular HBV RNA using infected HepaRG cells and primary human hepatocytes. Representative compounds from the sulfonamide carboxamide and heteroaryldihydropyrimidine series of CAMs were evaluated and compared to nucleos(t)ide analogs as inhibitors of the viral polymerase. The results showed that CAMs blocked extracellular HBV RNA with efficiencies similar to those with which they blocked pregenomic RNA (pgRNA) encapsidation, HBV DNA replication, and Dane particle production. Nucleos(t)ide analogs inhibited viral replication and virion production but not encapsidation or production of extracellular HBV RNA. Profiling of HBV RNA from both culture supernatants and patient serum showed that extracellular viral RNA consisted of pgRNA and spliced pgRNA variants with an internal deletion(s) but still retained the sequences at both the 5′ and 3′ ends. Similar variants were detected in the supernatants of infected cells with and without nucleos(t)ide analog treatment. Overall, our data demonstrate that HBV CAMs represent direct antiviral agents with a profile differentiated from that of nucleos(t)ide analogs, including the inhibition of extracellular pgRNA and spliced pgRNA. PMID:28559265

Crystal structures of the ternary complex of APH(4)-Ia/Hph with hygromycin B and an ATP analog using a thermostable mutant.

PubMed

Iino, Daisuke; Takakura, Yasuaki; Fukano, Kazuhiro; Sasaki, Yasuyuki; Hoshino, Takayuki; Ohsawa, Kanju; Nakamura, Akira; Yajima, Shunsuke

2013-07-01

Aminoglycoside 4-phosphotransferase-Ia (APH(4)-Ia)/Hygromycin B phosphotransferase (Hph) inactivates the aminoglycoside antibiotic hygromycin B (hygB) via phosphorylation. The crystal structure of the binary complex of APH(4)-Ia with hygB was recently reported. To characterize substrate recognition by the enzyme, we determined the crystal structure of the ternary complex of non-hydrolyzable ATP analog AMP-PNP and hygB with wild-type, thermostable Hph mutant Hph5, and apo-mutant enzyme forms. The comparison between the ternary complex and apo structures revealed that Hph undergoes domain movement upon binding of AMP-PNP and hygB. This was about half amount of the case of APH(9)-Ia. We also determined the crystal structures of mutants in which the conserved, catalytically important residues Asp198 and Asn203, and the non-conserved Asn202, were converted to Ala, revealing the importance of Asn202 for catalysis. Hph5 contains five amino acid substitutions that alter its thermostability by 16°C; its structure revealed that 4/5 mutations in Hph5 are located in the hydrophobic core and appear to increase thermostability by strengthening hydrophobic interactions. Copyright © 2013 Elsevier Inc. All rights reserved.

Synthesis and in vitro study of benzofuran hydrazone derivatives as novel alpha-amylase inhibitor.

PubMed

Taha, Muhammad; Shah, Syed Adnan Ali; Imran, Syahrul; Afifi, Muhammad; Chigurupati, Sridevi; Selvaraj, Manikandan; Rahim, Fazal; Ullah, Hayat; Zaman, Khalid; Vijayabalan, Shantini

2017-12-01

The α-amylase acts as attractive target to treat type-2 diabetes mellitus. Therefore in discovering a small molecule as α-amylase inhibitor, we have synthesized benzofuran carbohydrazide analogs (1-25), characterized through different spectroscopic techniques such as 1 HNMR and EI-MS. All screened analog shows good α-amylase inhibitory potentials with IC 50 value ranging between 1.078±0.19 and 2.926±0.05µM when compared with acarbose having IC 50 =0.62±0.22µM. Only nine analogs among the series such as analogs 3, 5, 7, 8, 10, 12, 21, 23 and 24 exhibit good inhibitory potential with IC 50 values 1.644±0.128, 1.078±0.19, 1.245±0.25, 1.843±0.19, 1.350±0.24, 1.629±0.015, 1.353±0.232, 1.359±0.119 and 1.488±0.07µM when compare with standard drug acarbose. All other analogs showed good to moderate α-amylase inhibitory potentials. The SAR study was conducted on the basis of substituent difference at the phenyl ring. The binding interaction between analogs and active site of enzyme was confirmed by docking studies. Copyright © 2017 Elsevier Inc. All rights reserved.

Membrane Orientation and Lateral Diffusion of BODIPY-Cholesterol as a Function of Probe Structure

PubMed Central

Solanko, Lukasz M.; Honigmann, Alf; Midtiby, Henrik Skov; Lund, Frederik W.; Brewer, Jonathan R.; Dekaris, Vjekoslav; Bittman, Robert; Eggeling, Christian; Wüstner, Daniel

2013-01-01

Cholesterol tagged with the BODIPY fluorophore via the central difluoroboron moiety of the dye (B-Chol) is a promising probe for studying intracellular cholesterol dynamics. We synthesized a new BODIPY-cholesterol probe (B-P-Chol) with the fluorophore attached via one of its pyrrole rings to carbon-24 of cholesterol (B-P-Chol). Using two-photon fluorescence polarimetry in giant unilamellar vesicles and in the plasma membrane (PM) of living intact and actin-disrupted cells, we show that the BODIPY-groups in B-Chol and B-P-Chol are oriented perpendicular and almost parallel to the bilayer normal, respectively. B-Chol is in all three membrane systems much stronger oriented than B-P-Chol. Interestingly, we found that the lateral diffusion in the PM was two times slower for B-Chol than for B-P-Chol, although we found no difference in lateral diffusion in model membranes. Stimulated emission depletion microscopy, performed for the first time, to our knowledge, with fluorescent sterols, revealed that the difference in lateral diffusion of the BODIPY-cholesterol probes was not caused by anomalous subdiffusion, because diffusion of both analogs in the PM was free but not hindered. Our combined measurements show that the position and orientation of the BODIPY moiety in cholesterol analogs have a severe influence on lateral diffusion specifically in the PM of living cells. PMID:24209853

Synthesis and biological evaluation of some novel 1-substituted fentanyl analogs in Swiss albino mice

PubMed Central

Yadav, Shiv Kumar; Maurya, Chandra Kant; Gupta, Pradeep Kumar; Jain, Ajai Kumar; Ganesan, Kumaran

2014-01-01

Fentanyl [N-(1-phenethyl-4-piperidinyl)propionanilide] is a potent opioid analgesic agent, but a has narrow therapeutic index. We reported earlier on the synthesis and bioefficacy of fentanyl and its 1-substituted analogs (1–4) in mice. Here we report the synthesis and biological evaluation of four additional analogs, viz. N-isopropyl-3-(4-(N-phenylpropionamido)piperidin-1-yl)propanamide (5), N-t-butyl-3-(4-(N-phenylpropionamido)piperidin-1-yl)propanamide (6), isopropyl 2-[4-(N-phenylpropionamido)piperidin-1-yl]propionate (7) and t-butyl 2-[4-(N-phenylpropionamido)piperidin-1-yl]propionate (8). The median lethal dose (LD50) determined by intravenous, intraperitoneal and oral routes suggests these analogs to be comparatively less toxic than fentanyl. On the basis of observational assessment on spontaneous activities of the central, peripheral, and autonomic nervous systems, all the analogs were found to be similar to fentanyl. Naloxone hydrochloride abolished the neurotoxic effects of these analogs, thereby ascertaining their opioid receptor-mediated effects. All the analogs displayed significant analgesic effects, measured by formalin-induced hind paw licking and tail immersion tests at their respective median effective dose (ED50). They also exhibited 8–12 fold increase in therapeutic index over fentanyl. However, 5 and 6 alone produced lower ED50 (20.5 and 21.0 µg/kg, respectively) and higher potency ratio (1.37 and 1.33, respectively) compared to fentanyl. They could thus be considered for further studies on pain management. PMID:26109885

Convergent synthesis of double point modified analogs of 1α,25-dihydroxyvitamin D2 for biological evaluation.

