Sample records for negative selection activities
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Alós, Josep; Palmer, Miquel; Arlinghaus, Robert
2012-01-01
Together with life-history and underlying physiology, the behavioural variability among fish is one of the three main trait axes that determines the vulnerability to fishing. However, there are only a few studies that have systematically investigated the strength and direction of selection acting on behavioural traits. Using in situ fish behaviour revealed by telemetry techniques as input, we developed an individual-based model (IBM) that simulated the Lagrangian trajectory of prey (fish) moving within a confined home range (HR). Fishers exhibiting various prototypical fishing styles targeted these fish in the model. We initially hypothesised that more active and more explorative individuals would be systematically removed under all fished conditions, in turn creating negative selection differentials on low activity phenotypes and maybe on small HR. Our results partly supported these general predictions. Standardised selection differentials were, on average, more negative on HR than on activity. However, in many simulation runs, positive selection pressures on HR were also identified, which resulted from the stochastic properties of the fishes’ movement and its interaction with the human predator. In contrast, there was a consistent negative selection on activity under all types of fishing styles. Therefore, in situations where catchability depends on spatial encounters between human predators and fish, we would predict a consistent selection towards low activity phenotypes and have less faith in the direction of the selection on HR size. Our study is the first theoretical investigation on the direction of fishery-induced selection of behaviour using passive fishing gears. The few empirical studies where catchability of fish was measured in relation to passive fishing techniques, such as gill-nets, traps or recreational fishing, support our predictions that fish in highly exploited situations are, on average, characterised by low swimming activity, stemming, in part, from negative selection on swimming activity. PMID:23110164
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Zikherman, Julie; Lau, Tannia; Leitges, Michael; Weiss, Arthur
2014-01-01
Protein kinase Cδ (PKCδ) deficiency causes autoimmune pathology in humans and mice and is crucial for the maintenance of B cell homeostasis. However, the mechanisms underlying autoimmune disease in PKCδ deficiency remain poorly defined. Here, we address the antigen-dependent and -independent roles of PKCδ in B cell development, repertoire selection, and antigen responsiveness. We demonstrate that PKCδ is rapidly phosphorylated downstream of both the B cell receptor (BCR) and the B cell-activating factor (BAFF) receptor. We found that PKCδ is essential for antigen-dependent negative selection of splenic transitional B cells and is required for activation of the proapoptotic Ca2+-Erk pathway that is selectively activated during B cell-negative selection. Unexpectedly, we also identified a previously unrecognized role for PKCδ as a proximal negative regulator of BCR signaling that substantially impacts survival and proliferation of mature follicular B cells. As a consequence of these distinct roles, PKCδ deficiency leads to the survival and development of a B cell repertoire that is not only aberrantly autoreactive but also hyperresponsive to antigen stimulation. PMID:24515435
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Thymic selection threshold defined by compartmentalization of Ras/MAPK signalling.
Daniels, Mark A; Teixeiro, Emma; Gill, Jason; Hausmann, Barbara; Roubaty, Dominique; Holmberg, Kaisa; Werlen, Guy; Holländer, Georg A; Gascoigne, Nicholas R J; Palmer, Ed
2006-12-07
A healthy individual can mount an immune response to exogenous pathogens while avoiding an autoimmune attack on normal tissues. The ability to distinguish between self and non-self is called 'immunological tolerance' and, for T lymphocytes, involves the generation of a diverse pool of functional T cells through positive selection and the removal of overtly self-reactive thymocytes by negative selection during T-cell ontogeny. To elucidate how thymocytes arrive at these cell fate decisions, here we have identified ligands that define an extremely narrow gap spanning the threshold that distinguishes positive from negative selection. We show that, at the selection threshold, a small increase in ligand affinity for the T-cell antigen receptor leads to a marked change in the activation and subcellular localization of Ras and mitogen-activated protein kinase (MAPK) signalling intermediates and the induction of negative selection. The ability to compartmentalize signalling molecules differentially in the cell endows the thymocyte with the ability to convert a small change in analogue input (affinity) into a digital output (positive versus negative selection) and provides the basis for establishing central tolerance.
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Zapata, Luis; Pich, Oriol; Serrano, Luis; Kondrashov, Fyodor A; Ossowski, Stephan; Schaefer, Martin H
2018-05-31
Natural selection shapes cancer genomes. Previous studies used signatures of positive selection to identify genes driving malignant transformation. However, the contribution of negative selection against somatic mutations that affect essential tumor functions or specific domains remains a controversial topic. Here, we analyze 7546 individual exomes from 26 tumor types from TCGA data to explore the portion of the cancer exome under negative selection. Although we find most of the genes neutrally evolving in a pan-cancer framework, we identify essential cancer genes and immune-exposed protein regions under significant negative selection. Moreover, our simulations suggest that the amount of negative selection is underestimated. We therefore choose an empirical approach to identify genes, functions, and protein regions under negative selection. We find that expression and mutation status of negatively selected genes is indicative of patient survival. Processes that are most strongly conserved are those that play fundamental cellular roles such as protein synthesis, glucose metabolism, and molecular transport. Intriguingly, we observe strong signals of selection in the immunopeptidome and proteins controlling peptide exposition, highlighting the importance of immune surveillance evasion. Additionally, tumor type-specific immune activity correlates with the strength of negative selection on human epitopes. In summary, our results show that negative selection is a hallmark of cell essentiality and immune response in cancer. The functional domains identified could be exploited therapeutically, ultimately allowing for the development of novel cancer treatments.
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Enhanced HTS hit selection via a local hit rate analysis.
Posner, Bruce A; Xi, Hualin; Mills, James E J
2009-10-01
The postprocessing of high-throughput screening (HTS) results is complicated by the occurrence of false positives (inactive compounds misidentified as active by the primary screen) and false negatives (active compounds misidentified as inactive by the primary screen). An activity cutoff is frequently used to select "active" compounds from HTS data; however, this approach is insensitive to both false positives and false negatives. An alternative method that can minimize the occurrence of these artifacts will increase the efficiency of hit selection and therefore lead discovery. In this work, rather than merely using the activity of a given compound, we look at the presence and absence of activity among all compounds in its "chemical space neighborhood" to give a degree of confidence in its activity. We demonstrate that this local hit rate (LHR) analysis method outperforms hit selection based on ranking by primary screen activity values across ten diverse high throughput screens, spanning both cell-based and biochemical assay formats of varying biology and robustness. On average, the local hit rate analysis method was approximately 2.3-fold and approximately 1.3-fold more effective in identifying active compounds and active chemical series, respectively, than selection based on primary activity alone. Moreover, when applied to finding false negatives, this method was 2.3-fold better than ranking by primary activity alone. In most cases, novel hit series were identified that would have otherwise been missed. Additional uses of and observations regarding this HTS analysis approach are also discussed.
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ERIC Educational Resources Information Center
Pritchard, Verena E.; Neumann, Ewald; Rucklidge, Julia J.
2008-01-01
Selective attention has durable consequences for behavior and neural activation. Negative priming (NP) effects are assumed to reflect a critical inhibitory component of selective attention. The performance of adolescents with Attention Deficit/Hyperactivity Disorder (ADHD) was assessed across two conceptually based NP tasks within a selective…
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Freeze or Flee? Negative Stimuli Elicit Selective Responding
ERIC Educational Resources Information Center
Estes, Zachary; Verges, Michelle
2008-01-01
Humans preferentially attend to negative stimuli. A consequence of this automatic vigilance for negative valence is that negative words elicit slower responses than neutral or positive words on a host of cognitive tasks. Some researchers have speculated that negative stimuli elicit a general suppression of motor activity, akin to the freezing…
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Zhou, Liqing; Lu, Jia; Chen, Guopeng; Dong, Li; Yao, Yujia
2017-01-01
Background/Study Context: Socioemotional selectivity theory (SST) states that the positivity effect is a result of older adults' emotion regulation and that older adults derive more emotional satisfaction from prioritizing positive information processing. The authors explored whether the positivity effect appeared when the negative aging stereotype was activated in older adults and also whether the effect differed between mixed and unmixed valence conditions. Sixty younger (18-23 years of age) and 60 older (60-87 years of age) adults were randomly assigned to a control group and a priming group, in which the negative aging stereotype was activated. All the participants were asked to select 15 words that best described the elderly from a mixed-word list (positive and negative words were mixed together) and from an unmixed-word list (positive and negative words were separated). Older adults in the control group selected more positive words, whereas among younger adults, selection did not differ by valence in either the mixed- or unmixed-word list conditions. There were no differences between the positive and negative word choices of the younger and older adults in the priming group. We calculated the differences between the numbers of positive and negative words, and the differences in the older adults' word choices were larger than those among the younger adults; the differences were also larger in the control group than in the priming group. The positivity effect worked by choosing positive stimuli rather than avoiding negative stimuli. The role of emotion regulation in older adults was limited, and when the positivity effect faced the effect of the negative aging stereotype, the negative stereotype effect was dominant. Future research should explore the changes in the positivity effect in the face of a positive aging stereotype and what roles other factors (e.g., activation level of the stereotype, arousal level of affective words) might play.
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Schmidt, Nathan W.; Wong, Gerard C. L.
2013-01-01
Short cationic, amphipathic antimicrobial peptides are multi-functional molecules that have roles in host defense as direct microbicides and modulators of the immune response. While a general mechanism of microbicidal activity involves the selective disruption and permeabilization of cell membranes, the relationships between peptide sequence and membrane activity are still under investigation. Here, we review the diverse functions that AMPs collectively have in host defense, and show that these functions can be multiplexed with a membrane mechanism of activity derived from the generation of negative Gaussian membrane curvature. As AMPs preferentially generate this curvature in model bacterial cell membranes, the selective generation of negative Gaussian curvature provides AMPs with a broad mechanism to target microbial membranes. The amino acid constraints placed on AMPs by the geometric requirement to induce negative Gaussian curvature are consistent with known AMP sequences. This ‘saddle-splay curvature selection rule’ is not strongly restrictive so AMPs have significant compositional freedom to multiplex membrane activity with other useful functions. The observation that certain proteins involved in cellular processes which require negative Gaussian curvature contain domains with similar motifs as AMPs, suggests this rule may be applicable to other curvature-generating proteins. Since our saddle-splay curvature design rule is based upon both a mechanism of activity and the existing motifs of natural AMPs, we believe it will assist the development of synthetic antimicrobials. PMID:24778573
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Altering calcium influx for selective destruction of breast tumor.
Yu, Han-Gang; McLaughlin, Sarah; Newman, Mackenzie; Brundage, Kathleen; Ammer, Amanda; Martin, Karen; Coad, James
2017-03-04
Human triple-negative breast cancer has limited therapeutic choices. Breast tumor cells have depolarized plasma membrane potential. Using this unique electrical property, we aim to develop an effective selective killing of triple-negative breast cancer. We used an engineered L-type voltage-gated calcium channel (Cec), activated by membrane depolarization without inactivation, to induce excessive calcium influx in breast tumor cells. Patch clamp and flow cytometry were used in testing the killing selectivity and efficiency of human breast tumor cells in vitro. Bioluminescence and ultrasound imaging were used in studies of human triple-negative breast cancer cell MDA-MB-231 xenograft in mice. Histological staining, immunoblotting and immunohistochemistry were used to investigate mechanism that mediates Cec-induced cell death. Activating Cec channels expressed in human breast cancer MCF7 cells produced enormous calcium influx at depolarized membrane. Activating the wild-type Cav1.2 channels expressed in MCF7 cells also produced a large calcium influx at depolarized membrane, but this calcium influx was diminished at the sustained membrane depolarization due to channel inactivation. MCF7 cells expressing Cec died when the membrane potential was held at -10 mV for 1 hr, while non-Cec-expressing MCF7 cells were alive. MCF7 cell death was 8-fold higher in Cec-expressing cells than in non-Cec-expressing cells. Direct injection of lentivirus containing Cec into MDA-MB-231 xenograft in mice inhibited tumor growth. Activated caspase-3 protein was detected only in MDA-MB-231 cells expressing Cec, along with a significantly increased expression of activated caspase-3 in xenograft tumor treated with Cec. We demonstrated a novel strategy to induce constant calcium influx that selectively kills human triple-negative breast tumor cells.
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42 CFR 431.980 - Eligibility review procedures.
Code of Federal Regulations, 2011 CFR
2011-10-01
... Estimating Improper Payments in Medicaid and CHIP § 431.980 Eligibility review procedures. (a) Active case reviews. The agency must verify eligibility for all selected active cases for Medicaid and CHIP for the... must review all selected negative cases for Medicaid and CHIP for the review month to determine whether...
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42 CFR 431.980 - Eligibility review procedures.
Code of Federal Regulations, 2012 CFR
2012-10-01
... Estimating Improper Payments in Medicaid and CHIP § 431.980 Eligibility review procedures. (a) Active case reviews. The agency must verify eligibility for all selected active cases for Medicaid and CHIP for the... must review all selected negative cases for Medicaid and CHIP for the review month to determine whether...
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42 CFR 431.980 - Eligibility review procedures.
Code of Federal Regulations, 2013 CFR
2013-10-01
... Estimating Improper Payments in Medicaid and CHIP § 431.980 Eligibility review procedures. (a) Active case reviews. The agency must verify eligibility for all selected active cases for Medicaid and CHIP for the... must review all selected negative cases for Medicaid and CHIP for the review month to determine whether...
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42 CFR 431.980 - Eligibility review procedures.
Code of Federal Regulations, 2014 CFR
2014-10-01
... Estimating Improper Payments in Medicaid and CHIP § 431.980 Eligibility review procedures. (a) Active case reviews. The agency must verify eligibility for all selected active cases for Medicaid and CHIP for the... must review all selected negative cases for Medicaid and CHIP for the review month to determine whether...
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Freeze or flee? Negative stimuli elicit selective responding.
Estes, Zachary; Verges, Michelle
2008-08-01
Humans preferentially attend to negative stimuli. A consequence of this automatic vigilance for negative valence is that negative words elicit slower responses than neutral or positive words on a host of cognitive tasks. Some researchers have speculated that negative stimuli elicit a general suppression of motor activity, akin to the freezing response exhibited by animals under threat. Alternatively, we suggest that negative stimuli only elicit slowed responding on tasks for which stimulus valence is irrelevant for responding. To discriminate between these motor suppression and response-relevance hypotheses, we elicited both lexical decisions and valence judgments of negative words and positive words. Relative to positive words (e.g., kitten), negative words (e.g., spider) elicited slower lexical decisions but faster valence judgments. Results therefore indicate that negative stimuli do not cause a generalized motor suppression. Rather, negative stimuli elicit selective responding, with faster responses on tasks for which stimulus valence is response-relevant.
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Badura, Petr; Madarasova Geckova, Andrea; Sigmundova, Dagmar; Sigmund, Erik; van Dijk, Jitse P; Reijneveld, Sijmen A
2018-06-02
We aimed to assess the associations of involvement in selected unstructured activities (UA) with health-risk behaviours and academic achievement and the degree to which the participation in organized leisure-time activities (OLTA) changes these associations. Using a sample of 6935 Czech adolescents aged 13 and 15 years, we investigated adolescents' weekly involvement in hanging out, visiting shopping malls for fun and meeting friends after 8 p.m., OLTA and engagement in three health-risk behaviours and academic achievement. Weekly involvement in the selected UA was associated with higher odds for regular smoking, being drunk, having early sexual intercourse and low academic achievement. Concurrent participation in OLTA did not buffer these negative outcomes, except for sexual experience. However, those highly engaged only in UA were more likely to participate in the health-risk behaviours and report worse academic achievement than those participating in any OLTA concurrently. The selected UA are strongly associated with an increased occurrence of adolescents' health-risk behaviours and low academic achievement. Concurrent participation in OLTA does not buffer these negative outcomes significantly, but adolescents engaged only in UA consistently report the least favourable outcomes.
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Aberrant antibody affinity selection in SHIP-deficient B cells.
Leung, Wai-Hang; Tarasenko, Tatiana; Biesova, Zuzana; Kole, Hemanta; Walsh, Elizabeth R; Bolland, Silvia
2013-02-01
The strength of the Ag receptor signal influences development and negative selection of B cells, and it might also affect B-cell survival and selection in the GC. Here, we have used mice with B-cell-specific deletion of the 5'-inositol phosphatase SHIP as a model to study affinity selection in cells that are hyperresponsive to Ag and cytokine receptor stimulation. In the absence of SHIP, B cells have lower thresholds for Ag- and interferon (IFN)-induced activation, resulting in augmented negative selection in the BM and enhanced B-cell maturation in the periphery. Despite a tendency to spontaneously downregulate surface IgM expression, SHIP deficiency does not alter anergy induction in response to soluble hen-egg lysozyme Ag in the MDA4 transgenic model. SHIP-deficient B cells spontaneously produce isotype-switched antibodies; however, they are poor responders in immunization and infection models. While SHIP-deficient B cells form GCs and undergo mutation, they are not properly selected for high-affinity antibodies. These results illustrate the importance of negative regulation of B-cell responses, as lower thresholds for B-cell activation promote survival of low affinity and deleterious receptors to the detriment of optimal Ab affinity maturation. © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
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Clonal deletion of thymocytes can occur in the cortex with no involvement of the medulla
McCaughtry, Tom M.; Baldwin, Troy A.; Wilken, Matthew S.; Hogquist, Kristin A.
2008-01-01
The thymic medulla is generally held to be a specialized environment for negative selection. However, many self-reactive thymocytes first encounter ubiquitous self-antigens in the cortex. Cortical epithelial cells are vital for positive selection, but whether such cells can also promote negative selection is controversial. We used the HYcd4 model, where T cell receptor for antigen (TCR) expression is appropriately timed and a ubiquitous self-antigen drives clonal deletion in male mice. We demonstrated unambiguously that this deletion event occurs in the thymic cortex. However, the kinetics in vivo indicated that apoptosis was activated asynchronously relative to TCR activation. We found that radioresistant antigen-presenting cells and, specifically, cortical epithelial cells do not efficiently induce apoptosis, although they do cause TCR activation. Rather, thymocytes undergoing clonal deletion were preferentially associated with rare CD11c+ cortical dendritic cells, and elimination of such cells impaired deletion. PMID:18936237
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Miyake, Yoshie; Okamoto, Yasumasa; Onoda, Keiichi; Shirao, Naoko; Okamoto, Yuri; Otagaki, Yoko; Yamawaki, Shigeto
2010-04-15
Eating disorders (EDs) are associated with abnormalities of body image perception. The aim of the present study was to investigate the functional abnormalities in brain systems during processing of negative words concerning body images in patients with EDs. Brain responses to negative words concerning body images (task condition) and neutral words (control condition) were measured using functional magnetic resonance imaging in 36 patients with EDs (12 with the restricting type anorexia nervosa; AN-R, 12 with the binging-purging type anorexia nervosa; AN-BP, and 12 with bulimia nervosa; BN) and 12 healthy young women. Participants were instructed to select the most negative word from each negative body-image word set and to select the most neutral word from each neutral word set. In the task relative to the control condition, the right amygdala was activated both in patients with AN-R and in patients with AN-BP. The left medial prefrontal cortex (mPFC) was activated both in patients with BN and in patients with AN-BP. It is suggested that these brain activations may be associated with abnormalities of body image perception. Amygdala activation may be involved in fearful emotional processing of negative words concerning body image and strong fears of gaining weight. One possible interpretation of the finding of mPFC activation is that it may reflect an attempt to regulate the emotion invoked by the stimuli. These abnormal brain functions may help provide better accounts of the psychopathological mechanisms underlying EDs. Copyright 2009 Elsevier Inc. All rights reserved.
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Augmenting Trastuzumab Therapy Against Breast Cancer Through Selective Activation of NK Cells
2013-10-01
selection and assessed for purity (>90% purity as defined by CD3-CD56+ flow cytometry ) and activation (>50% expression of CD137). Breast cancer cell lines...at a ratio of 1:1. After 24 hours, NK cells were isolated by negative selection and assessed for purity (>90% purity as defined by CD3-CD56+ flow ... cytometry ) and activation (>50% expression of CD137). Chromium-labeled breast cancer cell lines including MCF7 (A), BT474M1 (B), HER18 (C), and SKBR3
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Calcium alloy as active material in secondary electrochemical cell
Roche, Michael F.; Preto, Sandra K.; Martin, Allan E.
1976-01-01
Calcium alloys such as calcium-aluminum and calcium-silicon, are employed as active material within a rechargeable negative electrode of an electrochemical cell. Such cells can use a molten salt electrolyte including calcium ions and a positive electrode having sulfur, sulfides, or oxides as active material. The calcium alloy is selected to prevent formation of molten calcium alloys resulting from reaction with the selected molten electrolytic salt at the cell operating temperatures.
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Daffner, Kirk R; Zhuravleva, Tatyana Y; Sun, Xue; Tarbi, Elise C; Haring, Anna E; Rentz, Dorene M; Holcomb, Phillip J
2012-02-01
Numerous studies have demonstrated that selective attention to color is associated with a larger neural response under attend than ignore conditions, but have not addressed whether this difference reflects enhanced activity under attend or suppressed activity under ignore. In this study, a color-neutral condition was included, which presented stimuli physically identical to those under attend and ignore conditions, but in which color was not task relevant. Attention to color did not modulate the early sensory-evoked P1 and N1 components. Traditional ERP markers of early selection (the anterior Selection Positivity and posterior Selection Negativity) did not differ between the attend and neutral conditions, arguing against a mechanism of enhanced activity. However, there were markedly reduced responses under the ignore relative to the neutral condition, consistent with the view that early selection mechanisms reflect suppression of neural activity under the ignore condition. Copyright © 2011 Elsevier B.V. All rights reserved.
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Neural correlates of preparatory and regulatory control over positive and negative emotion.
Seo, Dongju; Olman, Cheryl A; Haut, Kristen M; Sinha, Rajita; MacDonald, Angus W; Patrick, Christopher J
2014-04-01
This study used functional magnetic resonance imaging to investigate brain activation during preparatory and regulatory control while participants (N = 24) were instructed either to simply view or decrease their emotional response to, pleasant, neutral or unpleasant pictures. A main effect of emotional valence on brain activity was found in the right precentral gyrus, with greater activation during positive than negative emotion regulation. A main effect of regulation phase was evident in the bilateral anterior prefrontal cortex (PFC), precuneus, posterior cingulate cortex, right putamen and temporal and occipital lobes, with greater activity in these regions during preparatory than regulatory control. A valence X regulation interaction was evident in regions of ventromedial PFC and anterior cingulate cortex, reflecting greater activation while regulating negative than positive emotion, but only during active emotion regulation (not preparation). Conjunction analyses revealed common brain regions involved in differing types of emotion regulation including selected areas of left lateral PFC, inferior parietal lobe, temporal lobe, right cerebellum and bilateral dorsomedial PFC. The right lateral PFC was additionally activated during the modulation of both positive and negative valence. Findings demonstrate significant modulation of brain activity during both preparation for, and active regulation of positive and negative emotional states.
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Napping and the Selective Consolidation of Negative Aspects of Scenes
Payne, Jessica D.; Kensinger, Elizabeth A.; Wamsley, Erin; Spreng, R. Nathan; Alger, Sara; Gibler, Kyle; Schacter, Daniel L.; Stickgold, Robert
2018-01-01
After information is encoded into memory, it undergoes an offline period of consolidation that occurs optimally during sleep. The consolidation process not only solidifies memories, but also selectively preserves aspects of experience that are emotionally salient and relevant for future use. Here, we provide evidence that an afternoon nap is sufficient to trigger preferential memory for emotional information contained in complex scenes. Selective memory for negative emotional information was enhanced after a nap compared to wakefulness in two control conditions designed to carefully address interference and time-of-day confounds. Although prior evidence has connected negative emotional memory formation to rapid eye movement (REM) sleep physiology, we found that non-REM delta activity and the amount of slow wave sleep (SWS) in the nap were robustly related to the selective consolidation of negative information. These findings suggest that the mechanisms underlying memory consolidation benefits associated with napping and nighttime sleep are not always the same. Finally, we provide preliminary evidence that the magnitude of the emotional memory benefit conferred by sleep is equivalent following a nap and a full night of sleep, suggesting that selective emotional remembering can be economically achieved by taking a nap. PMID:25706830
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The Effects of Vocal Activity and Race of Applicant on Job Selection Interview Decisions.
ERIC Educational Resources Information Center
Byrd, Marquita L.
1981-01-01
Research on the effect of vocal activity and race of the applicant on evaluations in job interviews indicated that: 1) minimal vocal activity negatively influenced evaluation; 2) Black applicants were evaluated differently from White applicants; and 3) vocal activity was more important in interview evaluations than race. (Author/MJL)
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Kolarič, Anja; Švajger, Urban; Tomašič, Tihomir; Brox, Regine; Frank, Theresa; Minovski, Nikola; Tschammer, Nuska; Anderluh, Marko
2018-05-11
Based on the previously published pyrazolopyridine-based hit compound for which negative allosteric modulation of both CXCR3 and CXCR4 receptors was disclosed, we designed, synthesized and biologically evaluated a set of novel, not only negative, but also positive allosteric modulators with preserved pyrazolopyridine core. Compound 9e is a dual negative modulator, inhibiting G protein activity of both receptors. For CXCR4 receptor para-substituted aromatic group of compounds distinguishes between negative and positive modulation. Para-methoxy substitution leads to functional antagonism, while para-chloro triggers agonism. Additionally, we discovered that chemotaxis is not completely correlated with G protein pathways. This is the first work in which we have on a series of compounds successfully demonstrated that it is possible to produce selective as well as dual-acting modulators of chemokine receptors, which is very promising for future research in the field of discovery of selective or dual modulators of chemokine receptors. Copyright © 2018 Elsevier Masson SAS. All rights reserved.
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Le Galliard, J-F; Paquet, M; Mugabo, M
2015-05-01
Temperament traits are seen in many animal species, and recent evolutionary models predict that they could be maintained by heterogeneous selection. We tested this prediction by examining density-dependent selection in juvenile common lizards Zootoca vivipara scored for activity, boldness and sociability at birth and at the age of 1 year. We measured three key life-history traits (juvenile survival, body growth rate and reproduction) and quantified selection in experimental populations at five density levels ranging from low to high values. We observed consistent individual differences for all behaviours on the short term, but only for activity and one boldness measure across the first year of life. At low density, growth selection favoured more sociable lizards, whereas viability selection favoured less active individuals. A significant negative correlational selection on activity and boldness existed for body growth rate irrespective of density. Thus, behavioural traits were characterized by limited ontogenic consistency, and natural selection was heterogeneous between density treatments and fitness traits. This confirms that density-dependent selection plays an important role in the maintenance of individual differences in exploration-activity and sociability. © 2015 European Society For Evolutionary Biology. Journal of Evolutionary Biology © 2015 European Society For Evolutionary Biology.
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Notthoff, Nanna; Klomp, Peter; Doerwald, Friederike; Scheibe, Susanne
2016-09-01
Although physical activity is an effective way to cope with ageing-related impairments, few older people are motivated to turn their sedentary lifestyle into an active one. Recent evidence suggests that walking can be more effectively promoted in older adults with positive messages about the benefits of walking than with negative messages about the risks of inactivity. This study examined motivation and memory as the supposed mechanisms underlying the greater effectiveness of positively framed compared to negatively framed messages for promoting activity. Older adults ( N = 53, age 60-87 years) were introduced to six physical activity programmes that were randomly paired with either positively framed or negatively framed messages. Participants indicated how motivated they were to participate in each programme by providing ratings on attractiveness, suitability, capability and intention. They also completed surprise free recall and recognition tests. Respondents felt more motivated to participate in physical activity programmes paired with positively framed messages than in those with negatively framed ones. They also had better recognition memory for positively framed than negatively framed messages, and misremembered negatively framed messages to be positively framed. Findings support the notion that socioemotional selectivity theory-a theory of age-related changes in motivation-is a useful basis for health intervention design.
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Negative stiffness and modulated states in active nematics.
Srivastava, Pragya; Mishra, Prashant; Marchetti, M Cristina
2016-10-04
We examine the dynamics of an active nematic liquid crystal on a frictional substrate. When frictional damping dominates over viscous dissipation, we eliminate flow in favor of active stresses to obtain a minimal dynamical model for the nematic order parameter, with elastic constants renormalized by activity. The renormalized elastic constants can become negative at large activity, leading to the selection of spatially inhomogeneous patterns via a mechanism analogous to that responsible for modulated phases arising at an equilibrium Lifshitz point. Tuning activity and the degree of nematic order in the passive system, we obtain a linear stability phase diagram that exhibits a nonequilibrium tricritical point where ordered, modulated and disordered phases meet. Numerical solution of the nonlinear equations yields a succession of spatial structures of increasing complexity with increasing activity, including kink walls and active turbulence, as observed in experiments on microtubule bundles confined at an oil-water interface. Our work provides a minimal model for an overdamped active nematic that reproduces all the nonequilibrium structures seen in simulations of the full active nematic hydrodynamics and provides a framework for understanding some of the mechanisms for selection of the nonequilibrium patterns in the language of equilibrium critical phenomena.
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Wanner, Juergen; Schmidt, Erich; Bail, Stefanie; Jirovetz, Leopold; Buchbauer, Gerhard; Gochev, Velizar; Girova, Tanya; Atanasova, Teodora; Stoyanova, Albena
2010-09-01
The chemical composition of essential oils of cabreuva (Myrocarpus fastigiatus Allemao, Fabaceae) from Brazil, cedarwood (Juniperus ashei, Cupressaceae) from Texas, Juniper berries (Juniperus communis L., Cupressaceae) and myrrh (Commiphora myrrha (Nees) Engl., Burseraceae) were analyzed using GC/FID and GC/MS. The antimicrobial activity of these essential oils and some of their main compounds were tested against eleven different strains of Gram-positive and Gram-negative bacteria by using agar diffusion and agar serial dilution methods. Animal and plant pathogens, food poisoning and spoilage bacteria were selected. The volatile oils exhibited considerable inhibitory effects against all tested organisms, except Pseudomonas, using both test methods. Higher activity was observed against Gram-positive strains in comparison with Gram-negative bacteria. Cabreuva oil from Brazil showed similar results, but in comparison with the other oils tested, only when higher concentrations of oil were used.
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Asymmetric bagging and feature selection for activities prediction of drug molecules.
Li, Guo-Zheng; Meng, Hao-Hua; Lu, Wen-Cong; Yang, Jack Y; Yang, Mary Qu
2008-05-28
Activities of drug molecules can be predicted by QSAR (quantitative structure activity relationship) models, which overcomes the disadvantages of high cost and long cycle by employing the traditional experimental method. With the fact that the number of drug molecules with positive activity is rather fewer than that of negatives, it is important to predict molecular activities considering such an unbalanced situation. Here, asymmetric bagging and feature selection are introduced into the problem and asymmetric bagging of support vector machines (asBagging) is proposed on predicting drug activities to treat the unbalanced problem. At the same time, the features extracted from the structures of drug molecules affect prediction accuracy of QSAR models. Therefore, a novel algorithm named PRIFEAB is proposed, which applies an embedded feature selection method to remove redundant and irrelevant features for asBagging. Numerical experimental results on a data set of molecular activities show that asBagging improve the AUC and sensitivity values of molecular activities and PRIFEAB with feature selection further helps to improve the prediction ability. Asymmetric bagging can help to improve prediction accuracy of activities of drug molecules, which can be furthermore improved by performing feature selection to select relevant features from the drug molecules data sets.
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Negative Electrode For An Alkaline Cell
Coco, Isabelle; Cocciantelli, Jean-Michel; Villenave, Jean-Jacques
1998-07-14
The present invention concerns a negative electrode for an alkaline cell, comprising a current collector supporting a paste containing an electrochemically active material and a binder, characterized in that said binder is a polymer containing hydrophilic and hydrophobic groups, said polymer being selected from an acrylic homopolymer, copolymer and terpolymer, an unsaturated organic acid copolymer and an unsaturated acid anhydride copolymer.
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NASA Astrophysics Data System (ADS)
Kwak, Kyuju; Kumar, S. Senthil; Lee, Dongil
2012-06-01
We report here the selective determination of dopamine (DA) using quantum-sized gold nanoparticles coated with charge selective ligands. Glutathione protected gold nanoparticles (GS-Au25) were synthesized and immobilized into a sol-gel matrix via thiol linkers. The GS-Au25 modified sol-gel electrode was found to show excellent electrocatalytic activity towards the oxidation of DA but no activity towards the oxidation of ascorbic acid. The role of electrostatic charge in the selective electrocatalytic activity of GS-Au25 was verified by voltammetry of redox markers carrying opposite charges. The pH dependent sensitivity for the determination of DA further confirmed the charge screening effect of GS-Au25. Mechanistic investigation revealed that the selectivity is attained by the selective formation of an electrostatic complex between the negatively charged GS-Au25 and DA cation. The GS-Au25 modified sol-gel electrode also showed excellent selectivity for DA in the presence of an interferent, ascorbic acid.We report here the selective determination of dopamine (DA) using quantum-sized gold nanoparticles coated with charge selective ligands. Glutathione protected gold nanoparticles (GS-Au25) were synthesized and immobilized into a sol-gel matrix via thiol linkers. The GS-Au25 modified sol-gel electrode was found to show excellent electrocatalytic activity towards the oxidation of DA but no activity towards the oxidation of ascorbic acid. The role of electrostatic charge in the selective electrocatalytic activity of GS-Au25 was verified by voltammetry of redox markers carrying opposite charges. The pH dependent sensitivity for the determination of DA further confirmed the charge screening effect of GS-Au25. Mechanistic investigation revealed that the selectivity is attained by the selective formation of an electrostatic complex between the negatively charged GS-Au25 and DA cation. The GS-Au25 modified sol-gel electrode also showed excellent selectivity for DA in the presence of an interferent, ascorbic acid. Electronic supplementary information (ESI) available: TEM image of GS-Au25, SWV of GS-Au25 in solution, effect of scan rate on the CV of GS-Au25ME, CVs of DA and AA at the bare GCE and CVs of GS-Au25ME at different pHs. See DOI: 10.1039/c2nr30481c
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7 CFR 275.14 - Review processing.
Code of Federal Regulations, 2010 CFR
2010-01-01
... addition, the sample of active and negative cases shall be selected in accordance with the sampling techniques described in the Quality Control Sampling Handbook, FNS Handbook 311. (c) Worksheets. The...
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DOE Office of Scientific and Technical Information (OSTI.GOV)
Knosp, B.; Jordy, C.; Blanchard, P.
