Inferring genome-wide functional modulatory network: a case study on NF-κB/RelA transcription factor.

PubMed

Li, Xueling; Zhu, Min; Brasier, Allan R; Kudlicki, Andrzej S

2015-04-01

How different pathways lead to the activation of a specific transcription factor (TF) with specific effects is not fully understood. We model context-specific transcriptional regulation as a modulatory network: triplets composed of a TF, target gene, and modulator. Modulators usually affect the activity of a specific TF at the posttranscriptional level in a target gene-specific action mode. This action may be classified as enhancement, attenuation, or inversion of either activation or inhibition. As a case study, we inferred, from a large collection of expression profiles, all potential modulations of NF-κB/RelA. The predicted modulators include many proteins previously not reported as physically binding to RelA but with relevant functions, such as RNA processing, cell cycle, mitochondrion, ubiquitin-dependent proteolysis, and chromatin modification. Modulators from different processes exert specific prevalent action modes on distinct pathways. Modulators from noncoding RNA, RNA-binding proteins, TFs, and kinases modulate the NF-κB/RelA activity with specific action modes consistent with their molecular functions and modulation level. The modulatory networks of NF-κB/RelA in the context epithelial-mesenchymal transition (EMT) and burn injury have different modulators, including those involved in extracellular matrix (FBN1), cytoskeletal regulation (ACTN1), and metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), a long intergenic nonprotein coding RNA, and tumor suppression (FOXP1) for EMT, and TXNIP, GAPDH, PKM2, IFIT5, LDHA, NID1, and TPP1 for burn injury.

Molecular mode of action of NKP-1339 - a clinically investigated ruthenium-based drug - involves ER- and ROS-related effects in colon carcinoma cell lines.

PubMed

Flocke, Lea S; Trondl, Robert; Jakupec, Michael A; Keppler, Bernhard K

2016-06-01

Sodium trans-[tetrachloridobis(1H-indazole)ruthenate(III)] (NKP-1339) is a clinically investigated ruthenium-based metal complex, which shows promising results in solid tumors, such as non-small cell lung cancer, colorectal carcinoma, and most distinctively in gastrointestinal neuroendocrine tumors. In previous studies, fast binding to albumin as well as transferrin could be shown. The enhanced permeability and retention (EPR) effect, which is diversely being exploited for tumor targeting, could therefore be applicable for NKP-1339. Here we studied the serum dependence of its biological activity in various methods, influencing its cellular accumulation, cytotoxicity as well as the generation of reactive oxygen species (ROS). ROS lead to Nrf2 activation, which is known to activate antioxidant response gene transcription. GRP78 down-regulation on the protein level suggests ER associated protein degradation (ERAD) as a mode of action, as RNA levels are only mildly affected. Another important part for the mode of action is endoplasmic reticulum (ER) stress, as different factors are highly upregulated on the protein level. For example PERK, a transmembrane receptor which is released by GRP78 when the ER is disturbed, is upregulated and phosphorylated. EIF2α is phosphorylated, which leads to an inhibition of CAP-dependent translation and other stress responses. The transcription factor CHOP (DDIT3), which promotes ER stress dependent apoptosis, is time and concentration dependently upregulated. Finally cytotoxicity tests could prove that inhibition of ER stress and ER stress-mediated apoptosis leads to decreased cytotoxic effects of NKP-1339, which highlights the involvement of this mechanism in the mode of action.

Anticancer Properties of Distinct Antimalarial Drug Classes

PubMed Central

Hooft van Huijsduijnen, Rob; Guy, R. Kiplin; Chibale, Kelly; Haynes, Richard K.; Peitz, Ingmar; Kelter, Gerhard; Phillips, Margaret A.; Vennerstrom, Jonathan L.; Yuthavong, Yongyuth; Wells, Timothy N. C.

2013-01-01

We have tested five distinct classes of established and experimental antimalarial drugs for their anticancer potential, using a panel of 91 human cancer lines. Three classes of drugs: artemisinins, synthetic peroxides and DHFR (dihydrofolate reductase) inhibitors effected potent inhibition of proliferation with IC50s in the nM- low µM range, whereas a DHODH (dihydroorotate dehydrogenase) and a putative kinase inhibitor displayed no activity. Furthermore, significant synergies were identified with erlotinib, imatinib, cisplatin, dasatinib and vincristine. Cluster analysis of the antimalarials based on their differential inhibition of the various cancer lines clearly segregated the synthetic peroxides OZ277 and OZ439 from the artemisinin cluster that included artesunate, dihydroartemisinin and artemisone, and from the DHFR inhibitors pyrimethamine and P218 (a parasite DHFR inhibitor), emphasizing their shared mode of action. In order to further understand the basis of the selectivity of these compounds against different cancers, microarray-based gene expression data for 85 of the used cell lines were generated. For each compound, distinct sets of genes were identified whose expression significantly correlated with compound sensitivity. Several of the antimalarials tested in this study have well-established and excellent safety profiles with a plasma exposure, when conservatively used in malaria, that is well above the IC50s that we identified in this study. Given their unique mode of action and potential for unique synergies with established anticancer drugs, our results provide a strong basis to further explore the potential application of these compounds in cancer in pre-clinical or and clinical settings. PMID:24391728

Neurobehavioral perspectives on the distinction between fear and anxiety

PubMed Central

Perusini, Jennifer N.

2015-01-01

In this review, we discuss the usefulness of the distinction between fear and anxiety. The clinical use of the labels is ambiguous, often defining one in terms of the other. We first consider what a useful, objective, and scientifically valid definition would entail and then evaluate several fear/anxiety distinctions that have been made in the neurobiological literature. A strong distinction should specify the difference in conditions that lead to fear versus anxiety. Additionally, fear and anxiety should generate distinct sets of behaviors. Ideally, the two states should be supported by distinguishable neuroanatomical circuits. Such a conceptualization would be consistent with the National Institute of Mental Health's Research Domain Criteria (RDoc). The majority of neurobiological approaches to the fear versus anxiety distinction fail to differentiate the two states in terms of behavior, often using the exact same behavioral measures as indicators. Of the two that do, only Predatory Imminence Theory provides a distinction both in terms of cause and effect. Indeed, that approach provides a ready distinction of anxiety, fear, and panic in terms of both antecedent conditions and response selection rules. Additionally, it appeals to distinct neural circuits to generate these modes of action. PMID:26286652

Transition Metal Intercalators as Anticancer Agents—Recent Advances

PubMed Central

Deo, Krishant M.; Pages, Benjamin J.; Ang, Dale L.; Gordon, Christopher P.; Aldrich-Wright, Janice R.

2016-01-01

The diverse anticancer utility of cisplatin has stimulated significant interest in the development of additional platinum-based therapies, resulting in several analogues receiving clinical approval worldwide. However, due to structural and mechanistic similarities, the effectiveness of platinum-based therapies is countered by severe side-effects, narrow spectrum of activity and the development of resistance. Nonetheless, metal complexes offer unique characteristics and exceptional versatility, with the ability to alter their pharmacology through facile modifications of geometry and coordination number. This has prompted the search for metal-based complexes with distinctly different structural motifs and non-covalent modes of binding with a primary aim of circumventing current clinical limitations. This review discusses recent advances in platinum and other transition metal-based complexes with mechanisms of action involving intercalation. This mode of DNA binding is distinct from cisplatin and its derivatives. The metals focused on in this review include Pt, Ru and Cu along with examples of Au, Ni, Zn and Fe complexes; these complexes are capable of DNA intercalation and are highly biologically active. PMID:27809241

Cogena, a novel tool for co-expressed gene-set enrichment analysis, applied to drug repositioning and drug mode of action discovery.

PubMed

Jia, Zhilong; Liu, Ying; Guan, Naiyang; Bo, Xiaochen; Luo, Zhigang; Barnes, Michael R

2016-05-27

Drug repositioning, finding new indications for existing drugs, has gained much recent attention as a potentially efficient and economical strategy for accelerating new therapies into the clinic. Although improvement in the sensitivity of computational drug repositioning methods has identified numerous credible repositioning opportunities, few have been progressed. Arguably the "black box" nature of drug action in a new indication is one of the main blocks to progression, highlighting the need for methods that inform on the broader target mechanism in the disease context. We demonstrate that the analysis of co-expressed genes may be a critical first step towards illumination of both disease pathology and mode of drug action. We achieve this using a novel framework, co-expressed gene-set enrichment analysis (cogena) for co-expression analysis of gene expression signatures and gene set enrichment analysis of co-expressed genes. The cogena framework enables simultaneous, pathway driven, disease and drug repositioning analysis. Cogena can be used to illuminate coordinated changes within disease transcriptomes and identify drugs acting mechanistically within this framework. We illustrate this using a psoriatic skin transcriptome, as an exemplar, and recover two widely used Psoriasis drugs (Methotrexate and Ciclosporin) with distinct modes of action. Cogena out-performs the results of Connectivity Map and NFFinder webservers in similar disease transcriptome analyses. Furthermore, we investigated the literature support for the other top-ranked compounds to treat psoriasis and showed how the outputs of cogena analysis can contribute new insight to support the progression of drugs into the clinic. We have made cogena freely available within Bioconductor or https://github.com/zhilongjia/cogena . In conclusion, by targeting co-expressed genes within disease transcriptomes, cogena offers novel biological insight, which can be effectively harnessed for drug discovery and repositioning, allowing the grouping and prioritisation of drug repositioning candidates on the basis of putative mode of action.

Fast, Temperature-Sensitive and Clathrin-Independent Endocytosis at Central Synapses.

PubMed

Delvendahl, Igor; Vyleta, Nicholas P; von Gersdorff, Henrique; Hallermann, Stefan

2016-05-04

The fusion of neurotransmitter-filled vesicles during synaptic transmission is balanced by endocytotic membrane retrieval. Despite extensive research, the speed and mechanisms of synaptic vesicle endocytosis have remained controversial. Here, we establish low-noise time-resolved membrane capacitance measurements that allow monitoring changes in surface membrane area elicited by single action potentials and stronger stimuli with high-temporal resolution at physiological temperature in individual bona-fide mature central synapses. We show that single action potentials trigger very rapid endocytosis, retrieving presynaptic membrane with a time constant of 470 ms. This fast endocytosis is independent of clathrin but mediated by dynamin and actin. In contrast, stronger stimuli evoke a slower mode of endocytosis that is clathrin, dynamin, and actin dependent. Furthermore, the speed of endocytosis is highly temperature dependent with a Q10 of ∼3.5. These results demonstrate that distinct molecular modes of endocytosis with markedly different kinetics operate at central synapses. Copyright © 2016 Elsevier Inc. All rights reserved.

Interaction vs. observation: distinctive modes of social cognition in human brain and behavior? A combined fMRI and eye-tracking study

PubMed Central

Tylén, Kristian; Allen, Micah; Hunter, Bjørk K.; Roepstorff, Andreas

2012-01-01

Human cognition has usually been approached on the level of individual minds and brains, but social interaction is a challenging case. Is it best thought of as a self-contained individual cognitive process aiming at an “understanding of the other,” or should it rather be approached as an collective, inter-personal process where individual cognitive components interact on a moment-to-moment basis to form coupled dynamics? In a combined fMRI and eye-tracking study we directly contrasted these models of social cognition. We found that the perception of situations affording social contingent responsiveness (e.g., someone offering or showing you an object) elicited activations in regions of the right posterior temporal sulcus and yielded greater pupil dilation corresponding to a model of coupled dynamics (joint action). In contrast, the social-cognitive perception of someone “privately” manipulating an object elicited activation in medial prefrontal cortex, the right inferior frontal gyrus and right inferior parietal lobus, regions normally associated with Theory of Mind and with the mirror neuron system. Our findings support a distinction in social cognition between social observation and social interaction, and demonstrate that simple ostensive cues may shift participants' experience, behavior, and brain activity between these modes. The identification of a distinct, interactive mode has implications for research on social cognition, both in everyday life and in clinical conditions. PMID:23267322

Neurobehavioral perspectives on the distinction between fear and anxiety.

PubMed

Perusini, Jennifer N; Fanselow, Michael S

2015-09-01

In this review, we discuss the usefulness of the distinction between fear and anxiety. The clinical use of the labels is ambiguous, often defining one in terms of the other. We first consider what a useful, objective, and scientifically valid definition would entail and then evaluate several fear/anxiety distinctions that have been made in the neurobiological literature. A strong distinction should specify the difference in conditions that lead to fear versus anxiety. Additionally, fear and anxiety should generate distinct sets of behaviors. Ideally, the two states should be supported by distinguishable neuroanatomical circuits. Such a conceptualization would be consistent with the National Institute of Mental Health's Research Domain Criteria (RDoc). The majority of neurobiological approaches to the fear versus anxiety distinction fail to differentiate the two states in terms of behavior, often using the exact same behavioral measures as indicators. Of the two that do, only Predatory Imminence Theory provides a distinction both in terms of cause and effect. Indeed, that approach provides a ready distinction of anxiety, fear, and panic in terms of both antecedent conditions and response selection rules. Additionally, it appeals to distinct neural circuits to generate these modes of action. © 2015 Perusini and Fanselow; Published by Cold Spring Harbor Laboratory Press.

Bacteria causing important diseases of citrus utilise distinct modes of pathogenesis to attack a common host.

PubMed

Vojnov, Adrián Alberto; do Amaral, Alexandre Morais; Dow, John Maxwell; Castagnaro, Atilio Pedro; Marano, Marìa Rosa

2010-06-01

In this review, we summarise the current knowledge on three pathogens that exhibit distinct tissue specificity and modes of pathogenesis in citrus plants. Xanthomonas axonopodis pv. citri causes canker disease and invades the host leaf mesophyll tissue through natural openings and can also survive as an epiphyte. Xylella fastidiosa and Candidatus Liberibacter are vectored by insects and proliferate in the vascular system of the host, either in the phloem (Candidatus Liberibacter) or xylem (X. fastidiosa) causing variegated chlorosis and huanglongbing diseases, respectively. Candidatus Liberibacter can be found within host cells and is thus unique as an intracellular phytopathogenic bacterium. Genome sequence comparisons have identified groups of species-specific genes that may be associated with the particular lifestyle, mode of transmission or symptoms produced by each phytopathogen. In addition, components that are conserved amongst bacteria may have diverse regulatory actions underpinning the different bacterial lifestyles; one example is the divergent role of the Rpf/DSF cell-cell signalling system in X. citri and X. fastidiosa. Biofilm plays a key role in epiphytic fitness and canker development in X. citri and in the symptoms produced by X. fastidiosa. Bacterial aggregation may be associated with vascular occlusion of the xylem vessels and symptomatology of variegated chlorosis.

Accelerating early anti-tuberculosis drug discovery by creating mycobacterial indicator strains that predict mode of action.

PubMed

Boot, Maikel; Commandeur, Susanna; Subudhi, Amit K; Bahira, Meriem; Smith, Trever C; Abdallah, Abdallah M; van Gemert, Mae; Lelièvre, Joël; Ballell, Lluís; Aldridge, Bree B; Pain, Arnab; Speer, Alexander; Bitter, Wilbert

2018-04-16

Due to the rise of drug resistant forms of tuberculosis there is an urgent need for novel antibiotics to effectively combat these cases and shorten treatment regimens. Recently, drug screens using whole cell analyses have been shown to be successful. However, current high-throughput screens focus mostly on stricto sensu life-death screening that give little qualitative information. In doing so, promising compound scaffolds or non-optimized compounds that fail to reach inhibitory concentrations are missed. To accelerate early TB drug discovery, we performed RNA sequencing on Mycobacterium tuberculosis and Mycobacterium marinum to map the stress responses that follow upon exposure to sub-inhibitory concentrations of antibiotics with known targets: ciprofloxacin, ethambutol, isoniazid, streptomycin and rifampicin. The resulting dataset comprises the first overview of transcriptional stress responses of mycobacteria to different antibiotics. We show that antibiotics can be distinguished based on their specific transcriptional stress fingerprint. Notably, this fingerprint was more distinctive in M. marinum. We decided to use this to our advantage and continue with this model organism. A selection of diverse antibiotic stress genes was used to construct stress reporters. In total, three functional reporters were constructed to respond to DNA damage, cell wall damage and ribosomal inhibition. Subsequently, these reporter strains were used to screen a small anti-TB compound library to predict the mode of action. In doing so, we could identify the putative mode of action for three novel compounds, which confirms our approach. Copyright © 2018 American Society for Microbiology.

Thyroid hormones and their effects: a new perspective.

PubMed

Hulbert, A J

2000-11-01

The thyroid hormones are very hydrophobic and those that exhibit biological activity are 3',5',3,5-L-tetraiodothyronine (T4), 3',5,3-L-triiodothyronine (T3), 3',5',3-L-triiodothyronine (rT3) and 3,5',-L-diiothyronine (3,5-T2). At physiological pH, dissociation of the phenolic -OH group of these iodothyronines is an important determinant of their physical chemistry that impacts on their biological effects. When non-ionized these iodothyronines are strongly amphipathic. It is proposed that iodothyronines are normal constituents of biological membranes in vertebrates. In plasma of adult vertebrates, unbound T4 and T3 are regulated in the picomolar range whilst protein-bound T4 and T3 are maintained in the nanomolar range. The function of thyroid-hormone-binding plasma proteins is to ensure an even distrubtion throughout the body. Various iodothyronines are produced by three types of membrane-bound cellular deiodinase enzyme systems in vertebrates. The distribution of deiodinases varies between tissues and each has a distinct developmental profile. Thyroid hormones. (1) the nuclear receptor mode is especially important in the thyroid hormone axis that controls plasma and cellular levels of these hormones. (2) These hormones are strongly associated with membranes in tissues and normally rigidify these membranes. (3) They also affect the acyl composition of membrane bilayers and it is suggested that this is due to the cells responding to thyroid-hormone-induced membrane rigidificataion. Both their immediate effects on the physical state of membranes and the consequent changes in membrane composition result in several other thyroid hormone effects. Effects on metabolism may be due primarily to membrane acyl changes. There are other actions of thyroid hormones involving membrane receptors and influences on cellular interactions with the extracellulara matrix. The effects of thyroid hormones are reviewed and appear to b combinations of these various modes of action. During development, vertebrates show a surge in T4 and other thyroid hormones, as well as distinctive profiles in the appearance of the deiodinase enzymes and nuclear receptors. Evidence from the use of analogues supports multiple modes of action. Re-examination of data from th early 1960s supports a membrane action. Findings from receptor 'knockout' mice supports an important role for receptors in the development of the thyroid axis. These iodothyronines may be better thought of as 'vitamone'-like molecules than traditional hormonal messengers.

Dark matter scenarios with multiple spin-2 fields

NASA Astrophysics Data System (ADS)

González Albornoz, N. L.; Schmidt-May, Angnis; von Strauss, Mikael

2018-01-01

We study ghost-free multimetric theories for (N+1) tensor fields with a coupling to matter and maximal global symmetry group SN×(Z2)N. Their mass spectra contain a massless mode, the graviton, and N massive spin-2 modes. One of the massive modes is distinct by being the heaviest, the remaining (N‑1) massive modes are simply identical copies of each other. All relevant physics can therefore be understood from the case N=2. Focussing on this case, we compute the full perturbative action up to cubic order and derive several features that hold to all orders in perturbation theory. The lighter massive mode does not couple to matter and neither of the massive modes decay into massless gravitons. We propose the lighter massive particle as a candidate for dark matter and investigate its phenomenology in the parameter region where the matter coupling is dominated by the massless graviton. The relic density of massive spin-2 can originate from a freeze-in mechanism or from gravitational particle production, giving rise to two different dark matter scenarios. The allowed parameter regions are very different from those in scenarios with only one massive spin-2 field and more accessible to experiments.

Mode of action of triflumezopyrim: A novel mesoionic insecticide which inhibits the nicotinic acetylcholine receptor.

PubMed

Cordova, Daniel; Benner, Eric A; Schroeder, Mark E; Holyoke, Caleb W; Zhang, Wenming; Pahutski, Thomas F; Leighty, Robert M; Vincent, Daniel R; Hamm, Jason C

2016-07-01

Triflumezopyrim, a newly commercialized molecule from DuPont Crop Protection, belongs to the novel class of mesoionic insecticides. This study characterizes the biochemical and physiological action of this novel insecticide. Using membranes from the aphid, Myzus persicae, triflumezopyrim was found to displace (3)H-imidacloprid with a Ki value of 43 nM with competitive binding results indicating that triflumezopyrim binds to the orthosteric site of the nicotinic acetylcholine receptor (nAChR). In voltage clamp studies using dissociated Periplaneta americana neurons, triflumezopyrim inhibits nAChR currents with an IC50 of 0.6 nM. Activation of nAChR currents was minimal and required concentrations ≥100 μM. Xenopus oocytes expressing chimeric nAChRs (Drosophila α2/chick β2) showed similar inhibitory effects from triflumezopyrim. In P. americana neurons, co-application experiments with acetylcholine reveal the inhibitory action of triflumezopyrim to be rapid and prolonged in nature. Such physiological action is distinct from other insecticides in IRAC Group 4 in which the toxicological mode of action is attributed to nAChR agonism. Mesoionic insecticides act via inhibition of the orthosteric binding site of the nAChR despite previous beliefs that such action would translate to poor insect control. Triflumezopyrim is the first commercialized insecticide from this class and provides outstanding control of hoppers, including the brown planthopper, Nilaparvata lugens, which is already displaying strong resistance to neonicotinoids such as imidacloprid. Copyright © 2016 Elsevier Ltd. All rights reserved.

Marine-derived angiogenesis inhibitors for cancer therapy.

PubMed

Wang, Ying-Qing; Miao, Ze-Hong

2013-03-15

Angiogenesis inhibitors have been successfully used for cancer therapy in the clinic. Many marine-derived natural products and their analogues have been reported to show antiangiogenic activities. Compared with the drugs in the clinic, these agents display interesting characteristics, including diverse sources, unique chemical structures, special modes of action, and distinct activity and toxicity profiles. This review will first provide an overview of the current marine-derived angiogenesis inhibitors based on their primary targets and/or mechanisms of action. Then, the marine-derived antiangiogenic protein kinase inhibitors will be focused on. And finally, the clinical trials of the marine-derived antiangiogenic agents will be discussed, with special emphasis on their application potentials, problems and possible coping strategies in their future development as anticancer drugs.

The phosphoenolpyruvate:sugar phosphotransferase system is involved in sensitivity to the glucosylated bacteriocin sublancin.

PubMed

Garcia De Gonzalo, C V; Denham, E L; Mars, R A T; Stülke, J; van der Donk, W A; van Dijl, J M

2015-11-01

The mode of action of a group of glycosylated antimicrobial peptides known as glycocins remains to be elucidated. In the current study of one glycocin, sublancin, we identified the phosphoenolpyruvate:sugar phosphotransferase system (PTS) of Bacillus species as a key player in bacterial sensitivity. Sublancin kills several Gram-positive bacteria, such as Bacillus species and Staphylococcus aureus, including methicillin-resistant S. aureus (MRSA). Unlike other classes of bacteriocins for which the PTS is involved in their mechanism of action, we show that the addition of PTS-requiring sugars leads to increased resistance rather than increased sensitivity, suggesting that sublancin has a distinct mechanism of action. Collectively, our present mutagenesis and genomic studies demonstrate that the histidine-containing phosphocarrier protein (HPr) and domain A of enzyme II (PtsG) in particular are critical determinants for bacterial sensitivity to sublancin. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Ultradian hormone stimulation induces glucocorticoid receptor-mediated pulses of gene transcription.

PubMed

Stavreva, Diana A; Wiench, Malgorzata; John, Sam; Conway-Campbell, Becky L; McKenna, Mervyn A; Pooley, John R; Johnson, Thomas A; Voss, Ty C; Lightman, Stafford L; Hager, Gordon L

2009-09-01

Studies on glucocorticoid receptor (GR) action typically assess gene responses by long-term stimulation with synthetic hormones. As corticosteroids are released from adrenal glands in a circadian and high-frequency (ultradian) mode, such treatments may not provide an accurate assessment of physiological hormone action. Here we demonstrate that ultradian hormone stimulation induces cyclic GR-mediated transcriptional regulation, or gene pulsing, both in cultured cells and in animal models. Equilibrium receptor-occupancy of regulatory elements precisely tracks the ligand pulses. Nascent RNA transcripts from GR-regulated genes are released in distinct quanta, demonstrating a profound difference between the transcriptional programs induced by ultradian and constant stimulation. Gene pulsing is driven by rapid GR exchange with response elements and by GR recycling through the chaperone machinery, which promotes GR activation and reactivation in response to the ultradian hormone release, thus coupling promoter activity to the naturally occurring fluctuations in hormone levels. The GR signalling pathway has been optimized for a prompt and timely response to fluctuations in hormone levels, indicating that biologically accurate regulation of gene targets by GR requires an ultradian mode of hormone stimulation.

Biology of the eremophilanes produced by Drechslera gigantea

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

Bunkers, G.J.

1989-01-01

A procedure, using high performance liquid chromatography to quantify eremophilane levels in culture filtrates of D. gigantea was developed. This procedure was used to study eremophilane production by D. gigantea under different cultural conditions. The structure-activity relationships of the eremophilanes were investigated using three different bioassays. No distinct functional groups or structural characteristics could be correlated to activity. However, in all three bioassays, the eremophilanes with the higher oxidation states were generally less active. To determine the mode of action, the effects of eremophilanes on the physiology of the plant were studied. Eremophilane bioactivities mimic the activity of known phytohormones.more » Comparative studies indicated that these activities seem not to be associated with induction of known phytohormones but are inherent properties of the eremophilane molecules. The eremophilanes were shown to inhibit protein synthesis both in vitro and in vivo. The proposed mode of action of the eremophilanes is inhibition of protein synthesis. Finally, the fate of the eremophilanes in planta was investigated. ({sup 14}C)-petasol was applied to detached oat leaves (Avena sativa cv. Park) and the radiolabel was traced.« less

Targeted Phenotypic Screening in Plasmodium falciparum and Toxoplasma gondii Reveals Novel Modes of Action of Medicines for Malaria Venture Malaria Box Molecules

PubMed Central

2018-01-01

ABSTRACT The Malaria Box collection includes 400 chemically diverse small molecules with documented potency against malaria parasite growth, but the underlying modes of action are largely unknown. Using complementary phenotypic screens against Plasmodium falciparum and Toxoplasma gondii, we report phenotype-specific hits based on inhibition of overall parasite growth, apicoplast segregation, and egress or host invasion, providing hitherto unavailable insights into the possible mechanisms affected. First, the Malaria Box library was screened against tachyzoite stage T. gondii and the half-maximal effective concentrations (EC50s) of molecules showing ≥80% growth inhibition at 10 µM were determined. Comparison of the EC50s for T. gondii and P. falciparum identified a subset of 24 molecules with nanomolar potency against both parasites. Thirty molecules that failed to induce acute growth inhibition in T. gondii tachyzoites in a 2-day assay caused delayed parasite death upon extended exposure, with at least three molecules interfering with apicoplast segregation during daughter cell formation. Using flow cytometry and microscopy-based examinations, we prioritized 26 molecules with the potential to inhibit host cell egress/invasion during asexual developmental stages of P. falciparum. None of the inhibitors affected digestive vacuole integrity, ruling out a mechanism mediated by broadly specific protease inhibitor activity. Interestingly, five of the plasmodial egress inhibitors inhibited ionophore-induced egress of T. gondii tachyzoites. These findings highlight the advantage of comparative and targeted phenotypic screens in related species as a means to identify lead molecules with a conserved mode of action. Further work on target identification and mechanism analysis will facilitate the development of antiparasitic compounds with cross-species efficacy. IMPORTANCE The phylum Apicomplexa includes many human and animal pathogens, such as Plasmodium falciparum (human malaria) and Toxoplasma gondii (human and animal toxoplasmosis). Widespread resistance to current antimalarials and the lack of a commercial vaccine necessitate novel pharmacological interventions with distinct modes of action against malaria. For toxoplasmosis, new drugs to effectively eliminate tissue-dwelling latent cysts of the parasite are needed. The Malaria Box antimalarial collection, managed and distributed by the Medicines for Malaria Venture, includes molecules of novel chemical classes with proven antimalarial efficacy. Using targeted phenotypic assays of P. falciparum and T. gondii, we have identified a subset of the Malaria Box molecules as potent inhibitors of plastid segregation and parasite invasion and egress, thereby providing early insights into their probable mode of action. Five molecules that inhibit the egress of both parasites have been identified for further mechanistic studies. Thus, the approach we have used to identify novel molecules with defined modes of action in multiple parasites can expedite the development of pan-active antiparasitic agents. PMID:29359192

Comparative toxicity of 20 herbicides to 5 periphytic algae and the relationship with mode of action.

PubMed

Nagai, Takashi; Taya, Kiyoshi; Yoda, Ikuko

2016-02-01

The authors used 5 species of periphytic algae to conduct toxicity assays of 20 herbicides. The 5 tested species represent riverine primary producers most likely to be affected by herbicides. A fluorescence microplate toxicity assay was used as an efficient and economical high-throughput assay. Toxicity characteristics were analyzed, focusing on their relationship to herbicide mode of action. The relative differences between 50% and 10% effect concentrations depended on herbicide mode of action, rather than tested species. Moreover, a clear relationship between sensitive species and herbicide mode of action was also observed. Green alga was most sensitive to herbicides of 2 mode of action groups: inhibitors of protoporphyrinogen oxidase and very long-chain fatty acid synthesis. Diatoms were most sensitive to herbicides of 1 mode of action group: 4-hydroxyphenyl-pyruvate-dioxygenase inhibitors. Cyanobacterium was most sensitive to herbicides of 1 mode of action group: inhibitors of acetolactate synthase. The species sensitivity distribution based on obtained data was also analyzed. The slopes of the species sensitivity distribution significantly differed among modes of action, suggesting that difference in species sensitivity is specific to the mode of action. In particular, differences in species sensitivity were markedly large for inhibitors of acetolactate synthase, protoporphyrinogen oxidase, and very long-chain fatty acid synthesis. The results clearly showed that a single algal species cannot represent the sensitivity of an algal assemblage. Therefore, multispecies algal toxicity data are essential for substances with specific modes of action. © 2015 SETAC.

Omacetaxine Mepesuccinate for Chronic Myeloid Leukemia.

PubMed

Rosshandler, Yasmin; Shen, Ann Q; Cortes, Jorge; Khoury, Hanna Jean

2016-05-01

Omacetaxine mepesuccinate is approved by the Food and Drug Administration in the United States for the treatment of chronic myeloid leukemia in chronic or accelerated phase resistant to two or more tyrosine kinase inhibitors. This review summarizes the mode of action, pharmacokinetics, efficacy and safety of omacetaxine mepesuccinate. Omacetaxine mepesuccinate has activity in chronic myeloid leukemia, especially in the chronic phase, regardless of the presence of ABL1 kinase domain mutations. Omacetaxine mepesuccinate has distinct but manageable adverse events profile. Omacetaxine mepesuccinate is a treatment option for a subset of patients with refractory chronic myeloid leukemia.

Science in a New Mode: Good Old (Theoretical) Science Versus Brave New (Commodified) Knowledge Production?

NASA Astrophysics Data System (ADS)

Knuuttila, Tarja

2013-10-01

The present transformation of the university system is conceptualized in terms of such terminologies as "Mode-2 knowledge production" and the "entrepreneurial university." What is remarkable about these analyses is how closely they link the generally accepted requirement of more socially relevant knowledge to the commercialization of university research. This paper critically examines the Mode-1/Mode-2 distinction through a combination of philosophical and empirical analysis. It argues that, from the perspective of actual scientific practice, this Mode-1/Mode-2 distinction and the related transition thesis do not stand closer scrutiny. Theoretical "Mode-1" science shares "Mode-2" features in being also problem-oriented, interventive and transdisciplinary. On the other hand, the empirical case on language technology demonstrates that even in "Mode-2"-like research, undertaken in the "context of application," scientists make a distinction between more difficult scientific problems and those that are considered more applied or commercial. Moreover, the case shows that the need to make such distinctions may even become more acute due to the compromises imposed by the commercialization of research.

77 FR 26549 - Workshop on Using Mode of Action To Support the Development of a Multipollutant Science Assessment

Federal Register 2010, 2011, 2012, 2013, 2014

2012-05-04

... which mode- of-action and toxicity pathways approaches may contribute to interpretation of cumulative... NAAQS Review Process. One of the sessions focused on using mode-of-action and toxicity pathways... possible ways by which mode-of-action and toxicity pathways approaches may contribute to interpretation of...

Weak measurements and quantum weak values for NOON states

NASA Astrophysics Data System (ADS)

Rosales-Zárate, L.; Opanchuk, B.; Reid, M. D.

2018-03-01

Quantum weak values arise when the mean outcome of a weak measurement made on certain preselected and postselected quantum systems goes beyond the eigenvalue range for a quantum observable. Here, we propose how to determine quantum weak values for superpositions of states with a macroscopically or mesoscopically distinct mode number, that might be realized as two-mode Bose-Einstein condensate or photonic NOON states. Specifically, we give a model for a weak measurement of the Schwinger spin of a two-mode NOON state, for arbitrary N . The weak measurement arises from a nondestructive measurement of the two-mode occupation number difference, which for atomic NOON states might be realized via phase contrast imaging and the ac Stark effect using an optical meter prepared in a coherent state. The meter-system coupling results in an entangled cat-state. By subsequently evolving the system under the action of a nonlinear Josephson Hamiltonian, we show how postselection leads to quantum weak values, for arbitrary N . Since the weak measurement can be shown to be minimally invasive, the weak values provide a useful strategy for a Leggett-Garg test of N -scopic realism.

Modulation of appetite and feeding behavior of the larval mosquito Aedes aegypti by the serotonin-selective reuptake inhibitor paroxetine: shifts between distinct feeding modes and the influence of feeding status.

PubMed

Kinney, Michael P; Panting, Nicholas D; Clark, Thomas M

2014-03-15

The effects of the serotonin-selective reuptake inhibitor paroxetine (2×10(-5) mol l(-1)) on behavior of the larval mosquito Aedes aegypti are described. Four discrete behavioral states dominate larval behavior: wriggling, two distinct types of feeding, and quiescence. Feeding behaviors consist of foraging along the bottom of the container (substrate browsing), and stationary filter feeding while suspended from the surface film. Fed larvae respond to paroxetine with increased wriggling, and reductions in both feeding behaviors. In contrast, food-deprived larvae treated with paroxetine show no change in the proportion of time spent wriggling or feeding, but shift from stationary filter feeding to substrate browsing. Thus, actions of paroxetine in fed larvae are consistent with suppression of appetite and stimulation of wriggling, whereas paroxetine causes food-deprived larvae to switch from one feeding behavior to another. Further analysis of unfed larvae revealed that paroxetine decreased the power stroke frequency during wriggling locomotion, but had no effect on the swimming velocity during either wriggling or substrate browsing. These data suggest that: (1) serotonergic pathways may trigger shifts between distinct behaviors by actions on higher level (brain) integrating centers where behaviors such as feeding and locomotion are coordinated; (2) these centers in fed and food-deprived larvae respond differently to serotonergic stimulation suggesting sensory feedback from feeding status; and (3) serotonergic pathways also modulate central pattern generators of the nerve cord where the bursts of action potentials originate that drive the rhythmic muscle contractions of wriggling.

Transportation Energy Futures Series: Freight Transportation Modal Shares: Scenarios for a Low-Carbon Future

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

Brogan, J. J.; Aeppli, A. E.; Beagan, D. F.

2013-03-01

Truck, rail, water, air, and pipeline modes each serve a distinct share of the freight transportation market. The current allocation of freight by mode is the product of technologic, economic, and regulatory frameworks, and a variety of factors -- price, speed, reliability, accessibility, visibility, security, and safety -- influence mode. Based on a comprehensive literature review, this report considers how analytical methods can be used to project future modal shares and offers insights on federal policy decisions with the potential to prompt shifts to energy-efficient, low-emission modes. There are substantial opportunities to reduce the energy used for freight transportation, butmore » it will be difficult to shift large volumes from one mode to another without imposing considerable additional costs on businesses and consumers. This report explores federal government actions that could help trigger the shifts in modal shares needed to reduce energy consumption and emissions. This is one in a series of reports produced as a result of the Transportation Energy Futures project, a Department of Energy-sponsored multi-agency effort to pinpoint underexplored strategies for reducing GHGs and petroleum dependence related to transportation.« less

Meta-diamide insecticides acting on distinct sites of RDL GABA receptor from those for conventional noncompetitive antagonists.

PubMed

Nakao, Toshifumi; Banba, Shinich; Nomura, Michikazu; Hirase, Kangetsu

2013-04-01

The RDL GABA receptor is an attractive target of insecticides. Here we demonstrate that meta-diamides [3-benzamido-N-(4-(perfluoropropan-2-yl)phenyl)benzamides] are a distinct class of RDL GABA receptor antagonists showing high insecticidal activity against Spodoptera litura. We also suggest that the mode of action of the meta-diamides is distinct from that of conventional noncompetitive antagonists (NCAs), such as fipronil, picrotoxin, lindane, dieldrin, and α-endosulfan. Using a membrane potential assay, we examined the effects of the meta-diamide 3-benzamido-N-(2-bromo-4-(perfluoropropan-2-yl)-6-(trifluoromethyl)phenyl)-2-fluorobenzamide (meta-diamide 7) and NCAs on mutant Drosophila RDL GABA receptors expressed in Drosophila Mel-2 cells. NCAs had little or no inhibitory activity against at least one of the three mutant receptors (A2'S, A2'G, and A2'N), which were reported to confer resistance to NCAs. In contrast, meta-diamide 7 inhibited all three A2' mutant receptors, at levels comparable to its activity with the wild-type receptor. Furthermore, the A2'S·T6'V mutation almost abolished the inhibitory effects of all NCAs. However, meta-diamide 7 inhibited the A2'S・T6'S mutant receptor at the same level as its activity with the wild-type receptor. In contrast, a G336M mutation in the third transmembrane domain of the RDL GABA receptor abolished the inhibitory activities of meta-diamide 7, although the G336M mutation had little effect on the inhibitory activities of conventional NCAs. Molecular modeling studies also suggested that the binding site of meta-diamides was different from those of NCAs. Meta-diamide insecticides are expected to be prominent insecticides effective against A2' mutant RDL GABA receptors with a different mode of action. Copyright © 2013 Elsevier Ltd. All rights reserved.

Mode of action characterization for adverse effect of propranolol in Daphnia magna based on behavior and physiology monitoring and metabolite profiling.

PubMed

Jeong, Tae-Yong; Yoon, Dahye; Kim, Suhkmann; Kim, Hyun Young; Kim, Sang Don

2018-02-01

Studies are underway to gather information about the mode of action (MOA) of emerging pollutants that could guide practical environmental decision making. Previously, we showed that propranolol, an active pharmaceutical ingredient, had adverse effects on Daphnia magna that were similar to its pharmaceutical action. In order to characterize the mode of action of propranolol in D. magna, which is suspected to be organ-specific pharmaceutical action or baseline toxicity, we performed time-series monitoring of behavior along with heart rate measurements and nuclear magnetic resonance (NMR) based metabolite profiling. Principle component analysis (PCA) and hierarchical clustering were used to categorize the mode of action of propranolol among 5 chemicals with different modes of action. The findings showed that the mode of action of propranolol in D. magna is organ-specific and vastly different from those of narcotics, even though metabolite regulation is similar between narcotic and non-narcotic candidates. The method applied in this study seems applicable to rapid characterization of the MOA of other cardiovascular pharmaceutical ingredients. Copyright © 2017 Elsevier Ltd. All rights reserved.

Mechanism of action of coumarin and silver(I)-coumarin complexes against the pathogenic yeast Candida albicans.

PubMed

Thati, Bhumika; Noble, Andy; Rowan, Raymond; Creaven, Bernadette S; Walsh, Maureen; McCann, Malachy; Egan, Denise; Kavanagh, Kevin

2007-08-01

The anti-fungal activity and mode of action of a range of silver(I)-coumarin complexes was examined. The most potent silver(I)-coumarin complexes, namely 7-hydroxycoumarin-3-carboxylatosilver(I), 6-hydroxycoumarin-3-carboxylatosilver(I) and 4-oxy-3-nitrocoumarinbis(1,10-phenanthroline)silver(I), had MIC80 values of between 69.1 and 4.6 microM against the pathogenic yeast Candida albicans. These compounds also reduced respiration, lowered the ergosterol content of cells and increased the trans-membrane leakage of amino acids. A number of the complexes disrupted cytochrome synthesis in the cell and induced the appearance of morphological features consistent with cell death by apoptosis. These compounds appear to act by disrupting the synthesis of cytochromes which directly affects the cell's ability to respire. A reduction in respiration leads to a depletion in ergosterol biosynthesis and a consequent disruption of the integrity of the cell membrane. Disruption of cytochrome biosynthesis may induce the onset of apoptosis which has been shown previously to be triggered by alteration in the location of cytochrome c. Silver(I)-coumarin complexes demonstrate good anti-fungal activity and manifest a mode of action distinct to that of the conventional azole and polyene drugs thus raising the possibility of their use when resistance to conventional drug has emerged or in combination with such drugs.

Structure-Activity Relationships of the Human Immunodeficiency Virus Type 1 Maturation Inhibitor PF-46396.

PubMed

Murgatroyd, Christopher; Pirrie, Lisa; Tran, Fanny; Smith, Terry K; Westwood, Nicholas J; Adamson, Catherine S

2016-09-15

HIV-1 maturation inhibitors are a novel class of antiretroviral compounds that consist of two structurally distinct chemical classes: betulinic acid derivatives and the pyridone-based compound PF-46396. It is currently believed that both classes act by similar modes of action to generate aberrant noninfectious particles via inhibition of CA-SP1 cleavage during Gag proteolytic processing. In this study, we utilized a series of novel analogues with decreasing similarity to PF-46396 to determine the chemical groups within PF-46396 that contribute to antiviral activity, Gag binding, and the relationship between these essential properties. A spectrum of antiviral activity (active, intermediate, and inactive) was observed across the analogue series with respect to CA-SP1 cleavage and HIV-1 (NL4-3) replication kinetics in Jurkat T cells. We demonstrate that selected inactive analogues are incorporated into wild-type (WT) immature particles and that one inactive analogue is capable of interfering with PF-46396 inhibition of CA-SP1 cleavage. Mutations that confer PF-46396 resistance can impose a defective phenotype on HIV-1 that can be rescued in a compound-dependent manner. Some inactive analogues retained the capacity to rescue PF-46396-dependent mutants (SP1-A3V, SP1-A3T, and CA-P157S), implying that they can also interact with mutant Gag. The structure-activity relationships observed in this study demonstrate that (i) the tert-butyl group is essential for antiviral activity but is not an absolute requirement for Gag binding, (ii) the trifluoromethyl group is optimal but not essential for antiviral activity, and (iii) the 2-aminoindan group is important for antiviral activity and Gag binding but is not essential, as its replacement is tolerated. Combinations of antiretroviral drugs successfully treat HIV/AIDS patients; however, drug resistance problems make the development of new mechanistic drug classes an ongoing priority. HIV-1 maturation inhibitors are novel as they target the Gag protein, specifically by inhibiting CA-SP1 proteolytic cleavage. The lack of high-resolution structural information of the CA-SP1 target in Gag has hindered our understanding of the inhibitor-binding pocket and maturation inhibitor mode of action. Therefore, we utilized analogues of the maturation inhibitor PF-46396 as chemical tools to determine the chemical components of PF-46396 that contribute to antiviral activity and Gag binding and the relationship between these essential properties. This is the first study to report structure-activity relationships of the maturation inhibitor PF-46396. PF-46396 is chemically distinct from betulinic acid-derived maturation inhibitors; therefore, our data provide a foundation of knowledge that will aid our understanding of how structurally distinct maturation inhibitors act by similar modes of action. Copyright © 2016 Murgatroyd et al.

Initial evaluation of developmental malformation as an end point in mixture toxicity hazard assessment for aquatic vertebrates

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

Dawson, D.A.; Wilke, T.S.

1991-04-01

The joint toxic action of three binary mixtures was determined for the embryo malformation endpoint of the aquatic FETAX (frog embryo teratogenesis assay: Xenopus) test system. Osteolathyrogenic compounds and short-chain carboxylic acids, representing separate, distinct modes of action for induction of malformation, were selected for testing in 96-hr, static-renewal tests. Three mixtures were tested for each combination, with each combination being tested on three separate occasions. Using toxic unit analysis, the combination of osteolathyrogens and the combination of carboxylic acids produced strictly additive (concentration addition) rates of malformation, while the combination of an osteolathyrogen and a carboxylic acid was less-than-additivemore » (response addition) for induction of malformation. Therefore, developmental malformation may have value as an endpoint in mixture toxicity hazard assessment.« less

Incretin therapies: highlighting common features and differences in the modes of action of glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors.

PubMed

Nauck, M

2016-03-01

Over the last few years, incretin-based therapies have emerged as important agents in the treatment of type 2 diabetes (T2D). These agents exert their effect via the incretin system, specifically targeting the receptor for the incretin hormone glucagon-like peptide 1 (GLP-1), which is partly responsible for augmenting glucose-dependent insulin secretion in response to nutrient intake (the 'incretin effect'). In patients with T2D, pharmacological doses/concentrations of GLP-1 can compensate for the inability of diabetic β cells to respond to the main incretin hormone glucose-dependent insulinotropic polypeptide, and this is therefore a suitable parent compound for incretin-based glucose-lowering medications. Two classes of incretin-based therapies are available: GLP-1 receptor agonists (GLP-1RAs) and dipeptidyl peptidase-4 (DPP-4) inhibitors. GLP-1RAs promote GLP-1 receptor (GLP-1R) signalling by providing GLP-1R stimulation through 'incretin mimetics' circulating at pharmacological concentrations, whereas DPP-4 inhibitors prevent the degradation of endogenously released GLP-1. Both agents produce reductions in plasma glucose and, as a result of their glucose-dependent mode of action, this is associated with low rates of hypoglycaemia; however, there are distinct modes of action resulting in differing efficacy and tolerability profiles. Furthermore, as their actions are not restricted to stimulating insulin secretion, these agents have also been associated with additional non-glycaemic benefits such as weight loss, improvements in β-cell function and cardiovascular risk markers. These attributes have made incretin therapies attractive treatments for the management of T2D and have presented physicians with an opportunity to tailor treatment plans. This review endeavours to outline the commonalities and differences among incretin-based therapies and to provide guidance regarding agents most suitable for treating T2D in individual patients. © 2015 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.

Global gene expression and Ingenuity biological functions analysis on PCBs 153 and 138 induced human PBMC in vitro reveals differential mode(s) of action in developing toxicities.

PubMed

Ghosh, Somiranjan; Zang, Shizhu; Mitra, Partha S; Ghimbovschi, Svetlana; Hoffman, Eric P; Dutta, Sisir K

2011-07-01

Several reports have indicated that low level of polychlorinated biphenyl (PCB) exposure can adversely affect a multitude of physiological disorders and diseases in in vitro, in vivo, and as reported in epidemiological studies. This investigation is focused on the possible contribution of two most prevalent PCB congeners in vitro in developing toxicities. We used PCBs 138 and 153 at the human equivalence level as model agents to test their specificity in developing toxicities. We chose a global approach using oligonucleotide microarray technology to investigate modulated gene expression for biological effects, upon exposure of PCBs, followed by Ingenuity Pathway Analysis (IPA), to understand the underlying consequence in developing disease and disorders. We performed in vitro studies with human peripheral blood mononuclear cells (PBMC), where PBMC cells were exposed to respective PCBs for 48 h. Overall, our observation on gene expression indicated that PCB produces a unique signature affecting different pathways, specific for each congener. While analyzing these data through IPA, the prominent and interesting disease and disorders were neurological disease, cancer, cardiovascular disease, respiratory disease, as well as endocrine system disorders, genetic disorders, and reproductive system disease. They showed strong resemblances with in vitro, in vivo, and in the epidemiological studies. A distinct difference was observed in renal and urological diseases, organisimal injury and abnormalities, dental disease, ophthalmic disease, and psychological disorders, which are only revealed by PCB 138 exposure, but not in PCB 153. The present study emphasizes the challenges of global gene expression in vitro and was correlated with the results of exposed human population. The microarray results give a molecular mechanistic insight and functional effects, following PCB exposure. The extent of changes in genes related to several possible mode(s) of action highlights the changes in cellular functions and signaling pathways that play major roles. In addition to understanding the pathways related to mode of action for chemicals, these data could lead to the identification of genomic signatures that could be used for screening of chemicals for their potential to cause disease and developmental disorders. Copyright © 2011 Elsevier Ltd. All rights reserved.

The Interaction between Interoceptive and Action States within a Framework of Predictive Coding

PubMed Central

Marshall, Amanda C.; Gentsch, Antje; Schütz-Bosbach, Simone

2018-01-01

The notion of predictive coding assumes that perception is an iterative process between prior knowledge and sensory feedback. To date, this perspective has been primarily applied to exteroceptive perception as well as action and its associated phenomenological experiences such as agency. More recently, this predictive, inferential framework has been theoretically extended to interoception. This idea postulates that subjective feeling states are generated by top–down inferences made about internal and external causes of interoceptive afferents. While the processing of motor signals for action control and the emergence of selfhood have been studied extensively, the contributions of interoceptive input and especially the potential interaction of motor and interoceptive signals remain largely unaddressed. Here, we argue for a specific functional relation between motor and interoceptive awareness. Specifically, we implicate interoceptive predictions in the generation of subjective motor-related feeling states. Furthermore, we propose a distinction between reflexive and pre-reflexive modes of agentic action control and suggest that interoceptive input may affect each differently. Finally, we advocate the necessity of continuous interoceptive input for conscious forms of agentic action control. We conclude by discussing further research contributions that would allow for a fuller understanding of the interaction between agency and interoceptive awareness. PMID:29515495

Action-Effect Associations in Voluntary and Cued Task-Switching.

PubMed

Sommer, Angelika; Lukas, Sarah

2017-01-01

The literature of action control claims that humans control their actions in two ways. In the stimulus-based approach, actions are triggered by external stimuli. In the ideomotor approach, actions are elicited endogenously and controlled by the intended goal. In the current study, our purpose was to investigate whether these two action control modes affect task-switching differently. We combined a classical task-switching paradigm with action-effect learning. Both experiments consisted of two experimental phases: an acquisition phase, in which associations between task, response and subsequent action effects were learned and a test phase, in which the effects of these associations were tested on task performance by presenting the former action effects as preceding effects, prior to the task (called practiced effects ). Subjects either chose freely between tasks (ideomotor action control mode) or they were cued as to which task to perform (sensorimotor action control mode). We aimed to replicate the consistency effect (i.e., task is chosen according to the practiced task-effect association) and non-reversal advantage (i.e., better task performance when the practiced effect matches the previously learned task-effect association). Our results suggest that participants acquired stable action-effect associations independently of the learning mode. The consistency effect (Experiment 1) could be shown, independent of the learning mode, but only on the response-level. The non-reversal advantage (Experiment 2) was only evident in the error rates and only for participants who had practiced in the ideomotor action control mode.

Action-Effect Associations in Voluntary and Cued Task-Switching

PubMed Central

Sommer, Angelika; Lukas, Sarah

2018-01-01

The literature of action control claims that humans control their actions in two ways. In the stimulus-based approach, actions are triggered by external stimuli. In the ideomotor approach, actions are elicited endogenously and controlled by the intended goal. In the current study, our purpose was to investigate whether these two action control modes affect task-switching differently. We combined a classical task-switching paradigm with action-effect learning. Both experiments consisted of two experimental phases: an acquisition phase, in which associations between task, response and subsequent action effects were learned and a test phase, in which the effects of these associations were tested on task performance by presenting the former action effects as preceding effects, prior to the task (called practiced effects). Subjects either chose freely between tasks (ideomotor action control mode) or they were cued as to which task to perform (sensorimotor action control mode). We aimed to replicate the consistency effect (i.e., task is chosen according to the practiced task-effect association) and non-reversal advantage (i.e., better task performance when the practiced effect matches the previously learned task-effect association). Our results suggest that participants acquired stable action-effect associations independently of the learning mode. The consistency effect (Experiment 1) could be shown, independent of the learning mode, but only on the response-level. The non-reversal advantage (Experiment 2) was only evident in the error rates and only for participants who had practiced in the ideomotor action control mode. PMID:29387027

Response to Comment on “Mode of Action (MOA) Assignment Classifications for Ecotoxicology: An Evaluation of Approaches”

EPA Science Inventory

This letter to the editor that does not have an abstract. It explains mode of action in aquatic toxicology, and rebuts comments about our mode of action classification caused by confusion of the commenter.

Further characterization of Bacillus subtilis antibiotic biosensors and their use for antibacterial mode-of-action studies.

PubMed

Mariner, Katherine R; Ooi, Nicola; Roebuck, Deborah; O'Neill, Alex J; Chopra, Ian

2011-04-01

We further examined the usefulness of previously reported Bacillus subtilis biosensors for antibacterial mode-of-action studies. The biosensors could not detect the tRNA synthetase inhibitors mupirocin, indolmycin, and borrelidin, some inhibitors of peptidoglycan synthesis, and most membrane-damaging agents. However, the biosensors confirmed the modes of action of several RNA polymerase inhibitors and DNA intercalators and provided new insights into the possible modes of action of ciprofloxacin, anhydrotetracycline, corralopyronin, 8-hydroxyquinoline, and juglone.

Intracellular microlasers

NASA Astrophysics Data System (ADS)

Humar, Matjaž; Hyun Yun, Seok

2015-09-01

Optical microresonators, which confine light within a small cavity, are widely exploited for various applications ranging from the realization of lasers and nonlinear devices to biochemical and optomechanical sensing. Here we use microresonators and suitable optical gain materials inside biological cells to demonstrate various optical functions in vitro including lasing. We explore two distinct types of microresonator—soft and hard—that support whispering-gallery modes. Soft droplets formed by injecting oil or using natural lipid droplets support intracellular laser action. The laser spectra from oil-droplet microlasers can chart cytoplasmic internal stress (˜500 pN μm-2) and its dynamic fluctuations at a sensitivity of 20 pN μm-2 (20 Pa). In a second form, whispering-gallery modes within phagocytized polystyrene beads of different sizes enable individual tagging of thousands of cells easily and, in principle, a much larger number by multiplexing with different dyes.

Galerkin analysis of kinematic dynamos in the von Kármán geometry

NASA Astrophysics Data System (ADS)

Marié, L.; Normand, C.; Daviaud, F.

2006-01-01

We investigate dynamo action by solving the kinematic dynamo problem for velocity fields of the von Kármán type between two coaxial counter-rotating propellers in a cylinder. A Galerkin method is implemented that takes advantage of the symmetries of the flow and their subsequent influence on the nature of the magnetic field at the dynamo threshold. Distinct modes of instability have been identified that differ by their spatial and temporal behaviors. Our calculations give the result that a stationary and antisymmetric mode prevails at the dynamo threshold. We then present a quantitative analysis of the results based on the parametric study of four interaction coefficients obtained by reduction of our initially large eigenvalue problem. We propose these coefficients to measure the relative importance of the different mechanisms at play in the von Kármán kinematic dynamo.

Omics methods for probing the mode of action of natural phytotoxins

USDA-ARS?s Scientific Manuscript database

For a little over a decade, omics methods (transcriptomics, proteomics, metabolomics, and physionomics) have been used to discover and probe the mode of action of both synthetic and natural phytotoxins. For mode of action discovery, the strategy for each of these approaches is to generate an omics...

Genetically altered mice for evaluation of mode-of-action (MOA)

EPA Science Inventory

Genetically altered mice for evaluation of mode-of-action (MOA). Barbara D. Abbott, Cynthia J. Wolf, Kaberi P. Das, Christopher S. Lau. (Presented by B. Abbott). This presentation provides an example of the use of genetically modified mice to determine the mode-of-action of r...

Inhibition in motor imagery: a novel action mode switching paradigm.

PubMed

Rieger, Martina; Dahm, Stephan F; Koch, Iring

2017-04-01

Motor imagery requires that actual movements are prevented (i.e., inhibited) from execution. To investigate at what level inhibition takes place in motor imagery, we developed a novel action mode switching paradigm. Participants imagined (indicating only start and end) and executed movements from start buttons to target buttons, and we analyzed trial sequence effects. Trial sequences depended on current action mode (imagination or execution), previous action mode (pure blocks/same mode, mixed blocks/same mode, or mixed blocks/other mode), and movement sequence (action repetition, hand repetition, or hand alternation). Results provided evidence for global inhibition (indicated by switch benefits in execution-imagination (E-I)-sequences in comparison to I-I-sequences), effector-specific inhibition (indicated by hand repetition costs after an imagination trial), and target inhibition (indicated by target repetition benefits in I-I-sequences). No evidence for subthreshold motor activation or action-specific inhibition (inhibition of the movement of an effector to a specific target) was obtained. Two (global inhibition and effector-specific inhibition) of the three observed mechanisms are active inhibition mechanisms. In conclusion, motor imagery is not simply a weaker form of execution, which often is implied in views focusing on similarities between imagination and execution.

Minimalist Model Systems Reveal Similarities and Differences between Membrane Interaction Modes of MCL1 and BAK*

PubMed Central

Landeta, Olatz; Landajuela, Ane; Garcia-Saez, Ana; Basañez, Gorka

2015-01-01

Proteins belonging to the BCL2 family are key modulators of apoptosis that establish a complex network of interactions among themselves and with other cellular factors to regulate cell fate. It is well established that mitochondrial membranes are the main locus of action of all BCL2 family proteins, but it is difficult to obtain a precise view of how BCL2 family members operate at the native mitochondrial membrane environment during apoptosis. Here, we used minimalist model systems and multiple fluorescence-based techniques to examine selected membrane activities of MCL1 and BAK under apoptotic-like conditions. We show that three distinct apoptosis-related factors (i.e. the BCL2 homology 3 ligand cBID, the mitochondrion-specific lipid cardiolipin, and membrane geometrical curvature) all promote membrane association of BCL2-like structural folds belonging to both MCL1 and BAK. However, at the same time, the two proteins exhibited distinguishing features in their membrane association modes under apoptotic-like conditions. In addition, scanning fluorescence cross-correlation spectroscopy and FRET measurements revealed that the BCL2-like structural fold of MCL1, but not that of BAK, forms stable heterodimeric complexes with cBID in a manner adjustable by membrane cardiolipin content and curvature degree. Our results add significantly to a growing body of evidence indicating that the mitochondrial membrane environment plays a complex and active role in the mode of action of BCL2 family proteins. PMID:25987560

Differential gene expression in Daphnia magna suggests distinct modes of action and bioavailability for ZnO nanoparticles and Zn ions.

PubMed

Poynton, Helen C; Lazorchak, James M; Impellitteri, Christopher A; Smith, Mark E; Rogers, Kim; Patra, Manomita; Hammer, Katherine A; Allen, H Joel; Vulpe, Chris D

2011-01-15

Zinc oxide nanoparticles (ZnO NPs) are being rapidly developed for use in consumer products, wastewater treatment, and chemotherapy providing several possible routes for ZnO NP exposure to humans and aquatic organisms. Recent studies have shown that ZnO NPs undergo rapid dissolution to Zn(2+), but the relative contribution of Zn(2+) to ZnO NP bioavailability and toxicity is not clear. We show that a fraction of the ZnO NPs in suspension dissolves, and this fraction cannot account for the toxicity of the ZnO NP suspensions to Daphnia magna. Gene expression profiling of D. magna exposed to ZnO NPs or ZnSO(4) at sublethal concentrations revealed distinct modes of toxicity. There was also little overlap in gene expression between ZnO NPs and SiO(x) NPs, suggesting specificity for the ZnO NP expression profile. ZnO NPs effected expression of genes involved in cytoskeletal transport, cellular respiration, and reproduction. A specific pattern of differential expression of three biomarker genes including a multicystatin, ferritin, and C1q containing gene were confirmed for ZnO NP exposure and provide a suite of biomarkers for identifying environmental exposure to ZnO NPs and differentiating between NP and ionic exposure.

Use of omics methods to determine the mode of action of natural phytotoxins

USDA-ARS?s Scientific Manuscript database

Technology has greatly increased the power of omics methods to profile transcription, protein, and metabolite responses to phytotoxins. These methods hold promise as a tool for providing clues to the modes of action of such compounds. However, to date, only two putative modes of action have been fou...

Development of an in vitro Hepatocyte Model to Investigate Chemical Mode of Action

EPA Science Inventory

There is a clear need to identify and characterize the potential of liver in vitro models that can be used to replace animals for mode of action analysis. Our goal is to use in vitro models for mode of action prediction which recapitulate critical cellular processes underlying in...

Omics methods for probing the mode of action of natural and synthetic phytotoxins.

PubMed

Duke, Stephen O; Bajsa, Joanna; Pan, Zhiqiang

2013-02-01

For a little over a decade, omics methods (transcriptomics, proteomics, metabolomics, and physionomics) have been used to discover and probe the mode of action of both synthetic and natural phytotoxins. For mode of action discovery, the strategy for each of these approaches is to generate an omics profile for phytotoxins with known molecular targets and to compare this library of responses to the responses of compounds with unknown modes of action. Using more than one omics approach enhances the probability of success. Generally, compounds with the same mode of action generate similar responses with a particular omics method. Stress and detoxification responses to phytotoxins can be much clearer than effects directly related to the target site. Clues to new modes of action must be validated with in vitro enzyme effects or genetic approaches. Thus far, the only new phytotoxin target site discovered with omics approaches (metabolomics and physionomics) is that of cinmethylin and structurally related 5-benzyloxymethyl-1,2-isoxazolines. These omics approaches pointed to tyrosine amino-transferase as the target, which was verified by enzyme assays and genetic methods. In addition to being a useful tool of mode of action discovery, omics methods provide detailed information on genetic and biochemical impacts of phytotoxins. Such information can be useful in understanding the full impact of natural phytotoxins in both agricultural and natural ecosystems.

A Cross-Species Mode of Action (Moa) Information Assessment: A Case Study of Bisphenol a (BPA)

EPA Science Inventory

EPA has released a report entitled, A Cross-Species Mode of Action Information Assessment: A Case Study of Bisphenol A [EPA/600/R-50/044F] . This report describes an approach to predict chemical effects and mode of action (MOA) for animal species without data from MOA i...

A Bayesian network model for predicting aquatic toxicity mode of action using two dimensional theoretical molecular descriptors-abstract

EPA Science Inventory

The mode of toxic action (MoA) has been recognized as a key determinant of chemical toxicity but MoA classification in aquatic toxicology has been limited. We developed a Bayesian network model to classify aquatic toxicity mode of action using a recently published dataset contain...

Position and mode dependent optical detection back-action in cantilever beam resonators

NASA Astrophysics Data System (ADS)

Larsen, T.; Schmid, S.; Dohn, S.; Sader, J. E.; Boisen, A.; Villanueva, L. G.

2017-03-01

Optical detection back-action in cantilever resonant or static detection presents a challenge when striving for state-of-the-art performance. The origin and possible routes for minimizing optical back-action have received little attention in literature. Here, we investigate the position and mode dependent optical back-action on cantilever beam resonators. A high power heating laser (100 µW) is scanned across a silicon nitride cantilever while its effect on the first three resonance modes is detected via a low-power readout laser (1 µW) positioned at the cantilever tip. We find that the measured effect of back-action is not only dependent on position but also the shape of the resonance mode. Relevant silicon nitride material parameters are extracted by fitting finite element (FE) simulations to the temperature-dependent frequency response of the first three modes. In a second round of simulations, using the extracted parameters, we successfully fit the FEM results with the measured mode and position dependent back-action. From the simulations, we can conclude that the observed frequency tuning is due to temperature induced changes in stress. Effects of changes in material properties and dimensions are negligible. Finally, different routes for minimizing the effect of this optical detection back-action are described, allowing further improvements of cantilever-based sensing in general.

Predicting herbicide mixture effects on multiple algal species using mixture toxicity models.

PubMed

Nagai, Takashi

2017-10-01

The validity of the application of mixture toxicity models, concentration addition and independent action, to a species sensitivity distribution (SSD) for calculation of a multisubstance potentially affected fraction was examined in laboratory experiments. Toxicity assays of herbicide mixtures using 5 species of periphytic algae were conducted. Two mixture experiments were designed: a mixture of 5 herbicides with similar modes of action and a mixture of 5 herbicides with dissimilar modes of action, corresponding to the assumptions of the concentration addition and independent action models, respectively. Experimentally obtained mixture effects on 5 algal species were converted to the fraction of affected (>50% effect on growth rate) species. The predictive ability of the concentration addition and independent action models with direct application to SSD depended on the mode of action of chemicals. That is, prediction was better for the concentration addition model than the independent action model for the mixture of herbicides with similar modes of action. In contrast, prediction was better for the independent action model than the concentration addition model for the mixture of herbicides with dissimilar modes of action. Thus, the concentration addition and independent action models could be applied to SSD in the same manner as for a single-species effect. The present study to validate the application of the concentration addition and independent action models to SSD supports the usefulness of the multisubstance potentially affected fraction as the index of ecological risk. Environ Toxicol Chem 2017;36:2624-2630. © 2017 SETAC. © 2017 SETAC.