PubMed

Nadkarni, Sharmin; Chodyński, Michał; Krajewski, Krzysztof; Cmoch, Piotr; Marcinkowska, Ewa; Brown, Geoffrey; Kutner, Andrzej

2016-11-01

There is a long lasting controversy over the biological activity of vitamin D 2 as compared to vitamin D 3 in terms of maintaining of calcium homeostasis and raising the level of circulating 25-OH-D. To shed more light on this relationship we synthesized 1α,25-dihydroxyvitamin D 2 , by a novel convergent strategy, to compare this compound directly with the activity of 1α,25-dihydroxyvitamin D 3 . The same synthetic strategy also provided a series of (5E,7E) geometric isomers of the natural 1α,25-dihydroxyvitamin D 2 as well as a series of double point modified analogs of its (24R)-epimer, including C-22 hydroxy derivatives. The structure of the new analogs was determined by 1 H and 13 C NMR as well as by mass spectrometry. The influence of (5E,7E) modification, alone or in combination with additional modifications in the side chain, on the activity profile and metabolic deactivation of analogs of 1α,25-dihydroxyvitamin D 2 still remains unknown. (5E,7E) modification in the structure of new analogs of 1α,25-dihydroxyvitamin D 2 is expected to give analogs with no influence on calcium level, as was previously obtained for the analogs of 1α,25-dihydroxyvitamin D 3 . Investigation of the affinities for the vitamin D receptor and cell differentiation, transcriptional and calcium activities of the most active form of vitamin D 2 and of (5E,7E) analogs, compared to 1α,25-dihydroxyvitamin D 3 , is underway in the collaborating laboratories. Copyright © 2015 Elsevier Ltd. All rights reserved.

Understanding High Rate Behavior Through Low Rate Analog

DTIC Science & Technology

2014-04-28

uni- axial compression over all rates tested at 20 °C; (b) True yield stress as a function of strain rate...of temperature. (a) (b) Figure 11. Representative behaviour of PPVC-2. (a) True stress-true strain response in uni- axial compression over all...pages 33 of 78 (a) (b) Figure 15. Representative behaviour of PPVC-6. (a) True stress-true strain response in uni- axial compression

Formation and decay of resonance states in 9Be and 9B nuclei: Microscopic three-cluster model investigations

NASA Astrophysics Data System (ADS)

Vasilevsky, V. S.; Katō, K.; Takibayev, N. Zh.

2017-09-01

We study the nature of the low-lying resonance states in mirror nuclei 9Be and 9B. Investigations are performed within a three-cluster model. The model makes use of the hyperspherical harmonics, which provides a convenient description of the three-cluster continuum. The dominant three-cluster configurations α +α +n and α +α +p in 9Be and 9B, respectively, are taken into account. Dominant decay channels for all resonance states in 9Be and 9B are explored. Much attention is paid to the controversial 1 /2+ resonance states in both nuclei. We study effects of the Coulomb interaction on the energy and width of three-cluster resonances in the mirror nuclei 9Be and 9B. We also search for the Hoyle-analog state, which is a key step for alternative ways to synthesize 9Be and 9B in triple collisions of clusters in a stellar environment.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Li, Yang; Gong, Hao; Sun, Yue

Highlights: Black-Right-Pointing-Pointer We dissect how individual disulfide bond affects the amyloidogenicity of insulin. Black-Right-Pointing-Pointer A controlled reduction system for insulin is established in this study. Black-Right-Pointing-Pointer Disulfide breakage is associated with unfolding and increased amyloidogenicity. Black-Right-Pointing-Pointer Breakage of A6-A11 is associated with significantly increased cytotoxicity. Black-Right-Pointing-Pointer Analogs without A6-A11 have a higher potency to form high order toxic oligomers. -- Abstract: Disulfide bonds play a critical role in the stability and folding of proteins. Here, we used insulin as a model system, to investigate the role of its individual disulfide bond during the amyloid formation of insulin. Tris(2-carboxyethyl)phosphine (TCEP) wasmore » applied to reduce two of the three disulfide bonds in porcine insulin and the reduced disulfide bonds were then alkylated by iodoacetamide. Three disulfide bond-modified insulin analogs, INS-2 (lack of A6-A11), INS-3 (lack of A7-B7) and INS-6 (lack of both A6-A11 and A7-B7), were obtained. Far-UV circular dichroism (CD) spectroscopy results indicated that the secondary structure of INS-2 was the closest to insulin under neutral conditions, followed by INS-3 and INS-6, whereas in an acidic solution all analogs were essentially unfolded. To test how these modifications affect the amyloidogenicity of insulin, thioflavin-T (ThT) fluorescence and transmission electronic microscopy (TEM) were performed. Our results showed that all analogs were more prone to aggregation than insulin, with the order of aggregation rates being INS-6 > INS-3 > INS-2. Cross-linking of unmodified proteins (PICUP) assay results showed that analogs without A6-A11 (INS-2 and INS-6) have a higher potential for oligomerization than insulin and INS-3, which is accompanied with a higher cytotoxicity as the hemolytic assays of human erythrocytes suggested. The results indicated that breakage of A7-B7 induced more unfolding of the insulin structure and a higher amyloidogenicity than breakage of A6-A11, but breakage of A6-A11 caused a significant cytotoxicity increase and a higher potency to form high order toxic oligomers.« less

Crystallization, Preliminary X-ray Analysis and Biophysical Characterization of HPr Kinase/Phosphatase of Mycoplasma pneumoniae

DOE Office of Scientific and Technical Information (OSTI.GOV)

Steinhauer, K.