1998-05-01
Laves phase alloys of compositions (Zr, Ti)(Ni, Mn, M){sub x} where M = Cr, V, Co, Al, and 1.9 < x < 2.1 with hexagonal C14 or cubic C15 structure have been studied in order to select the most suitable AB{sub 2} alloys as an active material for nickel-metal hydride (Ni-MH) batteries. With the selected alloy, feasibility of MH negative electrodes using industrial technology and containing more than 97% of the alloy powder has been demonstrated. 22 Ah Ni-MH batteries for electric vehicle application have been assembled, and 600 cycles have been achieved at steady C/3 charge and discharge ratesmore » and 80% depth of discharge.« less
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Kosowska-Shick, Klaudia; Credito, Kim L.; Pankuch, Glenn A.; DeWasse, Bonifacio; McGhee, Pamela; Appelbaum, Peter C.
2007-01-01
LBM415 is a peptide deformylase inhibitor active against gram-positive bacterial species and some gram-negative species. In multiselection studies, LBM415 had low MICs against all Streptococcus pneumoniae strains tested, regardless of their genotype, and selected resistant clones after 14 to 50 days. MIC increases correlated with changes mostly in the 70GXGXAAXQ77 motif in peptide deformylase. The postantibiotic effect of LBM415 ranged from 0.3 to 1.4 h. PMID:17116666
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Kosowska-Shick, Klaudia; Credito, Kim L; Pankuch, Glenn A; DeWasse, Bonifacio; McGhee, Pamela; Appelbaum, Peter C
2007-02-01
LBM415 is a peptide deformylase inhibitor active against gram-positive bacterial species and some gram-negative species. In multiselection studies, LBM415 had low MICs against all Streptococcus pneumoniae strains tested, regardless of their genotype, and selected resistant clones after 14 to 50 days. MIC increases correlated with changes mostly in the 70GXGXAAXQ77 motif in peptide deformylase. The postantibiotic effect of LBM415 ranged from 0.3 to 1.4 h.
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Alloy, L B; Lipman, A J
1992-05-01
In this commentary we examine Swann, Wenzlaff, Krull, and Pelham's (1992) findings with respect to each of 5 central propositions in self-verification theory. We conclude that although the data are consistent with self-verification theory, none of the 5 components of the theory have been demonstrated convincingly as yet. Specifically, we argue that depressed subjects' selection of social feedback appears to be balanced or evenhanded rather than biased toward negative feedback and that there is little evidence to indicate that depressives actively seek negative appraisals. Furthermore, we suggest that the studies are silent with respect to the motivational postulates of self-verification theory and that a variety of competing cognitive and motivational models can explain Swann et al.'s findings as well as self-verification theory.
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Wencewicz, Timothy A.; Miller, Marvin J.
2013-01-01
Chemical syntheses and biological evaluation of biscatecholate-monohydroxamate mixed ligand sideromycins utilizing the carbacephalosporin β-lactam antibiotic loracarbef and the fluo-roquinolone antibiotic ciprofloxacin are described. The mixed ligand β-lactam sideromycin (1b) had remarkably selective and extremely potent antibacterial activity against the Gram negative pathogen Acinetobacter baumannii ATCC 17961 (MIC = 0.0078 μM). The antibacterial activity of the β-lactam sideromycin was inversely related to the iron(III) concentration in the testing media and was antagonized by the presence of the competing parent siderophore. These data suggested that active transport of the mixed ligand β-lactam sideromycin across the outer cell membrane of A. baumannii via siderophore uptake pathways was responsible for the selective and potent antibacterial activity. PMID:23614627
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Procyanidins Negatively Affect the Activity of the Phosphatases of Regenerating Liver
Stadlbauer, Sven; Rios, Pablo; Ohmori, Ken; Suzuki, Keisuke; Köhn, Maja
2015-01-01
Natural polyphenols like oligomeric catechins (procyanidins) derived from green tea and herbal medicines are interesting compounds for pharmaceutical research due to their ability to protect against carcinogenesis in animal models. It is nevertheless still unclear how intracellular pathways are modulated by polyphenols. Monomeric polyphenols were shown to affect the activity of some protein phosphatases (PPs). The three phosphatases of regenerating liver (PRLs) are close relatives and promising therapeutic targets in cancer. In the present study we show that several procyanidins inhibit the activity of all three members of the PRL family in the low micromolar range, whereas monomeric epicatechins show weak inhibitory activity. Increasing the number of catechin units in procyanidins to more than three does not further enhance the potency. Remarkably, the tested procyanidins showed selectivity in vitro when compared to other PPs, and over 10-fold selectivity toward PRL-1 over PRL-2 and PRL-3. As PRL overexpression induces cell migration compared to control cells, the effect of procyanidins on this phenotype was studied. Treatment with procyanidin C2 led to a decrease in cell migration of PRL-1- and PRL-3-overexpressing cells, suggesting the compound-dependent inhibition of PRL-promoted cell migration. Treatment with procyanidin B3 led to selective suppression of PRL-1 overexpressing cells, thereby corroborating the selectivity toward PRL-1- over PRL-3 in vitro. Together, our results show that procyanidins negatively affect PRL activity, suggesting that PRLs could be targets in the polypharmacology of natural polyphenols. Furthermore, they are interesting candidates for the development of PRL-1 inhibitors due to their low cellular toxicity and the selectivity within the PRL family. PMID:26226290
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Introducing Bayesian thinking to high-throughput screening for false-negative rate estimation.
Wei, Xin; Gao, Lin; Zhang, Xiaolei; Qian, Hong; Rowan, Karen; Mark, David; Peng, Zhengwei; Huang, Kuo-Sen
2013-10-01
High-throughput screening (HTS) has been widely used to identify active compounds (hits) that bind to biological targets. Because of cost concerns, the comprehensive screening of millions of compounds is typically conducted without replication. Real hits that fail to exhibit measurable activity in the primary screen due to random experimental errors will be lost as false-negatives. Conceivably, the projected false-negative rate is a parameter that reflects screening quality. Furthermore, it can be used to guide the selection of optimal numbers of compounds for hit confirmation. Therefore, a method that predicts false-negative rates from the primary screening data is extremely valuable. In this article, we describe the implementation of a pilot screen on a representative fraction (1%) of the screening library in order to obtain information about assay variability as well as a preliminary hit activity distribution profile. Using this training data set, we then developed an algorithm based on Bayesian logic and Monte Carlo simulation to estimate the number of true active compounds and potential missed hits from the full library screen. We have applied this strategy to five screening projects. The results demonstrate that this method produces useful predictions on the numbers of false negatives.
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Impaired periamygdaloid-cortex prodynorphin is characteristic of opiate addiction and depression.
Anderson, Sarah Ann R; Michaelides, Michael; Zarnegar, Parisa; Ren, Yanhua; Fagergren, Pernilla; Thanos, Panayotis K; Wang, Gene-Jack; Bannon, Michael; Neumaier, John F; Keller, Eva; Volkow, Nora D; Hurd, Yasmin L
2013-12-01
Negative affect is critical for conferring vulnerability to opiate addiction as reflected by the high comorbidity of opiate abuse with major depressive disorder (MDD). Rodent models implicate amygdala prodynorphin (Pdyn) as a mediator of negative affect; however, evidence of PDYN involvement in human negative affect is limited. Here, we found reduced PDYN mRNA expression in the postmortem human amygdala nucleus of the periamygdaloid cortex (PAC) in both heroin abusers and MDD subjects. Similar to humans, rats that chronically self-administered heroin had reduced Pdyn mRNA expression in the PAC at a time point associated with a negative affective state. Using the in vivo functional imaging technology DREAMM (DREADD-assisted metabolic mapping, where DREADD indicates designer receptors exclusively activated by designer drugs), we found that selective inhibition of Pdyn-expressing neurons in the rat PAC increased metabolic activity in the extended amygdala, which is a key substrate of the extrahypothalamic brain stress system. In parallel, PAC-specific Pdyn inhibition provoked negative affect-related physiological and behavioral changes. Altogether, our translational study supports a functional role for impaired Pdyn in the PAC in opiate abuse through activation of the stress and negative affect neurocircuitry implicated in addiction vulnerability.
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Guo, Shuohan; Zhang, Xiaohan; Zheng, Mei; Zhang, Xiaowei; Min, Chengchun; Wang, Zengtao; Cheon, Seung Hoon; Oak, Min-Ho; Nah, Seung-Yeol; Kim, Kyeong-Man
2015-10-01
Among the multiple G protein-coupled receptor (GPCR) endocytic pathways, clathrin-mediated endocytosis (CME) and caveolar endocytosis are more extensively characterized than other endocytic pathways. A number of endocytic inhibitors have been used to block CME; however, systemic studies to determine the selectivity of these inhibitors are needed. Clathrin heavy chain or caveolin1-knockdown cells have been employed to determine the specificity of various chemical and molecular biological tools for CME and caveolar endocytosis. Sucrose, concanavalin A, and dominant negative mutants of dynamin blocked other endocytic pathways, in addition to CME. In particular, concanavalin A nonspecifically interfered with the signaling of several GPCRs tested in the study. Decreased pH, monodansylcadaverine, and dominant negative mutants of epsin were more specific for CME than other treatments were. A recently introduced CME inhibitor, Pitstop2™, showed only marginal selectivity for CME and interfered with receptor expression on the cell surface. Blockade of receptor endocytosis by epsin mutants and knockdown of the clathrin heavy chain enhanced the β2AR-mediated ERK activation. Overall, our studies show that previous experimental results should be interpreted with discretion if they included the use of endocytic inhibitors that were previously thought to be CME-selective. In addition, our study shows that endocytosis of β2 adrenoceptor through clathrin-mediated pathway has negative effects on ERK activation. Copyright © 2015 Elsevier B.V. All rights reserved.
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Muddukrishna, B S; Pai, Vasudev; Lobo, Richard; Pai, Aravinda
2017-11-22
In the present study, five important binary fingerprinting techniques were used to model novel flavones for the selective inhibition of Tankyrase I. From the fingerprints used: the fingerprint atom pairs resulted in a statistically significant 2D QSAR model using a kernel-based partial least square regression method. This model indicates that the presence of electron-donating groups positively contributes to activity, whereas the presence of electron withdrawing groups negatively contributes to activity. This model could be used to develop more potent as well as selective analogues for the inhibition of Tankyrase I. Schematic representation of 2D QSAR work flow.
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Age-related perspectives and emotion processing.
Lynchard, Nicholas A; Radvansky, Gabriel A
2012-12-01
Emotion is processed differently in younger and older adults. Older adults show a positivity effect, whereas younger adults show a negativity effect. Socioemotional selectivity theory suggests that these effects can be elicited in any age group when age-related perspectives are manipulated. To examine this, younger and older adults were oriented to actual and age-contrasting possible selves. Emotion activations were assessed using lexical decision. In line with socioemotional selectivity theory, shifts in emotion orientation varied according to perspective, with both younger and older adults showing a negativity effect when a younger adult perspective was taken and a positivity effect when an older adult perspective was taken. 2013 APA, all rights reserved
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Considering the Role and Nature of the Scientist: The Case of Darwin and Evolution
ERIC Educational Resources Information Center
Aydin, Serap Öz
2015-01-01
For many students, preconceived notions about Darwin are among the most significant obstacles in learning about the theory of evolution by natural selection. I present an activity designed to eliminate this obstacle and encourage empathizing with Darwin, utilizing the history-of-science approach. Through the activity, students' negative thoughts…
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Moreb, Eirik Adim; Hoover, Benjamin; Yaseen, Adam; Valyasevi, Nisakorn; Roecker, Zoe; Menacho-Melgar, Romel; Lynch, Michael D
2017-12-15
Phage-derived "recombineering" methods are utilized for bacterial genome editing. Recombineering results in a heterogeneous population of modified and unmodified chromosomes, and therefore selection methods, such as CRISPR-Cas9, are required to select for edited clones. Cells can evade CRISPR-Cas-induced cell death through recA-mediated induction of the SOS response. The SOS response increases RecA dependent repair as well as mutation rates through induction of the umuDC error prone polymerase. As a result, CRISPR-Cas selection is more efficient in recA mutants. We report an approach to inhibiting the SOS response and RecA activity through the expression of a mutant dominant negative form of RecA, which incorporates into wild type RecA filaments and inhibits activity. Using a plasmid-based system in which Cas9 and recA mutants are coexpressed, we can achieve increased efficiency and consistency of CRISPR-Cas9-mediated selection and recombineering in E. coli, while reducing the induction of the SOS response. To date, this approach has been shown to be independent of recA genotype and host strain lineage. Using this system, we demonstrate increased CRISPR-Cas selection efficacy with over 10 000 guides covering the E. coli chromosome. The use of dominant negative RecA or homologues may be of broad use in bacterial CRISPR-Cas-based genome editing where the SOS pathways are present.
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Redesigned Spider Peptide with Improved Antimicrobial and Anticancer Properties.
Troeira Henriques, Sónia; Lawrence, Nicole; Chaousis, Stephanie; Ravipati, Anjaneya S; Cheneval, Olivier; Benfield, Aurélie H; Elliott, Alysha G; Kavanagh, Angela Maria; Cooper, Matthew A; Chan, Lai Yue; Huang, Yen-Hua; Craik, David J
2017-09-15
Gomesin, a disulfide-rich antimicrobial peptide produced by the Brazilian spider Acanthoscurria gomesiana, has been shown to be potent against Gram-negative bacteria and to possess selective anticancer properties against melanoma cells. In a recent study, a backbone cyclized analogue of gomesin was shown to be as active but more stable than its native form. In the current study, we were interested in improving the antimicrobial properties of the cyclic gomesin, understanding its selectivity toward melanoma cells and elucidating its antimicrobial and anticancer mode of action. Rationally designed analogues of cyclic gomesin were examined for their antimicrobial potency, selectivity toward cancer cells, membrane-binding affinity, and ability to disrupt cell and model membranes. We improved the activity of cyclic gomesin by ∼10-fold against tested Gram-negative and Gram-positive bacteria without increasing toxicity to human red blood cells. In addition, we showed that gomesin and its analogues are more toxic toward melanoma and leukemia cells than toward red blood cells and act by selectively targeting and disrupting cancer cell membranes. Preference toward some cancer types is likely dependent on their different cell membrane properties. Our findings highlight the potential of peptides as antimicrobial and anticancer leads and the importance of selectively targeting cancer cell membranes for drug development.
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Post-error Brain Activity Correlates With Incidental Memory for Negative Words
Senderecka, Magdalena; Ociepka, Michał; Matyjek, Magdalena; Kroczek, Bartłomiej
2018-01-01
The present study had three main objectives. First, we aimed to evaluate whether short-duration affective states induced by negative and positive words can lead to increased error-monitoring activity relative to a neutral task condition. Second, we intended to determine whether such an enhancement is limited to words of specific valence or is a general response to arousing material. Third, we wanted to assess whether post-error brain activity is associated with incidental memory for negative and/or positive words. Participants performed an emotional stop-signal task that required response inhibition to negative, positive or neutral nouns while EEG was recorded. Immediately after the completion of the task, they were instructed to recall as many of the presented words as they could in an unexpected free recall test. We observed significantly greater brain activity in the error-positivity (Pe) time window in both negative and positive trials. The error-related negativity amplitudes were comparable in both the neutral and emotional arousing trials, regardless of their valence. Regarding behavior, increased processing of emotional words was reflected in better incidental recall. Importantly, the memory performance for negative words was positively correlated with the Pe amplitude, particularly in the negative condition. The source localization analysis revealed that the subsequent memory recall for negative words was associated with widespread bilateral brain activity in the dorsal anterior cingulate cortex and in the medial frontal gyrus, which was registered in the Pe time window during negative trials. The present study has several important conclusions. First, it indicates that the emotional enhancement of error monitoring, as reflected by the Pe amplitude, may be induced by stimuli with symbolic, ontogenetically learned emotional significance. Second, it indicates that the emotion-related enhancement of the Pe occurs across both negative and positive conditions, thus it is preferentially driven by the arousal content of an affective stimuli. Third, our findings suggest that enhanced error monitoring and facilitated recall of negative words may both reflect responsivity to negative events. More speculatively, they can also indicate that post-error activity of the medial prefrontal cortex may selectively support encoding for negative stimuli and contribute to their privileged access to memory. PMID:29867408
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Paying attention to emotion: an fMRI investigation of cognitive and emotional stroop tasks.
Compton, Rebecca J; Banich, Marie T; Mohanty, Aprajita; Milham, Michael P; Herrington, John; Miller, Gregory A; Scalf, Paige E; Webb, Andrew; Heller, Wendy
2003-06-01
In this research, we investigated the degree to which brain systems involved in ignoring emotionally salient information differ from those involved in ignoring nonemotional information. The design allowed examination of regional brain activity, using fMRI during color-word and emotional Stroop tasks. Twelve participants indicated the color of words while ignoring word meaning in conditions in which neutral words were contrasted to emotionally negative, emotionally positive, and incongruent color words. Dorsolateral frontal lobe activity was increased by both negative and incongruent color words, indicating a common system for maintaining an attentional set in the presence of salient distractors. In posterior regions of the brain, activity depended on the nature of the information to be ignored. Ignoring color-incongruent words increased left parietal activity and decreased parahippocampal gyrus activity, whereas ignoring negative emotional words increased bilateral occipito-temporal activity and decreased amygdala activity. The results indicate that emotion and attention are intimately related via a network of regions that monitor for salient information, maintain attention on the task, suppress irrelevant information, and select appropriate responses.
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Li, Luowei; Sampat, Keeran; Hu, Nancy; Zakari, Julia; Yuspa, Stuart H
2006-02-10
Skin keratinocytes are subject to frequent chemical and physical injury and have developed elaborate cell survival mechanisms to compensate. Among these, the Akt/protein kinase B (PKB) pathway protects keratinocytes from the toxic effects of ultraviolet light (UV). In contrast, the protein kinase C (PKC) family is involved in several keratinocyte death pathways. During an examination of potential interactions among these two pathways, we found that the insulin-like growth factor (IGF-1) activates both the PKC and the Akt signaling pathways in cultured primary mouse keratinocytes as indicated by increased phospho-PKC and phospho-Ser-473-Akt. IGF-1 also selectively induced translocation of PKCdelta and PKCepsilon from soluble to particulate fractions in mouse keratinocytes. Furthermore, the PKC-specific inhibitor, GF109203X, increased IGF-1-induced phospho-Ser-473-Akt and Akt kinase activity and enhanced IGF-1 protection from UVC-induced apoptosis. Selective activation of PKC by 12-O-tetradecanoylphorbol-13-acetate (TPA) reduced phospho-Ser-473-Akt, suggesting that activation of PKC inhibits Akt activity. TPA also attenuated IGF-1 and epidermal growth factor-induced phospho-Ser-473-Akt, reduced Akt kinase activity, and blocked IGF-1 protection from UVC-induced apoptosis. The inhibition of Akt activity by TPA was reduced by inhibitors of protein phosphatase 2A, and TPA stimulated the association of phosphatase 2A with Akt. Individual PKC isoforms were overexpressed in cultured keratinocytes by transduction with adenoviral vectors or inhibited with PKC-selective inhibitors. These studies indicated that PKCdelta and PKCepsilon were selectively potent at causing dephosphorylation of Akt and modifying cell survival, whereas PKCalpha enhanced phosphorylation of Akt on Ser-473. Our results suggested that activation of PKCdelta and PKCepsilon provide a negative regulation for Akt phosphorylation and kinase activity in mouse keratinocytes and serve as modulators of cell survival pathways in response to external stimuli.
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Effects of Gymnastics Activities on Bone Accrual during Growth: A Systematic Review.
Jürimäe, Jaak; Gruodyte-Raciene, Rita; Baxter-Jones, Adam D G
2018-06-01
The amount of bone gained during childhood and adolescence impacts greatly on lifetime skeletal health. The purpose of this review is to summarize current evidence of the effects of gymnastics activities on bone mineral accrual during growth and to describe possible factors that influence bone mineral gains. The PubMed and SportDiscus databases were searched, and a total of 24 articles met the selection criteria and were included in this review. Artistic and rhythmic gymnasts presented higher bone mineral density and content values compared to untrained controls, despite possible negative effects associated with hormonal levels, dietary restrictions and body fat. The results suggest that gymnasts had similar bone turnover values compared to untrained controls. High-intensity mechanical loading of gymnastics activity appears to increase bone development and counterbalance negative effects, such as later pubertal development, lower body fat mass and lower hormone levels. In conclusion, gymnasts present higher bone mineral values in comparison with untrained controls. The osteogenic effect of gymnastics athletic activity has a positive influence on bone mineral accrual and overcomes the possible negative influence of high athletic activity that may cause negative energy balance and low body fat mass which are associated with lower bone accrual.
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Decoys Selection in Benchmarking Datasets: Overview and Perspectives
Réau, Manon; Langenfeld, Florent; Zagury, Jean-François; Lagarde, Nathalie; Montes, Matthieu
2018-01-01
Virtual Screening (VS) is designed to prospectively help identifying potential hits, i.e., compounds capable of interacting with a given target and potentially modulate its activity, out of large compound collections. Among the variety of methodologies, it is crucial to select the protocol that is the most adapted to the query/target system under study and that yields the most reliable output. To this aim, the performance of VS methods is commonly evaluated and compared by computing their ability to retrieve active compounds in benchmarking datasets. The benchmarking datasets contain a subset of known active compounds together with a subset of decoys, i.e., assumed non-active molecules. The composition of both the active and the decoy compounds subsets is critical to limit the biases in the evaluation of the VS methods. In this review, we focus on the selection of decoy compounds that has considerably changed over the years, from randomly selected compounds to highly customized or experimentally validated negative compounds. We first outline the evolution of decoys selection in benchmarking databases as well as current benchmarking databases that tend to minimize the introduction of biases, and secondly, we propose recommendations for the selection and the design of benchmarking datasets. PMID:29416509
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Antistaphylococcal activity of DX-619, a new des-F(6)-quinolone, compared to those of other agents.
Bogdanovich, Tatiana; Esel, Duygu; Kelly, Linda M; Bozdogan, Bülent; Credito, Kim; Lin, Gengrong; Smith, Kathy; Ednie, Lois M; Hoellman, Dianne B; Appelbaum, Peter C
2005-08-01
The in vitro activity of DX-619, a new des-F(6)-quinolone, was tested against staphylococci and compared to those of other antimicrobials. DX-619 had the lowest MIC ranges/MIC(50)s/MIC(90)s (microg/ml) against 131 Staphylococcus aureus strains (32), and ciprofloxacin (>32/>32). Raised quinolone MICs were associated with mutations in GyrA (S84L) and single or double mutations in GrlA (S80F or Y; E84K, G, or V) in all S. aureus strains tested. A recent vancomycin-resistant S. aureus (VRSA) strain (Hershey) was resistant to available quinolones and was inhibited by DX-619 at 0.25 microg/ml and sitafloxacin at 1.0 microg/ml. Vancomycin (except VRSA), linezolid, ranbezolid, tigecycline, and quinupristin-dalfopristin were active against all strains, and teicoplanin was active against S. aureus but less active against coagulase-negative staphylococci. DX-619 produced resistant mutants with MICs of 1 to >32 microg/ml after <50 days of selection compared to 16 to >32 microg/ml for ciprofloxacin, sitafloxacin, moxifloxacin, and gatifloxacin. DX-619 and sitafloxacin were also more active than other tested drugs against selected mutants and had the lowest mutation frequencies in single-step resistance selection. DX-619 and sitafloxacin were bactericidal against six quinolone-resistant (including the VRSA) and seven quinolone-susceptible strains tested, whereas gatifloxacin, moxifloxacin, levofloxacin, and ciprofloxacin were bactericidal against 11, 10, 7, and 5 strains at 4x MIC after 24 h, respectively. DX-619 was also bactericidal against one other VRSA strain, five vancomycin-intermediate S. aureus strains, and four vancomycin-intermediate coagulase-negative staphylococci. Linezolid, ranbezolid, and tigecycline were bacteriostatic and quinupristin-dalfopristin, teicoplanin, and vancomycin were bactericidal against two, eight, and nine strains, and daptomycin and oritavancin were rapidly bactericidal against all strains, including the VRSA. DX-619 has potent in vitro activity against staphylococci, including methicillin-, ciprofloxacin-, and vancomycin-resistant strains.
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Bim-mediated apoptosis is not necessary for thymic negative selection to ubiquitous self-antigens.
Hu, Qian; Sader, Alyssa; Parkman, Julia C; Baldwin, Troy A
2009-12-15
T cell education in the thymus is critical for establishing a functional, yet self-tolerant, T cell repertoire. Negative selection is a key process in enforcing self-tolerance. There are many questions that surround the mechanism of negative selection, but it is currently held that apoptosis initiated by Bim and/or Nur77 is critical for negative selection. Recent studies, however, have questioned the necessity of Bim in maintaining both central and peripheral T cell tolerance. To reconcile these apparently contradictory findings, we examined the role of Bim in negative selection in the well-characterized, physiological HY(cd4) mouse model. We found that while Bim expression was required for CD4(+)CD8(+) double-positive thymocyte apoptosis, it was not required for negative selection. Furthermore, Bim deficiency did not alter the frequency or affinity of male reactive cells that escape negative selection in an oligoclonal repertoire. Collectively, these studies indicate that negative selection occurs efficiently in the absence of apoptosis and suggest that the current paradigm of negative selection requiring apoptosis be revisited.
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Kasten, Chelsea R; Zhang, Yanping; Mackie, Ken; Boehm, Stephen L
2018-05-01
Cannabis use is linked to positive and negative outcomes. Identifying genetic targets of susceptibility to the negative effects of cannabinoid use is of growing importance. The current study sought to complete short-term selective breeding for adolescent sensitivity and resistance to the locomotor effects of a single 10 mg/kg THC dose in the open field. Selection for THC-locomotor sensitivity was moderately heritable, with the greatest estimates of heritability seen in females from the F2 to S3 generations. Selection for locomotor sensitivity also resulted in increased anxiety-like activity in the open field. These results are the first to indicate that adolescent THC-locomotor sensitivity can be influenced via selective breeding. Development of lines with a genetic predisposition for THC-sensitivity or resistance to locomotor effects allow for investigation of risk factors, differences in consequences of THC use, identification of correlated behavioral responses, and detection of genetic targets that may contribute to heightened cannabinoid sensitivity.
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ERP markers of target selection discriminate children with high vs. low working memory capacity.
Shimi, Andria; Nobre, Anna Christina; Scerif, Gaia
2015-01-01
Selective attention enables enhancing a subset out of multiple competing items to maximize the capacity of our limited visual working memory (VWM) system. Multiple behavioral and electrophysiological studies have revealed the cognitive and neural mechanisms supporting adults' selective attention of visual percepts for encoding in VWM. However, research on children is more limited. What are the neural mechanisms involved in children's selection of incoming percepts in service of VWM? Do these differ from the ones subserving adults' selection? Ten-year-olds and adults used a spatial arrow cue to select a colored item for later recognition from an array of four colored items. The temporal dynamics of selection were investigated through EEG signals locked to the onset of the memory array. Both children and adults elicited significantly more negative activity over posterior scalp locations contralateral to the item to-be-selected for encoding (N2pc). However, this activity was elicited later and for longer in children compared to adults. Furthermore, although children as a group did not elicit a significant N2pc during the time-window in which N2pc was elicited in adults, the magnitude of N2pc during the "adult time-window" related to their behavioral performance during the later recognition phase of the task. This in turn highlights how children's neural activity subserving attention during encoding relates to better subsequent VWM performance. Significant differences were observed when children were divided into groups of high vs. low VWM capacity as a function of cueing benefit. Children with large cue benefits in VWM capacity elicited an adult-like contralateral negativity following attentional selection of the to-be-encoded item, whereas children with low VWM capacity did not. These results corroborate the close coupling between selective attention and VWM from childhood and elucidate further the attentional mechanisms constraining VWM performance in children.
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Laudy, Agnieszka E; Kulińska, Ewa; Tyski, Stefan
2017-01-11
The potential role of non-antibiotic medicinal products in the treatment of multidrug-resistant Gram-negative bacteria has recently been investigated. It is highly likely that the presence of efflux pumps may be one of the reasons for the weak activity of non-antibiotics, as in the case of some non-steroidal anti-inflammatory drugs (NSAIDs), against Gram-negative rods. The activity of eight drugs of potential non-antibiotic activity, active substance standards, and relevant medicinal products were analysed with and without of efflux pump inhibitors against 180 strains of five Gram-negative rod species by minimum inhibitory concentration (MIC) value determination in the presence of 1 mM MgSO₄. Furthermore, the influence of non-antibiotics on the susceptibility of clinical strains to quinolones with or without PAβN (Phe-Arg-β-naphthylamide) was investigated. The impacts of PAβN on the susceptibility of bacteria to non-antibiotics suggests that amitriptyline, alendronate, nicergoline, and ticlopidine are substrates of efflux pumps in Gram-negative rods. Amitriptyline/Amitriptylinum showed the highest direct antibacterial activity, with MICs ranging 100-800 mg/L against all studied species. Significant decreases in the MIC values of other active substances (acyclovir, atorvastatin, and famotidine) tested with pump inhibitors were not observed. The investigated non-antibiotic medicinal products did not alter the MICs of quinolones in the absence and in the presence of PAβN to the studied clinical strains of five groups of species.
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Isolation of the antibiotic pseudopyronine B and SAR evaluation of C3/C6 alkyl analogs.
Bouthillette, Leah M; Darcey, Catherine A; Handy, Tess E; Seaton, Sarah C; Wolfe, Amanda L
2017-06-15
Natural products are an abundant source of structurally diverse compounds with antibacterial activity that can be used to develop new and potent antibiotics. One such class of natural products is the pseudopyronines. Here we present the isolation of pseudopyronine B (2) from a Pseudomonas species found in garden soil in Western North Carolina, and SAR evaluation of C3 and C6 alkyl analogs of the natural product for antibacterial activity against Gram-positive and Gram-negative bacteria. We found a direct relationship between antibacterial activity and C3/C6 alkyl chain length. For inhibition of Gram-positive bacteria, alkyl chain lengths between 6 and 7 carbons were found to be the most active (IC 50 =0.04-3.8µg/mL) whereas short alkyl chain analogs showed modest activity against Gram-negative bacteria (IC 50 =223-304µg/mL). This demonstrates the potential for this class of natural products to be optimized for selective activity against either Gram-positive or Gram-negative bacteria. Copyright © 2017 Elsevier Ltd. All rights reserved.
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Comparative activity of carbapenem testing (the COMPACT study) in Turkey
2012-01-01
Background Recent evidence indicates that Gram-negative bacterial pathogens, the most common of which are Pseudomonas spp., Enterobacteriaceae, and Acinetobacter baumannii, are frequent causes of hospital-acquired infections. This study aims to evaluate the in vitro activity of doripenem and comparator carbapenem antibiotics against Gram-negative clinical isolates collected from COMParative Activity of Carbapenem Testing (COMPACT) study centres in Turkey. Methods Ten centres in Turkey were invited to submit Pseudomonas aeruginosa, Enterobacteriaceae, and other Gram-negative isolates from intensive care unit (ICU)/non-ICU patients with complicated intra-abdominal infections, bloodstream infections, or nosocomial pneumonia, including ventilator-associated pneumonia, between May and October 2008. Susceptibility was determined by each centre using E-test. A central laboratory performed species confirmation as well as limited susceptibility and quality-control testing. Results Five hundred and ninety six isolates were collected. MIC90 values for doripenem, meropenem, and imipenem, respectively, were 32, ≥ 64, and ≥ 64 mg/L against Pseudomonas spp.; 0.12, 0.12, and 0.5 mg/L against Enterobacteriaceae; and ≥ 64 mg/L for each against other Gram-negative isolates. In determining the susceptibility of hospital isolates of selected Gram-negative pathogens to doripenem, imipenem, and meropenem, we found that against all pathogens combined, the MIC90 for ICU compared with non-ICU isolates was higher. Conclusions Doripenem showed similar or slightly better activity than meropenem and better activity than imipenem against the Gram-negative pathogens collected in Turkey. PMID:22340940
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Montanari, Maria Pia; Mingoia, Marina; Varaldo, Pietro Emanuele
2001-01-01
AF 3013, the active metabolite of prulifloxacin, was tested to determine its inhibitory and bactericidal activities against 396 nosocomial and 258 community Italian isolates. Compared with that of ciprofloxacin, its activity (assessed in MIC and minimal bactericidal concentration tests) was generally similar or greater against gram-positive bacteria and greater against gram-negative bacteria. In time-kill assays using selected isolates, its bactericidal activity was comparable to that of ciprofloxacin. PMID:11709353
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Filippi, Massimo; Riccitelli, Gianna; Falini, Andrea; Di Salle, Francesco; Vuilleumier, Patrik; Comi, Giancarlo; Rocca, Maria A.
2010-01-01
Empathy and affective appraisals for conspecifics are among the hallmarks of social interaction. Using functional MRI, we hypothesized that vegetarians and vegans, who made their feeding choice for ethical reasons, might show brain responses to conditions of suffering involving humans or animals different from omnivores. We recruited 20 omnivore subjects, 19 vegetarians, and 21 vegans. The groups were matched for sex and age. Brain activation was investigated using fMRI and an event-related design during observation of negative affective pictures of human beings and animals (showing mutilations, murdered people, human/animal threat, tortures, wounds, etc.). Participants saw negative-valence scenes related to humans and animals, alternating with natural landscapes. During human negative valence scenes, compared with omnivores, vegetarians and vegans had an increased recruitment of the anterior cingulate cortex (ACC) and inferior frontal gyrus (IFG). More critically, during animal negative valence scenes, they had decreased amygdala activation and increased activation of the lingual gyri, the left cuneus, the posterior cingulate cortex and several areas mainly located in the frontal lobes, including the ACC, the IFG and the middle frontal gyrus. Nonetheless, also substantial differences between vegetarians and vegans have been found responding to negative scenes. Vegetarians showed a selective recruitment of the right inferior parietal lobule during human negative scenes, and a prevailing activation of the ACC during animal negative scenes. Conversely, during animal negative scenes an increased activation of the inferior prefrontal cortex was observed in vegans. These results suggest that empathy toward non conspecifics has different neural representation among individuals with different feeding habits, perhaps reflecting different motivational factors and beliefs. PMID:20520767
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Antimicrobial Activity and Cell Selectivity of Synthetic and Biosynthetic Cationic Polymers
Venkatesh, Mayandi; Barathi, Veluchamy Amutha; Goh, Eunice Tze Leng; Anggara, Raditya; Fazil, Mobashar Hussain Urf Turabe; Ng, Alice Jie Ying; Harini, Sriram; Aung, Thet Tun; Fox, Stephen John; Liu, Shouping; Barkham, Timothy Mark Sebastian; Loh, Xian Jun
2017-01-01
ABSTRACT The mammalian and microbial cell selectivity of synthetic and biosynthetic cationic polymers has been investigated. Among the polymers with peptide backbones, polymers containing amino side chains display greater antimicrobial activity than those with guanidine side chains, whereas ethylenimines display superior activity over allylamines. The biosynthetic polymer ε-polylysine (εPL) is noncytotoxic to primary human dermal fibroblasts at concentrations of up to 2,000 μg/ml, suggesting that the presence of an isopeptide backbone has greater cell selectivity than the presence of α-peptide backbones. Both εPL and linear polyethylenimine (LPEI) exhibit bactericidal properties by depolarizing the cytoplasmic membrane and disrupt preformed biofilms. εPL displays broad-spectrum antimicrobial properties against antibiotic-resistant Gram-negative and Gram-positive strains and fungi. εPL elicits rapid bactericidal activity against both Gram-negative and Gram-positive bacteria, and its biocompatibility index is superior to those of cationic antiseptic agents and LPEI. εPL does not interfere with the wound closure of injured rabbit corneas. In a rabbit model of bacterial keratitis, the topical application of εPL (0.3%, wt/vol) decreases the bacterial burden and severity of infections caused by Pseudomonas aeruginosa and Staphylococcus aureus strains. In vivo imaging studies confirm that εPL-treated corneas appeared transparent and nonedematous compared to untreated infected corneas. Taken together, our results highlight the potential of εPL in resolving topical microbial infections. PMID:28784676
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Ternary complex factor SAP-1 is required for Erk-mediated thymocyte positive selection.