Evaluation of the preparation of the coronal part of the mesial canals of lower molars.

PubMed

Sinan, A; Georgelin-Gurgel, M; Diemer, F

2011-03-01

Canal entrances can be flared using specific, low speed, continuously rotating Ni-Ti instruments. Two such instruments were evaluated for their capacity to flare the canal entrance while respecting the initial canal axis. Lower molars (n = 20) with two distinct mesial canals were prepared to within 2.5 mm of the pulp chamber floor using Bramante's technique. Canal entrances were flared with a QUANTEC FLARE LX or an ENDOFLARE. They both had a 0.12 taper and a #25 tip diameter. The instruments were first inserted in the canals using an axial movement and then withdrawn with a selective circumferential brushing action. Photographs taken before and after each preparation were compared. No ledging or significant modification of the working length was noted. The centre of mass was displaced on average by 0.138 mm with no brushing action and 0.274 mm with brushing action. In most cases (87.5%), the centre of mass was displaced mesially. The two instruments behaved in an identical mode, both before (p = 0.3497) and after (p = 0.9304) the brushing action. Ni-Ti flaring instruments can be used to flare the canal entrance with little displacement of the initial canal axis, even when a brushing action is used.

Dissecting modes of action of non-genotoxic carcinogens in primary mouse hepatocytes.

PubMed

Schaap, Mirjam M; Zwart, Edwin P; Wackers, Paul F K; Huijskens, Ilse; van de Water, Bob; Breit, Timo M; van Steeg, Harry; Jonker, Martijs J; Luijten, Mirjam

2012-11-01

Under REACH, the European Community Regulation on chemicals, the testing strategy for carcinogenicity is based on in vitro and in vivo genotoxicity assays. Given that non-genotoxic carcinogens are negative for genotoxicity and chronic bioassays are no longer regularly performed, this class of carcinogens will go undetected. Therefore, test systems detecting non-genotoxic carcinogens, or even better their modes of action, are required. Here, we investigated whether gene expression profiling in primary hepatocytes can be used to distinguish different modes of action of non-genotoxic carcinogens. For this, primary mouse hepatocytes were exposed to 16 non-genotoxic carcinogens with diverse modes of action. Upon profiling, pathway analysis was performed to obtain insight into the biological relevance of the observed changes in gene expression. Subsequently, both a supervised and an unsupervised comparison approach were applied to recognize the modes of action at the transcriptomic level. These analyses resulted in the detection of three of eight compound classes, that is, peroxisome proliferators, metalloids and skin tumor promotors. In conclusion, gene expression profiles in primary hepatocytes, at least in rodent hepatocytes, appear to be useful to detect some, certainly not all, modes of action of non-genotoxic carcinogens.

An analysis toolbox to explore mesenchymal migration heterogeneity reveals adaptive switching between distinct modes

PubMed Central

Shafqat-Abbasi, Hamdah; Kowalewski, Jacob M; Kiss, Alexa; Gong, Xiaowei; Hernandez-Varas, Pablo; Berge, Ulrich; Jafari-Mamaghani, Mehrdad; Lock, John G; Strömblad, Staffan

2016-01-01

Mesenchymal (lamellipodial) migration is heterogeneous, although whether this reflects progressive variability or discrete, 'switchable' migration modalities, remains unclear. We present an analytical toolbox, based on quantitative single-cell imaging data, to interrogate this heterogeneity. Integrating supervised behavioral classification with multivariate analyses of cell motion, membrane dynamics, cell-matrix adhesion status and F-actin organization, this toolbox here enables the detection and characterization of two quantitatively distinct mesenchymal migration modes, termed 'Continuous' and 'Discontinuous'. Quantitative mode comparisons reveal differences in cell motion, spatiotemporal coordination of membrane protrusion/retraction, and how cells within each mode reorganize with changed cell speed. These modes thus represent distinctive migratory strategies. Additional analyses illuminate the macromolecular- and cellular-scale effects of molecular targeting (fibronectin, talin, ROCK), including 'adaptive switching' between Continuous (favored at high adhesion/full contraction) and Discontinuous (low adhesion/inhibited contraction) modes. Overall, this analytical toolbox now facilitates the exploration of both spontaneous and adaptive heterogeneity in mesenchymal migration. DOI: http://dx.doi.org/10.7554/eLife.11384.001 PMID:26821527

Modes of action of microbially-produced phytotoxins.

PubMed

Duke, Stephen O; Dayan, Franck E

2011-08-01

Some of the most potent phytotoxins are synthesized by microbes. A few of these share molecular target sites with some synthetic herbicides, but many microbial toxins have unique target sites with potential for exploitation by the herbicide industry. Compounds from both non-pathogenic and pathogenic microbes are discussed. Microbial phytotoxins with modes of action the same as those of commercial herbicides and those with novel modes of action of action are covered. Examples of the compounds discussed are tentoxin, AAL-toxin, auscaulitoxin aglycone, hydantocidin, thaxtomin, and tabtoxin.

Effect of surface tension on global modes of confined wake flows

NASA Astrophysics Data System (ADS)

Tammisola, Outi; Lundell, Fredrik; Söderberg, L. Daniel

2011-01-01

Many wake flows are susceptible to self-sustained oscillations, such as the well-known von Kármán vortex street behind a cylinder that makes a rope beat against a flagpole at a distinct frequency on a windy day. One appropriate method to study these global instabilities numerically is to look at the growth rates of the linear temporal global modes. If all growth rates for all modes are negative for a certain flow field then a self-sustained oscillation should not occur. On the other hand, if one growth rate for one mode is slightly positive, the oscillation will approximately obtain the frequency and shape of this global mode. In our study, we first introduce surface tension between two fluids to the wake-flow problem. Then we investigate its effects on the global linear instability of a spatially developing wake with two co-flowing immiscible fluids. The inlet profile consists of two uniform layers, which makes the problem easily parametrizable. The fluids are assumed to have the same density and viscosity, with the result that the interface position becomes dynamically important solely through the action of surface tension. Two wakes with different parameter values and surface tension are studied in detail. The results show that surface tension has a strong influence on the oscillation frequency, growth rate, and shape of the global mode(s). Finally, we make an attempt to confirm and explain the surface-tension effect based on a local stability analysis of the same flow field in the streamwise position of maximum reverse flow.

Conceptual Framework of Modes of Problem Solving Action (MPSA): Implications for Internet Teaching and Learning.

ERIC Educational Resources Information Center

Lai, Su-Huei

The conceptual framework of the Modes of Problem Solving Action (MPSA) model integrates Dewey's pragmatism, critical science theory, and theory regarding the three modes of inquiry. The MPSA model is formulated in the shape of a matrix. Horizontally, there are the following modes: technical, interpretive, and emancipating. Vertically, there are…

Role of electron back action on photons in hybridizing double-layer graphene plasmons with localized photons.

PubMed

Huang, Danhong; Iurov, Andrii; Gumbs, Godfrey

2018-05-23

In this paper, we deal with the electromagnetic coupling between an incident surface-plasmon-polariton wave and relativistic electrons in two graphene layers. Our previous investigation was limited to single-layer graphene (Iurov et al 2017 Phys. Rev. B 96 081408). However, the present work, is both an expanded and extended version of this previous Phys. Rev. B paper after having included very detailed theoretical formalisms and extensive comparisons of results from either one or two graphene layers embedded in a dielectric medium. The additional retarded Coulomb interaction between two graphene layers will compete with the coupling between the single graphene layer and the surface of a conductor. Consequently, some distinctive features, such as triply-hybridized absorption peaks and a new acoustic-like graphene plasmon mode within the anticrossing region, have been found for the double-layer graphene system. Physically, our theory is self-consistent, in comparison with a commonly adopted perturbative theory, for studying hybrid light-plasmon modes and the electron back action on photons. Instead of usual radiation or grating-deflection field coupling, a surface-plasmon-polariton localized field coupling is introduced with completely different dispersion relations for radiative (small wave numbers) and evanescent (large wave numbers) field modes. Technically, the exactly calculated effective scattering matrix for this theory can be employed to construct an effective-medium theory in order to improve the accuracy of the well-known finite-difference time-domain method for solving Maxwell's equations numerically. Practically, the predicted triply-hybridized absorption peaks can excite polaritons only, giving rise to a possible polariton-condensation based laser.

Role of electron back action on photons in hybridizing double-layer graphene plasmons with localized photons

NASA Astrophysics Data System (ADS)

Huang, Danhong; Iurov, Andrii; Gumbs, Godfrey

2018-05-01

In this paper, we deal with the electromagnetic coupling between an incident surface-plasmon-polariton wave and relativistic electrons in two graphene layers. Our previous investigation was limited to single-layer graphene (Iurov et al 2017 Phys. Rev. B 96 081408). However, the present work, is both an expanded and extended version of this previous Phys. Rev. B paper after having included very detailed theoretical formalisms and extensive comparisons of results from either one or two graphene layers embedded in a dielectric medium. The additional retarded Coulomb interaction between two graphene layers will compete with the coupling between the single graphene layer and the surface of a conductor. Consequently, some distinctive features, such as triply-hybridized absorption peaks and a new acoustic-like graphene plasmon mode within the anticrossing region, have been found for the double-layer graphene system. Physically, our theory is self-consistent, in comparison with a commonly adopted perturbative theory, for studying hybrid light-plasmon modes and the electron back action on photons. Instead of usual radiation or grating-deflection field coupling, a surface-plasmon-polariton localized field coupling is introduced with completely different dispersion relations for radiative (small wave numbers) and evanescent (large wave numbers) field modes. Technically, the exactly calculated effective scattering matrix for this theory can be employed to construct an effective-medium theory in order to improve the accuracy of the well-known finite-difference time-domain method for solving Maxwell’s equations numerically. Practically, the predicted triply-hybridized absorption peaks can excite polaritons only, giving rise to a possible polariton-condensation based laser.

Correlating antimicrobial activity and model membrane leakage induced by nylon-3 polymers and detergents

PubMed Central

Hovakeemian, Sara G.; Liu, Runhui; Gellman, Samuel H.; Heerklotz, Heiko

2015-01-01

Most antimicrobial peptides act upon target microorganisms by permeabilizing their membranes. The mode of action is often assessed by vesicle leakage experiments that use model membranes, with the assumption that biological activity arises from permeabilization of the lipid bilayer. The current work aims to extend the interpretation of vesicle leakage results and examine the correlation between vesicle leakage and antimicrobial activity. To this end, we used a lifetime-based leakage assay with calcein-loaded vesicles to study the membrane permeabilizing properties of a novel antifungal polymer poly-NM, two of its analogs, and a series of detergents. In conjunction, the biological activities of these compounds against Candida albicans were assessed and correlated with data from vesicle leakage. Poly-NM induces all-or-none leakage in polar yeast lipid vesicles at the polymer’s MIC, 3 μg/mL. At this and higher concentrations, complete leakage after an initial lag time was observed. Concerted activity tests imply that this polymer acts independently of the detergent octyl glucoside (OG) for both vesicle leakage and activity against C. albicans spheroplasts. In addition, Poly-NM was found to have negligible activity against zwitterionic vesicles and red blood cells. Our results provide a consistent, detailed picture of the mode of action of Poly-NM: this polymer induces membrane leakage by electrostatic lipid clustering. In contrast, Poly-MM:CO, a nylon-3 polymer comprised of both cationic and hydrophobic segments, seems to act by a different mechanism that involves membrane asymmetry stress. Vesicle leakage for this polymer is transient (limited to <100%) and graded, non-specific among zwitterionic and polar yeast lipid vesicles, additive with detergent action, and correlates poorly with biological activity. Based on these results, we conclude that comprehensive leakage experiments can provide a detailed description of the mode of action of membrane permeabilizing compounds. Without this thorough approach, it would have been logical to assume that the two nylon-3 polymers we examined act via similar mechanisms; it is surprising that their mechanisms are so distinct. Some, but not all mechanisms of vesicle permeabilization allow for antimicrobial activity. PMID:26234884

Correlating antimicrobial activity and model membrane leakage induced by nylon-3 polymers and detergents.

PubMed

Hovakeemian, Sara G; Liu, Runhui; Gellman, Samuel H; Heerklotz, Heiko

2015-09-14

Most antimicrobial peptides act upon target microorganisms by permeabilizing their membranes. The mode of action is often assessed by vesicle leakage experiments that use model membranes, with the assumption that biological activity correlates with the permeabilization of the lipid bilayer. The current work aims to extend the interpretation of vesicle leakage results and examine the correlation between vesicle leakage and antimicrobial activity. To this end, we used a lifetime-based leakage assay with calcein-loaded vesicles to study the membrane permeabilizing properties of a novel antifungal polymer poly-NM, two of its analogs, and a series of detergents. In conjunction, the biological activities of these compounds against Candida albicans were assessed and correlated with data from vesicle leakage. Poly-NM induces all-or-none leakage in polar yeast lipid vesicles at the polymer's MIC, 3 μg mL(-1). At this and higher concentrations, complete leakage after an initial lag time was observed. Concerted activity tests imply that this polymer acts independently of the detergent octyl glucoside (OG) for both vesicle leakage and activity against C. albicans spheroplasts. In addition, poly-NM was found to have negligible activity against zwitterionic vesicles and red blood cells. Our results provide a consistent, detailed picture of the mode of action of poly-NM: this polymer induces membrane leakage by electrostatic lipid clustering. In contrast, poly-MM:CO, a nylon-3 polymer comprised of both cationic and hydrophobic segments, seems to act by a different mechanism that involves membrane asymmetry stress. Vesicle leakage for this polymer is transient (limited to <100%) and graded, non-specific among zwitterionic and polar yeast lipid vesicles, additive with detergent action, and correlates poorly with biological activity. Based on these results, we conclude that comprehensive leakage experiments can provide a detailed description of the mode of action of membrane permeabilizing compounds. Without this thorough approach, it would have been logical to assume that the two nylon-3 polymers we examined act via similar mechanisms; it is surprising that their mechanisms are so distinct. Some, but not all mechanisms of vesicle permeabilization allow for antimicrobial activity.

The Dual Edema-Preventing Molecular Mechanism of the Crataegus Extract WS 1442 Can Be Assigned to Distinct Phytochemical Fractions.

PubMed

Fuchs, Simone; Bischoff, Iris; Willer, Elisabeth A; Bräutigam, Jacqueline; Bubik, Martin F; Erdelmeier, Clemens A J; Koch, Egon; Faleschini, Maria T; De Mieri, Maria; Bauhart, Milena; Zahler, Stefan; Hensel, Andreas; Hamburger, Matthias; Potterat, Olivier; Fürst, Robert

2017-05-01

The hawthorn ( Crataegus spp.) extract WS 1442 is used against mild forms of chronic heart failure. This disease is associated with endothelial barrier dysfunction and edema formation. We have recently shown that WS 1442 protects against this dysfunction by a dual mechanism: it both promotes endothelial barrier integrity by activation of a barrier-enhancing pathway (cortactin activation) and inhibits endothelial hyperpermeability by blocking a barrier disruptive pathway (calcium signaling). In this study, we aimed to identify the bioactive compounds responsible for these actions by using a bioactivity-guided fractionation approach. From the four fractions generated from WS 1442 by successive elution with water, 95 % ethanol, methanol, and 70 % acetone, only the water fraction was inactive, whereas the other three triggered a reduction of endothelial hyperpermeability. Analyses of intracellular calcium levels and cortactin phosphorylation were used as readouts to estimate the bioactivity of subfractions and isolated compounds. Interestingly, only the ethanolic fraction interfered with the calcium signaling, whereas only the methanolic fraction led to an activation of cortactin. Thus, the dual mode of action of WS 1442 could be clearly assigned to two distinct fractions. Although the identification of the calcium-active substance(s) was not successful, we could exclude an involvement of phenolic compounds. Cortactin activation, however, could be clearly attributed to oligomeric procyanidins with a distinct degree of polymerization. Taken together, our study provides the first approach to identify the active constituents of WS 1442 that address different cellular pathways leading to the inhibition of endothelial barrier dysfunction. Georg Thieme Verlag KG Stuttgart · New York.

Mini Review: Mode of Action of Mosquito Repellents

DTIC Science & Technology

2013-01-01

Mini review: Mode of action of mosquito repellents Joseph C. Dickens ⇑, Jonathan D. Bohbot United States Department of Agriculture, Agricultural...Modulation a b s t r a c t The mode of action of mosquito repellents remains a controversial topic. However, electrophysiological studies and molecular...annoyance that can disrupt outdoor activities. The use of repellents decreases contacts between mosquitoes and their hosts, and may even lower the rate of

Mode of action of mosquito repellents

USDA-ARS?s Scientific Manuscript database

The mode of action of mosquito repellents remains a controversial topic. However, electrophysiological studies and molecular approaches have provided a better understanding of how repellents exert their effects. Here, we briefly discuss various notions of repellent action and present the current sta...

Modes of Action of Microbially-Produced Phytotoxins

PubMed Central

Duke, Stephen O.; Dayan, Franck E.

2011-01-01

Some of the most potent phytotoxins are synthesized by microbes. A few of these share molecular target sites with some synthetic herbicides, but many microbial toxins have unique target sites with potential for exploitation by the herbicide industry. Compounds from both non-pathogenic and pathogenic microbes are discussed. Microbial phytotoxins with modes of action the same as those of commercial herbicides and those with novel modes of action of action are covered. Examples of the compounds discussed are tentoxin, AAL-toxin, auscaulitoxin aglycone, hydantocidin, thaxtomin, and tabtoxin. PMID:22069756

Chemical structure-guided design of dynapyrazoles, cell-permeable dynein inhibitors with a unique mode of action

PubMed Central

Steinman, Jonathan B; Santarossa, Cristina C; Miller, Rand M; Yu, Lola S; Serpinskaya, Anna S; Furukawa, Hideki; Morimoto, Sachie; Tanaka, Yuta; Nishitani, Mitsuyoshi; Asano, Moriteru; Zalyte, Ruta; Ondrus, Alison E; Johnson, Alex G; Ye, Fan; Nachury, Maxence V; Fukase, Yoshiyuki; Aso, Kazuyoshi; Foley, Michael A; Gelfand, Vladimir I; Chen, James K; Carter, Andrew P; Kapoor, Tarun M

2017-01-01

Cytoplasmic dyneins are motor proteins in the AAA+ superfamily that transport cellular cargos toward microtubule minus-ends. Recently, ciliobrevins were reported as selective cell-permeable inhibitors of cytoplasmic dyneins. As is often true for first-in-class inhibitors, the use of ciliobrevins has in part been limited by low potency. Moreover, suboptimal chemical properties, such as the potential to isomerize, have hindered efforts to improve ciliobrevins. Here, we characterized the structure of ciliobrevins and designed conformationally constrained isosteres. These studies identified dynapyrazoles, inhibitors more potent than ciliobrevins. At single-digit micromolar concentrations dynapyrazoles block intraflagellar transport in the cilium and lysosome motility in the cytoplasm, processes that depend on cytoplasmic dyneins. Further, we find that while ciliobrevins inhibit both dynein's microtubule-stimulated and basal ATPase activity, dynapyrazoles strongly block only microtubule-stimulated activity. Together, our studies suggest that chemical-structure-based analyses can lead to inhibitors with improved properties and distinct modes of inhibition. DOI: http://dx.doi.org/10.7554/eLife.25174.001 PMID:28524820

A designed inhibitor of a CLC antiporter blocks function through a unique binding mode

PubMed Central

Howery, Andrew E.; Elvington, Shelley; Abraham, Sherwin J.; Choi, Kee-Hyun; Phillips, Sabrina; Ryan, Christopher M.; Sanford, R. Lea; Simpson-Dworschak, Sierra; Almqvist, Jonas; Tran, Kevin; Chew, Thomas A.; Zachariae, Ulrich; Andersen, Olaf S.; Whitelegge, Julian; Matulef, Kimberly; Du Bois, Justin; Maduke, Merritt C.

2012-01-01

SUMMARY The lack of small-molecule inhibitors for anion-selective transporters and channels has impeded our understanding of the complex mechanisms that underlie ion passage. The ubiquitous CLC “Chloride Channel” family represents a unique target for biophysical and biochemical studies because its distinctive protein fold supports both passive chloride channels and secondary-active chloride-proton transporters. Here, we describe the synthesis and characterization of the first specific small-molecule inhibitor directed against a CLC antiporter (ClC-ec1). This compound, 4,4′-octanamidostilbene-2,2′-disulfonate (OADS), inhibits ClC-ec1 with low micromolar affinity and has no specific effect on a CLC channel (ClC-1). Inhibition of ClC-ec1 occurs by binding to two distinct intracellular sites. The location of these sites and the lipid-dependence of inhibition suggest potential mechanisms of action. The discovery of this compound will empower research to elucidate differences between antiporter and channel mechanisms and to develop treatments for CLC-mediated disorders. PMID:23177200

Identification and Characterization of Inhibitors of West Nile Virus

PubMed Central

Puig-Basagoiti, Francesc; Qing, Min; Dong, Hongping; Zhang, Bo; Zou, Gang; Yuan, Zhiming

2011-01-01

Although flaviviruses cause significant human diseases, no antiviral therapy is currently available for clinical treatment of these pathogens. To identify flavivirus inhibitors, we performed a high-throughput screening of compound libraries using cells containing luciferase-reporting replicon of West Nile viruses (WNV). Five novel small molecular inhibitors of WNV were identified from libraries containing 96,958 compounds. The inhibitors suppress epidemic strain of WNV in cell culture, with EC50 (50% effective concentration) values of <10 µM and TI (therapeutic index) values of >10. Viral titer reduction assays, using various flaviviruses and nonflaviviruses, showed that the compounds have distinct antiviral spectra. Mode-of-action analysis showed that the inhibitors block distinct steps of WNV replication: four compounds inhibit viral RNA syntheses, while the other compound suppresses both viral translation and RNA syntheses. Biochemical enzyme assays showed that two compounds selectively inhibit viral RNA-dependent RNA polymerase (RdRp), while another compound specifically inhibits both RdRp and methyltransferase. The identified compounds could potentially be developed for treatment of flavivirus infections. PMID:19501258

Vaccine adjuvant technology: from mechanistic concepts to practical applications.

PubMed

Degen, Winfried G J; Jansen, Theo; Schijns, Virgil E J C

2003-04-01

Distinct types of immune responses are required for efficient elimination of different pathogens. Programming of the desired type of immune response by safe nonreplicating vaccines requires suitable vaccine adjuvants. Adjuvants largely determine the magnitude and quality of immune responses specific for the coadministered antigen. Unfortunately, rational vaccine design requiring a rational choice of vaccine adjuvant, is hampered by a lack of knowledge about the mechanism(s) of vaccine adjuvant activity. The current review addresses different critical immunological processes possibly explaining adjuvant functions. In addition, we discuss traditional vaccine adjuvant formulations and their possible mode of action. Finally, we reflect on the latest technologies for the identification of novel adjuvants using molecular analysis of immune activation and functional genomics.

Einstein’s quadrupole formula from the kinetic-conformal Hořava theory

NASA Astrophysics Data System (ADS)

Bellorín, Jorge; Restuccia, Alvaro

We analyze the radiative and nonradiative linearized variables in a gravity theory within the family of the nonprojectable Hořava theories, the Hořava theory at the kinetic-conformal point. There is no extra mode in this formulation, the theory shares the same number of degrees of freedom with general relativity. The large-distance effective action, which is the one we consider, can be given in a generally-covariant form under asymptotically flat boundary conditions, the Einstein-aether theory under the condition of hypersurface orthogonality on the aether vector. In the linearized theory, we find that only the transverse-traceless tensorial modes obey a sourced wave equation, as in general relativity. The rest of variables are nonradiative. The result is gauge-independent at the level of the linearized theory. For the case of a weak source, we find that the leading mode in the far zone is exactly Einstein’s quadrupole formula of general relativity, if some coupling constants are properly identified. There are no monopoles nor dipoles in this formulation, in distinction to the nonprojectable Horava theory outside the kinetic-conformal point. We also discuss some constraints on the theory arising from the observational bounds on Lorentz-violating theories.

Discovery of a Potent BTK Inhibitor with a Novel Binding Mode by Using Parallel Selections with a DNA-Encoded Chemical Library.

PubMed

Cuozzo, John W; Centrella, Paolo A; Gikunju, Diana; Habeshian, Sevan; Hupp, Christopher D; Keefe, Anthony D; Sigel, Eric A; Soutter, Holly H; Thomson, Heather A; Zhang, Ying; Clark, Matthew A

2017-05-04

We have identified and characterized novel potent inhibitors of Bruton's tyrosine kinase (BTK) from a single DNA-encoded library of over 110 million compounds by using multiple parallel selection conditions, including variation in target concentration and addition of known binders to provide competition information. Distinct binding profiles were observed by comparing enrichments of library building block combinations under these conditions; one enriched only at high concentrations of BTK and was competitive with ATP, and another enriched at both high and low concentrations of BTK and was not competitive with ATP. A compound representing the latter profile showed low nanomolar potency in biochemical and cellular BTK assays. Results from kinetic mechanism of action studies were consistent with the selection profiles. Analysis of the co-crystal structure of the most potent compound demonstrated a novel binding mode that revealed a new pocket in BTK. Our results demonstrate that profile-based selection strategies using DNA-encoded libraries form the basis of a new methodology to rapidly identify small molecule inhibitors with novel binding modes to clinically relevant targets. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

A reflection and evaluation model of comparative thinking.

PubMed

Markman, Keith D; McMullen, Matthew N

2003-01-01

This article reviews research on counterfactual, social, and temporal comparisons and proposes a Reflection and Evaluation Model (REM) as an organizing framework. At the heart of the model is the assertion that 2 psychologically distinct modes of mental simulation operate during comparative thinking: reflection, an experiential ("as if") mode of thinking characterized by vividly simulating that information about the comparison standard is true of, or part of, the self; and evaluation, an evaluative mode of thinking characterized by the use of information about the standard as a reference point against which to evaluate one's present standing. Reflection occurs when information about the standard is included in one's self-construal, and evaluation occurs when such information is excluded. The result of reflection is that standard-consistent cognitions about the self become highly accessible, thereby yielding affective assimilation; whereas the result of evaluation is that comparison information is used as a standard against which one's present standing is evaluated, thereby yielding affective contrast. The resulting affect leads to either an increase or decrease in behavioral persistence as a function of the type of task with which one is engaged, and a combination of comparison-derived causal inferences and regulatory focus strategies direct one toward adopting specific future action plans.

SGRL can regulate chlorophyll metabolism and contributes to normal plant growth and development in Pisum sativum L.

PubMed

Bell, Andrew; Moreau, Carol; Chinoy, Catherine; Spanner, Rebecca; Dalmais, Marion; Le Signor, Christine; Bendahmane, Abdel; Klenell, Markus; Domoney, Claire

2015-12-01

Among a set of genes in pea (Pisum sativum L.) that were induced under drought-stress growth conditions, one encoded a protein with significant similarity to a regulator of chlorophyll catabolism, SGR. This gene, SGRL, is distinct from SGR in genomic location, encoded carboxy-terminal motif, and expression through plant and seed development. Divergence of the two encoded proteins is associated with a loss of similarity in intron/exon gene structure. Transient expression of SGRL in leaves of Nicotiana benthamiana promoted the degradation of chlorophyll, in a manner that was distinct from that shown by SGR. Removal of a predicted transmembrane domain from SGRL reduced its activity in transient expression assays, although variants with and without this domain reduced SGR-induced chlorophyll degradation, indicating that the effects of the two proteins are not additive. The combined data suggest that the function of SGRL during growth and development is in chlorophyll re-cycling, and its mode of action is distinct from that of SGR. Studies of pea sgrL mutants revealed that plants had significantly lower stature and yield, a likely consequence of reduced photosynthetic efficiencies in mutant compared with control plants under conditions of high light intensity.

Small angle X-ray scattering as a high-throughput method to classify antimicrobial modes of action.

PubMed

von Gundlach, A R; Garamus, V M; Gorniak, T; Davies, H A; Reischl, M; Mikut, R; Hilpert, K; Rosenhahn, A

2016-05-01

Multi-drug resistant bacteria are currently undermining our health care system worldwide. While novel antimicrobial drugs, such as antimicrobial peptides, are urgently needed, identification of new modes of action is money and time consuming, and in addition current approaches are not available in a high throughput manner. Here we explore how small angle X-ray scattering (SAXS) as high throughput method can contribute to classify the mode of action for novel antimicrobials and therefore supports fast decision making in drug development. Using data bases for natural occurring antimicrobial peptides or predicting novel artificial peptides, many candidates can be discovered that will kill a selected target bacterium. However, in order to narrow down the selection it is important to know if these peptides follow all the same mode of action. In addition, the mode of action should be different from conventional antibiotics, in consequence peptide candidates can be developed further into drugs against multi-drug resistant bacteria. Here we used one short antimicrobial peptide with unknown mode of action and compared the ultrastructural changes of Escherichia coli cells after treatment with the peptide to cells treated with classic antibiotics. The key finding is that SAXS as a structure sensitive tool provides a rapid feedback on drug induced ultrastructural alterations in whole E. coli cells. We could demonstrate that ultrastructural changes depend on the used antibiotics and their specific mode of action. This is demonstrated using several well characterized antimicrobial compounds and the analysis of resulting SAXS curves by principal component analysis. To understand the result of the PCA analysis, the data is correlated with TEM images. In contrast to real space imaging techniques, SAXS allows to obtain nanoscale information averaged over approximately one million cells. The measurement takes only seconds, while conventional tests to identify a mode of action require days or weeks per single substance. The antimicrobial peptide showed a different mode of action as all tested antibiotics including polymyxin B and is therefore a good candidate for further drug development. We envision SAXS to become a useful tool within the high-throughput screening pipeline of modern drug discovery. This article is part of a Special Issue entitled: Antimicrobial peptides edited by Karl Lohner and Kai Hilpert. Copyright © 2015 Elsevier B.V. All rights reserved.

Normal modes in an overmoded circular waveguide coated with lossy material

NASA Technical Reports Server (NTRS)

Lee, C. S.; Lee, S. W.; Chuang, S. L.

1985-01-01

The normal modes in an overmoded waveguide coated with a lossy material are analyzed, particularly for their attenuation properties as a function of coating material, layer thickness, and frequency. When the coating material is not too lossy, the low-order modes are highly attenuated even with a thin layer of coating. This coated guide serves as a mode suppressor of the low-order modes, which can be particularly useful for reducing the radar cross section (RCS) of a cavity structure such as a jet inlet. When the coating material is very lossy, low-order modes fall into two distinct groups: highly and lowly attenuated modes. However, as a/lambda (a = radius of the cylinder; lambda = the free-space wavelength) increases, the separation between these two groups becomes less distinctive. The attenuation constants of most of the low-order modes become small, and decrease as a function of lambda sup 2/a sup 3.

Mode(s) of action of arsenic-induced tumors and toxicity.

EPA Science Inventory

Although arsenic has long been known for its toxicity and carcinogenicity, it is unknown exactly how these adverse health effects ocurr. Three of the biggest unresolved issues in arsenic exposures and adverse health effects are (a) what is (are) the mode of action (MOA)(s) of ar...

Bridging the Gap to Non-toxic Fungal Control: Lupinus-Derived Blad-Containing Oligomer as a Novel Candidate to Combat Human Pathogenic Fungi

PubMed Central

Pinheiro, Ana M.; Carreira, Alexandra; Prescott, Thomas A. K.; Ferreira, Ricardo B.; Monteiro, Sara A.

2017-01-01

The lack of antifungal drugs with novel modes of action reaching the clinic is a serious concern. Recently a novel antifungal protein referred to as Blad-containing oligomer (BCO) has received regulatory approval as an agricultural antifungal agent. Interestingly its spectrum of antifungal activity includes human pathogens such as Candida albicans, however, its mode of action has yet to be elucidated. Here we demonstrate that BCO exerts its antifungal activity through inhibition of metal ion homeostasis which results in apoptotic cell death in C. albicans. HIP HOP profiling in Saccharomyces cerevisiae using a panel of signature strains that are characteristic for common modes of action identified hypersensitivity in yeast lacking the iron-dependent transcription factor Aft1 suggesting restricted iron uptake as a mode of action. Furthermore, global transcriptome profiling in C. albicans also identified disruption of metal ion homeostasis as a potential mode of action. Experiments were carried out to assess the effect of divalent metal ions on the antifungal activity of BCO revealing that BCO activity is antagonized by metal ions such as Mn2+, Zn2+, and Fe2+. The transcriptome profile also implicated sterol synthesis as a possible secondary mode of action which was subsequently confirmed in sterol synthesis assays in C. albicans. Animal models for toxicity showed that BCO is generally well tolerated and presents a promising safety profile as a topical applied agent. Given its potent broad spectrum antifungal activity and novel multitarget mode of action, we propose BCO as a promising new antifungal agent for the topical treatment of fungal infections. PMID:28702011

Bridging the Gap to Non-toxic Fungal Control: Lupinus-Derived Blad-Containing Oligomer as a Novel Candidate to Combat Human Pathogenic Fungi.

PubMed

Pinheiro, Ana M; Carreira, Alexandra; Prescott, Thomas A K; Ferreira, Ricardo B; Monteiro, Sara A

2017-01-01

The lack of antifungal drugs with novel modes of action reaching the clinic is a serious concern. Recently a novel antifungal protein referred to as Blad-containing oligomer (BCO) has received regulatory approval as an agricultural antifungal agent. Interestingly its spectrum of antifungal activity includes human pathogens such as Candida albicans , however, its mode of action has yet to be elucidated. Here we demonstrate that BCO exerts its antifungal activity through inhibition of metal ion homeostasis which results in apoptotic cell death in C. albicans . HIP HOP profiling in Saccharomyces cerevisiae using a panel of signature strains that are characteristic for common modes of action identified hypersensitivity in yeast lacking the iron-dependent transcription factor Aft1 suggesting restricted iron uptake as a mode of action. Furthermore, global transcriptome profiling in C. albicans also identified disruption of metal ion homeostasis as a potential mode of action. Experiments were carried out to assess the effect of divalent metal ions on the antifungal activity of BCO revealing that BCO activity is antagonized by metal ions such as Mn 2+ , Zn 2+ , and Fe 2+ . The transcriptome profile also implicated sterol synthesis as a possible secondary mode of action which was subsequently confirmed in sterol synthesis assays in C. albicans . Animal models for toxicity showed that BCO is generally well tolerated and presents a promising safety profile as a topical applied agent. Given its potent broad spectrum antifungal activity and novel multitarget mode of action, we propose BCO as a promising new antifungal agent for the topical treatment of fungal infections.

Attitudes Regarding Action Learning: Undergraduate vs. Graduate Business Students

ERIC Educational Resources Information Center

Rosenstein, Alvin; Ashley, Allan; Gupta, Rakesh; Ulin, Kristin

2008-01-01

Previous research in our Action Learning Program demonstrated that although undergraduates preferred the Action Learning mode to the traditional lecture and discussion mode of instruction, they missed the familiar structure of the more traditional pedagogy. Consequently increased structure was implemented in both an undergraduate and graduate…

How benthic diatoms within natural communities respond to eight common herbicides with different modes of action.

PubMed

Wood, Rebecca J; Mitrovic, Simon M; Lim, Richard P; Kefford, Ben J

2016-07-01

Herbicides are common pollutants of rivers in agricultural regions. These contaminants include various types of chemicals with different modes of toxic action. Herbicides can have toxic effects on freshwater benthic diatoms, the base of the aquatic food web. We examined the effects of (non-mixture) herbicide exposure to the health of diatoms for eight common herbicides with three different modes of action; the photosystem II (PSII) inhibitors: atrazine, simazine, hexazinone, tebuthiuron and diuron; two auxinic herbicides: MCPA and 2,4-D; and the EPSP synthase inhibitor: glyphosate. Benthic diatoms within riverine communities were exposed to each herbicide in rapid toxicity tests at concentrations of 50, 200 and 500μgL(-1). The most sensitive taxa were Gomphonema spp. and Encyonema gracilis. Navicula cryptotenella was the most tolerant to herbicide exposure. There was no significant effect of the different herbicide modes of action at the community level. Herbicide mode of action did not alter which taxa were most sensitive within the community and sensitivity rankings of the dominant diatom taxa were similar for each of the eight herbicides. The consistency of the results between herbicides suggests that freshwater benthic diatoms may be suitable in situ indicators for detecting the toxicity of herbicides with differing modes of action. Copyright © 2016 Elsevier B.V. All rights reserved.

Remembered study mode: support for the distinctiveness account of the production effect.

PubMed

Ozubko, Jason D; Major, Jennifer; MacLeod, Colin M

2014-01-01

The production effect is the finding that words spoken aloud at study are subsequently remembered better than are words read silently at study. According to the distinctiveness account, aloud words are remembered better because the act of speaking those words aloud is encoded and later recovery of this information can be used to infer that those words were studied. An alternative account (the strength-based account) is that memory strength is simply greater for words read aloud. To discriminate these two accounts, we investigated study mode judgements (i.e., "aloud"/"silent"/"new" ratings): The strength-based account predicts that "aloud" responses should positively correlate with memory strength, whereas the distinctiveness account predicts that accuracy of study mode judgements will be independent of memory strength. Across three experiments, where the strength of some silent words was increased by repetition, study mode was discriminable regardless of strength-even when the strength of aloud and repeated silent items was equivalent. Consistent with the distinctiveness account, we conclude that memory for "aloudness" is independent of memory strength and a likely candidate to explain the production effect.

Action Potentials Initiate in the Axon Initial Segment and Propagate Through Axon Collaterals Reliably in Cerebellar Purkinje Neurons

PubMed Central

Foust, Amanda; Popovic, Marko; Zecevic, Dejan; McCormick, David A.

2010-01-01

Purkinje neurons are the output cells of the cerebellar cortex and generate spikes in two distinct modes, known as simple and complex spikes. Revealing the point of origin of these action potentials, and how they conduct into local axon collaterals, is important for understanding local and distal neuronal processing and communication. By utilizing a recent improvement in voltage sensitive dye imaging technique that provided exceptional spatial and temporal resolution, we were able to resolve the region of spike initiation as well as follow spike propagation into axon collaterals for each action potential initiated on single trials. All fast action potentials, for both simple and complex spikes, whether occurring spontaneously or in response to a somatic current pulse or synaptic input, initiated in the axon initial segment. At discharge frequencies of less than approximately 250 Hz, spikes propagated faithfully through the axon and axon collaterals, in a saltatory manner. Propagation failures were only observed for very high frequencies or for the spikelets associated with complex spikes. These results demonstrate that the axon initial segment is a critical decision point in Purkinje cell processing and that the properties of axon branch points are adjusted to maintain faithful transmission. PMID:20484631

Differential regulation of microtubule severing by APC underlies distinct patterns of projection neuron and interneuron migration

PubMed Central

Eom, Tae-Yeon; Stanco, Amelia; Guo, Jiami; Wilkins, Gary; Deslauriers, Danielle; Yan, Jessica; Monckton, Chase; Blair, Josh; Oon, Eesim; Perez, Abby; Salas, Eduardo; Oh, Adrianna; Ghukasyan, Vladimir; Snider, William D.; Rubenstein, John L. R.; Anton, E. S.

2014-01-01

Coordinated migration of distinct classes of neurons to appropriate positions leads to the formation of functional neuronal circuitry in the cerebral cortex. Two major classes of cortical neurons, interneurons and projection neurons, utilize distinctly different modes (radial vs. tangential) and routes of migration to arrive at their final positions in the cerebral cortex. Here, we show that adenomatous polyposis coli (APC) modulates microtubule (MT) severing in interneurons to facilitate tangential mode of interneuron migration, but not the glial-guided, radial migration of projection neurons. APC regulates the stability and activity of the MT severing protein p60-katanin in interneurons to promote the rapid remodeling of neuronal processes necessary for interneuron migration. These findings reveal how severing and restructuring of MTs facilitate distinct modes of neuronal migration necessary for laminar organization of neurons in the developing cerebral cortex. PMID:25535916

Autodyne effect in a single-mode Er fibre laser and the possibility of its usage for recognising the evaporated biotissue type

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

Dmitriev, A K; Konovalov, A N; Ul'yanov, V A

2015-12-31

The autodyne signal arising in an Er fibre laser in the course of evaporating biological models of different types is studied and the possibility of recognising the biotissue type using the method of autodyne detection of the backscattered Doppler signal is assessed. In the experiments we modelled the process of surgical intervention using the contact (hole perforation with the Er laser fibre) and noncontact (surface evaporation with the focused radiation) regimes of impact on different biological models. The amplitude – frequency characteristic of the autodyne detection for the Er fibre laser is measured and the initial spectra of the backscatteredmore » Doppler signal arising under the action of laser radiation on the samples of biological models are obtained. The experiments have shown that the spectra of the backscattered Doppler signal, arising in the course of the contact and noncontact action of the Er fibre laser on different biological models, demonstrate clear-cut distinctions. (control of laser radiation parameters)« less

Detection and Quantification of Ribosome Inhibition by Aminoglycoside Antibiotics in Living Bacteria Using an Orthogonal Ribosome-Controlled Fluorescent Reporter.

PubMed

Huang, Shijie; Zhu, Xuechen; Melançon, Charles E

2016-01-15

The ribosome is the quintessential antibacterial drug target, with many structurally and mechanistically distinct classes of antibacterial agents acting by inhibiting ribosome function. Detecting and quantifying ribosome inhibition by small molecules and investigating their binding modes and mechanisms of action are critical to antibacterial drug discovery and development efforts. To develop a ribosome inhibition assay that is operationally simple, yet provides direct information on the drug target and the mechanism of action, we have developed engineered E. coli strains harboring an orthogonal ribosome-controlled green fluorescent protein (GFP) reporter that produce fluorescent signal when the orthogonal ribosome is inhibited. As a proof of concept, we demonstrate that these strains, when coexpressing homogeneous populations of aminoglycoside resistant ribosomes, act as sensitive and quantitative detectors of ribosome inhibition by a set of 12 structurally diverse aminoglycoside antibiotics. We suggest that this strategy can be extended to quantifying ribosome inhibition by other drug classes.

A novel toxicogenomics-based approach to categorize (non-)genotoxic carcinogens.

PubMed

Schaap, Mirjam M; Wackers, Paul F K; Zwart, Edwin P; Huijskens, Ilse; Jonker, Martijs J; Hendriks, Giel; Breit, Timo M; van Steeg, Harry; van de Water, Bob; Luijten, Mirjam

2015-12-01

Alternative methods to detect non-genotoxic carcinogens are urgently needed, as this class of carcinogens goes undetected in the current testing strategy for carcinogenicity under REACH. A complicating factor is that non-genotoxic carcinogens act through several distinctive modes of action, which makes prediction of their carcinogenic property difficult. We have recently demonstrated that gene expression profiling in primary mouse hepatocytes is a useful approach to categorize non-genotoxic carcinogens according to their modes of action. In the current study, we improved the methods used for analysis and added mouse embryonic stem cells as a second in vitro test system, because of their features complementary to hepatocytes. Our approach involved an unsupervised analysis based on the 30 most significantly up- and down-regulated genes per chemical. Mouse embryonic stem cells and primary mouse hepatocytes were exposed to a selected set of chemicals and subsequently subjected to gene expression profiling. We focused on non-genotoxic carcinogens, but also included genotoxic carcinogens and non-carcinogens to test the robustness of this approach. Application of the optimized comparison approach resulted in improved categorization of non-genotoxic carcinogens. Mouse embryonic stem cells were a useful addition, especially for genotoxic substances, but also for detection of non-genotoxic carcinogens that went undetected by primary hepatocytes. The approach presented here is an important step forward to categorize chemicals, especially those that are carcinogenic.

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

Villard, L.; Lossi, A.M.; Fontes, M.

We have previously reported the isolation of a gene from Xq13 that codes for a putative regulator of transcription (XNP) and has now been shown to be the gene involved in the X-linked {alpha}-thalassemia with mental retardation (ATR-X) syndrome. The widespread expression and numerous domains present in the putative protein suggest that this gene could be involved in other phenotypes. The predominant expression of the gene in the developing brain, as well as its association with neuron differentiation, indicates that mutations of this gene might result in a mental retardation (MR) phenotype. In this paper we present a family withmore » a splice junction mutation in XNP that results in the skipping of an exon and in the introduction of a stop codon in the middle of the XNP-coding sequence. Only the abnormal transcript is expressed in two first cousins presenting the classic ATR-X phenotype (with {alpha}-thalassemia and HbH inclusions). In a distant cousin presenting a similar dysmorphic MR phenotype but not having thalassemia, {approximately}30% of the XNP transcripts are normal. These data demonstrate that the mode of action of the XNP gene product on globin expression is distinct from its mode of action in brain development and facial morphogenesis and suggest that other dysmorphic mental retardation phenotypes, such as Juberg-Marsidi or some sporadic cases of Coffin-Lowry, could be due to mutations in XNP. 20 refs., 5 figs., 2 tabs.« less

Literature-based compound profiling: application to toxicogenomics.

PubMed

Frijters, Raoul; Verhoeven, Stefan; Alkema, Wynand; van Schaik, René; Polman, Jan

2007-11-01

To reduce continuously increasing costs in drug development, adverse effects of drugs need to be detected as early as possible in the process. In recent years, compound-induced gene expression profiling methodologies have been developed to assess compound toxicity, including Gene Ontology term and pathway over-representation analyses. The objective of this study was to introduce an additional approach, in which literature information is used for compound profiling to evaluate compound toxicity and mode of toxicity. Gene annotations were built by text mining in Medline abstracts for retrieval of co-publications between genes, pathology terms, biological processes and pathways. This literature information was used to generate compound-specific keyword fingerprints, representing over-represented keywords calculated in a set of regulated genes after compound administration. To see whether keyword fingerprints can be used for assessment of compound toxicity, we analyzed microarray data sets of rat liver treated with 11 hepatotoxicants. Analysis of keyword fingerprints of two genotoxic carcinogens, two nongenotoxic carcinogens, two peroxisome proliferators and two randomly generated gene sets, showed that each compound produced a specific keyword fingerprint that correlated with the experimentally observed histopathological events induced by the individual compounds. By contrast, the random sets produced a flat aspecific keyword profile, indicating that the fingerprints induced by the compounds reflect biological events rather than random noise. A more detailed analysis of the keyword profiles of diethylhexylphthalate, dimethylnitrosamine and methapyrilene (MPy) showed that the differences in the keyword fingerprints of these three compounds are based upon known distinct modes of action. Visualization of MPy-linked keywords and MPy-induced genes in a literature network enabled us to construct a mode of toxicity proposal for MPy, which is in agreement with known effects of MPy in literature. Compound keyword fingerprinting based on information retrieved from literature is a powerful approach for compound profiling, allowing evaluation of compound toxicity and analysis of the mode of action.

Exploring the distinction between experimental resonant modes and theoretical eigenmodes: from vibrating plates to laser cavities.

PubMed

Tuan, P H; Wen, C P; Yu, Y T; Liang, H C; Huang, K F; Chen, Y F

2014-02-01

Experimentally resonant modes are commonly presumed to correspond to eigenmodes in the same bounded domain. However, the one-to-one correspondence between theoretical eigenmodes and experimental observations is never reached. Theoretically, eigenmodes in numerous classical and quantum systems are the solutions of the homogeneous Helmholtz equation, whereas resonant modes should be solved from the inhomogeneous Helmholtz equation. In the present paper we employ the eigenmode expansion method to derive the wave functions for manifesting the distinction between eigenmodes and resonant modes. The derived wave functions are successfully used to reconstruct a variety of experimental results including Chladni figures generated from the vibrating plate, resonant patterns excited from microwave cavities, and lasing modes emitted from the vertical cavity.

Explanation of non-additive effects in mixtures of similar mode of action chemicals.

PubMed

Kamo, Masashi; Yokomizo, Hiroyuki

2015-09-01

Many models have been developed to predict the combined effect of drugs and chemicals. Most models are classified into two additive models: independent action (IA) and concentration addition (CA). It is generally considered if the modes of action of chemicals are similar then the combined effect obeys CA; however, many empirical studies report nonlinear effects deviating from the predictions by CA. Such deviations are termed synergism and antagonism. Synergism, which leads to a stronger toxicity, requires more careful management, and hence it is important to understand how and which combinations of chemicals lead to synergism. In this paper, three types of chemical reactions are mathematically modeled and the cause of the nonlinear effects among chemicals with similar modes of action was investigated. Our results show that combined effects obey CA only when the modes of action are exactly the same. Contrary to existing knowledge, combined effects are generally nonlinear even if the modes of action of the chemicals are similar. Our results further show that the nonlinear effects vanish out when the chemical concentrations are low, suggesting that the current management procedure of assuming CA is rarely inappropriate because environmental concentrations of chemicals are generally low. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Brillouin Study of the Quantization of Acoustic Modes in Nanospheres

NASA Astrophysics Data System (ADS)

Kuok, M. H.; Lim, H. S.; Ng, S. C.; Liu, N. N.; Wang, Z. K.

2003-06-01

The vibrational modes in three-dimensional ordered arrays of unembedded SiO2 nanospheres have been studied by Brillouin light scattering. Multiple distinct Brillouin peaks are observed whose frequencies are found to be inversely proportional to the diameter (≈200 340 nm) of the nanospheres, in agreement with Lamb’s theory. This is the first Brillouin observation of acoustic mode quantization in a nanoparticle arising from spatial confinement. The distinct spectral peaks measured afford an unambiguous assignment of seven surface and inner acoustic modes. Interestingly, the relative intensities and polarization dependence of the Brillouin spectrum do not agree with the predictions made for Raman scattering.

Brillouin study of the quantization of acoustic modes in nanospheres.

PubMed

Kuok, M H; Lim, H S; Ng, S C; Liu, N N; Wang, Z K

2003-06-27

The vibrational modes in three-dimensional ordered arrays of unembedded SiO2 nanospheres have been studied by Brillouin light scattering. Multiple distinct Brillouin peaks are observed whose frequencies are found to be inversely proportional to the diameter (approximately 200-340 nm) of the nanospheres, in agreement with Lamb's theory. This is the first Brillouin observation of acoustic mode quantization in a nanoparticle arising from spatial confinement. The distinct spectral peaks measured afford an unambiguous assignment of seven surface and inner acoustic modes. Interestingly, the relative intensities and polarization dependence of the Brillouin spectrum do not agree with the predictions made for Raman scattering.

Bacteriocins from Lactobacillus plantarum – production, genetic organization and mode of action

PubMed Central

Todorov, Svetoslav D.

2009-01-01

Bacteriocins are biologically active proteins or protein complexes that display a bactericidal mode of action towards usually closely related species. Numerous strains of bacteriocin producing Lactobacillus plantarum have been isolated in the last two decades from different ecological niches including meat, fish, fruits, vegetables, and milk and cereal products. Several of these plantaricins have been characterized and the aminoacid sequence determined. Different aspects of the mode of action, fermentation optimization and genetic organization of the bacteriocin operon have been studied. However, numerous of bacteriocins produced by different Lactobacillus plantarum strains have not been fully characterized. In this article, a brief overview of the classification, genetics, characterization, including mode of action and production optimization for bacteriocins from Lactic Acid Bacteria in general, and where appropriate, with focus on bacteriocins produced by Lactobacillus plantarum, is presented. PMID:24031346

DIFFICULTY OF MODE OF ACTION DETERMINATION FOR TRICHLOROETHYLENE: AN EXAMPLE OF COMPLEX INTERACTIONS OF METABOLITES AND OTHER CHEMICAL EXPOSURES (Journal Article)

EPA Science Inventory

The mode(s) of action (MOA) of a pollutant for adverse health effects may be dependent on the mixture of metabolites resulting from exposure to a single agent and may also be affected by co-exposure to pollutants that have similar targets or affected pathways. Trichloroethylene ...

Cone-Deciphered Modes of Problem Solving Action (MPSA Cone): Alternative Perspectives on Diversified Professions.

ERIC Educational Resources Information Center

Lai, Su-Huei

A conceptual framework of the modes of problem-solving action has been developed on the basis of a simple relationship cone to assist individuals in diversified professions in inquiry and implementation of theory and practice in their professional development. The conceptual framework is referred to as the Cone-Deciphered Modes of Problem Solving…

Evidence for distinct modes of solar activity

NASA Astrophysics Data System (ADS)

Usoskin, I. G.; Hulot, G.; Gallet, Y.; Roth, R.; Licht, A.; Joos, F.; Kovaltsov, G. A.; Thébault, E.; Khokhlov, A.

2014-02-01

Aims: The Sun shows strong variability in its magnetic activity, from Grand minima to Grand maxima, but the nature of the variability is not fully understood, mostly because of the insufficient length of the directly observed solar activity records and of uncertainties related to long-term reconstructions. Here we present a new adjustment-free reconstruction of solar activity over three millennia and study its different modes. Methods: We present a new adjustment-free, physical reconstruction of solar activity over the past three millennia, using the latest verified carbon cycle, 14C production, and archeomagnetic field models. This great improvement allowed us to study different modes of solar activity at an unprecedented level of details. Results: The distribution of solar activity is clearly bi-modal, implying the existence of distinct modes of activity. The main regular activity mode corresponds to moderate activity that varies in a relatively narrow band between sunspot numbers 20 and 67. The existence of a separate Grand minimum mode with reduced solar activity, which cannot be explained by random fluctuations of the regular mode, is confirmed at a high confidence level. The possible existence of a separate Grand maximum mode is also suggested, but the statistics is too low to reach a confident conclusion. Conclusions: The Sun is shown to operate in distinct modes - a main general mode, a Grand minimum mode corresponding to an inactive Sun, and a possible Grand maximum mode corresponding to an unusually active Sun. These results provide important constraints for both dynamo models of Sun-like stars and investigations of possible solar influence on Earth's climate. Data are only available at the CDS via anonymous ftp to http://cdsarc.u-strasbg.fr (ftp://130.79.128.5) or via http://cdsarc.u-strasbg.fr/viz-bin/qcat?J/A+A/562/L10

Efficiency in Rule- vs. Plan-Based Movements Is Modulated by Action-Mode.

PubMed

Scheib, Jean P P; Stoll, Sarah; Thürmer, J Lukas; Randerath, Jennifer

2018-01-01

The rule/plan motor cognition (RPMC) paradigm elicits visually indistinguishable motor outputs, resulting from either plan- or rule-based action-selection, using a combination of essentially interchangeable stimuli. Previous implementations of the RPMC paradigm have used pantomimed movements to compare plan- vs. rule-based action-selection. In the present work we attempt to determine the generalizability of previous RPMC findings to real object interaction by use of a grasp-to-rotate task. In the plan task, participants had to use prospective planning to achieve a comfortable post-handle rotation hand posture. The rule task used implementation intentions (if-then rules) leading to the same comfortable end-state. In Experiment A, we compare RPMC performance of 16 healthy participants in pantomime and real object conditions of the experiment, within-subjects. Higher processing efficiency of rule- vs. plan-based action-selection was supported by diffusion model analysis. Results show a significant response-time increase in the pantomime condition compared to the real object condition and a greater response-time advantage of rule-based vs. plan-based actions in the pantomime compared to the real object condition. In Experiment B, 24 healthy participants performed the real object RPMC task in a task switching vs. a blocked condition. Results indicate that plan-based action-selection leads to longer response-times and less efficient information processing than rule-based action-selection in line with previous RPMC findings derived from the pantomime action-mode. Particularly in the task switching mode, responses were faster in the rule compared to the plan task suggesting a modulating influence of cognitive load. Overall, results suggest an advantage of rule-based action-selection over plan-based action-selection; whereby differential mechanisms appear to be involved depending on the action-mode. We propose that cognitive load is a factor that modulates the advantageous effect of implementation intentions in motor cognition on different levels as illustrated by the varying speed advantages and the variation in diffusion parameters per action-mode or condition, respectively.

Team reasoning: Solving the puzzle of coordination.

PubMed

Colman, Andrew M; Gold, Natalie

2017-11-03

In many everyday activities, individuals have a common interest in coordinating their actions. Orthodox game theory cannot explain such intuitively obvious forms of coordination as the selection of an outcome that is best for all in a common-interest game. Theories of team reasoning provide a convincing solution by proposing that people are sometimes motivated to maximize the collective payoff of a group and that they adopt a distinctive mode of reasoning from preferences to decisions. This also offers a compelling explanation of cooperation in social dilemmas. A review of team reasoning and related theories suggests how team reasoning could be incorporated into psychological theories of group identification and social value orientation theory to provide a deeper understanding of these phenomena.

Significance of beating observed in earthquake responses of buildings

USGS Publications Warehouse

Çelebi, Mehmet; Ghahari, S. F.; Taciroglu, E.

2016-01-01

The beating phenomenon observed in the recorded responses of a tall building in Japan and another in the U.S. are examined in this paper. Beating is a periodic vibrational behavior caused by distinctive coupling between translational and torsional modes that typically have close frequencies. Beating is prominent in the prolonged resonant responses of lightly damped structures. Resonances caused by site effects also contribute to accentuating the beating effect. Spectral analyses and system identification techniques are used herein to quantify the periods and amplitudes of the beating effects from the strong motion recordings of the two buildings. Quantification of beating effects is a first step towards determining remedial actions to improve resilient building performance to strong earthquake induced shaking.

Recent insights into the mode of action of memantine and ketamine

PubMed Central

Johnson, Jon W.; Glasgow, Nathan G.; Povysheva, Nadezhda V.

2014-01-01

The clinical benefits of the glutamate receptor antagonists memantine and ketamine have helped sustain optimism that glutamate receptors represent viable targets for development of therapeutic drugs. Both memantine and ketamine antagonize N-methyl-d-aspartate receptors (NMDARs), a glutamate receptor subfamily, by blocking the receptor-associated ion channel. Although many of the basic characteristics of NMDAR inhibition by memantine and ketamine appear similar, their effects on humans and to a lesser extent on rodents are strongly divergent. Some recent research suggests that preferential inhibition by memantine and ketamine of distinct NMDAR subpopulations may contribute to the drugs' differential clinical effects. Here we review studies that shed light on possible explanations for differences between the effects of memantine and ketamine. PMID:25462293

Dosage Mutator Genes in Saccharomyces cerevisiae: A Novel Mutator Mode-of-Action of the Mph1 DNA Helicase.

PubMed

Ang, J Sidney; Duffy, Supipi; Segovia, Romulo; Stirling, Peter C; Hieter, Philip

2016-11-01

Mutations that cause genome instability are considered important predisposing events that contribute to initiation and progression of cancer. Genome instability arises either due to defects in genes that cause an increased mutation rate (mutator phenotype), or defects in genes that cause chromosome instability (CIN). To extend the catalog of genome instability genes, we systematically explored the effects of gene overexpression on mutation rate, using a forward-mutation screen in budding yeast. We screened ∼5100 plasmids, each overexpressing a unique single gene, and characterized the five strongest mutators, MPH1 (mutator phenotype 1), RRM3, UBP12, PIF1, and DNA2 We show that, for MPH1, the yeast homolog of Fanconi Anemia complementation group M (FANCM), the overexpression mutator phenotype is distinct from that of mph1Δ. Moreover, while four of our top hits encode DNA helicases, the overexpression of 48 other DNA helicases did not cause a mutator phenotype, suggesting this is not a general property of helicases. For Mph1 overexpression, helicase activity was not required for the mutator phenotype; in contrast Mph1 DEAH-box function was required for hypermutation. Mutagenesis by MPH1 overexpression was independent of translesion synthesis (TLS), but was suppressed by overexpression of RAD27, a conserved flap endonuclease. We propose that binding of DNA flap structures by excess Mph1 may block Rad27 action, creating a mutator phenotype that phenocopies rad27Δ. We believe this represents a novel mutator mode-of-action and opens up new prospects to understand how upregulation of DNA repair proteins may contribute to mutagenesis. Copyright © 2016 by the Genetics Society of America.

Actions of 3-[2′-phosphonomethyl[1,1′-biphenyl]-3-yl]alanine (PMBA) on cloned glycine receptors

PubMed Central

Hosie, Alastair M; Akagi, Hiroyuki; Ishida, Michiko; Shinozaki, Haruhiko

1999-01-01

PMBA is a novel antagonist of strychnine-sensitive glycine receptors in the rat spinal cord, however, its mode of action is unknown. The actions of PMBA on rat glycine receptor α1 and α2 homomers in Xenopus oocytes were studied under two-electrode voltage-clamp. Co-application of PMBA and glycine to both α1 and α2 homomers yielded inward currents which decayed to a steady-state. Responses rose slowly to the same steady-state amplitude following a 2 min pre-incubation in PMBA. Strychnine, but not picrotoxinin, showed similar antagonism to PMBA. The potency of PMBA was independent of membrane potential between −100 and 0 mV. When tested against EC50 concentrations of glycine, PMBA was almost equally potent on α1 (IC50, 406±41 nM: Hill coefficient, 1.5±0.2) and α2 (IC50, 539±56 nM; Hill coefficient, 1.4±0.2) homomers. PMBA (1–10 μM) and strychnine (200 nM) reduced the potency of glycine and the amplitude of the maximal agonist response of α1 and α2 homomers. In 10 μM PMBA, two distinct classes of glycine response were observed on α2, only a single class of responses were observed on α1. There are similarities in PMBA and strychnine antagonism, although these compounds are structurally distinct. The possibility that PMBA interacts at two binding sites which differ in α1 and α2 subunits is discussed. PMBA may provide a lead structure for novel antagonists with which to investigate structural differences in glycine receptor at α1 and α2 subunits. PMID:10205013

Clobazam and its active metabolite N-desmethylclobazam display significantly greater affinities for α₂- versus α₁-GABA(A)-receptor complexes.

PubMed

Jensen, Henrik Sindal; Nichol, Kathryn; Lee, Deborah; Ebert, Bjarke

2014-01-01

Clobazam (CLB), a 1,5-benzodiazepine (BZD), was FDA-approved in October 2011 for the adjunctive treatment of seizures associated with Lennox-Gastaut syndrome (LGS) in patients 2 years and older. BZDs exert various CNS effects through allosteric modulation of GABAA receptors. The structurally distinct, 1,4-BZD clonazepam (CLN) is also approved to treat LGS. The precise mechanisms of action and clinical efficacy of both are unknown. Data show that the GABAA α₁-subunit-selective compound zolpidem [ZOL] exhibits hypnotic/sedative effects. Conversely, data from knock-in mice carrying BZD binding site mutations suggest that the α₂ subunit mediates anticonvulsant effects, without sedative actions. Hence, the specific pattern of interactions across the GABAA receptor complexes of BZDs might be reflected in their clinical efficacies and adverse effect profiles. In this study, GABAA-receptor binding affinities of CLB, N-desmethylclobazam (N-CLB, the major metabolite of CLB), CLN, and ZOL were characterized with native receptors from rat-brain homogenates and on cloned receptors from HEK293 cells transfected with combinations of α (α₁, α₂, α₃, or α₅), β₂, and γ₂ subtypes. Our results demonstrate that CLB and N-CLB have significantly greater binding affinities for α₂- vs. α₁-receptor complexes, a difference not observed for CLN, for which no distinction between α₂ and α₁ receptors was observed. Our experiments with ZOL confirmed the high preference for α₁ receptors. These results provide potential clues to a new understanding of the pharmacologic modes of action of CLB and N-CLB.

Clobazam and Its Active Metabolite N-desmethylclobazam Display Significantly Greater Affinities for α2- versus α1-GABAA–Receptor Complexes

PubMed Central

Jensen, Henrik Sindal; Nichol, Kathryn; Lee, Deborah; Ebert, Bjarke

2014-01-01

Clobazam (CLB), a 1,5-benzodiazepine (BZD), was FDA-approved in October 2011 for the adjunctive treatment of seizures associated with Lennox-Gastaut syndrome (LGS) in patients 2 years and older. BZDs exert various CNS effects through allosteric modulation of GABAA receptors. The structurally distinct, 1,4-BZD clonazepam (CLN) is also approved to treat LGS. The precise mechanisms of action and clinical efficacy of both are unknown. Data show that the GABAA α1-subunit–selective compound zolpidem [ZOL] exhibits hypnotic/sedative effects. Conversely, data from knock-in mice carrying BZD binding site mutations suggest that the α2 subunit mediates anticonvulsant effects, without sedative actions. Hence, the specific pattern of interactions across the GABAA receptor complexes of BZDs might be reflected in their clinical efficacies and adverse effect profiles. In this study, GABAA-receptor binding affinities of CLB, N-desmethylclobazam (N-CLB, the major metabolite of CLB), CLN, and ZOL were characterized with native receptors from rat-brain homogenates and on cloned receptors from HEK293 cells transfected with combinations of α (α1, α2, α3, or α5), β2, and γ2 subtypes. Our results demonstrate that CLB and N-CLB have significantly greater binding affinities for α2- vs. α1-receptor complexes, a difference not observed for CLN, for which no distinction between α2 and α1 receptors was observed. Our experiments with ZOL confirmed the high preference for α1 receptors. These results provide potential clues to a new understanding of the pharmacologic modes of action of CLB and N-CLB. PMID:24533090

Bacteriocins from Lactobacillus plantarum - production, genetic organization and mode of action: produção, organização genética e modo de ação.