2002-01-01

The Mycoplasma pneumoniae HPr kinase/phosphatase (HPrK/P) is a member of a large family of enzymes which are central to carbon regulation in Gram-positive bacteria. The full-length M. pneumonia HPrK/P was crystallized from solutions of polyethylene glycol 8000 and KCl or NaCl which also contained the non-hydrolysable ATP analog adenosine 5'-[{beta},{gamma}-methylene]triphosphate (AMPPCP). The crystals belong to the orthorhombic space group P2{sub 1}2{sub 1}2{sub 1}, with unit-cell parameters a = 117.1, b = 127.7, c = 170.7 {angstrom}. A complete X-ray intensity data set has been collected and processed to 2.50 {angstrom} resolution. The slow self-rotation function revealed the presence of amore » sixfold axis. Dynamic light-scattering (DLS) experiments indicated a molecular weight of 197 kDa for HPrK/P in the absence of AMPPCP and of 217 kDa in the presence of the ATP analog. Thus, the biophysical and crystallographic data suggest that HPrK/P is a functional hexamer that undergoes an ATP-binding-induced conformational change.« less

Atmospheric degradation mechanisms of hydrogen containing chlorofluorocarbons (HCFC) and fluorocarbons (HFC)

NASA Technical Reports Server (NTRS)

Zellner, Reinhard

1990-01-01

The current knowledge of atmospheric degradation of hydrogen containing chlorofluorocarbons (HCFC 22 (CHClF2), HCFC 123 (CHCl2CF3), HCFC 124 (CHClFCF3), HCFC 141b (CFCl2CH3), HCFC 142b (CF2ClCH3)) and fluorocarbons (HFC 125 (CHF2CF3), HFC 134a (CH2FCF3), HFC 152a (CHF2CH3)) is assessed. Except for the initiation reaction by OH radicals, there are virtually no experimental data available concerning the subsequent oxidative breakdown of these molecules. However, from an analogy to the degradation mechanisms of simple alkanes, some useful guidelines as to the expected intermediates and final products can be derived. A noteable exception from this analogy, however, appears for the oxi-radicals. Here, halogen substitution induces new reaction types (C-Cl and C-C bond ruptures) which are unknown to the unsubstituted analogues and which modify the nature of the expected carbonyl products. Based on an evaluation of these processes using estimated bond strength data, the following simplified rules with regards to the chlorine content of the HCFC's may be deduced: (1) HCFC's containing one chlorine atom such as 22 and 142b seem to release their chlorine content essentially instantaneous with the initial attack on the parent by OH radicals, and for HCFC 124, such release is apparently prevented; (2) HCFC's such as 123 and 141b with two chlorine atoms are expected to release only one of these instantaneously; and the second chlorine atom may be stored in potentially long-lived carbonyl compounds such as CF3CClO or CClFO.

Joint Transmit and Receive Filter Optimization for Sub-Nyquist Delay-Doppler Estimation

NASA Astrophysics Data System (ADS)

Lenz, Andreas; Stein, Manuel S.; Swindlehurst, A. Lee

2018-05-01

In this article, a framework is presented for the joint optimization of the analog transmit and receive filter with respect to a parameter estimation problem. At the receiver, conventional signal processing systems restrict the two-sided bandwidth of the analog pre-filter $B$ to the rate of the analog-to-digital converter $f_s$ to comply with the well-known Nyquist-Shannon sampling theorem. In contrast, here we consider a transceiver that by design violates the common paradigm $B\\leq f_s$. To this end, at the receiver, we allow for a higher pre-filter bandwidth $B>f_s$ and study the achievable parameter estimation accuracy under a fixed sampling rate when the transmit and receive filter are jointly optimized with respect to the Bayesian Cram\\'{e}r-Rao lower bound. For the case of delay-Doppler estimation, we propose to approximate the required Fisher information matrix and solve the transceiver design problem by an alternating optimization algorithm. The presented approach allows us to explore the Pareto-optimal region spanned by transmit and receive filters which are favorable under a weighted mean squared error criterion. We also discuss the computational complexity of the obtained transceiver design by visualizing the resulting ambiguity function. Finally, we verify the performance of the optimized designs by Monte-Carlo simulations of a likelihood-based estimator.

Discovery and evaluation of novel anti-inflammatory derivatives of natural bioactive curcumin

PubMed Central

Zhang, Yali; Jiang, Xin; Peng, Kesong; Chen, Chengwei; Fu, Lili; Wang, Zhe; Feng, Jianpeng; Liu, Zhiguo; Zhang, Huajie; Liang, Guang; Pan, Zheer

2014-01-01

Curcumin is a natural active product that has various pharmacological activities such as anti-inflammatory effects. Here, we report the synthesis and evaluation of 34 monocarbonyl curcumin analogs as novel anti-inflammatory agents. Among the analogs, the symmetrical heterocyclic type displayed the strongest inhibition of lipopolysaccharide (LPS)-stimulated expression of pro-inflammatory cytokines in macrophages. Analogs S1–S5 and AS29 reduced tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) production in a dose-dependent manner and also displayed excellent stability and low cytotoxicity in vitro. In addition, analog S1 dose-dependently inhibited LPS-induced extracellular signal-regulated kinase (ERK) phosphorylation. Furthermore, analogs S1 and S4 displayed a significant protective effect on LPS-induced septic death in mouse models, with 40% and 50% survival rates, respectively. These data demonstrate that the heterocyclic monocarbonyl curcumin analogs have potential therapeutic effects in acute inflammatory diseases. PMID:25395833

Caffeic acid phenethyl ester downregulates phospholipase D1 via direct binding and inhibition of NFκB transactivation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Park, Mi Hee; Kang, Dong Woo; Jung, Yunjin

2013-12-06

Highlights: •We found CAFÉ, a natural product that suppresses expression and activity of PLD1. •CAPE decreased PLD1 expression by inhibiting NFκB transactivation. •CAPE rapidly inhibited PLD activity via its binding to a Cys837 of PLD1. •PLD1 downregulation by CAPE inhibited invasion and proliferation of glioma cells. -- Abstract: Upregulation of phospholipase D (PLD) is functionally linked with oncogenic signals and tumorigenesis. Caffeic acid phenethyl ester (CAPE) is an active compound of propolis extract that exhibits anti-proliferative, anti-inflammatory, anti-oxidant, and antineoplastic properties. In this study, we demonstrated that CAPE suppressed the expression of PLD1 at the transcriptional level via inhibition ofmore » binding of NFκB to PLD1 promoter. Moreover, CAPE, but not its analogs, bound to a Cys837 residue of PLD1 and inhibited enzymatic activity of PLD. CAPE also decreased activation of matrix metalloproteinases-2 induced by phosphatidic acid, a product of PLD activity. Ultimately, CAPE-induced downregulation of PLD1 suppressed invasion and proliferation of glioma cells. Taken together, the results of this study indicate that CAPE might contribute to anti-neoplastic effect by targeting PLD1.« less

Infrared Laser Stark Spectroscopy and AB Initio Computations of the OH\\cdotsCO Complex

NASA Astrophysics Data System (ADS)

Liang, Tao; Raston, Paul; Douberly, Gary

2014-06-01

Following the sequential pick-up of OH and CO by helium nanodroplets, the infrared depletion spectrum is measured in the fundamental OH stretching region. Although several potentially accessible minima exist on the associated OH + CO reactive potential energy surface [e.g. J. Ma, J. Li, and H. Guo, J. Phys. Chem. Lett. 3 (2012) 2482], such as the weakly bound OH-OC dimer and the chemically bound HOCO molecule, we only observe the weakly bound OH-CO dimer. The rovibrational spectrum of this complex displays narrow (0.02 cm-1) Lorentzian shaped peaks with spacings that are characteristic of a linear complex with unquenched electronic angular momentum, similar to what was previously observed in the gas phase [M.I. Lester, B.V. Pond, D.T. Anderson, L.B. Harding, and A.F. Wagner, J. Chem. Phys. 113 (2000) 9889]. Analogous spectra involving OD were collected, for which we also only observe the OD-CO isomer. From the Stark spectra, the dipole moments for OH-CO are determined to be 1.85(3) and 1.89(3) D for v=0 and v=1, respectively, while the analogous dipole moments for OD-CO are determined to be 1.88(8) and 1.94(5) D. The computed equilibrium ground state dipole moment at the CCSD(T)/Def2-TZVPD level of theory is 2.185 D, in disagreement with experiment. The role of vibrational averaging is investigated via the solution of a three-dimensional vibrational Schrödinger equation, which is constructed in internal bond-angle coordinates. The computed expectation value of the ground state dipole moment is in excellent agreement with experiment, indicating a floppy molecular complex.