Costello, Patrick S; Nicolas, Robert H; Watanabe, Yasuyuki; Rosewell, Ian; Treisman, Richard
2004-03-01
Thymocyte selection and differentiation requires extracellular signal-regulated kinase (Erk) signaling, but transcription factor substrates of Erk in thymocytes are unknown. We have characterized the function of SAP-1 (Elk4), an Erk-regulated transcription factor, in thymocyte development. Early thymocyte development was normal, but single-positive thymocyte and peripheral T cell numbers were reduced, reflecting a T cell-autonomous defect. T cell receptor-induced activation of SAP-1 target genes such as Egr1 was substantially impaired in double-positive thymocytes, although Erk activation was normal. Analysis of T cell receptor transgenes showed that positive selection was reduced by 80-90% in SAP-1-deficient mice; heterozygous mice showed a moderate defect. Negative selection was unimpaired. SAP-1 thus directly links Erk signaling to the transcriptional events required for thymocyte positive selection.
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Potential strategies for the eradication of multidrug-resistant Gram-negative bacterial infections.
Huwaitat, Rawan; McCloskey, Alice P; Gilmore, Brendan F; Laverty, Garry
2016-07-01
Antimicrobial resistance is one of the leading threats to society. The increasing burden of multidrug-resistant Gram-negative infection is particularly concerning as such bacteria are demonstrating resistance to nearly all currently licensed therapies. Various strategies have been hypothesized to treat multidrug-resistant Gram-negative infections including: targeting the Gram-negative outer membrane; neutralization of lipopolysaccharide; inhibition of bacterial efflux pumps and prevention of protein folding. Silver and silver nanoparticles, fusogenic liposomes and nanotubes are potential strategies for extending the activity of licensed, Gram-positive selective, antibiotics to Gram-negatives. This may serve as a strategy to fill the current void in pharmaceutical development in the short term. This review outlines the most promising strategies that could be implemented to solve the threat of multidrug-resistant Gram-negative infections.
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Nesting behavior of house mice (Mus domesticus) selected for increased wheel-running activity.
Carter, P A; Swallow, J G; Davis, S J; Garland, T
2000-03-01
Nest building was measured in "active" (housed with access to running wheels) and "sedentary" (without wheel access) mice (Mus domesticus) from four replicate lines selected for 10 generations for high voluntary wheel-running behavior, and from four randombred control lines. Based on previous studies of mice bidirectionally selected for thermoregulatory nest building, it was hypothesized that nest building would show a negative correlated response to selection on wheel-running. Such a response could constrain the evolution of high voluntary activity because nesting has also been shown to be positively genetically correlated with successful production of weaned pups. With wheel access, selected mice of both sexes built significantly smaller nests than did control mice. Without wheel access, selected females also built significantly smaller nests than did control females, but only when body mass was excluded from the statistical model, suggesting that body mass mediated this correlated response to selection. Total distance run and mean running speed on wheels was significantly higher in selected mice than in controls, but no differences in amount of time spent running were measured, indicating a complex cause of the response of nesting to selection for voluntary wheel running.
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Selective and nonselective transfer: positive and negative priming in a multiple-task environment.
Leboe, Jason P; Whittlesea, Bruce W A; Milliken, Bruce
2005-09-01
Processing of a probe stimulus can be affected either positively or negatively by presenting a related stimulus immediately before it. According to structural accounts, such effects occur because processing of the prime activates or inhibits the mental representation of the probe before it is presented. In contrast, transfer-appropriate processing accounts suggest that success in processing a probe depends on resources made available by earlier experiences of related stimuli. The authors manipulated the similarity between the prime and probe on color, lexical status, and orthographic structure, requiring either lexical decision or color identification on each. The authors observed a complex pattern of positive and negative transfer that cannot easily be explained through activation-inhibition of mental structures. Instead, that pattern provides evidence in favor of transfer-appropriate processing.
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Repetition-Related Reductions in Neural Activity during Emotional Simulations of Future Events.
Szpunar, Karl K; Jing, Helen G; Benoit, Roland G; Schacter, Daniel L
2015-01-01
Simulations of future experiences are often emotionally arousing, and the tendency to repeatedly simulate negative future outcomes has been identified as a predictor of the onset of symptoms of anxiety. Nonetheless, next to nothing is known about how the healthy human brain processes repeated simulations of emotional future events. In this study, we present a paradigm that can be used to study repeated simulations of the emotional future in a manner that overcomes phenomenological confounds between positive and negative events. The results show that pulvinar nucleus and orbitofrontal cortex respectively demonstrate selective reductions in neural activity in response to frequently as compared to infrequently repeated simulations of negative and positive future events. Implications for research on repeated simulations of the emotional future in both non-clinical and clinical populations are discussed.
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Storbeck, Justin; Watson, Philip
2014-12-01
Prior research has suggested that emotion and working memory domains are integrated, such that positive affect enhances verbal working memory, whereas negative affect enhances spatial working memory (Gray, 2004; Storbeck, 2012). Simon (1967) postulated that one feature of emotion and cognition integration would be reciprocal connectedness (i.e., emotion influences cognition and cognition influences emotion). We explored whether affective judgments and attention to affective qualities are biased by the activation of verbal and spatial working memory mind-sets. For all experiments, participants completed a 2-back verbal or spatial working memory task followed by an endorsement task (Experiments 1 & 2), word-pair selection task (Exp. 3), or attentional dot-probe task (Exp. 4). Participants who had an activated verbal, compared with spatial, working memory mind-set were more likely to endorse pictures (Exp. 1) and words (Exp. 2) as being more positive and to select the more positive word pair out of a set of word pairs that went 'together best' (Exp. 3). Additionally, people who completed the verbal working memory task took longer to disengage from positive stimuli, whereas those who completed the spatial working memory task took longer to disengage from negative stimuli (Exp. 4). Interestingly, across the 4 experiments, we observed higher levels of self-reported negative affect for people who completed the spatial working memory task, which was consistent with their endorsement and attentional bias toward negative stimuli. Therefore, emotion and working memory may have a reciprocal connectedness allowing for bidirectional influence.
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Distinct roles of three frontal cortical areas in reward-guided behavior
Noonan, M.P.; Mars, R.B.; Rushworth, M.F.S
2011-01-01
Functional magnetic resonance imaging (fMRI) was used to measure activity in three frontal cortical areas, lateral orbitofrontal cortex (lOFC), medial orbitofrontal cortex/ventromedial frontal cortex (mOFC/vmPFC), and anterior cingulate cortex (ACC) when expectations about type of reward, and not just reward presence or absence, could be learned. Two groups of human subjects learned twelve stimulus-response pairings. In one group (Consistent), correct performances of a given pairing were always reinforced with a specific reward outcome whereas in the other group (Inconsistent), correct performances were reinforced with randomly selected rewards. MOFC/vmPFC and lOFC were not distinguished by simple differences in relative preference for positive and negative outcomes. Instead lOFC activity reflected updating of reward-related associations specific to reward type; lOFC was active whenever informative outcomes allowed updating of reward-related associations regardless of whether the outcomes were positive or negative and the effects were greater when consistent stimulus-outcome and response-outcome mappings were present. A psycho-physiological interaction (PPI) analysis demonstrated changed coupling between lOFC and brain areas for visual object representation, such as perirhinal cortex, and reward-guided learning, such as amygdala, ventral striatum, and habenula /mediodorsal thalamus. By contrast mOFC/vmPFC activity reflected expected values of outcomes and occurrence of positive outcomes, irrespective of consistency of outcome mappings. The third frontal cortical region, ACC, reflected the use of reward type information to guide response selection. ACC activity reflected the probability of selecting the correct response, was greater when consistent outcome mappings were present, and was related to individual differences in propensity to select the correct response. PMID:21976525
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Credito, Kim L; Appelbaum, Peter C
2004-11-01
Agar dilution MIC was used to compare activities of OPT-80, linezolid, vancomycin, teicoplanin, quinupristin/dalfopristin, amoxicillin/clavulanate, imipenem, clindamycin, and metronidazole against 350 gram-positive and -negative anaerobes. OPT-80 was active against gram-positive strains only, especially Clostridium spp. (85 strains tested, including 21 strains of C. difficile), with MICs ranging between
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Emotion disrupts neural activity during selective attention in psychopathy
Spielberg, Jeffrey M.; Heller, Wendy; Herrington, John D.; Engels, Anna S.; Warren, Stacie L.; Crocker, Laura D.; Sutton, Bradley P.; Miller, Gregory A.
2013-01-01
Dimensions of psychopathy are theorized to be associated with distinct cognitive and emotional abnormalities that may represent unique neurobiological risk factors for the disorder. This hypothesis was investigated by examining whether the psychopathic personality dimensions of fearless-dominance and impulsive-antisociality moderated neural activity and behavioral responses associated with selective attention and emotional processing during an emotion-word Stroop task in 49 adults. As predicted, the dimensions evidenced divergent selective-attention deficits and sensitivity to emotional distraction. Fearless-dominance was associated with disrupted attentional control to positive words, and activation in right superior frontal gyrus mediated the relationship between fearless-dominance and errors to positive words. In contrast, impulsive-antisociality evidenced increased behavioral interference to both positive and negative words and correlated positively with recruitment of regions associated with motivational salience (amygdala, orbitofrontal cortex, insula), emotion regulation (temporal cortex, superior frontal gyrus) and attentional control (dorsal anterior cingulate cortex). Individuals high on both dimensions had increased recruitment of regions related to attentional control (temporal cortex, rostral anterior cingulate cortex), response preparation (pre-/post-central gyri) and motivational value (orbitofrontal cortex) in response to negative words. These findings provide evidence that the psychopathy dimensions represent dual sets of risk factors characterized by divergent dysfunction in cognitive and affective processes. PMID:22210673
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Emotion disrupts neural activity during selective attention in psychopathy.
Sadeh, Naomi; Spielberg, Jeffrey M; Heller, Wendy; Herrington, John D; Engels, Anna S; Warren, Stacie L; Crocker, Laura D; Sutton, Bradley P; Miller, Gregory A
2013-03-01
Dimensions of psychopathy are theorized to be associated with distinct cognitive and emotional abnormalities that may represent unique neurobiological risk factors for the disorder. This hypothesis was investigated by examining whether the psychopathic personality dimensions of fearless-dominance and impulsive-antisociality moderated neural activity and behavioral responses associated with selective attention and emotional processing during an emotion-word Stroop task in 49 adults. As predicted, the dimensions evidenced divergent selective-attention deficits and sensitivity to emotional distraction. Fearless-dominance was associated with disrupted attentional control to positive words, and activation in right superior frontal gyrus mediated the relationship between fearless-dominance and errors to positive words. In contrast, impulsive-antisociality evidenced increased behavioral interference to both positive and negative words and correlated positively with recruitment of regions associated with motivational salience (amygdala, orbitofrontal cortex, insula), emotion regulation (temporal cortex, superior frontal gyrus) and attentional control (dorsal anterior cingulate cortex). Individuals high on both dimensions had increased recruitment of regions related to attentional control (temporal cortex, rostral anterior cingulate cortex), response preparation (pre-/post-central gyri) and motivational value (orbitofrontal cortex) in response to negative words. These findings provide evidence that the psychopathy dimensions represent dual sets of risk factors characterized by divergent dysfunction in cognitive and affective processes.
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Seo, Jeho; Cho, Hojin; Kim, Gun Tae; Kim, Chul Hoon; Kim, Dong Goo
2017-10-01
Episodic experiences of stress have been identified as the leading cause of major depressive disorder (MDD). The occurrence of MDD is profoundly influenced by the individual's coping strategy, rather than the severity of the stress itself. Resting brain activity has been shown to alter in several mental disorders. However, the functional relationship between resting brain activity and coping strategies has not yet been studied. In the present study, we observed different patterns of resting brain activity in rats that had determined either positive (resilient to stress) or negative (vulnerable to stress) coping strategies, and examined whether modulation of the preset resting brain activity could influence the behavioral phenotype associated with negative coping strategy (i.e., depressive-like behaviors). We used a learned helplessness paradigm-a well-established model of MDD-to detect coping strategies. Differences in resting state brain activity between animals with positive and negative coping strategies were assessed using 18 F-fluorodeoxyglucose positron emission tomography (FDG-PET). Glutamatergic stimulation was used to modulate resting brain activity. After exposure to repeated uncontrollable stress, seven of 23 rats exhibited positive coping strategies, while eight of 23 rats exhibited negative coping strategies. Increased resting brain activity was observed only in the left ventral dentate gyrus of the positive coping rats using FDG-PET. Furthermore, glutamatergic stimulation of the left dentate gyrus abolished depressive-like behaviors in rats with negative coping strategies. Increased resting brain activity in the left ventral dentate gyrus helps animals to select positive coping strategies in response to future stress. Copyright © 2016 Elsevier Inc. All rights reserved.
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Jonkman, L M; Kenemans, J L; Kemner, C; Verbaten, M N; van Engeland, H
2004-07-01
This study was aimed at investigating whether attention-deficit hyperactivity disorder (ADHD) children suffer from specific early selective attention deficits in the visual modality with the aid of event-related brain potentials (ERPs). Furthermore, brain source localization was applied to identify brain areas underlying possible deficits in selective visual processing in ADHD children. A two-channel visual color selection task was administered to 18 ADHD and 18 control subjects in the age range of 7-13 years and ERP activity was derived from 30 electrodes. ADHD children exhibited lower perceptual sensitivity scores resulting in poorer target selection. The ERP data suggested an early selective-attention deficit as manifested in smaller frontal positive activity (frontal selection positivity; FSP) in ADHD children around 200 ms whereas later occipital and fronto-central negative activity (OSN and N2b; 200-400 ms latency) appeared to be unaffected. Source localization explained the FSP by posterior-medial equivalent dipoles in control subjects, which may reflect the contribution of numerous surrounding areas. ADHD children have problems with selective visual processing that might be caused by a specific early filtering deficit (absent FSP) occurring around 200 ms. The neural sources underlying these problems have to be further identified. Source localization also suggested abnormalities in the 200-400 ms time range, pertaining to the distribution of attention-modulated activity in lateral frontal areas.
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Nociception, pain, negative moods and behavior selection
Baliki, Marwan N.; Apkarian, A. Vania
2015-01-01
Recent neuroimaging studies suggest that the brain adapts with pain, as well as imparts risk for developing chronic pain. Within this context we revisit the concepts for nociception, acute and chronic pain, and negative moods relative to behavior selection. We redefine nociception as the mechanism protecting the organism from injury; while acute pain as failure of avoidant behavior; and a mesolimbic threshold process that gates the transformation of nociceptive activity to conscious pain. Adaptations in this threshold process are envisioned to be critical for development of chronic pain. We deconstruct chronic pain into four distinct phases, each with specific mechanisms; and outline current state of knowledge regarding these mechanisms: The limbic brain imparting risk, while mesolimbic learning processes reorganizing the neocortex into a chronic pain state. Moreover, pain and negative moods are envisioned as a continuum of aversive behavioral learning, which enhance survival by protecting against threats. PMID:26247858
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Masschelein, J; Jenner, M; Challis, G L
2017-07-01
Covering: up to 2017The overwhelming majority of antibiotics in clinical use originate from Gram-positive Actinobacteria. In recent years, however, Gram-negative bacteria have become increasingly recognised as a rich yet underexplored source of novel antimicrobials, with the potential to combat the looming health threat posed by antibiotic resistance. In this article, we have compiled a comprehensive list of natural products with antimicrobial activity from Gram-negative bacteria, including information on their biosynthetic origin(s) and molecular target(s), where known. We also provide a detailed discussion of several unusual pathways for antibiotic biosynthesis in Gram-negative bacteria, serving to highlight the exceptional biocatalytic repertoire of this group of microorganisms.
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Urfer, Matthias; Bogdanovic, Jasmina; Lo Monte, Fabio; Moehle, Kerstin; Zerbe, Katja; Omasits, Ulrich; Ahrens, Christian H.; Pessi, Gabriella; Eberl, Leo; Robinson, John A.
2016-01-01
Increasing antibacterial resistance presents a major challenge in antibiotic discovery. One attractive target in Gram-negative bacteria is the unique asymmetric outer membrane (OM), which acts as a permeability barrier that protects the cell from external stresses, such as the presence of antibiotics. We describe a novel β-hairpin macrocyclic peptide JB-95 with potent antimicrobial activity against Escherichia coli. This peptide exhibits no cellular lytic activity, but electron microscopy and fluorescence studies reveal an ability to selectively disrupt the OM but not the inner membrane of E. coli. The selective targeting of the OM probably occurs through interactions of JB-95 with selected β-barrel OM proteins, including BamA and LptD as shown by photolabeling experiments. Membrane proteomic studies reveal rapid depletion of many β-barrel OM proteins from JB-95-treated E. coli, consistent with induction of a membrane stress response and/or direct inhibition of the Bam folding machine. The results suggest that lethal disruption of the OM by JB-95 occurs through a novel mechanism of action at key interaction sites within clusters of β-barrel proteins in the OM. These findings open new avenues for developing antibiotics that specifically target β-barrel proteins and the integrity of the Gram-negative OM. PMID:26627837
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Recurrent Activation of Neural Circuits during Attention to Global and Local Visual Information.
Iglesias-Fuster, Jorge; Piña-Novo, Daniela; Ontivero-Ortega, Marlis; Lage-Castellanos, Agustín; Valdés-Sosa, Mitchell
2018-05-28
The attentional selection of different hierarchical level within compound (Navon) figures has been studied with event related potentials (ERPs), by controlling the ERPs obtained during attention to the global or the local echelon. These studies, using the canonical Navon figures, have produced contradictory results, with doubts regarding the scalp distribution of the effects. Moreover, the evidence about the temporal evolution of the processing of these two levels is not clear. Here, we unveiled global and local letters at distinct times, which enabled separation of their ERP responses. We combine this approach with the temporal generalization methodology, a novel multivariate technique which facilitates exploring the temporal structure of these ERPs. Opposite lateralization patterns were obtained for the selection negativities generated when attending global and local distracters (D statistics, p < .005), with maxima in right and left occipito-temporal scalp regions, respectively (η2 = .111, p < .01; η2 = .042, p < .04). However, both discrimination negativities elicited when comparing targets and distractors at the global or the local level were lateralized to the left hemisphere (η2 = .25, p < .03 and η2 = .142, p < .05 respectively). Recurrent activation patterns were found for both global and local stimuli, with scalp topographies corresponding to early preparatory stages reemerging during the attentional selection process, thus indicating recursive attentional activation. This implies that selective attention to global and local hierarchical levels recycles similar neural correlates at different time points. These neural correlates appear to be mediated by visual extra-striate areas.
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Apolipoprotein L1 confers pH-switchable ion permeability to phospholipid vesicles.
Bruno, Jonathan; Pozzi, Nicola; Oliva, Jonathan; Edwards, John C
2017-11-03
Apolipoprotein L1 (ApoL1) is a human serum protein conferring resistance to African trypanosomes, and certain ApoL1 variants increase susceptibility to some progressive kidney diseases. ApoL1 has been hypothesized to function like a pore-forming colicin and has been reported to have permeability effects on both intracellular and plasma membranes. Here, to gain insight into how ApoL1 may function in vivo , we used vesicle-based ion permeability, direct membrane association, and intrinsic fluorescence to study the activities of purified recombinant ApoL1. We found that ApoL1 confers chloride-selective permeability to preformed phospholipid vesicles and that this selectivity is strongly pH-sensitive, with maximal activity at pH 5 and little activity above pH 7. When ApoL1 and lipid were allowed to interact at low pH and were then brought to neutral pH, chloride permeability was suppressed, and potassium permeability was activated. Both chloride and potassium permeability linearly correlated with the mass of ApoL1 in the reaction mixture, and both exhibited lipid selectivity, requiring the presence of negatively charged lipids for activity. Potassium, but not chloride, permease activity required the presence of calcium ions in both the association and activation steps. Direct assessment of ApoL1-lipid associations confirmed that ApoL1 stably associates with phospholipid vesicles, requiring low pH and the presence of negatively charged phospholipids for maximal binding. Intrinsic fluorescence of ApoL1 supported the presence of a significant structural transition when ApoL1 is mixed with lipids at low pH. This pH-switchable ion-selective permeability may explain the different effects of ApoL1 reported in intracellular and plasma membrane environments. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.
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Credito, Kim L.; Appelbaum, Peter C.
2004-01-01
Agar dilution MIC was used to compare activities of OPT-80, linezolid, vancomycin, teicoplanin, quinupristin/dalfopristin, amoxicillin/clavulanate, imipenem, clindamycin, and metronidazole against 350 gram-positive and -negative anaerobes. OPT-80 was active against gram-positive strains only, especially Clostridium spp. (85 strains tested, including 21 strains of C. difficile), with MICs ranging between ≤0.016 and 0.25 μg/ml. PMID:15504874
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Deconstructing Ras Signaling in the Thymus
Kortum, Robert L.; Sommers, Connie L.; Pinski, John M.; Alexander, Clayton P.; Merrill, Robert K.; Li, Wenmei; Love, Paul E.
2012-01-01
Thymocytes must transit at least two distinct developmental checkpoints, governed by signals that emanate from either the pre-T cell receptor (pre-TCR) or the TCR to the small G protein Ras before emerging as functional T lymphocytes. Recent studies have shown a role for the Ras guanine exchange factor (RasGEF) Sos1 at the pre-TCR checkpoint. At the second checkpoint, the quality of signaling through the TCR is interrogated to ensure the production of an appropriate T cell repertoire. Although RasGRP1 is the only confirmed RasGEF required at the TCR checkpoint, current models suggest that the intensity and character of Ras activation, facilitated by both Sos and RasGRP1, will govern the boundary between survival (positive selection) and death (negative selection) at this stage. Using mouse models, we have assessed the independent and combined roles for the RasGEFs Sos1, Sos2, and RasGRP1 during thymocyte development. Although Sos1 was the dominant RasGEF at the pre-TCR checkpoint, combined Sos1/RasGRP1 deletion was required to effectively block development at this stage. Conversely, while RasGRP1 deletion efficiently blocked positive selection, combined RasGRP1/Sos1 deletion was required to block negative selection. This functional redundancy in RasGEFs during negative selection may act as a failsafe mechanism ensuring appropriate central tolerance. PMID:22586275
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Liston, Adrian; Hardy, Kristine; Pittelkow, Yvonne; Wilson, Susan R; Makaroff, Lydia E; Fahrer, Aude M; Goodnow, Christopher C
2007-01-01
T cells in the thymus undergo opposing positive and negative selection processes so that the only T cells entering circulation are those bearing a T cell receptor (TCR) with a low affinity for self. The mechanism differentiating negative from positive selection is poorly understood, despite the fact that inherited defects in negative selection underlie organ-specific autoimmune disease in AIRE-deficient people and the non-obese diabetic (NOD) mouse strain Here we use homogeneous populations of T cells undergoing either positive or negative selection in vivo together with genome-wide transcription profiling on microarrays to identify the gene expression differences underlying negative selection to an Aire-dependent organ-specific antigen, including the upregulation of a genomic cluster in the cytogenetic band 2F. Analysis of defective negative selection in the autoimmune-prone NOD strain demonstrates a global impairment in the induction of the negative selection response gene set, but little difference in positive selection response genes. Combining expression differences with genetic linkage data, we identify differentially expressed candidate genes, including Bim, Bnip3, Smox, Pdrg1, Id1, Pdcd1, Ly6c, Pdia3, Trim30 and Trim12. The data provide a molecular map of the negative selection response in vivo and, by analysis of deviations from this pathway in the autoimmune susceptible NOD strain, suggest that susceptibility arises from small expression differences in genes acting at multiple points in the pathway between the TCR and cell death.
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Liston, Adrian; Hardy, Kristine; Pittelkow, Yvonne; Wilson, Susan R; Makaroff, Lydia E; Fahrer, Aude M; Goodnow, Christopher C
2007-01-01
Background T cells in the thymus undergo opposing positive and negative selection processes so that the only T cells entering circulation are those bearing a T cell receptor (TCR) with a low affinity for self. The mechanism differentiating negative from positive selection is poorly understood, despite the fact that inherited defects in negative selection underlie organ-specific autoimmune disease in AIRE-deficient people and the non-obese diabetic (NOD) mouse strain Results Here we use homogeneous populations of T cells undergoing either positive or negative selection in vivo together with genome-wide transcription profiling on microarrays to identify the gene expression differences underlying negative selection to an Aire-dependent organ-specific antigen, including the upregulation of a genomic cluster in the cytogenetic band 2F. Analysis of defective negative selection in the autoimmune-prone NOD strain demonstrates a global impairment in the induction of the negative selection response gene set, but little difference in positive selection response genes. Combining expression differences with genetic linkage data, we identify differentially expressed candidate genes, including Bim, Bnip3, Smox, Pdrg1, Id1, Pdcd1, Ly6c, Pdia3, Trim30 and Trim12. Conclusion The data provide a molecular map of the negative selection response in vivo and, by analysis of deviations from this pathway in the autoimmune susceptible NOD strain, suggest that susceptibility arises from small expression differences in genes acting at multiple points in the pathway between the TCR and cell death. PMID:17239257
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Investigating a memory-based account of negative priming: support for selection-feature mismatch.
MacDonald, P A; Joordens, S
2000-08-01
Using typical and modified negative priming tasks, the selection-feature mismatch account of negative priming was tested. In the modified task, participants performed selections on the basis of a semantic feature (e.g., referent size). This procedure has been shown to enhance negative priming (P. A. MacDonald, S. Joordens, & K. N. Seergobin, 1999). Across 3 experiments, negative priming occurred only when the repeated item mismatched in terms of the feature used as the basis for selections. When the repeated item was congruent on the selection feature across the prime and probe displays, positive priming arose. This pattern of results appeared in both the ignored- and the attended-repetition conditions. Negative priming does not result from previously ignoring an item. These findings strongly support the selection-feature mismatch account of negative priming and refute both the distractor inhibition and the episodic-retrieval explanations.
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Antistaphylococcal Activity of DX-619, a New Des-F(6)-Quinolone, Compared to Those of Other Agents
Bogdanovich, Tatiana; Esel, Duygu; Kelly, Linda M.; Bozdogan, Bülent; Credito, Kim; Lin, Gengrong; Smith, Kathy; Ednie, Lois M.; Hoellman, Dianne B.; Appelbaum, Peter C.
2005-01-01
The in vitro activity of DX-619, a new des-F(6)-quinolone, was tested against staphylococci and compared to those of other antimicrobials. DX-619 had the lowest MIC ranges/MIC50s/MIC90s (μg/ml) against 131 Staphylococcus aureus strains (≤0.002 to 2.0/0.06/0.5) and 128 coagulase-negative staphylococci (0.004 to 0.25/0.016/0.125). Among strains tested, 76 S. aureus strains and 51 coagulase-negative staphylococci were resistant to ciprofloxacin. DX-619 had the lowest MIC50/MIC90 values against 127 quinolone-resistant staphylococci (0.125/0.5), followed by sitafloxacin (0.5/4), moxifloxacin (2/8), gatifloxacin (4/16), levofloxacin (16/>32), and ciprofloxacin (>32/>32). Raised quinolone MICs were associated with mutations in GyrA (S84L) and single or double mutations in GrlA (S80F or Y; E84K, G, or V) in all S. aureus strains tested. A recent vancomycin-resistant S. aureus (VRSA) strain (Hershey) was resistant to available quinolones and was inhibited by DX-619 at 0.25 μg/ml and sitafloxacin at 1.0 μg/ml. Vancomycin (except VRSA), linezolid, ranbezolid, tigecycline, and quinupristin-dalfopristin were active against all strains, and teicoplanin was active against S. aureus but less active against coagulase-negative staphylococci. DX-619 produced resistant mutants with MICs of 1 to >32 μg/ml after <50 days of selection compared to 16 to >32 μg/ml for ciprofloxacin, sitafloxacin, moxifloxacin, and gatifloxacin. DX-619 and sitafloxacin were also more active than other tested drugs against selected mutants and had the lowest mutation frequencies in single-step resistance selection. DX-619 and sitafloxacin were bactericidal against six quinolone-resistant (including the VRSA) and seven quinolone-susceptible strains tested, whereas gatifloxacin, moxifloxacin, levofloxacin, and ciprofloxacin were bactericidal against 11, 10, 7, and 5 strains at 4× MIC after 24 h, respectively. DX-619 was also bactericidal against one other VRSA strain, five vancomycin-intermediate S. aureus strains, and four vancomycin-intermediate coagulase-negative staphylococci. Linezolid, ranbezolid, and tigecycline were bacteriostatic and quinupristin-dalfopristin, teicoplanin, and vancomycin were bactericidal against two, eight, and nine strains, and daptomycin and oritavancin were rapidly bactericidal against all strains, including the VRSA. DX-619 has potent in vitro activity against staphylococci, including methicillin-, ciprofloxacin-, and vancomycin-resistant strains. PMID:16048943
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Eguchi, Hisashi; Tsuda, Yoko; Tsukahara, Teruomi; Washizuka, Shinsuke; Kawakami, Norito; Nomiyama, Tetsuo
2012-08-01
To investigate the association of workplace occupational mental health (OMH) and related activities with psychological distress of workers in Japan. A total of 121 workplaces and their 3540 workers were surveyed using questionnaires assessing selected workplace OMH activities, demographic characteristics, psychological distress, and psychosocial work environment of the workers. A multilevel analysis was conducted. Promotion of communication correlated significantly and negatively with psychological distress among workers after adjusting for the covariates (P < 0.01). Occupational mental health activities correlated marginally significantly and negatively with psychological distress (P = 0.06). Their moderating effect for the worker-level association between psychosocial work environment and psychological distress was not significant. The findings suggest that promotion of communication in the workplace is associated with reduced psychological distress among workers. In addition, OMH activities may also be useful in reducing psychological distress.
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Electrochemical supercapacitors
Rudge, Andrew J.; Ferraris, John P.; Gottesfeld, Shimshon
1996-01-01
A new class of electrochemical capacitors provides in its charged state a positive electrode including an active material of a p-doped material and a negative electrode including an active material of an n-doped conducting polymer, where the p-doped and n-doped materials are separated by an electrolyte. In a preferred embodiment, the positive and negative electrode active materials are selected from conducting polymers consisting of polythiophene, polymers having an aryl group attached in the 3-position, polymers having aryl and alkyl groups independently attached in the 3- and 4-positions, and polymers synthesized from bridged dimers having polythiophene as the backbone. A preferred electrolyte is a tetraalykyl ammonium salt, such as tetramethylammonium trifluoromethane sulphonate (TMATFMS), that provides small ions that are mobile through the active material, is soluble in acetonitrile, and can be used in a variety of capacitor configurations.
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Ajore, Ram; Raiser, David; McConkey, Marie; Jöud, Magnus; Boidol, Bernd; Mar, Brenton; Saksena, Gordon; Weinstock, David M; Armstrong, Scott; Ellis, Steven R; Ebert, Benjamin L; Nilsson, Björn
2017-04-01
Heterozygous inactivating mutations in ribosomal protein genes (RPGs) are associated with hematopoietic and developmental abnormalities, activation of p53, and altered risk of cancer in humans and model organisms. Here we performed a large-scale analysis of cancer genome data to examine the frequency and selective pressure of RPG lesions across human cancers. We found that hemizygous RPG deletions are common, occurring in about 43% of 10,744 cancer specimens and cell lines. Consistent with p53-dependent negative selection, such lesions are underrepresented in TP53 -intact tumors ( P ≪ 10 -10 ), and shRNA-mediated knockdown of RPGs activated p53 in TP53 -wild-type cells. In contrast, we did not see negative selection of RPG deletions in TP53 -mutant tumors. RPGs are conserved with respect to homozygous deletions, and shRNA screening data from 174 cell lines demonstrate that further suppression of hemizygously deleted RPGs inhibits cell growth. Our results establish RPG haploinsufficiency as a strikingly common vulnerability of human cancers that associates with TP53 mutations and could be targetable therapeutically. © 2017 The Authors. Published under the terms of the CC BY 4.0 license.
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Pooryasin, Atefeh; Fiala, André
2015-09-16
Animals show different levels of activity that are reflected in sensory responsiveness and endogenously generated behaviors. Biogenic amines have been determined to be causal factors for these states of arousal. It is well established that, in Drosophila, dopamine and octopamine promote increased arousal. However, little is known about factors that regulate arousal negatively and induce states of quiescence. Moreover, it remains unclear whether global, diffuse modulatory systems comprehensively affecting brain activity determine general states of arousal. Alternatively, individual aminergic neurons might selectively modulate the animals' activity in a distinct behavioral context. Here, we show that artificially activating large populations of serotonin-releasing neurons induces behavioral quiescence and inhibits feeding and mating. We systematically narrowed down a role of serotonin in inhibiting endogenously generated locomotor activity to neurons located in the posterior medial protocerebrum. We identified neurons of this cell cluster that suppress mating, but not feeding behavior. These results suggest that serotonin does not uniformly act as global, negative modulator of general arousal. Rather, distinct serotoninergic neurons can act as inhibitory modulators of specific behaviors. An animal's responsiveness to external stimuli and its various types of endogenously generated, motivated behavior are highly dynamic and change between states of high activity and states of low activity. It remains unclear whether these states are mediated by unitary modulatory systems globally affecting brain activity, or whether distinct neurons modulate specific neuronal circuits underlying particular types of behavior. Using the model organism Drosophila melanogaster, we find that activating large proportions of serotonin-releasing neurons induces behavioral quiescence. Moreover, distinct serotonin-releasing neurons that we genetically isolated and identified negatively affect aspects of mating behavior, but not food uptake. This demonstrates that individual serotoninergic neurons can modulate distinct types of behavior selectively. Copyright © 2015 the authors 0270-6474/15/3512792-21$15.00/0.