PubMed

Todorov, Svetoslav D

2009-04-01

Bacteriocins are biologically active proteins or protein complexes that display a bactericidal mode of action towards usually closely related species. Numerous strains of bacteriocin producing Lactobacillus plantarum have been isolated in the last two decades from different ecological niches including meat, fish, fruits, vegetables, and milk and cereal products. Several of these plantaricins have been characterized and the aminoacid sequence determined. Different aspects of the mode of action, fermentation optimization and genetic organization of the bacteriocin operon have been studied. However, numerous of bacteriocins produced by different Lactobacillus plantarum strains have not been fully characterized. In this article, a brief overview of the classification, genetics, characterization, including mode of action and production optimization for bacteriocins from Lactic Acid Bacteria in general, and where appropriate, with focus on bacteriocins produced by Lactobacillus plantarum, is presented.

Nonclassicality and Entanglement in multimode radiation fields under the action of classicality preserving devices

NASA Astrophysics Data System (ADS)

Chaturvedi, S.

2011-09-01

In this work we examine the possibilities of converting quantum optical nonclassicality into entanglement in multimode under the action of classicality preserving devices such as beamsplitters. While the single mode case is amenable to a complete analysis, non availability of certain crucial results in the classical theory of moments in the multimode situations forces us to treat these cases with lesser degree of generality by taking recourse to the familiar Mandel matrix and its extensions. We generalize the Mandel matrix from one-mode states to the two-mode situation, leading to a natural classification of states with varying levels of nonclassicality. For two-mode states we present a single test which, if successful, simultaneouly witnesses nonclassicality as well as NPT entanglement. We develop a test for NPT entanglement after beamsplitter action on a nonclassical state, designed in such a way that it remains `close' to that for nonclassicality. In the same spirit we analyse the result of three-mode `beamsplitter' action after coupling to an ancilla in the Fock ground state. The concept of genuine tripartite entanglement and scalar measures of nonclassicality at the Mandel level for two mode systems are discussed and illustrated with the help of several examples.

Hsp40 function in yeast prion propagation: Amyloid diversity necessitates chaperone functional complexity.

PubMed

Sporn, Zachary A; Hines, Justin K

2015-01-01

Yeast prions are heritable protein-based elements, most of which are formed of amyloid aggregates that rely on the action of molecular chaperones for transmission to progeny. Prions can form distinct amyloid structures, known as 'strains' in mammalian systems, that dictate both pathological progression and cross-species infection barriers. In yeast these same amyloid structural polymorphisms, called 'variants', dictate the intensity of prion-associated phenotypes and stability in mitosis. We recently reported that [PSI(+)] prion variants differ in the fundamental domain requirements for one chaperone, the Hsp40/J-protein Sis1, which are mutually exclusive between 2 different yeast prions, demonstrating a functional plurality for Sis1. Here we extend that analysis to incorporate additional data that collectively support the hypothesis that Sis1 has multiple functional roles that can be accomplished by distinct sets of domains. These functions are differentially required by distinct prions and prion variants. We also present new data regarding Hsp104-mediated prion elimination and show that some Sis1 functions, but not all, are conserved in the human homolog Hdj1/DNAJB1. Importantly, of the 10 amyloid-based prions indentified to date in Saccharomyces cerevisiae, the chaperone requirements of only 4 are known, leaving a great diversity of amyloid structures, and likely modes of amyloid-chaperone interaction, largely unexplored.

Motor command inhibition and the representation of response mode during motor imagery.

PubMed

Scheil, Juliane; Liefooghe, Baptist

2018-05-01

Research on motor imagery proposes that overt actions during motor imagery can be avoided by proactively signaling subthreshold motor commands to the effectors and by invoking motor-command inhibition. A recent study by Rieger, Dahm, and Koch (2017) found evidence in support of motor command inhibition, which indicates that MI cannot be completed on the sole basis of subthreshold motor commands. However, during motor imagery, participants know in advance when a covert response is to be made and it is thus surprising such additional motor-command inhibition is needed. Accordingly, the present study tested whether the demand to perform an action covertly can be proactively integrated by investigating the formation of task-specific action rules during motor imagery. These task-specific action rules relate the decision rules of a task to the mode in which these rules need to be applied (e.g., if smaller than 5, press the left key covertly). To this end, an experiment was designed in which participants had to switch between two numerical judgement tasks and two response modes: covert responding and overt responding. First, we observed markers of motor command inhibition and replicated the findings of Rieger and colleagues. Second, we observed evidence suggesting that task-specific action rules are created for the overt response mode (e.g., if smaller than 5, press the left key). In contrast, for the covert response mode, no task-specific action rules are formed and decision rules do not include mode-specific information (e.g., if smaller than 5, left). Copyright © 2018 Elsevier B.V. All rights reserved.

Framework for community functioning: synthesis of stress gradient and resource partitioning concepts

PubMed Central

2017-01-01

To understand how communities function and generate abundance, I develop a framework integrating elements from the stress gradient and resource partitioning concepts. The framework suggests that guild abundance depends on environmental and spatial factors but also on inter-guild interactions (competitor or facilitator richness), which can alter the fundamental niche of constituent species in negative (competition) or positive direction (facilitation). Consequently, the environmental and spatial mechanisms driving guild abundance would differ across guilds and interaction modes. Using continental data on stream diatoms and physico-chemistry, the roles of these mechanisms were tested under three interaction modes—shared preference, distinct preference, and facilitative, whereby pairs of guilds exhibited, respectively, a dominance-tolerance tradeoff along a eutrophication gradient, specialization along a pH gradient, or a donor-recipient relationship along a nitrogen gradient. Representative of the shared preference mode were the motile (dominant) and low profile (tolerant) guilds, of the distinct preference mode—the acidophilous and alkaliphilous (low profile) guilds, and of the facilitative mode—nitrogen fixers (donors) and motile species (recipients). In each mode, the influences of environment, space (latitude and longitude), and competitor or facilitator richness on guild density were assessed by variance partitioning. Pure environment constrained most strongly the density of the dominant, the acidophilous, and the recipient guild in the shared preference, distinct preference, and facilitative mode, respectively, while spatial effects were important only for the low profile guild. Higher competitor richness was associated with lower density of the tolerant guild in the shared preference mode, both guilds in the distinct preference mode, and the donor guild in the facilitative mode. Conversely, recipient density in the facilitative mode increased with donor richness in stressful nitrogen-poor environments. Thus, diatom guild abundance patterns were determined primarily by biotic and/or environmental impacts and, with the exception of the low profile guild, were insensitive to spatial effects. This framework identifies major sources of variability in diatom guild abundance with implications for the understanding of biodiversity-ecosystem functioning. PMID:29018618

The Use of Mode of Action Information in Risk Assessment: Quantitative Key Events/Dose-Response Framework for Modeling the Dose-Response for Key Events

EPA Science Inventory

The HESI RISK21 project formed the Dose-Response/Mode-of-Action Subteam to develop strategies for using all available data (in vitro, in vivo, and in silico) to advance the next-generation of chemical risk assessments. A goal of the Subteam is to enhance the existing Mode of Act...

First-principles study of crystallographic slip modes in ω-Zr.

PubMed

Kumar, Anil; Kumar, M Arul; Beyerlein, Irene J

2017-08-21

We use first-principles density functional theory to study the preferred modes of slip in the high-pressure ω phase of Zr. The generalized stacking fault energy surfaces associated with shearing on nine distinct crystallographic slip modes in the hexagonal ω-Zr crystal are calculated, from which characteristics such as ideal shear stress, the dislocation Burgers vector, and possible accompanying atomic shuffles, are extracted. Comparison of energy barriers and ideal shear stresses suggests that the favorable modes are prismatic 〈c〉, prismatic-II [Formula: see text] and pyramidal-II 〈c + a〉, which are distinct from the ground state hexagonal close packed α phase of Zr. Operation of these three modes can accommodate any deformation state. The relative preferences among the identified slip modes are examined using a mean-field crystal plasticity model and comparing the calculated deformation texture with the measurement. Knowledge of the basic crystallographic modes of slip is critical to understanding and analyzing the plastic deformation behavior of ω-Zr or mixed α-ω phase-Zr.

Locomotion defects, together with Pins, regulates heterotrimeric G-protein signaling during Drosophila neuroblast asymmetric divisions

PubMed Central

Yu, Fengwei; Wang, Hongyan; Qian, Hongliang; Kaushik, Rachna; Bownes, Mary; Yang, Xiaohang; Chia, William

2005-01-01

Heterotrimeric G proteins mediate asymmetric division of Drosophila neuroblasts. Free Gβγ appears to be crucial for the generation of an asymmetric mitotic spindle and consequently daughter cells of distinct size. However, how Gβγ is released from the inactive heterotrimer remains unclear. Here we show that Locomotion defects (Loco) interacts and colocalizes with Gαi and, through its GoLoco motif, acts as a guanine nucleotide dissociation inhibitor (GDI) for Gαi. Simultaneous removal of the two GoLoco motif proteins, Loco and Pins, results in defects that are essentially indistinguishable from those observed in Gβ13F or Gγ1 mutants, suggesting that Loco and Pins act synergistically to release free Gβγ in neuroblasts. Furthermore, the RGS domain of Loco can also accelerate the GTPase activity of Gαi to regulate the equilibrium between the GDP- and the GTP-bound forms of Gαi. Thus, Loco can potentially regulate heterotrimeric G-protein signaling via two distinct modes of action during Drosophila neuroblast asymmetric divisions. PMID:15937221

On Strong Anticipation

PubMed Central

Stepp, N.; Turvey, M. T.

2009-01-01

We examine Dubois's (2003) distinction between weak anticipation and strong anticipation. Anticipation is weak if it arises from a model of the system via internal simulations. Anticipation is strong if it arises from the system itself via lawful regularities embedded in the system's ordinary mode of functioning. The assumption of weak anticipation dominates cognitive science and neuroscience and in particular the study of perception and action. The assumption of strong anticipation, however, seems to be required by anticipation's ubiquity. It is, for example, characteristic of homeostatic processes at the level of the organism, organs, and cells. We develop the formal distinction between strong and weak anticipation by elaboration of anticipating synchronization, a phenomenon arising from time delays in appropriately coupled dynamical systems. The elaboration is conducted in respect to (a) strictly physical systems, (b) the defining features of circadian rhythms, often viewed as paradigmatic of biological behavior based in internal models, (c) Pavlovian learning, and (d) forward models in motor control. We identify the common thread of strongly anticipatory systems and argue for its significance in furthering understanding of notions such as “internal”, “model” and “prediction”. PMID:20191086

Inositol polyphosphates intersect with signaling and metabolic networks via two distinct mechanisms.

PubMed

Wu, Mingxuan; Chong, Lucy S; Perlman, David H; Resnick, Adam C; Fiedler, Dorothea

2016-11-01

Inositol-based signaling molecules are central eukaryotic messengers and include the highly phosphorylated, diffusible inositol polyphosphates (InsPs) and inositol pyrophosphates (PP-InsPs). Despite the essential cellular regulatory functions of InsPs and PP-InsPs (including telomere maintenance, phosphate sensing, cell migration, and insulin secretion), the majority of their protein targets remain unknown. Here, the development of InsP and PP-InsP affinity reagents is described to comprehensively annotate the interactome of these messenger molecules. By using the reagents as bait, >150 putative protein targets were discovered from a eukaryotic cell lysate (Saccharomyces cerevisiae). Gene Ontology analysis of the binding partners revealed a significant overrepresentation of proteins involved in nucleotide metabolism, glucose metabolism, ribosome biogenesis, and phosphorylation-based signal transduction pathways. Notably, we isolated and characterized additional substrates of protein pyrophosphorylation, a unique posttranslational modification mediated by the PP-InsPs. Our findings not only demonstrate that the PP-InsPs provide a central line of communication between signaling and metabolic networks, but also highlight the unusual ability of these molecules to access two distinct modes of action.

PHYSIOLOCIGALLY BASED PHARMACOKINETIC (PBPK) MODELING AND MODE OF ACTION IN DOSE-RESPONSE ASSESSMENT

EPA Science Inventory

PHYSIOLOGICALLY BASED PHARMACOKINETIC (PBPK) MODELING AND MODE OF ACTION IN DOSE-RESPONSE ASSESSMENT. Barton HA. Experimental Toxicology Division, National Health and Environmental Effects Laboratory, ORD, U.S. EPA
Dose-response analysis requires quantitatively linking infor...

Mode of action from dose-response microarray data: case study using 10 environmental chemicals

EPA Science Inventory

Ligand-activated nuclear receptors regulate many biological processes through complex interactions with biological macromolecules. Certain xenobiotics alter nuclear receptor signaling through direct or indirect interactions. Defining the mode of action of such xenobiotics is di...

Recent developments in naturally derived antimalarials: cryptolepine analogues.

PubMed

Wright, Colin W

2007-06-01

Increasing resistance of Plasmodium falciparum to commonly used antimalarial drugs has made the need for new agents increasingly urgent. In this paper, the potential of cryptolepine, an alkaloid from the West African shrub Cryptolepis sanguinolenta, as a lead towards new antimalarial agents is discussed. Several cryptolepine analogues have been synthesized that have promising in-vitro and in-vivo antimalarial activity. Studies on the antimalarial modes of action of these analogues indicate that they may have different or additional modes of action to the parent compound. Elucidation of the mode of action may facilitate the development of more potent antimalarial cryptolepine analogues.

Perspectives for elucidating the ethylenediurea (EDU) mode of action for protection against O3 phytotoxicity.

PubMed

Agathokleous, Evgenios

2017-08-01

Ethylenediurea (EDU) has been widely studied for its effectiveness to protect plants against injuries caused by surface ozone (O 3 ), however its mode of action remains unclear. So far, there is not a unified methodological approach and thus the methodology is quite arbitrary, thereby making it more difficult to generalize findings and understand the EDU mode of action. This review examines the question of whether potential N addition to plants by EDU is a fundamental underlying mechanism in protecting against O 3 phytotoxicity. Yet, this review proposes an evidence-based hypothesis that EDU may protect plants against O 3 deleterious effects upon generation of EDU-induced hormesis, i.e. by activating plant defense at low doses. This hypothesis challenges the future research directions. Revealing a hormesis-based EDU mode of action in protecting plants against O 3 toxicity would have further implications to ecotoxicology and environmental safety. Furthermore, this review discusses the need for further studies on plant metabolism under EDU treatment through relevant experimental approach, and attempts to set the bases for approaching a unified methodology that will contribute in revealing the EDU mode of action. In this framework, focus is given to the main EDU application methods. Copyright © 2017 Elsevier Inc. All rights reserved.

Biochemical correlates in an animal model of depression

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

Johnson, J.O.

1986-01-01

A valid animal model of depression was used to explore specific adrenergic receptor differences between rats exhibiting aberrant behavior and control groups. Preliminary experiments revealed a distinct upregulation of hippocampal beta-receptors (as compared to other brain regions) in those animals acquiring a response deficit as a result of exposure to inescapable footshock. Concurrent studies using standard receptor binding techniques showed no large changes in the density of alpha-adrenergic, serotonergic, or dopaminergic receptor densities. This led to the hypothesis that the hippocampal beta-receptor in responses deficient animals could be correlated with the behavioral changes seen after exposure to the aversive stimulus.more » Normalization of the behavior through the administration of antidepressants could be expected to reverse the biochemical changes if these are related to the mechanism of action of antidepressant drugs. This study makes three important points: (1) there is a relevant biochemical change in the hippocampus of response deficient rats which occurs in parallel to a well-defined behavior, (2) the biochemical and behavioral changes are normalized by antidepressant treatments exhibiting both serotonergic and adrenergic mechanisms of action, and (3) the mode of action of antidepressants in this model is probably a combination of serotonergic and adrenergic influences modulating the hippocampal beta-receptor. These results are discussed in relation to anatomical and biochemical aspects of antidepressant action.« less

Dramatic performance of Clostridium thermocellum explained by its wide range of cellulase modalities.

PubMed

Xu, Qi; Resch, Michael G; Podkaminer, Kara; Yang, Shihui; Baker, John O; Donohoe, Bryon S; Wilson, Charlotte; Klingeman, Dawn M; Olson, Daniel G; Decker, Stephen R; Giannone, Richard J; Hettich, Robert L; Brown, Steven D; Lynd, Lee R; Bayer, Edward A; Himmel, Michael E; Bomble, Yannick J

2016-02-01

Clostridium thermocellum is the most efficient microorganism for solubilizing lignocellulosic biomass known to date. Its high cellulose digestion capability is attributed to efficient cellulases consisting of both a free-enzyme system and a tethered cellulosomal system wherein carbohydrate active enzymes (CAZymes) are organized by primary and secondary scaffoldin proteins to generate large protein complexes attached to the bacterial cell wall. This study demonstrates that C. thermocellum also uses a type of cellulosomal system not bound to the bacterial cell wall, called the "cell-free" cellulosomal system. The cell-free cellulosome complex can be seen as a "long range cellulosome" because it can diffuse away from the cell and degrade polysaccharide substrates remotely from the bacterial cell. The contribution of these two types of cellulosomal systems in C. thermocellum was elucidated by characterization of mutants with different combinations of scaffoldin gene deletions. The primary scaffoldin, CipA, was found to play the most important role in cellulose degradation by C. thermocellum, whereas the secondary scaffoldins have less important roles. Additionally, the distinct and efficient mode of action of the C. thermocellum exoproteome, wherein the cellulosomes splay or divide biomass particles, changes when either the primary or secondary scaffolds are removed, showing that the intact wild-type cellulosomal system is necessary for this essential mode of action. This new transcriptional and proteomic evidence shows that a functional primary scaffoldin plays a more important role compared to secondary scaffoldins in the proper regulation of CAZyme genes, cellodextrin transport, and other cellular functions.

Efficiency in Rule- vs. Plan-Based Movements Is Modulated by Action-Mode

PubMed Central

Scheib, Jean P. P.; Stoll, Sarah; Thürmer, J. Lukas; Randerath, Jennifer

2018-01-01

The rule/plan motor cognition (RPMC) paradigm elicits visually indistinguishable motor outputs, resulting from either plan- or rule-based action-selection, using a combination of essentially interchangeable stimuli. Previous implementations of the RPMC paradigm have used pantomimed movements to compare plan- vs. rule-based action-selection. In the present work we attempt to determine the generalizability of previous RPMC findings to real object interaction by use of a grasp-to-rotate task. In the plan task, participants had to use prospective planning to achieve a comfortable post-handle rotation hand posture. The rule task used implementation intentions (if-then rules) leading to the same comfortable end-state. In Experiment A, we compare RPMC performance of 16 healthy participants in pantomime and real object conditions of the experiment, within-subjects. Higher processing efficiency of rule- vs. plan-based action-selection was supported by diffusion model analysis. Results show a significant response-time increase in the pantomime condition compared to the real object condition and a greater response-time advantage of rule-based vs. plan-based actions in the pantomime compared to the real object condition. In Experiment B, 24 healthy participants performed the real object RPMC task in a task switching vs. a blocked condition. Results indicate that plan-based action-selection leads to longer response-times and less efficient information processing than rule-based action-selection in line with previous RPMC findings derived from the pantomime action-mode. Particularly in the task switching mode, responses were faster in the rule compared to the plan task suggesting a modulating influence of cognitive load. Overall, results suggest an advantage of rule-based action-selection over plan-based action-selection; whereby differential mechanisms appear to be involved depending on the action-mode. We propose that cognitive load is a factor that modulates the advantageous effect of implementation intentions in motor cognition on different levels as illustrated by the varying speed advantages and the variation in diffusion parameters per action-mode or condition, respectively. PMID:29593612

THE REACTIVE OXYGEN SPECIES (ROS) THEORY OF ARSENIC CARCINOGENESIS

EPA Science Inventory

At this time, there is not a scientific consensus on the mechanisms/modes of action for arsenic carcinogenesis. Proposed mechanisms/modes of action for arsenic carcinogenesis include but are not limited to clastogenic effects, mutation, oxidative stress (via ROS and other chemic...

OXIDATIVE STRESS AS A POSSIBLE MODE OF ACTION FOR ARSENIC CARCINOGENESIS

EPA Science Inventory

Abstract

Many modes of action for arsenic carcinogenesis have been proposed, but few theories have a substantial mass of supporting data. Three stronger theories of arsenic carcinogenesis are production of chromosomal abnormalities, promotion of carcinogenesis and oxidati...

Remembering to Prepare: The Benefits (and Costs) of High Working Memory Capacity

ERIC Educational Resources Information Center

Richmond, Lauren L.; Redick, Thomas S.; Braver, Todd S.

2015-01-01

The dual mechanisms of control framework postulates that cognitive control can operate in 2 distinct modes: a "proactive" preparatory mode and a "reactive" wait-and-see mode. Importantly, the 2 modes are associated with both costs and benefits in cognitive performance. Here we explore this framework, in terms of its…

Evidence for sparse synergies in grasping actions.

PubMed

Prevete, Roberto; Donnarumma, Francesco; d'Avella, Andrea; Pezzulo, Giovanni

2018-01-12

Converging evidence shows that hand-actions are controlled at the level of synergies and not single muscles. One intriguing aspect of synergy-based action-representation is that it may be intrinsically sparse and the same synergies can be shared across several distinct types of hand-actions. Here, adopting a normative angle, we consider three hypotheses for hand-action optimal-control: sparse-combination hypothesis (SC) - sparsity in the mapping between synergies and actions - i.e., actions implemented using a sparse combination of synergies; sparse-elements hypothesis (SE) - sparsity in synergy representation - i.e., the mapping between degrees-of-freedom (DoF) and synergies is sparse; double-sparsity hypothesis (DS) - a novel view combining both SC and SE - i.e., both the mapping between DoF and synergies and between synergies and actions are sparse, each action implementing a sparse combination of synergies (as in SC), each using a limited set of DoFs (as in SE). We evaluate these hypotheses using hand kinematic data from six human subjects performing nine different types of reach-to-grasp actions. Our results support DS, suggesting that the best action representation is based on a relatively large set of synergies, each involving a reduced number of degrees-of-freedom, and that distinct sets of synergies may be involved in distinct tasks.

Prediction error induced motor contagions in human behaviors.

PubMed

Ikegami, Tsuyoshi; Ganesh, Gowrishankar; Takeuchi, Tatsuya; Nakamoto, Hiroki

2018-05-29

Motor contagions refer to implicit effects on one's actions induced by observed actions. Motor contagions are believed to be induced simply by action observation and cause an observer's action to become similar to the action observed. In contrast, here we report a new motor contagion that is induced only when the observation is accompanied by prediction errors - differences between actions one observes and those he/she predicts or expects. In two experiments, one on whole-body baseball pitching and another on simple arm reaching, we show that the observation of the same action induces distinct motor contagions, depending on whether prediction errors are present or not. In the absence of prediction errors, as in previous reports, participants' actions changed to become similar to the observed action, while in the presence of prediction errors, their actions changed to diverge away from it, suggesting distinct effects of action observation and action prediction on human actions. © 2018, Ikegami et al.

Spontaneous bacteriocin resistance in Listeria monocytogenes as a susceptibility screen for identifying different mechanisms of resistance and modes of action by bacteriocins of lactic acid bacteria.

PubMed

Macwana, Sunita; Muriana, Peter M

2012-01-01

A practical system was devised for grouping bacteriocins of lactic acid bacteria (LAB) based on mode of action as determined by changes in inhibitory activity to spontaneously-acquired bacteriocin resistance (Bac(R)). Wild type Listeria monocytogenes 39-2 was sensitive to five bacteriocins produced by 3 genera of LAB: pediocin PA-1 and pediocin Bac3 (Pediococcus), lacticin FS97 and lacticin FS56 (Lactococcus), and curvaticin FS47 (Lactobacillus). A spontaneous Bac(R) derivative of L. monocytogenes 39-2 obtained by selective recovery against lacticin FS56 provided complete resistance to the bacteriocin made by Lactococcus lactis FS56. The lacticin FS56-resistant strain of L. monocyotgenes 39-2 was also cross-resistant to curvaticin FS47 and pediocin PA-1, but not to lacticin FS97 or pediocin Bac3. The same pattern of cross-resistance was also observed with Bac(R) isolates obtained with L. monocytogenes Scott A-2. A spontaneous mutation that renders a strain cross-resistant to different bacteriocins indicates that they share a common mechanism of resistance due to similar modes of action of the bacteriocins. Spontaneous resistance was acquired to other bacteriocins (in aggregate) by following the same procedure against which the Bac(R) strain was still sensitive. In subsequent challenge assays, mixtures of bacteriocins of different modes of action provided greater inhibition than mixtures of bacteriocins of the same mode of action (as determined by our screening method). This study identifies a methodical approach to classify bacteriocins into functional groups based on mechanism of resistance (i.e., mode of action) that could be used for identifying the best mixture of bacteriocins for use as biopreservatives. Copyright © 2011 Elsevier B.V. All rights reserved.

New developments in the evolution and application of the WHO/IPCS framework on mode of action/species concordance analysis.

PubMed

Meek, M E; Boobis, A; Cote, I; Dellarco, V; Fotakis, G; Munn, S; Seed, J; Vickers, C

2014-01-01

The World Health Organization/International Programme on Chemical Safety mode of action/human relevance framework has been updated to reflect the experience acquired in its application and extend its utility to emerging areas in toxicity testing and non-testing methods. The underlying principles have not changed, but the framework's scope has been extended to enable integration of information at different levels of biological organization and reflect evolving experience in a much broader range of potential applications. Mode of action/species concordance analysis can also inform hypothesis-based data generation and research priorities in support of risk assessment. The modified framework is incorporated within a roadmap, with feedback loops encouraging continuous refinement of fit-for-purpose testing strategies and risk assessment. Important in this construct is consideration of dose-response relationships and species concordance analysis in weight of evidence. The modified Bradford Hill considerations have been updated and additionally articulated to reflect increasing experience in application for cases where the toxicological outcome of chemical exposure is known. The modified framework can be used as originally intended, where the toxicological effects of chemical exposure are known, or in hypothesizing effects resulting from chemical exposure, using information on putative key events in established modes of action from appropriate in vitro or in silico systems and other lines of evidence. This modified mode of action framework and accompanying roadmap and case examples are expected to contribute to improving transparency in explicitly addressing weight of evidence considerations in mode of action/species concordance analysis based on both conventional data sources and evolving methods. Copyright © 2013 John Wiley & Sons, Ltd. The World Health Organization retains copyright and all other rights in the manuscript of this article as submitted for publication.

THE REACTIVE OXYGEN SPECIES (ROS) THEORY OF ARSENIC CARCINOGENESIS

EPA Science Inventory

Arsenic is a human carcinogen in skin, lung, liver, urinary bladder
and kidney. At this time, there is not a scientific consensus on the
mechanisms/modes of action for arsenic carcinogenesis. Proposed
mechanisms/modes of action for arsenic carcinogenesi...

Mode of Action (MOA) Assignment Classifications for Ecotoxicology: An Evaluation of approaches

EPA Science Inventory

The mode of toxic action (MOA) is recognized as a key determinant of chemical toxicity and as an alternative to chemical class-based predictive toxicity modeling. However, MOA classification has never been standardized in ecotoxicology, and a comprehensive comparison of classific...

Discovering modes of action for therapeutic compounds using a genome-wide screen of yeast heterozygotes.

PubMed

Lum, Pek Yee; Armour, Christopher D; Stepaniants, Sergey B; Cavet, Guy; Wolf, Maria K; Butler, J Scott; Hinshaw, Jerald C; Garnier, Philippe; Prestwich, Glenn D; Leonardson, Amy; Garrett-Engele, Philip; Rush, Christopher M; Bard, Martin; Schimmack, Greg; Phillips, John W; Roberts, Christopher J; Shoemaker, Daniel D

2004-01-09

Modern medicine faces the challenge of developing safer and more effective therapies to treat human diseases. Many drugs currently in use were discovered without knowledge of their underlying molecular mechanisms. Understanding their biological targets and modes of action will be essential to design improved second-generation compounds. Here, we describe the use of a genome-wide pool of tagged heterozygotes to assess the cellular effects of 78 compounds in Saccharomyces cerevisiae. Specifically, lanosterol synthase in the sterol biosynthetic pathway was identified as a target of the antianginal drug molsidomine, which may explain its cholesterol-lowering effects. Further, the rRNA processing exosome was identified as a potential target of the cell growth inhibitor 5-fluorouracil. This genome-wide screen validated previously characterized targets or helped identify potentially new modes of action for over half of the compounds tested, providing proof of this principle for analyzing the modes of action of clinically relevant compounds.

A Mini HIP HOP Assay Uncovers a Central Role for Copper and Zinc in the Antifungal Mode of Action of Allicin.

PubMed

Prescott, Thomas A K; Panaretou, Barry

2017-05-10

Garlic contains the organosulfur compound allicin which exhibits potent antifungal activity. Here we demonstrate the use of a highly simplified yeast chemical genetic screen to characterize its mode of action. By screening 24 validated yeast gene deletion "signature" strains for which hypersensitivity is characteristic for common antifungal modes of action, yeast lacking the high affinity Cu 2+ transporter Ctr1 was found to be hypersensitive to allicin. Focusing on transition metal related genes identified two more hypersensitive strains lacking the Cu 2+ and Zn 2+ transcription factors Mac1 and Zap1. Hypersensitivity in these strains was reversed by the addition of Cu 2+ and Zn 2+ ions, respectively. The results suggest the antifungal activity of allicin is mediated through restricted Cu 2+ and Zn 2+ uptake or inhibition of Cu 2+ and Zn 2+ metalloproteins. As certain antimicrobial modes of action are much more common than others, the approach taken here provides a useful way to identify them early on.

Unrelated solubility-enhancing fusion partners MBP and NusA utilize a similar mode of action

PubMed Central

Raran-Kurussi, Sreejith; Waugh, David S.

2014-01-01

The tendency of recombinant proteins to accumulate in the form of insoluble aggregates in Escherichia coli is a major hindrance to their overproduction. One of the more effective approaches to circumvent this problem is to use translation fusion partners (solubility-enhancers, SEs). E. coli maltose binding protein (MBP) and N-utilization substance A (NusA) are arguably the most effective solubilizing agents that have been discovered so far. Here, we show that although these two proteins are structurally, functionally, and physiochemically distinct, they influence the solubility and folding of their fusion partners in a very similar manner. These SEs act as “holdases” that prevent the aggregation of their fusion partners. Subsequent folding of the passenger proteins, when it occurs, is either spontaneous or chaperone-mediated. PMID:24942647

Antimalarials inhibit hematin crystallization by unique drug–surface site interactions

PubMed Central

Olafson, Katy N.; Nguyen, Tam Q.; Rimer, Jeffrey D.; Vekilov, Peter G.

2017-01-01

In malaria pathophysiology, divergent hypotheses on the inhibition of hematin crystallization posit that drugs act either by the sequestration of soluble hematin or their interaction with crystal surfaces. We use physiologically relevant, time-resolved in situ surface observations and show that quinoline antimalarials inhibit β-hematin crystal surfaces by three distinct modes of action: step pinning, kink blocking, and step bunch induction. Detailed experimental evidence of kink blocking validates classical theory and demonstrates that this mechanism is not the most effective inhibition pathway. Quinolines also form various complexes with soluble hematin, but complexation is insufficient to suppress heme detoxification and is a poor indicator of drug specificity. Collectively, our findings reveal the significance of drug–crystal interactions and open avenues for rationally designing antimalarial compounds. PMID:28559329

Homology Models of Melatonin Receptors: Challenges and Recent Advances

PubMed Central

Pala, Daniele; Lodola, Alessio; Bedini, Annalida; Spadoni, Gilberto; Rivara, Silvia

2013-01-01

Melatonin exerts many of its actions through the activation of two G protein-coupled receptors (GPCRs), named MT1 and MT2. So far, a number of different MT1 and MT2 receptor homology models, built either from the prototypic structure of rhodopsin or from recently solved X-ray structures of druggable GPCRs, have been proposed. These receptor models differ in the binding modes hypothesized for melatonin and melatonergic ligands, with distinct patterns of ligand-receptor interactions and putative bioactive conformations of ligands. The receptor models will be described, and they will be discussed in light of the available information from mutagenesis experiments and ligand-based pharmacophore models. The ability of these ligand-receptor complexes to rationalize structure-activity relationships of known series of melatonergic compounds will be commented upon. PMID:23584026

The effects of stress on attentional resources

NASA Technical Reports Server (NTRS)

Hancock, P. A.; Chignell, M. H.

1986-01-01

A new perspective is presented from which to view the action of stress on human behavior. At a behavioral level, the action of stress is related to notions of human attention and an indication of an isomorphic relationship between modes of control at a physiological and behavioral level is presented. Examples of this phenomenon are extracted from performance under heat stress, since this is one of the most simple stress circumstances. It is suggested that stress sufficient to overcome adaptive capability, that is efficient homeostasis, acts to drain attentional resources. The manner in which such resources fail approximates that function typical of a positive feedback system, which also characterizes the breakdown of physiological response under severe environmental stress. The end point of this draining sequence is the absence of all attentional resources, which is taken to be unconsciousness, to be rapidly followed by the failure of physiological adaptability upon which life sustaining functions depend. This overall picture preserves the inverted-U shaped relationship between stress and performance, yet is in distinct contrast to the traditional arousal account of such behavior. The theoretical and practical ramifications of these observations are explored.

Microbiota-based Signature of Gingivitis Treatments: A Randomized Study.

PubMed

Huang, Shi; Li, Zhen; He, Tao; Bo, Cunpei; Chang, Jinlan; Li, Lin; He, Yanyan; Liu, Jiquan; Charbonneau, Duane; Li, Rui; Xu, Jian

2016-04-20

Plaque-induced gingivitis can be alleviated by various treatment regimens. To probe the impacts of various anti-gingivitis treatments on plaque microflora, here a double blinded, randomized controlled trial of 91 adults with moderate gingivitis was designed with two anti-gingivitis regimens: the brush-alone treatment and the brush-plus-rinse treatment. In the later group, more reduction in both Plaque Index (TMQHI) and Gingival Index (mean MGI) at Day 3, Day 11 and Day 27 was evident, and more dramatic changes were found between baseline and other time points for both supragingival plaque microbiota structure and salivary metabonomic profiles. A comparison of plaque microbiota changes was also performed between these two treatments and a third dataset where 50 subjects received regimen of dental scaling. Only Actinobaculum, TM7 and Leptotrichia were consistently reduced by all the three treatments, whereas the different microbial signatures of the three treatments during gingivitis relieve indicate distinct mechanisms of action. Our study suggests that microbiota based signatures can serve as a valuable approach for understanding and potentially comparing the modes of action for clinical treatments and oral-care products in the future.

Microbiota-based Signature of Gingivitis Treatments: A Randomized Study

PubMed Central

Huang, Shi; Li, Zhen; He, Tao; Bo, Cunpei; Chang, Jinlan; Li, Lin; He, Yanyan; Liu, Jiquan; Charbonneau, Duane; Li, Rui; Xu, Jian

2016-01-01

Plaque-induced gingivitis can be alleviated by various treatment regimens. To probe the impacts of various anti-gingivitis treatments on plaque microflora, here a double blinded, randomized controlled trial of 91 adults with moderate gingivitis was designed with two anti-gingivitis regimens: the brush-alone treatment and the brush-plus-rinse treatment. In the later group, more reduction in both Plaque Index (TMQHI) and Gingival Index (mean MGI) at Day 3, Day 11 and Day 27 was evident, and more dramatic changes were found between baseline and other time points for both supragingival plaque microbiota structure and salivary metabonomic profiles. A comparison of plaque microbiota changes was also performed between these two treatments and a third dataset where 50 subjects received regimen of dental scaling. Only Actinobaculum, TM7 and Leptotrichia were consistently reduced by all the three treatments, whereas the different microbial signatures of the three treatments during gingivitis relieve indicate distinct mechanisms of action. Our study suggests that microbiota based signatures can serve as a valuable approach for understanding and potentially comparing the modes of action for clinical treatments and oral-care products in the future. PMID:27094556

Bodily-visual practices and turn continuation

PubMed Central

Ford, Cecilia E.; Thompson, Sandra A.; Drake, Veronika

2012-01-01

This paper considers points in turn construction where conversation researchers have shown that talk routinely continues beyond possible turn completion, but where we find bodily-visual behavior doing such turn extension work. The bodily-visual behaviors we examine share many features with verbal turn extensions, but we argue that embodied movements have distinct properties that make them well-suited for specific kinds of social action, including stance display and by-play in sequences framed as subsidiary to a simultaneous and related verbal exchange. Our study is in line with a research agenda taking seriously the point made by Goodwin (2000a, b, 2003), Hayashi (2003, 2005), Iwasaki (2009), and others that scholars seeking to account for practices in language and social interaction do themselves a disservice if they privilege the verbal dimension; rather, as suggested in Stivers/Sidnell (2005), each semiotic system/modality, while coordinated with others, has its own organization. With the current exploration of bodily-visual turn extensions, we hope to contribute to a growing understanding of how these different modes of organization are managed concurrently and in concert by interactants in carrying out their everyday social actions. PMID:23526861

dRGT theory of massive gravity from spontaneous symmetry breaking

NASA Astrophysics Data System (ADS)

Torabian, Mahdi

2018-05-01

In this note we propose a topological action for a Poincare times diffeomorphism invariant gauge theory. We show that there is Higgs phase where the gauge symmetry is spontaneous broken to a diagonal Lorentz subgroup and gives the Einstein-Hilbert action plus the dRGT potential terms. In this vacuum, there are five (three from Goldstone modes) propagating degrees of freedom which form polarizations of a massive spin 2 particle, an extra healthy heavy scalar (Higgs) mode and no Boulware-Deser ghost mode. We further show that the action can be derived in a limit from a topological de Sitter invariant gauge theory in 4 dimensions.

Lattice gauge action suppressing near-zero modes of H{sub W}

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

Fukaya, Hidenori; Hashimoto, Shoji; Kaneko, Takashi

2006-11-01

We propose a lattice action including unphysical Wilson fermions with a negative mass m{sub 0} of the order of the inverse lattice spacing. With this action, the exact zero mode of the Hermitian Wilson-Dirac operator H{sub W}(m{sub 0}) cannot appear and near-zero modes are strongly suppressed. By measuring the spectral density {rho}({lambda}{sub W}), we find a gap near {lambda}{sub W}=0 on the configurations generated with the standard and improved gauge actions. This gap provides a necessary condition for the proof of the exponential locality of the overlap-Dirac operator by Hernandez, Jansen, and Luescher. Since the number of near-zero modes ismore » small, the numerical cost to calculate the matrix sign function of H{sub W}(m{sub 0}) is significantly reduced, and the simulation including dynamical overlap fermions becomes feasible. We also introduce a pair of twisted mass pseudofermions to cancel the unwanted higher mode effects of the Wilson fermions. The gauge coupling renormalization due to the additional fields is then minimized. The topological charge measured through the index of the overlap-Dirac operator is conserved during continuous evolutions of gauge field variables.« less

Neuropeptides as Regulators of Behavior in Insects.

PubMed

Schoofs, Liliane; De Loof, Arnold; Van Hiel, Matthias Boris

2017-01-31

Neuropeptides are by far the largest and most diverse group of signaling molecules in multicellular organisms. They are ancient molecules important in regulating a multitude of processes. Their small proteinaceous character allowed them to evolve and radiate quickly into numerous different molecules. On average, hundreds of distinct neuropeptides are present in animals, sometimes with unique classes that do not occur in distantly related species. Acting as neurotransmitters, neuromodulators, hormones, or growth factors, they are extremely diverse and are involved in controlling growth, development, ecdysis, digestion, diuresis, and many more physiological processes. Neuropeptides are also crucial in regulating myriad behavioral actions associated with feeding, courtship, sleep, learning and memory, stress, addiction, and social interactions. In general, behavior ensures that an organism can survive in its environment and is defined as any action that can change an organism's relationship to its surroundings. Even though the mode of action of neuropeptides in insects has been vigorously studied, relatively little is known about most neuropeptides and only a few model insects have been investigated. Here, we provide an overview of the roles neuropeptides play in insect behavior. We conclude that multiple neuropeptides need to work in concert to coordinate certain behaviors. Additionally, most neuropeptides studied to date have more than a single function.

Comparison of Global and Mode of Action-Based Models for Aquatic Toxicity

EPA Science Inventory

The ability to estimate aquatic toxicity for a wide variety of chemicals is a critical need for ecological risk assessment and chemical regulation. The consensus in the literature is that mode of action (MOA) based QSAR (Quantitative Structure Activity Relationship) models yield ...

Mode of Action for Reproductive and Hepatic Toxicity Inferred from a Genomic Study of Triazole Antifungals

EPA Science Inventory

The mode of action for the reproductive toxicity of triazole antifungals have been previously characterized by an observed increased in serum testosterone, hepatotoxicity, and reduced insemination and fertility indices. In order to refine our mechanistic understanding of these m...

Mode of Action Profiles for Pesticide Compounds with Rodent Liver Tumor Outcomes

EPA Science Inventory

Mode of action (MOA) provides a central framework for assessing human relevance of adverse health outcomes observed in nonclinical safety studies. The goal of this study was to characterize MOA profiles for known rodent liver tumorigens identified from a database of pesticides as...

Use of Gene Expression Changes in Blood to Elucidate Mechanistic Indicators of Childhood Asthma (MICA)

EPA Science Inventory

Risk assessment increasingly relies more heavily on mode of action, thus the identification of human bioindicators of disease becomes all the more important. Genomic methods represent a tool for both mode of action determination and bioindicator identification. The Mechanistic In...

U.S. EPA framework for determining mutagenic mode of action for carcinogens

EPA Science Inventory

U.S. EPA's Guidelines for Carcinogen Risk Assessment (Cancer Guidelines) specify that information on a chemical's mode of action (MOA) is key to the risk assessment process. MOA determines conditions under which a chemical is considered to be carcinogenic, appropriate low dose ex...

A Critical Review of Mode of Action (MOA) Assignment Classifications for Ecotoxicology

EPA Science Inventory

There are various structure-based classification schemes to categorize chemicals based on mode of action (MOA) which have been applied for both eco and human health toxicology. With increasing calls to assess thousands of chemicals, some of which have little available informatio...

INSIGHTS INTO THE CARCINOGENIC MODE OF ACTION OF ARSENIC

EPA Science Inventory

That arsenic can induce cancer in humans has been known since the late 17th century, yet how arsenic induces cancer has been the subject of numerous scientific publications. Various modes of action (MOA) have been proposed for arsenic's carcinogenicity. In this paper we review o...

A TOXICOLOGICAL VIEW OF ISSUES AND APPROACHES

EPA Science Inventory

Mode of action (MOA) is a powerful approach which can be used to improve extrapolations and understanding of relevance from studies of animals to humans, to inform differential susceptible states, and from high to low doses. In using mode of action, a key event is identified whi...

ARSENIC MODE OF ACTION AND DEVELOPING A BBDR MODEL

EPA Science Inventory

The current USEPA cancer risk assessment for inorganic arsenic is based on a linear extrapolation of the epidemiological data from exposed populations in Taiwan. However, proposed key events in the mode of action (MoA) for arsenic-induced cancer (which may include altered DNA me...

Computational Chemistry-based Acute Aquatic Toxicity Mode of Action Assignment

EPA Science Inventory

The ability to determine the mode of action (MOA) for a diverse group of chemicals is a critical part of ecological risk assessment and chemical regulation. However, existing MOA assignment approaches in ecotoxicology have been limited to a relatively few MOAs, have high uncertai...

Systems Biology & Mode of Action Based Risk Assessment

EPA Science Inventory

The application of systems biology for risk assessment of environmental chemicals is a national extension of its use in pharmaceutical research. The basis for this is the concept of a key event network that builds on existing mode of action frameworks for risk assessment. The a...

Consistency of FMEA used in the validation of analytical procedures.

PubMed

Oldenhof, M T; van Leeuwen, J F; Nauta, M J; de Kaste, D; Odekerken-Rombouts, Y M C F; Vredenbregt, M J; Weda, M; Barends, D M

2011-02-20

In order to explore the consistency of the outcome of a Failure Mode and Effects Analysis (FMEA) in the validation of analytical procedures, an FMEA was carried out by two different teams. The two teams applied two separate FMEAs to a High Performance Liquid Chromatography-Diode Array Detection-Mass Spectrometry (HPLC-DAD-MS) analytical procedure used in the quality control of medicines. Each team was free to define their own ranking scales for the probability of severity (S), occurrence (O), and detection (D) of failure modes. We calculated Risk Priority Numbers (RPNs) and we identified the failure modes above the 90th percentile of RPN values as failure modes needing urgent corrective action; failure modes falling between the 75th and 90th percentile of RPN values were identified as failure modes needing necessary corrective action, respectively. Team 1 and Team 2 identified five and six failure modes needing urgent corrective action respectively, with two being commonly identified. Of the failure modes needing necessary corrective actions, about a third were commonly identified by both teams. These results show inconsistency in the outcome of the FMEA. To improve consistency, we recommend that FMEA is always carried out under the supervision of an experienced FMEA-facilitator and that the FMEA team has at least two members with competence in the analytical method to be validated. However, the FMEAs of both teams contained valuable information that was not identified by the other team, indicating that this inconsistency is not always a drawback. Copyright © 2010 Elsevier B.V. All rights reserved.

Z mode radiation in Jupiter's magnetosphere - The source of Jovian continuum radiation

NASA Technical Reports Server (NTRS)

Barbosa, D. D.; Kurth, W. S.; Moses, S. L.; Scarf, F. L.

1990-01-01

Observations of Z-mode waves in Jupiter's magnetosphere are analyzed. The assumption that the frequency of the intensity minimum, which isolates the signal, corresponds to the electron plasma frequency provides a consistent interpretation of all spectral features in terms of plasma resonances and cutoffs. It is shown that the continuum radiation is composed of both left-hand and right-hand polarized waves with distinct cutoffs observed at the plasma frequency and right-hand cutoff frequency, respectively. It is found that the Z-mode peak frequency lies close to the left-hand cutoff frequency, suggesting that the observed characteristics of the emission are the result of wave reflection at the cutoff layer. Another distinct emission occurring near the upper hybrid resonance frequency is detected simultaneously with the Z mode. The entire set of observations gives strong support to the linear mode theory of the conversion of upper hybrid waves to continuum radiation mediated by the Z mode via the Budden radio window mechanism.

Botulinum toxin: A review of the mode of action in migraine.

PubMed

Do, T P; Hvedstrup, J; Schytz, H W

2018-05-01

Botulinum toxin serotype A (BoNT/A) was originally used in neurology for the treatment of dystonia and blepharospasms, but is now clinically used worldwide for the treatment of chronic migraine. Still, the possible mode of action of BoNT/A in migraine is not fully known. However, the mode of action of BoNT/A has been investigated in experimental pain as well as migraine models, which may elucidate the underlying mechanisms in migraine. The aim of this study was to review studies on the possible mode of action of BoNT/A in relation to chronic migraine treatment. Observations suggest that the mode of action of BoNT/A may not be limited to the injection site, but also includes anatomically connected sites due to axonal transport. The mechanisms behind the effect of BoNT/A in chronic migraine may also include modulation of neurotransmitter release, changes in surface expression of receptors and cytokines as well as enhancement of opioidergic transmission. Clinical and experimental studies with botulinum toxin in the last decade have advanced our understanding of headache and other pain states. More research into botulinum toxin as treatment for headache is warranted as it can be an attractive alternative for patients who do not respond positively to other drugs. © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

First-principles study of crystallographic slip modes in ω-Zr

DOE PAGES

Kumar, Anil; Kumar, M. Arul; Beyerlein, Irene Jane

2017-08-21

We use first-principles density functional theory to study the preferred modes of slip in the high-pressure ω phase of Zr. The generalized stacking fault energy surfaces associated with shearing on nine distinct crystallographic slip modes in the hexagonal ω-Zr crystal are calculated, from which characteristics such as ideal shear stress, the dislocation Burgers vector, and possible accompanying atomic shuffles, are extracted. Comparison of energy barriers and ideal shear stresses suggests that the favorable modes are prismatic < c >, prismatic-II <101¯0> and pyramidal-II < c+a >, which are distinct from the ground state hexagonal close packed α phase of Zr.more » Operation of these three modes can accommodate any deformation state. The relative preferences among the identified slip modes are examined using a mean-field crystal plasticity model and comparing the calculated deformation texture with the measurement. In conclusion, knowledge of the basic crystallographic modes of slip is critical to understanding and analyzing the plastic deformation behavior of ω-Zr or mixed α-ω phase-Zr.« less

MODE OF ACTION: NEUROTOXICITY INDUCED BY THYROID HORMONE DISRUPTION DURING DEVELOPMENT - HEARING LOSS RESULTING FROM EXPOSURE TO PHAHS.

EPA Science Inventory

A manuscript summarizes a workshop aimed at developing a framework to determine the relevancy of animal modes-of-action for extrapolation to humans. This specific report used animal data on the neurodevelopmental effects of hypothyroidism to test the framework. Propylthiouracil,...

Predicting modes of toxic action from chemical structure

EPA Science Inventory

Like many of the papers in the ET&C top 100 list, the development of the fathead minnow database and the assignment of modes of action to the 617 chemicals therein was the result of a comprehensive research effort by a multidisciplinary team of researchers with expertise in quant...

An evaluation of the mode of action framework for mutagenic carcinogens: chromium (VI)

EPA Science Inventory

In response to the 2005 revised U.S Environmental Protection Agency’s (EPA) Cancer Guidelines, a strategy is being developed to determine whether a carcinogen operates through a mutagenic mode of action (MOA). This information is necessary for EPA to decide whether age-dependent ...

Discovery of new herbicide modes of action with natural phytotoxins

USDA-ARS?s Scientific Manuscript database

About 20 modes of action (MOAs) are utilized by commercial herbicides, and almost 30 years have passed since the last new MOA was introduced. Rapidly increasing evolution of resistance to herbicides with these MOAs has greatly increased the need for herbicides with new MOAs. Combinatorial chemistry ...

Development of a Quantitative Model Incorporating Key Events in a Hepatoxic Mode of Action to Predict Tumor Incidence

EPA Science Inventory

Biologically-Based Dose Response (BBDR) modeling of environmental pollutants can be utilized to inform the mode of action (MOA) by which compounds elicit adverse health effects. Chemicals that produce tumors are typically described as either genotoxic or non-genotoxic. One common...

Relationships between aquatic toxicity, chemical hydrophobicity and mode of action: log kow QSARs revisited

EPA Science Inventory

Relationships between chemical hydrophobicity and toxicity have been shown for nearly 100 years in both mammals and fish, typically using the log of the octanol:water partition coefficient (kow). The current study reassessed the influence of mode of action (MOA) on aquatic toxici...

Mode of action of insect repellents

USDA-ARS?s Scientific Manuscript database

The mode of action of DEET and other insect repellents has been a topic of interest since the discovery of DEET in the mid twentieth century. Nearly 60 years have passed since DEET applied topically to the skin was shown to be effective in preventing mosquito bites. With the discovery and characte...

An evaluation of the mode of action framework for mutagenic carcinogens: Chromium (VI): SOT.

EPA Science Inventory

In response to the 2005 revised U.S Environmental Protection Agency’s (EPA) Cancer Guidelines, a strategy is being developed to determine whether a carcinogen operates through a mutagenic mode of action (MOA). This information is necessary for EPA to decide whether age-dependent ...

MODE OF ACTION: NEUROTOXICITY INDUCED BY DEVELOPMENTAL THYROID HORMONE INSUFFICIENCY -- NEUROLOGICAL ABNORMALITIES RESULTING FROM EXPOSURE TO PROPYLTHIOURACIL.

EPA Science Inventory

A manuscript summarizes a workshop aimed at developing a framework to determine the relevancy of animal modes-of-action for extrapolation to humans. This specific report used animal data on neurodevelopmental effects of thyroid hormone disruption to test the framework. Polyhaloge...

MOAtox: A comprehensive mode of action and acute aquatic toxicity database for predictive model development (SETAC abstract)

EPA Science Inventory

The mode of toxic action (MOA) has been recognized as a key determinant of chemical toxicity and as an alternative to chemical class-based predictive toxicity modeling. However, the development of quantitative structure activity relationship (QSAR) and other models has been limit...

MOAtox: A Comprehensive Mode of Action and Acute Aquatic Toxicity Database for Predictive Model Development

EPA Science Inventory

tThe mode of toxic action (MOA) has been recognized as a key determinant of chemical toxicity andas an alternative to chemical class-based predictive toxicity modeling. However, the development ofquantitative structure activity relationship (QSAR) and other models has been limite...

Mode of Action (MOA) Assignment Classifications for Ecotoxicology: Evaluation of Available Methods

EPA Science Inventory

There are various structure-based classification schemes to categorize chemicals based on mode of action (MOA) which have been applied for both eco and human toxicology. With increasing calls to assess 1000s of chemicals, some of which have little available information other tha...

Prediction of aquatic toxicity mode of action using linear discriminant and random forest models

EPA Science Inventory

The ability to determine the mode of action (MOA) for a diverse group of chemicals is a critical part of ecological risk assessment and chemical regulation. However, existing MOA assignment approaches in ecotoxicology have been limited to a relatively few MOAs, have high uncertai...

Semiotic Work: Applied Linguistics and a Social Semiotic Account of Multimodality

ERIC Educational Resources Information Center

Kress, Gunther

2015-01-01

This article imagines a tussle between Multimodality, focused on "modes," and Applied Linguistics (AL), based on "language." A Social Semiotic approach to MM treats "speech" and "writing" as modes with distinct affordances, and, as all modes, treats them as "partial" means of communication. The…

Dopamine transport by the serotonin transporter: a mechanistically distinct mode of substrate translocation

PubMed Central

Larsen, Mads Breum; Sonders, Mark S.; Mortensen, Ole Valente; Larson, Gaynor A.; Zahniser, Nancy R.; Amara, Susan G.

2011-01-01

The serotonin transporter (SERT) is the principal mechanism for terminating serotonin (5HT) signals in the nervous system and is a site of action for a variety of psychoactive drugs including antidepressants, amphetamines, and cocaine. Here we show that human SERTs (hSERTs) and rat SERTs are capable of robust dopamine (DA) uptake through a process that differs mechanistically from 5HT transport in several unanticipated ways. DA transport by hSERT has a higher maximum velocity than 5HT transport, requires significantly higher Na+ and Cl− concentrations to sustain transport, is inhibited non-competitively by 5HT and is more sensitive to SERT inhibitors, including selective serotonin reuptake inhibitors (SSRIs). We use a thiol reactive methane thiosulfonate (MTS) reagent to modify a conformationally-sensitive cysteine residue to demonstrate that hSERT spends more time in an outward facing conformation when transporting DA than when transporting 5HT. Co-transfection of an inactive or an MTS-sensitive SERT with wild type SERT subunits reveals an absence of cooperative interactions between subunits during DA, but not 5HT transport. To establish the physiological relevance of this mechanism for DA clearance, we show using in vivo high-speed chronoamperometry that SERT has the capacity to clear extracellularly applied DA in the hippocampal CA3 region of anesthetized rats. Together, these observations suggest the possibility that SERT serves as a DA transporter in vivo and highlight the idea that there can be distinct modes of transport of alternative physiological substrates by SERT. PMID:21525301

Educational Modes of Thinking in Neo-Confucianism: A Traditional Lens for Rethinking Modern Education

ERIC Educational Resources Information Center

Hwang, Keumjoong

2013-01-01

This article discusses the distinctive educational modes of thinking in Neo-Confucianism, with an interest of extracting Confucian reflective views for modern education of traditionally Confucian East Asia. Neo-Confucian typical modes of thinking on education are characterized as "heart-mind centered" and "learning as…

Confucian Rationalism

ERIC Educational Resources Information Center

Lam, Chi-Ming

2014-01-01

Nowadays, there is still a widely held view that the Chinese and Western modes of thought are quite distinct from each other. In particular, the Chinese mode of thought derived from Confucianism is considered as comparatively less rational than the Western one. In this article, I first argue that although the analogical mode of argumentation,…

Efficacy and mode of action of an immunomodulator herbal preparation containing Echinacea, wild indigo, and white cedar.

PubMed

Wüstenberg, P; Henneicke-von Zepelin, H H; Köhler, G; Stammwitz, U

1999-01-01

Using the example of an allopathic herbal combined preparation containing Echinacea root, wild indigo root, and white cedar leaf tips (Echinaceae radix + Baptisiae tinctoriae radix + Thujae occidentalis herba = Esberitox N), the efficacy and mode of action of a phytoimmunomodulator, or immune system enhancer, is described. Efficacy of the immunomodulator has been demonstrated in studies of acute viral respiratory tract infections and infections requiring antibiotic therapy. In a recent study compliant to GCP, the therapeutic superiority of the herbal immunomodulator over placebo was confirmed as statistically significant and clinically relevant. The present overview describes a model of the antigen-independent mode of action of phytoimmunomodulation ("immunobalancing").

Neurotoxicity of Persistent Organic Pollutants: Possible Mode(s) of Action and Further Considerations

PubMed Central

Kodavanti, Prasada Rao S.

2005-01-01

Persistent organic pollutants (POPs) are long-lived toxic organic compounds and are of major concern for human and ecosystem health. Although the use of most POPs is banned in most countries, some organochlorine pesticides are still being used in several parts of the world. Although environmental levels of some POPs such as polychlorinated biphenyls (PCBs) have declined, newly emerging POPs such as polybrominated diphenyl ethers (PBDEs) have been increasing considerably. Exposure to POPs has been associated with a wide spectrum of effects including reproductive, developmental, immunologic, carcinogenic, and neurotoxic effects. It is of particular concern that neurotoxic effects of some POPs have been observed in humans at low environmental concentrations. This review focuses on PCBs as a representative chemical class of POPs and discusses the possible mode(s) of action for the neurotoxic effects with emphasis on comparing dose-response and structure-activity relationships (SAR) with other structurally related chemicals. There is sufficient epidemiological and experimental evidence showing that PCB exposure is associated with motor and cognitive deficits in humans and animal models. Although several potential mode(s) of actions were postulated for PCB-induced neurotoxic effects, changes in neurotransmitter systems, altered intracellular signalling processes, and thyroid hormone imbalance are predominant ones. These three potential mechanisms are discussed in detail in vitro and in vivo. In addition, SAR was conducted on other structurally similar chemicals to see if they have a common mode(s) of action. Relative potency factors for several of these POPs were calculated based on their effects on intracellular signalling processes. This is a comprehensive review comparing molecular effects at the cellular level to the neurotoxic effects seen in the whole animal for environmentally relevant POPs. PMID:18648619

Functional genomic approaches for understanding the mode of action of Bacillus sp biocontrol strains

USDA-ARS?s Scientific Manuscript database

Complete genome sequencing of several Bacillus sp. strains has shed new light on the mode of action of these antagonists of plant pathogens. The use of genomic data mining tools provided the ability to quickly determine the potential of these strains to produce bioactive secondary metabolites. Our B...

Triclosan Decreases Rat Thyroxine: Mode-of-Action, Developmental Susceptibility and Human Relevance

EPA Science Inventory

Triclosan (TCS) decreases serum thyroxine (T4) in the rat. In vivo and in vitro approaches were used to address three uncertainties: by what mode-of-action (MOA) does TCS decrease T4; does TCS decrease T4 developmentally; and, are effects observed in rats relevant to humans? To t...

Triclosan Disrupts Thyroxine: Contribution of Hepatic Transport to the Mode of Action

EPA Science Inventory

Triclosan (5-chloro-2-(2,4-dichlorophenoxy)phenol) (TCS) decreases serum thyroxine (T4) in rats. In previous work, TCS upregulated Phase I and II hepatic metabolism after 4-day exposures in rats. A major data gap in our characterization of the mode of action (MOA) of TCS-induced ...

Developmental Triclosan Exposure Decreases Maternal,Fetal, and Early Neonatal Thyroxine: Dynamic and Kinetic Data Support for a Mode-of-Action

EPA Science Inventory

This work tests the mode-of-action (MOA) hypothesis that perinatal triclosan (TCS) exposure decreases circulating thyroxine (T4) concentrations via activation of pregnane X and/or constitutive androstane receptors (PXR, CAR), resulting in up-regulation of hepatic catabolism and e...

USE OF BIOLOGICALLY BASED COMPUTATIONAL MODELING IN MODE OF ACTION-BASED RISK ASSESSMENT – AN EXAMPLE OF CHLOROFORM

EPA Science Inventory

The objective of current work is to develop a new cancer dose-response assessment for chloroform using a physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) model. The PBPK/PD model is based on a mode of action in which the cytolethality of chloroform occurs when the ...

Transcriptional profile of diurnon-induces toxicity on the urinary bladder of male wistar rats to inform mode of action

EPA Science Inventory

Diuron (3-(3,4-dichlorophenyl)-1,1-dimethylurea) is a substituted urea herbicide that induces rat urinary bladder urothelial tumors at high dietary levels (2500 ppm). The specific mode of action and molecular alterations triggered by diuron, however, have not been clarified. Th...

Evaluation of key events in the mode of action for a carry-over carcinogen in mice

EPA Science Inventory

Evaluation of key events in the mode of action for a carry-over carcinogen in mice Charles E. Wood, April D. Lake, Greg Olson, Michael H. George, Susan D. Hester, Anthony B. DeAngelo Introduction: Early life environmental exposures are established determinants for adverse health...

Cognitive Restructuring in the Treatment of Social Phobia: Efficacy and Mode of Action.

ERIC Educational Resources Information Center

Taylor, Steven; Woody, Sheila; Koch, William J.; McLean, Peter; Paterson, Randy J.; Anderson, Kent W.

1997-01-01

Examines whether cognitive restructuring (CR) contributes to treatment efficacy and investigates its mode of action for therapeutic effects. Results, based on 60 persons with generalized social phobia, indicate that CR reduced social phobia and negative social cognitions and increased positive cognitions. CR did not enhance the effects of…

77 FR 58213 - Actions on Special Permit Applications

Federal Register 2010, 2011, 2012, 2013, 2014

2012-09-19

... DEPARTMENT OF TRANSPORTATION Pipeline and Hazardous Materials Safety Administration Actions on.... ACTION: Notice of actions on Special Permit Applications. SUMMARY: In accordance with the procedures... actions on special permits applications in (August to August 2012). The mode of transportation involved...

Nonlinear optics in the LP(02) higher-order mode of a fiber.

PubMed

Chen, Y; Chen, Z; Wadsworth, W J; Birks, T A

2013-07-29

The distinct disperion properties of higher-order modes in optical fibers permit the nonlinear generation of radiation deeper into the ultraviolet than is possible with the fundamental mode. This is exploited using adiabatic, broadband mode convertors to couple light efficiently from an input fundamental mode and also to return the generated light to an output fundamental mode over a broad spectral range. For example, we generate visible and UV supercontinuum light in the LP(02) mode of a photonic crystal fiber from sub-ns pulses with a wavelength of 532 nm.

Scalable Active Optical Access Network Using Variable High-Speed PLZT Optical Switch/Splitter

NASA Astrophysics Data System (ADS)

Ashizawa, Kunitaka; Sato, Takehiro; Tokuhashi, Kazumasa; Ishii, Daisuke; Okamoto, Satoru; Yamanaka, Naoaki; Oki, Eiji

This paper proposes a scalable active optical access network using high-speed Plumbum Lanthanum Zirconate Titanate (PLZT) optical switch/splitter. The Active Optical Network, called ActiON, using PLZT switching technology has been presented to increase the number of subscribers and the maximum transmission distance, compared to the Passive Optical Network (PON). ActiON supports the multicast slot allocation realized by running the PLZT switch elements in the splitter mode, which forces the switch to behave as an optical splitter. However, the previous ActiON creates a tradeoff between the network scalability and the power loss experienced by the optical signal to each user. It does not use the optical power efficiently because the optical power is simply divided into 0.5 to 0.5 without considering transmission distance from OLT to each ONU. The proposed network adopts PLZT switch elements in the variable splitter mode, which controls the split ratio of the optical power considering the transmission distance from OLT to each ONU, in addition to PLZT switch elements in existing two modes, the switching mode and the splitter mode. The proposed network introduces the flexible multicast slot allocation according to the transmission distance from OLT to each user and the number of required users using three modes, while keeping the advantages of ActiON, which are to support scalable and secure access services. Numerical results show that the proposed network dramatically reduces the required number of slots and supports high bandwidth efficiency services and extends the coverage of access network, compared to the previous ActiON, and the required computation time for selecting multicast users is less than 30msec, which is acceptable for on-demand broadcast services.