Inhibition of Delta-induced Notch signaling using fucose analogs

PubMed Central

Schneider, Michael; Kumar, Vivek; Nordstrøm, Lars Ulrik; Feng, Lei; Takeuchi, Hideyuki; Hao, Huilin; Luca, Vincent C.; Garcia, K. Christopher; Stanley, Pamela; Wu, Peng; Haltiwanger, Robert S.

2017-01-01

Notch is a cell-surface receptor that controls cell fate decisions and is regulated by O-glycans attached to epidermal growth factor-like (EGF) repeats in its extracellular domain. Protein O-fucosyltransferase 1 (Pofut1) modifies EGF repeats with O-fucose and is essential for Notch signaling. Constitutive activation of Notch signaling has been associated with a variety of human malignancies. Therefore, tools for inhibiting Notch activity are being developed as cancer therapeutics. Towards this end, we screened L-fucose analogs for their effects on Notch signaling. Two analogs, 6-alkynyl and 6-alkenyl fucose, were substrates of Pofut1 and were incorporated directly into Notch EGF repeats in cells. Both analogs were potent inhibitors of binding to and activation of Notch1 by Notch ligands Dll1 and Dll4, but not by Jag1. Mutagenesis and modeling studies suggest that incorporation of the analogs into EGF8 of Notch1 markedly reduces the ability of Delta ligands to bind and activate Notch1. PMID:29176671

14 CFR Appendix E to Part 91 - Airplane Flight Recorder Specifications

Code of Federal Regulations, 2010 CFR

2010-01-01

... altitude resolution) −20° to 40° or 100% of usable range ±2° 1 0.8%3 Radio Transmitter Keying (Discrete) On/Off 1 TE Flaps (Discrete or Analog) Each discrete position (U, D, T/O, AAP) OR 1 LE Flaps (Discrete or Analog) Analog 0-100% range ±3% 1 1%3 Each discrete position (U, D, T/O, AAP) OR 1 Thrust Reverser, Each...

Isospin symmetry of Tz =±3/2→±1/2 Gamow-Teller transitions in A=41 nuclei

NASA Astrophysics Data System (ADS)

Fujita, Y.; Shimbara, Y.; Adachi, T.; Berg, G. P.; Brown, B. A.; Fujita, H.; Hatanaka, K.; Kamiya, J.; Nakanishi, K.; Sakemi, Y.; Sasaki, S.; Shimizu, Y.; Tameshige, Y.; Uchida, M.; Wakasa, T.; Yosoi, M.

2004-11-01

Under the assumption that isospin T is a good quantum number, isobaric analog states and various analogous transitions are expected in isobars with mass number A . The strengths of Tz =±3/2→±1/2 analogous Gamow-Teller (GT) transitions and analogous M1 transitions within the A=41 isobar quartet are compared in detail. The Tz =+3/2→+1/2 GT transitions from the Jπ = 3/2+ ground state of 41K leading to excited Jπ = 1/2+ , 3/2+ , and 5/2+ states in 41Ca were measured using the ( 3He ,t) charge-exchange reaction. With a high energy resolution of 35 keV , many fragmented states were observed, and the GT strength distribution was determined up to 10 MeV excitation energy ( Ex ) . The main part of the strength was concentrated in the Ex =4 6 MeV region. A shell-model calculation could reproduce the concentration, but not so well details of the strength distribution. The obtained distribution was further compared with two results of 41Ti β decay studying the analogous Tz =-3/2→-1/2 GT strengths. They reported contradicting distributions. One-to-one correspondences of analogous transitions and analog states were assigned up to Ex =6 MeV in the comparison with one of these 41Ti β -decay results. Combining the spectroscopic information of the analog states in 41Ca and 41Sc , the most probable Jπ values were deduced for each pair of analog states. It was found that 5/2+ states carry the main part of the observed GT strength, while much less GT strength was carried by 1/2+ and 3/2+ states. The gross features of the GT strength distributions for each J were similar for the isospin analogous Tz =±3/2→±1/2 transitions, but the details were somewhat different. From the difference of the distributions, isospin-asymmetry matrix elements of ≈8 keV were deduced. The Coulomb displacement energy, which is sensitive to the configuration of states, showed a sudden increase of about 50 keV at the excitation energy of 3.8 MeV . The strengths of several M1 transitions to the IAS in 41Ca were compared with the strengths of analogous GT transitions. It was found that ratios of the M1 and GT transition strengths were similar, suggesting that the contributions of the ℓτ term in M1 transitions are small.

Polyketides from Pestalotiopsis zonata and structure revision of pestalrones A and B.

PubMed

Xu, Xin; Liu, Chang; Dong, Ya-Jing; Liu, Fang-Ru; Xu, Xiu-Mei; Li, De-Sheng; Li, Dan-Yi; Li, Zhan-Lin

2017-11-23

The structures of pestalrones A-B were revised via reinterpretation of the NMR data and a brief chemical transformation from the co-occurring polyketides, in our investigation on the secondary metabolites of Pestalotiopsis zonata, which also afforded a new α-pyrone derivative, pestazonatic acid, and four known analogs.

Influence of molecular structure on the tolerogenicity of bacterial dextrans. I. The alpha1--6-linked epitope of dextran B512.

PubMed Central

Howard, J G; Vicari, G; Courtenay, B M

1975-01-01

Native dextran B512 is a near-linear glucose polymer with 96 per cent alpha1--6 and 4 per cent alpha1--3 linkages and a molecular weight (mol. wt) of 8 X 10(7). Sheep RBC sensitized with its O-stearoyl derivative (prepared by a modified method) have been used satisfactorily in direct PFC assays. B512 immunizes BALB/c mice optimally with doses of 1--10 mug and produces B-cell tolerance with 1 mg upwards. The specificity of the response determined by PFC inhibition analysis, is directed towards an alpha1--6-linked epitope. High dose tolerance is not preceded by immunity and is stable on cell transfer to irradiated recipients in which responsiveness becomes perceptible after 4--6 weeks. Progressive depolymerization of this polysaccharide reduces immunogenicity and tolerogenicity, both of which are extinguished when the mol. wt falls to 2 X 10(4). Optimal immunization with B512 is succeeded by partial tolerance (previously characterized by analogous levan experiments as a B-cell exhaustion process). The tolerance threshold dose of B512 is reduced 1000-fold during immunosuppression with cyclophosphamide. PFC inhibition studies supported the contention that tolerogenicity of polysaccharides is influenced by their overall binding capacities. A direct relationship between inhibitory and tolerogenic activities was found both with B512 fractions of varying mol. wt and with heterologous dextrans. The similarities between B512 and levan argue against the association of a highly branched structure with greater tolerogenicity. The effect of reducing the percentage of alpha1--6 linkages in dextrans suggests, however, that epitope density probably plays a contributory role in determining the outcome of interaction between polysaccharides and B cells. PMID:52612

Supplementing lactating dairy cows with a vitamin B12 precursor, 5,6-dimethylbenzimidazole, increases the apparent ruminal synthesis of vitamin B12.