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NASA Astrophysics Data System (ADS)
Harrison, David J.; Saito, Laurel; Markee, Nancy; Herzog, Serge
2017-11-01
To examine the impact of a hybrid-flipped model utilising active learning techniques, the researchers inverted one section of an undergraduate fluid mechanics course, reduced seat time, and engaged in active learning sessions in the classroom. We compared this model to the traditional section on four performance measures. We employed a propensity score method entailing a two-stage regression analysis that considered eight covariates to address the potential bias of treatment selection. First, we estimated the probability score based on the eight covariates, and second, we used the inverse of the probability score as a regression weight on the performance of learners who did not select into the hybrid course. Results suggest that enrolment in the hybrid-flipped section had a marginally significant negative impact on the total course score and a significant negative impact on homework performance, possibly because of poor video usage by the hybrid-flipped learners. Suggested considerations are also discussed.
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Selective Androgen Receptor Downregulators (SARDs): A New Prostate Cancer Therapy
2006-10-01
of the androgen receptor messenger RNA and functional inhibition of androgen receptor activity by a hammerhead ribozyme . Mol Endocrinol, 12: 1558...cleavage of the androgen receptor messenger RNA and functional inhibition of androgen receptor activity by a hammerhead ribozyme . Mol Endocrinol...used to down-regulate the AR include antisense oligonucleotides (9, 10), ribozyme treatments (11, 12), AR dominant negatives (13) and small
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Occurrence of toxicity among protease, amylase, and color mutants of a nontoxic soy sauce koji mold
DOE Office of Scientific and Technical Information (OSTI.GOV)
Kalayanamitr, A.; Bhumiratana, A.; Flegel, T.W.
A soy sauce koji mold, Aspergillus flavus var. columnaris Raper and Fennel (ATCC 44310), was treated with UV irradiation to obtain mutant strains possessing high protease activities, high amylase activities, and light-colored conidia. Selected mutant strains were tested for toxicity, and some were found acutely toxic to weanling rats, although all were negative for aflatoxin production.
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Anodes for rechargeable lithium batteries
Thackeray, Michael M.; Kepler, Keith D.; Vaughey, John T.
2003-01-01
A negative electrode (12) for a non-aqueous electrochemical cell (10) with an intermetallic host structure containing two or more elements selected from the metal elements and silicon, capable of accommodating lithium within its crystallographic host structure such that when the host structure is lithiated it transforms to a lithiated zinc-blende-type structure. Both active elements (alloying with lithium) and inactive elements (non-alloying with lithium) are disclosed. Electrochemical cells and batteries as well as methods of making the negative electrode are disclosed.
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Continuous directed evolution of aminoacyl-tRNA synthetases
Bryson, David I.; Fan, Chenguang; Guo, Li-Tao; Miller, Corwin; Söll, Dieter; Liu, David R.
2017-01-01
Directed evolution of orthogonal aminoacyl-tRNA synthetases (AARSs) enables site-specific installation of non-canonical amino acids (ncAAs) into proteins. Traditional evolution techniques typically produce AARSs with greatly reduced activity and selectivity compared to their wild-type counterparts. We designed phage-assisted continuous evolution (PACE) selections to rapidly produce highly active and selective orthogonal AARSs through hundreds of generations of evolution. PACE of a chimeric Methanosarcina spp. pyrrolysyl-tRNA synthetase (PylRS) improved its enzymatic efficiency (kcat/KMtRNA) 45-fold compared to the parent enzyme. Transplantation of the evolved mutations into other PylRS-derived synthetases improved yields of proteins containing non-canonical residues up to 9.7-fold. Simultaneous positive and negative selection PACE over 48 h greatly improved the selectivity of a promiscuous Methanocaldococcus jannaschii tyrosyl-tRNA synthetase variant for site-specific incorporation of p-iodo-L-phenylalanine. These findings offer new AARSs that increase the utility of orthogonal translation systems and establish the capability of PACE to efficiently evolve orthogonal AARSs with high activity and amino acid specificity. PMID:29035361
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The neural substrates of driving at a safe distance: a functional MRI study.
Uchiyama, Yuji; Ebe, Kazutoshi; Kozato, Akio; Okada, Tomohisa; Sadato, Norihiro
2003-12-11
An important driving skill is the ability to maintain a safe distance from a preceding car. To determine the neural substrates of this skill we performed functional magnetic resonance imaging of simulated driving in 21 subjects. Subjects used a joystick to adjust their own driving speed in order to maintain a constant distance from a preceding car traveling at varying speeds. The task activated multiple brain regions. Activation of the cerebellum may reflect visual feedback during smooth tracking of the preceding car. Co-activation of the basal ganglia, thalamus and premotor cortex is related to movement selection. Activation of a premotor-parietal network is related to visuo-motor co-ordination. Task performance was negatively correlated with anterior cingulate activity, consistent with the role of this region in error detection and response selection.
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2017-01-01
General locomotor activity (GLA) in poultry has attracted attention, as it negatively influences production costs (energy expenditure and feed consumption) and welfare parameters (bone strength, litter quality, feather pecking and cannibalism). Laying hen lines diverging in the average level of spontaneous locomotor activity in the home pen were developed by genetic selection using the founder New Hampshire line. Activity was recorded using RFID technology at around five weeks of age during four to five days in the home pen. After initial phenotyping, the least active birds were selected for the low activity line and the most active for the high activity line, with no gene transfer between lines. In each of six generations, approximately ten sires were mated to twenty dams producing 158 to 334 offspring per line per generation. The response to selection was rapid and of a considerable magnitude. In sixth generation, the level of GLA was approximately halved in the low and doubled in the high line compared to the control (7.2, 14.9 and 28.7 recordings/h). Estimated heritability of locomotor activity in the low and high line was 0.38 and 0.33, respectively. Males, in general, were more active than females. High line birds were significantly heavier than low line birds. In fourth, fifth, and sixth generation, low as well as high line birds were lighter than control line birds. This selection experiment demonstrates variation in heritability for GLA and, as a result, genetically diverged lines have been developed. These lines can be used as models for further studies of underlying physiological, neural and molecular genetic mechanisms of spontaneous locomotor activity. PMID:28796792
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Kjaer, Joergen B
2017-01-01
General locomotor activity (GLA) in poultry has attracted attention, as it negatively influences production costs (energy expenditure and feed consumption) and welfare parameters (bone strength, litter quality, feather pecking and cannibalism). Laying hen lines diverging in the average level of spontaneous locomotor activity in the home pen were developed by genetic selection using the founder New Hampshire line. Activity was recorded using RFID technology at around five weeks of age during four to five days in the home pen. After initial phenotyping, the least active birds were selected for the low activity line and the most active for the high activity line, with no gene transfer between lines. In each of six generations, approximately ten sires were mated to twenty dams producing 158 to 334 offspring per line per generation. The response to selection was rapid and of a considerable magnitude. In sixth generation, the level of GLA was approximately halved in the low and doubled in the high line compared to the control (7.2, 14.9 and 28.7 recordings/h). Estimated heritability of locomotor activity in the low and high line was 0.38 and 0.33, respectively. Males, in general, were more active than females. High line birds were significantly heavier than low line birds. In fourth, fifth, and sixth generation, low as well as high line birds were lighter than control line birds. This selection experiment demonstrates variation in heritability for GLA and, as a result, genetically diverged lines have been developed. These lines can be used as models for further studies of underlying physiological, neural and molecular genetic mechanisms of spontaneous locomotor activity.
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Du, Yongli; Zhang, Yanhui; Ling, Hao; Li, Qunyi; Shen, Jingkang
2018-01-20
PTP1B serving as a key negative regulator of insulin signaling is a novel target for type 2 diabetes and obesity. Modification at ring B of N-{4-[(3-Phenyl-ureido)-methyl]-phenyl}-methane-sulfonamide template to interact with residues Arg47 and Lys41 in the C site of PTP1B by molecular docking aided design resulted in the discovery of a series of novel high potent and selective inhibitors of PTP1B. The structure activity relationship interacting with the C site of PTP1B was well illustrated. Compounds 8 and 18 were shown to be the high potent and most promising PTP1B inhibitors with cellular activity and great selectivity over the highly homologous TCPTP and other PTPs. Copyright © 2017 Elsevier Masson SAS. All rights reserved.
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Liu, Peihong; Du, Yongli; Song, Lianhua; Shen, Jingkang; Li, Qunyi
2016-08-08
Protein tyrosine phosphatase 1B (PTP1B) as a key negative regulator of both insulin and leptin receptor pathways has been an attractive therapeutic target for the treatment of type 2 diabetes mellitus (T2DM) and obesity. With the goal of enhancing potency and selectivity of the PTP1B inhibitors, a series of methyl salicylate derivatives as ABC type PTP1B inhibitors (P1-P7) were discovered. More importantly, compound P6 exhibited high potent inhibitory activity (IC50 = 50 nM) for PTP1B with 15-fold selectivity over T-cell PTPase (TCPTP). Further studies on cellular activities revealed that compound P6 could enhance insulin-mediated insulin receptor β (IRβ) phosphorylation and insulin-stimulated glucose uptake. Copyright © 2016 Elsevier Masson SAS. All rights reserved.
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Autoinducer-2-like activity associated with foods and its interaction with food additives.
Lu, Lingeng; Hume, Michael E; Pillai, Suresh D
2004-07-01
The autoinducer-2 (AI-2) molecule produced by bacteria as part of quorum sensing is considered to be a universal inducer signal in bacteria because it reportedly influences gene expression in a variety of both gram-negative and gram-positive bacteria. The objective of this study was to determine whether selected fresh produce and processed foods have AI-2-like activity and whether specific food additives can act as AI-2 mimics and result in AI-2-like activity. The luminescence-based response of the reporter strain Vibrio harveyi BB170 was used as the basis for determining AI-2 activity in the selected foods and food ingredients. Maximum AI-2 activity was seen on the frozen fish sample (203-fold, compared with the negative control) followed by tomato, cantaloupe, carrots, tofu, and milk samples. Interestingly, some samples were capable of inhibiting AI-2 activity. Turkey patties showed the highest inhibition (99.8% compared with the positive control) followed by chicken breast (97.5%), homemade cheeses (93.7%), beef steak (90.6%), and beef patties (84.4%). AI-2 activity was almost totally inhibited by sodium propionate, whereas sodium benzoate caused 93.3% inhibition, compared with 75% inhibition by sodium acetate. Sodium nitrate did not have any appreciable effect, even at 200 ppm. Understanding the relationships that exist between AI-2 activity on foods and the ecology of pathogens and food spoilage bacteria on foods could yield clues about factors controlling food spoilage and pathogen virulence.
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Feedback regulation of mitochondria by caspase-9 in the B cell receptor-mediated apoptosis.
Eeva, J; Nuutinen, U; Ropponen, A; Mättö, M; Eray, M; Pellinen, R; Wahlfors, J; Pelkonen, J
2009-12-01
During the germinal centre reaction (GC), B cells with non-functional or self-reactive antigen receptors are negatively selected by apoptosis to generate B cell repertoire with appropriate antigen specificities. We studied the molecular mechanism of Fas/CD95- and B cell receptor (BCR)-induced apoptosis to shed light on the signalling events involved in the negative selection of GC B cells. As an experimental model, we used human follicular lymphoma (FL) cell line HF1A3, which originates from a GC B cell, and transfected HF1A3 cell lines overexpressing Bcl-x(L), c-FLIP(long) or dominant negative (DN) caspase-9. Fas-induced apoptosis was dependent on the caspase-8 activation, since the overexpression of c-FLIP(long), a natural inhibitor of caspase-8 activation, blocked apoptosis induced by Fas. In contrast, caspase-9 activation was not involved in Fas-induced apoptosis. BCR-induced apoptosis showed the typical characteristics of mitochondria-dependent (intrinsic) apoptosis. Firstly, the activation of caspase-9 was involved in BCR-induced DNA fragmentation, while caspase-8 showed only marginal role. Secondly, overexpression of Bcl-x(L) could block all apoptotic changes induced by BCR. As a novel finding, we demonstrate that caspase-9 can enhance the cytochrome-c release and collapse of mitochondrial membrane potential (DeltaPsi(m)) during BCR-induced apoptosis. The requirement of different signalling pathways in apoptosis induced by BCR and Fas may be relevant, since Fas- and BCR-induced apoptosis can thus be regulated independently, and targeted to different subsets of GC B cells.
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Wiswede, Daniel; Taubner, Svenja; Münte, Thomas F.; Roth, Gerhard; Strüber, Daniel; Wahl, Klaus; Krämer, Ulrike M.
2011-01-01
In order to further understand the mechanisms involved in planning an aggressive act, we conducted an event-related potential (ERP) study of young men with and without a history of violence. Participants completed a competitive reaction time task (based on the Taylor aggression paradigm) against a virtual opponent. In "passive" blocks, participants were punished by the opponent when losing the trial but could not punish, when winning, whereas in "active" blocks, participants were able to punish the opponent when winning, but were not punished when losing. Participants selected punishment strength in a decision phase prior to each reaction time task and were informed whether they had won or lost in the outcome phase. Additionally, a flanker task was conducted to assess basic performance monitoring. Violent participants selected stronger punishments, especially in "active" blocks. During the decision phase, a frontal P200 was more pronounced for violent participants, whereas non-violent participants showed an enhanced frontal negativity around 300 ms. The P200 might reflect the decision to approach the opponent at a very early state, the latter negativity could reflect inhibition processes, leading to a more considerate reaction in non-violent participants. During the outcome phase, a Feedback-Related Negativity was seen in both groups. This effect was most pronounced when losing entailed a subsequent inability to retaliate. The groups did not differ in the flanker task, indicating intact basic performance monitoring. Our data suggest that the planning of an aggressive act is associated with distinct brain activity and that such activity is differentially represented in violent and non-violent individuals. PMID:21811638
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Wiswede, Daniel; Taubner, Svenja; Münte, Thomas F; Roth, Gerhard; Strüber, Daniel; Wahl, Klaus; Krämer, Ulrike M
2011-01-01
In order to further understand the mechanisms involved in planning an aggressive act, we conducted an event-related potential (ERP) study of young men with and without a history of violence. Participants completed a competitive reaction time task (based on the Taylor aggression paradigm) against a virtual opponent. In "passive" blocks, participants were punished by the opponent when losing the trial but could not punish, when winning, whereas in "active" blocks, participants were able to punish the opponent when winning, but were not punished when losing. Participants selected punishment strength in a decision phase prior to each reaction time task and were informed whether they had won or lost in the outcome phase. Additionally, a flanker task was conducted to assess basic performance monitoring. Violent participants selected stronger punishments, especially in "active" blocks. During the decision phase, a frontal P200 was more pronounced for violent participants, whereas non-violent participants showed an enhanced frontal negativity around 300 ms. The P200 might reflect the decision to approach the opponent at a very early state, the latter negativity could reflect inhibition processes, leading to a more considerate reaction in non-violent participants. During the outcome phase, a Feedback-Related Negativity was seen in both groups. This effect was most pronounced when losing entailed a subsequent inability to retaliate. The groups did not differ in the flanker task, indicating intact basic performance monitoring. Our data suggest that the planning of an aggressive act is associated with distinct brain activity and that such activity is differentially represented in violent and non-violent individuals.
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Effects of Gymnastics Activities on Bone Accrual during Growth: A Systematic Review
Jürimäe, Jaak; Gruodyte-Raciene, Rita; Baxter-Jones, Adam D. G.
2018-01-01
The amount of bone gained during childhood and adolescence impacts greatly on lifetime skeletal health. The purpose of this review is to summarize current evidence of the effects of gymnastics activities on bone mineral accrual during growth and to describe possible factors that influence bone mineral gains. The PubMed and SportDiscus databases were searched, and a total of 24 articles met the selection criteria and were included in this review. Artistic and rhythmic gymnasts presented higher bone mineral density and content values compared to untrained controls, despite possible negative effects associated with hormonal levels, dietary restrictions and body fat. The results suggest that gymnasts had similar bone turnover values compared to untrained controls. High-intensity mechanical loading of gymnastics activity appears to increase bone development and counterbalance negative effects, such as later pubertal development, lower body fat mass and lower hormone levels. In conclusion, gymnasts present higher bone mineral values in comparison with untrained controls. The osteogenic effect of gymnastics athletic activity has a positive influence on bone mineral accrual and overcomes the possible negative influence of high athletic activity that may cause negative energy balance and low body fat mass which are associated with lower bone accrual. Key points Children and adolescent gymnasts present higher bone mineral density and content values compared to untrained controls, despite a variety of possible negative factors. Gymnastics activity with high-impact mechanical loading appears to be especially osteogenic to achieve maximum possible peak bone accrual during growth and maturation. Skeletal benefits of gymnastics activity in childhood are maintained for several years after retirement from gymnastics trainings in young adulthood. PMID:29769826
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Hrušková, Kateřina; Potůčková, Eliška; Opálka, Lukáš; Hergeselová, Tereza; Hašková, Pavlína; Kovaříková, Petra; Šimůnek, Tomáš; Vávrová, Kateřina
2018-05-23
Aroylhydrazone iron chelators such as salicylaldehyde isonicotinoyl hydrazone (SIH) protect various cells against oxidative injury and display antineoplastic activities. Previous studies have shown that a nitro-substituted hydrazone, namely, NHAPI, displayed markedly improved plasma stability, selective antitumor activity, and moderate antioxidant properties. In this study, we prepared four series of novel NHAPI derivatives and explored their iron chelation activities, anti- or pro-oxidant effects, protection against model oxidative injury in the H9c2 cell line derived from rat embryonic cardiac myoblasts, cytotoxicities to the corresponding noncancerous H9c2 cells, and antiproliferative activities against the MCF-7 human breast adenocarcinoma and HL-60 human promyelocytic leukemia cell lines. Nitro substitution had both negative and positive effects on the examined properties, and we identified new structure-activity relationships. Naphthyl and biphenyl derivatives showed selective antiproliferative action, particularly in the breast adenocarcinoma MCF-7 cell line, where they exceeded the selectivity of the parent compound NHAPI. Of particular interest is a compound prepared from 2-hydroxy-5-methyl-3-nitroacetophenone and biphenyl-4-carbohydrazide, which protected cardiomyoblasts against oxidative injury at 1.8 ± 1.2 μM with 24-fold higher selectivity than SIH. These compounds will serve as leads for further structural optimization and mechanistic studies.
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Wierońska, Joanna M; Kłeczek, Natalia; Woźniak, Monika; Gruca, Piotr; Łasoń-Tyburkiewicz, Magdalena; Papp, Mariusz; Brański, Piotr; Burnat, Grzegorz; Pilc, Andrzej
2015-09-01
Diverse preclinical studies exploiting the modulation of the GABAergic and/or glutamatergic system in brain via metabotropic receptors suggest their potential therapeutic utility. GS39783 and CDPPB, positive allosteric modulators of GABAB and mGlu5 receptors, were previously shown to reverse behavioral phenotypes in animal models to mimic selected (predominantly positive) symptoms of schizophrenia. In the present study we investigated the activity of selected GABAB (GS39783 and CGP7930) and mGlu5 (CDPPB) positive allosteric modulators. We focused mainly on the aspects of their efficacy in the models of negative and cognitive symptoms of schizophrenia. We used modified swim test, social interactions (models of negative symptoms) and novel object recognition (model of cognitive disturbances). The activity of the compounds was also tested in haloperidol-induced catalepsy test. The mutual interaction between GABAB/mGlu5 ligands was investigated as well. In the second part of the study, DHPG-induced PI hydrolysis in the presence of GABAB receptor antagonist (SKF97541), and SKF97541-induced inhibition of cAMP formation in the presence of DHPG, was performed. Both mGlu5 and GABAB receptor modulators effectively reversed MK-801-induced deficits in behavioral models of schizophrenia. Moreover, the concomitant administration of sub-effective doses of CDPPB and GS39783 induced a clear antipsychotic-like effect in all the procedures used, except DOI-induced head twitches. The concomitant administration of group I mGlu and GABAB agonists did not displayed any synergistic effects in vitro. Summing up, an activation of both types of receptor may be a promising mechanism for the development of novel antipsychotic drugs, efficacious toward positive, negative and cognitive symptoms. Copyright © 2015 Elsevier Ltd. All rights reserved.
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A Negative Selection Immune System Inspired Methodology for Fault Diagnosis of Wind Turbines.
Alizadeh, Esmaeil; Meskin, Nader; Khorasani, Khashayar
2017-11-01
High operational and maintenance costs represent as major economic constraints in the wind turbine (WT) industry. These concerns have made investigation into fault diagnosis of WT systems an extremely important and active area of research. In this paper, an immune system (IS) inspired methodology for performing fault detection and isolation (FDI) of a WT system is proposed and developed. The proposed scheme is based on a self nonself discrimination paradigm of a biological IS. Specifically, the negative selection mechanism [negative selection algorithm (NSA)] of the human body is utilized. In this paper, a hierarchical bank of NSAs are designed to detect and isolate both individual as well as simultaneously occurring faults common to the WTs. A smoothing moving window filter is then utilized to further improve the reliability and performance of the FDI scheme. Moreover, the performance of our proposed scheme is compared with another state-of-the-art data-driven technique, namely the support vector machines (SVMs) to demonstrate and illustrate the superiority and advantages of our proposed NSA-based FDI scheme. Finally, a nonparametric statistical comparison test is implemented to evaluate our proposed methodology with that of the SVM under various fault severities.
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Chemical function based pharmacophore generation of endothelin-A selective receptor antagonists.
Funk, Oliver F; Kettmann, Viktor; Drimal, Jan; Langer, Thierry
2004-05-20
Both quantitative and qualitative chemical function based pharmacophore models of endothelin-A (ET(A)) selective receptor antagonists were generated by using the two algorithms HypoGen and HipHop, respectively, which are implemented in the Catalyst molecular modeling software. The input for HypoGen is a training set of 18 ET(A) antagonists exhibiting IC(50) values ranging between 0.19 nM and 67 microM. The best output hypothesis consists of five features: two hydrophobic (HY), one ring aromatic (RA), one hydrogen bond acceptor (HBA), and one negative ionizable (NI) function. The highest scoring Hip Hop model consists of six features: three hydrophobic (HY), one ring aromatic (RA), one hydrogen bond acceptor (HBA), and one negative ionizable (NI). It is the result of an input of three highly active, selective, and structurally diverse ET(A) antagonists. The predictive power of the quantitative model could be approved by using a test set of 30 compounds, whose activity values spread over 6 orders of magnitude. The two pharmacophores were tested according to their ability to extract known endothelin antagonists from the 3D molecular structure database of Derwent's World Drug Index. Thereby the main part of selective ET(A) antagonistic entries was detected by the two hypotheses. Furthermore, the pharmacophores were used to screen the Maybridge database. Six compounds were chosen from the output hit lists for in vitro testing of their ability to displace endothelin-1 from its receptor. Two of these are new potential lead compounds because they are structurally novel and exhibit satisfactory activity in the binding assay.
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Wang, Liang; Zhu, Yihan; Wang, Jian-Qiang; Liu, Fudong; Huang, Jianfeng; Meng, Xiangju; Basset, Jean-Marie; Han, Yu; Xiao, Feng-Shou
2015-01-01
Efficient synthesis of stable two-dimensional (2D) noble metal catalysts is a challenging topic. Here we report the facile synthesis of 2D gold nanosheets via a wet chemistry method, by using layered double hydroxide as the template. Detailed characterization with electron microscopy and X-ray photoelectron spectroscopy demonstrates that the nanosheets are negatively charged and [001] oriented with thicknesses varying from single to a few atomic layers. X-ray absorption spectroscopy reveals unusually low gold–gold coordination numbers. These gold nanosheets exhibit high catalytic activity and stability in the solvent-free selective oxidation of carbon–hydrogen bonds with molecular oxygen. PMID:25902034
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Wang, Liang; Zhu, Yihan; Wang, Jian-Qiang; Liu, Fudong; Huang, Jianfeng; Meng, Xiangju; Basset, Jean-Marie; Han, Yu; Xiao, Feng-Shou
2015-04-22
Efficient synthesis of stable two-dimensional (2D) noble metal catalysts is a challenging topic. Here we report the facile synthesis of 2D gold nanosheets via a wet chemistry method, by using layered double hydroxide as the template. Detailed characterization with electron microscopy and X-ray photoelectron spectroscopy demonstrates that the nanosheets are negatively charged and [001] oriented with thicknesses varying from single to a few atomic layers. X-ray absorption spectroscopy reveals unusually low gold-gold coordination numbers. These gold nanosheets exhibit high catalytic activity and stability in the solvent-free selective oxidation of carbon-hydrogen bonds with molecular oxygen.
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NASA Astrophysics Data System (ADS)
Wang, Liang; Zhu, Yihan; Wang, Jian-Qiang; Liu, Fudong; Huang, Jianfeng; Meng, Xiangju; Basset, Jean-Marie; Han, Yu; Xiao, Feng-Shou
2015-04-01
Efficient synthesis of stable two-dimensional (2D) noble metal catalysts is a challenging topic. Here we report the facile synthesis of 2D gold nanosheets via a wet chemistry method, by using layered double hydroxide as the template. Detailed characterization with electron microscopy and X-ray photoelectron spectroscopy demonstrates that the nanosheets are negatively charged and [001] oriented with thicknesses varying from single to a few atomic layers. X-ray absorption spectroscopy reveals unusually low gold-gold coordination numbers. These gold nanosheets exhibit high catalytic activity and stability in the solvent-free selective oxidation of carbon-hydrogen bonds with molecular oxygen.
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Prevention of ER-Negative Breast Cancer
Li, Yuxin
2014-01-01
The successful demonstration that the selective estrogen receptor modulators (SERMs) tamoxifen and raloxifene reduce the risk of breast cancer has stimulated great interest in using drugs to prevent breast cancer in high-risk women. In addition, recent results from breast cancer treatment trials suggest that aromatase inhibitors may be even more effective at preventing breast cancer than are SERMs. However, while SERMs and aromatase inhibitors do prevent the development of many estrogen-receptor (ER)-positive breast cancers, these drugs do not prevent the development of ER-negative breast cancer. Thus, there is an urgent need to identify agents that can prevent ER-negative breast cancer. We have studied the cancer preventative activity of several classes of drugs for their ability to prevent ER-negative breast cancer in preclinical models. Results from these studies demonstrate that rexinoids (analogs of retinoids that bind and activate RXR receptors), tyrosine kinase inhibitors (such as EGFR inhibitors and dual kinase inhibitors that block EGFR and HER2/neu signaling), and cyclo-oxygenase 2 (COX-2) inhibitors all prevent ER-negative breast cancer in transgenic mice that develop ER-negative breast cancer. Other promising agents now under investigation include vitamin D and vitamin D analogs, drugs that activate PPAR-gamma nuclear receptors, and statins. Many of these agents are now being tested in early phase cancer prevention clinical trials to determine whether they will show activity in breast tissue and whether they are safe for use in high-risk women without breast cancer. The current status of these studies will be reviewed. It is anticipated that in the future, drugs that effectively prevent ER-negative breast cancer will be used in combination with hormonal agents such SERMs or aromatase inhibitors to prevent all forms of breast cancer. PMID:19213564
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Behavioral neuroscience of emotion in aging.
Kaszniak, Alfred W; Menchola, Marisa
2012-01-01
Recent research on emotion and aging has revealed a stability of emotional experience from adulthood to older age, despite aging-related decrements in the perception and categorization of emotionally relevant stimuli. Research also shows that emotional expression remains intact with aging. In contrast, other studies provide evidence for an age-related decrease in autonomic nervous system physiological arousal, particularly in response to emotionally negative stimuli, and for shifts in central nervous system physiologic response to emotional stimuli, with increased prefrontal cortex activation and decreased amygdala activation in aging. Research on attention and memory for emotional information supports a decreased processing of negative emotional stimuli (i.e., a decrease in the negativity effect seen in younger adults), and a relative increase in the processing of emotionally positive stimuli (positivity effect). These physiological response and attentional/memory preference differences across increasingly older groups have been interpreted, within socioemotional selectivity theory, as reflecting greater motivation for emotion regulation with aging. According to this theory, as persons age, their perceived future time horizon shrinks, and a greater value is placed upon cultivating close, familiar, and meaningful relationships and other situations that give rise to positive emotional experience, and avoiding, or shifting attention from, those people and situations that are likely to elicit negative emotion. Even though there are central nervous system structural changes in emotion-relevant brain regions with aging, this shift in socioemotional selectivity, and perhaps the decreased autonomic nervous system physiological arousal of emotion with aging, facilitate enhanced emotion regulation with aging.
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Specialized proteasome subunits play an essential role in thymic selection of CD8+ T cells
Kincaid, Eleanor Z.; Murata, Shigeo; Tanaka, Keiji; Rock, Kenneth L.
2016-01-01
The cells that stimulate positive selection express different specialized proteasome β-subunits than all other cells, including those involved in negative selection. Mice that lack all four specialized proteasome β-subunits, and therefore express only constitutive proteasomes in all cells, had a profound defect in the generation of CD8+ T cells. While a defect in positive selection would reflect an inability to generate the appropriate positively selecting peptides, a block at negative selection would point to the potential need to switch peptides between positive and negative selection to avoid the two processes often cancelling each other out. We found that the block in T cell development occurred around the checkpoints of positive and, surprisingly, also negative selection. PMID:27294792
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USDA-ARS?s Scientific Manuscript database
Colistin (polymyxin E) is a cationic polypeptide antibiotic that has broad-spectrum activity against Gram-negative bacteria. It is classified as critically important in human medicine for treating hard-to-treat multi-drug resistant infections. Recently a plasmid-mediated colistin resistance gene (mc...
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Kwapis, Janine L; Alaghband, Yasaman; López, Alberto J; White, André O; Campbell, Rianne R; Dang, Richard T; Rhee, Diane; Tran, Ashley V; Carl, Allison E; Matheos, Dina P; Wood, Marcelo A
2017-01-01
Histone acetylation is a fundamental epigenetic mechanism that is dynamically regulated during memory formation. Histone acetyltransferases (HATs) and histone deacetylases (HDACs) compete to modulate histone acetylation, allowing for rapid changes in acetylation in response to a learning event. HDACs are known to be powerful negative regulators of memory formation, but it is not clear whether this function depends on HDAC enzymatic activity per se. Here, we tested whether the enzymatic activity of an individual Class I HDAC, HDAC3, has a role in fear memory formation in subregions of the hippocampus and amygdala. We found that fear conditioning drove expression of the immediate early genes cFos and Nr4a2 in the hippocampus, which coincided with reduced HDAC3 occupancy at these promoters. Using a dominant-negative, deacetylase-dead point mutant virus (AAV-HDAC3(Y298H)-v5), we found that selectively blocking HDAC3 deacetylase activity in either the dorsal hippocampus or basal nucleus of the amygdala enhanced context fear without affecting tone fear. Blocking HDAC3 activity in the lateral nucleus of the amygdala, on the other hand, enhanced tone, but not context fear memory. These results show for the first time that the enzymatic activity of HDAC3 functions to negatively regulate fear memory formation. Further, HDAC3 activity regulates different aspects of fear memory in the basal and lateral subregions of the amygdala. Thus, the deacetylase activity of HDAC3 is a powerful negative regulator of fear memory formation in multiple subregions of the fear circuit. PMID:27924874
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Weber, Tatjana; Sommer, Monika; Hajak, Göran; Müller, Jürgen
2004-11-01
Functional MRI was used to test the effects of the deficient emotional responsiveness of psychopathic patients on cognitive processes. We used a Simon-paradigm, in which ten healthy volunteers and ten patients with a diagnosis of "psychopathy" (defined by Hare Psychopathy Checklist Revised) have to select their spatially defined responses on the basis of a nonspatial stimuli feature. For the emotion induction pictures from the International Affective Picture System (IAPS) were selected. At the beginning and intermediated by the Simon-paradigm blocks of positive, negative or neutral pictures were presented. Patients with "psychopathy" exhibited untypical activation patterns in amygdala and prefrontal regions during interferences between negative or positive stimulations and cognitive tasks. These results demonstrated disturbed regulation of emotion-cognition-interaction in "psychopathy" according to PCL-R.
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Laxton, Adrian W; Neimat, Joseph S; Davis, Karen D; Womelsdorf, Thilo; Hutchison, William D; Dostrovsky, Jonathan O; Hamani, Clement; Mayberg, Helen S; Lozano, Andres M
2013-11-15
The subcallosal cingulate and adjacent ventromedial prefrontal cortex (collectively referred to here as the subcallosal cortex or SCC) have been identified as key brain areas in emotional processing. The SCC's role in affective valuation as well as severe mood and motivational disturbances, such as major depression, has been largely inferred from measures of neuronal population activity using functional neuroimaging. On the basis of imaging studies, it is unclear whether the SCC predominantly processes 1) negatively valenced affective content, 2) affective arousal, or 3) category-specific affective information. To clarify these putative functional roles of the SCC, we measured single neuron activity in the SCC of 15 human subjects undergoing deep brain stimulation for depression while they viewed emotionally evocative images grouped into categories that varied in emotional valence (pleasantness) and arousal. We found that the majority of responsive neurons were modulated by specific emotion categories, rather than by valence or arousal alone. Moreover, although these emotion-category-specific neurons responded to both positive and negative emotion categories, a significant majority were selective for negatively valenced emotional content. These findings reveal that single SCC neuron activity reflects the automatic valuational processing and implicit emotion categorization of visual stimuli. Furthermore, because of the predominance of neuronal signals in SCC conveying negative affective valuations and the increased activity in this region among depressed people, the effectiveness of depression therapies that alter SCC neuronal activity may relate to the down-regulation of a previously negative emotional processing bias. © 2013 Society of Biological Psychiatry.