SU-E-T-87: A TG-100 Approach for Quality Improvement of Associated Dosimetry Equipment

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

Manger, R; Pawlicki, T; Kim, G

2015-06-15

Purpose: Dosimetry protocols devote so much time to the discussion of ionization chamber choice, use and performance that is easy to forget about the importance of the associated dosimetry equipment (ADE) in radiation dosimetry - barometer, thermometer, electrometer, phantoms, triaxial cables, etc. Improper use and inaccuracy of these devices may significantly affect the accuracy of radiation dosimetry. The purpose of this study is to evaluate the risk factors in the monthly output dosimetry procedure and recommend corrective actions using a TG-100 approach. Methods: A failure mode and effects analysis (FMEA) of the monthly linac output check procedure was performed tomore » determine which steps and failure modes carried the greatest risk. In addition, a fault tree analysis (FTA) was performed to expand the initial list of failure modes making sure that none were overlooked. After determining the failure modes with the highest risk priority numbers (RPNs), 11 physicists were asked to score corrective actions based on their ease of implementation and potential impact. The results were aggregated into an impact map to determine the implementable corrective actions. Results: Three of the top five failure modes were related to the thermometer and barometer. The two highest RPN-ranked failure modes were related to barometric pressure inaccuracy due to their high lack-of-detectability scores. Six corrective actions were proposed to address barometric pressure inaccuracy, and the survey results found the following two corrective actions to be implementable: 1) send the barometer for recalibration at a calibration laboratory and 2) check the barometer accuracy against the local airport and correct for elevation. Conclusion: An FMEA on monthly output measurements displayed the importance of ADE for accurate radiation dosimetry. When brainstorming for corrective actions, an impact map is helpful for visualizing the overall impact versus the ease of implementation.« less

The partially filled viscous ring damper.

NASA Technical Reports Server (NTRS)

Alfriend, K. T.

1973-01-01

The problem of a spinning satellite with a partially filled viscous ring damper is investigated. It is shown that there are two distinct modes of motion, the nutation-synchronous mode and spin-synchronous mode. From an approximate solution of the equations of motion a time constant is obtained for each mode. From a consideration of the fluid dynamics several methods are developed for determining the damping constant.

Segmenting Dynamic Human Action via Statistical Structure

ERIC Educational Resources Information Center

Baldwin, Dare; Andersson, Annika; Saffran, Jenny; Meyer, Meredith

2008-01-01

Human social, cognitive, and linguistic functioning depends on skills for rapidly processing action. Identifying distinct acts within the dynamic motion flow is one basic component of action processing; for example, skill at segmenting action is foundational to action categorization, verb learning, and comprehension of novel action sequences. Yet…

Toxicity of 13 different antibiotics towards freshwater green algae Pseudokirchneriella subcapitata and their modes of action.

PubMed

Fu, Ling; Huang, Tao; Wang, Shuo; Wang, Xiaohong; Su, Limin; Li, Chao; Zhao, Yuanhui

2017-02-01

Although modes of action (MOAs) play a key role in the understanding of the toxic mechanism of chemicals, the MOAs have not been investigated for antibiotics to green algae. This paper is to discriminate excess toxicity from baseline level and investigate the MOAs of 13 different antibiotics to algae by using the determined toxicity values. Comparison of the toxicities shows that the inhibitors of protein synthesis to bacteria, such as azithromycin, doxycycline, florfenicol and oxytetracycline, exhibit significantly toxic effects to algae. On the other hand, the cell wall synthesis inhibitors, such as cefotaxime and amoxicillin, show relatively low toxic effects to the algae. The concentrations determined by HPLC indicate that quinocetone and amoxicillin can be easily photodegraded or hydrolyzed during the toxic tests. The toxic effects of quinocetone and amoxicillin to the algae are attributed to not only their parent compounds, but also their metabolites. Investigation on the mode of action shows that, except rifampicin, all the tested antibiotics exhibit excess toxicity to Pseudokirchneriella subcapitata (P. subcapitata). These antibiotics can be identified as reactive modes of action to the algae. They act as electrophilic mechanism of action to P. subcapitata. These results are valuable for the understanding of the toxic mechanism to algae. Copyright © 2016 Elsevier Ltd. All rights reserved.

77 FR 42360 - Actions on Special Permit Applications

Federal Register 2010, 2011, 2012, 2013, 2014

2012-07-18

... DEPARTMENT OF TRANSPORTATION Pipeline and Hazardous Materials Safety Administration Actions on... Safety Administration (PHMSA), DOT. ACTION: Notice of actions on Special Permit Applications. SUMMARY: In... given of the actions on special permits applications in (June to June 2012). The mode of transportation...

Dramatic performance of Clostridium thermocellum explained by its wide range of cellulase modalities

DOE PAGES

Xu, Qi; Resch, Michael G.; Podkaminer, Kara; ...

2016-02-05

Clostridium thermocellum is the most efficient microorganism for solubilizing lignocellulosic biomass known to date. Its high cellulose digestion capability is attributed to efficient cellulases consisting of both a free-enzyme system and a tethered cellulosomal system wherein carbohydrate active enzymes (CAZymes) are organized by primary and secondary scaffoldin proteins to generate large protein complexes attached to the bacterial cell wall. This study demonstrates that C. thermocellum also uses a type of cellulosomal system not bound to the bacterial cell wall, called the “cell-free” cellulosomal system. The cell-free cellulosome complex can be seen as a “long range cellulosome” because it can diffusemore » away from the cell and degrade polysaccharide substrates remotely from the bacterial cell. The contribution of these two types of cellulosomal systems in C. thermocellum was elucidated by characterization of mutants with different combinations of scaffoldin gene deletions. The primary scaffoldin, CipA, was found to play the most important role in cellulose degradation by C. thermocellum, whereas the secondary scaffoldins have less important roles. Additionally, the distinct and efficient mode of action of the C. thermocellum exoproteome, wherein the cellulosomes splay or divide biomass particles, changes when either the primary or secondary scaffolds are removed, showing that the intact wild-type cellulosomal system is necessary for this essential mode of action. As a result, this new transcriptional and proteomic evidence shows that a functional primary scaffoldin plays a more important role compared to secondary scaffoldins in the proper regulation of CAZyme genes, cellodextrin transport, and other cellular functions.« less

Dramatic performance of Clostridium thermocellum explained by its wide range of cellulase modalities

PubMed Central

Xu, Qi; Resch, Michael G.; Podkaminer, Kara; Yang, Shihui; Baker, John O.; Donohoe, Bryon S.; Wilson, Charlotte; Klingeman, Dawn M.; Olson, Daniel G.; Decker, Stephen R.; Giannone, Richard J.; Hettich, Robert L.; Brown, Steven D.; Lynd, Lee R.; Bayer, Edward A.; Himmel, Michael E.; Bomble, Yannick J.

2016-01-01

Clostridium thermocellum is the most efficient microorganism for solubilizing lignocellulosic biomass known to date. Its high cellulose digestion capability is attributed to efficient cellulases consisting of both a free-enzyme system and a tethered cellulosomal system wherein carbohydrate active enzymes (CAZymes) are organized by primary and secondary scaffoldin proteins to generate large protein complexes attached to the bacterial cell wall. This study demonstrates that C. thermocellum also uses a type of cellulosomal system not bound to the bacterial cell wall, called the “cell-free” cellulosomal system. The cell-free cellulosome complex can be seen as a “long range cellulosome” because it can diffuse away from the cell and degrade polysaccharide substrates remotely from the bacterial cell. The contribution of these two types of cellulosomal systems in C. thermocellum was elucidated by characterization of mutants with different combinations of scaffoldin gene deletions. The primary scaffoldin, CipA, was found to play the most important role in cellulose degradation by C. thermocellum, whereas the secondary scaffoldins have less important roles. Additionally, the distinct and efficient mode of action of the C. thermocellum exoproteome, wherein the cellulosomes splay or divide biomass particles, changes when either the primary or secondary scaffolds are removed, showing that the intact wild-type cellulosomal system is necessary for this essential mode of action. This new transcriptional and proteomic evidence shows that a functional primary scaffoldin plays a more important role compared to secondary scaffoldins in the proper regulation of CAZyme genes, cellodextrin transport, and other cellular functions. PMID:26989779

Direct Activation of Epac by Sulfonylurea is Isoform Selective

PubMed Central

Herbst, Katie J.; Coltharp, Carla; Amzel, L. Mario; Zhang, Jin

2011-01-01

Summary Commonly used as a treatment for Type II diabetes, sulfonylureas (SUs) stimulate insulin secretion from pancreatic β cells by binding to sulfonylurea receptors. Recently, SUs have been shown to also activate exchange protein directly activated by cAMP 2 (Epac2), however little is known about this molecular action. Using biosensor imaging and biochemical analysis, we show that SUs activate Epac2 and the downstream signaling via direct binding to Epac2. We further identify R447 of Epac2 to be critically involved in SU binding. This distinct binding site from cAMP points to a new mode of allosteric activation of Epac2. We also show that SUs selectively activate Epac2 isoform, but not the closely related Epac1, further establishing SUs as a new class of isoform-selective enzyme activators. PMID:21338921

The polyene antifungals, amphotericin B and nystatin, cause cell death in Saccharomyces cerevisiae by a distinct mechanism to amphibian-derived antimicrobial peptides.

PubMed

Serhan, George; Stack, Colin M; Perrone, Gabriel G; Morton, Charles Oliver

2014-05-12

There is a pressing need to identify novel antifungal drug targets to aid in the therapy of life-threatening mycoses and overcome increasing drug resistance. Identifying specific mechanisms of action of membrane-interacting antimicrobial drugs on the model fungus Saccharomyces cerevisiae is one avenue towards addressing this issue. The S. cerevisiae deletion mutants Δizh2, Δizh3, Δaif1 and Δstm1 were demonstrated to be resistant to amphibian-derived antimicrobial peptides (AMPs). The purpose of this study was to examine whether AMPs and polyene antifungals have a similar mode of action; this was done by comparing the relative tolerance of the mutants listed above to both classes of antifungal. In support of previous findings on solid media it was shown that Δizh2 and Δizh3 mutants had increased resistance to both amphotericin B (1-2 μg ml-1) and nystatin (2.5 - 5 μg ml-1) in liquid culture, after acute exposure. However, Δaif1 and Δstm1 had wild-type levels of susceptibility to these polyenes. The generation of reactive oxygen species (ROS) after exposure to amphotericin B was also reduced in Δizh2 and Δizh3. These data indicated that polyene antifungal and AMPs may act via distinct mechanisms of inducing cell death in S. cerevisiae. Further understanding of the mechanism(s) involved in causing cell death and the roles of IZH2 and IZH3 in drug susceptibility may help to inform improved drug design and treatment of fungal pathogens.

Vibrational spectroscopy of metal methanesulfonates: M = Na, Cs, Cu, Ag, Cd

NASA Astrophysics Data System (ADS)

Parker, Stewart F.; Zhong, Lisha

2018-04-01

In this work, we have used a combination of vibrational spectroscopy (infrared, Raman and inelastic neutron scattering) and periodic density functional theory to investigate six metal methanesulfonate compounds that exhibit four different modes of complexation of the methanesulfonate ion: ionic, monodentate, bidentate and pentadentate. We found that the transition energies of the modes associated with the methyl group (C-H stretches and deformations, methyl rock and torsion) are essentially independent of the mode of coordination. The SO3 modes in the Raman spectra also show little variation. In the infrared spectra, there is a clear distinction between ionic (i.e. not coordinated) and coordinated forms of the methanesulfonate ion. This is manifested as a splitting of the asymmetric S-O stretch modes of the SO3 moiety. Unfortunately, no further differentiation between the various modes of coordination: unidentate, bidentate etc … is possible with the compounds examined. While it is likely that such a distinction could be made, this will require a much larger dataset of compounds for which both structural and spectroscopic data are available than that available here.

Lasing by driven atoms-cavity system in collective strong coupling regime.

PubMed

Sawant, Rahul; Rangwala, S A

2017-09-12

The interaction of laser cooled atoms with resonant light is determined by the natural linewidth of the excited state. An optical cavity is another optically resonant system where the loss from the cavity determines the resonant optical response of the system. The near resonant combination of an optical Fabry-Pérot cavity with laser cooled and trapped atoms couples two distinct optical resonators via light and has great potential for precision measurements and the creation of versatile quantum optics systems. Here we show how driven magneto-optically trapped atoms in collective strong coupling regime with the cavity leads to lasing at a frequency red detuned from the atomic transition. Lasing is demonstrated experimentally by the observation of a lasing threshold accompanied by polarization and spatial mode purity, and line-narrowing in the outcoupled light. Spontaneous emission into the cavity mode by the driven atoms stimulates lasing action, which is capable of operating as a continuous wave laser in steady state, without a seed laser. The system is modeled theoretically, and qualitative agreement with experimentally observed lasing is seen. Our result opens up a range of new measurement possibilities with this system.

A comparative study on pathological features of transgenic rat lines expressing either three or four repeat misfolded tau.

PubMed

Valachova, Bernadeta; Brezovakova, Veronika; Bugos, Ondrej; Jadhav, Santosh; Smolek, Tomas; Novak, Petr; Zilka, Norbert

2018-08-01

Human tauopathies represent a heterogeneous group of neurodegenerative disorders characterized by distinct clinical features, typical histopathological structures, and defined ratio(s) of three-repeat and four-repeat tau isoforms within pathological aggregates. How the optional microtubule-binding repeat of tau influences this differentiation of pathologies is understudied. We have previously generated and characterized transgenic rodent models expressing human truncated tau aa151-391 with either three (SHR24) or four microtubule-binding repeats (SHR72). Here, we compare the behavioral and neuropathological hallmarks of these two transgenic lines using a battery of tests for sensorimotor, cognitive, and neurological functions over the age range of 3.5-15 months. Progression of sensorimotor and neurological deficits was similar in both transgenic lines; however, the lifespan of transgenic line SHR72 expressing truncated four-repeat tau was markedly shorter than SHR24. Moreover, the expression of three or four-repeat tau induced distinct neurofibrillary pathology in these lines. Transgenic lines displayed different distribution of tau pathology and different type of neurofibrillary tangles. Our results suggest that three- and four-repeat isoforms of tau may display different modes of action in the diseased brain. © 2018 Wiley Periodicals, Inc.

Lechebnaia pedagogika: The Concept and Practice of Therapy in Russian Defectology, c. 1880–1936

PubMed Central

Byford, Andy

2018-01-01

Therapy is not simply a domain or form of medical practice, but also a metaphor for and a performance of medicine, of its functions and status, of its distinctive mode of action upon the world. This article examines medical treatment or therapy (in Russian lechenie), as concept and practice, in what came to be known in Russia as defectology (defektologiia) – the discipline and occupation concerned with the study and care of children with developmental pathologies, disabilities and special needs. Defectology formed an impure, occupationally ambiguous, therapeutic field, which emerged between different types of expertise in the niche populated by children considered ‘difficult to cure’, ‘difficult to teach’, and ‘difficult to discipline’. The article follows the multiple genealogy of defectological therapeutics in the medical, pedagogical and juridical domains, across the late tsarist and early Soviet eras. It argues that the distinctiveness of defectological therapeutics emerged from the tensions between its biomedical, sociopedagogical and moral-juridical framings, resulting in ambiguous hybrid forms, in which medical treatment strategically interlaced with education or upbringing, on the one hand, and moral correction, on the other. PMID:29199930

Developing Toxicogenomics as a Research Tool by Applying Benchmark Dose-Response Modeling to inform Chemical Mode of Action and Tumorigenic Potency

EPA Science Inventory

ABSTRACT Results of global gene expression profiling after short-term exposures can be used to inform tumorigenic potency and chemical mode of action (MOA) and thus serve as a strategy to prioritize future or data-poor chemicals for further evaluation. This compilation of cas...

A Typology of Actional-Operational Modes in Earth Science and Implications for Science Literacy Instruction

ERIC Educational Resources Information Center

Wilson, Amy Alexandra

2013-01-01

Framed in theories of social semiotics, this multiple case study describes and categorizes the actional-operational modes used by three middle school earth science teachers throughout the course of one school year. Data included fieldnotes, photographs, and video recordings of classroom instructions as well as periodic interviews with the…

Transcriptomic dose-and-time-course indicators of early key events in a cytotoxicity-mediated mode of action for rodent urinary bladder tumorigenesis

EPA Science Inventory

TRANSCRIPTOMIC DOSE- AND TIME-COURSE INDICATORS OF EARLY KEY EVENTS IN A CYTOTOXICITY-MEDIATED MODE OF ACTION FOR RODENT URINARY BLADDER TUMORIGENESISDiuron is a substituted urea compound used globally as an herbicide. Urinary bladder tumors were induced in rats after chronic die...

A Bayesian network model for predicting aquatic toxicity mode of action using two dimensional theoretical molecular descriptors

EPA Science Inventory

The mode of toxic action (MoA) has been recognized as a key determinant of chemical toxicity, but development of predictive MoA classification models in aquatic toxicology has been limited. We developed a Bayesian network model to classify aquatic toxicity MoA using a recently pu...

Odorant receptor modulation: Ternary paradigm for mode of action of insect repellents

USDA-ARS?s Scientific Manuscript database

The modulation of insect behavior for the purpose of controlling the spread of infectious diseases has been the task of a few insect repellents for which the mechanistic modes of action on odorant receptors (ORs) are unclear. Here, we study the effects of the repellents DEET and IR3535, and a novel ...

DOSE RESPONSE FROM HIGH THROUGHPUT GENE EXPRESSION STUDIES AND THE INFLUENCE OF TIME AND CELL LINE ON INFERRED MODE OF ACTION BY ONTOLOGIC ENRICHMENT (SOT)

EPA Science Inventory

Gene expression with ontologic enrichment and connectivity mapping tools is widely used to infer modes of action (MOA) for therapeutic drugs. Despite progress in high-throughput (HT) genomic systems, strategies suitable to identify industrial chemical MOA are needed. The L1000 is...

Use of Electroencephalography (EEG) to Assess CNS Changes Produced by Pesticides with different Modes of Action: Effects of Permethrin, Deltamethrin, Fipronil, Imidacloprid, Carbaryl, and Triadimefon

EPA Science Inventory

The electroencephalogram (EEG) is an apical measure, capable of detecting changes in brain neuronal activity produced by internal or external stimuli. We assessed whether pesticides with different modes of action produced different changes in the EEG of adult male Long-Evans rats...

SOME INSIGHTS INTO THE MODE OF ACTION OF BUTADIENE BY EXAMINING THE GENOTOXICITY OF ITS METABOLITES

EPA Science Inventory

1,3-Butadiene (BTD) is an important commodity chemical and air pollutant that has been shown to be a potent carcinogen in mice, and to a lesser extent, a carcinogen in rats. To better assess butadiene's carcinogenic risk to humans, it is important to understand its mode of action...

How important is thermodynamics for identifying elementary flux modes?

PubMed Central

Peres, Sabine; Jolicœur, Mario; Moulin, Cécile

2017-01-01

We present a method for computing thermodynamically feasible elementary flux modes (tEFMs) using equilibrium constants without need of internal metabolite concentrations. The method is compared with the method based on a binary distinction between reversible and irreversible reactions. When all reactions are reversible, adding the constraints based on equilibrium constants reduces the number of elementary flux modes (EFMs) by a factor of two. Declaring in advance some reactions as irreversible, based on reliable biochemical expertise, can in general reduce the number of EFMs by a greater factor. But, even in this case, computing tEFMs can rule out some EFMs which are biochemically irrelevant. We applied our method to two published models described with binary distinction: the monosaccharide metabolism and the central carbon metabolism of Chinese hamster ovary cells. The results show that the binary distinction is in good agreement with biochemical observations. Moreover, the suppression of the EFMs that are not consistent with the equilibrium constants appears to be biologically relevant. PMID:28222104

Improving the treatment planning and delivery process of Xoft electronic skin brachytherapy.

PubMed

Manger, Ryan; Rahn, Douglas; Hoisak, Jeremy; Dragojević, Irena

2018-05-14

To develop an improved Xoft electronic skin brachytherapy process and identify areas of further improvement. A multidisciplinary team conducted a failure modes and effects analysis (FMEA) by developing a process map and a corresponding list of failure modes. The failure modes were scored for their occurrence, severity, and detectability, and a risk priority number (RPN) was calculated for each failure mode as the product of occurrence, severity, and detectability. Corrective actions were implemented to address the higher risk failure modes, and a revised process was generated. The RPNs of the failure modes were compared between the initial process and final process to assess the perceived benefits of the corrective actions. The final treatment process consists of 100 steps and 114 failure modes. The FMEA took approximately 20 person-hours (one physician, three physicists, and two therapists) to complete. The 10 most dangerous failure modes had RPNs ranging from 336 to 630. Corrective actions were effective at addressing most failure modes (10 riskiest RPNs ranging from 189 to 310), yet the RPNs were higher than those published for alternative systems. Many of these high-risk failure modes remained due to hardware design limitations. FMEA helps guide process improvement efforts by emphasizing the riskiest steps. Significant risks are apparent when using a Xoft treatment unit for skin brachytherapy due to hardware limitations such as the lack of several interlocks, a short source lifespan, and variability in source output. The process presented in this article is expected to reduce but not eliminate these risks. Copyright © 2018 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.

The Statistics of Radio Astronomical Polarimetry: Disjoint, Superposed, and Composite Samples

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

Straten, W. van; Tiburzi, C., E-mail: willem.van.straten@aut.ac.nz

2017-02-01

A statistical framework is presented for the study of the orthogonally polarized modes of radio pulsar emission via the covariances between the Stokes parameters. To accommodate the typically heavy-tailed distributions of single-pulse radio flux density, the fourth-order joint cumulants of the electric field are used to describe the superposition of modes with arbitrary probability distributions. The framework is used to consider the distinction between superposed and disjoint modes, with particular attention to the effects of integration over finite samples. If the interval over which the polarization state is estimated is longer than the timescale for switching between two or moremore » disjoint modes of emission, then the modes are unresolved by the instrument. The resulting composite sample mean exhibits properties that have been attributed to mode superposition, such as depolarization. Because the distinction between disjoint modes and a composite sample of unresolved disjoint modes depends on the temporal resolution of the observing instrumentation, the arguments in favor of superposed modes of pulsar emission are revisited, and observational evidence for disjoint modes is described. In principle, the four-dimensional covariance matrix that describes the distribution of sample mean Stokes parameters can be used to distinguish between disjoint modes, superposed modes, and a composite sample of unresolved disjoint modes. More comprehensive and conclusive interpretation of the covariance matrix requires more detailed consideration of various relevant phenomena, including temporally correlated subpulse modulation (e.g., jitter), statistical dependence between modes (e.g., covariant intensities and partial coherence), and multipath propagation effects (e.g., scintillation and scattering).« less

Unraveling the Complexity of Critical Consciousness, Political Efficacy, and Political Action among Marginalized Adolescents

ERIC Educational Resources Information Center

Diemer, Matthew A.; Rapa, Luke J.

2016-01-01

This research examines the complex patterns by which distinct dimensions of critical consciousness may lead marginalized adolescents toward distinct forms of political action. Structural equation modeling was applied to nationally representative data from the Civic Education Study (2,811 ninth graders; M[subscript age] = 14.6), first establishing…

Individual differences in action co-representation: not personal distress or subclinical psychotic experiences but sex composition modulates joint action performance.

PubMed

van der Weiden, Anouk; Aarts, Henk; Prikken, Merel; van Haren, Neeltje E M

2016-02-01

Successful social interaction requires the ability to integrate as well as distinguish own and others' actions. Normally, the integration and distinction of self and other are a well-balanced process, occurring without much effort or conscious attention. However, not everyone is blessed with the ability to balance self-other distinction and integration, resulting in personal distress in reaction to other people's emotions or even a loss of self [e.g., in (subclinical) psychosis]. Previous research has demonstrated that the integration and distinction of others' actions cause interference with one's own action performance (commonly assessed with a social Simon task). The present study had two goals. First, as previous studies on the social Simon effect employed relatively small samples (N < 50 per test), we aimed for a sample size that allowed us to test the robustness of the action interference effect. Second, we tested to what extent action interference reflects individual differences in traits related to self-other distinction (i.e., personal distress in reaction to other people's emotions and subclinical psychotic symptoms). Based on a questionnaire study among a large sample (N = 745), we selected a subsample (N = 130) of participants scoring low, average, or high on subclinical psychotic symptoms, or on personal distress. The selected participants performed a social Simon task. Results showed a robust social Simon effect, regardless of individual differences in personal distress or subclinical psychotic symptoms. However, exploratory analyses revealed that the sex composition of interaction pairs modulated social Simon effects. Possible explanations for these findings are discussed.

Predicting drug-target interactions using restricted Boltzmann machines.

PubMed

Wang, Yuhao; Zeng, Jianyang

2013-07-01

In silico prediction of drug-target interactions plays an important role toward identifying and developing new uses of existing or abandoned drugs. Network-based approaches have recently become a popular tool for discovering new drug-target interactions (DTIs). Unfortunately, most of these network-based approaches can only predict binary interactions between drugs and targets, and information about different types of interactions has not been well exploited for DTI prediction in previous studies. On the other hand, incorporating additional information about drug-target relationships or drug modes of action can improve prediction of DTIs. Furthermore, the predicted types of DTIs can broaden our understanding about the molecular basis of drug action. We propose a first machine learning approach to integrate multiple types of DTIs and predict unknown drug-target relationships or drug modes of action. We cast the new DTI prediction problem into a two-layer graphical model, called restricted Boltzmann machine, and apply a practical learning algorithm to train our model and make predictions. Tests on two public databases show that our restricted Boltzmann machine model can effectively capture the latent features of a DTI network and achieve excellent performance on predicting different types of DTIs, with the area under precision-recall curve up to 89.6. In addition, we demonstrate that integrating multiple types of DTIs can significantly outperform other predictions either by simply mixing multiple types of interactions without distinction or using only a single interaction type. Further tests show that our approach can infer a high fraction of novel DTIs that has been validated by known experiments in the literature or other databases. These results indicate that our approach can have highly practical relevance to DTI prediction and drug repositioning, and hence advance the drug discovery process. Software and datasets are available on request. Supplementary data are available at Bioinformatics online.

Toward actionable science: Empowering ecologists to engage in the process of translation through decision-maker and stakeholder partnerships

NASA Astrophysics Data System (ADS)

Enquist, C.; Jackson, S. T.; Garfin, G. M.

2017-12-01

Translational ecology is an approach by which ecologists, stakeholders, and decision-makers work collaboratively to develop and deliver ecological research that, ideally, results in actionable science that leads to improved environmental decision-making. We analyzed a diverse array of real-world case studies and distilled six principles that characterize the practice of translational ecology: communication, commitment, collaboration, engagement, process, and decision-framing. In this talk, we highlight a subset of the case studies that illustrate these principles. Notably, we found that translational ecology is distinct from both basic and applied ecological research. As a practice, the approach deliberately extends research beyond theory or opportunistic applications, motivated by a search for outcomes that directly serve the needs of natural resource managers and decision-makers. Translational ecology is also distinct from knowledge co-production in that it does not require deep engagement between collaborators, although incorporating differing modes of co-production relative to the decision context, associated time frame, and available financial resources can greatly enhance the translational approach. Although there is a need for incentives to pursue in this type of work, we found that the creativity and context-specific knowledge of resource managers, practitioners, and decision-makers informs and enriches the scientific process, helping shape actionable science. Moreover, the process of addressing research questions arising from on-the-ground management issues, rather than from the top-down or expert-oriented perspectives of traditional science, can foster the long-term trust and commitment that is critical for long-term, sustained engagement between partners. Now, perhaps more than ever, the climate and environmental issues facing society are complex, often politicized, and value-laden. We argue that ecological science should play a key role in informing these problems and ecologists can engage as important partners committed to finding solutions. More broadly, scientists that embrace translational approaches are poised to make science-informed decision-making a reality in the face of a rapidly changing global environment.

Dendritic Slow Dynamics Enables Localized Cortical Activity to Switch between Mobile and Immobile Modes with Noisy Background Input

PubMed Central

Kurashige, Hiroki; Câteau, Hideyuki

2011-01-01

Mounting lines of evidence suggest the significant computational ability of a single neuron empowered by active dendritic dynamics. This motivates us to study what functionality can be acquired by a network of such neurons. The present paper studies how such rich single-neuron dendritic dynamics affects the network dynamics, a question which has scarcely been specifically studied to date. We simulate neurons with active dendrites networked locally like cortical pyramidal neurons, and find that naturally arising localized activity – called a bump – can be in two distinct modes, mobile or immobile. The mode can be switched back and forth by transient input to the cortical network. Interestingly, this functionality arises only if each neuron is equipped with the observed slow dendritic dynamics and with in vivo-like noisy background input. If the bump activity is considered to indicate a point of attention in the sensory areas or to indicate a representation of memory in the storage areas of the cortex, this would imply that the flexible mode switching would be of great potential use for the brain as an information processing device. We derive these conclusions using a natural extension of the conventional field model, which is defined by combining two distinct fields, one representing the somatic population and the other representing the dendritic population. With this tool, we analyze the spatial distribution of the degree of after-spike adaptation and explain how we can understand the presence of the two distinct modes and switching between the modes. We also discuss the possible functional impact of this mode-switching ability. PMID:21931635

A multiple-scenario assessment of the effect of a continuous-care, guideline-based decision support system on clinicians' compliance to clinical guidelines.

PubMed

Shalom, Erez; Shahar, Yuval; Parmet, Yisrael; Lunenfeld, Eitan

2015-04-01

To quantify the effect of a new continuous-care guideline (GL)-application engine, the Picard decision support system (DSS) engine, on the correctness and completeness of clinicians' decisions relative to an established clinical GL, and to assess the clinicians' attitudes towards a specific DSS. Thirty-six clinicians, including residents at different training levels and board-certified specialists at an academic OB/GYN department that handles around 15,000 deliveries annually, agreed to evaluate our continuous-care guideline-based DSS and to perform a cross-over assessment of the effects of using our guideline-based DSS. We generated electronic patient records that realistically simulated the longitudinal course of six different clinical scenarios of the preeclampsia/eclampsia/toxemia (PET) GL, encompassing 60 different decision points in total. Each clinician managed three scenarios manually without the Picard DSS engine (Non-DSS mode) and three scenarios when assisted by the Picard DSS engine (DSS mode). The main measures in both modes were correctness and completeness of actions relative to the PET GL. Correctness was further decomposed into necessary and redundant actions, relative to the guideline and the actual patient data. At the end of the assessment, a questionnaire was administered to the clinicians to assess their perceptions regarding use of the DSS. With respect to completeness, the clinicians applied approximately 41% of the GL's recommended actions in the non-DSS mode. Completeness increased to the performance of approximately 93% of the guideline's recommended actions, when using the DSS mode. With respect to correctness, approximately 94.5% of the clinicians' decisions in the non-DSS mode were correct. However, these included 68% of the actions that were correct but redundant, given the patient's data (e.g., repeating tests that had been performed), and 27% of the actions, which were necessary in the context of the GL and of the given scenario. Only 5.5% of the decisions were definite errors. In the DSS mode, 94% of the clinicians' decisions were correct, which included 3% that were correct but redundant, and 91% of the actions that were correct and necessary in the context of the GL and of the given scenario. Only 6% of the DSS-mode decisions were erroneous. The DSS was assessed by the clinicians as potentially useful. Support from the GL-based DSS led to uniformity in the quality of the decisions, regardless of the particular clinician, any particular clinical scenario, any particular decision point, or any decision type within the scenarios. Using the DSS dramatically enhances completeness (i.e., performance of guideline-based recommendations) and seems to prevent the performance of most of the redundant actions, but does not seem to affect the rate of performance of incorrect actions. The redundancy rate is enhanced by similar recent findings in recent studies. Clinicians mostly find this support to be potentially useful for their daily practice. A continuous-care GL-based DSS, such as the Picard DSS engine, has the potential to prevent most errors of omission by ensuring uniformly high quality of clinical decision making (relative to a GL-based norm), due to the increased adherence (i.e., completeness) to the GL, and most of the errors of commission that increase therapy costs, by reducing the rate of redundant actions. However, to prevent clinical errors of commission, the DSS needs to be accompanied by additional modules, such as automated control of the quality of the physician's actual actions. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Moral Judgment and Distributive Justice

ERIC Educational Resources Information Center

Gunzburger, David W.; And Others

1977-01-01

This research focused on the modes of distributive justice employed by individuals differing in the maturity of their moral judgments. Distinctions were made between five modes of distribution response: self interest, parity, equity, social responsibility, and individual responsibility. (MS)

Long Non-coding RNAs and their Role in Metastasis

PubMed Central

WEIDLE, ULRICH H; BIRZELE, FABIAN; KOLLMORGEN, GWEN; RÜGER, RÜDIGER

2017-01-01

The perception of long non-coding RNAs as chunk RNA and transcriptional noise has been steadily replaced by their role as validated targets for a diverse set of physiological processes in the past few years. However, for the vast majority of lncRNAs their precise mode of action and physiological function remain to be uncovered. A large body of evidence has revealed their essential role in all stages of cancirogenesis and metastasis. In this review we focus on the role of lncRNAs in metastasis. We grouped selected lncRNAs into three categories based on in vitro and in vivo mode of action-related studies and clinical relevance for metastasis. Grouped according to their mode of action, in category I we discuss lncRNAs such as CCAT2, DREH, LET, NKILA, treRNA, HOTAIR, H19, FENDRR, lincROR, MALAT, GClnc1, BCAR4, SCHLAP1 and lncRNA ATP, all lncRNAs with in vitro and in vivo metastasis-related data and clinical significance. In category II we discuss lncRNAs CCAT1, PCAT1, PTENgp1, GPLINC, MEG3, ZEB2-AS, LCT13, ANRIL, NBAT1 and lncTCF7 all characterized by their mode of action in vitro and clinical significance, but pending or preliminary in vivo data. Finally, under category III, we discuss lncRNAs BANCR, FRLnc1, SPRY4-IT1 and LIMT with partially or poorly-resolved mode of action and varying degree of validation in clinical metastasis. Finally we discuss metastasis-related translational aspects of lncRNAs. PMID:28446530

Meta-analysis of fish early life stage tests-Association of toxic ratios and acute-to-chronic ratios with modes of action.

PubMed

Scholz, Stefan; Schreiber, Rene; Armitage, James; Mayer, Philipp; Escher, Beate I; Lidzba, Annegret; Léonard, Marc; Altenburger, Rolf

2018-04-01

Fish early life stage (ELS) tests (Organisation for Economic Co-operation and Development test guideline 210) are widely conducted to estimate chronic fish toxicity. In these tests, fish are exposed from the embryonic to the juvenile life stages. To analyze whether certain modes of action are related to high toxic ratios (i.e., ratios between baseline toxicity and experimental effect) and/or acute-to-chronic ratios (ACRs) in the fish ELS test, effect concentrations (ECs) for 183 compounds were extracted from the US Environmental Protection Agency's ecotoxicity database. Analysis of ECs of narcotic compounds indicated that baseline toxicity could be observed in the fish ELS test at similar concentrations as in the acute fish toxicity test. All nonnarcotic modes of action were associated with higher toxic ratios, with median values ranging from 4 to 9.3 × 10 4 (uncoupling < reactivity < neuromuscular toxicity < methemoglobin formation < endocrine disruption < extracellular matrix formation inhibition). Four modes of action were also found to be associated with high ACRs: 1) lysyl oxidase inhibition leading to notochord distortion, 2) putative methemoglobin formation or hemolytic anemia, 3) endocrine disruption, and 4) compounds with neuromuscular toxicity. For the prediction of ECs in the fish ELS test with alternative test systems, endpoints targeted to the modes of action of compounds with enhanced toxic ratios or ACRs could be used to trigger fish ELS tests or even replace these tests. Environ Toxicol Chem 2018;37:955-969. © 2018 SETAC. © 2018 SETAC.

Properties and actions of bridged diphenyl acaricides.

PubMed Central

March, R B

1976-01-01

The properties and actions of the bridged diphenyl acaricides are discussed. These pesticides, which are more or less structurally related to DDT, were the first of the specific acaricides to be developed. They exhibit remarkable properties of specificity, being primarily toxic to phytophagous mites but of very low toxicity to most nontarget species, including insects, fish, birds, and mammals. Although many important facets of their broad mode of action are understood, virtually nothing is known of their primary mode of action or the underlying bases of their specificities. In most ways they are model compounds for integrated control and pest management activities and thus merit greater attention than they have received to elucidate the fundamentals underlying their unusual properties and actions. PMID:789071

Cross-Species Coherence in Effects and Modes of Action in Support of Causality Determinations in the U.S. Environmental Protection Agency’s Integrated Science Assessment for Lead

EPA Science Inventory

The peer-reviewed literature on the health and ecological effects of lead (Pb) indicates common effects and underlying modes of action across multiple organisms for several endpoints. Based on such observations, the United States Environmental Protection Agency (EPA) applied a cr...

Enzymatic modification of a model homogalacturonan with the thermally tolerant pectin methylesterase from citrus: I. Nanostructural characterization, enzyme mode of action and effect of pH

USDA-ARS?s Scientific Manuscript database

Methyl ester distribution in pectin homogalacturonan has a major influence on functionality. Enzymatic engineering of pectin nanostructure for tailoring functionality can expand pectin’s role as a food formulating agent and its in situ modification in prepared foods. We report on the mode of action ...

4-AMINOBIPHENYL & DNA REACTIVITY: CASE STUDY WITHIN THE CONTEXT OF THE 2006 IPCS HUMAN RELEVANCE FRAMEWORK FOR ANALYSIS OF A CANCER MODE OF ACTION FOR HUMANS

EPA Science Inventory

The IPCS Human Relevance Framework was evaluated for a DNA-reactive (genotoxic) carcinogen, 4-aminobiphenyl, based on a wealth of data in animals and humans. The mode of action involves metabolic activation by N-hydroxylation, followed by N-esterification leading to the formation...

Mesenchymal stem/stromal cells (MSCs): role as guardians of inflammation.

PubMed

Prockop, Darwin J; Oh, Joo Youn

2012-01-01

Recent observations have demonstrated that one of the functions of mesenchymal stem/stromal cells (MSCs) is to serve as guardians against excessive inflammatory responses. One mode of action of the cells is that they are activated to express the interleukin (IL)-1 receptor antagonist. A second mode of action is to create a negative feedback loop in which tumor necrosis factor-α (TNF-α) and other proinflammatory cytokines from resident macrophages activate MSCs to secrete the multifunctional anti-inflammatory protein TNF-α stimulated gene/protein 6 (TSG-6). The TSG-6 then reduces nuclear factor-κB (NF-κB) signaling in the resident macrophages and thereby modulates the cascade of proinflammatory cytokines. A third mode of action is to create a second negative feedback loop whereby lipopolysaccharide, TNF-α, nitric oxide, and perhaps other damage-associated molecular patterns (DAMPs) from injured tissues and macrophages activate MSCs to secrete prostaglandin E(2) (PGE(2)). The PGE(2) converts macrophages to the phenotype that secretes IL-10. There are also suggestions that MSCs may produce anti-inflammatory effects through additional modes of action including activation to express the antireactive oxygen species protein stanniocalcin-1.

Transient stimulation of distinct subpopulations of striatal neurons mimics changes in action value

PubMed Central

Tai, Lung-Hao; Lee, A. Moses; Benavidez, Nora; Bonci, Antonello; Wilbrecht, Linda

2012-01-01

In changing environments animals must adaptively select actions to achieve their goals. In tasks involving goal-directed action selection, striatal neural activity has been shown to represent the value of competing actions. Striatal representations of action value could potentially bias responses toward actions of higher value. However, no study to date has demonstrated the direct impact of distinct striatal pathways in goal-directed action selection. Here we show in mice that transient optogenetic stimulation of dorsal striatal dopamine D1 and D2 receptor-expressing neurons during decision-making introduces opposing biases in the distribution of choices. The effect of stimulation on choice is dependent on recent reward history and mimics an additive change in the action value. While stimulation prior to and during movement initiation produces a robust bias in choice behavior, this bias is significantly diminished when stimulation is delayed after response initiation. Together, our data demonstrate the role of striatal activity in goal-directed action selection. PMID:22902719

Comparison of modal superposition methods for the analytical solution to moving load problems.

DOT National Transportation Integrated Search

1994-01-01

The response of bridge structures to moving loads is investigated using modal superposition methods. Two distinct modal superposition methods are available: the modedisplacement method and the mode-acceleration method. While the mode-displacement met...

Evidence for multiple modes of neutrophil serine protease recognition by the EAP family of Staphylococcal innate immune evasion proteins.

PubMed

Stapels, Daphne A C; Woehl, Jordan L; Milder, Fin J; Tromp, Angelino T; van Batenburg, Aernoud A; de Graaf, Wilco C; Broll, Samuel C; White, Natalie M; Rooijakkers, Suzan H M; Geisbrecht, Brian V

2018-02-01

Neutrophils contain high levels of chymotrypsin-like serine proteases (NSPs) within their azurophilic granules that have a multitude of functions within the immune system. In response, the pathogen Staphylococcus aureus has evolved three potent inhibitors (Eap, EapH1, and EapH2) that protect the bacterium as well as several of its secreted virulence factors from the degradative action of NSPs. We previously showed that these so-called EAP domain proteins represent a novel class of NSP inhibitors characterized by a non-covalent inhibitory mechanism and a distinct target specificity profile. Based upon high levels of structural homology amongst the EAP proteins and the NSPs, as well as supporting biochemical data, we predicted that the inhibited complex would be similar for all EAP/NSP pairs. However, we present here evidence that EapH1 and EapH2 bind the canonical NSP, Neutrophil Elastase (NE), in distinct orientations. We discovered that alteration of EapH1 residues at the EapH1/NE interface caused a dramatic loss of affinity and inhibition of NE, while mutation of equivalent positions in EapH2 had no effect on NE binding or inhibition. Surprisingly, mutation of residues in an altogether different region of EapH2 severely impacted both the NE binding and inhibitory properties of EapH2. Even though EapH1 and EapH2 bind and inhibit NE and a second NSP, Cathepsin G, equally well, neither of these proteins interacts with the structurally related, but non-proteolytic granule protein, azurocidin. These studies expand our understanding of EAP/NSP interactions and suggest that members of this immune evasion protein family are capable of diverse target recognition modes. © 2017 The Protein Society.

A lesson from Bombinins H, mildly cationic diastereomeric antimicrobial peptides from Bombina skin.

PubMed

Mangoni, Maria Luisa

2013-12-01

Gene-encoded peptide antibiotics represent fascinating molecules for the development of new antimicrobials with a new mode of action: and one of the richest sources is amphibian skin. In particular, the skin of the fire-bellied toad Bombina genus contains mildly cationic antimicrobial peptides (AMPs), named bombinins H, with attractive properties. Indeed, some members of this peptide family coexist in skin secretions as isomers in which a single D-amino acid (alloisoleucine or leucine) is incorporated as a result of a post-translational modification of the respective gene-encoded Lamino acid. Here, a brief overview of the genes coding for these peptides, their spectrum of antimicrobial activities, mechanism of action and interactions with biological or model membranes is reported. Remarkably, a single D-amino acid substitution represents a unique approach developed by Nature not only to modulate the peptide stability in vivo, but also to confer the all-L peptide and its diastereomer distinctive biological features. Overall, such findings should assist in the generation of new peptide-based anti-infective agents, which are urgently needed because of the growing emergence of microbial strains resistant to conventional antimicrobials.

A monofunctional platinum(II)-based anticancer agent from a salicylanilide derivative: Synthesis, antiproliferative activity, and transcription inhibition.

PubMed

Wang, Beilei; Wang, Zhigang; Ai, Fujin; Tang, Wai Kin; Zhu, Guangyu

2015-01-01

Cationic monofunctional platinum(II)-based anticancer agents with a general formula of cis-[Pt(NH3)2(N-donor)Cl](+) have recently drawn significant attention due to their unique mode of action, distinctive anticancer spectrum, and promising antitumor activity both in vitro and in vivo. Understanding the mechanism of action of novel monofunctional platinum compounds through rational drug design will aid in the further development of active agents. In this study, we synthesized and evaluated a monofunctional platinum-based anticancer agent SA-Pt containing a bulky salicylanilide moiety. The antiproliferative activity of SA-Pt was close to that of cisplatin. Mechanism studies revealed that SA-Pt entered HeLa cells more efficiently than cisplatin, blocked the cell cycle at the S-phase, and induced apoptosis. The compound bound to DNA as effectively as cisplatin, but did not block RNA polymerase II-mediated transcription as strongly as cisplatin, indicating that once the compound formed Pt-DNA lesions, the salicylanilide group was more easily recognized and removed. This study not only enriches the family of monofunctional platinum-based anticancer agents but also guides the design of more potent monofunctional platinum complexes. Copyright © 2014 Elsevier Inc. All rights reserved.

The proposal of architecture for chemical splitting to optimize QSAR models for aquatic toxicity.

PubMed

Colombo, Andrea; Benfenati, Emilio; Karelson, Mati; Maran, Uko

2008-06-01

One of the challenges in the field of quantitative structure-activity relationship (QSAR) analysis is the correct classification of a chemical compound to an appropriate model for the prediction of activity. Thus, in previous studies, compounds have been divided into distinct groups according to their mode of action or chemical class. In the current study, theoretical molecular descriptors were used to divide 568 organic substances into subsets with toxicity measured for the 96-h lethal median concentration for the Fathead minnow (Pimephales promelas). Simple constitutional descriptors such as the number of aliphatic and aromatic rings and a quantum chemical descriptor, maximum bond order of a carbon atom divide compounds into nine subsets. For each subset of compounds the automatic forward selection of descriptors was applied to construct QSAR models. Significant correlations were achieved for each subset of chemicals and all models were validated with the leave-one-out internal validation procedure (R(2)(cv) approximately 0.80). The results encourage to consider this alternative way for the prediction of toxicity using QSAR subset models without direct reference to the mechanism of toxic action or the traditional chemical classification.

Aspects of a Distinct Cytotoxicity of Selenium Salts and Organic Selenides in Living Cells with Possible Implications for Drug Design.

PubMed

Estevam, Ethiene Castellucci; Witek, Karolina; Faulstich, Lisa; Nasim, Muhammad Jawad; Latacz, Gniewomir; Domínguez-Álvarez, Enrique; Kieć-Kononowicz, Katarzyna; Demasi, Marilene; Handzlik, Jadwiga; Jacob, Claus

2015-07-31

Selenium is traditionally considered as an antioxidant element and selenium compounds are often discussed in the context of chemoprevention and therapy. Recent studies, however, have revealed a rather more colorful and diverse biological action of selenium-based compounds, including the modulation of the intracellular redox homeostasis and an often selective interference with regulatory cellular pathways. Our basic activity and mode of action studies with simple selenium and tellurium salts in different strains of Staphylococcus aureus (MRSA) and Saccharomyces cerevisiae indicate that such compounds are sometimes not particularly toxic on their own, yet enhance the antibacterial potential of known antibiotics, possibly via the bioreductive formation of insoluble elemental deposits. Whilst the selenium and tellurium compounds tested do not necessarily act via the generation of Reactive Oxygen Species (ROS), they seem to interfere with various cellular pathways, including a possible inhibition of the proteasome and hindrance of DNA repair. Here, organic selenides are considerably more active compared to simple salts. The interference of selenium (and tellurium) compounds with multiple targets could provide new avenues for the development of effective antibiotic and anticancer agents which may go well beyond the traditional notion of selenium as a simple antioxidant.

Utility of Failure Mode and Effect Analysis to Improve Safety in Suctioning by Orotracheal Tube.

PubMed

Vázquez-Valencia, Agustín; Santiago-Sáez, Andrés; Perea-Pérez, Bernardo; Labajo-González, Elena; Albarrán-Juan, Maria Elena

2017-02-01

The objective of the study was to use the Failure Mode and Effect Analysis (FMEA) tool to analyze the technique of secretion suctioning on patients with an endotracheal tube who were admitted into an intensive care unit. Brainstorming was carried out within the service to determine the potential errors most frequent in the process. After this, the FMEA was applied, including its stages, prioritizing risk in accordance with the risk prioritization number (RPN), selecting improvement actions in which they have an RPN of more than 300. We obtained 32 failure modes, of which 13 surpassed an RPN of 300. After our result, 21 improvement actions were proposed for those failure modes with RPN scores above 300. FMEA allows us to ascertain possible failures so as to later propose improvement actions for those which have an RPN of more than 300. Copyright © 2016 American Society of PeriAnesthesia Nurses. Published by Elsevier Inc. All rights reserved.

Distinct neural substrates for visual short-term memory of actions.

PubMed

Cai, Ying; Urgolites, Zhisen; Wood, Justin; Chen, Chuansheng; Li, Siyao; Chen, Antao; Xue, Gui

2018-06-26

Fundamental theories of human cognition have long posited that the short-term maintenance of actions is supported by one of the "core knowledge" systems of human visual cognition, yet its neural substrates are still not well understood. In particular, it is unclear whether the visual short-term memory (VSTM) of actions has distinct neural substrates or, as proposed by the spatio-object architecture of VSTM, shares them with VSTM of objects and spatial locations. In two experiments, we tested these two competing hypotheses by directly contrasting the neural substrates for VSTM of actions with those for objects and locations. Our results showed that the bilateral middle temporal cortex (MT) was specifically involved in VSTM of actions because its activation and its functional connectivity with the frontal-parietal network (FPN) were only modulated by the memory load of actions, but not by that of objects/agents or locations. Moreover, the brain regions involved in the maintenance of spatial location information (i.e., superior parietal lobule, SPL) was also recruited during the maintenance of actions, consistent with the temporal-spatial nature of actions. Meanwhile, the frontoparietal network (FPN) was commonly involved in all types of VSTM and showed flexible functional connectivity with the domain-specific regions, depending on the current working memory tasks. Together, our results provide clear evidence for a distinct neural system for maintaining actions in VSTM, which supports the core knowledge system theory and the domain-specific and domain-general architectures of VSTM. © 2018 Wiley Periodicals, Inc.

Cortico-basal ganglia networks subserving goal-directed behavior mediated by conditional visuo-goal association

PubMed Central

Hoshi, Eiji

2013-01-01

Action is often executed according to information provided by a visual signal. As this type of behavior integrates two distinct neural representations, perception and action, it has been thought that identification of the neural mechanisms underlying this process will yield deeper insights into the principles underpinning goal-directed behavior. Based on a framework derived from conditional visuomotor association, prior studies have identified neural mechanisms in the dorsal premotor cortex (PMd), dorsolateral prefrontal cortex (dlPFC), ventrolateral prefrontal cortex (vlPFC), and basal ganglia (BG). However, applications resting solely on this conceptualization encounter problems related to generalization and flexibility, essential processes in executive function, because the association mode involves a direct one-to-one mapping of each visual signal onto a particular action. To overcome this problem, we extend this conceptualization and postulate a more general framework, conditional visuo-goal association. According to this new framework, the visual signal identifies an abstract behavioral goal, and an action is subsequently selected and executed to meet this goal. Neuronal activity recorded from the four key areas of the brains of monkeys performing a task involving conditional visuo-goal association revealed three major mechanisms underlying this process. First, visual-object signals are represented primarily in the vlPFC and BG. Second, all four areas are involved in initially determining the goals based on the visual signals, with the PMd and dlPFC playing major roles in maintaining the salience of the goals. Third, the cortical areas play major roles in specifying action, whereas the role of the BG in this process is restrictive. These new lines of evidence reveal that the four areas involved in conditional visuomotor association contribute to goal-directed behavior mediated by conditional visuo-goal association in an area-dependent manner. PMID:24155692

Sensitivity of species to chemicals: dose-response characteristics for various test types (coldbloodedLC50, cold-blooded LR50 and warm-blooded LD50) and modes of action

EPA Science Inventory

While sensitivity of model species to common toxicants has been addressed, a systematic analysis of inter-species variability for different test types, modes of action and species is as yet lacking. Hence, the aim of the present study was to identify similarities and differences ...

GENE EXPRESSION PROFILING IN TESTIS AND LIVER OF MICE TO IDENTIFY MODES OF ACTION OF CONAZOLE TOXICITIES

EPA Science Inventory

Gene Expression Profiling in Testis and Liver of Mice to Identify MODES OF ACTION OF Conazole TOXICITies

Amber K. Goetz1, Wenjun Bao2, Judith E. Schmid2, Carmen Wood2, Hongzu Ren2, Deborah S. Best2, Rachel N. Murrell1, John C. Rockett2, Michael G. Narotsky2, Douglas C. Wol...

Odorant Receptor Modulation: Ternary Paradigm for Mode of Action of Insect Repellents

DTIC Science & Technology

2012-01-01

Introduction Perception of chemicals in the environment by insects begins when compounds activate ionotropic receptors , gustatory recep- tors and odorant...Author’s personal copy Odorant receptor modulation: Ternary paradigm for mode of action of insect repellents Jonathan D. Bohbot, Joseph C. Dickens...Received in revised form 12 December 2011 Accepted 9 January 2012 Keywords: Odorant receptor Insect repellent Insurmountable antagonist Aedes aegypti

Resolving dual binding conformations of cellulosome cohesin-dockerin complexes using single-molecule force spectroscopy.

PubMed

Jobst, Markus A; Milles, Lukas F; Schoeler, Constantin; Ott, Wolfgang; Fried, Daniel B; Bayer, Edward A; Gaub, Hermann E; Nash, Michael A

2015-10-31

Receptor-ligand pairs are ordinarily thought to interact through a lock and key mechanism, where a unique molecular conformation is formed upon binding. Contrary to this paradigm, cellulosomal cohesin-dockerin (Coh-Doc) pairs are believed to interact through redundant dual binding modes consisting of two distinct conformations. Here, we combined site-directed mutagenesis and single-molecule force spectroscopy (SMFS) to study the unbinding of Coh:Doc complexes under force. We designed Doc mutations to knock out each binding mode, and compared their single-molecule unfolding patterns as they were dissociated from Coh using an atomic force microscope (AFM) cantilever. Although average bulk measurements were unable to resolve the differences in Doc binding modes due to the similarity of the interactions, with a single-molecule method we were able to discriminate the two modes based on distinct differences in their mechanical properties. We conclude that under native conditions wild-type Doc from Clostridium thermocellum exocellulase Cel48S populates both binding modes with similar probabilities. Given the vast number of Doc domains with predicted dual binding modes across multiple bacterial species, our approach opens up new possibilities for understanding assembly and catalytic properties of a broad range of multi-enzyme complexes.

Raman spectroscopy, electronic microscopy and SPME-GC-MS to elucidate the mode of action of a new antimicrobial food packaging material.

PubMed

Clemente, Isabel; Aznar, Margarita; Salafranca, Jesús; Nerín, Cristina

2017-02-01

One critical challenge when developing a new antimicrobial packaging material is to demonstrate the mode of action of the antimicrobials incorporated into the packaging. For this task, several analytical techniques as well as microbiology are required. In this work, the antimicrobial properties of benzyl isothiocyanate, allyl isothiocyanate and essential oils of cinnamon and oregano against several moulds and bacteria have been evaluated. Benzyl isothiocyanate showed the highest antimicrobial activity and it was selected for developing the new active packaging material. Scanning electron microscopy and Raman spectroscopy were successfully used to demonstrate the mode of action of benzyl isothiocyanate on Escherichia coli. Bacteria exhibited external modifications such as oval shape and the presence of septum surface, but they did not show any disruption or membrane damage. To provide data on the in vitro action of benzyl isothiocyanate and the presence of inhibition halos, the transfer mechanism to the cells was assessed using solid-phase microextraction-gas chromatography-mass spectrometry. Based on the transfer system, action mechanism and its stronger antimicrobial activity, benzyl isothiocyanate was incorporated to two kinds of antimicrobial labels. The labels were stable and active for 140 days against two mould producers of ochratoxin A; Penicillium verrucosum is more sensitive than Aspergillus ochraceus. Details about the analytical techniques and the results obtained are shown and discussed. Graphical Abstract Antimicrobial evaluation of pure compounds, incorporation in the packaging and study for mode of action on S. coli by Raman, SEM and SPME-GC-MS.

Do Endogenous and Exogenous Action Control Compete for Perception?

ERIC Educational Resources Information Center

Pfister, Roland; Heinemann, Alexander; Kiesel, Andrea; Thomaschke, Roland; Janczyk, Markus

2012-01-01

Human actions are guided either by endogenous action plans or by external stimuli in the environment. These two types of action control seem to be mediated by neurophysiologically and functionally distinct systems that interfere if an endogenously planned action suddenly has to be performed in response to an exogenous stimulus. In this case, the…

Magnetization dynamics of Ni80Fe20 nanowires with continuous width modulation

NASA Astrophysics Data System (ADS)

Xiong, L. L.; Kostylev, M.; Adeyeye, A. O.

2017-06-01

A systematic investigation of the magnetization reversal and the dynamic behaviors of uncoupled Ni80Fe20 nanowires (NWs) with artificial continuous width modulation is presented. In contrast with the single resonance mode observed in the homogeneous NWs from the broadband ferromagnetic resonance spectroscopy, the NWs with continuous width modulation display three to five distinct resonance modes with increasing wire thickness in the range from 5 to 70 nm due to the nonuniform demagnetizing field. The highest frequency mode and the frequency difference between the two distinct highest modes are shown to be markedly sensitive to the NW thickness. Interestingly, we found that these modes can be described in terms of the quantization of the standing spin waves due to confined varied width. In addition, the easy axis coercive field for the width modulated NWs is much higher than homogeneous NWs of the same thickness when less than 70 nm. Our experimental results are in good qualitative agreement with the micromagnetic simulations. The results may find potential applications in the design and optimization of tunable magnonic filters.

Identification of an iridium(III) complex with anti-bacterial and anti-cancer activity

PubMed Central

Lu, Lihua; Liu, Li-Juan; Chao, Wei-chieh; Zhong, Hai-Jing; Wang, Modi; Chen, Xiu-Ping; Lu, Jin-Jian; Li, Ruei-nian; Ma, Dik-Lung; Leung, Chung-Hang

2015-01-01

Group 9 transition metal complexes have been widely explored as therapeutic agents due to their unique geometry, their propensity to undergo ligand exchanges with biomolecules and their diverse steric and electronic properties. These metal complexes can offer distinct modes of action in living organisms compared to carbon-based molecules. In this study, we investigated the antimicrobial and anti-proliferative abilities of a series of cyclometallated iridium(III) complexes. The iridium(III) complex 1 inhibited the growth of S. aureus with MIC and MBC values of 3.60 and 7.19 μM, respectively, indicating its potent bactericidal activity. Moreover, complex 1 also exhibited cytotoxicity against a number of cancer cell lines, with particular potency against ovarian, cervical and melanoma cells. This cyclometallated iridium(III) complex is the first example of a substitutionally-inert, Group 9 organometallic compound utilized as a direct and selective inhibitor of S. aureus. PMID:26416333

Study Approach of Antioxidant Properties in Foods: Update and Considerations.

PubMed

Durazzo, Alessandra

2017-02-28

The assessment of interactions between natural antioxidants and other food matrix components represents the main step in the investigation of total antioxidant properties, in terms of potential health benefits. The diversity of chemical structures of natural compounds, besides their possible interactions, as well as the biological role and different modes of action makes it difficult to assess a single and reliable procedure for the evaluation of antioxidant activity. Today, much attention is given to the distinction between extractable and non-extractable antioxidants as a key tool in the description of the nutritional and healthy properties of food matrices. The starting point for the investigation of antioxidant effects of food extracts is the analysis of antioxidant properties of pure compounds and their interactions. Another complementary approach could be represented by the study of how different biologically active compound-rich extracts contribute to the total antioxidant capacity.

Unsymmetric Mono- and Dinuclear Platinum(IV) Complexes Featuring an Ethylene Glycol Moiety: Synthesis, Characterization, and Biological Activity

PubMed Central

Pichler, Verena; Heffeter, Petra; Valiahdi, Seied M.; Kowol, Christian R.; Egger, Alexander; Berger, Walter; Jakupec, Michael A.; Galanski, Markus; Keppler, Bernhard K.

2014-01-01

Eight novel mononuclear and two dinuclear platinum(IV) complexes were synthesized and characterized by elemental analysis, one- and two-dimensional NMR spectroscopy, mass spectrometry, and reversed-phase HPLC (log kw) and in one case by X-ray diffraction. Cytotoxicity of the compounds was studied in three human cancer cell lines (CH1, SW480, and A549) by means of the MTT assay, featuring IC50 values to the low micromolar range. Furthermore a selected set of compounds was investigated in additional cancer cell lines (P31 and P31/cis, A2780 and A2780/cis, SW1573, 2R120, and 2R160) with regard to their resistance patterns, offering a distinctly different scheme compared to cisplatin. To gain further insights into the mode of action, drug uptake, DNA synthesis inhibition, cell cycle effects, and induction of apoptosis were determined for two characteristic substances. PMID:23194425

Study Approach of Antioxidant Properties in Foods: Update and Considerations

PubMed Central

Durazzo, Alessandra

2017-01-01

The assessment of interactions between natural antioxidants and other food matrix components represents the main step in the investigation of total antioxidant properties, in terms of potential health benefits. The diversity of chemical structures of natural compounds, besides their possible interactions, as well as the biological role and different modes of action makes it difficult to assess a single and reliable procedure for the evaluation of antioxidant activity. Today, much attention is given to the distinction between extractable and non-extractable antioxidants as a key tool in the description of the nutritional and healthy properties of food matrices. The starting point for the investigation of antioxidant effects of food extracts is the analysis of antioxidant properties of pure compounds and their interactions. Another complementary approach could be represented by the study of how different biologically active compound-rich extracts contribute to the total antioxidant capacity. PMID:28264480

Passion at a Distance

NASA Astrophysics Data System (ADS)

Howard, Don

In 1984, Abner Shimony invented the expression, "passion at a distance," to characterize the distinctive relationship of two entangled quantum mechanical systems [1]. It is neither the local causality of pushes, pulls, and central forces familiar from classical mechanics and electrodynamics, nor the non-local causality of instantaneous or just superluminal action at a distance that would spell trouble for relativity theory. This mode of connection of entangled systems has them feeling one another's presence and properties enough to ensure the strong correlations revealed in the Bell experiments, correlations that undergird everything from superfluidity and superconductivity to quantum computing and quantum teleportation, but not in a way that permits direct control of one by manipulation of the other. Intended to echo Aristotle's distinguishing of "potentiality" from "actuality" as different senses of "being," Shimony's "passion at a distance" is all about tendency and propensity, not the concreteness whose misplacement in realm of the physical was lamented by Alfred North Whitehead.

Epitope-dependent mechanisms of CD27 neutralization revealed by X-ray crystallography

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

Obmolova, Galina; Teplyakov, Alexey; Malia, Thomas J.

CD27 is a T and B cell co-stimulatory protein of the TNF receptor superfamily dependent on the availability of the TNF-like ligand CD70. Two anti-CD27 neutralizing monoclonal antibodies were obtained from mouse hybridoma and subsequently humanized and optimized for binding the target. The two antibodies are similar in terms of their CD27-binding affinity and ability to block NF-κB signaling, however their clearance rates in monkeys are very different. The pharmacokinetics profiles could be epitope dependent. To identify the epitopes, we determined the crystal structure of the ternary complex between CD27 and the Fab fragments of these non-competing antibodies. The structuremore » reveals the binding modes of the antibodies suggesting that their mechanisms of action are distinctly different and provides a possible explanation of the in vivo data.« less

Direct observation of TALE protein dynamics reveals a two-state search mechanism

PubMed Central

Cuculis, Luke; Abil, Zhanar; Zhao, Huimin; Schroeder, Charles M.

2015-01-01

Transcription activator-like effector (TALE) proteins are a class of programmable DNA-binding proteins for which the fundamental mechanisms governing the search process are not fully understood. Here we use single-molecule techniques to directly observe TALE search dynamics along DNA templates. We find that TALE proteins are capable of rapid diffusion along DNA using a combination of sliding and hopping behaviour, which suggests that the TALE search process is governed in part by facilitated diffusion. We also observe that TALE proteins exhibit two distinct modes of action during the search process—a search state and a recognition state—facilitated by different subdomains in monomeric TALE proteins. Using TALE truncation mutants, we further demonstrate that the N-terminal region of TALEs is required for the initial non-specific binding and subsequent rapid search along DNA, whereas the central repeat domain is required for transitioning into the site-specific recognition state. PMID:26027871

Direct observation of TALE protein dynamics reveals a two-state search mechanism.

PubMed

Cuculis, Luke; Abil, Zhanar; Zhao, Huimin; Schroeder, Charles M

2015-06-01

Transcription activator-like effector (TALE) proteins are a class of programmable DNA-binding proteins for which the fundamental mechanisms governing the search process are not fully understood. Here we use single-molecule techniques to directly observe TALE search dynamics along DNA templates. We find that TALE proteins are capable of rapid diffusion along DNA using a combination of sliding and hopping behaviour, which suggests that the TALE search process is governed in part by facilitated diffusion. We also observe that TALE proteins exhibit two distinct modes of action during the search process-a search state and a recognition state-facilitated by different subdomains in monomeric TALE proteins. Using TALE truncation mutants, we further demonstrate that the N-terminal region of TALEs is required for the initial non-specific binding and subsequent rapid search along DNA, whereas the central repeat domain is required for transitioning into the site-specific recognition state.

Disintegration of cruciform and G-quadruplex structures during the course of helicase-dependent amplification (HDA).