PubMed

Brito, A; Chiquette, J; Stabler, S P; Allen, R H; Girard, C L

2015-01-01

Cobalamin (CBL), the biologically active form of vitamin B12, and its analogs, are produced by bacteria only if cobalt supply is adequate. The analogs differ generally by the nucleotide moiety of the molecule. In CBL, 5,6-dimethylbenzimidazole (5,6-DMB) is the base in the nucleotide moiety. The present study aimed to determine if a supplement of 5,6-DMB could increase utilization of dietary cobalt for synthesis of CBL and change ruminal fermentation, nutrient digestibility, omasal flow of nutrients and ruminal protozoa counts. Eight ruminally cannulated multiparous Holstein cows (mean±standard deviation=238±21 days in milk and 736±47 kg of BW) were used in a crossover design. Cows were randomly assigned to a daily supplement of a gelatin capsule containing 1.5 g of 5,6-DMB via the rumen cannula or no supplement. Each period lasted 29 days and consisted of 21 days for treatment adaptation and 8 days for data and samples collection. Five corrinoids, CBL and four cobamides were detected in the total mixed ration and the omasal digesta from both treatments. The dietary supplement of 5,6-DMB increased (P=0.02) apparent ruminal synthesis of CBL from 14.6 to 19.6 (s.e.m. 0.8) mg/day but had no effect (P>0.1) on apparent ruminal synthesis of the four analogs. The supplement of 5,6-DMB had no effect (P>0.1) on milk production and composition, or on protozoal count, ruminal pH and concentrations of volatile fatty acids and ammonia nitrogen in rumen content. The supplement had also no effect (P>0.1) on intake, omasal flow and apparent ruminal digestibility of dry matter, organic matter, NDF, ADF and nitrogenous fractions. Plasma concentration of CBL was not affected by treatments (P=0.98). Providing a preformed part of the CBL molecule, that is, 5,6-DMB, increased by 34% the apparent ruminal synthesis of CBL by ruminal bacteria but had no effect on ruminal fermentation or protozoa count and it was not sufficient to increase plasma concentrations of the vitamin. Even though the efficiency of cobalt utilization for apparent synthesis of CBL was increased from 2.0% to 2.7% by the 5,6-DMB supplement, this improved efficiency was still very low. Further research is needed to identify the factors affecting efficiency of utilization of cobalt for synthesis of CBL by the bacterial populations in rumen.

Overcoming immune tolerance in chronic hepatitis B by therapeutic vaccination.

PubMed

Dembek, Claudia; Protzer, Ulrike; Roggendorf, Michael

2018-05-08

The currently used nucleoside analogs (i.e. entecavir and tenofovir) with high barrier-to-resistance efficiently suppress viral replication, limit inflammation and reduce the sequelae of chronic hepatitis B, but cannot cure the disease and thus have to be applied long-term. Therapeutic vaccination as an approach to cure chronic hepatitis B has shown promising pre-clinical results, nevertheless the proof of its efficacy in clinical trials is still missing. This may be partially due to suboptimal vaccine design. A main obstacle in chronic hepatitis B, however, is the high load of viral antigens expressed and secreted, which has been proposed to cause antigen-specific immune tolerance. Reduction of the viral antigen load is therefore considered a key factor for success of immune-based therapies. Although nucleoside analogs do not reduce viral antigen expression, new antiviral strategies are becoming available. Targeting viral translation by siRNA or targeting release of HBsAg from infected hepatocytes by nucleic acid polymers both reduce the antigen load. They may be considered as pre-treatment for therapeutic vaccination to increase the potential to elicit an HBV-specific immune response able to control and cure chronic HBV infection. Copyright © 2018 Elsevier B.V. All rights reserved.

Face-capping μ3-BO in B6(BO)7-: boron oxide analogue of B6H7- with rhombic 4c-2e bonds.

PubMed

Guo, Jin-Chang; Lu, Hai-Gang; Zhai, Hua-Jin; Li, Si-Dian

2013-11-14

Using the first-principle approaches, we predict a B6(BO)7(-) cluster with a face-capping μ(3)-BO, which is the boron oxide analogue of closo-B6H7(-) with a face-capping μ(3)-H. Detailed topological analysis of electron density clearly reveals the existence of three rhombic 4c-2e bonds around the B/H apex in both C3v B6(BO)7(-) and C3v B6H7(-), which possesses similar electron densities at their bond and ring critical points. The adaptive natural density partitioning (AdNDP) analysis provides a direct and visual picture of the B-B-B-B/H 4c-2e bonds for the first time. Adiabatic and vertical electron detachment energies of the concerned monoanions are calculated to facilitate their future photoelectron spectroscopy measurements and characterizations. The presence of the B6(BO)7(-) and B6H7(-) clusters extends the BO/H isolobal analogy to the whole μ(n)-BO/H series (n = 1, 2, and 3) and enriches the chemistry of boronyl.

21 CFR 862.3640 - Morphine test system.

Code of Federal Regulations, 2010 CFR

2010-04-01

...) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Toxicology Test Systems § 862... monitoring levels of morphine and its analogs to ensure appropriate therapy. (b) Classification. Class II. ...

Cap analogs modified with 1,2-dithiodiphosphate moiety protect mRNA from decapping and enhance its translational potential

PubMed Central

Strenkowska, Malwina; Grzela, Renata; Majewski, Maciej; Wnek, Katarzyna; Kowalska, Joanna; Lukaszewicz, Maciej; Zuberek, Joanna; Darzynkiewicz, Edward; Kuhn, Andreas N.; Sahin, Ugur; Jemielity, Jacek

2016-01-01

Along with a growing interest in mRNA-based gene therapies, efforts are increasingly focused on reaching the full translational potential of mRNA, as a major obstacle for in vivo applications is sufficient expression of exogenously delivered mRNA. One method to overcome this limitation is chemically modifying the 7-methylguanosine cap at the 5′ end of mRNA (m7Gppp-RNA). We report a novel class of cap analogs designed as reagents for mRNA modification. The analogs carry a 1,2-dithiodiphosphate moiety at various positions along a tri- or tetraphosphate bridge, and thus are termed 2S analogs. These 2S analogs have high affinities for translation initiation factor 4E, and some exhibit remarkable resistance against the SpDcp1/2 decapping complex when introduced into RNA. mRNAs capped with 2S analogs combining these two features exhibit high translation efficiency in cultured human immature dendritic cells. These properties demonstrate that 2S analogs are potentially beneficial for mRNA-based therapies such as anti-cancer immunization. PMID:27903882

Digitally balanced detection for optical tomography.