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Panda, Sujogya Kumar; Mohanta, Yugal Kishore; Padhi, Laxmipriya; Park, Young-Hwan; Mohanta, Tapan Kumar; Bae, Hanhong
2016-03-14
The global burden of bacterial infections is very high and has been exacerbated by increasing resistance to multiple antibiotics. Antibiotic resistance leads to failed treatment of infections, which can ultimately lead to death. To overcome antibiotic resistance, it is necessary to identify new antibacterial agents. In this study, a total of 662 plant extracts (diverse parts) from 222 plant species (82 families, 177 genera) were screened for antibacterial activity using the agar cup plate method. The aqueous and methanolic extracts were prepared from diverse plant parts and screened against eight bacterial (two Gram-positive and six Gram-negative) species, most of which are involved in common infections with multiple antibiotic resistance. The methanolic extracts of several plants were shown to have zones of inhibition ≥ 12 mm against both Gram-positive and Gram-negative bacteria. The minimum inhibitory concentration was calculated only with methanolic extracts of selected plants, those showed zone of inhibition ≥ 12 mm against both Gram-positive and Gram-negative bacteria. Several extracts had minimum inhibitory concentration ≤ 1 mg/mL. Specifically Adhatoda vasica, Ageratum conyzoides, Alangium salvifolium, Alpinia galanga, Andrographis paniculata, Anogeissus latifolia, Annona squamosa, A. reticulate, Azadirachta indica, Buchanania lanzan, Cassia fistula, Celastrus paniculatus, Centella asiatica, Clausena excavate, Cleome viscosa, Cleistanthus collinus, Clerodendrum indicum, Croton roxburghii, Diospyros melanoxylon, Eleutherine bulbosa, Erycibe paniculata, Eryngium foetidum, Garcinia cowa, Helicteres isora, Hemidesmus indicus, Holarrhena antidysenterica, Lannea coromandelica, Millettia extensa, Mimusops elengi, Nyctanthes arbor-tristis, Oroxylum indicum, Paederia foetida, Pterospermum acerifolium, Punica granatum, Semecarpus anacardium, Spondias pinnata, Terminalia alata and Vitex negundo were shown to have significant antimicrobial activity. The species listed here were shown to have anti-infective activity against both Gram-positive and Gram-negative bacteria. These results may serve as a guide for selecting plant species that could yield the highest probability of finding promising compounds responsible for the antibacterial activities against a broad spectrum of bacterial species. Further investigation of the phytochemicals from these plants will help to identify the lead compounds for drug discovery.
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Peixoto, Maria Manuela; Nobre, Pedro
2017-04-01
Despite the existence of conceptual models of sexual dysfunction based on cognitive theory, few studies have tested the role of vulnerability factors such as sexual beliefs as moderators of the activation of cognitive schemas in response to negative sexual events. To test the moderator role of dysfunctional sexual beliefs in the association between the frequency of negative sexual episodes and the activation of incompetence schemas in gay and heterosexual men. Five-hundred seventy-five men (287 gay, 288 heterosexual) who completed an online survey on cognitive-affective dimensions and sexual functioning were selected from a larger database. Hierarchical regression analyses were conducted to test the hypothesis that dysfunctional sexual beliefs moderate the association between the frequency of unsuccessful sexual episodes and the activation of incompetence schemas. Participants completed the Sexual Dysfunctional Beliefs Questionnaire and the Questionnaire of Cognitive Schemas Activated in Sexual Context. Findings indicated that men's ability for always being ready for sex, to satisfy the partner, and to maintain an erection until ending sexual activity constitute "macho" beliefs that moderate the activation of incompetence schemas when unsuccessful sexual events occur in gay and heterosexual men. In addition, activation of incompetence schemas in response to negative sexual events in gay men was moderated by the endorsement of conservative attitudes toward moderate sexuality. The main findings suggested that psychological interventions targeting dysfunctional sexual beliefs could help de-catastrophize the consequences of negative sexual events and facilitate sexual functioning. Despite being a web-based study, it represents the first attempt to test the moderator role of dysfunctional sexual beliefs in the association between the frequency of unsuccessful sexual episodes and the activation of incompetence schemas in gay and heterosexual men. Overall, findings support the role of sexual beliefs as facilitators of the activation of incompetence schemas in the face of negative sexual events in gay and heterosexual men, emphasizing the need to develop treatment and prevention strategies aimed at challenging common male beliefs about sexuality. Peixoto MM, Nobre P. "Macho" Beliefs Moderate the Association Between Negative Sexual Episodes and Activation of Incompetence Schemas in Sexual Context, in Gay and Heterosexual Men. J Sex Med 2017;14:518-525. Copyright © 2017 International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.
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Effect of Encapsulation on Antimicrobial Activity of Herbal Extracts with Lysozyme
Matouskova, Petra; Bokrova, Jitka; Benesova, Pavla
2016-01-01
Summary Resistance of microorganisms to antibiotics has increased. The use of natural components with antimicrobial properties can be of great significance to reduce this problem. The presented work is focused on the study of the effect of encapsulation of selected plant and animal antimicrobial substances (herbs, spices, lysozyme and nisin) on their activity and stability. Antimicrobial components were packaged into liposomes and polysaccharide particles (alginate, chitosan and starch). Antimicrobial activity was tested against two Gram-positive (Bacillus subtilis and Micrococcus luteus) and two Gram-negative (Escherichia coli and Serratia marcescens) bacteria. Encapsulation was successful in all types of polysaccharide particles and liposomes. The prepared particles exhibited very good long-term stability, especially in aqueous conditions. Antimicrobial activity was retained in all types of particles. Liposomes with encapsulated herb and spice extracts exhibited very good inhibitory effect against all tested bacterial strains. Most of herbal extracts had very good antimicrobial effect against the tested Gram-negative bacterial strains, while Gram-positive bacteria were more sensitive to lysozyme particles. Thus, particles with co-encapsulated herbs and lysozyme are more active against different types of bacteria, and more stable and more effective during long-term storage. Particles with encapsulated mixture of selected plant extracts and lysozyme could be used as complex antimicrobial preparation with controlled release in the production of food and food supplements, pharmaceutical and cosmetic industries. PMID:27956862
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Schomberg, Jessica; Schöne, Benjamin; Gruber, Thomas; Quirin, Markus
2016-06-01
Previous research has demonstrated that negative affect influences attentional processes. Here, we investigate whether pre-experimental negative affect predicts a hypervigilant neural response as indicated by increased event-related potential amplitudes in response to neutral and positive visual stimuli. In our study, seventeen male participants filled out the German version of the positive and negative affect schedule (Watson et al. in J Pers Soc Psychol 54:1063-1070, 1988; Krohne et al. in Diagnostica 42:139-156, 1996) and subsequently watched positive (erotica, extreme sports, beautiful women) and neutral (daily activities) photographs while electroencephalogram was recorded. In line with our hypothesis, low state negative affect but not (reduced) positive affect predicted an increase in the first positive event-related potential amplitude P1 as a typical marker of increased selective attention. As this effect occurred in response to non-threatening picture conditions, negative affect may foster an individual's general hypervigilance, a state that has formerly been associated with psychopathology only.
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Li, Jianying; Xu, Cheng; Cao, Xiaohua; Gao, Qiang; Wang, Yan; Wang, Yanfang; Peng, Juyi; Zhang, Kerang
2013-01-01
A large number of studies have demonstrated that depression patients have cognitive dysfunction. With recently developed brain functional imaging, studies have focused on changes in brain function to investigate cognitive changes. However, there is still controversy regarding abnormalities in brain functions or correlation between cognitive impairment and brain function changes. Thus, it is important to design an emotion-related task for research into brain function changes. We selected positive, neutral, and negative pictures from the International Affective Picture System. Patients with major depressive disorder were asked to judge emotion pictures. In addition, functional MRI was performed to synchronously record behavior data and imaging data. Results showed that the total correct rate for recognizing pictures was lower in patients compared with normal controls. Moreover, the consistency for recognizing pictures for depressed patients was worse than normal controls, and they frequently recognized positive pictures as negative pictures. The consistency for recognizing pictures was negatively correlated with the Hamilton Depression Rating Scale. Functional MRI suggested that the activation of some areas in the frontal lobe, temporal lobe, parietal lobe, limbic lobe, and cerebellum was enhanced, but that the activation of some areas in the frontal lobe, parietal lobe and occipital lobe was weakened while the patients were watching positive and neutral pictures compared with normal controls. The activation of some areas in the frontal lobe, temporal lobe, parietal lobe, and limbic lobe was enhanced, but the activation of some areas in the occipital lobe were weakened while the patients were watching the negative pictures compared with normal controls. These findings indicate that patients with major depressive disorder have negative cognitive disorder and extensive brain dysfunction. Thus, reduced activation of the occipital lobe may be an initiating factor for cognitive disorder in depressed patients. PMID:25206466
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Neural basis of stereotype-induced shifts in women's mental rotation performance
Helt, Molly; Jacobs, Emily; Sullivan, Kerry
2007-01-01
Recent negative focus on women's academic abilities has fueled disputes over gender disparities in the sciences. The controversy derives, in part, from women's relatively poorer performance in aptitude tests, many of which require skills of spatial reasoning. We used functional magnetic imaging to examine the neural structure underlying shifts in women's performance of a spatial reasoning task induced by positive and negative stereotypes. Three groups of participants performed a task involving imagined rotations of the self. Prior to scanning, the positive stereotype group was exposed to a false but plausible stereotype of women's superior perspective-taking abilities; the negative stereotype group was exposed to the pervasive stereotype that men outperform women on spatial tasks; and the control group received neutral information. The significantly poorer performance we found in the negative stereotype group corresponded to increased activation in brain regions associated with increased emotional load. In contrast, the significantly improved performance we found in the positive stereotype group was associated with increased activation in visual processing areas and, to a lesser degree, complex working memory processes. These findings suggest that stereotype messages affect the brain selectively, with positive messages producing relatively more efficient neural strategies than negative messages. PMID:18985116
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Neural basis of stereotype-induced shifts in women's mental rotation performance.
Wraga, Maryjane; Helt, Molly; Jacobs, Emily; Sullivan, Kerry
2007-03-01
Recent negative focus on women's academic abilities has fueled disputes over gender disparities in the sciences. The controversy derives, in part, from women's relatively poorer performance in aptitude tests, many of which require skills of spatial reasoning. We used functional magnetic imaging to examine the neural structure underlying shifts in women's performance of a spatial reasoning task induced by positive and negative stereotypes. Three groups of participants performed a task involving imagined rotations of the self. Prior to scanning, the positive stereotype group was exposed to a false but plausible stereotype of women's superior perspective-taking abilities; the negative stereotype group was exposed to the pervasive stereotype that men outperform women on spatial tasks; and the control group received neutral information. The significantly poorer performance we found in the negative stereotype group corresponded to increased activation in brain regions associated with increased emotional load. In contrast, the significantly improved performance we found in the positive stereotype group was associated with increased activation in visual processing areas and, to a lesser degree, complex working memory processes. These findings suggest that stereotype messages affect the brain selectively, with positive messages producing relatively more efficient neural strategies than negative messages.
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Martin, F; Reinbolt, J; Dirheimer, G; Gangloff, J; Eriani, G
1996-01-01
Elements that confer identity to a tRNA in the cellular environment, where all aminoacyl-tRNA synthetases are competing for substrates, may be delineated by in vivo experiments using suppressor tRNAs. Here we describe the selection of active Escherichia coli tRNAAsp amber mutants and analyze their identity. Starting from a library containing randomly mutated tRNA(CUA)Asp genes, we isolated four amber suppressors presenting either lysine, alanine, or glutamine activity. Two of them, presenting mainly alanine or lysine activity, were further submitted to a second round of mutagenesis selection in order to improve their efficiency of suppression. Eleven suppressors were isolated, each containing two or three mutations. Ten presented identities of the two parental mutants, whereas one had switched from lysine to arginine identity. Analysis of the different mutants revealed (or confirmed for some nucleotides) their role as positive and/or negative determinants in AlaRS, LysRS, and ArgRS recognition. More generally, it appears that tRNAAsp presents identity characteristics closely related to those of tRNALys, as well as a structural basis for acquiring alanine or arginine identity upon moderate mutational changes; these consist of addition or suppression of the corresponding positive or negative determinants, as well as tertiary interactions. Failure to isolate aspartic acid-inserting suppressors is probably due to elimination of the important G34 identity element and its replacement by an antideterminant when changing the anticodon of the tRNAAsp to the CUA triplet. PMID:8809018
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Verdeny-Vilalta, O; Fox, C W; Wise, D H; Moya-Laraño, J
2015-06-01
Ecological networks incorporate myriad biotic interactions that determine the selection pressures experienced by the embedded populations. We argue that within food webs, the negative scaling of abundance with body mass and foraging theory predict that the selective advantages of larger egg size should be smaller for sit-and-wait than active-hunting generalist predators, leading to the evolution of a difference in egg size between them. Because body mass usually scales negatively with predator abundance and constrains predation rate, slightly increasing egg mass should simultaneously allow offspring to feed on more prey and escape from more predators. However, the benefits of larger offspring would be relatively smaller for sit-and-wait predators because (i) due to their lower mobility, encounters with other predators are less common, and (ii) they usually employ a set of alternative hunting strategies that help to subdue relatively larger prey. On the other hand, for active predators, which need to confront prey as they find them, body-size differences may be more important in subduing prey. This difference in benefits should lead to the evolution of larger egg sizes in active-hunting relative to sit-and-wait predators. This prediction was confirmed by a phylogenetically controlled analysis of 268 spider species, supporting the view that the structure of ecological networks may serve to predict relevant selective pressures acting on key life history traits. © 2015 European Society For Evolutionary Biology. Journal of Evolutionary Biology © 2015 European Society For Evolutionary Biology.
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Working hours, coping skills, and psychological health in Japanese daytime workers.
Otsuka, Yasumasa; Sasaki, Takeshi; Iwasaki, Kenji; Mori, Ippei
2009-01-01
This study examined the relationship between coping skills, working hours, and psychological health among Japanese daytime workers. Self-administered questionnaires were mailed to a randomly selected sample of 2,000 workers who were members of a pre-recruited market research panel. A total of 1,821 participants responded (response rate=91.1%). Participants completed a questionnaire regarding working hours, coping skills, and psychological health (negative emotions, fatigue, and concentration/activity levels). Analyses of covariance were conducted to determine the relations of number of working hours, coping skills, and their interactions to psychological health with control for sex, age, drinking, job type, and employment type. Results revealed that working hours were significantly associated with fatigue and concentration/activity levels. High levels of instrumental support and positive reframing were significantly associated with low levels of negative emotions, fatigue, and concentration/activity levels. High levels of self-blame, denial, substance use, venting, self-distraction, religion, and behavioral disengagement were significantly associated with high levels of negative emotions, fatigue, and concentration/activity levels. This study suggests that improving coping skills such as using instrumental support or positive reframing may reduce the adverse health effects of long working hours.
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Negative aging stereotypes and their relation with psychosocial variables in the elderly population.
Sánchez Palacios, C; Trianes Torres, M V; Blanca Mena, M J
2009-01-01
This study explores whether there is a relationship between the level of belief in negative aging stereotypes in 65-year-old people and their results concerning some psychosocial variables. These were selected for their relevance for health and well being in elderly people. These were: living situation, responsibilities toward others, subjective health, frequency of medical appointments, subjective age, participation in community social activities and regular physical activity. The sample consisted of 757 people of low educational level, ranged from 65 to 96 years. Age and gender were homogeneously distributed. Participants were non-institutionalized people. Firstly, the psychosocial variables under focus were assessed by means of seven questions. Secondly, a questionnaire about negative aging stereotypes (CENVE) was administered. It was composed of three factors: health, motivational-social and character-personality. Results show that a high score in negative stereotypes is significantly associated to the studied variables, except for living situation, showing a worse quality of life (QoL) profile. Results are discussed in terms of their utility for assessment and psychosocial intervention, which is meant to improve health in the elderly.
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Reduced striatal dopamine DA D2 receptor function in dominant-negative GSK-3 transgenic mice.
Gomez-Sintes, Raquel; Bortolozzi, Analia; Artigas, Francesc; Lucas, José J
2014-09-01
Glycogen synthase kinase-3 (GSK-3) is a serine/threonine kinase with constitutive activity involved in cellular architecture, gene expression, cell proliferation, fate decision and apoptosis, among others. GSK-3 expression is particularly high in brain where it may be involved in neurological and psychiatric disorders such as Alzheimer׳s disease, bipolar disorder and major depression. A link with schizophrenia is suggested by the antipsychotic drug-induced GSK-3 regulation and by the involvement of the Akt/GSK-3 pathway in dopaminergic neurotransmission. Taking advantage of the previous development of dominant negative GSK-3 transgenic mice (Tg) showing a selective reduction of GSK-3 activity in forebrain neurons but not in dopaminergic neurons, we explored the relationship between GSK-3 and dopaminergic neurotransmission in vivo. In microdialysis experiments, local quinpirole (DA D2-R agonist) in dorsal striatum reduced dopamine (DA) release significantly less in Tg mice than in wild-type (WT) mice. However, local SKF-81297 (selective DA D1-R agonist) in dorsal striatum reduced DA release equally in both control and Tg mice indicating a comparable function of DA D1-R in the direct striato-nigral pathway. Likewise, systemic quinpirole administration - acting preferentially on presynaptic DA D2- autoreceptors to modulate DA release-reduced striatal DA release similarly in both control and Tg mice. Quinpirole reduced locomotor activity and induced c-fos expression in globus pallidus (both striatal DA D2-R-mediated effects) significantly more in WT than in Tg mice. Taking together, the present results show that dominant negative GSK-3 transgenic mice show reduced DA D2-R-mediated function in striatum and further support a link between dopaminergic neurotransmission and GSK-3 activity. Copyright © 2014 Elsevier B.V. and ECNP. All rights reserved.
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Antimicrobial peptides with selective antitumor mechanisms: prospect for anticancer applications.
Deslouches, Berthony; Di, Y Peter
2017-07-11
In the last several decades, there have been significant advances in anticancer therapy. However, the development of resistance to cancer drugs and the lack of specificity related to actively dividing cells leading to toxic side effects have undermined these achievements. As a result, there is considerable interest in alternative drugs with novel antitumor mechanisms. In addition to the recent approach using immunotherapy, an effective but much cheaper therapeutic option of pharmaceutical drugs would still provide the best choice for cancer patients as the first line treatment. Ribosomally synthesized cationic antimicrobial peptides (AMPs) or host defense peptides (HDP) display broad-spectrum activity against bacteria based on electrostatic interactions with negatively charged lipids on the bacterial surface. Because of increased proportions of phosphatidylserine (negatively charged) on the surface of cancer cells compared to normal cells, cationic amphipathic peptides could be an effective source of anticancer agents that are both selective and refractory to current resistance mechanisms. We reviewed herein the prospect for AMP application to cancer treatment, with a focus on modes of action of cationic AMPs.
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Young children seek out biased information about social groups.
Over, Harriet; Eggleston, Adam; Bell, Jenny; Dunham, Yarrow
2018-05-01
Understanding the origins of prejudice necessitates exploring the ways in which children participate in the construction of biased representations of social groups. We investigate whether young children actively seek out information that supports and extends their initial intergroup biases. In Studies 1 and 2, we show that children choose to hear a story that contains positive information about their own group and negative information about another group rather than a story that contains negative information about their own group and positive information about the other group. In a third study, we show that children choose to present biased information to others, thus demonstrating that the effects of information selection can start to propagate through social networks. In Studies 4 and 5, we further investigate the nature of children's selective information seeking and show that children prefer ingroup-favouring information to other types of biased information and even to balanced, unbiased information. Together, this work shows that children are not merely passively recipients of social information; they play an active role in the creation and transmission of intergroup attitudes. © 2017 John Wiley & Sons Ltd.
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Antimicrobial peptides with selective antitumor mechanisms: prospect for anticancer applications
Deslouches, Berthony; Di, Y. Peter
2017-01-01
In the last several decades, there have been significant advances in anticancer therapy. However, the development of resistance to cancer drugs and the lack of specificity related to actively dividing cells leading to toxic side effects have undermined these achievements. As a result, there is considerable interest in alternative drugs with novel antitumor mechanisms. In addition to the recent approach using immunotherapy, an effective but much cheaper therapeutic option of pharmaceutical drugs would still provide the best choice for cancer patients as the first line treatment. Ribosomally synthesized cationic antimicrobial peptides (AMPs) or host defense peptides (HDP) display broad-spectrum activity against bacteria based on electrostatic interactions with negatively charged lipids on the bacterial surface. Because of increased proportions of phosphatidylserine (negatively charged) on the surface of cancer cells compared to normal cells, cationic amphipathic peptides could be an effective source of anticancer agents that are both selective and refractory to current resistance mechanisms. We reviewed herein the prospect for AMP application to cancer treatment, with a focus on modes of action of cationic AMPs. PMID:28422728
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Bostean, Georgiana
2014-01-01
Latino immigrants, particularly Mexican, have some health advantages over U.S.-born Mexicans and Whites. Because of their lower socioeconomic status, this phenomenon has been called the epidemiologic “Hispanic Paradox.” While cultural theories have dominated explanations for the Paradox, the role of selective migration has been inadequately addressed. This study is among the few to combine Mexican and U.S. data to examine health selectivity in activity limitation, self-rated health, and chronic conditions among Mexican immigrants, ages 18 and over. Drawing on theories of selective migration, this study tested the “healthy migrant” and “salmon-bias” hypotheses by comparing the health of Mexican immigrants in the U.S. to non-migrants in Mexico, and to return migrants in Mexico. Results suggest that there are both healthy migrant and salmon-bias effects in activity limitation, but not other health aspects. In fact, consistent with prior research, immigrants are negatively selected on self-rated health. Future research should consider the complexities of migrants’ health profiles and examine selection mechanisms alongside other factors such as acculturation. PMID:22618355
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Bostean, Georgiana
2013-06-01
Latino immigrants, particularly Mexican, have some health advantages over U.S.-born Mexicans and Whites. Because of their lower socioeconomic status, this phenomenon has been called the epidemiologic "Hispanic Paradox." While cultural theories have dominated explanations for the Paradox, the role of selective migration has been inadequately addressed. This study is among the few to combine Mexican and U.S. data to examine health selectivity in activity limitation, self-rated health, and chronic conditions among Mexican immigrants, ages 18 and over. Drawing on theories of selective migration, this study tested the "healthy migrant" and "salmon-bias" hypotheses by comparing the health of Mexican immigrants in the U.S. to non-migrants in Mexico, and to return migrants in Mexico. Results suggest that there are both healthy migrant and salmon-bias effects in activity limitation, but not other health aspects. In fact, consistent with prior research, immigrants are negatively selected on self-rated health. Future research should consider the complexities of migrants' health profiles and examine selection mechanisms alongside other factors such as acculturation.
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DOE Office of Scientific and Technical Information (OSTI.GOV)
NONE
1998-01-01
This decision document presents the Selected Remedy for Oregon Gulch OU10 within the California Gulch Superfund Site in Leadville, Colorado. The Selected Remedy includes active management of the seep currently discharging at the toe of the Oregon Gulch Tailing Impoundment during the interim period from implementation until the seep does not negatively impact surface water quality. Active management of the seep discharge will be performed during non-freezing conditions and will include collection and either pumping or transport of the collected flow to the Yak Tunnel Treatment Plant or other suitable treatment options. Design of the Selected Remedy will include amore » drain system at the toe of the embankment to allow the seep discharge to flow unrestricted and to be collected in a controlled manner.« less
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Weed, Michael R; Bookbinder, Mark; Polino, Joseph; Keavy, Deborah; Cardinal, Rudolf N; Simmermacher-Mayer, Jean; Cometa, Fu-ni L; King, Dalton; Thangathirupathy, Srinivasan; Macor, John E; Bristow, Linda J
2016-01-01
Antidepressant activity of N-methyl-D-aspartate (NMDA) receptor antagonists and negative allosteric modulators (NAMs) has led to increased investigation of their behavioral pharmacology. NMDA antagonists, such as ketamine, impair cognition in multiple species and in multiple cognitive domains. However, studies with NR2B subtype-selective NAMs have reported mixed results in rodents including increased impulsivity, no effect on cognition, impairment or even improvement of some cognitive tasks. To date, the effects of NR2B-selective NAMs on cognitive tests have not been reported in nonhuman primates. The current study evaluated two selective NR2B NAMs, CP101,606 and BMT-108908, along with the nonselective NMDA antagonists, ketamine and AZD6765, in the nonhuman primate Cambridge Neuropsychological Test Automated Battery (CANTAB) list-based delayed match to sample (list-DMS) task. Ketamine and the two NMDA NR2B NAMs produced selective impairments in memory in the list-DMS task. AZD6765 impaired performance in a non-specific manner. In a separate cohort, CP101,606 impaired performance of the nonhuman primate CANTAB visuo-spatial Paired Associates Learning (vsPAL) task with a selective impairment at more difficult conditions. The results of these studies clearly show that systemic administration of a selective NR2B NAM can cause transient cognitive impairment in multiple cognitive domains. PMID:26105137
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Martin, Mario; Contreras-Hernández, Enrique; Béjar, Javier; Esposito, Gennaro; Chávez, Diógenes; Glusman, Silvio; Cortés, Ulises; Rudomin, Pablo
2015-01-01
Previous studies aimed to disclose the functional organization of the neuronal networks involved in the generation of the spontaneous cord dorsum potentials (CDPs) generated in the lumbosacral spinal segments used predetermined templates to select specific classes of spontaneous CDPs. Since this procedure was time consuming and required continuous supervision, it was limited to the analysis of two specific types of CDPs (negative CDPs and negative positive CDPs), thus excluding potentials that may reflect activation of other neuronal networks of presumed functional relevance. We now present a novel procedure based in machine learning that allows the efficient and unbiased selection of a variety of spontaneous CDPs with different shapes and amplitudes. The reliability and performance of the present method is evaluated by analyzing the effects on the probabilities of generation of different classes of spontaneous CDPs induced by the intradermic injection of small amounts of capsaicin in the anesthetized cat, a procedure known to induce a state of central sensitization leading to allodynia and hyperalgesia. The results obtained with the selection method presently described allowed detection of spontaneous CDPs with specific shapes and amplitudes that are assumed to represent the activation of functionally coupled sets of dorsal horn neurones that acquire different, structured configurations in response to nociceptive stimuli. These changes are considered as responses tending to adequate transmission of sensory information to specific functional requirements as part of homeostatic adjustments. PMID:26379540
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Saxena, Ruchi; Chandra, Vishal; Manohar, Murli; Hajela, Kanchan; Debnath, Utsab; Prabhakar, Yenamandra S.; Saini, Karan Singh; Konwar, Rituraj; Kumar, Sandeep; Megu, Kaling; Roy, Bal Gangadhar; Dwivedi, Anila
2013-01-01
Inhibition of epidermal growth factor receptor (EGFR) signaling is considered to be a promising treatment strategy for estrogen receptor (ER)-negative breast tumors. We have investigated here the anti-breast cancer properties of a novel anti-proliferative benzopyran compound namely, 2-[piperidinoethoxyphenyl]-3-phenyl-2H-benzo(b)pyran (CDRI-85/287) in ER- negative and EGFR- overexpressing breast cancer cells. The benzopyran compound selectively inhibited the EGF-induced growth of MDA-MB 231 cells and ER-negative primary breast cancer cell culture. The compound significantly reduced tumor growth in xenograft of MDA-MB 231 cells in nude mice. The compound displayed better binding affinity for EGFR than inhibitor AG1478 as demonstrated by molecular docking studies. CDRI-85/287 significantly inhibited the activation of EGFR and downstream effectors MEK/Erk and PI-3-K/Akt. Subsequent inhibition of AP-1 promoter activity resulted in decreased transcription activation and expression of c-fos and c-jun. Dephosphorylation of downstream effectors FOXO-3a and NF-κB led to increased expression of p27 and decreased expression of cyclin D1 which was responsible for decreased phosphorylation of Rb and prevented the transcription of E2F- dependent genes involved in cell cycle progression from G1/S phase. The compound induced apoptosis via mitochondrial pathway and it also inhibited EGF-induced invasion of MDA-MB 231 cells as evidenced by decreased activity of MMP-9 and expression of CTGF. These results indicate that benzopyran compound CDRI-85/287 could constitute a powerful new chemotherapeutic agent against ER-negative and EGFR over-expressing breast tumors. PMID:23840429
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Zeng, Tao; Duan, Xiaolu; Zhu, Wei; Liu, Yang; Wu, Wenqi; Zeng, Guohua
2018-06-01
Hypercalciuria is a main risk factor for kidney stone formation. TRPV5 is the gatekeeper protein for mediating calcium transport and reabsorption in the kidney. In the present study, we tested the effect of TRPV5 activation with small activating RNA (saRNA), which could induce gene expression by targeting the promoter of the gene, on ethylene glycol (EG)-induced calcium oxalate (CaOx) crystals formation in rat kidney. Five pairs of RNA activation sequences targeting the promoter of rat TRPV5 were designed and synthesized. The synthesized saRNA with the strongest activating effect was selected, and transcellular calcium transportation was tested by Fura-2 analysis. Subsequently, Sprague-Dawley rats were equally divided into three groups and fed with water, 1% EG for 28 days after injecting the negative control saRNA, 1% EG for 28 days after injecting the selected TRPV5-saRNA, respectively. The CaOx crystal formation and the 24-h urine components were assessed. In vitro study, saRNA ds-320 could significantly activate the expression of TRPV5 and transcellular calcium transportation. In vivo study, after 28 days treatment of EG, rats pre-infected with saRNA ds-320 had lower urinary calcium excretion and renal CaOx crystals formation as compared to that pre-infected with negative control saRNA. Activation of TRVP5 with saRNA ds-320 could inhibit EG-induced calcium oxalate crystals formation via promoting urine calcium reabsorption and decreasing urine calcium excretion in rats.
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Filone, Claire Marie; Hodges, Erin N.; Honeyman, Brian; Bushkin, G. Guy; Boyd, Karla; Platt, Andrew; Ni, Feng; Strom, Kyle; Hensley, Lisa; Snyder, John K.; Connor, John H.
2013-01-01
There are no approved therapeutics for the most deadly nonsegmented negative-strand (NNS) RNA viruses, including Ebola (EBOV). To identify new chemical scaffolds for development of broad-spectrum antivirals, we undertook a prototype-based lead identification screen. Using the prototype NNS virus, vesicular stomatitis virus (VSV), multiple inhibitory compounds were identified. Three compounds were investigated for broad-spectrum activity, and inhibited EBOV infection. The most potent, CMLDBU3402, was selected for further study. CMLDBU3402 did not show significant activity against segmented negative-strand RNA viruses suggesting proscribed broad-spectrum activity. Mechanistic analysis indicated that CMLDBU3402 blocked VSV viral RNA synthesis and inhibited EBOV RNA transcription, demonstrating a consistent mechanism of action against genetically distinct viruses. The identification of this chemical backbone as a broad-spectrum inhibitor of viral RNA synthesis offers significant potential for the development of new therapies for highly pathogenic viruses. PMID:23521799
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Negative allosteric modulators that target human alpha4beta2 neuronal nicotinic receptors.
Henderson, Brandon J; Pavlovicz, Ryan E; Allen, Jerad D; González-Cestari, Tatiana F; Orac, Crina M; Bonnell, Andrew B; Zhu, Michael X; Boyd, R Thomas; Li, Chenglong; Bergmeier, Stephen C; McKay, Dennis B
2010-09-01
Allosteric modulation of neuronal nicotinic acetylcholine receptors (nAChRs) is considered to be one of the most promising approaches for therapeutics. We have previously reported on the pharmacological activity of several compounds that act as negative allosteric modulators (NAMs) of nAChRs. In the following studies, the effects of 30 NAMs from our small chemical library on both human alpha4beta2 (Halpha4beta2) and human alpha3beta4 (Halpha3beta4) nAChRs expressed in human embryonic kidney ts201 cells were investigated. During calcium accumulation assays, these NAMs inhibited nAChR activation with IC(50) values ranging from 2.4 microM to more than 100 microM. Several NAMs showed relative selectivity for Halpha4beta2 nAChRs with IC(50) values in the low micromolar range. A lead molecule, KAB-18, was identified that shows relative selectivity for Halpha4beta2 nAChRs. This molecule contains three phenyl rings, one piperidine ring, and one ester bond linkage. Structure-activity relationship (SAR) analyses of our data revealed three regions of KAB-18 that contribute to its relative selectivity. Predictive three-dimensional quantitative SAR (comparative molecular field analysis and comparative molecular similarity indices analysis) models were generated from these data, and a pharmacophore model was constructed to determine the chemical features that are important for biological activity. Using docking approaches and molecular dynamics on a Halpha4beta2 nAChR homology model, a binding mode for KAB-18 at the alpha/beta subunit interface that corresponds to the predicted pharmacophore is described. This binding mode was supported by mutagenesis studies. In summary, these studies highlight the importance of SAR, computational, and molecular biology approaches for the design and synthesis of potent and selective antagonists targeting specific nAChR subtypes.
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Negative Allosteric Modulators That Target Human α4β2 Neuronal Nicotinic Receptors
Henderson, Brandon J.; Pavlovicz, Ryan E.; Allen, Jerad D.; González-Cestari, Tatiana F.; Orac, Crina M.; Bonnell, Andrew B.; Zhu, Michael X.; Boyd, R. Thomas; Li, Chenglong; Bergmeier, Stephen C.
2010-01-01
Allosteric modulation of neuronal nicotinic acetylcholine receptors (nAChRs) is considered to be one of the most promising approaches for therapeutics. We have previously reported on the pharmacological activity of several compounds that act as negative allosteric modulators (NAMs) of nAChRs. In the following studies, the effects of 30 NAMs from our small chemical library on both human α4β2 (Hα4β2) and human α3β4 (Hα3β4) nAChRs expressed in human embryonic kidney ts201 cells were investigated. During calcium accumulation assays, these NAMs inhibited nAChR activation with IC50 values ranging from 2.4 μM to more than 100 μM. Several NAMs showed relative selectivity for Hα4β2 nAChRs with IC50 values in the low micromolar range. A lead molecule, KAB-18, was identified that shows relative selectivity for Hα4β2 nAChRs. This molecule contains three phenyl rings, one piperidine ring, and one ester bond linkage. Structure–activity relationship (SAR) analyses of our data revealed three regions of KAB-18 that contribute to its relative selectivity. Predictive three-dimensional quantitative SAR (comparative molecular field analysis and comparative molecular similarity indices analysis) models were generated from these data, and a pharmacophore model was constructed to determine the chemical features that are important for biological activity. Using docking approaches and molecular dynamics on a Hα4β2 nAChR homology model, a binding mode for KAB-18 at the α/β subunit interface that corresponds to the predicted pharmacophore is described. This binding mode was supported by mutagenesis studies. In summary, these studies highlight the importance of SAR, computational, and molecular biology approaches for the design and synthesis of potent and selective antagonists targeting specific nAChR subtypes. PMID:20551292
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Study of positive and negative plasma catalytic oxidation of ethylene.