PubMed

Li, Dawei; Lv, Bei; Zhang, Hao; Lee, Jasmine Yiqin; Li, Tianhu

2015-04-15

Unlike chemical damages on DNA, physical alterations of B-form of DNA occur commonly in organisms that serve as signals for specified cellular events. Although the modes of action for repairing of chemically damaged DNA have been well studied nowadays, the repairing mechanisms for physically altered DNA structures have not yet been understood. Our current in vitro studies show that both breakdown of stable non-B DNA structures and resumption of canonical B-conformation of DNA can take place during the courses of isothermal helicase-dependent amplification (HDA). The pathway that makes the non-B DNA structures repairable is presumably the relieving of the accumulated torsional stress that was caused by the positive supercoiling. Our new findings suggest that living organisms might have evolved this distinct and economical pathway for repairing their physically altered DNA structures. Copyright © 2015 Elsevier Ltd. All rights reserved.

United time-frequency spectroscopy for dynamics and global structure.

PubMed

Marian, Adela; Stowe, Matthew C; Lawall, John R; Felinto, Daniel; Ye, Jun

2004-12-17

Ultrashort laser pulses have thus far been used in two distinct modes. In the time domain, the pulses have allowed probing and manipulation of dynamics on a subpicosecond time scale. More recently, phase stabilization has produced optical frequency combs with absolute frequency reference across a broad bandwidth. Here we combine these two applications in a spectroscopic study of rubidium atoms. A wide-bandwidth, phase-stabilized femtosecond laser is used to monitor the real-time dynamic evolution of population transfer. Coherent pulse accumulation and quantum interference effects are observed and well modeled by theory. At the same time, the narrow linewidth of individual comb lines permits a precise and efficient determination of the global energy-level structure, providing a direct connection among the optical, terahertz, and radio-frequency domains. The mechanical action of the optical frequency comb on the atomic sample is explored and controlled, leading to precision spectroscopy with an appreciable reduction in systematic errors.

Structural insight into the mechanism of synergistic autoinhibition of SAD kinases

PubMed Central

Wu, Jing-Xiang; Cheng, Yun-Sheng; Wang, Jue; Chen, Lei; Ding, Mei; Wu, Jia-Wei

2015-01-01

The SAD/BRSK kinases participate in various important life processes, including neural development, cell cycle and energy metabolism. Like other members of the AMPK family, SAD contains an N-terminal kinase domain followed by the characteristic UBA and KA1 domains. Here we identify a unique autoinhibitory sequence (AIS) in SAD kinases, which exerts autoregulation in cooperation with UBA. Structural studies of mouse SAD-A revealed that UBA binds to the kinase domain in a distinct mode and, more importantly, AIS nestles specifically into the KD-UBA junction. The cooperative action of AIS and UBA results in an ‘αC-out' inactive kinase, which is conserved across species and essential for presynaptic vesicle clustering in C. elegans. In addition, the AIS, along with the KA1 domain, is indispensable for phospholipid binding. Taken together, these data suggest a model for synergistic autoinhibition and membrane activation of SAD kinases. PMID:26626945

Structural insight into the mechanism of synergistic autoinhibition of SAD kinases.

PubMed

Wu, Jing-Xiang; Cheng, Yun-Sheng; Wang, Jue; Chen, Lei; Ding, Mei; Wu, Jia-Wei

2015-12-02

The SAD/BRSK kinases participate in various important life processes, including neural development, cell cycle and energy metabolism. Like other members of the AMPK family, SAD contains an N-terminal kinase domain followed by the characteristic UBA and KA1 domains. Here we identify a unique autoinhibitory sequence (AIS) in SAD kinases, which exerts autoregulation in cooperation with UBA. Structural studies of mouse SAD-A revealed that UBA binds to the kinase domain in a distinct mode and, more importantly, AIS nestles specifically into the KD-UBA junction. The cooperative action of AIS and UBA results in an 'αC-out' inactive kinase, which is conserved across species and essential for presynaptic vesicle clustering in C. elegans. In addition, the AIS, along with the KA1 domain, is indispensable for phospholipid binding. Taken together, these data suggest a model for synergistic autoinhibition and membrane activation of SAD kinases.

Sensors based on visible collective resonances of plasmonic lattices

NASA Astrophysics Data System (ADS)

Sadeghi, Seyed M.; Wing, Waylin J.; Campbell, Quinn

2016-09-01

We show arrays of large gold nanodisks on glass substrates can support strong optical features with narrow spectral widths associated with their collective plasmonic-lattice modes. Our results show that these modes can offer significant sensitivity to the refractive index of the environment, far more than those of individual nanodisks. We show the visible collective modes supported by such arrays can distinctively detect a monolayer of biotin with high resolution. We use donor (CdSe/ZnS) and acceptor (CuInS/ZnS) quantum dots to investigate the field properties of these arrays after deposition of a thick layer of a silicon. We demonstrate a distinct increase of emission of CuInS/ZnS quantum dots, indicating the possibility of enhancement of energy transfer between these two types of quantum dots.

DNA reactivity as a mode of action and its relevance to cancer risk assessment.

PubMed

Preston, R Julian

2013-02-01

The ability of a chemical to induce mutations has long been a driver in the cancer risk assessment process. The default strategy has been that mutagenic chemicals demonstrate linear cancer dose responses, especially at low exposure levels. In the absence of additional confounding information, this is a reasonable approach, because risk assessment is appropriately considered as being protective of human health. The concept of mode of action has allowed for an opportunity to move off this default position; mutagenicity is now not considered as the driver but rather the mode of action is. In a more precise way, it is the set of key events that define a mode of action that is fundamental in defining the shape of a cancer dose response. A key event is an informative bioindicator of the cancer response and as such should be predictive of the tumor response, at least in a qualitative way. A clear example of the use of key events in cancer risk assessment is for DNA reactive chemicals. A series of such key events is initiated by the production of DNA damage in target cells from direct interaction of the chemical with DNA leading to the production of mutations by misreplication that results in enhanced cell replication. This enhanced cell replication eventually leads to the development of preneoplastic cells and ultimately overt neoplasms. The response of each of these key events to dose of the chemical can inform the cancer dose-response curve shape. Thus, the dose-response curve for any DNA-reactive chemical can be predicted from knowledge of its mode of action and the behavior of the induced key events.

Sensitivity of species to chemicals: dose-response characteristics for various test types (LC(50), LR(50) and LD(50)) and modes of action.

PubMed

Hendriks, A Jan; Awkerman, Jill A; de Zwart, Dick; Huijbregts, Mark A J

2013-11-01

While variable sensitivity of model species to common toxicants has been addressed in previous studies, a systematic analysis of inter-species variability for different test types, modes of action and species is as of yet lacking. Hence, the aim of the present study was to identify similarities and differences in contaminant levels affecting cold-blooded and warm-blooded species administered via different routes. To that end, data on lethal water concentrations LC50, tissue residues LR50 and oral doses LD50 were collected from databases, each representing the largest of its kind. LC50 data were multiplied by a bioconcentration factor (BCF) to convert them to internal concentrations that allow for comparison among species. For each endpoint data set, we calculated the mean and standard deviation of species' lethal level per compound. Next, the means and standard deviations were averaged by mode of action. Both the means and standard deviations calculated depended on the number of species tested, which is at odds with quality standard setting procedures. Means calculated from (BCF) LC50, LR50 and LD50 were largely similar, suggesting that different administration routes roughly yield similar internal levels. Levels for compounds interfering biochemically with elementary life processes were about one order of magnitude below that of narcotics disturbing membranes, and neurotoxic pesticides and dioxins induced death in even lower amounts. Standard deviations for LD50 data were similar across modes of action, while variability of LC50 values was lower for narcotics than for substances with a specific mode of action. The study indicates several directions to go for efficient use of available data in risk assessment and reduction of species testing. Copyright © 2013 Elsevier Inc. All rights reserved.

Longitudinal and Transverse Instability of Ion Acoustic Waves

NASA Astrophysics Data System (ADS)

Chapman, T.; Berger, R. L.; Cohen, B. I.; Banks, J. W.; Brunner, S.

2017-08-01

Ion acoustic waves are found to be susceptible to at least two distinct decay processes. Which process dominates depends on the parameters. In the cases examined, the decay channel where daughter modes propagate parallel to the mother mode is found to dominate at larger amplitudes, while the decay channel where the daughter modes propagate at angles to the mother mode dominates at smaller amplitudes. Both decay processes may occur simultaneously and with onset thresholds below those suggested by fluid theory, resulting in the eventual multidimensional collapse of the mother mode to a turbulent state.

Effect of amino acid substitution in the staphylococcal peptides warnericin RK and PSMα on their anti-Legionella and hemolytic activities.

PubMed

Marchand, Adrienne; Augenstreich, Jacques; Loiseau, Clémence; Verdon, Julien; Lecomte, Sophie; Berjeaud, Jean-Marc

2015-07-01

Warnericin RK from Staphylococcus warneri and PSMα from Staphylococcus epidermidis are anti-Legionella peptides which were differently classified in a previous study according to their mode of action. Indeed, warnericin RK is highly hemolytic with a bactericidal mode of action, whereas PSMα is poorly hemolytic with a bacteriostatic mode of action toward L. pneumophila. In order to find anti-Legionella peptides which are not hemolytic, a collection of peptides varying in sequence from warnericin RK to PSMα were designed and synthesized, and their anti-Legionella activities, in terms of growth inhibition, permeabilization, and bactericidal effect, as well as their hemolytic activities, were measured and compared. The results showed that some residues, at position 14 for both peptides for instance, were of major importance for bactericidal and hemolytic activities.

Insight into the mode of action of 2,4-dichlorophenoxyacetic acid (2,4-D) as an herbicide.

PubMed

Song, Yaling

2014-02-01

2,4-Dichlorophenoxyacetic acid (2,4-D) was the first synthetic herbicide to be commercially developed and has commonly been used as a broadleaf herbicide for over 60 years. It is a selective herbicide that kills dicots without affecting monocots and mimics natural auxin at the molecular level. Physiological responses of dicots sensitive to auxinic herbicides include abnormal growth, senescence, and plant death. The identification of auxin receptors, auxin transport carriers, transcription factors response to auxin, and cross-talk among phytohormones have shed light on the molecular action mode of 2,4-D as a herbicide. Here, the molecular action mode of 2,4-D is highlighted according to the latest findings, emphasizing the physiological process, perception, and signal transduction under herbicide treatment. © 2013 Institute of Botany, Chinese Academy of Sciences.

Discriminating toxicant classes by mode of action. 1. (Eco)toxicity profiles.

PubMed

Nendza, Monika; Wenzel, Andrea

2006-05-01

Predictive toxicology, particularly quantitative structure-activity relationships (QSARs), require classification of chemicals by mode of action (MOA). MOA is, however, not a constant property of a compound but it varies between species and may change with concentration and duration of exposure. A battery of MOA-specific in-vitro and low-complexity assays, featuring biomolecular targets for major classes of environmental pollutants, provides characteristic responses for (1.) classification of chemicals by MOA, (2.) identification of (eco)toxicity profiles of chemicals, (3.) identification of chemicals with specific MOAs, (4.) indication of most sensitive species, (5.) identification of chemicals that are outliers in QSARs and (6.) selection of appropriate QSARs for predictions. Chemicals covering nine distinct modes of toxic action (non-polar non-specific toxicants (n=14), polar non-specific toxicants (n=18), uncouplers of oxidative phosphorylation (n=25), inhibitors of photosynthesis (n=15), inhibitors of acetylcholinesterase (n=14), inhibitors of respiration (n=3), thiol-alkylating agents (n=9), reactives (irritants) (n=8), estrogen receptor agonists (n=9)) were tested for cytotoxicity in the neutralred assay, oxygen consumption in isolated mitochondria, oxygen production in algae, inhibition of AChE, reaction with GSH and activity in the yeast estrogen receptor assay. Data on in-vivo aquatic toxicity (LC50, EC50) towards fish, daphnids, algae and bacteria were collected from the literature for reasons of comparison and reference scaling. In the MOA-specific in-vitro test battery, most test chemicals are specifically active at low concentrations, though multiple effects do occur. Graphical and statistical evaluation of the individual classes versus MOA 1 (non-polar non-specific toxicants) identifies interactions related to predominant MOA. Discriminant analyses (DA) on subsets of the data revealed correct classifications between 70% (in-vivo data) and >90% (in-vitro data). Functional similarity of chemical substances is defined in terms of their (eco)toxicity profiles. Within each MOA class, the compounds share some properties related to the rate-limiting interactions, e.g., steric fit to the target site and/or reactivity with target biomolecules, revealing a specific pattern (fingerprint) of characteristic effects. The successful discrimination of toxicant classes by MOA is based on comprehensive characterization of test chemicals' properties related to interactions with target sites. The suite of aquatic in-vivo tests using fish, daphnids, algae and bacteria covers most acute effects, whilst long-term (latent) impacts are generally neglected. With the MOA-specific in-vitro test battery such distinctions are futile, because it focuses on isolated targets, i.e. it indicates the possible targets of a chemical regardless of the timescale of effects. The data analysis indicates that the in-vitro battery covers most effects in vivo and moreover provides additional aspects of the compounds' MOA. Translating in-vitro effects to in-vivo toxicity requires combining physiological and chemical knowledge about underlying processes. Comparison of the specific in-vitro effects of a compound with the respective sensitivities of aquatic organisms indicates particularly sensitive species. Classifications of toxicants by MOA based on physicochemical descriptors provides insight to interactions and directs to mechanistic QSARs.

Anticancer copper(II) phosphorus dendrimers are potent proapoptotic Bax activators.

PubMed

Mignani, Serge; El Brahmi, Nabil; Eloy, Laure; Poupon, Joel; Nicolas, Valérie; Steinmetz, Anke; El Kazzouli, Said; Bousmina, Mosto M; Blanchard-Desce, Mireille; Caminade, Anne-Marie; Majoral, Jean-Pierre; Cresteil, Thierry

2017-05-26

A multivalent phosphorus dendrimer 1G 3 and its corresponding Cu-complex, 1G 3 -Cu have been recently identified as agents retaining high antiproliferative potency. This antiproliferative capacity was preserved in cell lines overexpressing the efflux pump ABC B1, whereas cross-resistance was observed in ovarian cancer cell lines resistant to cisplatin. Theoretical 3D models were constructed: the dendrimers appear as irregularly shaped disk-like nano-objects of about 22 Å thickness and 49 Å diameter, which accumulated in cells after penetration by endocytosis. To get insight in their mode of action, cell death pathways have been examined in human cancer cell lines: early apoptosis was followed by secondary necrosis after multivalent phosphorus dendrimers exposure. The multivalent plain phosphorus dendrimer 1G 3 moderately activated caspase-3 activity, in contrast with the multivalent Cu-conjugated phosphorus dendrimer 1G 3 -Cu which strikingly reduced the caspase-3 content and activity. This decrease of caspase activity is not related to the presence of copper, since inorganic copper has no or little effect on caspase-3. Conversely the potent apoptosis activation could be related to a noticeable translocation of Bax to the mitochondria, resulting in the release of AIF into the cytosol, its translocation to the nucleus and a severe DNA fragmentation, without alteration of the cell cycle. The multivalent Cu-conjugated phosphorus dendrimer is more efficient than its non-complexed analog to activate this pathway in close relationship with the higher antiproliferative potency. Therefore, this multivalent Cu-conjugated phosphorus dendrimer 1G 3 -Cu can be considered as a new and promising first-in-class antiproliferative agent with a distinctive mode of action, inducing apoptosis tumor cell death through Bax activation pathway. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

On the surface of superfluids

NASA Astrophysics Data System (ADS)

Armas, Jay; Bhattacharya, Jyotirmoy; Jain, Akash; Kundu, Nilay

2017-06-01

Developing on a recent work on localized bubbles of ordinary relativistic fluids, we study the comparatively richer leading order surface physics of relativistic superfluids, coupled to an arbitrary stationary background metric and gauge field in 3 + 1 and 2 + 1 dimensions. The analysis is performed with the help of a Euclidean effective action in one lower dimension, written in terms of the superfluid Goldstone mode, the shape-field (characterizing the surface of the superfluid bubble) and the background fields. We find new terms in the ideal order constitutive relations of the superfluid surface, in both the parity-even and parity-odd sectors, with the corresponding transport coefficients entirely fixed in terms of the first order bulk transport coefficients. Some bulk transport coefficients even enter and modify the surface thermodynamics. In the process, we also evaluate the stationary first order parity-odd bulk currents in 2 + 1 dimensions, which follows from four independent terms in the superfluid effective action in that sector. In the second part of the paper, we extend our analysis to stationary surfaces in 3 + 1 dimensional Galilean superfluids via the null reduction of null superfluids in 4 + 1 dimensions. The ideal order constitutive relations in the Galilean case also exhibit some new terms similar to their relativistic counterparts. Finally, in the relativistic context, we turn on slow but arbitrary time dependence and answer some of the key questions regarding the time-dependent dynamics of the shape-field using the second law of thermodynamics. A linearized fluctuation analysis in 2 + 1 dimensions about a toy equilibrium configuration reveals some new surface modes, including parity-odd ones. Our framework can be easily applied to model more general interfaces between distinct fluid-phases.

Comparative Developmental Toxicity of Flavonoids Using an Integrative Zebrafish System

PubMed Central

Bugel, Sean M.; Bonventre, Josephine A.; Tanguay, Robert L.

2016-01-01

Flavonoids are a large, structurally diverse class of bioactive naturally occurring chemicals commonly detected in breast milk, soy based infant formulas, amniotic fluid, and fetal cord blood. The potential for pervasive early life stage exposures raises concerns for perturbation of embryogenesis, though developmental toxicity and bioactivity information is limited for many flavonoids. Therefore, we evaluated a suite of 24 flavonoid and flavonoid-like chemicals using a zebrafish embryo-larval toxicity bioassay—an alternative model for investigating developmental toxicity of environmentally relevant chemicals. Embryos were exposed to 1–50 µM of each chemical from 6 to 120 h postfertilization (hpf), and assessed for 26 adverse developmental endpoints at 24, 72, and 120 hpf. Behavioral changes were evaluated in morphologically normal animals at 24 and 72 hpf, at 120 hpf using a larval photomotor response (LPR) assay. Gene expression was comparatively evaluated for all compounds for effects on biomarker transcripts indicative of AHR (cyp1a) and ER (cyp19a1b, esr1, lhb, vtg) pathway bioactivity. Overall, 15 of 24 flavonoids elicited adverse effects on one or more of the developmental or behavioral endpoints. Hierarchical clustering and principle component analyses compared toxicity profiles and identified 3 distinct groups of bioactive flavonoids. Despite robust induction of multiple estrogen-responsive biomarkers, co-exposure with ER and GPER antagonists did not ameliorate toxicity, suggesting ER-independence and alternative modes of action. Taken together, these studies demonstrate that development is sensitive to perturbation by bioactive flavonoids in zebrafish that are not related to traditional estrogen receptor mode of action pathways. This integrative zebrafish platform provides a useful framework for evaluating flavonoid developmental toxicity and hazard prioritization. PMID:27492224

Induction of olfaction and cancer-related genes in mice fed a high-fat diet as assessed through the mode-of-action by network identification analysis.

PubMed

Choi, Youngshim; Hur, Cheol-Goo; Park, Taesun

2013-01-01

The pathophysiological mechanisms underlying the development of obesity and metabolic diseases are not well understood. To gain more insight into the genetic mediators associated with the onset and progression of diet-induced obesity and metabolic diseases, we studied the molecular changes in response to a high-fat diet (HFD) by using a mode-of-action by network identification (MNI) analysis. Oligo DNA microarray analysis was performed on visceral and subcutaneous adipose tissues and muscles of male C57BL/6N mice fed a normal diet or HFD for 2, 4, 8, and 12 weeks. Each of these data was queried against the MNI algorithm, and the lists of top 5 highly ranked genes and gene ontology (GO)-annotated pathways that were significantly overrepresented among the 100 highest ranked genes at each time point in the 3 different tissues of mice fed the HFD were considered in the present study. The 40 highest ranked genes identified by MNI analysis at each time point in the different tissues of mice with diet-induced obesity were subjected to clustering based on their temporal patterns. On the basis of the above-mentioned results, we investigated the sequential induction of distinct olfactory receptors and the stimulation of cancer-related genes during the development of obesity in both adipose tissues and muscles. The top 5 genes recognized using the MNI analysis at each time point and gene cluster identified based on their temporal patterns in the peripheral tissues of mice provided novel and often surprising insights into the potential genetic mediators for obesity progression.

Kinetic Modeling Sheds Light on the Mode of Action of Recombinant Factor VIIa on Thrombin Generation

DTIC Science & Technology

2011-01-01

Regular Article Kinetic modeling sheds light on the mode of action of recombinant factor VIIa on thrombin generation Alexander Y. Mitrophanov...its effects on the quantitative parameters of thrombin generation. For recombinant activated factor VII (rFVIIa) ― a promising hemostasis-inducing...modulate thrombin production , it is necessary to identify rFVIIa-induced effects that are compatible with the available biochemical knowledge about

Modeling of thermal mode of drying special purposes ceramic products in batch action chamber dryers

NASA Astrophysics Data System (ADS)

Lukianov, E. S.; Lozovaya, S. Yu; Lozovoy, N. M.

2018-03-01

The article is devoted to the modeling of batch action chamber dryers in the processing line for producing shaped ceramic products. At the drying stage, for various reasons, most of these products are warped and cracked due to the occurrence of irregular shrinkage deformations due to the action of capillary forces. The primary cause is an untruly organized drying mode due to imperfection of chamber dryers design specifically because of the heat-transfer agent supply method and the possibility of creating a uniform temperature field in the whole volume of the chamber.

Directionality in drug action on sodium-calcium exchange.

PubMed

Noble, D; Blaustein, M P

2007-03-01

In pathological conditions, the exchanger may generate deleterious calcium entry. A drug that inhibited calcium entry, while still allowing transport of calcium out of the cell would then seem attractive. In fact, this is impossible for thermodynamic reasons. Inhibitors may appear to be more effective when the exchanger is operating in net calcium entry mode than in calcium exit mode. This is, however, always attributable to differences in conditions because there is strong internal sodium dependence of drug action on the exchanger. When the exchanger is operating near equilibrium, drug action is found to be equally effective in both directions.

Thymus vulgaris essential oil and thymol against Alternaria alternata (Fr.) Keissler: effects on growth, viability, early infection and cellular mode of action.

PubMed

Perina, Fabiano J; Amaral, Douglas C; Fernandes, Rafael S; Labory, Claudia Rg; Teixeira, Glauco A; Alves, Eduardo

2015-10-01

In initial assays, Thymus vulgaris essential oil (TEO) has demonstrated activity against several plant-pathogenic fungi and has reduced the fungal diseases to levels comparable with commercial fungicides. Thus, the goal of this work was to identify the mode of action in fungi of TEO and its major compound thymol (TOH) at the cellular level using an ultrastructure approach. TEO from leaves and TOH had minimum inhibitory concentrations (MICs) of 500 and 250 µg mL(-1) respectively against A. alternata; under the same conditions, MIC for a commercial fungicide was 1250 µg mL(-1) . Ultrastructure analysis showed that TOH phenolic substance prevented fungal growth, reduced fungal viability and prevented the penetration in fruits by a cell wall/plasma membrane interference mode of action with organelles targeted for destruction in the cytoplasm. Such mode of action differs from protective and preventive-curative commercial fungicides used as pattern control. These findings suggest that TOH was responsible for the antifungal activity of TEO. Therefore, both the essential oil and its major substance have potential for use in the development of new phenolic structures and analogues to control Alternaria brown spot disease caused by Alternaria alternata. © 2014 Society of Chemical Industry.

Mode of Action and Heterologous Expression of the Natural Product Antibiotic Vancoresmycin.

PubMed

Kepplinger, Bernhard; Morton-Laing, Stephanie; Seistrup, Kenneth Holst; Marrs, Emma Claire Louise; Hopkins, Adam Paul; Perry, John David; Strahl, Henrik; Hall, Michael John; Errington, Jeff; Ellis Allenby, Nicholas Edward

2018-01-19

Antibiotics that interfere with the bacterial cytoplasmic membrane have long-term potential for the treatment of infectious diseases as this mode of action is anticipated to result in low resistance frequency. Vancoresmycin is an understudied natural product antibiotic consisting of a terminal tetramic acid moiety fused to a linear, highly oxygenated, stereochemically complex polyketide chain. Vancoresmycin shows minimum inhibitory concentrations (MICs) from 0.125 to 2 μg/mL against a range of clinically relevant, antibiotic-resistant Gram-positive bacteria. Through a comprehensive mode-of-action study, utilizing Bacillus subtilis reporter strains, DiSC 3 (5) depolarization assays, and fluorescence microscopy, we have shown that vancoresmycin selectively targets the cytoplasmic membrane of Gram-positive bacteria via a non-pore-forming, concentration-dependent depolarization mechanism. Whole genome sequencing of the producing strain allowed identification of the 141 kbp gene cluster encoding for vancoresmycin biosynthesis and a preliminary model for its biosynthesis. The size and complex structure of vancoresmycin could confound attempts to generate synthetic analogues. To overcome this problem and facilitate future studies, we identified, cloned, and expressed the 141 kbp biosynthetic gene cluster in Streptomyces coelicolor M1152. Elucidation of the mode-of-action of vancoresmycin, together with the heterologous expression system, will greatly facilitate further studies of this and related molecules.

Deciphering the mode of action of cell wall-inhibiting antibiotics using metabolic labeling of growing peptidoglycan in Streptococcus pyogenes.

PubMed

Sugimoto, Atsushi; Maeda, Asuka; Itto, Kaori; Arimoto, Hirokazu

2017-04-25

Because of the scanty pipeline of antibiotics newly obtained from nature, chemical modification of established drugs is one of the major streams of current antibacterial research. Intuitive and easy-to-use assays are critical for identifying drug candidates with novel modes of action. In this study, we demonstrated that metabolic fluorescent staining of growing cell walls is a powerful tool for mode-of-action analyses of antibiotics using Streptococcus pyogenes. A set of major cell-wall-inhibiting antibiotics (bacitracin, D-cycloserine, flavomycin, oxacillin, ramoplanin, and vancomycin) was employed to validate the potential of the assay. The mechanistic differences of these antibiotics were successfully observed. For instance, D-cycloserine treatment induced fluorescently stained, excessive peripheral cell wall growth. This may indicate that the switch from the peripheral growth stage to the succeeding septal growth was disturbed by the treatment. We then applied this assay to analyze a series of vancomycin derivatives. The assay was sufficiently sensitive to detect the effects of single-site chemical modification of vancomycin on its modes of action. This metabolic fluorescent labeling method is easy to perform, especially because it does not require radiolabeled substrates. Thus, it is suitable for the preliminary evaluation of antibacterial mechanisms during antibacterial research.

Inhibition of retinoic acid catabolism by minocycline: evidence for a novel mode of action?

PubMed

Regen, Francesca; Hildebrand, Martin; Le Bret, Nathalie; Herzog, Irmelin; Heuser, Isabella; Hellmann-Regen, Julian

2015-06-01

Retinoic acid (RA) represents an essential and highly potent endogenous retinoid with pronounced anti-inflammatory properties and potent anti-acne activity, and has recently been suggested to share a common anti-inflammatory mode of action with tetracycline antibiotics. We hypothesized that tetracyclines may directly interfere with RA homeostasis via inhibition of its local cytochrome P450 (CYP450)-mediated degradation, an essential component of tightly regulated skin RA homeostasis. To test this hypothesis, we performed controlled in vitro RA metabolism assays using rat skin microsomes and measured RA levels in a RA-synthesizing human keratinocyte cell line, both in the presence and in the absence of minocycline, a tetracycline popular in acne treatment. Interestingly, minocycline potently blocked RA degradation in rat skin microsomes, and strikingly enhanced RA levels in RA-synthesizing cell cultures, in a dose-dependent manner. These findings indicate a potential role for CYP-450-mediated RA metabolism in minocycline's pleiotropic mode of action and anti-acne efficacy and could account for the overlap between minocycline and RA-induced effects at the level of their molecular mode of action, but also clinically at the level of the rare side effect of pseudotumor cerebri, which is observed for both, RA and minocycline treatment. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Recognising and referring children exposed to domestic abuse: a multi-professional, proactive systems-based evaluation using a modified Failure Mode and Effects Analysis (FMEA).

PubMed

Ashley, Laura; Armitage, Gerry; Taylor, Julie

2017-03-01

Failure Modes and Effects Analysis (FMEA) is a prospective quality assurance methodology increasingly used in healthcare, which identifies potential vulnerabilities in complex, high-risk processes and generates remedial actions. We aimed, for the first time, to apply FMEA in a social care context to evaluate the process for recognising and referring children exposed to domestic abuse within one Midlands city safeguarding area in England. A multidisciplinary, multi-agency team of 10 front-line professionals undertook the FMEA, using a modified methodology, over seven group meetings. The FMEA included mapping out the process under evaluation to identify its component steps, identifying failure modes (potential errors) and possible causes for each step and generating corrective actions. In this article, we report the output from the FMEA, including illustrative examples of the failure modes and corrective actions generated. We also present an analysis of feedback from the FMEA team and provide future recommendations for the use of FMEA in appraising social care processes and practice. Although challenging, the FMEA was unequivocally valuable for team members and generated a significant number of corrective actions locally for the safeguarding board to consider in its response to children exposed to domestic abuse. © 2016 John Wiley & Sons Ltd.

Topological Quantum Espionage

NASA Astrophysics Data System (ADS)

Hou, Chang-Yu; Shtengel, Kirill; Refael, Gil

2014-03-01

Can one transfer information encoded in Majorana modes between two distinct platforms? Or must one read out the information before transferring it to a new medium? We explore this question, and find that not only can information be transfered, but in some cases a fermionic occupation number can be stored non-locally by Majorana modes localized in two distinct p-wave superconductors with opposite chirality, as long as some tunneling contact between the two exists. This work is supported in part by the DARPA- QuEST program, NSF award DMR-0748925, the Packard foundation and the IQIM, an NSF center supported in part by the Moore fundation.

Herbal therapy: A review of emerging pharmacological tools in the management of diabetes mellitus in Africa

PubMed Central

Kibiti, Cromwell Mwiti; Afolayan, Anthony Jide

2015-01-01

Background: Diabetes mellitus is a chronic physiological glucose metabolic disorder. It has affected millions of people all over the world thereby having a significant impact on quality of life. The management of diabetes includes both nonpharmacological and conventional interventions. Drawbacks in conventional therapy have led to seeking alternative therapy in herbal medicine. Therefore, the need to review, elucidate and classify their mode of action in therapy for diabetes disease arises. Materials and Methods: Comprehensive literature reports were used to review all conventional agents and herbal therapy used in the management of diabetes. An online database search was conducted for medicinal plants of African origin that have been investigated for their antidiabetic therapeutic potentials. Results: The results showed that of the documented sixty five plants used, fourteen inhibit intestinal absorption of glucose, three exhibit insulin-mimetic properties, seventeen stimulate insulin secretion from pancreatic beta cells, twelve enhance peripheral glucose uptake, one promotes regeneration of beta-cell of islets of Langerhans, thirteen ameliorate oxidative stress and twenty induces hypoglycemic effect (mode of action is still obscure). Thirteen of these plants have a duplicate mode of actions while one of them has three modes of actions. These agents have a similar mechanism of action as the conventional drugs. Conclusion: In conclusion, antidiabetic activities of these plants are well established; however, the molecular modulation remains unknown. It is envisaged that the use of herbal therapy will promote good health and improve the status of diabetic patients. PMID:26664014

Mode of action of Bacillus thuringiensis Cry and Cyt toxins and their potential for insect control

PubMed Central

Bravo, Alejandra; Gill, Sarjeet S.; Soberón, Mario

2007-01-01

Bacillus thuringiensis Cry and Cyt protein families are a diverse group of proteins with activity against insects of different orders - Lepidoptera, Coleoptera, Diptera and also against other invertebrates such as nematodes. Their primary action is to lyse midgut epithelial cells by inserting into the target membrane and forming pores. Among this group of proteins, members of the 3-Domain Cry family are used worldwide for insect control, and their mode of action has been characterized in some detail. Phylogenetic analyses established that the diversity of the 3-Domain Cry family evolved by the independent evolution of the three domains and by swapping of domain III among toxins. Like other pore-forming toxins (PFT) that affect mammals, Cry toxins interact with specific receptors located on the host cell surface and are activated by host proteases following receptor binding resulting in the formation of a pre-pore oligomeric structure that is insertion competent. In contrast, Cyt toxins directly interact with membrane lipids and insert into the membrane. Recent evidence suggests that Cyt synergize or overcome resistance to mosquitocidal-Cry proteins by functioning as a Cry-membrane bound receptor. In this review we summarize recent findings on the mode of action of Cry and Cyt toxins, and compare them to the mode of action of other bacterial PFT. Also, we discuss their use in the control of agricultural insect pests and insect vectors of human diseases. PMID:17198720

Characterization of Ventilatory Modes in Dragonfly Nymph

NASA Astrophysics Data System (ADS)

Roh, Chris; Saxton-Fox, Theresa; Gharib, Morteza

2013-11-01

A dragonfly nymph's highly modified hindgut has multiple ventilatory modes: hyperventilation (i.e. jet propulsion), gulping ventilation (extended expiratory phase) and normal ventilation. Each mode involves dynamic manipulation of the exit diameter and pressure. To study the different fluid dynamics associated with the three modes, Anisopteran larvae of the family Aeshnidae were tethered onto a rod for flow visualization. The result showed distinct flow structures. The hyperventilation showed a highly turbulent and powerful jet that occurred at high frequency. The gulping ventilation produced a single vortex at a moderate frequency. The normal ventilation showed two distinct vortices, a low-Reynolds number vortex, followed by a high-Reynolds number vortex. Furthermore, a correlation of the formation of the vortices with the movement of the sternum showed that the dragonfly is actively controlling the timing and the speed of the vortices to have them at equal distance from the jet exit at the onset of inspiration. This behavior prevents inspiration of the oxygen deficient expirated water, resulting in the maximization of the oxygen intake. Supported by NSF GRFP.

"Learning-in-Action" and "Learning Inaction": Advancing the Theory and Practice of Critical Action Learning

ERIC Educational Resources Information Center

Vince, Russ

2008-01-01

This paper seeks to improve our understanding of the emotional and political dynamics that are generated (and too often avoided) in action learning. The idea at the centre of the paper is a distinction between "learning-in-action" and "learning inaction". The phrase "learning-in-action" represents the value of action…

Task Analytic Models to Guide Analysis and Design: Use of the Operator Function Model to Represent Pilot-Autoflight System Mode Problems

NASA Technical Reports Server (NTRS)

Degani, Asaf; Mitchell, Christine M.; Chappell, Alan R.; Shafto, Mike (Technical Monitor)

1995-01-01

Task-analytic models structure essential information about operator interaction with complex systems, in this case pilot interaction with the autoflight system. Such models serve two purposes: (1) they allow researchers and practitioners to understand pilots' actions; and (2) they provide a compact, computational representation needed to design 'intelligent' aids, e.g., displays, assistants, and training systems. This paper demonstrates the use of the operator function model to trace the process of mode engagements while a pilot is controlling an aircraft via the, autoflight system. The operator function model is a normative and nondeterministic model of how a well-trained, well-motivated operator manages multiple concurrent activities for effective real-time control. For each function, the model links the pilot's actions with the required information. Using the operator function model, this paper describes several mode engagement scenarios. These scenarios were observed and documented during a field study that focused on mode engagements and mode transitions during normal line operations. Data including time, ATC clearances, altitude, system states, and active modes and sub-modes, engagement of modes, were recorded during sixty-six flights. Using these data, seven prototypical mode engagement scenarios were extracted. One scenario details the decision of the crew to disengage a fully automatic mode in favor of a semi-automatic mode, and the consequences of this action. Another describes a mode error involving updating aircraft speed following the engagement of a speed submode. Other scenarios detail mode confusion at various phases of the flight. This analysis uses the operator function model to identify three aspects of mode engagement: (1) the progress of pilot-aircraft-autoflight system interaction; (2) control/display information required to perform mode management activities; and (3) the potential cause(s) of mode confusion. The goal of this paper is twofold: (1) to demonstrate the use of the operator functio model methodology to describe pilot-system interaction while engaging modes And monitoring the system, and (2) to initiate a discussion of how task-analytic models might inform design processes. While the operator function model is only one type of task-analytic representation, the hypothesis of this paper is that some type of task analytic structure is a prerequisite for the design of effective human-automation interaction.

In Silico Models for Ecotoxicity of Pharmaceuticals.

PubMed

Roy, Kunal; Kar, Supratik

2016-01-01

Pharmaceuticals and their active metabolites are one of the significantly emerging environmental toxicants. The major routes of entry of pharmaceuticals into the environment are industries, hospitals, or direct disposal of unwanted or expired drugs made by the patient. The most important and distinct features of pharmaceuticals are that they are deliberately designed to have an explicit mode of action and designed to exert an effect on humans and other living systems. This distinctive feature makes pharmaceuticals and their metabolites different from other chemicals, and this necessitates the evaluation of the direct effects of pharmaceuticals in various environmental compartments as well as to living systems. In this background, the alarming situation of ecotoxicity of diverse pharmaceuticals have forced government and nongovernment regulatory authorities to recommend the application of in silico methods to provide quick information about the risk assessment and fate properties of pharmaceuticals as well as their ecological and indirect human health effects. This chapter aims to offer information regarding occurrence of pharmaceuticals in the environment, their persistence, environmental fate, and toxicity as well as application of in silico methods to provide information about the basic risk management and fate prediction of pharmaceuticals in the environment. Brief ideas about toxicity endpoints, available ecotoxicity databases, and expert systems employed for rapid toxicity predictions of ecotoxicity of pharmaceuticals are also discussed.

Symbolization and Fallacy.

ERIC Educational Resources Information Center

Hample, Dale

Research indicates that people have two distinct information processing modalities, one for verbal material and one for nonverbal material. The nonverbal mode is used for visual images and is characterized by creative and relatively undisciplined associations. The verbal mode deals with abstract stimuli and is restrained by logic and the need to…

Treatment of pediculosis capitis: a critical appraisal of the current literature.

PubMed

Feldmeier, Hermann

2014-10-01

Pediculosis capitis is the most common ectoparasitic disease in children in industrialized countries and extremely common in resource-poor communities of the developing world. The extensive use of pediculicides with a neurotoxic mode of action has led to the development and spread of resistant head lice populations all over the world. This triggered the development of compounds with other modes of action. The current literature on treatment approaches of head lice infestation was searched, and published randomized controlled trials were critically analyzed. The following compounds/family of compounds were identified: spinosad, a novel compound with a new neurotoxic mode of action, isopropyl myristate, 1,2-octanediol, ivermectin, plant-based products, and dimeticones. The efficacy and safety of these compounds are reviewed and recommendations for the treatment of pediculosis capitis in individuals as well as the interruption of ongoing epidemics are provided.

Time-lapse imaging points towards a non-toxic, mainly immune-driven mode of action of ingenol mebutate in the treatment of anogenital warts.

PubMed

Braun, Stephan Alexander; Bünemann, Erich; Baran, Julia; Homey, Bernhard; Gerber, Peter Arne

2018-02-20

Recently, it has been reported that ingenol mebutate (IM) is an effective treatment option for anogenital warts (AGW), inducing fast wart necrosis within 24 hours in vivo. With regard to its mode of action, IM is thought to act both as an inducer of direct cytotoxic effects and immunologic mechanisms. To distinguish whether the wart necrosis is mainly caused by cytotoxic effects, or whether immune mechanisms are leading, we used time-lapse imaging to analyse IM-treated warts ex vivo over 24 hours. Ex vivo IM-treated warts, which have been detached from the immune system, did not show destructive necrosis, pointing towards a primarily immune-driven mode of action of IM in the treatment of AGW. © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Potential of Plant Essential Oils and Their Components in Animal Agriculture - in vitro Studies on Antibacterial Mode of Action.

PubMed

O'Bryan, Corliss A; Pendleton, Sean J; Crandall, Philip G; Ricke, Steven C

2015-01-01

The antimicrobial activity of essential oils and their components has been recognized for several years. Essential oils are produced as secondary metabolites by many plants and can be distilled from all different portions of plants. The recent emergence of bacteria resistant to multiple antibiotics has spurred research into the use of essential oils as alternatives. Recent research has demonstrated that many of these essential oils have beneficial effects for livestock, including reduction of foodborne pathogens in these animals. Numerous studies have been made into the mode of action of essential oils, and the resulting elucidation of bacterial cell targets has contributed to new perspectives on countering antimicrobial resistance and pathogenicity of these bacteria. In this review, an overview of the current knowledge about the antibacterial mode of action of essential oils and their constituents is provided.

Neuroendocrine disruption without direct endocrine mode of action: Polychloro-biphenyls (PCBs) and bisphenol A (BPA) as case studies.

PubMed

Pinson, Anneline; Franssen, Delphine; Gérard, Arlette; Parent, Anne-Simone; Bourguignon, Jean-Pierre

Endocrine disruption is commonly thought to be restricted to a direct endocrine mode of action i.e. the perturbation of the activation of a given type of hormonal receptor by its natural ligand. Consistent with the WHO definition of an endocrine disrupter, a key issue is the "altered function(s) of the endocrine system". Such altered functions can result from different chemical interactions, beyond agonistic or antagonistic effect at a given receptor. Based on neuroendocrine disruption by polychlorinated biphenyls and bisphenol A, this paper proposes different mechanistic paradigms that can result in adverse health effects. They are a consequence of altered endocrine function(s) secondary to chemical interaction with different steps in the physiological regulatory processes, thus accounting for a possibly indirect endocrine mode of action. Copyright © 2017 Académie des sciences. Published by Elsevier Masson SAS. All rights reserved.

Potential of Plant Essential Oils and Their Components in Animal Agriculture – in vitro Studies on Antibacterial Mode of Action

PubMed Central

O’Bryan, Corliss A.; Pendleton, Sean J.; Crandall, Philip G.; Ricke, Steven C.

2015-01-01

The antimicrobial activity of essential oils and their components has been recognized for several years. Essential oils are produced as secondary metabolites by many plants and can be distilled from all different portions of plants. The recent emergence of bacteria resistant to multiple antibiotics has spurred research into the use of essential oils as alternatives. Recent research has demonstrated that many of these essential oils have beneficial effects for livestock, including reduction of foodborne pathogens in these animals. Numerous studies have been made into the mode of action of essential oils, and the resulting elucidation of bacterial cell targets has contributed to new perspectives on countering antimicrobial resistance and pathogenicity of these bacteria. In this review, an overview of the current knowledge about the antibacterial mode of action of essential oils and their constituents is provided. PMID:26664964

Simultaneous excitation of extremely high-Q-factor trapped and octupolar modes in terahertz metamaterials.

PubMed

Yang, Shengyan; Tang, Chengchun; Liu, Zhe; Wang, Bo; Wang, Chun; Li, Junjie; Wang, Li; Gu, Changzhi

2017-07-10

Achieving high-Q-factor resonances allows dramatic enhancement of performance of many plasmonic devices. However, the excitation of high-Q-factor resonance, especially multiple high-Q-factor resonances, has been a big challenge in traditional metamaterials due to the ohmic and radiation losses. Here, we experimentally demonstrate simultaneous excitation of double extremely sharp resonances in a terahertz metamaterial composed of mirror-symmetric-broken double split ring resonators (MBDSRRs). In a regular mirror-arranged SRR array, only the low-Q-factor dipole resonance can be excited with the external electric field perpendicular to the SRR gap. Breaking the mirror-symmetry of the metamaterial leads to the occurrence of two distinct otherwise inaccessible ultrahigh-Q-factor modes, which consists of one trapped mode in addition to an octupolar mode. By tuning the asymmetry parameter, the Q factor of the trapped mode can be linearly modulated, while the Q factor of the octupolar mode can be tailored exponentially. For specific degree of asymmetry, our simulations revealed a significantly high Q factor (Q>100) for the octupolar mode, which is more than one order of magnitude larger than that of conventional metamaterials. The mirror-symmetry-broken metamaterial offers the advantage of enabling access to two distinct high-Q-factor resonances which could be exploited for ultrasensitive sensors, multiband filters, and slow light devices.

Resolving dual binding conformations of cellulosome cohesin-dockerin complexes using single-molecule force spectroscopy

PubMed Central

Jobst, Markus A; Milles, Lukas F; Schoeler, Constantin; Ott, Wolfgang; Fried, Daniel B; Bayer, Edward A; Gaub, Hermann E; Nash, Michael A

2015-01-01

Receptor-ligand pairs are ordinarily thought to interact through a lock and key mechanism, where a unique molecular conformation is formed upon binding. Contrary to this paradigm, cellulosomal cohesin-dockerin (Coh-Doc) pairs are believed to interact through redundant dual binding modes consisting of two distinct conformations. Here, we combined site-directed mutagenesis and single-molecule force spectroscopy (SMFS) to study the unbinding of Coh:Doc complexes under force. We designed Doc mutations to knock out each binding mode, and compared their single-molecule unfolding patterns as they were dissociated from Coh using an atomic force microscope (AFM) cantilever. Although average bulk measurements were unable to resolve the differences in Doc binding modes due to the similarity of the interactions, with a single-molecule method we were able to discriminate the two modes based on distinct differences in their mechanical properties. We conclude that under native conditions wild-type Doc from Clostridium thermocellum exocellulase Cel48S populates both binding modes with similar probabilities. Given the vast number of Doc domains with predicteddual binding modes across multiple bacterial species, our approach opens up newpossibilities for understanding assembly and catalytic properties of a broadrange of multi-enzyme complexes. DOI: http://dx.doi.org/10.7554/eLife.10319.001 PMID:26519733

Antibacterial action mode of quaternized carboxymethyl chitosan/poly(amidoamine) dendrimer core-shell nanoparticles against Escherichia coli correlated with molecular chain conformation.

PubMed

Wen, Yan; Yao, Fanglian; Sun, Fang; Tan, Zhilei; Tian, Liang; Xie, Lei; Song, Qingchao

2015-03-01

The action mode of quaternized carboxymethyl chitosan/poly(amidoamine) dendrimer core-shell nanoparticles (CM-HTCC/PAMAM) against Escherichia coli (E. coli) was investigated via a combination of approaches including measurements of cell membrane integrity, outer membrane (OM) and inner membrane (IM) permeability, and scanning electron microscopy (SEM). CM-HTCC/PAMAM dendrimer nanoparticles likely acted in a sequent event-driven mechanism, beginning with the binding of positively charged groups from nanoparticle surface with negative cell surface, thereby causing the disorganization of cell membrane, and subsequent leakage of intracellular components which might ultimately lead to cell death. Moreover, the chain conformation of polymers was taken into account for a better understanding of the antibacterial action mode by means of viscosity and GPC measurements. High utilization ratio of positive charge and large specific surface area generated from a compacted conformation of CM-HTCC/PAMAM, significantly different from the extended conformation of HTCC, were proposed to be involved in the antibacterial action. Copyright © 2014 Elsevier B.V. All rights reserved.

Discovery and identification of O, O-diethyl O-(4-(5-phenyl-4, 5-dihydroisoxazol-3-yl) phenyl) phosphorothioate (XP-1408) as a novel mode of action of organophosphorus insecticides.

PubMed

Zeng, Zhigang; Yan, Ying; Wang, Bingfeng; Liu, Niu; Xu, Hanhong

2017-06-15

Organophosphorus (OP) insecticides play an important role in pest control. Many OP insecticides have been removed from the market because of their high toxicity to humans. We designed and synthesized a new OP insecticide with the goal of providing a low cost, and less toxic insecticide. The mode of action of O, O-diethyl O-(4-(5-phenyl-4, 5-dihydroisoxazol-3-yl) phenyl) phosphorothioate (XP-1408) was studied in Drosophila melanogaster. Bioassays showed that XP-1408 at a concentration of 50 mg/L delayed larval development. Molecular docking into Drosophila acetylcholinesterase (AChE) and voltage-gated sodium channels suggested that XP-1408 fitted into their active sites and could be inhibitory. Whole-cell patch clamp recordings indicated that XP-1408 exhibited synergistic effects involving the inhibition of cholinergic synaptic transmission and blockage of voltage-gated potassium (K v ) channels and sodium (Na v ) channels. In conclusion, the multiple actions of XP-1408 rendered it as a lead compound for formulating OP insecticides with a novel mode of action.

Uniform and Complementary Social Interaction: Distinct Pathways to Solidarity

PubMed Central

Koudenburg, Namkje; Postmes, Tom; Gordijn, Ernestine H.; van Mourik Broekman, Aafke

2015-01-01

We examine how different forms of co-action give rise to feelings of solidarity. We propose that (a) coordinated action elicits a sense of solidarity, and (b) the process through which such solidarity emerges differs for different forms of co-action. We suggest that whether solidarity within groups emerges from uniform action (e.g. synchronizing, as when people speak in unison) or from more complementary forms of action (e.g. alternating, when speaking in turns) has important consequences for the emergent position of individuals within the group. Uniform action relies on commonality, leaving little scope for individuality. In complementary action each individual makes a distinctive contribution to the group, thereby increasing a sense of personal value to the group, which should contribute to the emergence of solidarity. The predictions receive support from five studies, in which we study groups in laboratory and field settings. Results show that both complementary and uniform co-action increase a sense of solidarity compared to control conditions. However, in the complementary action condition, but not in the uniform action (or synchrony) condition, the effect on feelings of solidarity is mediated by a sense of personal value to the group. PMID:26047131

Uniform and Complementary Social Interaction: Distinct Pathways to Solidarity.

PubMed

Koudenburg, Namkje; Postmes, Tom; Gordijn, Ernestine H; van Mourik Broekman, Aafke

2015-01-01

We examine how different forms of co-action give rise to feelings of solidarity. We propose that (a) coordinated action elicits a sense of solidarity, and (b) the process through which such solidarity emerges differs for different forms of co-action. We suggest that whether solidarity within groups emerges from uniform action (e.g. synchronizing, as when people speak in unison) or from more complementary forms of action (e.g. alternating, when speaking in turns) has important consequences for the emergent position of individuals within the group. Uniform action relies on commonality, leaving little scope for individuality. In complementary action each individual makes a distinctive contribution to the group, thereby increasing a sense of personal value to the group, which should contribute to the emergence of solidarity. The predictions receive support from five studies, in which we study groups in laboratory and field settings. Results show that both complementary and uniform co-action increase a sense of solidarity compared to control conditions. However, in the complementary action condition, but not in the uniform action (or synchrony) condition, the effect on feelings of solidarity is mediated by a sense of personal value to the group.

Inhibition of the reverse mode of the Na+/Ca2+ exchange by KB-R7943 augments arrhythmogenicity in the canine heart during rapid heart rates.

PubMed

Shinada, Takuro; Hirayama, Yoshiyuki; Maruyama, Mitsunori; Ohara, Toshihiko; Yashima, Masaaki; Kobayashi, Yoshinori; Atarashi, Hirotsugu; Takano, Teruo

2005-07-01

To test the hypothesis that the reverse mode of the Na+/Ca2+ exchange augmented by a rapid heart rate has an antiarrhythmic effect by shortening the action potential duration, we examined the effects of KB-R7943 (2-[2-[4-(4-nitrobenzyloxy)phenyl]ethyl] isothiourea methanesulfonate), a selective inhibitor of the reverse mode of the Na+/Ca2+ exchange, to attenuate this effect. We recorded the electrocardiogram, monophasic action potential (MAP), and left ventricular pressure in canine beating hearts. In comparison to the control, KB-R7943 significantly increased the QTc value and MAP duration. MAP alternans and left ventricular pressure alternans were observed after changing the cycle length to 300 milliseconds in the control studies. KB-R7943 magnified both types of alternans and produced spatially discordant alternans between right and left ventricles. Early after-depolarizations and nonsustained ventricular tachycardia occurred in the presence of KB-R7943. Our data suggest that the reverse mode of the Na+/Ca2+ exchange may contribute to suppression of arrhythmias by abbreviating action potential duration under pathophysiological conditions. This conclusion is based on further confirmation by future studies of the specificity of KB-R7943 for block of the reverse mode of the Na+/Ca2+ exchange.

Gene expression patterns in rainbow trout, Oncorhynchus mykiss, exposed to a suite of model toxicants

PubMed Central

Hook, Sharon E.; Skillman, Ann D.; Small, Jack A.; Schultz, Irvin R.

2008-01-01

The increased availability and use of DNA microarrays has allowed the characterization of gene expression patterns associated with exposure to different toxicants. An important question is whether toxicant induced changes in gene expression in fish are sufficiently diverse to allow for identification of specific modes of action and/or specific contaminants. In theory, each class of toxicant may generate a gene expression profile unique to its mode of toxic action. In this study, isogenic (cloned) rainbow trout Oncorhynchus mykiss were exposed to sublethal levels of a series of model toxicants with varying modes of action, including ethynylestradiol (xeno-estrogen), 2,2,4,4′-tetrabromodiphenyl ether (BDE-47, thyroid active), diquat (oxidant stressor), chromium VI, and benzo[a]pyrene (BaP) for a period of 1–3 weeks. An additional experiment measured trenbolone (anabolic steroid; model androgen) induced gene expression changes in sexually mature female trout. Following exposure, fish were euthanized, livers removed and RNA extracted. Fluorescently labeled cDNA were generated and hybridized against a commercially available Atlantic Salmon/Trout array (GRASP project, University of Victoria) spotted with 16,000 cDNA’s. The slides were scanned to measure abundance of a given transcript in each sample relative to controls. Data were analyzed via Genespring (Silicon Genetics) to identify a list of up- and downregulated genes, as well as to determine gene clustering patterns that can be used as “expression signatures”. The results indicate each toxicant exposure caused between 64 and 222 genes to be significantly altered in expression. Most genes exhibiting altered expression responded to only one of the toxicants and relatively few were co-expressed in multiple treatments. For example, BaP and Diquat, both of which exert toxicity via oxidative stress, upregulated 28 of the same genes, of over 100 genes altered by either treatment. Other genes associated with steroidogenesis, p450 and estrogen responsive genes appear to be useful for selectively identifying toxicant mode of action in fish, suggesting a link between gene expression profile and mode of toxicity. Our array results showed good agreement with quantitative real time polymerase chain reaction (qRT PCR), which demonstrates that the arrays are an accurate measure of gene expression. The specificity of the gene expression profile in response to a model toxicant, the link between genes with altered expression and mode of toxic action, and the consistency between array and qRT PCR results all suggest that cDNA microarrays have the potential to screen environmental contaminants for biomarkers and mode of toxic action. PMID:16488489

Gene expression patterns in rainbow trout, Oncorhynchus mykiss, exposed to a suite of model toxicants.

PubMed

Hook, Sharon E; Skillman, Ann D; Small, Jack A; Schultz, Irvin R

2006-05-25

The increased availability and use of DNA microarrays has allowed the characterization of gene expression patterns associated with exposure to different toxicants. An important question is whether toxicant induced changes in gene expression in fish are sufficiently diverse to allow for identification of specific modes of action and/or specific contaminants. In theory, each class of toxicant may generate a gene expression profile unique to its mode of toxic action. In this study, isogenic (cloned) rainbow trout Oncorhynchus mykiss were exposed to sublethal levels of a series of model toxicants with varying modes of action, including ethynylestradiol (xeno-estrogen), 2,2,4,4'-tetrabromodiphenyl ether (BDE-47, thyroid active), diquat (oxidant stressor), chromium VI, and benzo[a]pyrene (BaP) for a period of 1-3 weeks. An additional experiment measured trenbolone (anabolic steroid; model androgen) induced gene expression changes in sexually mature female trout. Following exposure, fish were euthanized, livers removed and RNA extracted. Fluorescently labeled cDNA were generated and hybridized against a commercially available Atlantic Salmon/Trout array (GRASP project, University of Victoria) spotted with 16,000 cDNA's. The slides were scanned to measure abundance of a given transcript in each sample relative to controls. Data were analyzed via Genespring (Silicon Genetics) to identify a list of up- and downregulated genes, as well as to determine gene clustering patterns that can be used as "expression signatures". The results indicate each toxicant exposure caused between 64 and 222 genes to be significantly altered in expression. Most genes exhibiting altered expression responded to only one of the toxicants and relatively few were co-expressed in multiple treatments. For example, BaP and Diquat, both of which exert toxicity via oxidative stress, upregulated 28 of the same genes, of over 100 genes altered by either treatment. Other genes associated with steroidogenesis, p450 and estrogen responsive genes appear to be useful for selectively identifying toxicant mode of action in fish, suggesting a link between gene expression profile and mode of toxicity. Our array results showed good agreement with quantitative real time polymerase chain reaction (qRT PCR), which demonstrates that the arrays are an accurate measure of gene expression. The specificity of the gene expression profile in response to a model toxicant, the link between genes with altered expression and mode of toxic action, and the consistency between array and qRT PCR results all suggest that cDNA microarrays have the potential to screen environmental contaminants for biomarkers and mode of toxic action.

Entanglement and nonclassicality for multimode radiation-field states

NASA Astrophysics Data System (ADS)

Ivan, J. Solomon; Chaturvedi, S.; Ercolessi, E.; Marmo, G.; Morandi, G.; Mukunda, N.; Simon, R.

2011-03-01

Nonclassicality in the sense of quantum optics is a prerequisite for entanglement in multimode radiation states. In this work we bring out the possibilities of passing from the former to the latter, via action of classicality preserving systems like beam splitters, in a transparent manner. For single-mode states, a complete description of nonclassicality is available via the classical theory of moments, as a set of necessary and sufficient conditions on the photon number distribution. We show that when the mode is coupled to an ancilla in any coherent state, and the system is then acted upon by a beam splitter, these conditions turn exactly into signatures of negativity under partial transpose (NPT) entanglement of the output state. Since the classical moment problem does not generalize to two or more modes, we turn in these cases to other familiar sufficient but not necessary conditions for nonclassicality, namely the Mandel parameter criterion and its extensions. We generalize the Mandel matrix from one-mode states to the two-mode situation, leading to a natural classification of states with varying levels of nonclassicality. For two-mode states we present a single test that can, if successful, simultaneously show nonclassicality as well as NPT entanglement. We also develop a test for NPT entanglement after beam-splitter action on a nonclassical state, tracing carefully the way in which it goes beyond the Mandel nonclassicality test. The result of three-mode beam-splitter action after coupling to an ancilla in the ground state is treated in the same spirit. The concept of genuine tripartite entanglement, and scalar measures of nonclassicality at the Mandel level for two-mode systems, are discussed. Numerous examples illustrating all these concepts are presented.

Inhibition of ammonia monooxygenase in Nitrosomonas europaea by carbon disulfide.

PubMed Central

Hyman, M R; Kim, C Y; Arp, D J

1990-01-01

Carbon disulfide has long been recognized as a potent inhibitor of nitrification, and it is the likely active component in several nitrification inhibitors suitable for field use. The effects of this compound on Nitrosomonas europaea have been investigated, and the site of action has been determined. Low concentrations of CS2 (less than 400 microM) produced a time-dependent inhibition of ammonia-dependent O2 uptake but did not inhibit hydrazine-oxidizing activity. CS2 also produced distinct changes in difference spectra of whole cells. These results suggest that ammonia monooxygenase (AMO) is the site of action of CS2. Unlike the case for thiourea and acetylene, saturating concentrations of CS2 did not fully inhibit AMO, and the inhibition resulted in a low but significant rate of ammonia-dependent O2 uptake. The effects of CS2 were not competitive with respect to ammonia concentration, and the inhibition by CS2 did not require the turnover of AMO to take effect. The ability of CS2-treated cells to incorporate [14C]acetylene into the 28-kilodalton polypeptide of AMO was used to demonstrate that the effects of CS2 are compatible with a mode of action which involves a reduction of the rate of turnover of AMO without effects on the catalytic mechanism. It is proposed that CS2 may act on AMO by reversibly reacting with a suitable nucleophilic amino acid in close proximity to the active site copper. Images PMID:2118501

Amphetamine Elicits Opposing Actions on Readily Releasable and Reserve Pools for Dopamine

PubMed Central

Covey, Dan P.; Juliano, Steven A.; Garris, Paul A.

2013-01-01

Amphetamine, a highly addictive drug with therapeutic efficacy, exerts paradoxical effects on the fundamental communication modes employed by dopamine neurons in modulating behavior. While amphetamine elevates tonic dopamine signaling by depleting vesicular stores and driving non-exocytotic release through reverse transport, this psychostimulant also activates phasic dopamine signaling by up-regulating vesicular dopamine release. We hypothesized that these seemingly incongruent effects arise from amphetamine depleting the reserve pool and enhancing the readily releasable pool. This novel hypothesis was tested using in vivo voltammetry and stimulus trains of varying duration to access different vesicular stores. We show that amphetamine actions are stimulus dependent in the dorsal striatum. Specifically, amphetamine up-regulated vesicular dopamine release elicited by a short-duration train, which interrogates the readily releasable pool, but depleted release elicited by a long-duration train, which interrogates the reserve pool. These opposing actions of vesicular dopamine release were associated with concurrent increases in tonic and phasic dopamine responses. A link between vesicular depletion and tonic signaling was supported by results obtained for amphetamine in the ventral striatum and cocaine in both striatal sub-regions, which demonstrated augmented vesicular release and phasic signals only. We submit that amphetamine differentially targeting dopamine stores reconciles the paradoxical activation of tonic and phasic dopamine signaling. Overall, these results further highlight the unique and region-distinct cellular mechanisms of amphetamine and may have important implications for its addictive and therapeutic properties. PMID:23671560

Brain Connectivity Patterns Dissociate Action of Specific Acupressure Treatments in Fatigued Breast Cancer Survivors.

PubMed

Harris, Richard E; Ichesco, Eric; Cummiford, Chelsea; Hampson, Johnson P; Chenevert, Thomas L; Basu, Neil; Zick, Suzanna M

2017-01-01

Persistent fatigue is a pernicious symptom in many cancer survivors. Existing treatments are limited or ineffective and often lack any underlying biologic rationale. Acupressure is emerging as a promising new intervention for persistent cancer-related fatigue; however, the underlying mechanisms of action are unknown. Our previous investigations suggested that fatigued breast cancer survivors have alterations in brain neurochemistry within the posterior insula and disturbed functional connectivity to the default mode network (DMN), as compared to non-fatigued breast cancer survivors. Here, we investigated if insula and DMN connectivity were modulated by self-administered acupressure by randomizing breast cancer survivors ( n  = 19) to two distinct treatments: relaxing acupressure or stimulating acupressure. All participants underwent proton magnetic resonance spectroscopy of the posterior insula and functional connectivity magnetic resonance imaging at baseline and immediately following 6 weeks of acupressure self-treatment. As compared to baseline measures, relaxing acupressure decreased posterior insula to dorsolateral prefrontal cortex connectivity, whereas stimulating acupressure enhanced this connectivity ( p  < 0.05 corrected). For relaxing but not stimulating acupressure, reduced connectivity was associated with sleep improvement. In addition, connectivity of the DMN to the superior colliculus was increased with relaxing acupressure and decreased with stimulating acupressure, whereas DMN connectivity to the bilateral pulvinar was increased with stimulating and decreased with relaxing acupressure ( p  < 0.05 corrected). These data suggest that self-administered acupressure at different acupoints has specificity in relation to their mechanisms of action in fatigued breast cancer survivors.

The Challenge of Evaluating Action Learning

ERIC Educational Resources Information Center

Edmonstone, John

2015-01-01

The paper examines the benefits claimed for action learning at individual, organisational and inter-organisational levels. It goes on to identify both generic difficulties in evaluating development programmes and action learning specifically. The distinction between formative and summative evaluation is considered and a summative evaluation…

Affirmative Action and the Principle of Equality

ERIC Educational Resources Information Center

Sasseen, Robert F.

1976-01-01

A critical look is taken at affirmative action, which is called a preferential policy of proportional employment. The author suggests that affirmative action actually denies citizens equality of opportunity, writing racial distinctions into law and holding contempt for Blacks and other pretended beneficiaries. (LBH)

Student Career Decisions: The Limits of Rationality.

ERIC Educational Resources Information Center

Baumgardner, Steve R.; Rappoport, Leon

This study compares modes of cognitive functioning revealed in student selection of a college major. Students were interviewed in-depth concerning reasons for their choice of majors. Protocol data suggested two distinct modes of thinking were evident on an analytic-intuitive dimension. For operational purposes analytic thinking was defined by…

THE DRAMATIC MODE. LITERATURE CURRICULUM V, TEACHER VERSION.

ERIC Educational Resources Information Center

KITZHABER, ALBERT R.