PubMed

Hafiz, Rehan; Ozanyan, Krikor B

2007-10-01

Analog balanced Photodetection has found extensive usage for sensing of a weak absorption signal buried in laser intensity noise. This paper proposes schemes for compact, affordable, and flexible digital implementation of the already established analog balanced detection, as part of a multichannel digital tomography system. Variants of digitally balanced detection (DBD) schemes, suitable for weak signals on a largely varying background or weakly varying envelopes of high frequency carrier waves, are introduced analytically and elaborated in terms of algorithmic and hardware flow. The DBD algorithms are implemented on a low-cost general purpose reconfigurable hardware (field-programmable gate array), utilizing less than half of its resources. The performance of the DBD schemes compare favorably with their analog counterpart: A common mode rejection ratio of 50 dB was observed over a bandwidth of 300 kHz, limited mainly by the host digital hardware. The close relationship between the DBD outputs and those of known analog balancing circuits is discussed in principle and shown experimentally in the example case of propane gas detection.

Structure and coherence of reasoning ability in Down Syndrome adults and typically developing children.

PubMed

Natsopoulo, D; Christou, C; Koutselini, M; Raftopoulos, A; Karefillidou, C

2002-01-01

The present study investigates the ability of Down Syndrome (DS) adults to reason: (a) deductively with transitivity (linear and reverse relations) and categorical syllogisms (all-some relations); (b) inductively with classical verbal analogies and non-verbal analogical reasoning (Raven's Coloured Progressive Matrices); and (c) to retain information in short-term memory. The results have shown that: (i) The Down Syndrome adults did not differ from typically developing children, matched on expressive and verbal ability, in transitivity and non-verbal analogical thinking; (ii) they differed in categorical reasoning, classical verbal analogies and short-term memory. Application of a structural model demonstrated that, despite differences in slope means in the three measures, the structure of functioning within-and-across all domains of cognition tests and its growth pattern, equally reliable and coherent, goes in parallel for the Down Syndrome adults and the typically developing children. The results are discussed within the context of the two-group developmental and difference approach.

Novel C-1 Substituted Cocaine Analogs Unlike Cocaine or Benztropine

PubMed Central

Ali, Solav; Hashim, Audrey; Sheikh, Imran S.; Theddu, Naresh; Gaddiraju, Narendra V.; Mehrotra, Suneet; Schmitt, Kyle C.; Murray, Thomas F.; Sershen, Henry; Unterwald, Ellen M.; Davis, Franklin A.

2012-01-01

Despite a wealth of information on cocaine-like compounds, there is no information on cocaine analogs with substitutions at C-1. Here, we report on (R)-(−)-cocaine analogs with various C-1 substituents: methyl (2), ethyl (3), n-propyl (4), n-pentyl (5), and phenyl (6). Analog 2 was equipotent to cocaine as an inhibitor of the dopamine transporter (DAT), whereas 3 and 6 were 3- and 10-fold more potent, respectively. None of the analogs, however, stimulated mouse locomotor activity, in contrast to cocaine. Pharmacokinetic assays showed compound 2 occupied mouse brain rapidly, as cocaine itself; moreover, 2 and 6 were behaviorally active in mice in the forced-swim test model of depression and the conditioned place preference test. Analog 2 was a weaker inhibitor of voltage-dependent Na+ channels than cocaine, although 6 was more potent than cocaine, highlighting the need to assay future C-1 analogs for this activity. Receptorome screening indicated few significant binding targets other than the monoamine transporters. Benztropine-like “atypical” DAT inhibitors are known to display reduced cocaine-like locomotor stimulation, presumably by their propensity to interact with an inward-facing transporter conformation. However, 2 and 6, like cocaine, but unlike benztropine, exhibited preferential interaction with an outward-facing conformation upon docking in our DAT homology model. In summary, C-1 cocaine analogs are not cocaine-like in that they are not stimulatory in vivo. However, they are not benztropine-like in binding mechanism and seem to interact with the DAT similarly to cocaine. The present data warrant further consideration of these novel cocaine analogs for antidepressant or cocaine substitution potential. PMID:22895898

Plasma Physics Issues in Gas Discharge Laser Development

DTIC Science & Technology

1991-12-01

possible where the ArF exciplex was previously formed by 2 3 4 5 6 7 8 reactions analogous to those shown above. These formation R (1) reactions are...exothermic bv a few to many electronvolts. Fig. n. Energy levels of the K’F exciplex . Laser oscillation at 248 nm takes resulting in KrF(B. v) being formed...all on a due to the large momentum-transfer cross section of the Rg single device. which forms the exciplex . The cross sections for electron- Excited

Defense AT and L. Volume 44, Number 5

DTIC Science & Technology

2015-10-01

one requirement drives the solution. What sounds complex actually is fairly straightforward. A car -buying analogy can demonstrate how it works. Let’s...requirements have been handed to you (Figure 1). Your boss sums up the task: Select the best overall car that balances performance, roominess, ef- ficiency...To ta l S co re Car ACar B Car C Car D For example, first find the global weighting for the “Number of Days in the Shop” attribute by multiplying the

Interaction of Mimetic Analogs of Insect Kinin Neuropeptides with Arthropod Receptors

DTIC Science & Technology

2010-01-01

stagnalis.20 The amino acid sequence of the B. microplus receptor showed most similarity to the CG10626 Drosophila melanogaster gene product and to the...25 The A. aegypti cDNA encodes a 584 amino acid residue protein of predicted molecular mass of 65.2 kDa. The mosquito kinin receptor cDNA was...charged acid moiety.36,37 Within the core pentapeptide, the aromatic residues Phe1 and Trp4 are the most important for activity whereas a wide range

Bio-inspired multi-mode optic flow sensors for micro air vehicles

NASA Astrophysics Data System (ADS)

Park, Seokjun; Choi, Jaehyuk; Cho, Jihyun; Yoon, Euisik

2013-06-01

Monitoring wide-field surrounding information is essential for vision-based autonomous navigation in micro-air-vehicles (MAV). Our image-cube (iCube) module, which consists of multiple sensors that are facing different angles in 3-D space, can be applied to the wide-field of view optic flows estimation (μ-Compound eyes) and to attitude control (μ- Ocelli) in the Micro Autonomous Systems and Technology (MAST) platforms. In this paper, we report an analog/digital (A/D) mixed-mode optic-flow sensor, which generates both optic flows and normal images in different modes for μ- Compound eyes and μ-Ocelli applications. The sensor employs a time-stamp based optic flow algorithm which is modified from the conventional EMD (Elementary Motion Detector) algorithm to give an optimum partitioning of hardware blocks in analog and digital domains as well as adequate allocation of pixel-level, column-parallel, and chip-level signal processing. Temporal filtering, which may require huge hardware resources if implemented in digital domain, is remained in a pixel-level analog processing unit. The rest of the blocks, including feature detection and timestamp latching, are implemented using digital circuits in a column-parallel processing unit. Finally, time-stamp information is decoded into velocity from look-up tables, multiplications, and simple subtraction circuits in a chip-level processing unit, thus significantly reducing core digital processing power consumption. In the normal image mode, the sensor generates 8-b digital images using single slope ADCs in the column unit. In the optic flow mode, the sensor estimates 8-b 1-D optic flows from the integrated mixed-mode algorithm core and 2-D optic flows with an external timestamp processing, respectively.