Van Wesenbeeck, K; Hauchecorne, B; Lenaerts, S
2017-06-01
The effect of introducing a photocatalytically active coating inside a plasma unit is investigated. This technique combines the advantages of high product selectivity from catalysis and the fast start-up from plasma technology. In this study, a preselected TiO 2 coating is applied on the collector electrode of a DC corona discharge unit as non-thermal plasma reactor, in order to study the oxidation of ethylene. For both positive and negative polarities an enhanced mineralization is observed while the formation of by-products drastically decreases. The plasma catalytic unit gave the best results when using negative polarity at a voltage of 15 kV. This shows the potential of plasma catalysis as indoor air purification technology.
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Castro-Fernandez, Víctor; Herrera-Morande, Alejandra; Zamora, Ricardo; Merino, Felipe; Gonzalez-Ordenes, Felipe; Padilla-Salinas, Felipe; Pereira, Humberto M; Brandão-Neto, Jose; Garratt, Richard C; Guixe, Victoria
2017-09-22
One central goal in molecular evolution is to pinpoint the mechanisms and evolutionary forces that cause an enzyme to change its substrate specificity; however, these processes remain largely unexplored. Using the glycolytic ADP-dependent kinases of archaea, including the orders Thermococcales , Methanosarcinales , and Methanococcales , as a model and employing an approach involving paleoenzymology, evolutionary statistics, and protein structural analysis, we could track changes in substrate specificity during ADP-dependent kinase evolution along with the structural determinants of these changes. To do so, we studied five key resurrected ancestral enzymes as well as their extant counterparts. We found that a major shift in function from a bifunctional ancestor that could phosphorylate either glucose or fructose 6-phosphate (fructose-6-P) as a substrate to a fructose 6-P-specific enzyme was started by a single amino acid substitution resulting in negative selection with a ground-state mode against glucose and a subsequent 1,600-fold change in specificity of the ancestral protein. This change rendered the residual phosphorylation of glucose a promiscuous and physiologically irrelevant activity, highlighting how promiscuity may be an evolutionary vestige of ancestral enzyme activities, which have been eliminated over time. We also could reconstruct the evolutionary history of substrate utilization by using an evolutionary model of discrete binary characters, indicating that substrate uses can be discretely lost or acquired during enzyme evolution. These findings exemplify how negative selection and subtle enzyme changes can lead to major evolutionary shifts in function, which can subsequently generate important adaptive advantages, for example, in improving glycolytic efficiency in Thermococcales . © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.
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Two-stage microfluidic chip for selective isolation of circulating tumor cells (CTCs).
Hyun, Kyung-A; Lee, Tae Yoon; Lee, Su Hyun; Jung, Hyo-Il
2015-05-15
Over the past few decades, circulating tumor cells (CTCs) have been studied as a means of overcoming cancer. However, the rarity and heterogeneity of CTCs have been the most significant hurdles in CTC research. Many techniques for CTC isolation have been developed and can be classified into positive enrichment (i.e., specifically isolating target cells using cell size, surface protein expression, and so on) and negative enrichment (i.e., specifically eluting non-target cells). Positive enrichment methods lead to high purity, but could be biased by their selection criteria, while the negative enrichment methods have relatively low purity, but can isolate heterogeneous CTCs. To compensate for the known disadvantages of the positive and negative enrichments, in this study we introduced a two-stage microfluidic chip. The first stage involves a microfluidic magnetic activated cell sorting (μ-MACS) chip to elute white blood cells (WBCs). The second stage involves a geometrically activated surface interaction (GASI) chip for the selective isolation of CTCs. We observed up to 763-fold enrichment in cancer cells spiked into 5 mL of blood sample using the μ-MACS chip at 400 μL/min flow rate. Cancer cells were successfully separated with separation efficiencies ranging from 10.19% to 22.91% based on their EpCAM or HER2 surface protein expression using the GASI chip at a 100 μL/min flow rate. Our two-stage microfluidic chips not only isolated CTCs from blood cells, but also classified heterogeneous CTCs based on their characteristics. Therefore, our chips can contribute to research on CTC heterogeneity of CTCs, and, by extension, personalized cancer treatment. Copyright © 2014 Elsevier B.V. All rights reserved.
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van Helden, Suzanne F G; van den Dries, Koen; Oud, Machteld M; Raymakers, Reinier A P; Netea, Mihai G; van Leeuwen, Frank N; Figdor, Carl G
2010-02-01
Chronic infections are caused by microorganisms that display effective immune evasion mechanisms. Dendritic cell (DC)-dependent T cell-mediated adaptive immunity is one of the mechanisms that have evolved to prevent the occurrence of chronic bacterial infections. In turn, bacterial pathogens have developed strategies to evade immune recognition. In this study, we show that gram-negative and gram-positive bacteria differ in their ability to activate DCs and that gram-negative bacteria are far more effective inducers of DC maturation. Moreover, we observed that only gram-negative bacteria can induce loss of adhesive podosome structures in DCs, a response necessary for the induction of effective DC migration. We demonstrate that the ability of gram-negative bacteria to trigger podosome turnover and induce DC migration reflects their capacity to selectively activate TLR4. Examining mice defective in TLR4 signaling, we show that this DC maturation and migration are mainly Toll/IL-1 receptor domain-containing adaptor-inducing IFNbeta-dependent. Furthermore, we show that these processes depend on the production of PGs by these DCs, suggesting a direct link between TLR4-mediated signaling and arachidonic metabolism. These findings demonstrate that gram-positive and gram-negative bacteria profoundly differ in their capacity to activate DCs. We propose that this inability of gram-positive bacteria to induce DC maturation and migration is part of the armamentarium necessary for avoiding the induction of an effective cellular immune response and may explain the frequent involvement of these pathogens in chronic infections.
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Williams, R M; Rimsky, S; Buc, H
1996-08-01
Twelve different dominant negative mutants of the Escherichia coli nucleoid-associated protein, H-NS, have been selected and characterized in vivo. The mutants are all severely defective in promoter repression activity in a strain lacking H-NS, and they all disrupt the repression normally exerted by H-NS at two of its target promoters. From the locations of the alterations in these mutants, which result in both large truncations and amino acid substitutions, we propose that H-NAS contains at least two distinct domains. The in vitro protein-protein cross-linking data presented in this report indicate that the proposed N-terminal domain of H-NS has a role in H-NS multimerization. StpA is a protein with known structural and functional homologies to H-NS. We have analyzed the extent of these homologies by constructing and studying StpA mutants predicted to be dominant negative. Our data indicate that the substitutions and deletions found in dominant negative H-NS have similar effects in the context of StpA. We conclude that the domain organizations and functions in StpA and H-NS are closely related. Furthermore, dominant negative H-NS can disrupt the activity of native StpA, and reciprocally, dominant negative StpA can disrupt the activity of native H-NS. We demonstrate that the N-terminal domain of H-NS can be chemically cross-linked to both full-length H-NS and StpA. We account for these observations by proposing that H-NS and StpA have the ability to form hybrid species.
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Gramicidin A Mutants with Antibiotic Activity against Both Gram-Positive and Gram-Negative Bacteria.
Zerfas, Breanna L; Joo, Yechaan; Gao, Jianmin
2016-03-17
Antimicrobial peptides (AMPs) have shown potential as alternatives to traditional antibiotics for fighting infections caused by antibiotic-resistant bacteria. One promising example of this is gramicidin A (gA). In its wild-type sequence, gA is active by permeating the plasma membrane of Gram-positive bacteria. However, gA is toxic to human red blood cells at similar concentrations to those required for it to exert its antimicrobial effects. Installing cationic side chains into gA has been shown to lower its hemolytic activity while maintaining the antimicrobial potency. In this study, we present the synthesis and the antibiotic activity of a new series of gA mutants that display cationic side chains. Specifically, by synthesizing alkylated lysine derivatives through reductive amination, we were able to create a broad selection of structures with varied activities towards Staphylococcus aureus and methicillin-resistant S. aureus (MRSA). Importantly, some of the new mutants were observed to have an unprecedented activity towards important Gram-negative pathogens, including Escherichia coli, Klebsiella pneumoniae and Psuedomonas aeruginosa. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
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Robson, Jeffrey D.; Davidson, Dominique; Veillette, André
2004-01-01
Dok-3 is a Dok-related adaptor expressed in B cells and macrophages. Previously, we reported that Dok-3 is an inhibitor of B-cell activation in A20 B cells and that it associates with SHIP-1, a 5′ inositol-specific lipid phosphatase, as well as Csk, a negative regulator of Src kinases. Here, we demonstrate that Dok-3 suppresses B-cell activation by way of its interaction with SHIP-1, rather than Csk. Our biochemical analyses showed that the Dok-3-SHIP-1 complex acts by selectively inhibiting the B-cell receptor (BCR)-evoked activation of the Jun N-terminal protein kinase (JNK) cascade without affecting overall protein tyrosine phosphorylation or activation of previously described SHIP-1 targets like Btk and Akt/PKB. Studies of B cells derived from SHIP-1-deficient mice showed that BCR-triggered activation of JNK is enhanced in the absence of SHIP-1, implying that the Dok-3-SHIP-1 complex (or a related mechanism) is a physiological negative regulator of the JNK cascade in normal B cells. Together, these data elucidate the mechanism by which Dok-3 inhibits B-cell activation. Furthermore, they provide evidence that SHIP-1 can be a negative regulator of JNK signaling in B cells. PMID:14993273
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Karhukorpi, Jari; Päivänurmi, Marjut
2014-01-01
Aesculin hydrolysis (ESC) is one of the key reactions in differentiating pathogenic Yersinia enterocolitica biotypes 1B, 2, 3, 4 and 5 from the less-pathogenic biotype 1A. Because the ESC reaction is caused by β-glucosidase (βGLU) activity of the bacteria, we studied whether two commonly used methods (BBL CHROMagar Orientation and Vitek2 Gram-negative identification card) could be used in assessing βGLU activity of 74 Yersinia strains. Both methods were sensitive (100 % and 97 %) and specific (100 % and 100 %) in differentiating βGLU-positive YE BT1A from βGLU-negative Y. enterocolitica biotypes. For a subset of strains (n = 69), a new selective CHROMagar Yersinia showed excellent agreement with the strains' βGLU activity. Thus all the methods evaluated in this study may be used to differentiate between YE BT1A and other Y. enterocolitica biotypes.
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Tancredi, T; Temussi, P A; Picone, D; Amodeo, P; Tomatis, R; Salvadori, S; Marastoni, M; Santagada, V; Balboni, G
1991-05-01
The message domain of dermorphin (Tyr-D-Ala-Phe), a natural mu-opioid heptapeptide, has long been considered the main cause of the high mu selectivity of this peptide and of its analogues. The recent discovery, in the skin of Phyllomedusa sauvagei (i.e., the same natural source of dermorphin) and of Phyllomedusa bicolor of deltorphins, challenges this belief. Deltorphins, in fact, are three heptapeptides characterized by a message domain typical of mu-selective peptides, but endowed of an extremely high delta selectivity, the highest of all natural opioid peptides. A conformational analysis of dermorphin and deltorphins, based on nmr studies in DMSO and cryoprotective mixtures and internal energy calculations, showed that the enormous differences in receptor selectivity can be interpreted on the basis of receptor models for mu and delta opioids that recognize the same beta-turn in the N-terminal part, but discriminate for the conformation and polarity of the C-terminal part. Here we present the synthesis, biological activity, and conformational analysis in solution of three deltorphin analogues with very similar constitution, but with different net charge, different location of negative residues, or even without negative residues, which confirm these hypotheses and show that His4 can play a specific structural role.
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Baucom, Regina S; Mauricio, Rodney
2008-11-01
Evolutionary biologists explain the maintenance of intermediate levels of defense in plant populations as being due to trade-offs, or negative genetic covariances among ecologically important traits. Attempts at detecting trade-offs as constraints on the evolution of defense have not always been successful, leading some to conclude that such trade-offs rarely explain current levels of defense in the population. Using the agricultural pest Ipomoea purpurea, we measured correlations between traits involved in defense to glyphosate, the active ingredient in Roundup, a widely used herbicide. We found significant allocation costs of tolerance, as well as trade-offs between resistance and two measures of tolerance to glyphosate. Selection on resistance and tolerance exhibited differing patterns: tolerance to leaf damage was under negative directional selection, whereas resistance was under positive directional selection. The joint pattern of selection on resistance and tolerance to leaf damage indicated the presence of alternate peaks in the fitness landscape such that a combination of either high tolerance and low resistance, or high resistance and low tolerance was favored. The widespread use of this herbicide suggests that it is likely an important selective agent on weed populations. Understanding the evolutionary dynamics of herbicide defense traits is thus of increasing importance in the context of human-mediated evolution.
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Selective cytotoxic eremophilane-type sesquiterpenes from Penicillium citreonigrum.
Yuan, Wei-Hua; Goto, Masuo; Hsieh, Kan-Yen; Yuan, Bo; Zhao, Yu; Morris-Natschke, Susan L; Lee, Kuo-Hsiung
2015-01-01
One new eremophilane-type sesquiterpene (1, citreopenin) was isolated from Penicillium citreonigrum (HQ738282), and the structure was elucidated by a combination of spectroscopic data interpretation and single-crystal X-ray diffraction analysis using Cu Kα radiation (CCDC 1030588). Compound 1 showed weak activity against KB-VIN (IC50 = 11.0 ± 0.156 μM), while the known compound 3 exhibited selective cytotoxicity against MDA-MB-231 triple-negative breast cancer (TNBC) (IC50 = 5.42 ± 0.167 μM).
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Weak Negative and Positive Selection and the Drift Load at Splice Sites
Denisov, Stepan V.; Bazykin, Georgii A.; Sutormin, Roman; Favorov, Alexander V.; Mironov, Andrey A.; Gelfand, Mikhail S.; Kondrashov, Alexey S.
2014-01-01
Splice sites (SSs) are short sequences that are crucial for proper mRNA splicing in eukaryotic cells, and therefore can be expected to be shaped by strong selection. Nevertheless, in mammals and in other intron-rich organisms, many of the SSs often involve nonconsensus (Nc), rather than consensus (Cn), nucleotides, and beyond the two critical nucleotides, the SSs are not perfectly conserved between species. Here, we compare the SS sequences between primates, and between Drosophila fruit flies, to reveal the pattern of selection acting at SSs. Cn-to-Nc substitutions are less frequent, and Nc-to-Cn substitutions are more frequent, than neutrally expected, indicating, respectively, negative and positive selection. This selection is relatively weak (1 < |4Nes| < 4), and has a similar efficiency in primates and in Drosophila. Within some nucleotide positions, the positive selection in favor of Nc-to-Cn substitutions is weaker than the negative selection maintaining already established Cn nucleotides; this difference is due to site-specific negative selection favoring current Nc nucleotides. In general, however, the strength of negative selection protecting the Cn alleles is similar in magnitude to the strength of positive selection favoring replacement of Nc alleles, as expected under the simple nearly neutral turnover. In summary, although a fraction of the Nc nucleotides within SSs is maintained by selection, the abundance of deleterious nucleotides in this class suggests a substantial genome-wide drift load. PMID:24966225
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Riedel, Damien; Bocquet, Marie-Laure; Lesnard, Hervé; Lastapis, Mathieu; Lorente, Nicolas; Sonnet, Philippe; Dujardin, Gérald
2009-06-03
Selective electron-induced reactions of individual biphenyl molecules adsorbed in their weakly chemisorbed configuration on a Si(100) surface are investigated by using the tip of a low-temperature (5 K) scanning tunnelling microscope (STM) as an atomic size source of electrons. Selected types of molecular reactions are produced, depending on the polarity of the surface voltage during STM excitation. At negative surface voltages, the biphenyl molecule diffuses across the surface in its weakly chemisorbed configuration. At positive surface voltages, different types of molecular reactions are activated, which involve the change of adsorption configuration from the weakly chemisorbed to the strongly chemisorbed bistable and quadristable configurations. Calculated reaction pathways of the molecular reactions on the silicon surface, using the nudge elastic band method, provide evidence that the observed selectivity as a function of the surface voltage polarity cannot be ascribed to different activation energies. These results, together with the measured threshold surface voltages and the calculated molecular electronic structures via density functional theory, suggest that the electron-induced molecular reactions are driven by selective electron detachment (oxidation) or attachment (reduction) processes.
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Nandy, Ashis; Roy, Kunal; Saha, Achintya
2018-01-01
Metabolic syndrome is a matrix of different metabolic disorders which are the leading cause of death in human beings. Peroxysome proliferated activated receptor (PPAR) is a nuclear receptor involved in metabolism of fats and glucose. In order to explore structural requirements for selective PPAR modulators to control lipid and carbohydrate metabolism, the multi-cheminformatics studies have been performed. In silico modeling studies have been performed on a diverse set of PPAR modulators through quantitative structure-activity relationship (QSAR), pharmacophore mapping and docking studies. It is observed that the presence of an amide fragment (-CONHRPh) has a detrimental effect while an aliphatic ether linkage has a beneficial effect on PPARα modulation. On the other hand, the presence of an amide fragment has a positive effect on PPARδ modulation, but the aliphatic ether linkage and substituted aromatic ring in the molecular scaffold are very much essential for imparting potent and selective PPARγ modulation. Negative ionizable features (i.e. polar fragments) must be present in PPARδ and α modulators, but a hydrophobic feature is the prime requirement for PPARγ modulation. Here, the essential structural features have been explored for selective modulation of each subtype of PPAR in order to design new modulators with improved activity/selectivity. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.
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Joondan, Nausheen; Caumul, Prakashanand; Akerman, Matthew; Jhaumeer-Laulloo, Sabina
2015-02-01
A series of quaternary ammonium compounds (QUATS) derived from l-Phenylalanine have been synthesized and their antibacterial efficiencies were determined against various strains of Gram-positive and Gram-negative bacteria. The antibacterial activity increased with increasing chain length, exhibiting a cut-off effect at C14 for Gram-positive and C12 for Gram-negative bacteria. The l-Phenylalanine QUATS displayed enhanced antibacterial properties with a higher cut-off point compared to their corresponding l-Phenylalanine ester hydrochlorides. The CMC was correlated with the MIC, inferring that micellar activity contributes to the cut-off effect in antibacterial activity. The hemolytic activities (HC50) of the QUATS against human red blood cells were also determined to illustrate the selectivity of these QUATS for bacterial over mammalian cells. In general, the MIC was lower than the HC50, and assessment of the micellar contribution to the antibacterial and hemolytic evaluation in TBS as a common medium confirmed that these QUATS can act as antibacterial, yet non-toxic molecules at their monomer concentrations. The interaction of the QUATS with the phospholipid vesicles (1,2-dipalmitoyl-sn-glycero-3-phosphocholine, DPPC) in the presence of 1-anilino-8-naphthalene sulfonate (ANS) and 1,6-diphenyl-1,3,5-hexatriene (DPH) as fluorescence probes showed that the presence of the quaternary ammonium moiety causes an increase in hydrophobic interactions, thus causing an increase in antibacterial activity. Copyright © 2015 Elsevier Inc. All rights reserved.
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Lightweight, durable lead-acid batteries
Lara-Curzio, Edgar [Lenoir City, TN; An, Ke [Knoxville, TX; Kiggans, Jr., James O.; Dudney, Nancy J [Knoxville, TN; Contescu, Cristian I [Knoxville, TN; Baker, Frederick S [Oak Ridge, TN; Armstrong, Beth L [Clinton, TN
2011-09-13
A lightweight, durable lead-acid battery is disclosed. Alternative electrode materials and configurations are used to reduce weight, to increase material utilization and to extend service life. The electrode can include a current collector having a buffer layer in contact with the current collector and an electrochemically active material in contact with the buffer layer. In one form, the buffer layer includes a carbide, and the current collector includes carbon fibers having the buffer layer. The buffer layer can include a carbide and/or a noble metal selected from of gold, silver, tantalum, platinum, palladium and rhodium. When the electrode is to be used in a lead-acid battery, the electrochemically active material is selected from metallic lead (for a negative electrode) or lead peroxide (for a positive electrode).
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Lightweight, durable lead-acid batteries
Lara-Curzio, Edgar; An, Ke; Kiggans, Jr., James O; Dudney, Nancy J; Contescu, Cristian I; Baker, Frederick S; Armstrong, Beth L
2013-05-21
A lightweight, durable lead-acid battery is disclosed. Alternative electrode materials and configurations are used to reduce weight, to increase material utilization and to extend service life. The electrode can include a current collector having a buffer layer in contact with the current collector and an electrochemically active material in contact with the buffer layer. In one form, the buffer layer includes a carbide, and the current collector includes carbon fibers having the buffer layer. The buffer layer can include a carbide and/or a noble metal selected from of gold, silver, tantalum, platinum, palladium and rhodium. When the electrode is to be used in a lead-acid battery, the electrochemically active material is selected from metallic lead (for a negative electrode) or lead peroxide (for a positive electrode).
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Revisiting negative selection algorithms.
Ji, Zhou; Dasgupta, Dipankar
2007-01-01
This paper reviews the progress of negative selection algorithms, an anomaly/change detection approach in Artificial Immune Systems (AIS). Following its initial model, we try to identify the fundamental characteristics of this family of algorithms and summarize their diversities. There exist various elements in this method, including data representation, coverage estimate, affinity measure, and matching rules, which are discussed for different variations. The various negative selection algorithms are categorized by different criteria as well. The relationship and possible combinations with other AIS or other machine learning methods are discussed. Prospective development and applicability of negative selection algorithms and their influence on related areas are then speculated based on the discussion.
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Mimics of pramanicin derived from pyroglutamic acid and their antibacterial activity.
Tan, Song Wei Benjamin; Chai, Christina L L; Moloney, Mark G
2017-02-22
Mono and dihydroxypyrrolidinones are readily available by direct oxygenation of a pyroglutamate-derived bicyclic lactam with high diastereoselectivity, and these may be manipulated further in protected or unprotected form by Grignard addition to a pendant Weinreb amide to give acylhydroxypyrrolidinones, which are analogues of the natural product, pramanicin. Preliminary bioassay against S. aureus and E. coli indicated that some compounds exhibit selective Gram-negative antibacterial activity, and may offer promise for the development of novel systems suitable for antibacterial drug development.
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Broadening the Cloaking Bandwidth with Non-Foster Metasurfaces
NASA Astrophysics Data System (ADS)
Chen, Pai-Yen; Argyropoulos, Christos; Alù, Andrea
2013-12-01
We introduce the concept and practical design of broadband, ultrathin cloaks based on non-Foster, negatively capacitive metasurfaces. By using properly tailored, active frequency-selective screens conformal to an object, within the realm of a practical realization, we show that it is possible to drastically reduce the scattering over a wide frequency range in the microwave regime, orders of magnitude broader than any available passive cloaking technology. The proposed active cloak may impact not only invisibility and camouflaging, but also practical antenna and sensing applications.
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NASA Technical Reports Server (NTRS)
Riley, Danny A.; Sanger, James R.; Matloub, Hani S.; Yousif, N. John; Bain, James L. W.
1988-01-01
Carbonic anhydrase (CA) and cholinesterase (CE) histochemical staining of rabbit spinal nerve roots and dorsal root ganglia demonstrated that among the reactive myeliated axons, with minor exceptions, sensory axons were CA positive and CE negative whereas motor axons were CA negative and CE positive. The high specificity was achieved by adjusting reaction conditions to stain subpopulations of myelinated axons selectively while leaving 50 percent or so unstained. Fixation with glutaraldehyde appeared necessary for achieving selectivity. Following sciatic nerve transection, the reciprocal staining pattern persisted in damaged axons and their regenerating processes which formed neuromas within the proximal nerve stump. Within the neuromas, CA-stained sensory processes were elaborated earlier and in greater numbers than CE-stained regenerating motor processes. The present results indicate that histochemical axon typing can be exploited to reveal heterogeneous responses of motor and sensory axons to injury.
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Markers of preparatory attention predict visual short-term memory performance.
Murray, Alexandra M; Nobre, Anna C; Stokes, Mark G
2011-05-01
Visual short-term memory (VSTM) is limited in capacity. Therefore, it is important to encode only visual information that is most likely to be relevant to behaviour. Here we asked which aspects of selective biasing of VSTM encoding predict subsequent memory-based performance. We measured EEG during a selective VSTM encoding task, in which we varied parametrically the memory load and the precision of recall required to compare a remembered item to a subsequent probe item. On half the trials, a spatial cue indicated that participants only needed to encode items from one hemifield. We observed a typical sequence of markers of anticipatory spatial attention: early attention directing negativity (EDAN), anterior attention directing negativity (ADAN), late directing attention positivity (LDAP); as well as of VSTM maintenance: contralateral delay activity (CDA). We found that individual differences in preparatory brain activity (EDAN/ADAN) predicted cue-related changes in recall accuracy, indexed by memory-probe discrimination sensitivity (d'). Importantly, our parametric manipulation of memory-probe similarity also allowed us to model the behavioural data for each participant, providing estimates for the quality of the memory representation and the probability that an item could be retrieved. We found that selective encoding primarily increased the probability of accurate memory recall; that ERP markers of preparatory attention predicted the cue-related changes in recall probability. Copyright © 2011. Published by Elsevier Ltd.
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Trans-kingdom mimicry underlies ribosome customization by a poxvirus kinase.
Jha, Sujata; Rollins, Madeline G; Fuchs, Gabriele; Procter, Dean J; Hall, Elizabeth A; Cozzolino, Kira; Sarnow, Peter; Savas, Jeffrey N; Walsh, Derek
2017-06-29
Ribosomes have the capacity to selectively control translation through changes in their composition that enable recognition of specific RNA elements. However, beyond differential subunit expression during development, evidence for regulated ribosome specification within individual cells has remained elusive. Here we report that a poxvirus kinase phosphorylates serine/threonine residues in the human small ribosomal subunit protein, receptor for activated C kinase (RACK1), that are not phosphorylated in uninfected cells or cells infected by other viruses. These modified residues cluster in an extended loop in RACK1, phosphorylation of which selects for translation of viral or reporter mRNAs with 5' untranslated regions that contain adenosine repeats, so-called polyA-leaders. Structural and phylogenetic analyses revealed that although RACK1 is highly conserved, this loop is variable and contains negatively charged amino acids in plants, in which these leaders act as translational enhancers. Phosphomimetics and inter-species chimaeras have shown that negative charge in the RACK1 loop dictates ribosome selectivity towards viral RNAs. By converting human RACK1 to a charged, plant-like state, poxviruses remodel host ribosomes so that adenosine repeats erroneously generated by slippage of the viral RNA polymerase confer a translational advantage. Our findings provide insight into ribosome customization through trans-kingdom mimicry and the mechanics of species-specific leader activity that underlie poxvirus polyA-leaders.
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Trans-kingdom mimicry underlies ribosome customization by a poxvirus kinase
Jha, Sujata; Rollins, Madeline G.; Fuchs, Gabriele; Procter, Dean J.; Hall, Elizabeth A.; Cozzolino, Kira; Sarnow, Peter; Savas, Jeffrey N.; Walsh, Derek
2017-01-01
Ribosomes have the capacity to selectively control translation through changes in their composition that enable recognition of specific RNA elements1. However, beyond differential subunit expression during development2,3, evidence for regulated ribosome specification within individual cells has remained elusive1. Here, we report that a poxvirus kinase phosphorylates serine/threonine residues in the small ribosomal subunit protein, Receptor for Activated C Kinase (RACK1) that are not phosphorylated in uninfected cells or cells infected by other viruses. These modified residues cluster in an extended loop in RACK1, phosphorylation of which selects for translation of viral or reporter mRNAs whose 5’ untranslated regions (UTRs) contain adenosine repeats, so-called polyA-leaders. Structural and phylogenetic analysis revealed that although RACK1 is highly conserved, this loop is variable and contains negatively charged amino acids in plants, where these leaders act as translational enhancers for poorly understood reasons. Phosphomimetics and inter-species chimeras demonstrated that negative charge in the RACK1 loop dictates ribosome selectivity towards viral RNAs. By converting human RACK1 to a charged, plant-like state, poxviruses remodel host ribosomes so that adenosine repeats erroneously generated by slippage of the viral RNA polymerase4 confer a translational advantage. Our findings uncover ribosome customization through a novel trans-kingdom mimicry and the mechanics of species-specific leader activity that underlie the enigmatic poxvirus polyA-leaders4. PMID:28636603
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Dougherty, Thomas J.; Nayar, Asha; Newman, Joseph V.; Hopkins, Sussie; Stone, Gregory G.; Johnstone, Michele; Shapiro, Adam B.; Cronin, Mark; Reck, Folkert
2014-01-01
The need for new antibiotics that address serious Gram-negative infections is well recognized. Our efforts with a series of novel bacterial type II topoisomerase inhibitors (NBTIs) led to the discovery of NBTI 5463, an agent with improved activity over other NBTIs against Gram-negative bacteria, in particular against Pseudomonas aeruginosa (F. Reck, D. E. Ehmann, T. J. Dougherty, J. V. Newman, S. Hopkins, G. Stone, N. Agrawal, P. Ciaccio, J. McNulty, H. Barthlow, J. O'Donnell, K. Goteti, J. Breen, J. Comita-Prevoir, M. Cornebise, M. Cronin, C. J. Eyermann, B. Geng, G. R. Carr, L. Pandarinathan, X. Tang, A. Cottone, L. Zhao, N. Bezdenejnih-Snyder, submitted for publication). In the present work, NBTI 5463 demonstrated promising activity against a broad range of Gram-negative pathogens. In contrast to fluoroquinolones, the compound did not form a double-strand DNA cleavable complex with Escherichia coli DNA gyrase and DNA, but it was a potent inhibitor of both DNA gyrase and E. coli topoisomerase IV catalytic activities. In studies with P. aeruginosa, NBTI 5463 was bactericidal. Resistant mutants arose at a low rate, and the mutations were found exclusively in the nfxB gene, a regulator of the MexCD-OprJ efflux system. Levofloxacin-selected resistance mutations in GyrA did not result in decreased susceptibility to NBTI 5463. Animal infection studies demonstrated that NBTI 5463 was efficacious in mouse models of lung, thigh, and ascending urinary tract infections. PMID:24566174
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Do different salience cues compete for dominance in memory over a daytime nap?
Alger, Sara E; Chen, Shirley; Payne, Jessica D
2018-06-12
Information that is the most salient and important for future use is preferentially preserved through active processing during sleep. Emotional salience is a biologically adaptive cue that influences episodic memory processing through interactions between amygdalar and hippocampal activity. However, other cues that influence the importance of information, such as the explicit direction to remember or forget, interact with the inherent salience of information to determine its fate in memory. It is unknown how sleep-based processes selectively consolidate this complex information. The current study examined the development of memory for emotional and neutral information that was either cued to-be-remembered (TBR) or to-be-forgotten (TBF) across a daytime period including either napping or wakefulness. Baseline memory revealed dominance of the TBR cue, regardless of emotional salience. As anticipated, napping was found to preserve memory overall significantly better than remaining awake. Furthermore, we observed a trending interaction indicating that napping specifically enhanced the discrimination between the most salient information (negative TBR items) over other information. We found that memory for negative items was positively associated with the percentage of SWS obtained during a nap. Furthermore, the magnitude of the difference in memory between negative TBR items and negative TBF items increased with greater sleep spindle activity. Taken together, our results suggest that although the cue to actively remember or intentionally forget initially wins out, active processes during sleep facilitate the competition between salience cues to promote the most salient information in memory. Copyright © 2018 Elsevier Inc. All rights reserved.
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Affective bias as a rational response to the statistics of rewards and punishments.
Pulcu, Erdem; Browning, Michael
2017-10-04
Affective bias, the tendency to differentially prioritise the processing of negative relative to positive events, is commonly observed in clinical and non-clinical populations. However, why such biases develop is not known. Using a computational framework, we investigated whether affective biases may reflect individuals' estimates of the information content of negative relative to positive events. During a reinforcement learning task, the information content of positive and negative outcomes was manipulated independently by varying the volatility of their occurrence. Human participants altered the learning rates used for the outcomes selectively, preferentially learning from the most informative. This behaviour was associated with activity of the central norepinephrine system, estimated using pupilometry, for loss outcomes. Humans maintain independent estimates of the information content of distinct positive and negative outcomes which may bias their processing of affective events. Normalising affective biases using computationally inspired interventions may represent a novel approach to treatment development.
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Affective bias as a rational response to the statistics of rewards and punishments
Pulcu, Erdem
2017-01-01
Affective bias, the tendency to differentially prioritise the processing of negative relative to positive events, is commonly observed in clinical and non-clinical populations. However, why such biases develop is not known. Using a computational framework, we investigated whether affective biases may reflect individuals’ estimates of the information content of negative relative to positive events. During a reinforcement learning task, the information content of positive and negative outcomes was manipulated independently by varying the volatility of their occurrence. Human participants altered the learning rates used for the outcomes selectively, preferentially learning from the most informative. This behaviour was associated with activity of the central norepinephrine system, estimated using pupilometry, for loss outcomes. Humans maintain independent estimates of the information content of distinct positive and negative outcomes which may bias their processing of affective events. Normalising affective biases using computationally inspired interventions may represent a novel approach to treatment development. PMID:28976304
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NASA Astrophysics Data System (ADS)
Kaskow, Iveta; Decyk, Piotr; Sobczak, Izabela
2018-06-01
The goal of this work was to use ZnO as a support for gold and copper (Au-Cu system) or gold and silver (Au-Ag system) and comparison of the effect of copper and silver on the properties of gold and its activity in glycerol oxidation with oxygen in the liquid phase. The samples prepared were fully characterized by XRD, TEM techniques and UV-vis, XPS, ESR spectroscopic methods. It was found that the introduction of copper and silver changed the electronic state of gold loaded on ZnO by the electron transfer between metals. Three different metallic gold species were identified in calcined catalysts: (Au°)δ- (Au-ZnO), (Au°)η- (AuCu-ZnO) and (Au°)γ- (AuAg-ZnO), where δ-,η-,γ- indicate a different partial negative charge on metallic gold and γ > δ > η. The results showed that (Au°)η- centers (metallic gold with the lowest negative charge) formed on AuCu-ZnO were the most active in glycerol oxidation. The increase in the negative charge on metallic gold loaded on AuAg-ZnO reduced the gold activity in silver containing sample. The glyceric acid adsorption and desorption rate influenced the selectivity of the catalysts.
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State test-anxiety, selective attention and concentration in university students.