DISTINCTIONS BETWEEN THE NARRATIVE AND DRAMATIC MODES CAN BEST BE UNDERSTOOD BY EMPHASIZING WHAT IT MEANS TO THINK AND CREATE DRAMATICALLY. ALTHOUGH BOOKS (WHICH ARE READ) AND PLAYS (WHICH ARE SEEN) TREAT PLOT, CHARACTER, AND SETTING SIMILARLY, CONVENTIONS THAT PARTICULARLY DISTINGUISH THEATRICAL FORM ARE--(1) THE AUTHENTICATING REALITY OF THE…

On the ambiguity in the notion of transverse traceless modes of gravitational waves

NASA Astrophysics Data System (ADS)

Ashtekar, Abhay; Bonga, Béatrice

2017-09-01

Somewhat surprisingly, in many of the widely used monographs and review articles the term Transverse-Traceless modes of linearized gravitational waves is used to denote two entirely different notions. These treatments generally begin with a decomposition of the metric perturbation that is local in the momentum space (and hence non-local in physical space), and denote the resulting transverse traceless modes by h_{ab}^{TT}. However, while discussing gravitational waves emitted by an isolated system—typically in a later section—the relevant modes are extracted using a `projection operator' that is local in physical space. These modes are also called transverse-traceless and again labeled h_{ab}^{TT}, implying that this is just a reformulation of the previous notion. But the two notions are conceptually distinct and the difference persists even in the asymptotic region. We show that this confusion arises already in Maxwell theory that is often discussed as a prelude to the gravitational case. Finally, we discuss why the distinction has nonetheless remained largely unnoticed, and also point out that there are some important physical effects where only one of the notions gives the correct answer.

An action research study of secondary science assessment praxes

NASA Astrophysics Data System (ADS)

Ryan, Thomas Gerald

This practical participatory action research study illuminates the assessment praxes of four Ontario secondary level science teachers at one school using a facilitative approach. Participants were joined by a thematic concern, that is, a commitment to inform and improve assessment. Hence, two distinct sets of research questions emerged. The first involves the nature of assessment as we asked, what was the current state of assessment practice in secondary science? What were participants' initial understandings of assessment and actual practices at the onset of this research? To what extent did these initial understandings and actual practices change due to the illumination of assessment praxes through action research involvement? What was their level of awareness of current Ontario government pronouncements and in what ways did they implement this knowledge? The second theme, concerning the nature of action research, was realised by asking what did participants learn about action research? What other learning and professional gains were realised during this study? And, what did I learn about action research and assessment through my involvement in this study? Data were collected via supportive discussion groups, individual interviews, classroom visitations, journals and documentation. This professional development experience facilitated 'interactive professionalism' as teachers worked in a small group and interacted frequently in the course of planning, testing new ideas, attempting to solve different problems, and assess the effectiveness of those ideas. In addition, this action research effort was strategic and systematic, to attain a high degree of specific interactions, (personal interviews, group meetings, classroom observations, evidence collection). This series of deliberate and planned intentions helped participants solve assessment dilemmas. We developed an awareness and understanding of the need for more preservice and inservice assessment training. Participants realised the extent, and need to overcome their compartmentalisation, individualism and isolation. This reality was due to the design of their schedules, their school building and lack of common preparation times. Yet, in spite of the aforementioned, this inquiry supported and facilitated the transformation, improvement and enhanced understanding of assessment praxes. Participants learned how to professionally develop themselves using an action research mode of inquiry that supported teacher growth and development.

Unraveling the Complexity of Critical Consciousness, Political Efficacy, and Political Action Among Marginalized Adolescents.

PubMed

Diemer, Matthew A; Rapa, Luke J

2016-01-01

This research examines the complex patterns by which distinct dimensions of critical consciousness may lead marginalized adolescents toward distinct forms of political action. Structural equation modeling was applied to nationally representative data from the Civic Education Study (2,811 ninth graders; Mage  = 14.6), first establishing the measurement invariance of constructs across samples of poor or working class African American and Latino/a adolescents. Perceptions of societal inequality and aspirational beliefs that society ought to be more equal differentially predicted expected voting, conventional political action, and social action-while controlling for civic achievement and with nuances between ethnic and racial groups. Contrary to hypotheses and extant scholarship, political efficacy did not mediate or moderate relations between critical reflection and disparate forms of political action. © 2015 The Authors. Child Development © 2015 Society for Research in Child Development, Inc.

Catecholaminergic challenge uncovers distinct Pavlovian and instrumental mechanisms of motivated (in)action.

PubMed

Swart, Jennifer C; Froböse, Monja I; Cook, Jennifer L; Geurts, Dirk Em; Frank, Michael J; Cools, Roshan; den Ouden, Hanneke Em

2017-05-15

Catecholamines modulate the impact of motivational cues on action. Such motivational biases have been proposed to reflect cue-based, 'Pavlovian' effects. Here, we assess whether motivational biases may also arise from asymmetrical instrumental learning of active and passive responses following reward and punishment outcomes. We present a novel paradigm, allowing us to disentangle the impact of reward and punishment on instrumental learning from Pavlovian response biasing. Computational analyses showed that motivational biases reflect both Pavlovian and instrumental effects: reward and punishment cues promoted generalized (in)action in a Pavlovian manner, whereas outcomes enhanced instrumental (un)learning of chosen actions. These cue- and outcome-based biases were altered independently by the catecholamine enhancer melthylphenidate. Methylphenidate's effect varied across individuals with a putative proxy of baseline dopamine synthesis capacity, working memory span. Our study uncovers two distinct mechanisms by which motivation impacts behaviour, and helps refine current models of catecholaminergic modulation of motivated action.

The use of mode of action information in risk assessment: quantitative key events/dose-response framework for modeling the dose-response for key events.

PubMed

Simon, Ted W; Simons, S Stoney; Preston, R Julian; Boobis, Alan R; Cohen, Samuel M; Doerrer, Nancy G; Fenner-Crisp, Penelope A; McMullin, Tami S; McQueen, Charlene A; Rowlands, J Craig

2014-08-01

The HESI RISK21 project formed the Dose-Response/Mode-of-Action Subteam to develop strategies for using all available data (in vitro, in vivo, and in silico) to advance the next-generation of chemical risk assessments. A goal of the Subteam is to enhance the existing Mode of Action/Human Relevance Framework and Key Events/Dose Response Framework (KEDRF) to make the best use of quantitative dose-response and timing information for Key Events (KEs). The resulting Quantitative Key Events/Dose-Response Framework (Q-KEDRF) provides a structured quantitative approach for systematic examination of the dose-response and timing of KEs resulting from a dose of a bioactive agent that causes a potential adverse outcome. Two concepts are described as aids to increasing the understanding of mode of action-Associative Events and Modulating Factors. These concepts are illustrated in two case studies; 1) cholinesterase inhibition by the pesticide chlorpyrifos, which illustrates the necessity of considering quantitative dose-response information when assessing the effect of a Modulating Factor, that is, enzyme polymorphisms in humans, and 2) estrogen-induced uterotrophic responses in rodents, which demonstrate how quantitative dose-response modeling for KE, the understanding of temporal relationships between KEs and a counterfactual examination of hypothesized KEs can determine whether they are Associative Events or true KEs.

Evidence of an Intrinsic Intraseasonal Oscillation over Tropical South America During Austral Summer

NASA Technical Reports Server (NTRS)

Zhou, Jiayu; Lau, William K.-M.

2002-01-01

The intraseasonal variation (ISV) in the 30-60 day band, also known as Madden-Julian oscillation (MJO), has been studied for decades. Madden and Julian showed that the oscillation originated from the western Indian Ocean, propagated eastward, got enhanced over the maritime continent and weakened after passing over the dateline. Composite studies showed evidences of a signal in upper and lower level zonal wind propagating around the globe during an oscillation. Theoretical studies pointed out that the interaction with the warm ocean surface and the coupling with the convective and radiative processes in the atmosphere could manifest the oscillation, which propagates eastward via mutual feedbacks between the wave motions and the cumulus heating. Over tropical South America, no independent 30-60 day oscillation has been reported so far, despite that Amazon is the most distinct tropical convection center over the western hemisphere and the fluxes from its surface of tropical rainforests are close to that from the warm tropical ocean. Liebmann et al. showed a distinct spectral peak of 40-50 day oscillation in outgoing longwave radiation (OLR) over tropical South America and considered that was manifested by the MJO propagation. Nogues-Paegle et al. (2000) focused on a dipole pattern of the OLR anomaly with centers of action over the South Atlantic Convergence Zone (SACZ) and the subtropical plain. They used the regional 10-90 day filtered data and demonstrated this pattern could be represented by the fifth mode of the rotated empirical orthogonal function. Its principal component was further analyzed using the singular spectrum analysis. Their result showed two oscillatory modes with periods of 36-40 days and 22-28 days, of which the former was related to the MJO influence and the latter linked to the remote forcing over southwest of Australia, which produced a wave train propagating southeastward, rounding the southern tip of South America and returning back toward the northeast. The 22-28 day mode has distinct impact on SACZ, responsible for the regional seesaw pattern of alternating dry and wet conditions. In this study we will focus on the 30-60-day spectral band and investigate whether the independent oscillation source over tropical South America is existed. First, we will show the seasonal dependence of the tropical South American ISV in Section 3. Then, the leading principal modes of 30-60 day bandpass filtered 850-hPa velocity potential (VP850) will be computed to distinguish the stationary ISV over tropical South America (SISA) from the propagating MJO in the austral summertime in Section 4. The importance of SISA in representing the regional ISV over South America will be discussed. In Section 5, we will demonstrate the mass oscillation regime of SISA, which is well separated from that of MJO by the Andes, and the convective coupling with rainfall. The dynamical response of SISA and the impact on the South American summer monsoon (SASM) will be presented. Finally, we will give the concluding remarks.

Deciphering structure-activity relationships in a series of Tat/TAR inhibitors.

PubMed

Pascale, Lise; González, Alejandro López; Di Giorgio, Audrey; Gaysinski, Marc; Teixido Closa, Jordi; Tejedor, Roger Estrada; Azoulay, Stéphane; Patino, Nadia

2016-11-01

A series of pentameric "Polyamide Amino Acids" (PAAs) compounds derived from the same trimeric precursor have been synthesized and investigated as HIV TAR RNA ligands, in the absence and in the presence of a Tat fragment. All PAAs bind TAR with similar sub-micromolar affinities but their ability to compete efficiently with the Tat fragment strongly differs, IC50 ranging from 35 nM to >2 μM. While NMR and CD studies reveal that all PAA interact with TAR at the same site and induce globally the same RNA conformational change upon binding, a comparative thermodynamic study of PAA/TAR equilibria highlights distinct TAR binding modes for Tat competitor and non-competitor PAAs. This led us to suggest two distinct interaction modes that have been further validated by molecular modeling studies. While the binding of Tat competitor PAAs induces a contraction at the TAR bulge region, the binding of non-competitor ones widens it. This could account for the distinct PAA ability to compete with Tat fragment. Our work illustrates how comparative thermodynamic studies of a series of RNA ligands of same chemical family are of value for understanding their binding modes and for rationalizing structure-activity relationships.

Genetic analysis of the response to eleven Colletotrichum lindemuthianum races in a RIL population of common bean (Phaseolus vulgaris L.)

PubMed Central

2014-01-01

Background Bean anthracnose is caused by the fungus Colletotrichum lindemuthianum (Sacc. & Magnus) Lams.- Scrib. Resistance to C. lindemuthianum in common bean (Phaseolus vulgaris L.) generally follows a qualitative mode of inheritance. The pathogen shows extensive pathogenic variation and up to 20 anthracnose resistance loci (named Co-), conferring resistance to specific races, have been described. Anthracnose resistance has generally been investigated by analyzing a limited number of isolates or races in segregating populations. In this work, we analyzed the response against eleven C. lindemuthianum races in a recombinant inbred line (RIL) common bean population derived from the cross Xana × Cornell 49242 in which a saturated linkage map was previously developed. Results A systematic genetic analysis was carried out to dissect the complex resistance segregations observed, which included contingency analyses, subpopulations and genetic mapping. Twenty two resistance genes were identified, some with a complementary mode of action. The Cornell 49242 genotype carries a complex cluster of resistance genes at the end of linkage group (LG) Pv11 corresponding to the previously described anthracnose resistance cluster Co-2. In this position, specific resistance genes to races 3, 6, 7, 19, 38, 39, 65, 357, 449 and 453 were identified, with one of them showing a complementary mode of action. In addition, Cornell 49242 had an independent gene on LG Pv09 showing a complementary mode of action for resistance to race 453. Resistance genes in genotype Xana were located on three regions involving LGs Pv01, Pv02 and Pv04. All resistance genes identified in Xana showed a complementary mode of action, except for two controlling resistance to races 65 and 73 located on LG Pv01, in the position of the previously described anthracnose resistance cluster Co-1. Conclusions Results shown herein reveal a complex and specific interaction between bean and fungus genotypes leading to anthracnose resistance. Organization of specific resistance genes in clusters including resistance genes with different modes of action (dominant and complementary genes) was also confirmed. Finally, new locations for anthracnose resistance genes were identified in LG Pv09. PMID:24779442

Hybrid mode-locked erbium-doped all-fiber soliton laser with a distributed polarizer.

PubMed

Chernykh, D S; Krylov, A A; Levchenko, A E; Grebenyukov, V V; Arutunyan, N R; Pozharov, A S; Obraztsova, E D; Dianov, E M

2014-10-10

A soliton-type erbium-doped all-fiber ring laser hybrid mode-locked with a co-action of arc-discharge single-walled carbon nanotubes (SWCNTs) and nonlinear polarization evolution (NPE) is demonstrated. For the first time, to the best of our knowledge, boron nitride-doped SWCNTs were used as a saturable absorber for passive mode-locking initiation. Moreover, the NPE was introduced through the implementation of the short-segment polarizing fiber. Owing to the NPE action in the laser cavity, significant pulse length shortening as well as pulse stability improvement were observed as compared with a SWCNTs-only mode-locked laser. The shortest achieved pulse width of near transform-limited solitons was 222 fs at the output average power of 9.1 mW and 45.5 MHz repetition frequency, corresponding to the 0.17 nJ pulse energy.

Grasping the Muller-Lyer Illusion: The Contributions of Vision for Perception in Action

ERIC Educational Resources Information Center

van Doorn, Hemke; van der Kamp, John; Savelsbergh, Geert J. P.

2007-01-01

The present study examines the contributions of vision for perception processes in action. To this end, the influence of allocentric information on different action components (i.e., the selection of an appropriate mode of action, the pre-planning and online control of movement kinematics) is assessed. Participants (n = 10) were presented with a…

Detecting Threat-Related Intentional Actions of Others: Effects of Image Quality, Response Mode, and Target Cuing on Vigilance

ERIC Educational Resources Information Center

Parasuraman, Raja; de Visser, Ewart; Clarke, Ellen; McGarry, W. Ryan; Hussey, Elizabeth; Shaw, Tyler; Thompson, James C.

2009-01-01

Three experiments examined the vigilance performance of participants watching videos depicting intentional actions of an individual's hand reaching for and grasping an object--involving transporting or using either a gun or a hairdryer--in order to detect infrequent threat-related actions. Participants indicated detection of target actions either…

Topological interface modes in graphene multilayer arrays

NASA Astrophysics Data System (ADS)

Wang, Feng; Ke, Shaolin; Qin, Chengzhi; Wang, Bing; Long, Hua; Wang, Kai; Lu, Peixiang

2018-07-01

We investigate the topological interface modes of surface plasmon polaritons in a multilayer system composed of graphene waveguide arrays. The topological interface modes emerge when two topologically distinct graphene multilayer arrays are connected. In such multilayer system, the non-trivial topological interface modes and trivial modes coexist. By tuning the configuration of the graphene multilayer arrays, the associated non-trivial interface modes present robust against structural disorder. The total number of topological modes is related to that of graphene layers in a unit cell of the graphene multilayer array. The results provide a new paradigm for topologically protected plasmonics in the graphene multilayer arrays. The study suggests a promising approach to realize light transport and optical switching on a deep-subwavelength scale.

75 FR 77569 - Special Conditions: Gulfstream Model GVI Airplane; Electronic Flight Control System Mode...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-12-13

... Unusual Design Features The GVI will have a fly-by-wire electronic flight control system. This system... the design of the flight control system has multiple modes of operation, a means must be provided to... Control System Mode Annunciation AGENCY: Federal Aviation Administration (FAA), DOT. ACTION: Notice of...

Internally generated hippocampal sequences as a vantage point to probe future-oriented cognition.

PubMed

Pezzulo, Giovanni; Kemere, Caleb; van der Meer, Matthijs A A

2017-05-01

Information processing in the rodent hippocampus is fundamentally shaped by internally generated sequences (IGSs), expressed during two different network states: theta sequences, which repeat and reset at the ∼8 Hz theta rhythm associated with active behavior, and punctate sharp wave-ripple (SWR) sequences associated with wakeful rest or slow-wave sleep. A potpourri of diverse functional roles has been proposed for these IGSs, resulting in a fragmented conceptual landscape. Here, we advance a unitary view of IGSs, proposing that they reflect an inferential process that samples a policy from the animal's generative model, supported by hippocampus-specific priors. The same inference affords different cognitive functions when the animal is in distinct dynamical modes, associated with specific functional networks. Theta sequences arise when inference is coupled to the animal's action-perception cycle, supporting online spatial decisions, predictive processing, and episode encoding. SWR sequences arise when the animal is decoupled from the action-perception cycle and may support offline cognitive processing, such as memory consolidation, the prospective simulation of spatial trajectories, and imagination. We discuss the empirical bases of this proposal in relation to rodent studies and highlight how the proposed computational principles can shed light on the mechanisms of future-oriented cognition in humans. © 2017 New York Academy of Sciences.

Self-deception as self-signalling: a model and experimental evidence

PubMed Central

Mijović-Prelec, Danica; Prelec, Draz̆en

2010-01-01

Self-deception has long been the subject of speculation and controversy in psychology, evolutionary biology and philosophy. According to an influential ‘deflationary’ view, the concept is an over-interpretation of what is in reality an instance of motivationally biased judgement. The opposite view takes the interpersonal deception analogy seriously, and holds that some part of the self actively manipulates information so as to mislead the other part. Building on an earlier self-signalling model of Bodner and Prelec, we present a game-theoretic model of self-deception. We propose that two distinct mechanisms collaborate to produce overt expressions of belief: a mechanism responsible for action selection (including verbal statements) and an interpretive mechanism that draws inferences from actions and generates emotional responses consistent with the inferences. The model distinguishes between two modes of self-deception, depending on whether the self-deceived individual regards his own statements as fully credible. The paper concludes with a new experimental study showing that self-deceptive judgements can be reliably and repeatedly elicited with financial incentives in a categorization task, and that the degree of self-deception varies with incentives. The study also finds evidence of the two forms of self-deception. The psychological benefits of self-deception, as measured by confidence, peak at moderate levels. PMID:20026461

Sarcosine influences apoptosis and growth of prostate cells via cell-type specific regulation of distinct sets of genes.

PubMed

Rodrigo, Miguel A Merlos; Strmiska, Vladislav; Horackova, Eva; Buchtelova, Hana; Michalek, Petr; Stiborova, Marie; Eckschlager, Tomas; Adam, Vojtech; Heger, Zbynek

2018-02-01

Sarcosine is a widely discussed oncometabolite of prostate cells. Although several reports described connections between sarcosine and various phenotypic changes of prostate cancer (PCa) cells, there is still a lack of insights on the complex phenomena of its effects on gene expression patterns, particularly in non-malignant and non-metastatic cells. To shed more light on this phenomenon, we performed parallel microarray profiling of RNA isolated from non-malignant (PNT1A), malignant (22Rv1), and metastatic (PC-3) prostate cell lines treated with sarcosine. Microarray results were experimentally verified using semi-quantitative-RT-PCR, clonogenic assay, through testing of the susceptibility of cells pre-incubated with sarcosine to anticancer agents with different modes of actions (inhibitors of topoisomerase II, DNA cross-linking agent, antimicrotubule agent and inhibitor of histone deacetylases) and by evaluation of activation of executioner caspases 3/7. We identified that irrespective of the cell type, sarcosine stimulates up-regulation of distinct sets of genes involved in cell cycle and mitosis, while down-regulates expression of genes driving apoptosis. Moreover, it was found that in all cell types, sarcosine had pronounced stimulatory effects on clonogenicity. Except of an inhibitor of histone deacetylase valproic acid, efficiency of all agents was significantly (P < 0.05) decreased in sarcosine pre-incubated cells. Our comparative study brings evidence that sarcosine affects not only metastatic PCa cells, but also their malignant and non-malignant counterparts and induces very similar changes in cells behavior, but via distinct cell-type specific targets. © 2017 Wiley Periodicals, Inc.

Pyrrole-Based Antitubulin Agents: Two Distinct Binding Modalities Are Predicted for C-2 Analogues in the Colchicine Site

PubMed Central

2011-01-01

3,5-Dibromo-4-(3,4-dimethoxyphenyl)-1H-pyrrole-2-carboxylic acid ethyl ester is a promising antitubulin lead agent that targets the colchicine site of tubulin. C-2 analogues were synthesized and tested for microtubule depolymerizing and antiproliferative activity. Molecular modeling studies using both GOLD docking and HINT (Hydropathic INTeraction) scoring revealed two distinct binding modes that explain the structure–activity relationships and are in accord with the structural basis of colchicine binding to tubulin. The binding mode of higher activity compounds is buried deeper in the site and overlaps well with rings A and C of colchicine, while the lower activity binding mode shows fewer critical contacts with tubulin. The model distinguishes highly active compounds from those with weaker activities and provides novel insights into the colchicine site and compound design. PMID:22611477

Pyrrole-Based Antitubulin Agents: Two Distinct Binding Modalities are Predicted for C-2 Analogs in the Colchicine Site.

PubMed

Da, Chenxiao; Telang, Nakul; Barelli, Peter; Jia, Xin; Gupton, John T; Mooberry, Susan L; Kellogg, Glen E

2012-01-12

3,5-dibromo-4-(3,4-dimethoxyphenyl)-1H-pyrrole-2-carboxylic acid ethyl ester is a promising antitubulin lead agent that targets the colchicine site of tubulin. C-2 analogs were synthesized and tested for microtubule depolymerizing and antiproliferative activity. Molecular modeling studies using both GOLD docking and HINT (Hydropathic INTeraction) scoring revealed two distinct binding modes that explain the structural-activity relationships and are in accord with the structural basis of colchicine binding to tubulin. The binding mode of higher activity compounds is buried deeper in the site and overlaps well with rings A and C of colchicine, while the lower activity binding mode shows fewer critical contacts with tubulin. The model distinguishes highly active compounds from those with weaker activities and provides novel insights into the colchicine site and compound design.

The spectrum of static subtracted geometries

NASA Astrophysics Data System (ADS)

Andrade, Tomás; Castro, Alejandra; Cohen-Maldonado, Diego

2017-05-01

Subtracted geometries are black hole solutions of the four dimensional STU model with rather interesting ties to asymptotically flat black holes. A peculiar feature is that the solutions to the Klein-Gordon equation on this subtracted background can be organized according to representations of the conformal group SO(2, 2). We test if this behavior persists for the linearized fluctuations of gravitational and matter fields on static, electrically charged backgrounds of this kind. We find that there is a subsector of the modes that do display conformal symmetry, while some modes do not. We also discuss two different effective actions that describe these subtracted geometries and how the spectrum of quasinormal modes is dramatically different depending upon the action used.

Self-Efficacy for Therapeutic Mode Use among Occupational Therapy Students in Norway

ERIC Educational Resources Information Center

Opseth, Thea Moos; Carstensen, Tove; Yazdani, Farzaneh; Ellingham, Brian; Thørrisen, Mikkel Magnus; Bonsaksen, Tore

2017-01-01

Background: The intentional relationship model (IRM) proposes six distinct ways of relating to clients. A new instrument for measuring self-efficacy for using the therapeutic modes in occupational therapy practice was recently found to have good psychometric properties. To date, however, no research has investigated factors associated with…

Putative role of membranes in the HIV fusion inhibitor enfuvirtide mode of action at the molecular level.

PubMed Central

Veiga, Salomé; Henriques, Sónia; Santos, Nuno C; Castanho, Miguel

2004-01-01

Partition of the intrinsically fluorescent HIV fusion inhibitor enfuvirtide into lipidic membranes is relatively high (Delta G =6.6 kcal x mol(-1)) and modulated by cholesterol. A shallow position in the lipidic matrix makes it readily available for interaction with gp41. No conformational energetic barrier prevents enfuvirtide from being active in both aqueous solution and lipidic membranes. Lipidic membranes may play a key role in the enfuvirtide biochemical mode of action. PMID:14514352

Chemical genomic profiling via barcode sequencing to predict compound mode of action

PubMed Central

Piotrowski, Jeff S.; Simpkins, Scott W.; Li, Sheena C.; Deshpande, Raamesh; McIlwain, Sean; Ong, Irene; Myers, Chad L.; Boone, Charlie; Andersen, Raymond J.

2015-01-01

Summary Chemical genomics is an unbiased, whole-cell approach to characterizing novel compounds to determine mode of action and cellular target. Our version of this technique is built upon barcoded deletion mutants of Saccharomyces cerevisiae and has been adapted to a high-throughput methodology using next-generation sequencing. Here we describe the steps to generate a chemical genomic profile from a compound of interest, and how to use this information to predict molecular mechanism and targets of bioactive compounds. PMID:25618354

Raman intensity and vibrational modes of armchair CNTs

NASA Astrophysics Data System (ADS)

Hur, Jaewoong; Stuart, Steven J.

2017-07-01

Raman intensity changes and frequency patterns have been studied using the various armchair (n, n) to understand the variations of bond polarizability, in regard to changing diameters, lengths, and the number of atoms in the (n, n). The Raman intensity trends of the (n, n) are validated by those of Cn isomers. For frequency trends, similar frequency patterns and frequency inward shifts for the (n, n) are characterized. Also, VDOS trends of the (n, n) expressing Raman modes are interpreted. The decomposition of vibrational modes in the (n, n) into radial, longitudinal, and tangential mode is beneficially used to recognize the distinct characteristics of vibrational modes.

Mode switching in a multi-wavelength distributed feedback quantum cascade laser using an external micro-cavity

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

Sidler, Meinrad; Institute for Quantum Electronics, ETH Zurich, Wolfgang-Pauli-Strasse 16, 8093 Zurich; Rauter, Patrick

2014-02-03

We demonstrate a multi-wavelength distributed feedback (DFB) quantum cascade laser (QCL) operating in a lensless external micro-cavity and achieve switchable single-mode emission at three distinct wavelengths selected by the DFB grating, each with a side-mode suppression ratio larger than 30 dB. Discrete wavelength tuning is achieved by modulating the feedback experienced by each mode of the multi-wavelength DFB QCL, resulting from a variation of the external cavity length. This method also provides a post-fabrication control of the lasing modes to correct for fabrication inhomogeneities, in particular, related to the cleaved facets position.

Considering mutagenicity and genotoxicity in the cancer mode ...

EPA Pesticide Factsheets

It is well known that genotoxicity plays a significant role in the development of tumor formation. Mutations in somatic cells can play a key role early in cancer initiation and might affect other stages of the carcinogenic process. Determination of carcinogens that operate through a genotoxic mode of action entails evaluation of the available data. One way of determining if a chemical is acting through a genotoxic mechanism is to assemble the relevant data (human, animal, in vivo, in vitro) of individual genetic end points, evaluating the data against a current acceptance criteria (study quality, methodology used etc.), and determining the weight of evidence based on both the available data as well as evaluating against other existing information such as epidemiological data, ADME information etc. This presentation will lay-out key, currently available genotoxicity information on naphthalene, styrene and ethylbenzene. These three chemicals were chosen because all three chemicals cause mouse lung tumors, in particular bronchiolar-alveolar adenomas and carcinomas. This analysis of the data will enable further understanding of the mode of action of mouse lung tumor formation and species differences, which will impact the hazard identification and use of mode of action in the risk assessment of naphthalene, styrene, and ethylbenzene.

Investigation of magnetization dynamics in 2D Ni80Fe20 diatomic nanodot arrays

NASA Astrophysics Data System (ADS)

De, Anulekha; Mondal, Sucheta; Banerjee, Chandrima; Chaurasiya, Avinash K.; Mandal, Ruma; Otani, Yoshichika; Mitra, Rajib K.; Barman, Anjan

2017-09-01

Magnetization dynamics in Ni80Fe20 (Py) diatomic nanodots (nanodots of the same thickness but with large and small diameters that are closely placed to each other so as to act as a diatomic basis structure) embedded in 2D arrays have been investigated by the Brillouin light scattering technique. A distinct variation of resonant mode characteristics for different in-plane bias magnetic field applied along two different orientations of the lattice has been observed. Micromagnetic simulations reproduced the observed dynamical behaviour and revealed the variation of spatial distribution of collective modes of constituent single nanodots with different diameter and a diatomic unit forming the large array to understand the evolution of the magnetization dynamics from a single dot to the large array via a diatomic unit. The changes in mode frequency, spatial profiles of the modes, and appearance of new modes in a diatomic unit and its array from that of the constituent single dots indicate the strong magnetostatic interaction among the dots within the diatomic unit. Also, the occurrence of the new interacting mode at different frequencies for different orientations of the bias field indicates the change in the nature of interaction among the dots within the diatomic unit with bias magnetic field. The mode profiles also show distinct behaviour for smooth and rough-edged dots. This work motivates the study of magnonic band structure formation of such a dipolarly coupled nanodot array containing a complex double-dot unit cell.

GestuRe and ACtion Exemplar (GRACE) video database: stimuli for research on manners of human locomotion and iconic gestures.

PubMed

Aussems, Suzanne; Kwok, Natasha; Kita, Sotaro

2018-06-01

Human locomotion is a fundamental class of events, and manners of locomotion (e.g., how the limbs are used to achieve a change of location) are commonly encoded in language and gesture. To our knowledge, there is no openly accessible database containing normed human locomotion stimuli. Therefore, we introduce the GestuRe and ACtion Exemplar (GRACE) video database, which contains 676 videos of actors performing novel manners of human locomotion (i.e., moving from one location to another in an unusual manner) and videos of a female actor producing iconic gestures that represent these actions. The usefulness of the database was demonstrated across four norming experiments. First, our database contains clear matches and mismatches between iconic gesture videos and action videos. Second, the male actors and female actors whose action videos matched the gestures in the best possible way, perform the same actions in very similar manners and different actions in highly distinct manners. Third, all the actions in the database are distinct from each other. Fourth, adult native English speakers were unable to describe the 26 different actions concisely, indicating that the actions are unusual. This normed stimuli set is useful for experimental psychologists working in the language, gesture, visual perception, categorization, memory, and other related domains.

Distinct spatio-temporal profiles of beta-oscillations within visual and sensorimotor areas during action recognition as revealed by MEG.

PubMed

Pavlidou, Anastasia; Schnitzler, Alfons; Lange, Joachim

2014-05-01

The neural correlates of action recognition have been widely studied in visual and sensorimotor areas of the human brain. However, the role of neuronal oscillations involved during the process of action recognition remains unclear. Here, we were interested in how the plausibility of an action modulates neuronal oscillations in visual and sensorimotor areas. Subjects viewed point-light displays (PLDs) of biomechanically plausible and implausible versions of the same actions. Using magnetoencephalography (MEG), we examined dynamic changes of oscillatory activity during these action recognition processes. While both actions elicited oscillatory activity in visual and sensorimotor areas in several frequency bands, a significant difference was confined to the beta-band (∼20 Hz). An increase of power for plausible actions was observed in left temporal, parieto-occipital and sensorimotor areas of the brain, in the beta-band in successive order between 1650 and 2650 msec. These distinct spatio-temporal beta-band profiles suggest that the action recognition process is modulated by the degree of biomechanical plausibility of the action, and that spectral power in the beta-band may provide a functional interaction between visual and sensorimotor areas in humans. Copyright © 2014 Elsevier Ltd. All rights reserved.

Genetic and Modeling Approaches Reveal Distinct Components of Impulsive Behavior

PubMed Central

Nautiyal, Katherine M; Wall, Melanie M; Wang, Shuai; Magalong, Valerie M; Ahmari, Susanne E; Balsam, Peter D; Blanco, Carlos; Hen, René

2017-01-01

Impulsivity is an endophenotype found in many psychiatric disorders including substance use disorders, pathological gambling, and attention deficit hyperactivity disorder. Two behavioral features often considered in impulsive behavior are behavioral inhibition (impulsive action) and delayed gratification (impulsive choice). However, the extent to which these behavioral constructs represent distinct facets of behavior with discrete biological bases is unclear. To test the hypothesis that impulsive action and impulsive choice represent statistically independent behavioral constructs in mice, we collected behavioral measures of impulsivity in a single cohort of mice using well-validated operant behavioral paradigms. Mice with manipulation of serotonin 1B receptor (5-HT1BR) expression were included as a model of disordered impulsivity. A factor analysis was used to characterize correlations between the measures of impulsivity and to identify covariates. Using two approaches, we dissociated impulsive action from impulsive choice. First, the absence of 5-HT1BRs caused increased impulsive action, but not impulsive choice. Second, based on an exploratory factor analysis, a two-factor model described the data well, with measures of impulsive action and choice separating into two independent factors. A multiple-indicator multiple-causes analysis showed that 5-HT1BR expression and sex were significant covariates of impulsivity. Males displayed increased impulsivity in both dimensions, whereas 5-HT1BR expression was a predictor of increased impulsive action only. These data support the conclusion that impulsive action and impulsive choice are distinct behavioral phenotypes with dissociable biological influences that can be modeled in mice. Our work may help inform better classification, diagnosis, and treatment of psychiatric disorders, which present with disordered impulsivity. PMID:27976680

Analysis of how people with intellectual disabilities organize information using computerized guidance.

PubMed

Lussier-Desrochers, Dany; Sauzéon, Hélène; Consel, Charles; Roux, Jeannie; Balland, Émilie; Godin-Tremblay, Valérie; N'Kaoua, Bernard; Lachapelle, Yves

2017-04-01

Access to residential settings for people with intellectual disabilities (ID) contributes to their social participation, but presents particular challenges. Assistive technologies can help people perform activities of daily living. However, the majority of the computerized solutions offered use guidance modes with a fixed, unchanging sequencing that leaves little room for self-determination to emerge. The objective of the project was to develop a flexible guidance mode and to test it with participants, to describe their information organization methods. This research used a descriptive exploratory design and conducted a comparison between five participants with ID and five participants with no ID. The results showed a difference in the information organization methods for both categories of participants. The people with ID used more diversified organization methods (categorical, schematic, action-directed) than the neurotypical participants (visual, action-directed). These organization methods varied depending on the people, but also on the characteristics of the requested task. Furthermore, several people with ID presented difficulties when switching from virtual to real mode. These results demonstrate the importance of developing flexible guidance modes adapted to the users' cognitive strategies, to maximize their benefits. Studies using experimental designs will have to be conducted to determine the impacts of more-flexible guidance modes Implications for rehabilitation Intervention approaches favouring, self-determination, decision making, action analysis and results anticipation must be promoted with people with intellectual disabilities. Fixed and rigid technological guidance mode, like those currently favoured in interventions, is appropriate for only some people's profiles or may depend on the nature of the task. It seems that people with ID use a wide spectrum of organization strategies and that adapting guidance modes to all these strategies is relevant.

A Signature Pedagogy for Leadership Education: Preparing Principals through Participatory Action Research

ERIC Educational Resources Information Center

Sappington, Neil; Baker, Paul J.; Gardner, Dianne; Pacha, Joe

2010-01-01

This study proposes participatory action research as a signature pedagogy for principal preparation programs. Signature pedagogies bring professional knowledge and core values together in distinctive teaching and learning arrangements. A rationale and learning results are presented that describe key components of action research intended to help…

Action Research Approach on Mobile Learning Design for the Underserved

ERIC Educational Resources Information Center

Kim, Paul H.

2009-01-01

This paper discusses an action research study focused on developing a mobile learning model of literacy development for underserved migrant indigenous children in Latin America. The research study incorporated a cyclical action model with four distinctive stages (Strategize, Apply, Evaluate, and Reflect) designed to guide constituencies involved…

The Perceived Threat of Affirmative Action Policy

DTIC Science & Technology

1975-06-06

as- sumption was made that affirmative action threat was a phenomenon which was separate and distinct from general racial feelings. The...the respond- ents. However, affirmative action threat was found to be differentially related to general racial feelings at the .001 confidence...level. Thus, affirmative action threat feelings were not independent from general racial feelings. Based on the findings of this study, it was

Hadron spectrum in quenched lattice QCD and distribution of zero modes

NASA Astrophysics Data System (ADS)

Iwasaki, Yoichi

1989-06-01

I report the results of the calculation of the hadron spectrum with the standard one-plaquette gauge action on a 16★★3★48 lattice at β=5.85 in the quenched lattice QCD. The result remarkably agrees with that of quark potential models for the case where the quark mass is equal to or is larger than the strange quark mass, even when one uses the standard one-plaquette gauge action. This is contrary to what is stated in the literature. We clarify the reason of the discrepancy, paying close attention to systematic errors in numerical calculations. Further, I show the distribution of zero modes of quark matrix, both in the cases of a RG improved gauge action and the standard action, and discuss the difference between the two cases.

Electromagnetic coupling and array packing induce exchange of dominance on complex modes in 3D periodic arrays of spheres with large permittivity

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

Campione, Salvatore; Capolino, Filippo

In this study, we investigate the effect on wave propagation of array packing and electromagnetic coupling between spheres in a three-dimensional (3D) lattice of microspheres with large permittivity that exhibit strong magnetic polarizability. We report on the complex wavenumber of Bloch waves in the lattice when each sphere is assumed to possess both electric and magnetic dipoles and full electromagnetic coupling is accounted for. While for small material-filling fractions we always determine one dominant mode with low attenuation constant, the same does not happen for large filling fractions, when electromagnetic coupling is included. In the latter case we peculiarly observemore » two dominant modes with low attenuation constant, dominant in different frequency ranges. The filling fraction threshold for which two dominant modes appear varies for different metamaterial constituents, as proven by considering spheres made by either titanium dioxide or lead telluride. As further confirmation of our findings, we retrieve the complex propagation constant of the dominant mode(s) via a field fitting procedure employing two sets of waves (direct and reflected) pertaining to two distinct modes, strengthening the presence of the two distinct dominant modes for increasing filling fractions. However, given that one mode only, with transverse polarization, at any given frequency, is dominant and able to propagate inside the lattice, we are able to accurately treat the metamaterial that is known to exhibit artificial magnetism as a homogeneous material with effective parameters, such as the refractive index. Results clearly show that the account of both electric and magnetic scattering processes in evaluating all electromagnetic intersphere couplings is essential for a proper description of the electromagnetic propagation in lattices.« less

Electromagnetic coupling and array packing induce exchange of dominance on complex modes in 3D periodic arrays of spheres with large permittivity

DOE PAGES

Campione, Salvatore; Capolino, Filippo

2016-01-25

In this study, we investigate the effect on wave propagation of array packing and electromagnetic coupling between spheres in a three-dimensional (3D) lattice of microspheres with large permittivity that exhibit strong magnetic polarizability. We report on the complex wavenumber of Bloch waves in the lattice when each sphere is assumed to possess both electric and magnetic dipoles and full electromagnetic coupling is accounted for. While for small material-filling fractions we always determine one dominant mode with low attenuation constant, the same does not happen for large filling fractions, when electromagnetic coupling is included. In the latter case we peculiarly observemore » two dominant modes with low attenuation constant, dominant in different frequency ranges. The filling fraction threshold for which two dominant modes appear varies for different metamaterial constituents, as proven by considering spheres made by either titanium dioxide or lead telluride. As further confirmation of our findings, we retrieve the complex propagation constant of the dominant mode(s) via a field fitting procedure employing two sets of waves (direct and reflected) pertaining to two distinct modes, strengthening the presence of the two distinct dominant modes for increasing filling fractions. However, given that one mode only, with transverse polarization, at any given frequency, is dominant and able to propagate inside the lattice, we are able to accurately treat the metamaterial that is known to exhibit artificial magnetism as a homogeneous material with effective parameters, such as the refractive index. Results clearly show that the account of both electric and magnetic scattering processes in evaluating all electromagnetic intersphere couplings is essential for a proper description of the electromagnetic propagation in lattices.« less

Bacterial cell wall composition and the influence of antibiotics by cell-wall and whole-cell NMR

PubMed Central

Romaniuk, Joseph A. H.; Cegelski, Lynette

2015-01-01

The ability to characterize bacterial cell-wall composition and structure is crucial to understanding the function of the bacterial cell wall, determining drug modes of action and developing new-generation therapeutics. Solid-state NMR has emerged as a powerful tool to quantify chemical composition and to map cell-wall architecture in bacteria and plants, even in the context of unperturbed intact whole cells. In this review, we discuss solid-state NMR approaches to define peptidoglycan composition and to characterize the modes of action of old and new antibiotics, focusing on examples in Staphylococcus aureus. We provide perspectives regarding the selected NMR strategies as we describe the exciting and still-developing cell-wall and whole-cell NMR toolkit. We also discuss specific discoveries regarding the modes of action of vancomycin analogues, including oritavancin, and briefly address the reconsideration of the killing action of β-lactam antibiotics. In such chemical genetics approaches, there is still much to be learned from perturbations enacted by cell-wall assembly inhibitors, and solid-state NMR approaches are poised to address questions of cell-wall composition and assembly in S. aureus and other organisms. PMID:26370936

Two-mode back-action-evading measurements in cavity optomechanics

NASA Astrophysics Data System (ADS)

Woolley, M. J.; Clerk, A. A.

2013-06-01

We study theoretically a three-mode optomechanical system where two mechanical oscillators are coupled to a single cavity mode. By using two-tone (i.e., amplitude-modulated) driving of the cavity, it is possible to couple the cavity to a single collective quadrature of the mechanical oscillators. In such a way, a back-action-evading measurement of the collective mechanical quadrature is possible. We discuss how this can allow one to measure both quadratures of a mechanical force beyond the full quantum limit, paying close attention to the role of dissipation and experimental imperfections. We also describe how this scheme allows one to generate steady-state mechanical entanglement; namely, one can conditionally prepare an entangled, two-mode squeezed mechanical state. This entanglement can be verified directly from the measurement record by applying a generalized version of Duan's inequality; we also discuss how feedback can be used to produce unconditional entanglement.

Mirror neuron activation of musicians and non-musicians in response to motion captured piano performances.

PubMed

Hou, Jiancheng; Rajmohan, Ravi; Fang, Dan; Kashfi, Karl; Al-Khalil, Kareem; Yang, James; Westney, William; Grund, Cynthia M; O'Boyle, Michael W

2017-07-01

Mirror neurons (MNs) activate when performing an action and when an observer witnesses the same action performed by another individual. Functional magnetic resonance imaging (fMRI) and presentation of motion captured piano performances were used to identify differences in MN activation for musicians/non-musicians when viewing piano pieces played in a "Correct" mode (i.e., emphasis on technical correctness) or an "Enjoyment" mode (i.e., simply told to "enjoy" playing the piece). Results showed greater MN activation in a variety of brain regions for musicians, with these differences more pronounced in the "Enjoyment" mode. Our findings suggest that activation of MNs is not only initiated by the imagined action of an observed movement, but such activation is modulated by the level of musical expertise and knowledge of associated motor movements that the observer brings to the viewing situation. Enhanced MN activation in musicians may stem from imagining themselves actually playing the observed piece. Copyright © 2017 Elsevier Inc. All rights reserved.

Mode of Action of Lactoperoxidase as Related to Its Antimicrobial Activity: A Review

PubMed Central

Bafort, F.; Parisi, O.; Perraudin, J.-P.; Jijakli, M. H.

2014-01-01

Lactoperoxidase is a member of the family of the mammalian heme peroxidases which have a broad spectrum of activity. Their best known effect is their antimicrobial activity that arouses much interest in in vivo and in vitro applications. In this context, the proper use of lactoperoxidase needs a good understanding of its mode of action, of the factors that favor or limit its activity, and of the features and properties of the active molecules. The first part of this review describes briefly the classification of mammalian peroxidases and their role in the human immune system and in host cell damage. The second part summarizes present knowledge on the mode of action of lactoperoxidase, with special focus on the characteristics to be taken into account for in vitro or in vivo antimicrobial use. The last part looks upon the characteristics of the active molecule produced by lactoperoxidase in the presence of thiocyanate and/or iodide with implication(s) on its antimicrobial activity. PMID:25309750

A Subjective Rational Choice

NASA Astrophysics Data System (ADS)

Vinogradov, G. P.

2017-01-01

The problem of constructing a choice model of an agent with endogenous purposes of evolution is under debate. It is demonstrated that its solution requires the development of well-known methods of decision-making while taking into account the relation of action mode motivation to an agent’s ambition to implement subjectively understood interests and the environment state. The latter is submitted for consideration as a purposeful state situation model that exists only in the mind of an agent. It is the situation that is a basis for getting an insight into the agent’s ideas on the possible selected action mode results. The agent’s ambition to build his confidence in the feasibility of the action mode and the possibility of achieving the desired state requires him to use the procedures of forming an idea model based on the measured values of environment state. This leads to the gaming approach for the choice problem and its solution can be obtained on a set of trade-off alternatives.

Axinellamines as Broad-Spectrum Antibacterial Agents: Scalable Synthesis and Biology

PubMed Central

2015-01-01

Antibiotic-resistant bacteria present an ongoing challenge to both chemists and biologists as they seek novel compounds and modes of action to out-maneuver continually evolving resistance pathways, especially against Gram-negative strains. The dimeric pyrrole–imidazole alkaloids represent a unique marine natural product class with diverse primary biological activity and chemical architecture. This full account traces the strategy used to develop a second-generation route to key spirocycle 9, culminating in a practical synthesis of the axinellamines and enabling their discovery as broad-spectrum antibacterial agents, with promising activity against both Gram-positive and Gram-negative bacteria. While their detailed mode of antibacterial action remains unclear, the axinellamines appear to cause secondary membrane destabilization and impart an aberrant cellular morphology consistent with the inhibition of normal septum formation. This study serves as a rare example of a natural product initially reported to be devoid of biological activity surfacing as an active antibacterial agent with an intriguing mode of action. PMID:25328977

The cybernetics of TNF: Old views and newer ones.

PubMed

Wallach, David

2016-02-01

The proinflammatory cytokine tumor necrosis factor (TNF) orchestrates complex multicellular processes through a wide variety of changes that it induces in cell functions. At various stages of the study of TNF, attention has been drawn to one of three different modes of its action. The work that led to the discovery of this cytokine addressed situations in which it inflicts massive damage to tissues through a mode of action that appeared to be unrestricted. In the years that followed, attention was drawn to the existence of negative feedback mechanisms that do restrict TNF formation and function, and of reciprocal mechanisms for negatively regulating TNF-induced gene activation and of cell death. Most recently, the discovery of the critical role of TNF in chronic inflammatory diseases directed attention to the ability of TNF also to act with no apparent time restriction. Major gaps still remain in our knowledge of the cellular and molecular basis for these three modes of TNF action. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

Color vision predicts processing modes of goal activation during action cascading.

PubMed

Jongkees, Bryant J; Steenbergen, Laura; Colzato, Lorenza S

2017-09-01

One of the most important functions of cognitive control is action cascading: the ability to cope with multiple response options when confronted with various task goals. A recent study implicates a key role for dopamine (DA) in this process, suggesting higher D1 efficiency shifts the action cascading strategy toward a more serial processing mode, whereas higher D2 efficiency promotes a shift in the opposite direction by inducing a more parallel processing mode (Stock, Arning, Epplen, & Beste, 2014). Given that DA is found in high concentration in the retina and modulation of retinal DA release displays characteristics of D2-receptors (Peters, Schweibold, Przuntek, & Müller, 2000), color vision discrimination might serve as an index of D2 efficiency. We used color discrimination, assessed with the Lanthony Desaturated Panel D-15 test, to predict individual differences (N = 85) in a stop-change paradigm that provides a well-established measure of action cascading. In this task it is possible to calculate an individual slope value for each participant that estimates the degree of overlap in task goal activation. When the stopping process of a previous task goal has not finished at the time the change process toward a new task goal is initiated (parallel processing), the slope value becomes steeper. In case of less overlap (more serial processing), the slope value becomes flatter. As expected, participants showing better color vision were more prone to activate goals in a parallel manner as indicated by a steeper slope. Our findings suggest that color vision might represent a predictor of D2 efficiency and the predisposed processing mode of goal activation during action cascading. Copyright © 2017 Elsevier Ltd. All rights reserved.

The relevance of moral norms in distinct relational contexts: Purity versus harm norms regulate self-directed actions

PubMed Central

Dungan, James A.; Chakroff, Alek; Young, Liane

2017-01-01

Recent efforts to partition the space of morality have focused on the descriptive content of distinct moral domains (e.g., harm versus purity), or alternatively, the relationship between the perpetrator and victim of moral violations. Across three studies, we demonstrate that harm and purity norms are relevant in distinct relational contexts. Moral judgments of purity violations, compared to harm violations, are relatively more sensitive to the negative impact perpetrators have on themselves versus other victims (Study 1). This pattern replicates across a wide array of harm and purity violations varying in severity (Studies 2 and 3). Moreover, while perceptions of harm predict moral judgment consistently across relational contexts, perceptions of purity predict moral judgment more for self-directed actions, where perpetrators violate themselves, compared to dyadic actions, where perpetrators violate other victims (Study 3). Together, these studies reveal how an action’s content and its relational context interact to influence moral judgment, providing novel insights into the adaptive functions of harm and purity norms. PMID:28278214

When ignorance is no excuse: Different roles for intent across moral domains.

PubMed

Young, Liane; Saxe, Rebecca

2011-08-01

A key factor in legal and moral judgments is intent. Intent differentiates, for instance, murder from manslaughter. Is this true for all moral judgments? People deliver moral judgments of many kinds of actions, including harmful actions (e.g., assault) and purity violations (e.g., incest, consuming taboo substances). We show that intent is a key factor for moral judgments of harm, but less of a factor for purity violations. Based on the agent's innocent intent, participants judged accidental harms less morally wrong than accidental incest; based on the agent's guilty intent, participants judged failed attempts to harm more morally wrong than failed attempts to commit incest. These patterns were specific to moral judgments versus judgments of the agent's control, knowledge, or intent, the action's overall emotional salience, or participants' ratings of disgust. The current results therefore reveal distinct cognitive signatures of distinct moral domains, and may inform the distinct functional roles of moral norms. Copyright © 2011 Elsevier B.V. All rights reserved.

Synthesis and structure of a heptanuclear nickel(II) complex uniquely exhibiting four distinct binding modes, two of which are novel, for a hydroxamate ligand.

PubMed

Gaynor, Declan; Starikova, Zoya A; Ostrovsky, Sergei; Haase, Wolfgang; Nolan, Kevin B

2002-03-07

The reaction of 2-(dimethylamino)phenylhydroxamic acid (2-dmAphaH) with NiSO(4).6H2O gives the complex [Ni7(2-dmAphaH-1)2(2-dmApha)8(H2O)2]SO(4).15H2O uniquely exhibiting four distinct hydroxamate binding modes, two of which are novel, and showing both antiferromagnetic and ferromagnetic interactions in contrast to [Cu5(2-dmAphaH-1)4(HSO4)2(MeOH)2].2MeOH, a strongly antiferromagnetic metallacrown formed with CuSO(4).5H2O.

Why have no new herbicide modes of action appeared in recent years?

PubMed

Duke, Stephen O

2012-04-01

Herbicides with new modes of action are badly needed to manage the evolution of resistance of weeds to existing herbicides. Yet no major new mode of action has been introduced to the market place for about 20 years. There are probably several reasons for this. New potential products may have remained dormant owing to concerns that glyphosate-resistant (GR) crops have reduced the market for a new herbicide. The capture of a large fraction of the herbicide market by glyphosate with GR crops led to significantly diminished herbicide discovery efforts. Some of the reduced herbicide discovery research was also due to company consolidations and the availability of more generic herbicides. Another problem might be that the best herbicide molecular target sites may have already been discovered. However, target sites that are not utilized, for which there are inhibitors that are highly effective at killing plants, suggests that this is not true. Results of modern methods of target site discovery (e.g. gene knockout methods) are mostly not public, but there is no evidence of good herbicides with new target sites coming from these approaches. In summary, there are several reasons for a long dry period for new herbicide target sites; however, the relative magnitude of each is unclear. The economic stimulus to the herbicide industry caused by the evolution of herbicide-resistant weeds, especially GR weeds, may result in one or more new modes of action becoming available in the not too distant future. Copyright © 2011 Society of Chemical Industry.

Structure and Mode-of-Action of the Two-Peptide (Class-IIb) Bacteriocins.

PubMed

Nissen-Meyer, Jon; Oppegård, Camilla; Rogne, Per; Haugen, Helen Sophie; Kristiansen, Per Eugen

2010-03-01

This review focuses on the structure and mode-of-action of the two-peptide (class-IIb) bacteriocins that consist of two different peptides whose genes are next to each other in the same operon. Optimal antibacterial activity requires the presence of both peptides in about equal amounts. The two peptides are synthesized as preforms that contain a 15-30 residue double-glycine-type N-terminal leader sequence that is cleaved off at the C-terminal side of two glycine residues by a dedicated ABC-transporter that concomitantly transfers the bacteriocin peptides across cell membranes. Two-peptide bacteriocins render the membrane of sensitive bacteria permeable to a selected group of ions, indicating that the bacteriocins form or induce the formation of pores that display specificity with respect to the transport of molecules. Based on structure-function studies, it has been proposed that the two peptides of two-peptide bacteriocins form a membrane-penetrating helix-helix structure involving helix-helix-interacting GxxxG-motifs that are present in all characterized two-peptide bacteriocins. It has also been suggested that the membrane-penetrating helix-helix structure interacts with an integrated membrane protein, thereby triggering a conformational alteration in the protein, which in turn causes membrane-leakage. This proposed mode-of-action is similar to the mode-of-action of the pediocin-like (class-IIa) bacteriocins and lactococcin A (a class-IId bacteriocin), which bind to a membrane-embedded part of the mannose phosphotransferase permease in a manner that causes membrane-leakage and cell death.

Biophysical Mode-of-Action and Selectivity Analysis of Allosteric Inhibitors of Hepatitis C Virus (HCV) Polymerase.

PubMed

Abdurakhmanov, Eldar; Øie Solbak, Sara; Danielson, U Helena

2017-06-16

Allosteric inhibitors of hepatitis C virus (HCV) non-structural protein 5B (NS5B) polymerase are effective for treatment of genotype 1, although their mode of action and potential to inhibit other isolates and genotypes are not well established. We have used biophysical techniques and a novel biosensor-based real-time polymerase assay to investigate the mode-of-action and selectivity of four inhibitors against enzyme from genotypes 1b (BK and Con1) and 3a. Two thumb inhibitors (lomibuvir and filibuvir) interacted with all three NS5B variants, although the affinities for the 3a enzyme were low. Of the two tested palm inhibitors (dasabuvir and nesbuvir), only dasabuvir interacted with the 1b variant, and nesbuvir interacted with NS5B 3a. Lomibuvir, filibuvir and dasabuvir stabilized the structure of the two 1b variants, but not the 3a enzyme. The thumb compounds interfered with the interaction between the enzyme and RNA and blocked the transition from initiation to elongation. The two allosteric inhibitor types have different inhibition mechanisms. Sequence and structure analysis revealed differences in the binding sites for 1b and 3a variants, explaining the poor effect against genotype 3a NS5B. The indirect mode-of-action needs to be considered when designing allosteric compounds. The current approach provides an efficient strategy for identifying and optimizing allosteric inhibitors targeting HCV genotype 3a.

Determination of the action modes of cellulases from hydrolytic profiles over a time course using fluorescence-assisted carbohydrate electrophoresis.

PubMed

Zhang, Qing; Zhang, Xiaomei; Wang, Peipei; Li, Dandan; Chen, Guanjun; Gao, Peiji; Wang, Lushan

2015-03-01

Fluorescence-assisted carbohydrate electrophoresis (FACE) is a sensitive and simple method for the separation of oligosaccharides. It relies on labeling the reducing ends of oligosaccharides with a fluorophore, followed by PAGE. Concentration changes of oligosaccharides following hydrolysis of a carbohydrate polymer could be quantitatively measured continuously over time using the FACE method. Based on the quantitative analysis, we suggested that FACE was a relatively high-throughput, repeatable, and suitable method for the analysis of the action modes of cellulases. On account of the time courses of their hydrolytic profiles, the apparent processivity was used to show the different action modes of cellulases. Cellulases could be easily differentiated as exoglucanases, β-glucosidases, or endoglucanases. Moreover, endoglucanases from the same glycoside hydrolases family had a variety of apparent processivity, indicating the different modes of action. Endoglucanases with the same binding capacities and hydrolytic activities had similar oligosaccharide profiles, which aided in their classification. The hydrolytic profile of Trichoderma reesei Cel12A, an endoglucanases from T. reesei, contained glucose, cellobiose, and cellotriose, which revealed that it may have a new glucosidase activity, corresponding to that of EC 3.2.1.74. A hydrolysate study of a T. reesei Cel12A-N20A mutant demonstrated that the FACE method was sufficiently sensitive to detect the influence of a single-site mutation on enzymatic activity. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Assessment of Crack Path Prediction in Non-Proportional Mixed-Mode Fatigue

NASA Technical Reports Server (NTRS)

Highsmith, Shelby, Jr.; Johnson, Steve; Swanson, Gregory; Sayyah, Tarek; Pettit, Richard

2008-01-01

Non-proportional mixed-mode loading is present in many systems and a growing crack can experience any manner of mixed-mode loading. Prediction of the resulting crack path is important when assessing potential failure modes or when performing a failure investigation. Current crack path selection criteria are presented along with data for Inconel 718 under non-proportional mixed-mode loading. Mixed-mode crack growth can transition between path deflection mechanisms with very different orientations. Non-proportional fatigue loadings lack a single parameter for input to current crack path criteria. Crack growth transitions were observed in proportional and non-proportional FCG tests. Different paths displayed distinct fracture surface morphologies. New crack path drivers & transition criteria must be developed.

Index theorem and universality properties of the low-lying eigenvalues of improved staggered quarks.

PubMed

Follana, E; Hart, A; Davies, C T H

2004-12-10

We study various improved staggered quark Dirac operators on quenched gluon backgrounds in lattice QCD generated using a Symanzik-improved gluon action. We find a clear separation of the spectrum into would-be zero modes and others. The number of would-be zero modes depends on the topological charge as expected from the index theorem, and their chirality expectation value is large ( approximately 0.7). The remaining modes have low chirality and show clear signs of clustering into quartets and approaching the random matrix theory predictions for all topological charge sectors. We conclude that improvement of the fermionic and gauge actions moves the staggered quarks closer to the continuum limit where they respond correctly to QCD topology.

From current-driven to neoclassically driven tearing modes.

PubMed

Reimerdes, H; Sauter, O; Goodman, T; Pochelon, A

2002-03-11

In the TCV tokamak, the m/n = 2/1 island is observed in low-density discharges with central electron-cyclotron current drive. The evolution of its width has two distinct growth phases, one of which can be linked to a "conventional" tearing mode driven unstable by the current profile and the other to a neoclassical tearing mode driven by a perturbation of the bootstrap current. The TCV results provide the first clear observation of such a destabilization mechanism and reconcile the theory of conventional and neoclassical tearing modes, which differ only in the dominant driving term.

The Structure of Scientific Arguments by Secondary Science Teachers: Comparison of Experimental and Historical Science Topics

ERIC Educational Resources Information Center

Gray, Ron; Kang, Nam-Hwa

2014-01-01

Just as scientific knowledge is constructed using distinct modes of inquiry (e.g. experimental or historical), arguments constructed during science instruction may vary depending on the mode of inquiry underlying the topic. The purpose of this study was to examine whether and how secondary science teachers construct scientific arguments during…

Structure-activity relationship of tryptamine analogues on the heart of venus mercenaria

PubMed Central

Greenberg, M. J.

1960-01-01

A number of tryptamine analogues and other exciter agents have been tested on the heart of Venus mercenaria. The method of estimation of potency, especially for irreversibly acting compounds, is discussed. Specificity of action with respect to the site of action of 5-hydroxytryptamine is defined experimentally. The specific activity of tyramine and phenethylamine and the non-specific excitatory action of indole and skatole indicate that the indole ring is neither necessary nor sufficient for 5-hydroxytryptamine-like activity. Tryptamine analogues differ in mode of action as well as potency. Congeners without a 5-hydroxyl group tend to act more slowly and irreversibly as well as less strongly than 5-hydroxytryptamine. Methyl substitution also increases the time of action and difficulty of reversal. However, the potency of such compounds may be increased or decreased depending upon the position of substitution and the presence of the 5-hydroxyl group. The relations between structure and potency and mode of action are discussed. Suggestions are made concerning the effective conformation of the 5-hydroxytryptamine molecule and the nature of its receptor. ImagesFIG. 7 PMID:13708259

On the effects of viscosity on the stability of a trailing-line vortex

NASA Technical Reports Server (NTRS)

Duck, Peter W.; Khorrami, Mehdi R.

1991-01-01

The linear stability of the Batchelor (1964) vortex is investigated. Particular emphasis is placed on modes found recently in a numerical study by Khorrami (1991). These modes have a number of features very distinct from those found previously for this vortex, including exhibiting small growth rates at large Reynolds numbers and susceptibility to destabilization by viscosity. These modes are described using asymptotic techniques, producing results which compare favorably with fully numerical results at large Reynolds numbers.

Clockwork seesaw mechanisms

NASA Astrophysics Data System (ADS)

Park, Seong Chan; Shin, Chang Sub

2018-01-01

We propose new mechanisms for small neutrino masses based on clockwork mechanism. The Standard Model neutrinos and lepton number violating operators communicate through the zero mode of clockwork gears, one of the two couplings of the zero mode is exponentially suppressed by clockwork mechanism. Including all known examples for the clockwork realization of the neutrino masses, different types of models are realized depending on the profile and chirality of the zero mode fermion. Each type of realization would have phenomenologically distinctive features with the accompanying heavy neutrinos.

Combining growth-promoting genes leads to positive epistasis in Arabidopsis thaliana

PubMed Central

Vanhaeren, Hannes; Gonzalez, Nathalie; Coppens, Frederik; De Milde, Liesbeth; Van Daele, Twiggy; Vermeersch, Mattias; Eloy, Nubia B; Storme, Veronique; Inzé, Dirk

2014-01-01

Several genes positively influence final leaf size in Arabidopsis when mutated or overexpressed. The connections between these growth regulators are still poorly understood although such knowledge would further contribute to understand the processes driving leaf growth. In this study, we performed a combinatorial screen with 13 transgenic Arabidopsis lines with an increased leaf size. We found that from 61 analyzed combinations, 39% showed an additional increase in leaf size and most resulted from a positive epistasis on growth. Similar to what is found in other organisms in which such an epistasis assay was performed, only few genes were highly connected in synergistic combinations as we observed a positive epistasis in the majority of the combinations with samba, BRI1OE or SAUR19OE. Furthermore, positive epistasis was found with combinations of genes with a similar mode of action, but also with genes which affect distinct processes, such as cell proliferation and cell expansion. DOI: http://dx.doi.org/10.7554/eLife.02252.001 PMID:24843021

Selective mode of action of guanidine-containing non-peptides at human NPFF receptors.

PubMed

Findeisen, Maria; Würker, Cäcilia; Rathmann, Daniel; Meier, René; Meiler, Jens; Olsson, Roger; Beck-Sickinger, Annette G

2012-07-12

The binding pocket of both NPFF receptors was investigated, focusing on subtype-selective behavior. By use of four nonpeptidic compounds and the peptide mimetics RF9 and BIBP3226, agonistic and antagonistic properties were characterized. A set of Ala receptor mutants was generated. The binding pocket was narrowed down to the upper part of transmembrane helices V, VI, VII and the extracellular loop 2. Positions 5.27 and 6.59 have been shown to have a strong impact on receptor activation and were suggested to form an acidic, negatively charged binding pocket in both NPFF receptor subtypes. Additionally, position 7.35 was identified to play an important role in functional selectivity. According to docking experiments, the aryl group of AC-216 interacts with position 7.35 in the NPFF(1) but not in the NPFF(2) receptor. These results provide distinct insights into the receptor specific binding pockets, which is necessary for the development of drugs to address the NPFF system.

Selective mode of action of guanidine-containing non-peptides at human NPFF receptors

PubMed Central

Findeisen, Maria; Würker, Cäcilia; Rathmann, Daniel; Meier, René; Meiler, Jens; Olsson, Roger; Beck-Sickinger, Annette G.

2012-01-01

The binding pocket of both NPFF receptors was investigated, focusing on subtype-selective behavior. By using four non-peptidic compounds and the peptide mimetics RF9 and BIBP3226 agonistic and antagonistic properties were characterized. A set of Ala receptor mutants was generated, the binding pocket was narrowed down to the upper part of transmembrane helices V, VI, VII, and the extracellular loop 2. Positions 5.27 and 6.59 have been shown to have a strong impact on receptor activation and were suggested to form an acidic, negatively charged binding pocket in both NPFF receptor subtypes. Additionally, position 7.35 was identified to play an important role in functional selectivity. According to docking experiments, the aryl group of AC-216 interacts with position 7.35 in the NPFF1 but not in the NPFF2 receptor. These results provide distinct insights into the receptor specific binding pockets, which is necessary for the development of drugs to address the NPFF system. PMID:22708927

The antigen 43 structure reveals a molecular Velcro-like mechanism of autotransporter-mediated bacterial clumping

PubMed Central

Heras, Begoña; Totsika, Makrina; Peters, Kate M.; Paxman, Jason J.; Gee, Christine L.; Jarrott, Russell J.; Perugini, Matthew A.; Whitten, Andrew E.; Schembri, Mark A.