Stereo-specific Synthesis of Analogs of Nerve Agents And Their Utilization For Selection And Characterization of Paraoxonase (PON1) Catalytic Scavengers

PubMed Central

Ashani, Y.; Gupta, R.D.; Goldsmith, M.; Silman, I.; Sussman, J.L.; Tawfik, D. S.; Leader, H.

2010-01-01

Fluorogenic organophosphate inhibitors of acetylcholinesterase (AChE) homologous in structure to nerve agents provide useful probes for high throughput screening of mammalian paraoxonase (PON1) libraries generated by directed evolution of an engineered PON1 variant with wild-type like specificity (rePON1). Wt PON1 and rePON1 hydrolyze preferentially the less-toxic RP enantiomers of nerve agents and of their fluorogenic surrogates containing the fluorescent leaving group, 3-cyano-7-hydroxy-4-methylcoumarin (CHMC). To increase the sensitivity and reliability of the screening protocol so as to directly select rePON1 clones displaying stereo-preference towards the toxic SP enantiomer, and to determine accurately Km and kcat values for the individual isomers, two approaches were used to obtain the corresponding SP and RP isomers: (a) stereo-specific synthesis of the O-ethyl, O-n-propyl, and O-i-propyl analogs; (b) enzymic resolution of a racemic mixture of O-cyclohexyl methylphosphonylated CHMC. The configurational assignments of the SP and RP isomers, as well as their optical purity, were established by X-ray diffraction, reaction with sodium fluoride, hydrolysis by selected rePON1 variants, and inhibition of AChE. The SP configuration of the tested surrogates was established for the enantiomer with the more potent anti-AChE activity, with SP/RP inhibition ratios of 10–100, whereas the RP isomers of the O-ethyl and O-n-propyl were hydrolyzed by wt rePON1 about 600- and 70-fold faster, respectively, than the SP counterpart. Wt rePON1-induced RP/SP hydrolysis ratios for the O-cyclohexyl and O-i-propyl analogs are estimated to be ≫1000. The various SP enantiomers of O-alkyl-methylphosphonyl esters of CHMC provide suitable ligands for screening rePON1 libraries, and can expedite identification of variants with enhanced catalytic proficiency towards the toxic nerve agents. PMID:20303930

Differences in Mouse and Human Non-Memory B Cell Pools1

PubMed Central

Benitez, Abigail; Weldon, Abby J.; Tatosyan, Lynnette; Velkuru, Vani; Lee, Steve; Milford, Terry-Ann; Francis, Olivia L.; Hsu, Sheri; Nazeri, Kavoos; Casiano, Carlos M.; Schneider, Rebekah; Gonzalez, Jennifer; Su, Rui-Jun; Baez, Ineavely; Colburn, Keith; Moldovan, Ioana; Payne, Kimberly J.

2014-01-01

Identifying cross-species similarities and differences in immune development and function is critical for maximizing the translational potential of animal models. Co-expression of CD21 and CD24 distinguishes transitional and mature B cell subsets in mice. Here, we validate these markers for identifying analogous subsets in humans and use them to compare the non-memory B cell pools in mice and humans, across tissues, during fetal/neonatal and adult life. Among human CD19+IgM+ B cells, the CD21/CD24 schema identifies distinct populations that correspond to T1 (transitional 1), T2 (transitional 2), FM (follicular mature), and MZ (marginal zone) subsets identified in mice. Markers specific to human B cell development validate the identity of MZ cells and the maturation status of human CD21/CD24 non-memory B cell subsets. A comparison of the non-memory B cell pools in bone marrow (BM), blood, and spleen in mice and humans shows that transitional B cells comprise a much smaller fraction in adult humans than mice. T1 cells are a major contributor to the non-memory B cell pool in mouse BM where their frequency is more than twice that in humans. Conversely, in spleen the T1:T2 ratio shows that T2 cells are proportionally ∼8 fold higher in humans than mouse. Despite the relatively small contribution of transitional B cells to the human non-memory pool, the number of naïve FM cells produced per transitional B cell is 3-6 fold higher across tissues than in mouse. These data suggest differing dynamics or mechanisms produce the non-memory B cell compartments in mice and humans. PMID:24719464

Deactivation via ring opening: A quantum chemical study of the excited states of furan and comparison to thiophene

NASA Astrophysics Data System (ADS)

Gavrilov, Nemanja; Salzmann, Susanne; Marian, Christel M.

2008-06-01

Minimum nuclear arrangements of the ground and low-lying excited electronic states of furan were obtained by means of (time dependent) Kohn-Sham density functional theory. A combined density functional/multi-reference configuration interaction method (DFT/MRCI) was employed to compute the spectral properties at these points. Multiple minima were found on the first excited singlet (S 1) potential energy hypersurface with electronic structures S1, S2, S3 corresponding to the 1 1A 2 (π → 3s-Ryd), 1 1B 2 (π → π ∗), and 2 1A 1 (π → π ∗) states in the vertical absorption spectrum, respectively. In analogy to recently published studies in thiophene [S. Salzmann, M. Kleinschmidt, J. Tatchen, R. Weinkauf, C.M. Marian, Phys. Chem. Chem. Phys. 10 (2008) 380] a deactivation mechanism for electronically excited furan was detected that involves the opening of the pentacyclic ring. We found a nearly barrierless relaxation pathway from the Franck-Condon region along a C-O bond-breaking coordinate. Hereby the initially excited 1B 2 (π → π ∗) state undergoes a conical intersection with a 1B 1 (π → σ ∗) state. The system can return to the electronic ground state through a second conical intersection of the 1(π → σ ∗) state before the minimum of that B 1 state is reached.

Similarities between the discovery and regulation of pharmaceuticals and pesticides: in support of a better understanding of the risks and benefits of each

USDA-ARS?s Scientific Manuscript database

An argument by analogy is presented as a logical basis from which the role of pharmaceuticals and pesticides can be viewed in terms of contributing to human health. We will argue that what is true for pharmaceuticals (A) is also true for pesticides (B) and that logically if A=B then B cannot be fal...

Evaluation of insect CAP2b analogs with either an (E)-alkene, cis- or a trans-Pro isostere identifies the Pro orientation of antidiuretic activity

USDA-ARS?s Scientific Manuscript database

The CAP2b neuropeptide family plays an important role in the regulation of the processes of diuresis and/or antidiuresis in a vareity of insects. In particulare, CAP2b (pELYAFPRVamide) has been shown to elicit antidiuretic activity in the green stink bug Acrostemum hilare, an important pest of cott...