Fernández-Castillo, Antonio; Caurcel, María J
2015-08-01
The principal aim of this study was to assess the level of selective attention and mental concentration before exams in a sample of university students and to determine a possible relationship between anxiety and reduction of levels of attention in this circumstance. A total of 403 university students, 176 men and 227 women, aged from 18 to 46 years, participated in the study. Of them, 169 were first-year undergraduates, 118 were second to fourth-year undergraduates and 116 were postgraduate Master's degree students. All of them completed the Spanish version of the Spielberger State-Anxiety Inventory and the D2 Attention Test just before taking an exam. Our results showed that participants with lower levels of anxiety had higher levels of selective attention and mental concentration before the exam. These results specifically indicate that when anxiety levels are very high, this could over-activate the orientating and alerting functions and to reduce the capacity of attentional control. These processes could have a negative impact on specific attentional processes and become a negative influence on performance in exams. © 2014 International Union of Psychological Science.
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NASA Astrophysics Data System (ADS)
Darmon, David
2018-03-01
In the absence of mechanistic or phenomenological models of real-world systems, data-driven models become necessary. The discovery of various embedding theorems in the 1980s and 1990s motivated a powerful set of tools for analyzing deterministic dynamical systems via delay-coordinate embeddings of observations of their component states. However, in many branches of science, the condition of operational determinism is not satisfied, and stochastic models must be brought to bear. For such stochastic models, the tool set developed for delay-coordinate embedding is no longer appropriate, and a new toolkit must be developed. We present an information-theoretic criterion, the negative log-predictive likelihood, for selecting the embedding dimension for a predictively optimal data-driven model of a stochastic dynamical system. We develop a nonparametric estimator for the negative log-predictive likelihood and compare its performance to a recently proposed criterion based on active information storage. Finally, we show how the output of the model selection procedure can be used to compare candidate predictors for a stochastic system to an information-theoretic lower bound.
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Specialization of the DNA-Cleaving Activity of a Group I Ribozyme Through In Vitro Evolution
NASA Technical Reports Server (NTRS)
Tsang, Joyce; Joyce, Gerald F.
1996-01-01
In an earlier study, an in vitro evolution procedure was applied to a large population of variants of the Tetrahymena group 1 ribozyme to obtain individuals with a 10(exp 5)-fold improved ability to cleave a target single-stranded DNA substrate under simulated physiological conditions. The evolved ribozymes also showed a twofold improvement, compared to the wild-type, in their ability to cleave a single-stranded RNA substrate. Here, we report continuation of the in vitro evolution process using a new selection strategy to achieve both enhanced DNA and diminished RNA-cleavage activity. Our strategy combines a positive selection for DNA cleavage with a negative selection against RNA binding. After 36 "generations" of in vitro evolution, the evolved population showed an approx. 100-fold increase in the ratio of DNA to RNA-cleavage activity. Site-directed mutagenesis experiment confirmed the selective advantage of two covarying mutations within the catalytic core of ribozyme that are largely responsible for this modified behavior. The population of ribozymes has now undergone a total of 63 successive generations of evolution, resulting in an average 28 mutations relative to the wild-type that are responsible for the altered phenotype.
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Selection and Inhibition in Infancy: Evidence from the Spatial Negative Priming Paradigm
ERIC Educational Resources Information Center
Amso, D.; Johnson, S.P.
2005-01-01
We used a spatial negative priming (SNP) paradigm to examine visual selective attention in infants and adults using eye movements as the motor selection measure. In SNP, when a previously ignored location becomes the target to be selected, responses to it are impaired, providing a measure of inhibitory selection. Each trial consisted of a prime…
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Small Molecule Inhibition of microRNA-210 Reprograms an Oncogenic Hypoxic Circuit.
Costales, Matthew G; Haga, Christopher L; Velagapudi, Sai Pradeep; Childs-Disney, Jessica L; Phinney, Donald G; Disney, Matthew D
2017-03-08
A hypoxic state is critical to the metastatic and invasive characteristics of cancer. Numerous pathways play critical roles in cancer maintenance, many of which include noncoding RNAs such as microRNA (miR)-210 that regulates hypoxia inducible factors (HIFs). Herein, we describe the identification of a small molecule named Targapremir-210 that binds to the Dicer site of the miR-210 hairpin precursor. This interaction inhibits production of the mature miRNA, derepresses glycerol-3-phosphate dehydrogenase 1-like enzyme (GPD1L), a hypoxia-associated protein negatively regulated by miR-210, decreases HIF-1α, and triggers apoptosis of triple negative breast cancer cells only under hypoxic conditions. Further, Targapremir-210 inhibits tumorigenesis in a mouse xenograft model of hypoxic triple negative breast cancer. Many factors govern molecular recognition of biological targets by small molecules. For protein, chemoproteomics and activity-based protein profiling are invaluable tools to study small molecule target engagement and selectivity in cells. Such approaches are lacking for RNA, leaving a void in the understanding of its druggability. We applied Chemical Cross-Linking and Isolation by Pull Down (Chem-CLIP) to study the cellular selectivity and the on- and off-targets of Targapremir-210. Targapremir-210 selectively recognizes the miR-210 precursor and can differentially recognize RNAs in cells that have the same target motif but have different expression levels, revealing this important feature for selectively drugging RNAs for the first time. These studies show that small molecules can be rapidly designed to selectively target RNAs and affect cellular responses to environmental conditions, resulting in favorable benefits against cancer. Further, they help define rules for identifying druggable targets in the transcriptome.
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Liu, Xun; Hairston, Jacqueline; Schrier, Madeleine; Fan, Jin
2011-01-01
To better understand the reward circuitry in human brain, we conducted activation likelihood estimation (ALE) and parametric voxel-based meta-analyses (PVM) on 142 neuroimaging studies that examined brain activation in reward-related tasks in healthy adults. We observed several core brain areas that participated in reward-related decision making, including the nucleus accumbens (NAcc), caudate, putamen, thalamus, orbitofrontal cortex (OFC), bilateral anterior insula, anterior (ACC) and posterior (PCC) cingulate cortex, as well as cognitive control regions in the inferior parietal lobule and prefrontal cortex (PFC). The NAcc was commonly activated by both positive and negative rewards across various stages of reward processing (e.g., anticipation, outcome, and evaluation). In addition, the medial OFC and PCC preferentially responded to positive rewards, whereas the ACC, bilateral anterior insula, and lateral PFC selectively responded to negative rewards. Reward anticipation activated the ACC, bilateral anterior insula, and brain stem, whereas reward outcome more significantly activated the NAcc, medial OFC, and amygdala. Neurobiological theories of reward-related decision making should therefore distributed and interrelated representations of reward valuation and valence assessment into account. PMID:21185861
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Barriers to Leisure-Time Physical Activities in Individuals with Spinal Cord Injury.
Hwang, Eric J; Groves, Mary D; Sanchez, Jacqueline N; Hudson, Cassandra E; Jao, Rachel G; Kroll, Meghan E
2016-07-01
This study investigated the personal, environmental, and activity barriers to leisure-time physical activities (LTPAs) among individuals with spinal cord injury (SCI). A survey instrument was administered to 85 participants with SCI. Personal barriers to LTPAs included issues involving motivation, pain, scheduling, and financial resources. Environmental barriers marked the issues regarding availability and accessibility to specialized programs, activities, and professional services. Activity barriers included limitations in equipment, training, and personal skills required by the selected activities. Significant negative correlations were found between these barriers and the levels of physical activity and satisfaction with physical activity. While working with clients with SCI, occupational therapists should identify those LTPA barriers and possible solutions in order to establish individualized action plans for enhancing participation in LTPAs.
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Wojciak, Rafal W
2014-03-01
The aim of this study was to assess the influence of food-restricted diets (anorexia models) on iron management and activity of rats. 48 rats were divided into 6 groups: 1 control (K) and 5 testing groups (K/2, GI, GII, GIII, GIV). K was fed ad libitum. K/2 received half the portion of the diet of K. The other groups received 100% of the diet eaten by K, but with different models of food restriction: GI-1 day on, 1 day starvation; GII-2 days on, 2 days starvation; GIII-3 days on, 3 days starvation; and GIV-4 days on, 4 days starvation. As a result, all testing groups ate half of the diet consumed by the control group. The concentrations of iron in selected tissues, ferritin, and selected iron management parameters in blood were examined, as well as the animals' activities associated with food craving. The animal anorexia models used in this study had a significant influence on the blood concentrations of hemoglobin (p < 0.01), hematocrit (p < 0.05), RBC (p < 0.05), iron levels in liver (p < 0.05), kidney (p < 0.001), and heart (p < 0.05), the serum ferritin concentration (p < 0.001) and the rats activity (p < 0.001); whereas there was no influence on the other parameters. Generally, the statistically negative effects of starvation models on iron management parameters and activity of animals were observed. However, these effects were dependent on the model of anorexia more than on the quantity of food intake. The negative effect of food deprivation on iron deficiency and rat activities were observed in all groups; however, the strongest effect was noticed in those animals subject to chronic starvation. Acute deprivations caused the reduction of activity in the rats, however, chronic starvation caused an increase in the activity of the first phase of the experiment, followed by a decline in the subsequent phase. It is possible that stress and frustration as well as depression may be caused by insufficient food intake, and as a result, by iron deficiency in a diet similar to human anorexia. However, more animal/human comparison studies are necessary.
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Situation Selection and Modification for Emotion Regulation in Younger and Older Adults.
Livingstone, Kimberly M; Isaacowitz, Derek M
2015-11-01
This research investigated age differences in use and effectiveness of situation selection and situation modification for emotion regulation. Socioemotional selectivity theory suggests stronger emotional well-being goals in older age; emotion regulation may support this goal. Younger and older adults assigned to an emotion regulation or "just view" condition first freely chose to engage with negative, neutral, or positive material (situation selection), then chose to view or skip negative and positive material (situation modification), rating affect after each experience. In both tasks, older adults in both goal conditions demonstrated pro-hedonic emotion regulation, spending less time with negative material compared to younger adults. Younger adults in the regulate condition also engaged in pro-hedonic situation selection, but not modification. Whereas situation selection was related to affect, modification of negative material was not. This research supports more frequent pro-hedonic motivation in older age, as well as age differences in use of early-stage emotion regulation.
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Outhred, Tim; Das, Pritha; Felmingham, Kim L; Bryant, Richard A; Nathan, Pradeep J; Malhi, Gin S; Kemp, Andrew H
2014-07-01
Acute neural effects of antidepressant medication on emotion processing biases may provide the foundation on which clinical outcomes are based. Along with effects on positive and negative stimuli, acute effects on neutral stimuli may also relate to antidepressant efficacy, yet these effects are still to be investigated. The present study therefore examined the impact of a single dose of the selective serotonin reuptake inhibitor escitalopram (20 mg) on positive, negative and neutral stimuli using pharmaco-fMRI. Within a double-blind, randomized, placebo-controlled crossover design, healthy women completed 2 sessions of treatment administration and fMRI scanning separated by a 1-week washout period. We enrolled 36 women in our study. When participants were administered escitalopram relative to placebo, left amygdala activity was increased and right inferior frontal gyrus (IFG) activity was decreased during presentation of positive pictures (potentiation of positive emotion processing). In contrast, escitalopram was associated with decreased left amygdala and increased right IFG activity during presentation of negative pictures (attenuation of negative emotion processing). In addition, escitalopram decreased right IFG activity during the processing of neutral stimuli, akin to the effects on positive stimuli (decrease in negative appraisal). Although we used a women-only sample to reduce heterogeneity, our results may not generalize to men. Potential unblinding, which was related to the subjective occurrence of side effects, occurred in the study; however, manipulation check analyses demonstrated that results were not impacted. These novel findings demonstrate that a single dose of the commonly prescribed escitalopram facilitates a positive information processing bias. These findings provide an important lead for better understanding effects of antidepressant medication.
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Liu, Xiao Hong; Xu, Shuang Bing; Yuan, Jia; Li, Ben Hui; Zhang, Yan; Yuan, Qin; Li, Pin Dong; Li, Feng; Zhang, Wen Jie
2009-12-01
Interleukin-4 (IL-4)-induced Stat6 activities (phenotypes) vary among human cancer cells, of which the HT-29 cell line carries an active Stat6(high) phenotype, while Caco-2 carries a defective Stat6(null) phenotype, respectively. Cancer cells with Stat6(high) show resistance to apoptosis and exaggerated metastasis, suggesting the clinical significance of Stat6 phenotypes. We previously showed that Stat6(high) HT-29 cells exhibited low constitutive expression of Stat6-negative regulators SOCS-1 and SHP-1 because of gene hypermethylation. This study further examined the constitutive expression of other closely related SOCS family numbers including SOCS-3, SOCS-5, SOCS-7, and CISH using RT-PCR. Similar to SOCS-1 and SHP-1, Stat6(high) HT-29 cells expressed low constitutive mRNA of SOCS-3, SOCS-7, and CISH than Stat6(null) Caco-2 cells. Interestingly, DNA demethylation using 5-aza-2'-deoxycytidine in HT-29 cells up-regulated mRNA expression of the above genes, indicating a hypermethylation status, which was confirmed by methylation-specific sequencing in selected SOCS-3 gene. Furthermore, defective Stat6(null) Caco-2 exhibited impaired phosphorylation of Stat6 after IL-4 stimulation by flow cytometry, in keeping with the notion of an over-performed negative regulation. The findings that IL-4/Stat6 phenotypes show differential expression of multiple negative regulators suggest a model that a collective force of powerful negative regulators, directly and indirectly, acts on Stat6 activation, which may result in differential Stat6 phenotypes.
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Zahoor, Muhammad; Jan, Muhammad Rasul; Naz, Sumaira
2016-11-01
Glucose-6-phosphatase is a key enzyme of glucose metabolic pathways. Deficiency of this enzyme leads to glycogen storage disease. This enzyme also plays a negative role in diabetes mellitus disorder in which the catalytic activity of this enzyme increases. Thus there is need for activators to enhance the activity of glucose-6-phosphatase in glycogen storage disease of type 1b while in diabetes mellitus repressors are needed to reduce its activity. Crude extracts of apricot, fig, mulberry and apple fruits were investigated for their repressive/enhancive effects on glucose-6-phosphatase in vivo. Albino mice were used as experimental animal. All the selected extracts showed depressive effects on glucose-6-phosphatase, which shows that all these extracts can be used as antidiabetic supplement of food. The inhibitory pattern was competitive one, which was evident from the effect of increasing dose from 1g/Kg body weight to 3g/Kg body weight for all the selected fruit extracts. However fig and apple fruit extracts showed high repressive effects for high doses as compared to apricot and mulberry fruit extracts. None of these selected fruit extracts showed enhancive effect on glucose-6-phosphatase activity. All these fruits or their extracts can be used as antidiabetic dietary supplement for diabetes mellitus.
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Tan, Xiangping; Xie, Baoni; Wang, Junxing; He, Wenxiang; Wang, Xudong; Wei, Gehong
2014-01-01
Here the spatial distribution of soil enzymatic properties in agricultural land was evaluated on a county-wide (567 km(2)) scale in Changwu, Shaanxi Province, China. The spatial variations in activities of five hydrolytic enzymes were examined using geostatistical methods. The relationships between soil enzyme activities and other soil properties were evaluated using both an integrated total enzyme activity index (TEI) and the geometric mean of enzyme activities (GME). At the county scale, soil invertase, phosphatase, and catalase activities were moderately spatially correlated, whereas urease and dehydrogenase activities were weakly spatially correlated. Correlation analysis showed that both TEI and GME were better correlated with selected soil physicochemical properties than single enzyme activities. Multivariate regression analysis showed that soil OM content had the strongest positive effect while soil pH had a negative effect on the two enzyme activity indices. In addition, total phosphorous content had a positive effect on TEI and GME in orchard soils, whereas alkali-hydrolyzable nitrogen and available potassium contents, respectively, had negative and positive effects on these two enzyme indices in cropland soils. The results indicate that land use changes strongly affect soil enzyme activities in agricultural land, where TEI provides a sensitive biological indicator for soil quality.
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Dong, Guangheng; Potenza, Marc N
2016-02-01
Individuals with Internet gaming disorder (IGD) continue gaming despite adverse consequences. However, the precise mechanism underlying this behavior remains unknown. In this study, data from 20 IGD subjects and 16 otherwise comparable healthy control subjects (HCs) were recorded and compared when they were undergoing risk-taking and risky decision-making during functional magnetic resonance imaging (fMRI). During risk-taking and as compared to HCs, IGD subjects selected more risk-disadvantageous trials and demonstrated less activation of the anterior cingulate, posterior cingulate and middle temporal gyrus. During risky decision-making and as compared to HCs, IGD subjects showed shorter response times and less activations of the inferior frontal and superior temporal gyri. Taken together, data suggest that IGD subjects show impaired executive control in selecting risk-disadvantageous choices, and they make risky decisions more hastily and with less recruitment of regions implicated in impulse control. These results suggest a possible neurobiological underpinning for why IGD subjects may exhibit poor control over their game-seeking behaviors even when encountering negative consequences and provide possible therapeutic targets for interventions in this population. Copyright © 2015 Elsevier Ltd. All rights reserved.
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Dolan, Niamh; Gavin, Declan P; Eshwika, Ahmed; Kavanagh, Kevin; McGinley, John; Stephens, John C
2016-01-15
We report the synthesis, antibacterial evaluation of a series of thiourea-containing compounds. 1-(3,5-Bis(trifluoromethyl)phenyl)-3-((S)-(6-methoxyquinolin-4-yl)-((1S,2S,4S,5R)-5-vinylquinuclidin-2-yl)methyl)thiourea 5, was the most active against a range of Gram-positive and Gram-negative bacteria, and exhibited bacteriostatic activity against methicillin resistant Staphylococcus aureus (MRSA) comparable to that of the well-known antibacterial agent vancomycin. Quinoline thiourea 5 was subjected to a detailed structure-activity relationship study, with 5 and its derivatives evaluated for their bacteriostatic activity against both Gram-negative and Gram-positive bacteria. A number of structural features important for the overall activity of quinoline thiourea 5 have been identified. A selection of compounds, including 5, was also evaluated for their in vivo toxicity using the larvae of the Greater wax moth, Galleria mellonella. Compound 5, and a number of derivatives, were found to be non-toxic to the larvae of Galleria mellonella. A new class of antibiotic can result from the further development of this family of compounds. Copyright © 2015 Elsevier Ltd. All rights reserved.
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Weir, Jamie C
2018-05-10
Phenotypic polymorphism in cryptic species is widespread. This may evolve in response to search image use by predators exerting negative frequency-dependent selection on intraspecific colour morphs, 'apostatic selection'. Evidence exists to indicate search image formation by predators and apostatic selection operating on wild prey populations, though not to demonstrate search image use directly resulting in apostatic selection. The present study attempted to address this deficiency, using British Lepidoptera active in winter as a model system. It has been proposed that the typically polymorphic wing colouration of these species represents an anti-search image adaptation against birds. To test (a) for search image-driven apostatic selection, dimorphic populations of artificial moth-like models were established in woodland at varying relative morph frequencies and exposed to predation by natural populations of birds. In addition, to test (b) whether abundance and degree of polymorphism are correlated across British winter-active moths, as predicted where search image use drives apostatic selection, a series of phylogenetic comparative analyses were conducted. There was a positive relationship between artificial morph frequency and probability of predation, consistent with birds utilizing search images and exerting apostatic selection. Abundance and degree of polymorphism were found to be positively correlated across British Lepidoptera active in winter, though not across all taxonomic groups analysed. This evidence is consistent with polymorphism in this group having evolved in response to search image-driven apostatic selection and supports the viability of this mechanism as a means by which phenotypic and genetic variation may be maintained in natural populations. © 2018 European Society For Evolutionary Biology. Journal of Evolutionary Biology © 2018 European Society For Evolutionary Biology.
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Booiman, Thijs; Wit, Ferdinand W.; Girigorie, Arginell F.; Maurer, Irma; De Francesco, Davide; Sabin, Caroline A.; Harskamp, Agnes M.; Prins, Maria; Franceschi, Claudio; Deeks, Steven G.; Winston, Alan; Reiss, Peter
2017-01-01
HIV-1-positive individuals on successful antiretroviral therapy (ART) are reported to have higher rates of age-associated non-communicable comorbidities (AANCCs). HIV-associated immune dysfunction has been suggested to contribute to increased AANCC risk. Here we performed a cross-sectional immune phenotype analysis of T cells in ART-treated HIV-1-positive individuals with undetectable vireamia (HIV-positives) and HIV-1-negative individuals (HIV-negatives) over 45 years of age. In addition, two control groups were studied: HIV negative adults selected based on lifestyle and demographic factors (Co-morBidity in Relation to AIDS, or COBRA) and unselected age-matched donors from a blood bank. Despite long-term ART (median of 12.2 years), HIV-infected adults had lower CD4+ T-cell counts and higher CD8+ T-cell counts compared to well-matched HIV-negative COBRA participants. The proportion of CD38+HLA-DR+ and PD-1+ CD4+ T-cells was higher in HIV-positive cohort compared to the two HIV-negative cohorts. The proportion CD57+ and CD27−CD28− cells of both CD4+ and CD8+ T-cells in HIV-positives was higher compared to unselected adults (blood bank) as reported before but this difference was not apparent in comparison with well-matched HIV-negative COBRA participants. Multiple regression analysis showed that the presence of an increased proportion of terminally differentiated T cells was strongly associated with CMV infection. Compared to appropriately selected HIV-negative controls, HIV-positive individuals on ART with long-term suppressed viraemia exhibited incomplete immune recovery and increased immune activation/exhaustion. CMV infection rather than treated HIV infection appears to have more consistent effects on measures of terminal differentiation of T cells. PMID:28806406
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Kreplin, Ute; Fairclough, Stephen H
2013-01-01
The contemplation of visual art requires attention to be directed to external stimulus properties and internally generated thoughts. It has been proposed that the medial rostral prefrontal cortex (rPFC; BA10) plays a role in the maintenance of attention on external stimuli whereas the lateral area of the rPFC is associated with the preservation of attention on internal cognitions. An alternative hypothesis associates activation of medial rPFC with internal cognitions related to the self during emotion regulation. The aim of the current study was to differentiate activation within rPFC using functional near infrared spectroscopy (fNIRS) during the viewing of visual art selected to induce positive and negative valence, which were viewed under two conditions: (1) emotional introspection and (2) external object identification. Thirty participants (15 female) were recruited. Sixteen pre-rated images that represented either positive or negative valence were selected from an existing database of visual art. In one condition, participants were directed to engage in emotional introspection during picture viewing. The second condition involved a spot-the-difference task where participants compared two almost identical images, a viewing strategy that directed attention to external properties of the stimuli. The analysis revealed a significant increase of oxygenated blood in the medial rPFC during viewing of positive images compared to negative images. This finding suggests that the rPFC is involved during positive evaluations of visual art that may be related to judgment of pleasantness or attraction. The fNIRS data revealed no significant main effect between the two viewing conditions, which seemed to indicate that the emotional impact of the stimuli remained unaffected by the two viewing conditions.
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Van Strien, Jan W; Franken, Ingmar H A; Huijding, Jorg
2009-03-04
The early posterior negativity (EPN) reflects early selective visual processing of emotionally significant information. This study explored the association between fear of spiders and the EPN for spider pictures. Fifty women completed a Spider Phobia Questionnaire and watched the random rapid serial presentation of 600 neutral, 600 negatively valenced emotional, and 600 spider pictures (three pictures per second). The EPN was scored as the mean activity in the 225-300-ms time window at lateral occipital electrodes. Participants with higher scores on the phobia questionnaire showed larger (i.e. more negative) EPN amplitudes in response to spider pictures. The results suggest that the attentional capture of spider-related stimuli is an automatic response, which is modulated by the extent of spider fear.
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Rajasekaran, Ganesan; Kamalakannan, Radhakrishnan; Shin, Song Yub
2015-10-01
Temporin-1Tl (TL) is a 13-residue frog antimicrobial peptide (AMP) exhibiting potent antimicrobial and anti-inflammatory activity. To develop novel AMP with improved anti-inflammatory activity and antimicrobial selectivity, we designed and synthesized a series of TL analogs by substituting Trp, Arg and Lys at selected positions. Except for Escherichia coli and Staphylococcus epidermidis, all TL analogs exhibited retained or increased antimicrobial activity against seven bacterial strains including three methicillin-resistant Staphylococcus aureus strains compared with TL. TL-1 and TL-4 showed a little increase in antimicrobial selectivity, while TL-2 and TL-3 displayed slightly decreased antimicrobial selectivity because of their about twofold increased hemolytic activity. All TL analogs demonstrated greatly increased anti-inflammatory activity, evident by their higher inhibition of the production tumor necrosis factor-α (TNF-α) and nitric oxide and the mRNA expression of inducible nitric oxide synthase and TNF-α in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophage cells, compared with TL. Taken together, the peptide anti-inflammatory activity is as follows: TL-2 ≈ TL-3 ≈ TL-4 > TL-1 > TL. In addition, LPS binding ability of the peptides corresponded with their anti-inflammatory activity. These results apparently suggest that the anti-inflammatory activity of TL analogs is associated with the direct binding ability between these peptides and LPS. Collectively, our designed TL analogs possess improved anti-inflammatory activity and retain antimicrobial activity without a significant increase in hemolysis. Therefore, it is evident that our TL analogs constitute promising candidates for the development of peptide therapeutics for gram-negative bacterial infection. Copyright © 2015 European Peptide Society and John Wiley & Sons, Ltd.
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Carrera, D; de la Flor, M; Galera, J; Amillano, K; Gomez, M; Izquierdo, V; Aguilar, E; López, S; Martínez, M; Martínez, S; Serra, J M; Pérez, M; Martin, L
2016-01-01
The aim of our study was to evaluate sentinel lymph node biopsy as a diagnostic test for assessing the presence of residual metastatic axillary lymph nodes after neoadjuvant chemotherapy, replacing the need for a lymphadenectomy in negative selective lymph node biopsy patients. A multicentre, diagnostic validation study was conducted in the province of Tarragona, on women with T1-T3, N1-N2 breast cancer, who presented with a complete axillary response after neoadjuvant chemotherapy. Study procedures consisted of performing an selective lymph node biopsy followed by lymphadenectomy. A total of 53 women were included in the study. Surgical detection rate was 90.5% (no sentinel node found in 5 patients). Histopathological analysis of the lymphadenectomy showed complete disease regression of axillary nodes in 35.4% (17/48) of the patients, and residual axillary node involvement in 64.6% (31/48) of them. In lymphadenectomy positive patients, 28 had a positive selective lymph node biopsy (true positive), while 3 had a negative selective lymph node biopsy (false negative). Of the 28 true selective lymph node biopsy positives, the sentinel node was the only positive node in 10 cases. All lymphadenectomy negative cases were selective lymph node biopsy negative. These data yield a sensitivity of 93.5%, a false negative rate of 9.7%, and a global test efficiency of 93.7%. Selective lymph node biopsy after chemotherapy in patients with a complete axillary response provides valid and reliable information regarding axillary status after neoadjuvant treatment, and might prevent lymphadenectomy in cases with negative selective lymph node biopsy. Copyright © 2016 Elsevier España, S.L.U. and SEMNIM. All rights reserved.
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The Route to an Integrative Associative Memory Is Influenced by Emotion
Murray, Brendan D.; Kensinger, Elizabeth A.
2014-01-01
Though the hippocampus typically has been implicated in processes related to associative binding, special types of associations – such as those created by integrative mental imagery – may be supported by processes implemented in other medial temporal-lobe or sensory processing regions. Here, we investigated what neural mechanisms underlie the formation and subsequent retrieval of integrated mental images, and whether those mechanisms differ based on the emotionality of the integration (i.e., whether it contains an emotional item or not). Participants viewed pairs of words while undergoing a functional MRI scan. They were instructed to imagine the two items separately from one another (“non-integrative” study) or as a single, integrated mental image (“integrative” study). They provided ratings of how successful they were at generating vivid images that fit the instructions. They were then given a surprise associative recognition test, also while undergoing an fMRI scan. The cuneus showed parametric correspondence to increasing imagery success selectively during encoding and retrieval of emotional integrations, while the parahippocampal gyri and prefrontal cortices showed parametric correspondence during the encoding and retrieval of non-emotional integrations. Connectivity analysis revealed that selectively during negative integration, left amygdala activity was negatively correlated with frontal and hippocampal activity. These data indicate that individuals utilize two different neural routes for forming and retrieving integrations depending on their emotional content, and they suggest a potentially disruptive role for the amygdala on frontal and medial-temporal regions during negative integration. PMID:24427267
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Froeliger, Brett E.; Garland, Eric L.; Modlin, Leslie A.; McClernon, F. Joseph
2012-01-01
Mindfulness meditation involves attending to emotions without cognitive fixation of emotional experience. Over time, this practice is held to promote alterations in trait affectivity and attentional control with resultant effects on well-being and cognition. However, relatively little is known regarding the neural substrates of meditation effects on emotion and cognition. The present study investigated the neurocognitive correlates of emotion interference on cognition in Yoga practitioners and a matched control group (CG) underwent fMRI while performing an event-related affective Stroop task. The task includes image viewing trials and Stroop trials bracketed by neutral or negative emotional distractors. During image viewing trials, Yoga practitioners exhibited less reactivity in right dorsolateral prefrontal cortex (dlPFC) to negative as compared to neutral images; whereas the CG had the opposite pattern. A main effect of valence (negative > neutral) was observed in limbic regions (e.g., amygdala), of which the magnitude was inversely related to dlPFC activation. Exploratory analyses revealed that the magnitude of amygdala activation predicted decreased self-reported positive affect in the CG, but not among Yoga practitioners. During Stroop trials, Yoga practitioners had greater activation in ventrolateral prefrontal cortex (vlPFC) during Stroop trials when negative, compared to neutral, emotional distractor were presented; the CG exhibited the opposite pattern. Taken together, these data suggest that though Yoga practitioners exhibit limbic reactivity to negative emotional stimuli, such reactivity does not have downstream effects on later mood state. This uncoupling of viewing negative emotional images and affect among Yoga practitioners may be occasioned by their selective implementation of frontal executive-dependent strategies to reduce emotional interference during competing cognitive demands and not during emotional processing per se. PMID:22855674
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A brain-liver circuit regulates glucose homeostasis.
Pocai, Alessandro; Obici, Silvana; Schwartz, Gary J; Rossetti, Luciano
2005-01-01
Increased glucose production (GP) is the major determinant of fasting hyperglycemia in diabetes mellitus. Previous studies suggested that lipid metabolism within specific hypothalamic nuclei is a biochemical sensor for nutrient availability that exerts negative feedback on GP. Here we show that central inhibition of fat oxidation leads to selective activation of brainstem neurons within the nucleus of the solitary tract and the dorsal motor nucleus of the vagus and markedly decreases liver gluconeogenesis, expression of gluconeogenic enzymes, and GP. These effects require central activation of ATP-dependent potassium channels (K(ATP)) and descending fibers within the hepatic branch of the vagus nerve. Thus, hypothalamic lipid sensing potently modulates glucose metabolism via neural circuitry that requires the activation of K(ATP) and selective brainstem neurons and intact vagal input to the liver. This crosstalk between brain and liver couples central nutrient sensing to peripheral nutrient production and its disruption may lead to hyperglycemia.
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Ding, Shujing; Dudley, Ed; Chen, Lijuan; Plummer, Sue; Tang, Jiandong; Newton, Russell P; Brenton, A Gareth
2006-01-01
Ginkgo biloba is one of the most popular herbal nutritional supplements, with terpene lactones and flavonoids being the two major active components. An on-line purification high-performance liquid chromatography/mass spectrometry (HPLC/MS) method was successfully developed for the quantitative determination of flavonoids and terpene lactones excreted in human urine after ingesting the herbal supplement. Satisfactory separation was obtained using a C18 capillary column made in-house with sample clean-up and pre-concentration achieved using a C18 pre-column with column switching. High selectivity and limits of detection of 1-18 ng/mL were achieved using a selected ion monitoring (SIM) scan in negative ion mode; the on-line solid-phase extraction (SPE) recovery of the active components in Ginkgo biloba determined in this study was greater than 75%. Copyright 2006 John Wiley & Sons, Ltd.
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Chen, Luxi; Long, Chao; Youn, Jonghae; Lee, Jiyong
2018-06-11
We describe a "phenotypic cell-binding screen" by which therapeutic candidate targeting cancer cells of a particular phenotype can be isolated without knowledge of drug targets. Chemical library beads are incubated with cancer cells of the phenotype of interest in the presence of cancer cells lacking the phenotype of interest, and then the beads bound to only cancer cells of the phenotype of interest are selected as hits. We have applied this screening strategy in discovering a novel compound (LC129-8) targeting triple-negative breast cancer (TNBC). LC129-8 displayed highly specific binding to TNBC in cancer cell lines and patient-derived tumor tissues. LC129-8 exerted anti-TNBC activity by inducing apoptosis, inhibiting proliferation, reversing epithelial-mesenchymal transition, downregulating cancer stem cell activity and blocking in vivo tumor growth.
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ERIC Educational Resources Information Center
Frings, Christian; Feix, Silke; Rothig, Ulrike; Bruser, Charlotte; Junge, Miriam
2007-01-01
Reactions to stimuli that were shortly before presented as distractors are usually slowed down; this phenomenon is known as negative priming. Negative priming is an accepted index for tapping into selective control mechanisms. Although this effect is well established for adults, it has been claimed that children do not show negative priming.…
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Patzwald, Christiane; Curley, Charlotte A; Hauf, Petra; Elsner, Birgit
2018-05-01
Infants use others' emotional signals to regulate their own object-directed behavior and action reproduction, and they typically produce more actions after having observed positive as compared to negative emotional cues. This study explored infants' understanding of the referential specificity of others' emotional cues when being confronted with two actions that are accompanied by different emotional displays. Selective action reproduction was measured after 18-month-olds (N = 42) had observed two actions directed at the same object, one of which was modeled with a positive emotional expression and the other with a negative emotional expression. Across four trials with different objects, infants' first actions matched the positively-emoted actions more often than the negatively-emoted actions. In comparison with baseline-level, infants' initial performance changed only for the positively-emoted actions, in that it increased during test. Latencies to first object-touch during test did not differ when infants reproduced the positively- or negatively-emoted actions, respectively, indicating that infants related the cues to the respective actions rather than to the object. During demonstration, infants looked relatively longer at the object than at the model's face, with no difference in positive or negative displays. Infants during their second year of life thus capture the action-related referential specificity of others' emotional cues and seem to follow positive signals more readily when actively selecting which of two actions to reproduce preferentially. Copyright © 2018 Elsevier Inc. All rights reserved.