2014-01-01

Aggregation and biofilm formation are critical mechanisms for bacterial resistance to host immune factors and antibiotics. Autotransporter (AT) proteins, which represent the largest group of outer-membrane and secreted proteins in Gram-negative bacteria, contribute significantly to these phenotypes. Despite their abundance and role in bacterial pathogenesis, most AT proteins have not been structurally characterized, and there is a paucity of detailed information with regard to their mode of action. Here we report the structure–function relationships of Antigen 43 (Ag43a), a prototypic self-associating AT protein from uropathogenic Escherichia coli. The functional domain of Ag43a displays a twisted L-shaped β-helical structure firmly stabilized by a 3D hydrogen-bonded scaffold. Notably, the distinctive Ag43a L shape facilitates self-association and cell aggregation. Combining all our data, we define a molecular “Velcro-like” mechanism of AT-mediated bacterial clumping, which can be tailored to fit different bacterial lifestyles such as the formation of biofilms. PMID:24335802

Bacterial supersystem for alginate import/metabolism and its environmental and bioenergy applications.

PubMed

Hashimoto, Wataru; Kawai, Shigeyuki; Murata, Kousaku

2010-01-01

Distinct from most alginate-assimilating bacteria that secrete polysaccharide lyases extracellularly, a gram-negative bacterium, Sphingomonas sp. A1 (strain A1), can directly incorporate alginate into its cytoplasm, without degradation, through a "superchannel" consisting of a mouth-like pit on the cell surface, periplasmic binding proteins, and a cytoplasmic membrane-bound ATP-binding cassette transporter. Flagellin homologues function as cell surface alginate receptors essential for expressing the superchannel. Cytoplasmic alginate lyases with different substrate specificities and action modes degrade the polysaccharide to its constituent monosaccharides. The resultant monosaccharides, α-keto acids, are converted to a reduced form by NADPH-dependent reductase, and are finally metabolized in the TCA cycle. Transplantation of the strain A1 superchannel to xenobiotic-degrading sphingomonads enhances bioremediation through the propagation of bacteria with an elevated transport activity. Furthermore, strain A1 cells transformed with Zymomonas mobilis genes for pyruvate decarboxylase and alcohol dehydrogenase II produce considerable amounts of biofuel ethanol from alginate when grown statically. © 2010 Landes Bioscience

The Gram-positive model organism Bacillus subtilis does not form microscopically detectable cardiolipin-specific lipid domains.

PubMed

Pogmore, Alex-Rose; Seistrup, Kenneth H; Strahl, Henrik

2018-04-01

Rather than being homogenous diffusion-dominated structures, biological membranes can exhibit areas with distinct composition and characteristics, commonly termed as lipid domains. Arguably the most comprehensively studied examples in bacteria are domains formed by cardiolipin, which have been functionally linked to protein targeting, the cell division process and the mode of action of membrane-targeting antimicrobials. Cardiolipin domains were originally identified in the Gram-negative model organism Escherichia coli based on preferential staining by the fluorescent membrane dye nonylacridine orange (NAO), and later reported to also exist in other Gram-negative and -positive bacteria. Recently, the lipid-specificity of NAO has been questioned based on studies conducted in E. coli. This prompted us to reanalyse cardiolipin domains in the Gram-positive model organism Bacillus subtilis. Here we show that logarithmically growing B. subtilis does not form microscopically detectable cardiolipin-specific lipid domains, and that NAO is not a specific stain for cardiolipin in this organism.

Polyamines induce adaptive responses in water deficit stressed cucumber roots.

PubMed

Kubiś, Jan; Floryszak-Wieczorek, Jolanta; Arasimowicz-Jelonek, Magdalena

2014-01-01

The aim of this study was to investigate the effect of exogenous polyamines (PAs) on the membrane status and proline level in roots of water stressed cucumber (Cucumis sativus cv. Dar) seedlings. It was found that water shortage resulted in an increase of membrane injury, lipoxygenase (LOX) activity, lipid peroxidation and proline concentration in cucumber roots during progressive dehydration. PA pretreatment resulted in a distinct reduction of the injury index, and this effect was reflected by a lower stress-evoked LOX activity increase and lipid peroxide levels at the end of the stress period. In contrast, PA-supplied stressed roots displayed a higher proline accumulation. The presented results suggest that exogenous PAs are able to alleviate water deficit-induced membrane permeability and diminish LOX activity. Observed changes were accompanied by an accumulation of proline, suggesting that the accumulation of this osmolyte might be another possible mode of action for PAs to attain higher membrane stability, and in this way mitigate water deficit effects in roots of cucumber seedlings.

ESI-MS studies of the reactions of novel platinum(II) complexes containing O,O'-chelated acetylacetonate and sulfur ligands with selected model proteins.

PubMed

Marzo, Tiziano; De Pascali, Sandra A; Gabbiani, Chiara; Fanizzi, Francesco P; Messori, Luigi; Pratesi, Alessandro

2017-08-01

A group of mixed-ligand Pt(II) complexes bearing acetylacetonate and sulphur ligands were recently developed in the University of Lecce as a new class of prospective anticancer agents that manifested promising pharma-cological properties in preliminary in vitro and in vivo tests. Though modelled on the basis of cisplatin, these Pt(II) complexes turned out to exhibit a profoundly distinct mode of action as they were found to act mainly on non-genomic targets rather than on DNA. Accordingly, we have explored here their reactions with two representative model proteins through an established ESI-MS procedure with the aim to describe their general interaction mechanism with protein targets. A pronounced reactivity with the tested proteins was indeed documented; the nature of the resulting metallodrug-protein interactions could be characterised in depth in the various cases. Preferential binding to protein targets compared to DNA is supported by independent ICP-OES measurements. The implications of these findings are discussed.

In Vitro Characterization of Chain Depolymerization Activities of SUMO-Specific Proteases.

PubMed

Eckhoff, Julia; Dohmen, R Jürgen

2016-01-01

SUMO-specific proteases, known as Ulps in baker's yeast and SENPs in humans, have important roles in controlling the dynamics of SUMO-modified proteins. They display distinct modes of action and specificity, in that they may act on the SUMO precursor, mono-sumoylated, and/or polysumoylated proteins, and they might be specific for substrates with certain SUMO paralogs. SUMO chains may be dismantled either by endo or exo mechanisms. Biochemical characterization of a protease usually requires purification of the protein of interest. Developing a purification protocol, however, can be very difficult, and in some cases, isolation of a protease in its pure form may go along with a substantial loss of activity. To characterize the reaction mechanism of Ulps, we have developed an in vitro assay, which makes use of substrates endowed with artificial poly-SUMO chains of defined lengths, and S. cerevisiae Ulp enzymes in crude extract from E. coli. This fast and economic approach should be applicable to SUMO-specific proteases from other species as well.

Snakin: Structure, Roles and Applications of a Plant Antimicrobial Peptide.

PubMed

Oliveira-Lima, Marx; Benko-Iseppon, Ana Maria; Neto, Jose Ribamar Costa Ferreira; Rodriguez-Decuadro, Susana; Kido, Ederson Akio; Crovella, Sergio; Pandolfi, Valesca

2017-01-01

Snakins are plant antimicrobial peptides (AMPs) of the Snakin/GASA family, formed by three distinct regions: an N-terminal signal peptide; a variable site; and the GASA domain in the Cterminal region composed by twelve conserved cysteine residues that contribute to the biochemical stability of the molecule. These peptides are known to play different roles in response to a variety of biotic (i.e., induced by bacteria, fungi and nematode pathogens) and abiotic (salinity, drought and ROS) stressors, as well as in crosstalk promoted by plant hormones, with emphasis on abscisic and salicylic acid (ABA and SA, respectively). Such properties make snakin/GASA members promising biotechnological sources for potential therapeutic and agricultural applications. However, information regarding their tertiary structure, mode of action and function are not yet completely elucidated. The present review presents aspects of snakin structure, expression, functional studies and perspectives about the potential applications for agricultural and medical purposes. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Chiral Tricritical Point: A New Universality Class in Dirac Systems

NASA Astrophysics Data System (ADS)

Yin, Shuai; Jian, Shao-Kai; Yao, Hong

2018-05-01

Tricriticality, as a sister of criticality, is a fundamental and absorbing issue in condensed-matter physics. It has been verified that the bosonic Wilson-Fisher universality class can be changed by gapless fermionic modes at criticality. However, the counterpart phenomena at tricriticality have rarely been explored. In this Letter, we study a model in which a tricritical Ising model is coupled to massless Dirac fermions. We find that the massless Dirac fermions result in the emergence of a new tricritical point, which we refer to as the chiral tricritical point (CTP), at the phase boundary between the Dirac semimetal and the charge-density wave insulator. From functional renormalization group analysis of the effective action, we obtain the critical behaviors of the CTP, which are qualitatively distinct from both the tricritical Ising universality and the chiral Ising universality. We further extend the calculations of the chiral tricritical behaviors of Ising spins to the case of Heisenberg spins. The experimental relevance of the CTP in two-dimensional Dirac semimetals is also discussed.

The glucagon-miniglucagon interplay: a new level in the metabolic regulation.

PubMed

Bataille, Dominique; Fontés, Ghislaine; Costes, Safia; Longuet, Christine; Dalle, Stéphane

2006-07-01

Miniglucagon (glucagon 19-29) is the ultimate processing product of proglucagon, present in the glucagon-secreting granules of the alpha cells, at a close vicinity of the insulin-secreting beta cells. Co-released with glucagon and thanks to its original mode of action and its huge potency, it suppresses, inside the islet of Langerhans, the detrimental effect of glucagon on insulin secretion, while it leaves untouched the beneficial effect of glucagon on glucose competence of the beta cell. At the periphery, miniglucagon is processed at the surface of glucagon- and insulin-sensitive cells from circulating glucagon. At that level, it acts via a cellular pathway which uses initial molecular steps distinct from that of insulin which, when impaired, are involved in insulin resistence. This bypass allows miniglucagon to act as an insulin-like component, a characteristic which makes this peptide of particular interest from a pathophysiological and pharmacological point of views in understanding and treating metabolic diseases, such as the type 2 diabetes.

Passion at a Distance

NASA Astrophysics Data System (ADS)

Howard, Don

In 1984, Abner Shimony invented the expression, “passion at a distance,” to characterize the distinctive relationship of two entangled quantum mechanical systems [1]. It is neither the local causality of pushes, pulls, and central forces familiar from classical mechanics and electrodynamics, nor the non-local causality of instantaneous or just superluminal action at a distance that would spell trouble for relativity theory. This mode of connection of entangled systems has them feeling one another's presence and properties enough to ensure the strong correlations revealed in the Bell experiments, correlations that undergird everything from superfluidity and superconductivity to quantum computing and quantum teleportation, but not in a way that permits direct control of one by manipulation of the other. Intended to echo Aristotle's distinguishing of “potentiality” from “actuality” as different senses of “being,” Shimony's “passion at a distance” is all about tendency and propensity, not the concreteness whose misplacement in realm of the physical was lamented by Alfred North Whitehead.

A sphingolipid-dependent diffusion barrier confines ER stress to the yeast mother cell

PubMed Central

Clay, Lori; Caudron, Fabrice; Denoth-Lippuner, Annina; Boettcher, Barbara; Buvelot Frei, Stéphanie; Snapp, Erik Lee; Barral, Yves

2014-01-01

In many cell types, lateral diffusion barriers compartmentalize the plasma membrane and, at least in budding yeast, the endoplasmic reticulum (ER). However, the molecular nature of these barriers, their mode of action and their cellular functions are unclear. Here, we show that misfolded proteins of the ER remain confined into the mother compartment of budding yeast cells. Confinement required the formation of a lateral diffusion barrier in the form of a distinct domain of the ER-membrane at the bud neck, in a septin-, Bud1 GTPase- and sphingolipid-dependent manner. The sphingolipids, but not Bud1, also contributed to barrier formation in the outer membrane of the dividing nucleus. Barrier-dependent confinement of ER stress into the mother cell promoted aging. Together, our data clarify the physical nature of lateral diffusion barriers in the ER and establish the role of such barriers in the asymmetric segregation of proteotoxic misfolded proteins during cell division and aging. DOI: http://dx.doi.org/10.7554/eLife.01883.001 PMID:24843009

Freestanding Triboelectric Nanogenerator Enables Noncontact Motion-Tracking and Positioning.

PubMed

Guo, Huijuan; Jia, Xueting; Liu, Lue; Cao, Xia; Wang, Ning; Wang, Zhong Lin

2018-04-24

Recent development of interactive motion-tracking and positioning technologies is attracting increasing interests in many areas, such as wearable electronics, intelligent electronics, and the internet of things. For example, the so-called somatosensory technology can afford users strong empathy of immersion and realism due to their consistent interaction with the game. Here, we report a noncontact self-powered positioning and motion-tracking system based on a freestanding triboelectric nanogenerator (TENG). The TENG was fabricated by a nanoengineered surface in the contact-separation mode with the use of a free moving human body (hands or feet) as the trigger. The poly(tetrafluoroethylene) (PTFE) arrays based interactive interface can give an output of 222 V from casual human motions. Different from previous works, this device also responses to a small action at certain heights of 0.01-0.11 m from the device with a sensitivity of about 315 V·m -1 , so that the mechanical sensing is possible. Such a distinctive noncontact sensing feature promotes a wide range of potential applications in smart interaction systems.

Ultrastructural aspects of autoschizis: a new cancer cell death induced by the synergistic action of ascorbate/menadione on human bladder carcinoma cells.

PubMed

Gilloteaux, J; Jamison, J M; Arnold, D; Taper, H S; Summers, J L

2001-01-01

Scanning and transmission electron microscopy were employed to further characterize the cytotoxic effects of a ascorbic acid/menadione (or vitamin C/vitamin K3) combination on a human bladder carcinoma T24 cell line. Following 1-h treatment T24 cells display membrane and mitochondrial defects as well as excision of cytoplasmic fragments that contain no organelles. These continuous self-excisions reduce the cell size. Concomitant, nuclear changes, chromatin disassembly, nucleolar condensation and fragmentation, and decreased nuclear volume lead to cell death via a process similar to karyorrhexis and karyolysis. Because this cell death is achieved through a progressive loss of cytoplasm due to self-morsellation, the authors named this mode of cell death autoschizis (from the Greek autos, self, and schizein, to split, as defined in Scanning. 1998; 20: 564-575). This morphological characterization of autoschizic cell death confirms and extends the authors previous reports and demonstrates that this cell death is distinct from apoptosis.

Bromodomain and extraterminal inhibitors block the Epstein-Barr virus lytic cycle at two distinct steps.

PubMed

Keck, Kristin M; Moquin, Stephanie A; He, Amanda; Fernandez, Samantha G; Somberg, Jessica J; Liu, Stephanie M; Martinez, Delsy M; Miranda, Jj L

2017-08-11

Lytic infection by the Epstein-Barr virus (EBV) poses numerous health risks, such as infectious mononucleosis and lymphoproliferative disorder. Proteins in the bromodomain and extraterminal (BET) family regulate multiple stages of viral life cycles and provide promising intervention targets. Synthetic small molecules can bind to the bromodomains and disrupt function by preventing recognition of acetylated lysine substrates. We demonstrate that JQ1 and other BET inhibitors block two different steps in the sequential cascade of the EBV lytic cycle. BET inhibitors prevent expression of the viral immediate-early protein BZLF1. JQ1 alters transcription of genes controlled by the host protein BACH1, and BACH1 knockdown reduces BZLF1 expression. BET proteins also localize to the lytic origin of replication (OriLyt) genetic elements, and BET inhibitors prevent viral late gene expression. There JQ1 reduces BRD4 recruitment during reactivation to preclude replication initiation. This represents a rarely observed dual mode of action for drugs.

Distinct Sources of Deterministic and Stochastic Components of Action Timing Decisions in Rodent Frontal Cortex.

PubMed

Murakami, Masayoshi; Shteingart, Hanan; Loewenstein, Yonatan; Mainen, Zachary F

2017-05-17

The selection and timing of actions are subject to determinate influences such as sensory cues and internal state as well as to effectively stochastic variability. Although stochastic choice mechanisms are assumed by many theoretical models, their origin and mechanisms remain poorly understood. Here we investigated this issue by studying how neural circuits in the frontal cortex determine action timing in rats performing a waiting task. Electrophysiological recordings from two regions necessary for this behavior, medial prefrontal cortex (mPFC) and secondary motor cortex (M2), revealed an unexpected functional dissociation. Both areas encoded deterministic biases in action timing, but only M2 neurons reflected stochastic trial-by-trial fluctuations. This differential coding was reflected in distinct timescales of neural dynamics in the two frontal cortical areas. These results suggest a two-stage model in which stochastic components of action timing decisions are injected by circuits downstream of those carrying deterministic bias signals. Copyright © 2017 Elsevier Inc. All rights reserved.

Catecholaminergic challenge uncovers distinct Pavlovian and instrumental mechanisms of motivated (in)action

PubMed Central

Swart, Jennifer C; Froböse, Monja I; Cook, Jennifer L; Geurts, Dirk EM; Frank, Michael J; Cools, Roshan; den Ouden, Hanneke EM

2017-01-01

Catecholamines modulate the impact of motivational cues on action. Such motivational biases have been proposed to reflect cue-based, ‘Pavlovian’ effects. Here, we assess whether motivational biases may also arise from asymmetrical instrumental learning of active and passive responses following reward and punishment outcomes. We present a novel paradigm, allowing us to disentangle the impact of reward and punishment on instrumental learning from Pavlovian response biasing. Computational analyses showed that motivational biases reflect both Pavlovian and instrumental effects: reward and punishment cues promoted generalized (in)action in a Pavlovian manner, whereas outcomes enhanced instrumental (un)learning of chosen actions. These cue- and outcome-based biases were altered independently by the catecholamine enhancer melthylphenidate. Methylphenidate’s effect varied across individuals with a putative proxy of baseline dopamine synthesis capacity, working memory span. Our study uncovers two distinct mechanisms by which motivation impacts behaviour, and helps refine current models of catecholaminergic modulation of motivated action. DOI: http://dx.doi.org/10.7554/eLife.22169.001 PMID:28504638

[INVITED] On the mechanisms of single-pulse laser-induced backside wet etching

NASA Astrophysics Data System (ADS)

Tsvetkov, M. Yu.; Yusupov, V. I.; Minaev, N. V.; Akovantseva, A. A.; Timashev, P. S.; Golant, K. M.; Chichkov, B. N.; Bagratashvili, V. N.

2017-02-01

Laser-induced backside wet etching (LIBWE) of a silicate glass surface at interface with a strongly absorbing aqueous dye solution is studied. The process of crater formation and the generated optoacoustic signals under the action of single 5 ns laser pulses at the wavelength of 527 nm are investigated. The single-pulse mode is used to avoid effects of incubation and saturation of the etched depth. Significant differences in the mechanisms of crater formation in the ;soft; mode of laser action (at laser fluencies smaller than 150-170 J/cm2) and in the ;hard; mode (at higher laser fluencies) are observed. In the ;soft; single-pulse mode, LIBWE produces accurate craters with the depth of several hundred nanometers, good shape reproducibility and smooth walls. Estimates of temperature and pressure of the dye solution heated by a single laser pulse indicate that these parameters can significantly exceed the corresponding critical values for water. We consider that chemical etching of glass surface (or molten glass) by supercritical water, produced by laser heating of the aqueous dye solution, is the dominant mechanism responsible for the formation of crater in the ;soft; mode. In the ;hard; mode, the produced craters have ragged shape and poor pulse-to-pulse reproducibility. Outside the laser exposed area, cracks and splits are formed, which provide evidence for the shock induced glass fracture. By measuring the amplitude and spectrum of the generated optoacoustic signals it is possible to conclude that in the ;hard; mode of laser action, intense hydrodynamic processes induced by the formation and cavitation collapse of vapor-gas bubbles at solid-liquid interface are leading to the mechanical fracture of glass. The LIBWE material processing in the ;soft; mode, based on chemical etching in supercritical fluids (in particular, supercritical water) is very promising for structuring of optical materials.

Functional Dissociation between Perception and Action Is Evident Early in Life

ERIC Educational Resources Information Center

Hadad, Bat-Sheva; Avidan, Galia; Ganel, Tzvi

2012-01-01

The functional distinction between vision for perception and vision for action is well documented in the mature visual system. Ganel and colleagues recently provided direct evidence for this dissociation, showing that while visual processing for perception follows Weber's fundamental law of psychophysics, action violates this law. We tracked the…

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

Guardiola, John J.

Background: Occupational vinyl chloride (VC) exposures have been associated with toxicant-associated steatohepatitis and liver cancer. Metabolomics has been used to clarify mode of action in drug-induced liver injury but has not been performed following VC exposures. Methods: Plasma samples from 17 highly exposed VC workers without liver cancer and 27 unexposed healthy volunteers were obtained for metabolite extraction and GC/MS and LC/MS{sup 2} analysis. Following ion identification/quantification, Ingenuity pathway analysis was performed. Results: 613 unique named metabolites were identified. Of these, 189 metabolites were increased in the VC exposure group while 94 metabolites were decreased. Random Forest analysis indicated thatmore » the metabolite signature could separate the groups with 94% accuracy. VC exposures were associated with increased long chain (including arachidonic acid) and essential (including linoleic acid) fatty acids. Occupational exposure increased lipid peroxidation products including monohydroxy fatty acids (including 13-HODE); fatty acid dicarboxylates; and oxidized arachidonic acid products (including 5,9, and 15-HETE). Carnitine and carnitine esters were decreased, suggesting peroxisomal/mitochondrial dysfunction and alternate modes of lipid oxidation. Differentially regulated metabolites were shown to interact with extracellular-signal-regulated kinase 1/2 (ERK1/2), Akt, AMP-activated protein kinase (AMPK), and the N-Methyl-D-aspartate (NMDA) receptor. The top canonical pathways affected by occupational exposure included tRNA charging, nucleotide degradation, amino acid synthesis/degradation and urea cycle. Methionine and homocysteine was increased with decreased cysteine, suggesting altered 1-carbon metabolism. Conclusions: Occupational exposure generated a distinct plasma metabolome with markedly altered lipid and amino acid metabolites. ERK1/2, Akt, AMPK, and NMDA were identified as protein targets for vinyl chloride toxicity. - Highlights: • Occupational vinyl chloride exposure is linked to toxicant-associated steatohepatitis, liver cancer, and other diseases. • Vinyl chloride exposure led to a distinct plasma metabolome with markedly altered lipid and amino acid metabolites. • A metabolomics approach can provide useful information regarding exposure in chemical workers.« less

Failure mode and effects analysis drastically reduced potential risks in clinical trial conduct.

PubMed

Lee, Howard; Lee, Heechan; Baik, Jungmi; Kim, Hyunjung; Kim, Rachel

2017-01-01

Failure mode and effects analysis (FMEA) is a risk management tool to proactively identify and assess the causes and effects of potential failures in a system, thereby preventing them from happening. The objective of this study was to evaluate effectiveness of FMEA applied to an academic clinical trial center in a tertiary care setting. A multidisciplinary FMEA focus group at the Seoul National University Hospital Clinical Trials Center selected 6 core clinical trial processes, for which potential failure modes were identified and their risk priority number (RPN) was assessed. Remedial action plans for high-risk failure modes (RPN >160) were devised and a follow-up RPN scoring was conducted a year later. A total of 114 failure modes were identified with an RPN score ranging 3-378, which was mainly driven by the severity score. Fourteen failure modes were of high risk, 11 of which were addressed by remedial actions. Rescoring showed a dramatic improvement attributed to reduction in the occurrence and detection scores by >3 and >2 points, respectively. FMEA is a powerful tool to improve quality in clinical trials. The Seoul National University Hospital Clinical Trials Center is expanding its FMEA capability to other core clinical trial processes.

The action of the bacterial toxin, microcin B17, on DNA gyrase.

PubMed

Parks, William M; Bottrill, Andrew R; Pierrat, Olivier A; Durrant, Marcus C; Maxwell, Anthony

2007-04-01

Microcin B17 (MccB17) is a peptide-based bacterial toxin that targets DNA gyrase, the bacterial enzyme that introduces supercoils into DNA. The site and mode of action of MccB17 on gyrase are unclear. We review what is currently known about MccB17-gyrase interactions and summarise approaches to understanding its mode of action that involve modification of the toxin. We describe experiments in which treatment of the toxin at high pH leads to the deamidation of two asparagine residues to aspartates. The modified toxin was found to be inactive in vivo and in vitro, suggesting that the Asn residues are essential for activity. Following on from these studies we have used molecular modelling to suggest a 3D structure for microcin B17. We discuss the implications of this model for MccB17 action and investigate the possibility that it binds metal ions.

On the specificity and mode of action of a xylanase from Trametes hirsuta (Wulf.) Pilát.

PubMed

Kubacková, M; Karácsonyi, S; Bilisics, L; Toman, R

1979-11-01

The mode of action of the extracellular endo-(1 leads to 4)-beta-D-xylanase produced by Trametes hirsuta on a (4-0-methyl-D-glucurono)-D-xylan and a modified, essentially neutral D-xylan from white willow (Salix alba L.) has been studied. Xylotetraose and xylohexaose, together with aldotetraouronic and aldohexaouronic acids, were the main products. The acidic oligosaccharides had a 4-O-methyl-D-glucopyranosyluronic acid group attached to the non-reducing D-xylosyl end-group. The action pattern of the xylanase corresponds to that of a typical endo-enzyme that acts more readily in the middle of chain, and the specific region of its action appears to involve five D-xylosyl residues. The products of the enzymic treatment of the D-xylan have revealed a regular distribution of the 4-O-methyl-D-glucopyranosyluronic acid groups attached to the D-xylan backbone.

Emerging approaches in Parkinson’s disease – adjunctive role of safinamide

PubMed Central

Müller, Thomas

2016-01-01

Ongoing neuronal death in Parkinson’s disease (PD) causes an altered neurotransmission of various biogenic amines, particularly dopamine. As these changes do not follow a distinct pattern, they vary individually, and are differently pronounced. As a result, a heterogeneous onset of motor and nonmotor features occurs in each patient with PD during the whole course of the disease. PD actually describes a set of distinct diseases that manifest themselves in clinical syndromes with certain similarities but also great differences. This clinical picture responds to drugs with a broad spectrum of modes of actions better than to compounds with an exclusive focus on specific receptor subtypes. Therefore, safinamide is an ideal candidate for treatment of patients with PD, since its pharmacological profile includes reversible monoamine oxidase-B inhibition, blockade of voltage-dependent sodium channels, modulation of calcium channels, and inhibition of glutamate release. Safinamide is applied only once daily. Its oral dose ranges from 50 to 100 mg. Safinamide was well tolerated and safe in the clinical development program that demonstrated the amelioration of motor symptoms and OFF phenomena by safinamide when combined with dopamine agonists or levodopa. In the real world of maintenance of patients with PD, effects of safinamide application resemble therapy with classical monoamine oxidase inhibitors or amantadine in combination with other dopamine-substituting drugs. Safinamide is becoming increasingly available in the EU despite complex approval and pricing scenarios. PMID:27536120

Emerging approaches in Parkinson's disease - adjunctive role of safinamide.

PubMed

Müller, Thomas

2016-01-01

Ongoing neuronal death in Parkinson's disease (PD) causes an altered neurotransmission of various biogenic amines, particularly dopamine. As these changes do not follow a distinct pattern, they vary individually, and are differently pronounced. As a result, a heterogeneous onset of motor and nonmotor features occurs in each patient with PD during the whole course of the disease. PD actually describes a set of distinct diseases that manifest themselves in clinical syndromes with certain similarities but also great differences. This clinical picture responds to drugs with a broad spectrum of modes of actions better than to compounds with an exclusive focus on specific receptor subtypes. Therefore, safinamide is an ideal candidate for treatment of patients with PD, since its pharmacological profile includes reversible monoamine oxidase-B inhibition, blockade of voltage-dependent sodium channels, modulation of calcium channels, and inhibition of glutamate release. Safinamide is applied only once daily. Its oral dose ranges from 50 to 100 mg. Safinamide was well tolerated and safe in the clinical development program that demonstrated the amelioration of motor symptoms and OFF phenomena by safinamide when combined with dopamine agonists or levodopa. In the real world of maintenance of patients with PD, effects of safinamide application resemble therapy with classical monoamine oxidase inhibitors or amantadine in combination with other dopamine-substituting drugs. Safinamide is becoming increasingly available in the EU despite complex approval and pricing scenarios.

Potent and efficacious inhibition of CXCR2 signaling by biparatopic nanobodies combining two distinct modes of action.

PubMed

Bradley, M E; Dombrecht, B; Manini, J; Willis, J; Vlerick, D; De Taeye, S; Van den Heede, K; Roobrouck, A; Grot, E; Kent, T C; Laeremans, T; Steffensen, S; Van Heeke, G; Brown, Z; Charlton, S J; Cromie, K D

2015-02-01

Chemokines and chemokine receptors are key modulators in inflammatory diseases and malignancies. Here, we describe the identification and pharmacologic characterization of nanobodies selectively blocking CXCR2, the most promiscuous of all chemokine receptors. Two classes of selective monovalent nanobodies were identified, and detailed epitope mapping showed that these bind to distinct, nonoverlapping epitopes on the CXCR2 receptor. The N-terminal-binding or class 1 monovalent nanobodies possessed potencies in the single-digit nanomolar range but lacked complete efficacy at high agonist concentrations. In contrast, the extracellular loop-binding or class 2 monovalent nanobodies were of lower potency but were more efficacious and competitively inhibited the CXCR2-mediated functional response in both recombinant and neutrophil in vitro assays. In addition to blocking CXCR2 signaling mediated by CXCL1 (growth-related oncogene α) and CXCL8 (interleukin-8), both classes of nanobodies displayed inverse agonist behavior. Bivalent and biparatopic nanobodies were generated, respectively combining nanobodies from the same or different classes via glycine/serine linkers. Interestingly, receptor mutation and competition studies demonstrated that the biparatopic nanobodies were able to avidly bind epitopes within one or across two CXCR2 receptor molecules. Most importantly, the biparatopic nanobodies were superior over their monovalent and bivalent counterparts in terms of potency and efficacy. Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.

Distinct Roles of Chromatin Insulator Proteins in Control of the Drosophila Bithorax Complex

PubMed Central

Savitsky, Mikhail; Kim, Maria; Kravchuk, Oksana; Schwartz, Yuri B.

2016-01-01

Chromatin insulators are remarkable regulatory elements that can bring distant genomic sites together and block unscheduled enhancer–promoter communications. Insulators act via associated insulator proteins of two classes: sequence-specific DNA binding factors and “bridging” proteins. The latter are required to mediate interactions between distant insulator elements. Chromatin insulators are critical for correct expression of complex loci; however, their mode of action is poorly understood. Here, we use the Drosophila bithorax complex as a model to investigate the roles of the bridging proteins Cp190 and Mod(mdg4). The bithorax complex consists of three evolutionarily conserved homeotic genes Ubx, abd-A, and Abd-B, which specify anterior–posterior identity of the last thoracic and all abdominal segments of the fly. Looking at effects of CTCF, mod(mdg4), and Cp190 mutations on expression of the bithorax complex genes, we provide the first functional evidence that Mod(mdg4) acts in concert with the DNA binding insulator protein CTCF. We find that Mod(mdg4) and Cp190 are not redundant and may have distinct functional properties. We, for the first time, demonstrate that Cp190 is critical for correct regulation of the bithorax complex and show that Cp190 is required at an exceptionally strong Fub insulator to partition the bithorax complex into two topological domains. PMID:26715665

CACODYLIC ACID (DMAV): METABOLISM AND ...

EPA Pesticide Factsheets

The cacodylic acid (DMAV) issue paper discusses the metabolism and pharmacokinetics of the various arsenical chemicals; evaluates the appropriate dataset to quantify the potential cancer risk to the organic arsenical herbicides; provides an evaluation of the mode of carcinogenic action (MOA) for DMAV including a consideration of the key events for bladder tumor formation in rats, other potential modes of action; and also considers the human relevance of the proposed animal MOA. As part of tolerance reassessment under the Food Quality Protection Act for the August 3, 2006 deadline, the hazard of cacodylic acid is being reassessed.

IRA: Intrusion - Reaction - Appats

DTIC Science & Technology

2004-11-01

deuxième phase fut de mettre en œuvre un IDS au sein d’une plate-forme de tests afin d’en présenter les différents aspects. Les trois ...local et / ou distant vers le Responsable SSI 4 / Analyse 3.2.2 Modes d’action des IDS Trois modes d’actions sont caractéristiques des outils de...et la capture des informations. La figure suivante montre ce que pourrait être un honeynet. Trois réseaux séparés par un pare-feu : l’Internet

Distinct subunits in heteromeric kainate receptors mediate ionotropic and metabotropic function at hippocampal mossy fiber synapses.

PubMed

Ruiz, Arnaud; Sachidhanandam, Shankar; Utvik, Jo Kristian; Coussen, Françoise; Mulle, Christophe

2005-12-14

Heteromeric kainate receptors (KARs) containing both glutamate receptor 6 (GluR6) and KA2 subunits are involved in KAR-mediated EPSCs at mossy fiber synapses in CA3 pyramidal cells. We report that endogenous glutamate, by activating KARs, reversibly inhibits the slow Ca2+-activated K+ current I(sAHP) and increases neuronal excitability through a G-protein-coupled mechanism. Using KAR knockout mice, we show that KA2 is essential for the inhibition of I(sAHP) in CA3 pyramidal cells by low nanomolar concentrations of kainate, in addition to GluR6. In GluR6(-/-) mice, both ionotropic synaptic transmission and inhibition of I(sAHP) by endogenous glutamate released from mossy fibers was lost. In contrast, inhibition of I(sAHP) was absent in KA2(-/-) mice despite the preservation of KAR-mediated EPSCs. These data indicate that the metabotropic action of KARs did not rely on the activation of a KAR-mediated inward current. Biochemical analysis of knock-out mice revealed that KA2 was required for the interaction of KARs with Galpha(q/11)-proteins known to be involved in I(sAHP) modulation. Finally, the ionotropic and metabotropic actions of KARs at mossy fiber synapses were differentially sensitive to the competitive glutamate receptor ligands kainate (5 nM) and kynurenate (1 mM). We propose a model in which KARs could operate in two modes at mossy fiber synapses: through a direct ionotropic action of GluR6, and through an indirect G-protein-coupled mechanism requiring the binding of glutamate to KA2.

Three distinct modes of intron dynamics in the evolution of eukaryotes.

PubMed

Carmel, Liran; Wolf, Yuri I; Rogozin, Igor B; Koonin, Eugene V

2007-07-01

Several contrasting scenarios have been proposed for the origin and evolution of spliceosomal introns, a hallmark of eukaryotic genes. A comprehensive probabilistic model to obtain a definitive reconstruction of intron evolution was developed and applied to 391 sets of conserved genes from 19 eukaryotic species. It is inferred that a relatively high intron density was reached early, i.e., the last common ancestor of eukaryotes contained >2.15 introns/kilobase, and the last common ancestor of multicellular life forms harbored approximately 3.4 introns/kilobase, a greater intron density than in most of the extant fungi and in some animals. The rates of intron gain and intron loss appear to have been dropping during the last approximately 1.3 billion years, with the decline in the gain rate being much steeper. Eukaryotic lineages exhibit three distinct modes of evolution of the intron-exon structure. The primary, balanced mode, apparently, operates in all lineages. In this mode, intron gain and loss are strongly and positively correlated, in contrast to previous reports on inverse correlation between these processes. The second mode involves an elevated rate of intron loss and is prevalent in several lineages, such as fungi and insects. The third mode, characterized by elevated rate of intron gain, is seen only in deep branches of the tree, indicating that bursts of intron invasion occurred at key points in eukaryotic evolution, such as the origin of animals. Intron dynamics could depend on multiple mechanisms, and in the balanced mode, gain and loss of introns might share common mechanistic features.

Design, synthesis, antiviral activity and mode of action of phenanthrene-containing N-heterocyclic compounds inspired by the phenanthroindolizidine alkaloid antofine.

PubMed

Yu, Xiuling; Wei, Peng; Wang, Ziwen; Liu, Yuxiu; Wang, Lizhong; Wang, Qingmin

2016-02-01

The phenanthroindolizidine alkaloid antofine and its analogues have excellent antiviral activity against tobacco mosaic virus (TMV). To simplify the structure and the synthesis of the phenanthroindolizidine alkaloid, a series of phenanthrene-containing N-heterocyclic compounds (compounds 1 to 33) were designed and synthesised, based on the intermolecular interaction of antofine and TMV RNA, and systematically evaluated for their anti-TMV activity. Most of these compounds exhibited good to reasonable anti-TMV activity. The optimum compounds 5, 12 and 21 displayed higher activity than the lead compound antofine and commercial ribavirin. Compound 12 was chosen for field trials of antiviral efficacy against TMV, and was found to exhibit better activity than control plant virus inhibitors. Compounds 5 and 12 were chosen for mode of action studies. The changes in fluorescence intensity of compounds 5 and 12 on separated TMV RNA showed that these small molecules can also bind to TMV RNA, but the mode is very different from that of antofine. The compounds combining phenanthrene and an N-heterocyclic ring could maintain the anti-TMV activity of phenanthroindolizidines, but their modes of action are different from that of antofine. The present study lays a good foundation for us to find more efficient anti-plant virus reagents. © 2015 Society of Chemical Industry.

New Instability Mode in A Driven Granular Gas: Athermal and Thermal Convection

NASA Astrophysics Data System (ADS)

Shukla, Priyanka; Alam, Meheboob

2017-11-01

For a thermally-driven granular gas confined between two plates under gravity, we report a new instability mode which is found to be active at very small values of the heat-loss parameter. We show that the origin of this new mode is tied to the ``thermal'' mode of the well-studied Rayleigh-Benard convection. This is dubbed purely elastic instability since it survives even for perfectly elastic collisions (en = 1). The distinction of this new instability mode from its dissipative/athermal counterpart is clarified for the first time. Furthermore, a weakly nonlinear analysis using Stuart-Landau equation has been carried out for both instability modes, and the underlying bifurcation scenario (supercritical/subcritical) from each mode is elucidated. The resulting linear and nonlinear patterns with respect to inelasticity and gravity are compared.

Emotional modulation of control dilemmas: the role of positive affect, reward, and dopamine in cognitive stability and flexibility.

PubMed

Goschke, Thomas; Bolte, Annette

2014-09-01

Goal-directed action in changing environments requires a dynamic balance between complementary control modes, which serve antagonistic adaptive functions (e.g., to shield goals from competing responses and distracting information vs. to flexibly switch between goals and behavioral dispositions in response to significant changes). Too rigid goal shielding promotes stability but incurs a cost in terms of perseveration and reduced flexibility, whereas too weak goal shielding promotes flexibility but incurs a cost in terms of increased distractibility. While research on cognitive control has long been conducted relatively independently from the study of emotion and motivation, it is becoming increasingly clear that positive affect and reward play a central role in modulating cognitive control. In particular, evidence from the past decade suggests that positive affect not only influences the contents of cognitive processes, but also modulates the balance between complementary modes of cognitive control. In this article we review studies from the past decade that examined effects of induced positive affect on the balance between cognitive stability and flexibility with a focus on set switching and working memory maintenance and updating. Moreover, we review recent evidence indicating that task-irrelevant positive affect and performance-contingent rewards exert different and sometimes opposite effects on cognitive control modes, suggesting dissociations between emotional and motivational effects of positive affect. Finally, we critically review evidence for the popular hypothesis that effects of positive affect may be mediated by dopaminergic modulations of neural processing in prefrontal and striatal brain circuits, and we refine this "dopamine hypothesis of positive affect" by specifying distinct mechanisms by which dopamine may mediate effects of positive affect and reward on cognitive control. We conclude with a discussion of limitations of current research, point to central unresolved questions and outline perspective for future research on affective and motivational modulations of cognitive control modes. Copyright © 2014. Published by Elsevier Ltd.

Clumpak: a program for identifying clustering modes and packaging population structure inferences across K.

PubMed

Kopelman, Naama M; Mayzel, Jonathan; Jakobsson, Mattias; Rosenberg, Noah A; Mayrose, Itay

2015-09-01

The identification of the genetic structure of populations from multilocus genotype data has become a central component of modern population-genetic data analysis. Application of model-based clustering programs often entails a number of steps, in which the user considers different modelling assumptions, compares results across different predetermined values of the number of assumed clusters (a parameter typically denoted K), examines multiple independent runs for each fixed value of K, and distinguishes among runs belonging to substantially distinct clustering solutions. Here, we present Clumpak (Cluster Markov Packager Across K), a method that automates the postprocessing of results of model-based population structure analyses. For analysing multiple independent runs at a single K value, Clumpak identifies sets of highly similar runs, separating distinct groups of runs that represent distinct modes in the space of possible solutions. This procedure, which generates a consensus solution for each distinct mode, is performed by the use of a Markov clustering algorithm that relies on a similarity matrix between replicate runs, as computed by the software Clumpp. Next, Clumpak identifies an optimal alignment of inferred clusters across different values of K, extending a similar approach implemented for a fixed K in Clumpp and simplifying the comparison of clustering results across different K values. Clumpak incorporates additional features, such as implementations of methods for choosing K and comparing solutions obtained by different programs, models, or data subsets. Clumpak, available at http://clumpak.tau.ac.il, simplifies the use of model-based analyses of population structure in population genetics and molecular ecology. © 2015 John Wiley & Sons Ltd.

Theory on the mechanism of distal action of transcription factors: looping of DNA versus tracking along DNA

NASA Astrophysics Data System (ADS)

Murugan, R.

2010-10-01

In this paper, we develop a theory on the mechanism of distal action of the transcription factors, which are bound at their respective cis-regulatory enhancer modules on the promoter-RNA polymerase II (PR) complexes to initiate the transcription event in eukaryotes. We consider both the looping and tracking modes of their distal communication and calculate the mean first passage time that is required for the distal interactions of the complex of enhancer and transcription factor with the PR via both these modes. We further investigate how this mean first passage time is dependent on the length of the DNA segment (L, base-pairs) that connects the cis-regulatory binding site and the respective promoter. When the radius of curvature of this connecting segment of DNA is R that was induced upon binding of the transcription factor at the cis-acting element and RNAPII at the promoter in cis-positions, our calculations indicate that the looping mode of distal action will dominate when L is such that L > 2πR and the tracking mode of distal action will be favored when L < 2πR. The time required for the distal action will be minimum when L = 2πR where the typical value of R for the binding of histones will be R ~ 16 bps and L ~ 102 bps. It seems that the free energy associated with the binding of the transcription factor with its cis-acting element and the distance of this cis-acting element from the corresponding promoter of the gene of interest is negatively correlated. Our results suggest that the looping and tracking modes of distal action are concurrently operating on the transcription activation and the physics that determines the timescales associated with the looping/tracking in the mechanism of action of these transcription factors on the initiation of the transcription event must put a selection pressure on the distribution of the distances of cis-regulatory modules from their respective promoters of the genes. The computational analysis of the upstream sequences of promoters of various genes in the human and mouse genomes for the presence of putative cis-regulatory elements for a set of known transcription factors using the position weight matrices available with the JASPAR database indicates the presence of cis-acting elements with maximum probability at a distance of ~102 bps from the promoters which substantiates our theoretical predictions.

Teleporting a state inside a single bimodal high-Q cavity

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

Pires, Geisa; Baseia, B.; Avelar, A.T.

2005-06-15

We discuss a simplified scheme to teleport a state from one mode to another of the same bimodal cavity, with these two modes having distinct frequencies and orthogonal polarizations. The scheme employs two two-level (Rydberg) atoms plus classical fields (Ramsey zones) and selective atomic state detectors. The result has potential use for the manipulation of quantum information processing.

Distinct ice patterns on solid surfaces with various wettabilities

PubMed Central

Liu, Jie; Zhu, Chongqin; Liu, Kai; Jiang, Ying; Song, Yanlin; Francisco, Joseph S.; Zeng, Xiao Cheng; Wang, Jianjun

2017-01-01

No relationship has been established between surface wettability and ice growth patterns, although ice often forms on top of solid surfaces. Here, we report experimental observations obtained using a process specially designed to avoid the influence of nucleation and describe the wettability-dependent ice morphology on solid surfaces under atmospheric conditions and the discovery of two growth modes of ice crystals: along-surface and off-surface growth modes. Using atomistic molecular dynamics simulation analysis, we show that these distinct ice growth phenomena are attributable to the presence (or absence) of bilayer ice on solid surfaces with different wettability; that is, the formation of bilayer ice on hydrophilic surface can dictate the along-surface growth mode due to the structural match between the bilayer hexagonal ice and the basal face of hexagonal ice (ice Ih), thereby promoting rapid growth of nonbasal faces along the hydrophilic surface. The dramatically different growth patterns of ice on solid surfaces are of crucial relevance to ice repellency surfaces. PMID:29073045

Distinct ice patterns on solid surfaces with various wettabilities.

PubMed

Liu, Jie; Zhu, Chongqin; Liu, Kai; Jiang, Ying; Song, Yanlin; Francisco, Joseph S; Zeng, Xiao Cheng; Wang, Jianjun

2017-10-24

No relationship has been established between surface wettability and ice growth patterns, although ice often forms on top of solid surfaces. Here, we report experimental observations obtained using a process specially designed to avoid the influence of nucleation and describe the wettability-dependent ice morphology on solid surfaces under atmospheric conditions and the discovery of two growth modes of ice crystals: along-surface and off-surface growth modes. Using atomistic molecular dynamics simulation analysis, we show that these distinct ice growth phenomena are attributable to the presence (or absence) of bilayer ice on solid surfaces with different wettability; that is, the formation of bilayer ice on hydrophilic surface can dictate the along-surface growth mode due to the structural match between the bilayer hexagonal ice and the basal face of hexagonal ice (ice I h ), thereby promoting rapid growth of nonbasal faces along the hydrophilic surface. The dramatically different growth patterns of ice on solid surfaces are of crucial relevance to ice repellency surfaces. Published under the PNAS license.

Two ways to listen: Do L2-dominant bilinguals perceive stop voicing according to language mode?

PubMed Central

Antoniou, Mark; Tyler, Michael D.; Best, Catherine T.

2012-01-01

How listeners categorize two phones predicts the success with which they will discriminate the given phonetic distinction. In the case of bilinguals, such perceptual patterns could reveal whether the listener’s two phonological systems are integrated or separate. This is of particular interest when a given contrast is realized differently in each language, as is the case with Greek and English stop-voicing distinctions. We had Greek–English early sequential bilinguals and Greek and English monolinguals (baselines) categorize, rate, and discriminate stop-voicing contrasts in each language. All communication with each group of bilinguals occurred solely in one language mode, Greek or English. The monolingual groups showed the expected native-language constraints, each perceiving their native contrast more accurately than the opposing nonnative contrast. Bilinguals’ category-goodness ratings for the same physical stimuli differed, consistent with their language mode, yet their discrimination performance was unaffected by language mode and biased toward their dominant language (English). We conclude that bilinguals integrate both languages in a common phonetic space that is swayed by their long-term dominant language environment for discrimination, but that they selectively attend to language-specific phonetic information for phonologically motivated judgments (category-goodness ratings). PMID:22844163

The tropospheric biennial oscillation defined by a biennial mode of sea surface temperature and its impact on the atmospheric circulation and precipitation in the tropical eastern Indo-western Pacific region

NASA Astrophysics Data System (ADS)

Kim, Jinju; Kim, Kwang-Yul

2016-10-01

Temporal and spatial patterns of anomalous atmospheric circulation and precipitation over the Indo-Pacific region are analyzed in conjunction with the Tropospheric Biennial Oscillation as represented by the biennial mode of sea surface temperature anomalies (SSTA). The biennial components of key variables are identified independently of other variability via CSEOF analysis. Then, its impact on the Asian-Australian monsoon is examined. The biennial mode exhibits a seasonally distinctive atmospheric response over the tropical eastern Indo-western Pacific (EIWP) region (90°-150°E, 20°S-20°N). In boreal summer, local meridional circulation is a distinguishing characteristic over the tropical EIWP region, whereas a meridionally expanded branch of intensified zonal circulation develops in austral summer. Temporally varying evolution and distinct timing of SSTA phase transition in the Indian and Pacific Oceans is considered a main factor for this variation of circulation in the tropical EIWP region. The impact of the biennial mode is not the same between the two seasons, with different impacts over ocean areas in Asian monsoon and Australian monsoon regions.

Observations of a mode transition in a hydrogen hollow cathode discharge using phase resolved optical emission spectroscopy

NASA Astrophysics Data System (ADS)

Dixon, Sam; Charles, Christine; Dedrick, James; Gans, Timo; O'Connell, Deborah; Boswell, Rod

2014-07-01

Two distinct operational modes are observed in a radio frequency (rf) low pressure hydrogen hollow cathode discharge. The mode transition is characterised by a change in total light emission and differing expansion structures. An intensified CCD camera is used to make phase resolved images of Balmer α emission from the discharge. The low emission mode is consistent with a typical γ discharge, and appears to be driven by secondary electrons ejected from the cathode surface. The bright mode displays characteristics common to an inductive discharge, including increased optical emission, power factor, and temperature of the H2 gas. The bright mode precipitates the formation of a stationary shock in the expansion, observed as a dark region adjacent to the source-chamber interface.

Using thermally stimulated current (TSC) to investigate disorder in micronized drug substance produced at different milling energies.

PubMed

Forcino, Rachel; Brum, Jeffrey; Galop, Marc; Sun, Yan

2010-10-01

To investigate the use of thermally stimulated current (TSC) to characterize disorder resulting from micronization of a crystalline drug substance. Samples processed at different milling energies are characterized, and annealing studied. Molecular mobility in micronized drug substance was studied using TSC and compared to results from differential scanning calorimetry (DSC). The micronized drug substance TSC spectra are compared to crystalline and amorphous references. TSC shows distinct relaxation modes for micronized material in comparison to a single weak exotherm observed with DSC. Molecular mobility modes are unique for micronized material compared to the amorphous reference indicating physically distinct disorder compared to phase-separated amorphous material. Signals are ascribed as arising from crystal defects. TSC differentiates material processed at different milling energies showing reasonable correlation between the AUC of the α-relaxation and micronization energy. The annealing process of crystal defects in micronized drug appears to proceed differently for α and β relaxations. TSC proves sensitive to the crystal defects in the micronized drug substance studied here. The technique is able to differentiate distinct types of disorder and can be used to characterize noncrystalline regions arising from milling processes which are physically distinct from amorphous material.

On the Nature of Problems in Action Learning

ERIC Educational Resources Information Center

Edmonstone, John

2014-01-01

The article aims to explore the nature of problems in action learning. Beginning with Revans' distinction between problems and puzzles, it draws parallels with the notion of wicked and tame problems. It offers four means of considering problems in action learning--in terms of the locus of a set's work; from the viewpoint of an…

Mod 1 wind turbine generator failure modes and effects analysis

NASA Technical Reports Server (NTRS)

1979-01-01

A failure modes and effects analysis (FMEA) was directed primarily at identifying those critical failure modes that would be hazardous to life or would result in major damage to the system. Each subsystem was approached from the top down, and broken down to successive lower levels where it appeared that the criticality of the failure mode warranted more detail analysis. The results were reviewed by specialists from outside the Mod 1 program, and corrective action taken wherever recommended.

Partial Purification and Characterization of the Mode of Action of Enterocin S37: A Bacteriocin Produced by Enterococcus faecalis S37 Isolated from Poultry Feces

PubMed Central

Belguesmia, Y.; Choiset, Y.; Prévost, H.; Dalgalarrondo, M.; Chobert, J.-M.; Drider, D.

2010-01-01

The aim of this research was to purify and characterize the mode of action of enterocin S37, a bacteriocin produced by Enterococcus faecalis S37, a strain recently isolated from the chicken feces. Enterocin S37 has a molecular weight comprised between 4 and 5 kDa. It remained active after 1 h at 80oC and at pH values ranging from 4.0 to 9.0. Furthermore, cell-free supernatant of Enterococcus faecalis S37 and purified enterocin S37 were active against Gram-positive bacteria including Listeria monocytogenes EGDe, L. innocua F, Enterococcus faecalis JH2-2, and Lactobacillus brevis F145. The purification of enterocin S37 was performed by ammonium sulfate precipitation followed up by hydrophobic-interaction chromatography procedures. Treatment of enterocin S37 with proteinase K, α-chymotrypsin, and papain confirmed its proteinaceous nature, while its treatment with lysozyme and lipase resulted in no alteration of activity. Enterocin S37 is hydrophobic, anti-Listeria and likely acting by depletion of intracellular K+ ions upon action on KATP channels. This study contributed to gain more insights into the mode of action of enterocins. PMID:20811593

Partial purification and characterization of the mode of action of enterocin S37: a bacteriocin produced by Enterococcus faecalis S37 isolated from poultry feces.

PubMed

Belguesmia, Y; Choiset, Y; Prévost, H; Dalgalarrondo, M; Chobert, J-M; Drider, D

2010-01-01

The aim of this research was to purify and characterize the mode of action of enterocin S37, a bacteriocin produced by Enterococcus faecalis S37, a strain recently isolated from the chicken feces. Enterocin S37 has a molecular weight comprised between 4 and 5 kDa. It remained active after 1 h at 80(o)C and at pH values ranging from 4.0 to 9.0. Furthermore, cell-free supernatant of Enterococcus faecalis S37 and purified enterocin S37 were active against Gram-positive bacteria including Listeria monocytogenes EGDe, L. innocua F, Enterococcus faecalis JH2-2, and Lactobacillus brevis F145. The purification of enterocin S37 was performed by ammonium sulfate precipitation followed up by hydrophobic-interaction chromatography procedures. Treatment of enterocin S37 with proteinase K, alpha-chymotrypsin, and papain confirmed its proteinaceous nature, while its treatment with lysozyme and lipase resulted in no alteration of activity. Enterocin S37 is hydrophobic, anti-Listeria and likely acting by depletion of intracellular K(+) ions upon action on K(ATP) channels. This study contributed to gain more insights into the mode of action of enterocins.

Antifungal Activity of Eupolauridine and Its Action on DNA Topoisomerases

PubMed Central

Khan, Shabana I.; Nimrod, Alison C.; Mehrpooya, Mohammed; Nitiss, John L.; Walker, Larry A.; Clark, Alice M.

2002-01-01

The azafluoranthene alkaloid eupolauridine has previously been shown to have in vitro antifungal activity and selective inhibition of fungal topoisomerase I. The present study was undertaken to examine further its selectivity and mode of action. Eupolauridine completely inhibits the DNA relaxation activity of purified fungal topoisomerase I at 50 μg/ml, but it does not stabilize the cleavage complex of either human or fungal topoisomerase I. Cleavage complex stabilization is the mode of action of topoisomerase I targeting drugs of the camptothecin family. Also, unlike camptothecin, eupolauridine does not cause significant cytotoxicity in mammalian cells. To determine if the inhibition of topoisomerase I is the principal mode of antifungal action of eupolauridine, Saccharomyces cerevisiae strains with alterations in topoisomerase genes were used in clonogenic assays. The antifungal activity of eupolauridine was not diminished in the absence of topoisomerase I; rather, the cells lacking the enzyme were more sensitive to the drug. Cell-killing activity of eupolauridine was also more pronounced in cells that overexpressed topoisomerase II. In vitro assays with the purified yeast enzyme confirmed that eupolauridine stabilized topoisomerase II covalent complexes. These results indicate that a major target for fungal cell killing by eupolauridine is DNA topoisomerase II rather than topoisomerase I, but does not exclude the possibility that the drug also acts against other targets. PMID:12019091

Antifungal activity of eupolauridine and its action on DNA topoisomerases.

PubMed

Khan, Shabana I; Nimrod, Alison C; Mehrpooya, Mohammed; Nitiss, John L; Walker, Larry A; Clark, Alice M

2002-06-01

The azafluoranthene alkaloid eupolauridine has previously been shown to have in vitro antifungal activity and selective inhibition of fungal topoisomerase I. The present study was undertaken to examine further its selectivity and mode of action. Eupolauridine completely inhibits the DNA relaxation activity of purified fungal topoisomerase I at 50 microg/ml, but it does not stabilize the cleavage complex of either human or fungal topoisomerase I. Cleavage complex stabilization is the mode of action of topoisomerase I targeting drugs of the camptothecin family. Also, unlike camptothecin, eupolauridine does not cause significant cytotoxicity in mammalian cells. To determine if the inhibition of topoisomerase I is the principal mode of antifungal action of eupolauridine, Saccharomyces cerevisiae strains with alterations in topoisomerase genes were used in clonogenic assays. The antifungal activity of eupolauridine was not diminished in the absence of topoisomerase I; rather, the cells lacking the enzyme were more sensitive to the drug. Cell-killing activity of eupolauridine was also more pronounced in cells that overexpressed topoisomerase II. In vitro assays with the purified yeast enzyme confirmed that eupolauridine stabilized topoisomerase II covalent complexes. These results indicate that a major target for fungal cell killing by eupolauridine is DNA topoisomerase II rather than topoisomerase I, but does not exclude the possibility that the drug also acts against other targets.

Coherently coupling distinct spin ensembles through a high critical temperature superconducting resonator

NASA Astrophysics Data System (ADS)

Ghirri, Alberto; Bonizzoni, Claudio; Troiani, Filippo; Affronte, Marco

The problem of coupling remote ensembles of two-level systems through cavity photons is revisited by using molecular spin centers and a high critical temperature superconducting coplanar resonator. By using PyBTM organic radicals, we achieved the strong coupling regime with values of the cooperativity reaching 4300 at 2 K. We show that up to three distinct spin ensembles are simultaneously coupled through the resonator mode. The ensembles are made physically distinguishable by chemically varying the g-factor and by exploiting the inhomogeneities of the applied magnetic field. The coherent mixing of the spin and field modes is demonstrated by the observed multiple anticrossing, along with the simulations performed within the input-output formalism, and quantified by suitable entropic measures.

Multiple exposures to indoor contaminants: Derivation of benchmark doses and relative potency factors based on male reprotoxic effects.

PubMed

Fournier, K; Tebby, C; Zeman, F; Glorennec, P; Zmirou-Navier, D; Bonvallot, N

2016-02-01

Semi-Volatile Organic Compounds (SVOCs) are commonly present in dwellings and several are suspected of having effects on male reproductive function mediated by an endocrine disruption mode of action. To improve knowledge of the health impact of these compounds, cumulative toxicity indicators are needed. This work derives Benchmark Doses (BMD) and Relative Potency Factors (RPF) for SVOCs acting on the male reproductive system through the same mode of action. We included SVOCs fulfilling the following conditions: detection frequency (>10%) in French dwellings, availability of data on the mechanism/mode of action for male reproductive toxicity, and availability of comparable dose-response relationships. Of 58 SVOCs selected, 18 induce a decrease in serum testosterone levels. Six have sufficient and comparable data to derive BMDs based on 10 or 50% of the response. The SVOCs inducing the largest decrease in serum testosterone concentration are: for 10%, bisphenol A (BMD10 = 7.72E-07 mg/kg bw/d; RPF10 = 7,033,679); for 50%, benzo[a]pyrene (BMD50 = 0.030 mg/kg bw/d; RPF50 = 1630), and the one inducing the smallest one is benzyl butyl phthalate (RPF10 and RPF50 = 0.095). This approach encompasses contaminants from diverse chemical families acting through similar modes of action, and makes possible a cumulative risk assessment in indoor environments. The main limitation remains the lack of comparable toxicological data. Copyright © 2015 Elsevier Inc. All rights reserved.

Pathway Based Toxicology and Fit-for-Purpose Assays.

PubMed

Clewell, Rebecca A; McMullen, Patrick D; Adeleye, Yeyejide; Carmichael, Paul L; Andersen, Melvin E

The field of toxicity testing for non-pharmaceutical chemicals is in flux with multiple initiatives in North America and the EU to move away from animal testing to mode-of-action based in vitro assays. In this arena, there are still obstacles to overcome, such as developing appropriate cellular assays, creating pathway-based dose-response models and refining in vitro-in vivo extrapolation (IVIVE) tools. Overall, it is necessary to provide assurances that these new approaches are adequately protective of human and ecological health. Another major challenge for individual scientists and regulatory agencies is developing a cultural willingness to shed old biases developed around animal tests and become more comfortable with mode-of-action based assays in human cells. At present, most initiatives focus on developing in vitro alternatives and assessing how well these alternative methods reproduce past results related to predicting organism level toxicity in intact animals. The path forward requires looking beyond benchmarking against high dose animal studies. We need to develop targeted cellular assays, new cell biology-based extrapolation models for assessing regions of safety for chemical exposures in human populations, and mode-of-action-based approaches which are constructed on an understanding of human biology. Furthermore, it is essential that assay developers have the flexibility to 'validate' against the most appropriate mode-of-action data rather than against apical endpoints in high dose animal studies. This chapter demonstrates the principles of fit-for-purpose assay development using pathway-targeted case studies. The projects include p53-mdm2-mediated DNA-repair, estrogen receptor-mediated cell proliferation and PPARα receptor-mediated liver responses.

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

Chen, L.; McGruer, N. E.; Adams, G. G.

We report the observation of two distinct modes of rate-dependent behavior during contact cycling tests. One is a higher pull-off force at low cycling rates and the other is a higher pull-off force at high cycling rates. Subsequent investigation of these contacts using scanning electron microscopy (SEM) demonstrates that these two rate-dependent modes can be related to brittle and ductile separation modes. The former behavior is indicative of brittle separation, whereas the latter accompanies ductile separation. Thus by monitoring the rate dependence of the pull-off force, the type of separation mode can be identified during cycling without interrupting the testmore » to perform SEM.« less

Hand and mouth: Cortical correlates of lexical processing in British Sign Language and speechreading English

PubMed Central

Capek, Cheryl M.; Waters, Dafydd; Woll, Bencie; MacSweeney, Mairéad; Brammer, Michael J.; McGuire, Philip K.; David, Anthony S.; Campbell, Ruth

2012-01-01

Spoken languages use one set of articulators – the vocal tract, whereas signed languages use multiple articulators, including both manual and facial actions. How sensitive are the cortical circuits for language processing to the particular articulators that are observed? This question can only be addressed with participants who use both speech and a signed language. In this study, we used fMRI to compare the processing of speechreading and sign processing in deaf native signers of British Sign Language (BSL) who were also proficient speechreaders. The following questions were addressed: To what extent do these different language types rely on a common brain network? To what extent do the patterns of activation differ? How are these networks affected by the articulators that languages use? Common perisylvian regions were activated both for speechreading English words and for BSL signs. Distinctive activation was also observed reflecting the language form. Speechreading elicited greater activation in the left mid-superior temporal cortex than BSL, whereas BSL processing generated greater activation at the parieto-occipito-temporal junction in both hemispheres. We probed this distinction further within BSL, where manual signs can be accompanied by different sorts of mouth action. BSL signs with speech-like mouth actions showed greater superior temporal activation, while signs made with non-speech-like mouth actions showed more activation in posterior and inferior temporal regions. Distinct regions within the temporal cortex are not only differentially sensitive to perception of the distinctive articulators for speech and for sign, but also show sensitivity to the different articulators within the (signed) language. PMID:18284353

Loss of Gravitropism in Farnesene-Treated Arabidopsis Is Due to Microtubule Malformations Related to Hormonal and ROS Unbalance

PubMed Central

Araniti, Fabrizio; Graña, Elisa; Krasuska, Urszula; Bogatek, Renata; Reigosa, Manuel J.; Abenavoli, Maria Rosa; Sánchez-Moreiras, Adela M.

2016-01-01

Mode of action of farnesene, a volatile sesquiterpene commonly found in the essential oils of several plants, was deeply studied on the model species Arabidopsis thaliana. The effects of farnesene on the Arabidopsis root morphology were evaluated by different microscopic techniques. As well, microtubules immunolabeling, phytohormone measurements and ROS staining helped us to elucidate the single or multi-modes of action of this sesquiterpene on plant metabolism. Farnesene-treated roots showed a strong growth inhibition and marked modifications on morphology, important tissue alterations, cellular damages and anisotropic growth. Left-handed growth of farnesene-treated roots, reverted by taxol (a known microtubule stabilizer), was related to microtubule condensation and disorganization. As well, the inhibition of primary root growth, lateral root number, lateral root length, and both root hairs length and density could be explained by the strong increment in ethylene production and auxin content detected in farnesene-treated seedlings. Microtubule alteration and hormonal unbalance appear as important components in the mode of action of farnesene and confirm the strong phytotoxic potential of this sesquiterpene. PMID:27490179

Loss of Gravitropism in Farnesene-Treated Arabidopsis Is Due to Microtubule Malformations Related to Hormonal and ROS Unbalance.