Humanoid Robots: A New Kind of Tool

DTIC Science & Technology

2000-01-01

Breazeal (Ferrell), R. Irie, C. C. Kemp, M. J. Marjanovic , B. Scassellati, M. M. Williamson, Alternate Essences of Intelligence, AAAI 1998. 2 R. A. Brooks, C...Breazeal, M. J. Marjanovic , B. Scassellati, M. M. Williamson, The Cog Project: Building a Humanoid Robot, Computation fbr Metaphors, Analogy and...Functions, Vol. 608, 1990, New York Academy of Sciences, pp. 637-676. 7 M. J. Marjanovic , B. Scassellati, M. M. Williamson, Self-Taught Visually-Guided

Antigenic topology of chlamydial PorB protein and identification of targets for immune neutralization of infectivity.

PubMed

Kawa, Diane E; Stephens, Richard S

2002-05-15

The outer membrane protein PorB is a conserved chlamydial protein that functions as a porin and is capable of eliciting neutralizing Abs. A topological antigenic map was developed using overlapping synthetic peptides representing the Chlamydia trachomatis PorB sequence and polyclonal immune sera. To identify which antigenic determinants were surface accessible, monospecific antisera were raised to the PorB peptides and were used in dot-blot and ELISA-based absorption studies with viable chlamydial elementary bodies (EBs). The ability of the surface-accessible antigenic determinants to direct neutralizing Ab responses was investigated using standardized in vitro neutralization assays. Four major antigenic clusters corresponding to Phe(34)-Leu(59) (B1-2 and B1-3), Asp(112) -Glu(145) (B2-3 and B2-4), Gly(179)-Ala(225) (B3-2 to B3-4), and Val(261)-Asn(305) (B4-4 to B5-2) were identified. Collectively, the EB absorption and dot-blot assays established that the immunoreactive PorB Ags were exposed on the surface of chlamydial EBs. Peptide-specific antisera raised to the surface-accessible Ags neutralized chlamydial infectivity and demonstrated cross-reactivity to synthetic peptides representing analogous C. pneumoniae PorB sequences. Furthermore, neutralization of chlamydial infectivity by C. trachomatis PorB antisera was inhibited by synthetic peptides representing the surface-exposed PorB antigenic determinants. These findings demonstrate that PorB Ags may be useful for development of chlamydial vaccines.

4-Bromo-2,5-dimethoxyphenethylamine (2C-B): presence in the recreational drug market in Spain, pattern of use and subjective effects.

PubMed

Caudevilla-Gálligo, Fernando; Riba, Jordi; Ventura, Mireia; González, Débora; Farré, Magí; Barbanoj, Manel J; Bouso, José Carlos

2012-07-01

4-Bromo-2,5-dimethoxyphenethylamine (2C-B) is a psychoactive analogue of mescaline that is becoming increasingly popular as a rave and club drug. We investigated its presence in the illicit drug market in Spain, its pattern of use and profile of subjective effects. Drug material was analysed for 2C-B and information on pattern of use and subjective effects was obtained from recreational users. Scores were statistically compared with previously collected data on psychostimulants (d-amphetamine), entactogens (MDMA) and psychedelics (ayahuasca and Salvia divinorum). The percentage of samples containing 2C-B doubled between 2006 and 2009, evolved from powder to tablet form and showed low falsification rates. Respondents reported taking 2C-B orally in doses of about 20 mg. Subjective effects involved perceptual modifications analogous to those observed after ayahuasca and salvia but absent after amphetamine and MDMA. Pleasure and sociability effects did not differ from those after MDMA and incapacitation was lower than for the psychedelics used as comparators. In conclusion, we found 2C-B is consistently present in the illicit drug market in Spain. While it elicits perceptual modifications that are analogous to other psychedelics, the lower impairment and higher pleasurable effects make it comparable with entactogens.

Dihydroavenanthramide D inhibits human breast cancer cell invasion through suppression of MMP-9 expression

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lee, Young-Rae; Noh, Eun-Mi; Oh, Hyun Ju

2011-02-25

Research highlights: {yields} MMP-9 plays a pivotal role in the invasion of MCF-7 breast cancer cells. {yields} TPA stimulates MMP-9 expression through activation of MAPK/NF-{kappa}B and MAPK/AP-1 pathways. {yields} Dihydroavenanthramide D suppresses MMP-9 expression via inhibition of TPA-induced MAPK/NF-{kappa}B and MAPK/AP-1 activations. {yields} Dihydroavenanthramide D blocks cell invasion of MCF-7 breast cancer cells. -- Abstract: Dihydroavenanthramide D (DHAvD) is a synthetic analog to naturally occurring avenanthramide, which is the active component of oat. Previous study demonstrates that DHAvD strongly inhibits activation of nuclear factor-kappa B (NF-{kappa}B), which is a major component in cancer cell invasion. The present study investigated whethermore » DHAvD can modulate MMP-9 expression and cell invasion in MCF-7 human breast cancer cells. MMP-9 expression and cell invasion in response to 12-O-tetradecanoylphorbol-13-acetate (TPA) was increased, whereas these inductions were muted by DHAvD. DHAvD also suppressed activation of mitogen-activated protein kinase (MAPK), and MAPK-mediated nuclear factor-kappa B (NF-{kappa}B) and activator protein-1 (AP-1) activations in TPA-treated MCF-7 cells. The results indicate that DHAvD-mediated inhibition of TPA-induced MMP-9 expression and cell invasion involves the suppression of the MAPK/NF-{kappa}B and MAPK/AP-1 pathways in MCF-7 cells. DHAvD may have potential value in breast cancer metastasis.« less

Purification, structural characterization, and myotropic activity of a peptide related to des-Arg(9)-bradykinin from an elasmobranch fish, the little skate, Leucoraja erinacea.

PubMed

Anderson, W Gary; Leprince, Jérôme; Conlon, J Michael

2008-08-01

A bradykinin (BK)-related peptide was isolated from heat-denaturated plasma from an elasmobranch fish, the little skate, Leucoraja erinacea after incubation with porcine pancreatic kallikrein. The primary structure of the peptide (H-Gly-Ile-Thr-Ser-Trp-Leu-Pro-Phe-OH; skate BK) shows limited structural similarity to the mammalian B1 receptor agonist, des-Arg(9)-BK. The myotropic activities of synthetic skate BK, and the analog skate [Arg(9)]BK, were examined in isolated skate vascular and intestinal smooth muscle preparations. Skate BK produced a concentration-dependent constriction of the mesenteric artery (EC(50)=4.37x10(-8)M; maximum response=103.4+/-10.23% of the response to 60mM KCl) but the response to skate [Arg(9)]BK was appreciably weaker (response to 10(-6)M=73.0+/-23.4% of the response to 60mM KCl). Neither the first branchial gill arch nor the ventral aorta responded to either purified peptide. Skate BK also produced a concentration-dependent constriction of intestinal smooth muscle preparations (EC(50)=2.74x10(-7)M; maximum response 31.0+/-12.2% of the response to 10(-5)M acetylcholine). Skate [Arg(9)]BK was without effect on the intestinal preparation. The data provide evidence for the existence of the kallikrein-kinin system in a phylogenetically ancient vertebrate group and the greater potency of skate BK compared with the analog skate [Arg(9)]BK suggests that the receptor mediating vascular responses resembles the mammalian B1 receptor more closely than the B2 receptor.