PubMed

Araniti, Fabrizio; Graña, Elisa; Krasuska, Urszula; Bogatek, Renata; Reigosa, Manuel J; Abenavoli, Maria Rosa; Sánchez-Moreiras, Adela M

2016-01-01

Mode of action of farnesene, a volatile sesquiterpene commonly found in the essential oils of several plants, was deeply studied on the model species Arabidopsis thaliana. The effects of farnesene on the Arabidopsis root morphology were evaluated by different microscopic techniques. As well, microtubules immunolabeling, phytohormone measurements and ROS staining helped us to elucidate the single or multi-modes of action of this sesquiterpene on plant metabolism. Farnesene-treated roots showed a strong growth inhibition and marked modifications on morphology, important tissue alterations, cellular damages and anisotropic growth. Left-handed growth of farnesene-treated roots, reverted by taxol (a known microtubule stabilizer), was related to microtubule condensation and disorganization. As well, the inhibition of primary root growth, lateral root number, lateral root length, and both root hairs length and density could be explained by the strong increment in ethylene production and auxin content detected in farnesene-treated seedlings. Microtubule alteration and hormonal unbalance appear as important components in the mode of action of farnesene and confirm the strong phytotoxic potential of this sesquiterpene.

Tumor-Preferential Induction of Immune Responses and Epidermal Cell Death in Actinic Keratoses by Ingenol Mebutate

PubMed Central

Zibert, John R.; Schön, Margarete; Hald, Andreas; Hansen, Maria H.; Litman, Thomas; Schön, Michael P.

2016-01-01

The rapid and strong clinical efficacy of the first-in-class, ingenol mebutate, against actinic keratosis (AK) has resulted in its recent approval. We conducted the first comprehensive analysis of the cellular and molecular mode of action of topical ingenol mebutate 0.05% gel in both AK and uninvolved skin of 26 patients in a phase I, single-center, open-label, within-patient comparison. As early as 1 day after application, ingenol mebutate induced profound epidermal cell death, along with a strong infiltrate of CD4+ and CD8+ T-cells, neutrophils, and macrophages. Endothelial ICAM-1 activation became evident after 2 days. The reaction pattern was significantly more pronounced in AK compared with uninvolved skin, suggesting a tumor-preferential mode of action. Extensive molecular analyses and transcriptomic profiling of mRNAs and microRNAs demonstrated alterations in gene clusters functionally associated with epidermal development, inflammation, innate immunity, and response to wounding. Ingenol mebutate reveals a unique mode of action linking directly to anti-tumoral effects. Trial Registration: ClinicalTrials.gov NCT01387711 PMID:27612149

A herbicide structure-activity analysis of the antimalarial lead compound MMV007978 against Arabidopsis thaliana.

PubMed

Corral, Maxime G; Leroux, Julie; Tresch, Stefan; Newton, Trevor; Stubbs, Keith A; Mylne, Joshua S

2018-07-01

To fight herbicide-resistant weeds, new herbicides are needed; particularly ones with new modes of action. Building on the revelation that many antimalarial drugs are herbicidal, here we focus on the Medicines for Malaria Venture antimalarial lead compound MMV007978 that has herbicidal activity against the model plant Arabidopsis thaliana. Twenty-two variations of the lead compound thiophenyl motif revealed that change was tolerated provided ring size and charge were retained. MMV007978 was active against select monocot and dicot weeds, and physiological profiling indicated that its mode of action is related to germination and cell division. Of interest is the fact that the compound has a profile that is currently not found among known herbicides. We demonstrate that the antimalarial compound MMV007978 is also herbicidal and that exploiting lead compounds that are often understudied could lead to the identification of interesting herbicidal scaffolds. Further structural investigation of MMV007978 could provide improved herbicidal chemistries with a potential new mode of action. © 2018 Society of Chemical Industry. © 2018 Society of Chemical Industry.

Mode of action of leucocin K7 produced by Leuconostoc mesenteroides K7 against Listeria monocytogenes and its potential in milk preservation.

PubMed

Shi, Feng; Wang, Yanwei; Li, Yongfu; Wang, Xiaoyuan

2016-09-01

To investigate the mode of action of leucocin K7 against Listeria monocytogenes and to assess its inhibitory effect on Lis. monocytogenes in refrigerated milk. A bacteriocin-producing strain, Leuconostoc mesenteroides K7, was isolated from a fermented pickle. The bacteriocin, leucocin K7, exhibited antagonistic activity against Lis. monocytogenes with an MIC of 28 µg/ml. It was sensitive to proteaseS and displayed good thermal stability and broad active pH range. Leucocin K7 had no effect on the efflux of ATP from Lis. monocytogenes but triggered the efflux of K(+) and the intracellular hydrolysis of ATP. It also dissipated the transmembrane electrical potential completely and transmembrane pH gradient partially. It 80 AU/ml inhibited the growth of Lis. monocytogenes by 2.3-3.9 log units in milk; when combined with glycine (5 mg/ml), it completely eliminated viable Lis. monocytogenes over 7 days Leucocin K7 shows different mode of action from nisin and may have potential application in milk preservation.

Elucidating Duramycin's Bacterial Selectivity and Mode of Action on the Bacterial Cell Envelope.

PubMed

Hasim, Sahar; Allison, David P; Mendez, Berlin; Farmer, Abigail T; Pelletier, Dale A; Retterer, Scott T; Campagna, Shawn R; Reynolds, Todd B; Doktycz, Mitchel J

2018-01-01

The use of naturally occurring antimicrobial peptides provides a promising route to selectively target pathogenic agents and to shape microbiome structure. Lantibiotics, such as duramycin, are one class of bacterially produced peptidic natural products that can selectively inhibit the growth of other bacteria. However, despite longstanding characterization efforts, the microbial selectivity and mode of action of duramycin are still obscure. We describe here a suite of biological, chemical, and physical characterizations that shed new light on the selective and mechanistic aspects of duramycin activity. Bacterial screening assays have been performed using duramycin and Populus -derived bacterial isolates to determine species selectivity. Lipidomic profiles of selected resistant and sensitive strains show that the sensitivity of Gram-positive bacteria depends on the presence of phosphatidylethanolamine (PE) in the cell membrane. Further the surface and interface morphology were studied by high resolution atomic force microscopy and showed a progression of cellular changes in the cell envelope after treatment with duramycin for the susceptible bacterial strains. Together, these molecular and cellular level analyses provide insight into duramycin's mode of action and a better understanding of its selectivity.

[Therapeutic administration of immunoglobulins].

PubMed

Witte, T

2016-12-01

Intravenously administered immunoglobulins have multiple modes of action that are anti-inflammatory. They can therefore be beneficial in a number of autoimmune disorders. The aim of this article is to analyze and summarize studies on the administration of intravenous immunoglobulins in rheumatological diseases. A selective search and analysis of the literature was carried out related to the mode of action and efficacy of intravenous immunoglobulins in rheumatological diseases. Intravenous immunoglobulins have a broad mode of action and can therefore be beneficial in almost all autoimmune diseases. Conditions in which they are of special benefit include immunothrombopenia (ITP), Kawasaki disease and idiopathic inflammatory myopathies. In rare situations, they may also be indicated in systemic lupus erythematosus (SLE), Sjögren's syndrome and neuropathies, catastrophic antiphospholipid syndrome (APS), scleroderma, antineutrophil cytoplasmic antibody (ANCA) associated vasculitis, pyoderma gangrenosum and scleromyxedema. Severe adverse events are rare. In view of the high costs of the therapy, intravenous immunoglobulins are mostly applied in emergency situations, as salvage therapy when other standard therapies have failed or when severe infections are a contraindication to the administration of immunosuppressants.

Transcriptomic Dose-Response Analysis for Mode of Action ...

EPA Pesticide Factsheets

Microarray and RNA-seq technologies can play an important role in assessing the health risks associated with environmental exposures. The utility of gene expression data to predict hazard has been well documented. Early toxicogenomics studies used relatively high, single doses with minimal replication. Thus, they were not useful in understanding health risks at environmentally-relevant doses. Until the past decade, application of toxicogenomics in dose response assessment and determination of chemical mode of action has been limited. New transcriptomic biomarkers have evolved to detect chemical hazards in multiple tissues together with pathway methods to study biological effects across the full dose response range and critical time course. Comprehensive low dose datasets are now available and with the use of transcriptomic benchmark dose estimation techniques within a mode of action framework, the ability to incorporate informative genomic data into human health risk assessment has substantially improved. The key advantage to applying transcriptomic technology to risk assessment is both the sensitivity and comprehensive examination of direct and indirect molecular changes that lead to adverse outcomes. Book Chapter with topic on future application of toxicogenomics technologies for MoA and risk assessment

Metabonomic strategy for the investigation of the mode of action of the phytotoxin (5S,8R,13S,16R)-(-)-pyrenophorol using 1H nuclear magnetic resonance fingerprinting.

PubMed

Aliferis, Konstantinos A; Chrysayi-Tokousbalides, Maria

2006-03-08

The biochemical mode of action of (5S,8R,13S,16R)-(-)-pyrenophorol isolated from a Drechslera avenae pathotype was investigated by using metabolic fingerprinting. (1)H NMR spectra of crude leaf extracts from untreated Avena sterilis seedlings and A. sterilis seedlings treated with pyrenophorol were compared with those obtained from treatments with the herbicides diuron, glyphosate, mesotrione, norflurazon, oxadiazon, and paraquat. Multivariate analysis was carried out to group treatments according to the mode of action of the phytotoxic substances applied. Analysis results revealed that none of the herbicide treatments fitted the pyrenophorol model and indicate that the effect of the phytotoxin on A. sterilis differs than those caused by glyphosate, mesotrione, norflurazon, oxadiazon, paraquat, and diuron, which inhibit 5-enolpyruvylshikimate-3-phosphate synthase, 4-hydroxyphenyl-pyruvate-dioxygenase, phytoene desaturase, protoporphyrinogen oxidase, photosystem I, and photosystem II, respectively. The method applied, combined with appropriate data preprocessing and analysis, was found to be rapid for the screening of phytotoxic substances for metabolic effects.

Exposure of honey bees (Apis mellifera) to different classes of insecticides exhibit distinct molecular effect patterns at concentrations that mimic environmental contamination.

PubMed

Christen, Verena; Fent, Karl

2017-07-01

Pesticides are implicated in the decline of honey bee populations. Many insecticides are neurotoxic and act by different modes of actions. Although a link between insecticide exposure and changed behaviour has been made, molecular effects underlying these effects are poorly understood. Here we elucidated molecular effects at environmental realistic concentrations of two organophosphates, chlorpyrifos and malathion, the pyrethroid cypermethrin, and the ryanodine receptor activator, chlorantraniliprole. We assessed transcriptional alterations of selected genes at three exposure times (24 h, 48 h, 72 h) in caged honey bees exposed to different concentrations of these compounds. Our targeted gene expression concept focused on several transcripts, including nicotinic acetylcholine receptor α 1 and α 2 (nAChRα1, nAChRα2) subunits, the multifunctional gene vitellogenin, immune system related genes of three immune system pathways, genes belonging to the detoxification system and ER stress genes. Our data indicate a dynamic pattern of expressional changes at different exposure times. All four insecticides induced strong alterations in the expression of immune system related genes suggesting negative implications for honey bee health, as well as cytochrome P450 enzyme transcripts suggesting an interference with metabolism. Exposure to neurotoxic chlorpyrifos, malathion and cypermethrin resulted in up-regulation of nAChRα1 and nAChRα2. Moreover, alterations in the expression of vitellogenin occurred, which suggests implications on foraging activity. Chlorantraniliprole induced ER stress which may be related to toxicity. The comparison of all transcriptional changes indicated that the expression pattern is rather compound-specific and related to its mode of action, but clusters of common transcriptional changes between different compounds occurred. As transcriptional alterations occurred at environmental concentrations our data provide a molecular basis for observed adverse effects of these insecticides to bees. Copyright © 2017 Elsevier Ltd. All rights reserved.

Comparative genomic analysis of the multispecies probiotic-marketed product VSL#3.

PubMed

Douillard, François P; Mora, Diego; Eijlander, Robyn T; Wels, Michiel; de Vos, Willem M

2018-01-01

Several probiotic-marketed formulations available for the consumers contain live lactic acid bacteria and/or bifidobacteria. The multispecies product commercialized as VSL#3 has been used for treating various gastro-intestinal disorders. However, like many other products, the bacterial strains present in VSL#3 have only been characterized to a limited extent and their efficacy as well as their predicted mode of action remain unclear, preventing further applications or comparative studies. In this work, the genomes of all eight bacterial strains present in VSL#3 were sequenced and characterized, to advance insights into the possible mode of action of this product and also to serve as a basis for future work and trials. Phylogenetic and genomic data analysis allowed us to identify the 7 species present in the VSL#3 product as specified by the manufacturer. The 8 strains present belong to the species Streptococcus thermophilus, Lactobacillus acidophilus, Lactobacillus paracasei, Lactobacillus plantarum, Lactobacillus helveticus, Bifidobacterium breve and B. animalis subsp. lactis (two distinct strains). Comparative genomics revealed that the draft genomes of the S. thermophilus and L. helveticus strains were predicted to encode most of the defence systems such as restriction modification and CRISPR-Cas systems. Genes associated with a variety of potential probiotic functions were also identified. Thus, in the three Bifidobacterium spp., gene clusters were predicted to encode tight adherence pili, known to promote bacteria-host interaction and intestinal barrier integrity, and to impact host cell development. Various repertoires of putative signalling proteins were predicted to be encoded by the genomes of the Lactobacillus spp., i.e. surface layer proteins, LPXTG-containing proteins, or sortase-dependent pili that may interact with the intestinal mucosa and dendritic cells. Taken altogether, the individual genomic characterization of the strains present in the VSL#3 product confirmed the product specifications, determined its coding capacity as well as identified potential probiotic functions.

Comparative genomic analysis of the multispecies probiotic-marketed product VSL#3

PubMed Central

Mora, Diego; Eijlander, Robyn T.; Wels, Michiel; de Vos, Willem M.

2018-01-01

Several probiotic-marketed formulations available for the consumers contain live lactic acid bacteria and/or bifidobacteria. The multispecies product commercialized as VSL#3 has been used for treating various gastro-intestinal disorders. However, like many other products, the bacterial strains present in VSL#3 have only been characterized to a limited extent and their efficacy as well as their predicted mode of action remain unclear, preventing further applications or comparative studies. In this work, the genomes of all eight bacterial strains present in VSL#3 were sequenced and characterized, to advance insights into the possible mode of action of this product and also to serve as a basis for future work and trials. Phylogenetic and genomic data analysis allowed us to identify the 7 species present in the VSL#3 product as specified by the manufacturer. The 8 strains present belong to the species Streptococcus thermophilus, Lactobacillus acidophilus, Lactobacillus paracasei, Lactobacillus plantarum, Lactobacillus helveticus, Bifidobacterium breve and B. animalis subsp. lactis (two distinct strains). Comparative genomics revealed that the draft genomes of the S. thermophilus and L. helveticus strains were predicted to encode most of the defence systems such as restriction modification and CRISPR-Cas systems. Genes associated with a variety of potential probiotic functions were also identified. Thus, in the three Bifidobacterium spp., gene clusters were predicted to encode tight adherence pili, known to promote bacteria-host interaction and intestinal barrier integrity, and to impact host cell development. Various repertoires of putative signalling proteins were predicted to be encoded by the genomes of the Lactobacillus spp., i.e. surface layer proteins, LPXTG-containing proteins, or sortase-dependent pili that may interact with the intestinal mucosa and dendritic cells. Taken altogether, the individual genomic characterization of the strains present in the VSL#3 product confirmed the product specifications, determined its coding capacity as well as identified potential probiotic functions. PMID:29451876

Gene expression profiles following exposure to a developmental neurotoxicant, Aroclor 1254: Pathway analysis for possible mode(s) of action.

EPA Science Inventory

Epidemiological studies indicate that low levels of polychlorinated biphenyl (PCB) exposure can adversely affect neurocognitive development. In animal models, perturbations in calcium signaling, neurotransmitters, and thyroid hormones have been postulated as potential mechanisms...

P. falciparum in vitro killing rates allow to discriminate between different antimalarial mode-of-action.

PubMed

Sanz, Laura M; Crespo, Benigno; De-Cózar, Cristina; Ding, Xavier C; Llergo, Jose L; Burrows, Jeremy N; García-Bustos, Jose F; Gamo, Francisco-Javier

2012-01-01

Chemotherapy is still the cornerstone for malaria control. Developing drugs against Plasmodium parasites and monitoring their efficacy requires methods to accurately determine the parasite killing rate in response to treatment. Commonly used techniques essentially measure metabolic activity as a proxy for parasite viability. However, these approaches are susceptible to artefacts, as viability and metabolism are two parameters that are coupled during the parasite life cycle but can be differentially affected in response to drug actions. Moreover, traditional techniques do not allow to measure the speed-of-action of compounds on parasite viability, which is an essential efficacy determinant. We present here a comprehensive methodology to measure in vitro the direct effect of antimalarial compounds over the parasite viability, which is based on limiting serial dilution of treated parasites and re-growth monitoring. This methodology allows to precisely determine the killing rate of antimalarial compounds, which can be quantified by the parasite reduction ratio and parasite clearance time, which are key mode-of-action parameters. Importantly, we demonstrate that this technique readily permits to determine compound killing activities that might be otherwise missed by traditional, metabolism-based techniques. The analysis of a large set of antimalarial drugs reveals that this viability-based assay allows to discriminate compounds based on their antimalarial mode-of-action. This approach has been adapted to perform medium throughput screening, facilitating the identification of fast-acting antimalarial compounds, which are crucially needed for the control and possibly the eradication of malaria.

P. falciparum In Vitro Killing Rates Allow to Discriminate between Different Antimalarial Mode-of-Action

PubMed Central

Sanz, Laura M.; Crespo, Benigno; De-Cózar, Cristina; Ding, Xavier C.; Llergo, Jose L.; Burrows, Jeremy N.; García-Bustos, Jose F.; Gamo, Francisco-Javier

2012-01-01

Chemotherapy is still the cornerstone for malaria control. Developing drugs against Plasmodium parasites and monitoring their efficacy requires methods to accurately determine the parasite killing rate in response to treatment. Commonly used techniques essentially measure metabolic activity as a proxy for parasite viability. However, these approaches are susceptible to artefacts, as viability and metabolism are two parameters that are coupled during the parasite life cycle but can be differentially affected in response to drug actions. Moreover, traditional techniques do not allow to measure the speed-of-action of compounds on parasite viability, which is an essential efficacy determinant. We present here a comprehensive methodology to measure in vitro the direct effect of antimalarial compounds over the parasite viability, which is based on limiting serial dilution of treated parasites and re-growth monitoring. This methodology allows to precisely determine the killing rate of antimalarial compounds, which can be quantified by the parasite reduction ratio and parasite clearance time, which are key mode-of-action parameters. Importantly, we demonstrate that this technique readily permits to determine compound killing activities that might be otherwise missed by traditional, metabolism-based techniques. The analysis of a large set of antimalarial drugs reveals that this viability-based assay allows to discriminate compounds based on their antimalarial mode-of-action. This approach has been adapted to perform medium throughput screening, facilitating the identification of fast-acting antimalarial compounds, which are crucially needed for the control and possibly the eradication of malaria. PMID:22383983

Time-optimal thermalization of single-mode Gaussian states

NASA Astrophysics Data System (ADS)

Carlini, Alberto; Mari, Andrea; Giovannetti, Vittorio

2014-11-01

We consider the problem of time-optimal control of a continuous bosonic quantum system subject to the action of a Markovian dissipation. In particular, we consider the case of a one-mode Gaussian quantum system prepared in an arbitrary initial state and which relaxes to the steady state due to the action of the dissipative channel. We assume that the unitary part of the dynamics is represented by Gaussian operations which preserve the Gaussian nature of the quantum state, i.e., arbitrary phase rotations, bounded squeezing, and unlimited displacements. In the ideal ansatz of unconstrained quantum control (i.e., when the unitary phase rotations, squeezing, and displacement of the mode can be performed instantaneously), we study how control can be optimized for speeding up the relaxation towards the fixed point of the dynamics and we analytically derive the optimal relaxation time. Our model has potential and interesting applications to the control of modes of electromagnetic radiation and of trapped levitated nanospheres.

Distinct effects of reminding mortality and physical pain on the default-mode activity and activity underlying self-reflection.

PubMed

Shi, Zhenhao; Han, Shihui

2018-06-01

Behavioral research suggests that reminding both mortality and negative affect influences self-related thoughts. Using functional magnetic resonance imaging (MRI), we tested the hypothesis that reminders of mortality and physical pain decrease brain activity underlying self-related thoughts. Three groups of adults underwent priming procedures during which they answered questions pertaining to mortality, physical pain, or leisure time, respectively. Before and after priming, participants performed personality trait judgments on oneself or a celebrity, identified the font of words, or passively viewed a fixation. The default-mode activity and neural activity underlying self-reflection were identified by contrasting viewing a fixation vs. font judgment and trait judgments on oneself vs. a celebrity, respectively. The analyses of the pre-priming functional MRI (fMRI) data identified the default-mode activity in the posterior cingulate cortex (PCC), ventral medial prefrontal cortex (MPFC), and parahippocampal gyrus, and the activity underlying instructed self-reflection in both the ventral and dorsal regions of the MPFC. The analyses of the post-priming fMRI data revealed that, relative to leisure time priming, reminding mortality significantly reduced the default-mode PCC activity, and reminding physical pain significantly decreased the dorsal MPFC activity during instructed self-reflection. Our findings suggest distinct neural underpinnings of the effect of reminding morality and aversive emotion on default-mode and instructed self-reflection.

Oculomotor learning revisited: a model of reinforcement learning in the basal ganglia incorporating an efference copy of motor actions

PubMed Central

Fee, Michale S.

2012-01-01

In its simplest formulation, reinforcement learning is based on the idea that if an action taken in a particular context is followed by a favorable outcome, then, in the same context, the tendency to produce that action should be strengthened, or reinforced. While reinforcement learning forms the basis of many current theories of basal ganglia (BG) function, these models do not incorporate distinct computational roles for signals that convey context, and those that convey what action an animal takes. Recent experiments in the songbird suggest that vocal-related BG circuitry receives two functionally distinct excitatory inputs. One input is from a cortical region that carries context information about the current “time” in the motor sequence. The other is an efference copy of motor commands from a separate cortical brain region that generates vocal variability during learning. Based on these findings, I propose here a general model of vertebrate BG function that combines context information with a distinct motor efference copy signal. The signals are integrated by a learning rule in which efference copy inputs gate the potentiation of context inputs (but not efference copy inputs) onto medium spiny neurons in response to a rewarded action. The hypothesis is described in terms of a circuit that implements the learning of visually guided saccades. The model makes testable predictions about the anatomical and functional properties of hypothesized context and efference copy inputs to the striatum from both thalamic and cortical sources. PMID:22754501

Oculomotor learning revisited: a model of reinforcement learning in the basal ganglia incorporating an efference copy of motor actions.

PubMed

Fee, Michale S

2012-01-01

In its simplest formulation, reinforcement learning is based on the idea that if an action taken in a particular context is followed by a favorable outcome, then, in the same context, the tendency to produce that action should be strengthened, or reinforced. While reinforcement learning forms the basis of many current theories of basal ganglia (BG) function, these models do not incorporate distinct computational roles for signals that convey context, and those that convey what action an animal takes. Recent experiments in the songbird suggest that vocal-related BG circuitry receives two functionally distinct excitatory inputs. One input is from a cortical region that carries context information about the current "time" in the motor sequence. The other is an efference copy of motor commands from a separate cortical brain region that generates vocal variability during learning. Based on these findings, I propose here a general model of vertebrate BG function that combines context information with a distinct motor efference copy signal. The signals are integrated by a learning rule in which efference copy inputs gate the potentiation of context inputs (but not efference copy inputs) onto medium spiny neurons in response to a rewarded action. The hypothesis is described in terms of a circuit that implements the learning of visually guided saccades. The model makes testable predictions about the anatomical and functional properties of hypothesized context and efference copy inputs to the striatum from both thalamic and cortical sources.

2-(4-aminophenyl) benzothiazole: a potent and selective pharmacophore with novel mechanistic action towards various tumour cell lines.

PubMed

Dubey, Raghvendra; Shrivastava, Prabhat K; Basniwal, Pawan K; Bhattacharya, Snehendu; Moorthy, Narayana S Hari Narayana

2006-06-01

2-(4-aminophenyl) benzothiazole (CJM -126) (Table 1 (1) and its analogues represent a potent and highly selective class of antitumor agents. These compounds in nanomolar range elicit potent growth inhibition in human-derived breast, colon, ovarian and renal tumour cell lines. Metabolism of benzothiazole plays a central role in its mode of action. Cytocrome P450 isoform, CYP1A1, biotransforms benzothiazoles, to active, as well as inactive metabolites. In vitro studies had confirmed that N-oxidation and N-acetylation (only 3' halogen congener) as main active metabolic transformation (generating cytotoxic electrophilic species), while C-6 oxidation and N-acetylation (except 3' halogen congener) as inactive metabolic transformation pathway. Generation of an inactive metabolite 2-(4-aminophenyl)-6-hydoxybenzothiazole [6-OH 126, (Table 1) (10)] is blocked by fluorinated analogue, substituted around benzothiazole nucleus, especially at 5-position. National Cancer Institute (NCI), USA, confirms this series as a unique mechanistic class distinct from clinically used chemotherapeutic agents. Benzothiazoles are potent aryl hydrocarbon receptor (AhR) agonists, binding to AhR results in induction of CYP1A1, causes generation of electrophilic reactive species which forms DNA adduct, ultimately resulting in cell death by activation of apoptotic machinery. To overcome the poor physiochemical and pharmaceutical properties (bioavailability problem) of this compounds, prodrug of benzothiazole derivatives were synthesized, which are introduced in clinical trails.

Co-development of manner and path concepts in language, action, and eye-gaze behavior.

PubMed

Lohan, Katrin S; Griffiths, Sascha S; Sciutti, Alessandra; Partmann, Tim C; Rohlfing, Katharina J

2014-07-01

In order for artificial intelligent systems to interact naturally with human users, they need to be able to learn from human instructions when actions should be imitated. Human tutoring will typically consist of action demonstrations accompanied by speech. In the following, the characteristics of human tutoring during action demonstration will be examined. A special focus will be put on the distinction between two kinds of motion events: path-oriented actions and manner-oriented actions. Such a distinction is inspired by the literature pertaining to cognitive linguistics, which indicates that the human conceptual system can distinguish these two distinct types of motion. These two kinds of actions are described in language by more path-oriented or more manner-oriented utterances. In path-oriented utterances, the source, trajectory, or goal is emphasized, whereas in manner-oriented utterances the medium, velocity, or means of motion are highlighted. We examined a video corpus of adult-child interactions comprised of three age groups of children-pre-lexical, early lexical, and lexical-and two different tasks, one emphasizing manner more strongly and one emphasizing path more strongly. We analyzed the language and motion of the caregiver and the gazing behavior of the child to highlight the differences between the tutoring and the acquisition of the manner and path concepts. The results suggest that age is an important factor in the development of these action categories. The analysis of this corpus has also been exploited to develop an intelligent robotic behavior-the tutoring spotter system-able to emulate children's behaviors in a tutoring situation, with the aim of evoking in human subjects a natural and effective behavior in teaching to a robot. The findings related to the development of manner and path concepts have been used to implement new effective feedback strategies in the tutoring spotter system, which should provide improvements in human-robot interaction. Copyright © 2014 Cognitive Science Society, Inc.

Studying Townsend and glow modes in an atmospheric-pressure DBD using mass spectrometry

NASA Astrophysics Data System (ADS)

McKay, Kirsty; Donaghy, David; He, Feng; Bradley, James W.

2018-01-01

Ambient molecular beam mass spectrometry has been employed to examine the effects of the mode of operation and the excitation waveform on the ionic content of a helium-based atmospheric-pressure parallel plate dielectric barrier discharge. By applying 10 kHz microsecond voltage pulses with a nanosecond rise times and 10 kHz sinusoidal voltage waveforms, distinctly different glow and Townsend modes were produced, respectively. Results showed a significant difference in the dominant ion species between the two modes. In the Townsend mode, molecular oxygen ions, atomic oxygen anions and nitric oxide anions are the most abundant species, however, in the glow mode water clusters ions and hydrated nitric oxygen anions dominate. Several hypotheses are put forward to explain these differences, including low electron densities and energies in the Townsend mode, more efficient ionization of water molecules through penning ionization and charge exchange with other species in glow mode, and large temperature gradients due to the pulsed nature of the glow mode, leading to more favorable conditions for cluster formation.

Multithreading in vector processors

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

Evangelinos, Constantinos; Kim, Changhoan; Nair, Ravi

In one embodiment, a system includes a processor having a vector processing mode and a multithreading mode. The processor is configured to operate on one thread per cycle in the multithreading mode. The processor includes a program counter register having a plurality of program counters, and the program counter register is vectorized. Each program counter in the program counter register represents a distinct corresponding thread of a plurality of threads. The processor is configured to execute the plurality of threads by activating the plurality of program counters in a round robin cycle.

Spin Mode Switching at the Edge of a Quantum Hall System.

PubMed

Khanna, Udit; Murthy, Ganpathy; Rao, Sumathi; Gefen, Yuval

2017-11-03

Quantum Hall states can be characterized by their chiral edge modes. Upon softening the edge potential, the edge has long been known to undergo spontaneous reconstruction driven by charging effects. In this Letter we demonstrate a qualitatively distinct phenomenon driven by exchange effects, in which the ordering of the edge modes at ν=3 switches abruptly as the edge potential is made softer, while the ordering in the bulk remains intact. We demonstrate that this phenomenon is robust, and has many verifiable experimental signatures in transport.

Two aspects of feedforward postural control: anticipatory postural adjustments and anticipatory synergy adjustments.

PubMed

Klous, Miriam; Mikulic, Pavle; Latash, Mark L

2011-05-01

We used the framework of the uncontrolled manifold hypothesis to explore the relations between anticipatory synergy adjustments (ASAs) and anticipatory postural adjustments (APAs) during feedforward control of vertical posture. ASAs represent a drop in the index of a multimuscle-mode synergy stabilizing the coordinate of the center of pressure in preparation to an action. ASAs reflect early changes of an index of covariation among variables reflecting muscle activation, whereas APAs reflect early changes in muscle activation levels averaged across trials. The assumed purpose of ASAs is to modify stability of performance variables, whereas the purpose of APAs is to change magnitudes of those variables. We hypothesized that ASAs would be seen before APAs and that this finding would be consistent with regard to the muscle-mode composition defined on the basis of different tasks and phases of action. Subjects performed a voluntary body sway task and a quick, bilateral shoulder flexion task under self-paced and reaction time conditions. Surface muscle activity of 12 leg and trunk muscles was analyzed to identify sets of 4 muscle modes for each task and for different phases within the shoulder flexion task. Variance components in the muscle-mode space and indexes of multimuscle-mode synergy stabilizing shift of the center of pressure were computed. ASAs were seen ∼ 100-150 ms prior to the task initiation, before APAs. The results were consistent with respect to different sets of muscle modes defined over the two tasks and different shoulder flexion phases. We conclude that the preparation for a self-triggered postural perturbation is associated with two types of anticipatory adjustments, ASAs and APAs. They reflect different feedforward processes within the hypothetical hierarchical control scheme, resulting in changes in patterns of covariation of elemental variables and in their patterns averaged across trials, respectively. The results show that synergies quantified using dissimilar sets of muscle modes show similar feedforward changes in preparation to action.

Linking Language with Embodied and Teleological Representations of Action for Humanoid Cognition

PubMed Central

Lallee, Stephane; Madden, Carol; Hoen, Michel; Dominey, Peter Ford

2010-01-01

The current research extends our framework for embodied language and action comprehension to include a teleological representation that allows goal-based reasoning for novel actions. The objective of this work is to implement and demonstrate the advantages of a hybrid, embodied-teleological approach to action–language interaction, both from a theoretical perspective, and via results from human–robot interaction experiments with the iCub robot. We first demonstrate how a framework for embodied language comprehension allows the system to develop a baseline set of representations for processing goal-directed actions such as “take,” “cover,” and “give.” Spoken language and visual perception are input modes for these representations, and the generation of spoken language is the output mode. Moving toward a teleological (goal-based reasoning) approach, a crucial component of the new system is the representation of the subcomponents of these actions, which includes relations between initial enabling states, and final resulting states for these actions. We demonstrate how grammatical categories including causal connectives (e.g., because, if–then) can allow spoken language to enrich the learned set of state-action-state (SAS) representations. We then examine how this enriched SAS inventory enhances the robot's ability to represent perceived actions in which the environment inhibits goal achievement. The paper addresses how language comes to reflect the structure of action, and how it can subsequently be used as an input and output vector for embodied and teleological aspects of action. PMID:20577629

[Anti-infective treatments in urology].

PubMed

Bruyère, F; Boiteux, J-P; Sotto, A; Karsenty, G; Bastide, C; Guy, L; Lavigne, J-P

2013-11-01

To define the terms of use of vaccines, probiotics, and cranberry in urology. A literature search was conducted on MEDLINE for all these treatments used in urology. Modes of action, indications in urology and adverse effects have been detailed for each treatment. Vaccines have been published in urinary tract infections. Products for bacterial interference such as probiotics are also used, their properties are described. As for the cranberry widely used in recurrent urinary tract infections, efficacy and mode of action are discussed. The anti-E. coli vaccines, cranberry and probiotics may be useful in urinary tract infection. Copyright © 2013 Elsevier Masson SAS. All rights reserved.

Optimal parameters uncoupling vibration modes of oscillators

NASA Astrophysics Data System (ADS)

Le, K. C.; Pieper, A.

2017-07-01

This paper proposes a novel optimization concept for an oscillator with two degrees of freedom. By using specially defined motion ratios, we control the action of springs to each degree of freedom of the oscillator. We aim at showing that, if the potential action of the springs in one period of vibration, used as the payoff function for the conservative oscillator, is maximized among all admissible parameters and motions satisfying Lagrange's equations, then the optimal motion ratios uncouple vibration modes. A similar result holds true for the dissipative oscillator having dampers. The application to optimal design of vehicle suspension is discussed.

EFFECTS OF AZADIRACHTIN ON CUTICULAR PROTEINS OF SPODOPTERA LITURA (LEPIDOPTERA: NOCTUIDAE) VIS-A-VIS THE MODES OF APPLICATION.

PubMed

Yooboon, T; Pluempanupat, W; Koul, Opender; Bullangpoti, V

2015-01-01

Azadirachtin is a known botanical insecticide with multiple modes of action. Whether these effects have any relation with the modes of application, specifically during ecdysis process, has been the objective of the present study and accordingly the impairment, if any, among cuticular proteins of Spodoptera litura (Fab.) was determined. Azadirachtin was applied topically, via injection or oral administration. Azadirachtin administered via injection and topical applications severely impaired the ecdysis by 86.67 and 80.0%, respectively. However, this impairment via oral administration was significantly lower (73.33%). Using SDS-PAGE, the cuticular proteins were determined for treated insects under all the three modes of application. In all cases 6 protein bands (MW 9-34 kDa) were identified using markers as standard. In all treatments 3 induced proteins (MW. ~16, 20 and 23 kDa) and 1 reduced protein (~19 kDa) were observed. In case of the topical treatment a different induced protein of ~18 kDa was identified. The change in cuticular proteins, their possible role in ecdysis impairment vis-a-vis the mode of application of azadirachtin is being correlated. This will help in understanding the mode-of-action at cuticular level and also will allow developing a suitable application strategy under field conditions in insect pest management.

Failure mode and effects analysis drastically reduced potential risks in clinical trial conduct

PubMed Central

Baik, Jungmi; Kim, Hyunjung; Kim, Rachel

2017-01-01

Background Failure mode and effects analysis (FMEA) is a risk management tool to proactively identify and assess the causes and effects of potential failures in a system, thereby preventing them from happening. The objective of this study was to evaluate effectiveness of FMEA applied to an academic clinical trial center in a tertiary care setting. Methods A multidisciplinary FMEA focus group at the Seoul National University Hospital Clinical Trials Center selected 6 core clinical trial processes, for which potential failure modes were identified and their risk priority number (RPN) was assessed. Remedial action plans for high-risk failure modes (RPN >160) were devised and a follow-up RPN scoring was conducted a year later. Results A total of 114 failure modes were identified with an RPN score ranging 3–378, which was mainly driven by the severity score. Fourteen failure modes were of high risk, 11 of which were addressed by remedial actions. Rescoring showed a dramatic improvement attributed to reduction in the occurrence and detection scores by >3 and >2 points, respectively. Conclusions FMEA is a powerful tool to improve quality in clinical trials. The Seoul National University Hospital Clinical Trials Center is expanding its FMEA capability to other core clinical trial processes. PMID:29089745

Antibacterial free fatty acids: activities, mechanisms of action and biotechnological potential.

PubMed

Desbois, Andrew P; Smith, Valerie J

2010-02-01

Amongst the diverse and potent biological activities of free fatty acids (FFAs) is the ability to kill or inhibit the growth of bacteria. The antibacterial properties of FFAs are used by many organisms to defend against parasitic or pathogenic bacteria. Whilst their antibacterial mode of action is still poorly understood, the prime target of FFA action is the cell membrane, where FFAs disrupt the electron transport chain and oxidative phosphorylation. Besides interfering with cellular energy production, FFA action may also result from the inhibition of enzyme activity, impairment of nutrient uptake, generation of peroxidation and auto-oxidation degradation products or direct lysis of bacterial cells. Their broad spectrum of activity, non-specific mode of action and safety makes them attractive as antibacterial agents for various applications in medicine, agriculture and food preservation, especially where the use of conventional antibiotics is undesirable or prohibited. Moreover, the evolution of inducible FFA-resistant phenotypes is less problematic than with conventional antibiotics. The potential for commercial or biomedical exploitation of antibacterial FFAs, especially for those from natural sources, is discussed.

A neural network model of causative actions.

PubMed

Lee-Hand, Jeremy; Knott, Alistair

2015-01-01

A common idea in models of action representation is that actions are represented in terms of their perceptual effects (see e.g., Prinz, 1997; Hommel et al., 2001; Sahin et al., 2007; Umiltà et al., 2008; Hommel, 2013). In this paper we extend existing models of effect-based action representations to account for a novel distinction. Some actions bring about effects that are independent events in their own right: for instance, if John smashes a cup, he brings about the event of the cup smashing. Other actions do not bring about such effects. For instance, if John grabs a cup, this action does not cause the cup to "do" anything: a grab action has well-defined perceptual effects, but these are not registered by the perceptual system that detects independent events involving external objects in the world. In our model, effect-based actions are implemented in several distinct neural circuits, which are organized into a hierarchy based on the complexity of their associated perceptual effects. The circuit at the top of this hierarchy is responsible for actions that bring about independently perceivable events. This circuit receives input from the perceptual module that recognizes arbitrary events taking place in the world, and learns movements that reliably cause such events. We assess our model against existing experimental observations about effect-based motor representations, and make some novel experimental predictions. We also consider the possibility that the "causative actions" circuit in our model can be identified with a motor pathway reported in other work, specializing in "functional" actions on manipulable tools (Bub et al., 2008; Binkofski and Buxbaum, 2013).

Targeting specific azimuthal modes using wall changes in turbulent pipe flow

NASA Astrophysics Data System (ADS)

van Buren, Tyler; Hellström, Leo; Marusic, Ivan; Smits, Alexander

2017-11-01

We experimentally study turbulent pipe flow at Re =3486 using stereoscopic particle image velocimetry. Using pipe inserts with non-circular geometry to perturb the flow upstream of the measurement location, we excite specific naturally occurring energetic modes. We consider inserts that directly manipulate the flow momentum (vortex generators), and/or induce secondary flows through Reynolds stresses (sinusoidally varying wall shape). These inserts substantially change the mean flow, and produce distinct regions of low and high momentum corresponding to the mode being excited. The inserts add energy in the targeted modes while simultaneously reducing the energy in the non-excited azimuthal modes. In addition, inserts designed to excite two modes simultaneously exhibit non-linear interactions. Supported under ONR Grant N00014-15-1-2402, Program Manager/Director Thomas Fu and the Australian Research Council.

Ultralow mode-volume photonic crystal nanobeam cavities for high-efficiency coupling to individual carbon nanotube emitters

PubMed Central

Miura, R.; Imamura, S.; Ohta, R.; Ishii, A.; Liu, X.; Shimada, T.; Iwamoto, S.; Arakawa, Y.; Kato, Y. K.

2014-01-01

The unique emission properties of single-walled carbon nanotubes are attractive for achieving increased functionality in integrated photonics. In addition to being room-temperature telecom-band emitters that can be directly grown on silicon, they are ideal for coupling to nanoscale photonic structures. Here we report on high-efficiency coupling of individual air-suspended carbon nanotubes to silicon photonic crystal nanobeam cavities. Photoluminescence images of dielectric- and air-mode cavities reflect their distinctly different mode profiles and show that fields in the air are important for coupling. We find that the air-mode cavities couple more efficiently, and estimated spontaneous emission coupling factors reach a value as high as 0.85. Our results demonstrate advantages of ultralow mode-volumes in air-mode cavities for coupling to low-dimensional nanoscale emitters. PMID:25420679

14- to 16-Month-Olds Attend to Distinct Labels in an Inductive Reasoning Task.

PubMed

Switzer, Jessica L; Graham, Susan A

2017-01-01

We examined how naming objects with unique labels influenced infants' reasoning about the non-obvious properties of novel objects. Seventy 14- to 16-month-olds participated in an imitation-based inductive inference task during which they were presented with target objects possessing a non-obvious sound property, followed by test objects that varied in shape similarity in comparison to the target. Infants were assigned to one of two groups: a No Label group in which objects were introduced with a general attentional phrase (i.e., "Look at this one") and a Distinct Label group in which target and test objects were labeled with two distinct count nouns (i.e., fep vs. wug ). Infants in the Distinct Label group performed significantly fewer target actions on the high-similarity objects than infants in the No Label group but did not differ in performance of actions on the low-similarity object. Within the Distinct Label group, performance on the inductive inference task was related to age, but not to working memory, inhibitory control, or vocabulary. Within the No Label condition, performance on the inductive inference task was related to a measure of inhibitory control. Our findings suggest that between 14- and 16-months, infants begin to use labels to carve out distinct categories, even when objects are highly perceptually similar.

Learning Computer Science: Perceptions, Actions and Roles

ERIC Educational Resources Information Center

Berglund, Anders; Eckerdal, Anna; Pears, Arnold; East, Philip; Kinnunen, Paivi; Malmi, Lauri; McCartney, Robert; Mostrom, Jan-Erik; Murphy, Laurie; Ratcliffe, Mark; Schulte, Carsten; Simon, Beth; Stamouli, Ioanna; Thomas, Lynda

2009-01-01

This phenomenographic study opens the classroom door to investigate teachers' experiences of students learning difficult computing topics. Three distinct themes are identified and analysed. "Why" do students succeed or fail to learn these concepts? "What" actions do teachers perceive will ameliorate the difficulties facing…

Exploring implicit and explicit aspects of sense of agency

PubMed Central

Moore, J.W.; Middleton, D.; Haggard, P.; Fletcher, P.C.

2012-01-01

Sense of agency refers to the sense of initiating and controlling actions in order to influence events in the outside world. Recently, a distinction between implicit and explicit aspects of sense of agency has been proposed, analogous to distinctions found in other areas of cognition, notably learning. However, there is yet no strong evidence supporting separable implicit and explicit components of sense of agency. The so-called ‘Perruchet paradigm’ offers one of the few convincing demonstrations of separable implicit and explicit learning systems. We adopted this approach to evaluate the implicit–explicit distinction in the context of a simple task in which outcomes were probabilistically caused by actions. In line with our initial predictions, we found evidence of a dissociation. We discuss the implications of this result for theories of sense of agency. PMID:23143153

Models of morality

PubMed Central

Crockett, Molly J.

2013-01-01

Moral dilemmas engender conflicts between two traditions: consequentialism, which evaluates actions based on their outcomes, and deontology, which evaluates actions themselves. These strikingly resemble two distinct decision-making architectures: a model-based system that selects actions based on inferences about their consequences; and a model-free system that selects actions based on their reinforcement history. Here, I consider how these systems, along with a Pavlovian system that responds reflexively to rewards and punishments, can illuminate puzzles in moral psychology. PMID:23845564

Use of Microarray to Analyze Gene Expression Profiles of Acute Effects of Prochloraz on Fathead Minnows Pimephales promelas

EPA Science Inventory

Microarray technology is a powerful tool to investigate the gene expression profiles for thousands of genes simultaneously. In recent years, microarrays have been used to characterize environmental pollutants and identify molecular mode(s) of action of chemicals including endocri...

An Evaluation of the Mode of Action Framework for MutagenicCarcinogens Case Study II: Chromium (VI).

EPA Science Inventory

In response to the 2005 revised U.S Environmental Protection Agency’s (EPA) Cancer Guidelines, a strategy is being developed to include all mutagenicity and other genotoxicity data with any additional information to determine whether a carcinogen operates through a mutagenic mode...

78 FR 59372 - Certain Multiple Mode Outdoor Grills and Parts Thererof; Institution of Investigation

Federal Register 2010, 2011, 2012, 2013, 2014

2013-09-26

... INTERNATIONAL TRADE COMMISSION [Investigation No. 337-TA-895] Certain Multiple Mode Outdoor Grills and Parts Thererof; Institution of Investigation AGENCY: U.S. International Trade Commission. ACTION: Notice. SUMMARY: Notice is hereby given that a complaint was filed with the U.S. International Trade...

Interagency Dosimetry Project: Methods for Dosimetry Adjustment Based on Mode of Action

EPA Science Inventory

As the science of toxicology evolves, many laboratories are adding new testing protocols or assays in their programs directed at ascertaining mechanistic information on uptake and toxic action of chemicals. In response to the increasing complexity and comprehensiveness of these ...

Vibronic spectra of Cu(2+) in ZnTe

NASA Technical Reports Server (NTRS)

Volz, M. P.; Su, C.-H.; Lehoczky, S. L.; Szofran, F. R.

1992-01-01

Infrared-absorption spectra of substitutional Cu(2+) ions in ZnTe have been measured at 4.6 K. Several distinct absorption peaks are observed between 800 and 2000/cm. Absorption peaks at 1002 and 1069/cm are identified as zero-phonon lines arising from 2T2-2E transitions. Between 1069 and 2000/cm, several sets of sharp absorption lines are seen to recur regularly at an interval of 210/cm, corresponding to the LO phonon energy. Within each set distinct vibronic sidebands that cannot be identified with critical-point energies of TA, LA, TO or LO phonon modes are observed. A dynamic Jahn-Teller effect, involving coupling between a single-phonon mode and the electronic states of the 2E level, is proposed to account for the observed spectra.

Strigolactones: new plant hormones in action.

PubMed

Zwanenburg, Binne; Pospíšil, Tomáš; Ćavar Zeljković, Sanja

2016-06-01

The key step in the mode of action of strigolactones is the enzymatic detachment of the D-ring. The thus formed hydroxy butenolide induces conformational changes of the receptor pocket which trigger a cascade of reactions in the signal transduction. Strigolactones (SLs) constitute a new class of plant hormones which are of increasing importance in plant science. For the last 60 years, they have been known as germination stimulants for parasitic plants. Recently, several new bio-properties of SLs have been discovered such as the branching factor for arbuscular mycorrhizal fungi, regulation of plant architecture (inhibition of bud outgrowth and of shoot branching) and the response to abiotic factors, etc. To broaden horizons and encourage new ideas for identifying and synthesising new and structurally simple SLs, this review is focused on molecular aspects of this new class of plant hormones. Special attention has been given to structural features, the mode of action of these phytohormones in various biological actions, the design of SL analogs and their applications.

The comparison of the influence of centrifugal forces and the Sagnac effect on a rotating whispering gallery modes resonators

NASA Astrophysics Data System (ADS)

Filatov, Yuri V.; Shalymov, Egor V.; Venediktov, Vladimir Yu.; Dmitrieva, Anna D.

2016-10-01

The parameters of whispering gallery modes resonators can be significantly modified under the action of external factors, for instance, in the case of resonator movement. The effects, which take place in the moving resonators of whispering gallery modes, can be employed for measuring of the angular velocity. In this work we was compared the influence of centrifugal forces and the Sagnac effect on the eigenfrequencies (wavelengths) of whispering gallery modes resonators. Also work is devoted mutual relationships of the effects.

Evaluating Environmental Knowledge Dimension Convergence to Assess Educational Programme Effectiveness

ERIC Educational Resources Information Center

Liefländer, Anne K.; Bogner, Franz X.; Kibbe, Alexandra; Kaiser, Florian G.

2015-01-01

One aim of environmental education is fostering sustainable environmental action. Some environmental behaviour models suggest that this can be accomplished in part by improving people's knowledge. Recent studies have identified a distinct, psychometrically supported environmental knowledge structure consisting of system, action-related and…

Action Research Projects in Distance Education: A Manual.

ERIC Educational Resources Information Center

Ramakrishna, C. Pushpa; Prasad, V. S.

This manual, prepared by the Distance Education Council (India) presents guidelines for action research in distance education, balancing practical research activities with a sound theoretical research base. Chapter 1, "Scope, Purpose and Design of the Manual," suggests several definitions of research; draws distinctions between academic…

Understanding Participatory Action Research: A Qualitative Research Methodology Option

ERIC Educational Resources Information Center

MacDonald, Cathy

2012-01-01

Participatory Action Research (PAR) is a qualitative research methodology option that requires further understanding and consideration. PAR is considered democratic, equitable, liberating, and life-enhancing qualitative inquiry that remains distinct from other qualitative methodologies (Kach & Kralik, 2006). Using PAR, qualitative features of an…

Regret as Autobiographical Memory

ERIC Educational Resources Information Center

Davison, Ian M.; Feeney, Aidan

2008-01-01

We apply an autobiographical memory framework to the study of regret. Focusing on the distinction between regrets for specific and general events we argue that the temporal profile of regret, usually explained in terms of the action-inaction distinction, is predicted by models of autobiographical memory. In two studies involving participants in…

Emotion-based Dispositions to Rash Action: Positive and Negative Urgency

PubMed Central

Cyders, Melissa A.; Smith, Gregory T.

2008-01-01

Under heightened emotional states, individuals are more inclined to engage in ill-considered or rash actions than at other times. The authors present evidence for the existence of two related traits called positive and negative urgency. The traits refer to individual differences in the disposition to engage in rash action when experiencing extreme positive and negative affect, respectively. The authors provide evidence that these traits are distinct from other dispositions toward rash action, and that they play distinct roles in predicting problem levels of involvement in behaviors such as alcohol consumption, binge eating, drug use, and risky sexual behavior. The authors identify facilitative conditions for the emergence of the urgency traits from neuroscience. Certain gene polymorphisms are associated with low levels of serotonin and high levels of dopamine; that pattern of neurotransmitter activity in a brain system linking the orbitofrontal cortex and the amygdala appears to facilitate development of positive and negative urgency. The authors discuss the implications of this theory. PMID:18954158

Stress prompts habit behavior in humans.

PubMed

Schwabe, Lars; Wolf, Oliver T

2009-06-03

Instrumental behavior can be controlled by goal-directed action-outcome and habitual stimulus-response processes that are supported by anatomically distinct brain systems. Based on previous findings showing that stress modulates the interaction of "cognitive" and "habit" memory systems, we asked in the presented study whether stress may coordinate goal-directed and habit processes in instrumental learning. For this purpose, participants were exposed to stress (socially evaluated cold pressor test) or a control condition before they were trained to perform two instrumental actions that were associated with two distinct food outcomes. After training, one of these food outcomes was selectively devalued as subjects were saturated with that food. Next, subjects were presented the two instrumental actions in extinction. Stress before training in the instrumental task rendered participants' behavior insensitive to the change in the value of the food outcomes, that is stress led to habit performance. Moreover, stress reduced subjects' explicit knowledge of the action-outcome contingencies. These results demonstrate for the first time that stress promotes habits at the expense of goal-directed performance in humans.

Multi-Mode Excitation and Data Reduction for Fatigue Crack Characterization in Conducting Plates

NASA Technical Reports Server (NTRS)

Wincheski, B.; Namkung, M.; Fulton, J. P.; Clendenin, C. G.

1992-01-01

Advances in the technique of fatigue crack characterization by resonant modal analysis have been achieved through a new excitation mechanism and data reduction of multiple resonance modes. A non-contacting electromagnetic device is used to apply a time varying Lorentz force to thin conducting sheets. The frequency and direction of the Lorentz force are such that resonance modes are generated in the test sample. By comparing the change in frequency between distinct resonant modes of a sample, detecting and sizing of fatigue cracks are achieved and frequency shifts caused by boundary condition changes can be discriminated against. Finite element modeling has been performed to verify experimental results.

Differential T cell response against BK virus regulatory and structural antigens: A viral dynamics modelling approach.

PubMed

Blazquez-Navarro, Arturo; Schachtner, Thomas; Stervbo, Ulrik; Sefrin, Anett; Stein, Maik; Westhoff, Timm H; Reinke, Petra; Klipp, Edda; Babel, Nina; Neumann, Avidan U; Or-Guil, Michal

2018-05-01

BK virus (BKV) associated nephropathy affects 1-10% of kidney transplant recipients, leading to graft failure in about 50% of cases. Immune responses against different BKV antigens have been shown to have a prognostic value for disease development. Data currently suggest that the structural antigens and regulatory antigens of BKV might each trigger a different mode of action of the immune response. To study the influence of different modes of action of the cellular immune response on BKV clearance dynamics, we have analysed the kinetics of BKV plasma load and anti-BKV T cell response (Elispot) in six patients with BKV associated nephropathy using ODE modelling. The results show that only a small number of hypotheses on the mode of action are compatible with the empirical data. The hypothesis with the highest empirical support is that structural antigens trigger blocking of virus production from infected cells, whereas regulatory antigens trigger an acceleration of death of infected cells. These differential modes of action could be important for our understanding of BKV resolution, as according to the hypothesis, only regulatory antigens would trigger a fast and continuous clearance of the viral load. Other hypotheses showed a lower degree of empirical support, but could potentially explain the clearing mechanisms of individual patients. Our results highlight the heterogeneity of the dynamics, including the delay between immune response against structural versus regulatory antigens, and its relevance for BKV clearance. Our modelling approach is the first that studies the process of BKV clearance by bringing together viral and immune kinetics and can provide a framework for personalised hypotheses generation on the interrelations between cellular immunity and viral dynamics.

Essential Oils in Food Preservation: Mode of Action, Synergies, and Interactions with Food Matrix Components

PubMed Central

Hyldgaard, Morten; Mygind, Tina; Meyer, Rikke Louise

2012-01-01

Essential oils are aromatic and volatile liquids extracted from plants. The chemicals in essential oils are secondary metabolites, which play an important role in plant defense as they often possess antimicrobial properties. The interest in essential oils and their application in food preservation has been amplified in recent years by an increasingly negative consumer perception of synthetic preservatives. Furthermore, food-borne diseases are a growing public health problem worldwide, calling for more effective preservation strategies. The antibacterial properties of essential oils and their constituents have been documented extensively. Pioneering work has also elucidated the mode of action of a few essential oil constituents, but detailed knowledge about most of the compounds’ mode of action is still lacking. This knowledge is particularly important to predict their effect on different microorganisms, how they interact with food matrix components, and how they work in combination with other antimicrobial compounds. The main obstacle for using essential oil constituents as food preservatives is that they are most often not potent enough as single components, and they cause negative organoleptic effects when added in sufficient amounts to provide an antimicrobial effect. Exploiting synergies between several compounds has been suggested as a solution to this problem. However, little is known about which interactions lead to synergistic, additive, or antagonistic effects. Such knowledge could contribute to design of new and more potent antimicrobial blends, and to understand the interplay between the constituents of crude essential oils. The purpose of this review is to provide an overview of current knowledge about the antibacterial properties and antibacterial mode of action of essential oils and their constituents, and to identify research avenues that can facilitate implementation of essential oils as natural preservatives in foods. PMID:22291693

Essential oils in food preservation: mode of action, synergies, and interactions with food matrix components.

PubMed

Hyldgaard, Morten; Mygind, Tina; Meyer, Rikke Louise

2012-01-01

Essential oils are aromatic and volatile liquids extracted from plants. The chemicals in essential oils are secondary metabolites, which play an important role in plant defense as they often possess antimicrobial properties. The interest in essential oils and their application in food preservation has been amplified in recent years by an increasingly negative consumer perception of synthetic preservatives. Furthermore, food-borne diseases are a growing public health problem worldwide, calling for more effective preservation strategies. The antibacterial properties of essential oils and their constituents have been documented extensively. Pioneering work has also elucidated the mode of action of a few essential oil constituents, but detailed knowledge about most of the compounds' mode of action is still lacking. This knowledge is particularly important to predict their effect on different microorganisms, how they interact with food matrix components, and how they work in combination with other antimicrobial compounds. The main obstacle for using essential oil constituents as food preservatives is that they are most often not potent enough as single components, and they cause negative organoleptic effects when added in sufficient amounts to provide an antimicrobial effect. Exploiting synergies between several compounds has been suggested as a solution to this problem. However, little is known about which interactions lead to synergistic, additive, or antagonistic effects. Such knowledge could contribute to design of new and more potent antimicrobial blends, and to understand the interplay between the constituents of crude essential oils. The purpose of this review is to provide an overview of current knowledge about the antibacterial properties and antibacterial mode of action of essential oils and their constituents, and to identify research avenues that can facilitate implementation of essential oils as natural preservatives in foods.

Relationship of Metabolism and Cell Proliferation to the Mode of Action of Fluensulfone-Induced Mouse Lung Tumors. II: Additional Mechanistic Studies.

PubMed

Strupp, Christian; Bomann, Werner; Cohen, Samuel M; Weber, Klaus

2016-12-01

Fluensulfone is a nematicide for agricultural use. Chronic dietary exposure led to bronchiolo-alveolar hyperplasia and bronchiolo-alveolar adenomas in CD-1 mice but not in rats. Genotoxicity could be excluded as a mode of action (MOA). An earlier publication (Strupp, C., Banas, D. A., Cohen, S. M., Gordon, E. B., Jaeger, M., and Weber, K. (2012). Relationship of metabolism and cell proliferation to the mode of action of fluensulfone-induced mouse lung tumors: analysis of their human relevance using the IPCS framework. Toxicol. Sci. 128, 284-294.) reported MOA studies identifying the following key events: increased metabolism of fluensulfone by CYP2f2 in mouse lung Club cells, followed by local proliferation, finally leading to adenoma formation. Human lung microsomes were found not to metabolize fluensulfone. The Joint FAO/WHO Meeting on Pesticide Residues has reviewed the previous data and concluded that the MOA is plausible however some areas of uncertainty were identified. This publication provides additional data to address these. New cell proliferation studies in mice showed that the MOA is functionally independent of sex. A threshold of cell proliferation in Club cells correlating with the dose response for adenoma formation was shown. CYP2f2 knockout mice did not react to fluensulfone exposure with cell proliferation like wild-type mice, confirming the key role of this enzyme. The collective data for fluensulfone were evaluated according to the International Programme on Chemical Safety (IPCS) Mode of Action Framework which leads to the conclusion that the mouse-specific lung tumors after fluensulfone are not relevant to humans. © The Author 2016. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Distinguishing treatment from research: a functional approach

PubMed Central

Lewens, T

2006-01-01

The best way to distinguish treatment from research is by their functions. This mode of distinction fits well with the basic ethical work that needs to be carried out. The distinction needs to serve as an ethical flag, highlighting areas in which the goals of doctors and patients are more likely than usual to diverge. The distinction also allows us to illuminate and understand some otherwise puzzling elements of debates on research ethics: it shows the peculiarity of exclusive conceptions of the distinction between research and treatment; it allows us to frame questions about therapeutic obligations in the research context, and it allows us to consider whether there may be research obligations in the therapeutic context. PMID:16816045

Analysis of the partially filled viscous ring damper. [application as nutation damper for spinning satellite

NASA Technical Reports Server (NTRS)

Alfriend, K. T.

1973-01-01

A ring partially filled with a viscous fluid has been analyzed as a nutation damper for a spinning satellite. The fluid has been modelled as a rigid slug of finite length moving in a tube and resisted by a linear viscous force. It is shown that there are two distinct modes of motion, called the spin synchronous mode and the nutation synchronous mode. Time constants for each mode are obtained for both the symmetric and asymmetric satellite. The effects of a stop in the tube and an offset of the ring from the spin axis are also investigated. An analysis of test results is also given including a determination of the effect of gravity on the time constants in the two modes.

Hybrid surface-phonon-plasmon polariton modes in graphene/monolayer h-BN heterostructures.

PubMed

Brar, Victor W; Jang, Min Seok; Sherrott, Michelle; Kim, Seyoon; Lopez, Josue J; Kim, Laura B; Choi, Mansoo; Atwater, Harry

2014-07-09

Infrared transmission measurements reveal the hybridization of graphene plasmons and the phonons in a monolayer hexagonal boron nitride (h-BN) sheet. Frequency-wavevector dispersion relations of the electromagnetically coupled graphene plasmon/h-BN phonon modes are derived from measurement of nanoresonators with widths varying from 30 to 300 nm. It is shown that the graphene plasmon mode is split into two distinct optical modes that display an anticrossing behavior near the energy of the h-BN optical phonon at 1370 cm(-1). We explain this behavior as a classical electromagnetic strong-coupling with the highly confined near fields of the graphene plasmons allowing for hybridization with the phonons of the atomically thin h-BN layer to create two clearly separated new surface-phonon-plasmon-polariton (SPPP) modes.

Remarks of Assistant Attorney General, Civil Rights Division, before the Affirmative Action Association (Chicago, IL, September 20, 1984). September 20, 1984).

ERIC Educational Resources Information Center

Reynolds, Wm. Bradford

"Affirmative action" is the term typically used to refer to two contrasting values: the value of equal opportunity and the value of equal results. The Justice Department under the Reagan Administration, however, draws a clear distinction between the two, and is committed to the "original" meaning of affirmative action. That is,…

Mode of carcinogenic action of pesticides inducing thyroid follicular cell tumors in rodents.

PubMed

Hurley, P M

1998-08-01

Of 240 pesticides screened for carcinogenicity by the U.S. Environmental Protection Agency Office of Pesticide Programs, at least 24 (10%) produce thyroid follicular cell tumors in rodents. Thirteen of the thyroid carcinogens also induce liver tumors, mainly in mice, and 9 chemicals produce tumors at other sites. Some mutagenic data are available on all 24 pesticides producing thyroid tumors. Mutagenicity does not seem to be a major determinant in thyroid carcinogenicity, except for possibly acetochlor; evidence is less convincing for ethylene thiourea and etridiazole. Studies on thyroid-pituitary functioning, including indications of thyroid cell growth and/or changes in thyroxine, triiodothyronine, or thyroid-stimulating hormone levels, are available on 19 pesticides. No such antithyroid information is available for etridiazole, N-octyl bicycloheptene dicarboximide, terbutryn, triadimefon, and trifluralin. Of the studied chemicals, only bromacil lacks antithyroid activity under study conditions. Intrathyroidal and extrathyroidal sites of action are found: amitrole, ethylene thiourea, and mancozeb are thyroid peroxidase inhibitors; and acetochlor, clofentezine, fenbuconazole, fipronil, pendimethalin, pentachloronitrobenzene, prodiamine, pyrimethanil, and thiazopyr seem to enhance the hepatic metabolism and excretion of thyroid hormone. Thus, with 12 pesticides that mode of action judgments can be made, 11 disrupt thyroid-pituitary homeostasis only; no chemical is mutagenic only; and acetochlor may have both antithyroid and some mutagenic activity. More information is needed to identify other potential antithyroid modes of thyroid carcinogenic action.

Dynamic Triple-Mode Sorption and Outgassing in Materials.

PubMed

Sharma, Hom N; Harley, Stephen J; Sun, Yunwei; Glascoe, Elizabeth A

2017-06-07

Moisture uptake and outgassing can be detrimental to a system by altering the chemical and mechanical properties of materials within the system over time. In this work, we conducted isotherm experiments to investigate dynamic moisture sorption and desorption in markedly different materials, i.e., a polymeric material, Sylgard-184 and a ceramic aluminosilicate material, Zircar RS-1200, at different temperatures (30 °C-70 °C) by varying the water activity (0.0-0.90). Sylgard-184 showed a linear sorption and outgassing behavior with no-hysteresis over the entire temperature and water activity range considered here. Whereas, the sorption and outgassing of Zircar RS-1200 was highly non-linear with significant hysteresis, especially at higher water activities, at all temperatures considered here. The type of hysteresis suggested the presence of mesopores in Zircar RS-1200, whereas the lack of hysteresis in Sylgard-184 indicates that it has a nonporous structure. A diffusion model coupled with a dynamic, triple-mode sorption (Langmuir, Henry, and pooling modes) model employed in this study matched our experimental data very well and provides mechanistic insight into the processes. Our triple-mode sorption model was adaptive enough to (1) model these distinctly different materials and (2) predict sorption and outgassing under conditions that are distinctly different from the parameterization experiments.