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Singh, Pratichi; Dass, J Febin Prabhu
2018-05-07
IFNL3 gene plays a crucial role in immune defense against viruses. It induces the interferon stimulated genes (ISGs) with antiviral properties by activating the JAK-STAT pathway. In this study, we investigated the evolutionary force involved in shaping the IFNL3 gene to perform its downstream function as a regulatory gene in HCV clearance. We have selected 25 IFNL3 coding sequences with human gene as a reference sequence and constructed a phylogeny. Furthermore, rate of variation, substitution saturation test, phylogenetic informativeness and differential selection were also analysed. The codon evolution result suggests that nearly neutral mutation is the key pattern in shaping the IFNL3 evolution. The results were validated by subjecting the human IFNL3 protein variants to that of the native through a molecular dynamics simulation study. The molecular dynamics simulation clearly depicts the negative impact on the reported variants in human IFNL3 protein. However, these detrimental mutations (R157Q and R157W) were shown to be negatively selected in the evolutionary study of the mammals. Hence, the variation revealed a mild impact on the IFNL3 function and may be removed from the population through negative selection due to its high functional constraints. In a nutshell, our study may contribute the overall evidence in phylotyping and structural transformation that takes place in the non-synonymous substitutions of IFNL3 protein. Substantially, our obtained theoretical knowledge will lay the path to extend the experimental validation in HCV clearance. Copyright © 2018 Elsevier Ltd. All rights reserved.
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JIP1-Mediated JNK Activation Negatively Regulates Synaptic Plasticity and Spatial Memory.
Morel, Caroline; Sherrin, Tessi; Kennedy, Norman J; Forest, Kelly H; Avcioglu Barutcu, Seda; Robles, Michael; Carpenter-Hyland, Ezekiel; Alfulaij, Naghum; Standen, Claire L; Nichols, Robert A; Benveniste, Morris; Davis, Roger J; Todorovic, Cedomir
2018-04-11
The c-Jun N-terminal kinase (JNK) signal transduction pathway is implicated in learning and memory. Here, we examined the role of JNK activation mediated by the JNK-interacting protein 1 (JIP1) scaffold protein. We compared male wild-type mice with a mouse model harboring a point mutation in the Jip1 gene that selectively blocks JIP1-mediated JNK activation. These male mutant mice exhibited increased NMDAR currents, increased NMDAR-mediated gene expression, and a lower threshold for induction of hippocampal long-term potentiation. The JIP1 mutant mice also displayed improved hippocampus-dependent spatial memory and enhanced associative fear conditioning. These results were confirmed using a second JIP1 mutant mouse model that suppresses JNK activity. Together, these observations establish that JIP1-mediated JNK activation contributes to the regulation of hippocampus-dependent, NMDAR-mediated synaptic plasticity and learning. SIGNIFICANCE STATEMENT The results of this study demonstrate that c-Jun N-terminal kinase (JNK) activation induced by the JNK-interacting protein 1 (JIP1) scaffold protein negatively regulates the threshold for induction of long-term synaptic plasticity through the NMDA-type glutamate receptor. This change in plasticity threshold influences learning. Indeed, mice with defects in JIP1-mediated JNK activation display enhanced memory in hippocampus-dependent tasks, such as contextual fear conditioning and Morris water maze, indicating that JIP1-JNK constrains spatial memory. This study identifies JIP1-mediated JNK activation as a novel molecular pathway that negatively regulates NMDAR-dependent synaptic plasticity and memory. Copyright © 2018 the authors 0270-6474/18/383708-21$15.00/0.
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Shah, Neel H; Wang, Qi; Yan, Qingrong; Karandur, Deepti; Kadlecek, Theresa A; Fallahee, Ian R; Russ, William P; Ranganathan, Rama; Weiss, Arthur; Kuriyan, John
2016-01-01
The sequence of events that initiates T cell signaling is dictated by the specificities and order of activation of the tyrosine kinases that signal downstream of the T cell receptor. Using a platform that combines exhaustive point-mutagenesis of peptide substrates, bacterial surface-display, cell sorting, and deep sequencing, we have defined the specificities of the first two kinases in this pathway, Lck and ZAP-70, for the T cell receptor ζ chain and the scaffold proteins LAT and SLP-76. We find that ZAP-70 selects its substrates by utilizing an electrostatic mechanism that excludes substrates with positively-charged residues and favors LAT and SLP-76 phosphosites that are surrounded by negatively-charged residues. This mechanism prevents ZAP-70 from phosphorylating its own activation loop, thereby enforcing its strict dependence on Lck for activation. The sequence features in ZAP-70, LAT, and SLP-76 that underlie electrostatic selectivity likely contribute to the specific response of T cells to foreign antigens. DOI: http://dx.doi.org/10.7554/eLife.20105.001 PMID:27700984
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Concept Of Revitalization Of Selected Military Facilities Of Dragoons Barracks In Olsztyn
NASA Astrophysics Data System (ADS)
Zagroba, Marek
2015-12-01
Revitalization is a complex program to restore the functioning of the neglected urban areas in terms of spatial, economic and social. Revitalization activities on post-military facilities are stopping negative phenomena, such as degradation of space, social pathology or lack of proper functioning of the area, adapted to modern needs. The object of the work is to present some aspects with the revitalization of former military facilities in the area of the Artyleryjska Street in Olsztyn. The presented design concept aims to revitalize a neglected area of the barracks, which will enable the activation site and include it in the city urban space. The method adopted in this work is the architectural project of adapting selected post-military facilities for new functions, affecting the economic development and social integration of people.
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Willingness to pay for non angler recreation at the lower Snake River reservoirs
McKean, J.R.; Johnson, D.; Taylor, R.G.; Johnson, Richard L.
2005-01-01
This study applied the travel cost method to estimate demand for non angler recreation at the impounded Snake River in eastern Washington. Net value per person per recreation trip is estimated for the full non angler sample and separately for camping, boating, water-skiing, and swimming/picnicking. Certain recreation activities would be reduced or eliminated and new activities would be added if the dams were breached to protect endangered salmon and steelhead. The effect of breaching on non angling benefits was found by subtracting our benefits estimate from the projected non angling benefits with breaching. Major issues in demand model specification and definition of the price variables are discussed. The estimation method selected was truncated negative binomial regression with adjustment for self selection bias.
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NASA Astrophysics Data System (ADS)
Philip, Elizabath; Zeki Güngördü, M.; Pal, Sharmistha; Kung, Patrick; Kim, Seongsin Margaret
2017-09-01
In this article, recent progress and development of terahertz chiral metamaterials including stereometamaterials are thoroughly reviewed. This review mainly focuses on the fundamental principles of design and arrangement of meta-atoms in metamaterials exhibiting chirality with various asymmetry and symmetry and 2D and 3D configuration. Related optical and propagation properties in chiral metamaterials, such as optical activity, circular dichroism, and negative refraction for each different chiral metamaterials, are compared and investigated. Finally, comparison between chiral metamaterials with stereometamaterials in terms of the polarization selective operation along with the similarity and the distinction is addressed as well.
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Goodwin, Laura; Fairclough, Stephen H; Poole, Helen M
2013-06-01
Kolk et al.'s model of symptom perception underlines the effects of trait negative affect, selective attention and external stressors. The current study tested this model in 263 males and 498 females from an occupational sample. Trait negative affect was associated with symptom reporting in females only, and selective attention and psychological job demands were associated with symptom reporting in both genders. Health anxiety was associated with symptom reporting in males only. Future studies might consider the inclusion of selective attention, which was more strongly associated with symptom reporting than negative affect. Psychological job demands appear to influence symptom reporting in both males and females.
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Bouter, Hens; Schippers, Emile F; Luelmo, Saskia A C; Versteegh, Michael I M; Ros, Peter; Guiot, Henri F L; Frölich, Marijke; van Dissel, Jaap T
2002-01-01
Cardiopulmonary bypass predisposes the splanchnic region to inadequate perfusion and increases in gut permeability. Related to these changes, circulating endotoxin has been shown to rise during cardiac surgery, and may contribute to cytokine activation, high oxygen consumption, and fever ("postperfusion syndrome"). To a large extent, free endotoxin in the gut is a product of the proliferation of aerobic gram-negative bacteria and may be reduced by nonabsorbable antibiotics. To evaluate the effect of preoperative selective gut decontamination (SGD) on the incidence of endotoxemia and cytokine activation in patients undergoing open heart surgery. Prospective, randomized, placebo-controlled double-blind trial. Tertiary-care university teaching hospital. Preoperative administration for 5 to 7 days of oral nonabsorbable antibiotics (polymyxin B and neomycin) vs. placebo. The efficacy of SGD was assessed by culture of rectal swabs. Forty-four patients (median age 65 yrs, 29 males) were included in a pilot study to establish the sampling points of perioperative measurements. Seventy-eight consecutive patients (median age 65 yrs, 55 males) were enrolled for the prospective study; of these, 51 were randomly allocated to take SGD (n = 24) or placebo (n = 27); 27 were included in a control group (no medication). SGD but not placebo effectively reduced the number of rectal swabs that grew aerobic gram-negative bacteria (27% vs. 93%, respectively; p < .001). SGD did not affect the occurrence of perioperative endotoxemia, nor did it reduce the tumor necrosis factor-alpha, interleukin-10, or interleukin-6 concentrations (p > .20), as determined before surgery, upon aorta declamping, 30 mins into reperfusion, or 2 hrs after surgery. Also, SGD did not alter the incidence of postoperative fever or clinical outcome measures such as duration of artificial ventilation and intensive care unit and hospital stay. SGD effectively reduces the aerobic gram-negative bowel flora in cardiac surgery patients but fails to affect the incidence of perioperative endotoxemia and cytokine activation during cardiopulmonary bypass and the occurrence of a postperfusion syndrome.
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Son, Kiho; Mukherjee, Manali; McIntyre, Brendan A S; Eguez, Jose C; Radford, Katherine; LaVigne, Nicola; Ethier, Caroline; Davoine, Francis; Janssen, Luke; Lacy, Paige; Nair, Parameswaran
2017-10-01
Clinically relevant and reliable reports derived from in vitro research are dependent on the choice of cell isolation protocols adopted between different laboratories. Peripheral blood eosinophils are conventionally isolated using density-gradient centrifugation followed by immunomagnetic selection (positive/negative) while neutrophils follow a more simplified dextran-sedimentation methodology. With the increasing sophistication of molecular techniques, methods are now available that promise protocols with reduced user-manipulations, improved efficiency, and better yield without compromising the purity of enriched cell populations. These recent techniques utilize immunomagnetic particles with multiple specificities against differential cell surface markers to negatively select non-target cells from whole blood, greatly reducing the cost/time taken to isolate granulocytes. Herein, we compare the yield efficiencies, purity and baseline activation states of eosinophils/neutrophils isolated using one of these newer protocols that use immunomagnetic beads (MACSxpress isolation) vs. the standard isolation procedures. The study shows that the MACSxpress method consistently allowed higher yields per mL of peripheral blood compared to conventional methods (P<0.001, n=8, Wilcoxon paired test), with high isolation purities for both eosinophils (95.0±1.7%) and neutrophils (94.2±10.1%) assessed by two methods: Wright's staining and flow cytometry. In addition, enumeration of CD63 + (marker for eosinophil activation) and CD66b + (marker for neutrophil activation) cells within freshly isolated granulocytes, respectively, confirmed that conventional protocols using density-gradient centrifugation caused cellular activation of the granulocytes at baseline compared to the MACSxpress method. In conclusion, MACSxpress isolation kits were found to be superior to conventional techniques for consistent purifications of eosinophils and neutrophils that were suitable for activation assays involving degranulation markers. Copyright © 2017 Elsevier B.V. All rights reserved.
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Phosphonopeptides as Antibacterial Agents: Alaphosphin and Related Phosphonopeptides
Allen, John G.; Atherton, Frank R.; Hall, Michael J.; Hassall, Cedric H.; Holmes, Simon W.; Lambert, Robert W.; Nisbet, Louis J.; Ringrose, Peter S.
1979-01-01
Alaphosphin, l-alanyl-l-1-aminoethylphosphonic acid, was selected from a range of phosphonopeptides for evaluation in humans on the basis of its antibacterial activity, pharmacokinetics, and stability to intestinal and kidney peptidases. In vitro, the antibacterial action was antagonized by small peptides, resulting in low activity on peptone media. On an antagonist-free medium alaphosphin was bactericidal and rapidly lysed most susceptible gram-negative bacteria, but it was largely bacteriostatic and essentially nonlytic against gram-positive organisms. Its spectrum included most strains normally isolated from urinary tract infections, but potency was greatly reduced by very high inoculum levels and by alkaline pH. Although strains of Proteus and Pseudomonas were less susceptible to alaphosphin than were other common gram-negative bacteria, like other species they formed spheroplasts when exposed under appropriate conditions. Alaphosphin was equally effective against penicillin-susceptible and -resistant strains and showed no cross-resistance with known antibiotics. Good synergy and increased bactericidal activity were demonstrated with combinations of alaphosphin and d-cycloserine or β-lactam antibiotics. Images PMID:43113
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Angulo-Preckler, Carlos; Cid, Cristina; Oliva, Francesc; Avila, Conxita
2015-04-01
Competition for space is a remarkable ecological force, comparable to predation, producing a strong selective pressure on benthic invertebrates. Some invertebrates, thus, possess antimicrobial compounds to reduce surface bacterial growth. Antimicrobial inhibition is the first step in avoiding being overgrown by other organisms, which may have a negative impact in feeding, respiration, reproduction … The in situ inhibition of bacterial biofilm was used here as an indicator of antifouling activity by testing hydrophilic extracts of twelve Antarctic invertebrates. Using two different approaches (genetics and confocal techniques) different levels of activity were found in the tested organisms. In fact, differences within body parts of the studied organisms were determined, in agreement with the Optimal Defense Theory. Eight out of 15 extracts tested had negative effects on fouling after 28 days submerged in Antarctic waters. Thus, although chemical defenses may be quite species-specific in their ecological roles, these results suggest that different chemical strategies exist to deal with space competition. Copyright © 2015 Elsevier Ltd. All rights reserved.
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A research on the genotoxicity of stevia in human lymphocytes.
Uçar, Aslı; Yılmaz, Serkan; Yılmaz, Şemsigül; Kılıç, Mustafa Sefa
2018-04-01
Stevia extracts are obtained from Stevia rebaudiana commonly used as natural sweeteners. It is ∼250-300 times sweeter than sucrose. Common use of stevia prompted us to investigate its genotoxicity in human peripheral blood lymphocytes. Stevia (active ingredient steviol glycoside) was dissolved in pure water. Dose selection was done using ADI (acceptable daily intake) value. Negative control (pure water), 1, 2, 4, 8 and 16 μg/ml concentrations which were equivalent to ADI/4, ADI/2, ADI, ADI × 2 and ADI × 4 of Stevia were added to whole-blood culture. Two repetitive experiments were conducted. Our results showed that there was no significant difference in the induction of chromosomal aberrations and micronuclei between the groups treated with the concentrations of Stevia and the negative control at 24 and 48 h treatment periods. The data showed that stevia (active ingredient steviol glycosides) has no genotoxic activity in both test systems. Our results clearly supports previous findings.
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Falcao, Claudio Borges; Pérez-Peinado, Clara; de la Torre, Beatriz G; Mayol, Xavier; Zamora-Carreras, Héctor; Jiménez, M Ángeles; Rádis-Baptista, Gandhi; Andreu, David
2015-11-12
In silico dissection of crotalicidin (Ctn), a cathelicidin from a South American pit viper, yielded fragments Ctn[1-14] and Ctn[15-34], which were tested to ascertain to what extent they reproduced the structure and activity of the parent peptide. NMR data showing Ctn to be α-helical at the N-terminus and unstructured at the C-terminus were matched by similar data from the fragments. The peptides were tested against Gram-positive and -negative bacteria and for toxicity against both tumor and healthy cells. Despite its amphipathic α-helical structure, Ctn[1-14] was totally inert toward bacteria or eukaryotic cells. In contrast, unstructured Ctn[15-34] replicated the activity of parent Ctn against Gram-negative bacteria and tumor cells while being significantly less toxic toward eukaryotic cells. This selectivity for bacteria and tumor cells, plus a stability to serum well above that of Ctn, portrays Ctn[15-34] as an appealing candidate for further development as an anti-infective or antitumor lead.
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Einbond, Linda Saxe; Wu, Hsan-Au; Kashiwazaki, Ryota; He, Kan; Roller, Marc; Su, Tao; Wang, Xiaomei; Goldsberry, Sarah
2012-10-01
Studies indicate that extracts and purified components, including carnosic acid, from the herb rosemary display significant growth inhibitory activity on a variety of cancers. This paper examines the ability of rosemary/carnosic acid to inhibit the growth of human breast cancer cells and to synergize with curcumin. To do this, we treated human breast cancer cells with rosemary/carnosic acid and assessed effects on cell proliferation, cell cycle distribution, gene expression patterns, activity of the purified Na/K ATPase and combinations with curcumin. Rosemary/carnosic acid potently inhibits proliferation of ER-negative human breast cancer cells and induces G1 cell cycle arrest. Further, carnosic acid is selective for MCF7 cells transfected for Her2, indicating that Her2 may function in its action. To reveal primary effects, we treated ER-negative breast cancer cells with carnosic acid for 6h. At a low dose, 5 μg/ml (15 μM), carnosic acid activated the expression of 3 genes, induced through the presence of antioxidant response elements, including genes involved in glutathione biosynthesis (CYP4F3, GCLC) and transport (SLC7A11). At a higher dose, 20 μg/ml, carnosic acid activated the expression of antioxidant (AKR1C2, TNXRD1, HMOX1) and apoptosis (GDF15, PHLDA1, DDIT3) genes and suppressed the expression of inhibitor of transcription (ID3) and cell cycle (CDKN2C) genes. Carnosic acid exhibits synergy with turmeric/curcumin. These compounds inhibited the activity of the purified Na-K-ATPase which may contribute to this synergy. Rosemary/carnosic acid, alone or combined with curcumin, may be useful to prevent and treat ER-negative breast cancer. Copyright © 2012 Elsevier B.V. All rights reserved.
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Hershcovitch, A.
1984-02-13
A process for selectively neutralizing H/sup -/ ions in a magnetic field to produce an intense negative hydrogen ion beam with spin polarized protons. Characteristic features of the process include providing a multi-ampere beam of H/sup -/ ions that are
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Lepidopteran HMG-CoA reductase is a potential selective target for pest control
Li, Yuan-mei; Huang, Juan; Tobe, Stephen S.
2017-01-01
As a consequence of the negative impacts on the environment of some insecticides, discovery of eco-friendly insecticides and target has received global attention in recent years. Sequence alignment and structural comparison of the rate-limiting enzyme HMG-CoA reductase (HMGR) revealed differences between lepidopteran pests and other organisms, which suggested insect HMGR could be a selective insecticide target candidate. Inhibition of JH biosynthesis in vitro confirmed that HMGR inhibitors showed a potent lethal effect on the lepidopteran pest Manduca sexta, whereas there was little effect on JH biosynthesis in Apis mellifera and Diploptera punctata. The pest control application of these inhibitors demonstrated that they can be insecticide candidates with potent ovicidal activity, larvicidal activity and insect growth regulatory effects. The present study has validated that Lepidopteran HMGR can be a potent selective insecticide target, and the HMGR inhibitors (especially type II statins) could be selective insecticide candidates and lead compounds. Furthermore, we demonstrated that sequence alignment, homology modeling and structural comparison may be useful for determining potential enzymes or receptors which can be eco-friendly pesticide targets. PMID:28133568
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Lepidopteran HMG-CoA reductase is a potential selective target for pest control.
Li, Yuan-Mei; Kai, Zhen-Peng; Huang, Juan; Tobe, Stephen S
2017-01-01
As a consequence of the negative impacts on the environment of some insecticides, discovery of eco-friendly insecticides and target has received global attention in recent years. Sequence alignment and structural comparison of the rate-limiting enzyme HMG-CoA reductase (HMGR) revealed differences between lepidopteran pests and other organisms, which suggested insect HMGR could be a selective insecticide target candidate. Inhibition of JH biosynthesis in vitro confirmed that HMGR inhibitors showed a potent lethal effect on the lepidopteran pest Manduca sexta , whereas there was little effect on JH biosynthesis in Apis mellifera and Diploptera punctata . The pest control application of these inhibitors demonstrated that they can be insecticide candidates with potent ovicidal activity, larvicidal activity and insect growth regulatory effects. The present study has validated that Lepidopteran HMGR can be a potent selective insecticide target, and the HMGR inhibitors (especially type II statins) could be selective insecticide candidates and lead compounds. Furthermore, we demonstrated that sequence alignment, homology modeling and structural comparison may be useful for determining potential enzymes or receptors which can be eco-friendly pesticide targets.
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Counterfactual thinking affects the excitability of the motor cortex.
Vicario, Carmelo M; Rafal, Robert D; Avenanti, Alessio
2015-04-01
Evidence suggests that monetary reward and affective experiences induce activity in the cortical motor system. Nevertheless, it is unclear whether counterfactual thinking related to wrong choices that lead to monetary loss and regret affects motor excitability. Using transcranial magnetic stimulation (TMS) of the motor cortex, we measured corticospinal excitability of 2 groups of healthy humans asked to actively guess the winning key among two possible alternatives (choice group); or passively assist to monetary outcomes randomly selected by the computer program (follow group). Results document a selective increment of the corticospinal excitability when a monetary loss outcome followed the key selection (i.e., in the choice group). On the other hand, no change in corticospinal excitability was found when participants passively assisted to a monetary loss randomly selected by the computer program (i.e., follow group). These findings suggest that counterfactual thinking and the negative emotional experiences arising from choices causing monetary loss--i.e., "I would have won instead of lost money if I'd made a different choice"--are mapped in the motor system. Copyright © 2015 Elsevier Ltd. All rights reserved.
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Brand, Jennie E.; Xie, Yu
2009-01-01
We consider how the economic return to a college education varies across members of the U.S. population. Based on principles of comparative advantage, positive selection is commonly presumed, i.e., individuals who are most likely to select into college benefit most from college. Net of observed economic and non-economic factors influencing college attendance, we conjecture that individuals who are least likely to obtain a college education benefit most from college. We call this theory the negative selection hypothesis. To adjudicate between the two hypotheses, we study the effects of completing college on earnings by propensity score strata using an innovative hierarchical linear model with data from the National Longitudinal Survey of Youth 1979 and the Wisconsin Longitudinal Study. For both data sources, for men and for women, and for every observed stage of the life course, we find evidence suggesting negative selection. Results from auxiliary analyses lend further support to the negative selection interpretation of the results. PMID:20454549
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Situation Selection and Modification for Emotion Regulation in Younger and Older Adults
Livingstone, Kimberly M.; Isaacowitz, Derek M.
2016-01-01
This research investigated age differences in use and effectiveness of situation selection and situation modification for emotion regulation. Socioemotional selectivity theory suggests stronger emotional well-being goals in older age; emotion regulation may support this goal. Younger and older adults assigned to an emotion regulation or “just view” condition first freely chose to engage with negative, neutral, or positive material (situation selection), then chose to view or skip negative and positive material (situation modification), rating affect after each experience. In both tasks, older adults in both goal conditions demonstrated pro-hedonic emotion regulation, spending less time with negative material compared to younger adults. Younger adults in the regulate condition also engaged in pro-hedonic situation selection, but not modification. Whereas situation selection was related to affect, modification of negative material was not. This research supports more frequent pro-hedonic motivation in older age, as well as age differences in use of early-stage emotion regulation. PMID:26998196
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Enhancing the Performance of LibSVM Classifier by Kernel F-Score Feature Selection
NASA Astrophysics Data System (ADS)
Sarojini, Balakrishnan; Ramaraj, Narayanasamy; Nickolas, Savarimuthu
Medical Data mining is the search for relationships and patterns within the medical datasets that could provide useful knowledge for effective clinical decisions. The inclusion of irrelevant, redundant and noisy features in the process model results in poor predictive accuracy. Much research work in data mining has gone into improving the predictive accuracy of the classifiers by applying the techniques of feature selection. Feature selection in medical data mining is appreciable as the diagnosis of the disease could be done in this patient-care activity with minimum number of significant features. The objective of this work is to show that selecting the more significant features would improve the performance of the classifier. We empirically evaluate the classification effectiveness of LibSVM classifier on the reduced feature subset of diabetes dataset. The evaluations suggest that the feature subset selected improves the predictive accuracy of the classifier and reduce false negatives and false positives.
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Fitness costs and benefits of novel herbicide tolerance in a noxious weed
Baucom, Regina S.; Mauricio, Rodney
2004-01-01
Glyphosate, the active ingredient in the herbicide RoundUp, has increased dramatically in use over the past decade and constitutes a potent anthropogenic source of selection. In the southeastern United States, weedy morning glories have begun to develop tolerance to glyphosate, representing a unique opportunity to examine the evolutionary genetics of a novel trait. We found genetic variation for tolerance, indicating the potential for the population to respond to selection by glyphosate. However, the following significant evolutionary constraint exists: in the absence of glyphosate, tolerant genotypes produced fewer seeds than susceptible genotypes. The combination of strong positive directional selection in the presence of glyphosate and strong negative directional selection in its absence may indicate that the selective landscape of land use could drive the evolutionary trajectory of glyphosate tolerance. Understanding these evolutionary forces is imperative for devising comprehensive management strategies to help slow the rate of the evolution of tolerance. PMID:15326309
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Non-negative matrix factorization in texture feature for classification of dementia with MRI data
NASA Astrophysics Data System (ADS)
Sarwinda, D.; Bustamam, A.; Ardaneswari, G.
2017-07-01
This paper investigates applications of non-negative matrix factorization as feature selection method to select the features from gray level co-occurrence matrix. The proposed approach is used to classify dementia using MRI data. In this study, texture analysis using gray level co-occurrence matrix is done to feature extraction. In the feature extraction process of MRI data, we found seven features from gray level co-occurrence matrix. Non-negative matrix factorization selected three features that influence of all features produced by feature extractions. A Naïve Bayes classifier is adapted to classify dementia, i.e. Alzheimer's disease, Mild Cognitive Impairment (MCI) and normal control. The experimental results show that non-negative factorization as feature selection method able to achieve an accuracy of 96.4% for classification of Alzheimer's and normal control. The proposed method also compared with other features selection methods i.e. Principal Component Analysis (PCA).
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Lessons learned from Shuttle/Mir: psychosocial countermeasures
NASA Technical Reports Server (NTRS)
Kanas, Nick; Salnitskiy, Vyacheslav; Grund, Ellen M.; Gushin, Vadim; Weiss, Daniel S.; Kozerenko, Olga; Sled, Alexander; Marmar, Charles R.
2002-01-01
BACKGROUND: During future long-duration space missions, countermeasures need to be developed to deal with psychosocial issues that might impact negatively on crewmember performance and well-being. METHODS: In our recently completed NASA-funded study of 5 U.S. astronauts, 8 Russian cosmonauts, and 42 U.S. and 16 Russian mission control personnel who participated in the Shuttle/Mir program, we evaluated a number of important psychosocial issues such as group tension, cohesion, leadership role, and the displacement of negative emotions from crewmembers to people in mission control and from mission control personnel to management. RESULTS: Based on our findings, which are reviewed, a number of psychosocial countermeasures are suggested to help ameliorate the negative impact of potential psychosocial problems during future manned space missions. CONCLUSIONS: Crewmembers should be selected not only to rule out psychopathology but also to select-in for group compatibility and facility in a common language. Training should include briefings and team building related to a number of psychosocial issues and should involve both crewmembers and mission control personnel. During the mission, both experts on the ground and the crewmembers themselves should be alert to potential interpersonal problems, including the displacement of negative emotions from the crew to the ground. Supportive activities should consist of both individual and interpersonal strategies, including an awareness of changing leisure time needs. Finally, attention should be given to postmission readjustment and to supporting the families on Earth.
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Sex versus asex: An analysis of the role of variance conversion.
Lewis-Pye, Andrew E M; Montalbán, Antonio
2017-04-01
The question as to why most complex organisms reproduce sexually remains a very active research area in evolutionary biology. Theories dating back to Weismann have suggested that the key may lie in the creation of increased variability in offspring, causing enhanced response to selection. Under appropriate conditions, selection is known to result in the generation of negative linkage disequilibrium, with the effect of recombination then being to increase genetic variance by reducing these negative associations between alleles. It has therefore been a matter of significant interest to understand precisely those conditions resulting in negative linkage disequilibrium, and to recognise also the conditions in which the corresponding increase in genetic variation will be advantageous. Here, we prove rigorous results for the multi-locus case, detailing the build up of negative linkage disequilibrium, and describing the long term effect on population fitness for models with and without bounds on fitness contributions from individual alleles. Under the assumption of large but finite bounds on fitness contributions from alleles, the non-linear nature of the effect of recombination on a population presents serious obstacles in finding the genetic composition of populations at equilibrium, and in establishing convergence to those equilibria. We describe techniques for analysing the long term behaviour of sexual and asexual populations for such models, and use these techniques to establish conditions resulting in higher fitnesses for sexually reproducing populations. Copyright © 2017 Elsevier Inc. All rights reserved.
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Szczepanik, Joanna E; Furey, Maura L; Nugent, Allison C; Henter, Ioline D; Zarate, Carlos A; Lejuez, Carl W
2017-10-01
Anhedonia-defined as loss of interest or pleasure-is one of two core symptoms of major depressive disorder (MDD). Anhedonia may involve decreased enjoyment of potentially rewarding activities and decreased motivation to engage in such activities. Increased engagement with reinforcers-activities with the potential to be positive experiences-is a frequent target of cognitive-behavioral therapies. Nevertheless, how environmental reinforcers are perceived, and how decisions to approach or avoid them are made by individuals with MDD, is largely unknown. We developed an experimental Behavioral Approach Motivation Paradigm to study how activities are evaluated and approached in MDD. Twenty-one MDD participants and 23 healthy controls performed an experimental task that rated activity words for their hedonic value, then engaged in an approach-avoidance joystick task with each individual's unique set of 'liked' and 'disliked' activity words. A negative correlation was observed between anhedonia and the number of 'liked' activities across participants. No significant difference between approach and avoidance behavior was found in direct comparisons between healthy controls and MDD participants; however, weaker avoidance and greater approach toward 'disliked' activities was found in MDD participants. This suggests negative bias in selecting environmental opportunities, potentially further compromising access to hedonic experiences in MDD. Copyright © 2017. Published by Elsevier Ltd.
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Szczepanik, Joanna E.; Furey, Maura L.; Nugent, Allison C.; Henter, Ioline D.; Zarate, Carlos A.; Lejuez, Carl W.
2017-01-01
Anhedonia—defined as loss of interest or pleasure—is one of two core symptoms of major depressive disorder (MDD). Anhedonia may involve decreased enjoyment of potentially rewarding activities and decreased motivation to engage in such activities. Increased engagement with reinforcers—activities with the potential to be positive experiences—is a frequent target of cognitive-behavioral therapies. Nevertheless, how environmental reinforcers are perceived, and how decisions to approach or avoid them are made by individuals with MDD, is largely unknown. We developed an experimental Behavioral Approach Motivation Paradigm to study how activities are evaluated and approached in MDD. Twenty-one MDD participants and 23 healthy controls performed an experimental task that rated activity words for their hedonic value, then engaged in an approach-avoidance joystick task with each individual’s unique set of ‘liked’ and ‘disliked’ activity words. A negative correlation was observed between anhedonia and the number of ‘liked’ activities across participants. No significant difference between approach and avoidance behavior was found in direct comparisons between healthy controls and MDD participants; however, weaker avoidance and greater approach toward ‘disliked’ activities was found in MDD participants. This suggests negative bias in selecting environmental opportunities, potentially further compromising access to hedonic experiences in MDD. PMID:28806614
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Crowther, Jason E.; Martin, Randi C.
2014-01-01
Studies of semantic interference in language production have provided evidence for a role of cognitive control mechanisms in regulating the activation of semantic competitors during naming. The present study investigated the relationship between individual differences in cognitive control abilities, for both younger and older adults, and the degree of semantic interference in a blocked cyclic naming task. We predicted that individuals with lower working memory capacity (as measured by word span), lesser ability to inhibit distracting responses (as measured by Stroop interference), and a lesser ability to resolve proactive interference (as measured by a recent negatives task) would show a greater increase in semantic interference in naming, with effects being larger for older adults. Instead, measures of cognitive control were found to relate to specific indices of semantic interference in the naming task, rather than overall degree of semantic interference, and few interactions with age were found, with younger and older adults performing similarly. The increase in naming latencies across naming trials within a cycle was negatively correlated with word span for both related and unrelated conditions, suggesting a strategy of narrowing response alternatives based upon memory for the set of item names. Evidence for a role of inhibition in response selection was obtained, as Stroop interference correlated positively with the change in naming latencies across cycles for the related, but not unrelated, condition. In contrast, recent negatives interference correlated negatively with the change in naming latencies across unrelated cycles, suggesting that individual differences in this tap the degree of strengthening of links in a lexical network based upon prior exposure. Results are discussed in terms of current models of lexical selection and consequences for word retrieval in more naturalistic production. PMID:24478675
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Tchinda, Cedric F; Voukeng, Igor K; Beng, Veronique P; Kuete, Victor
2017-05-01
In the last 10 years, resistance in Gram-negative bacteria has been increasing. The present study was designed to evaluate the in vitro antibacterial activities of the methanol extracts of six Cameroonian medicinal plants Albizia adianthifolia , Alchornea laxiflora , Boerhavia diffusa , Combretum hispidum , Laportea ovalifolia and Scoparia dulcis against a panel of 15 multidrug resistant Gram-negative bacterial strains. The broth microdilution was used to determine the minimal inhibitory concentration (MIC) and minimal bactericidal concentration (MBC) of the extracts. The preliminary phytochemical screening of the extracts was conducted according to the reference qualitative phytochemical methods. Results showed that all extracts contained compounds belonging to the classes of polyphenols and triterpenes, other classes of chemicals being selectively distributed. The best antibacterial activities were recorded with bark and root extracts of A. adianthifolia as well as with L. ovalifolia extract, with MIC values ranging from 64 to 1024 μg/mL on 93.3% of the fifteen tested bacteria. The lowest MIC value of 64 μg/mL was recorded with A. laxiflora bark extract against Enterobacter aerogenes EA289. Finally, the results of this study provide evidence of the antibacterial activity of the tested plants and suggest their possible use in the control of multidrug resistant phenotypes.
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2014-01-01
Background The combination of single-switch access technology and scanning is the most promising means of augmentative and alternative communication for many children with severe physical disabilities. However, the physical impairment of the child and the technology’s limited ability to interpret the child’s intentions often lead to false positives and negatives (corresponding to accidental and missed selections, respectively) occurring at rates that frustrate the user and preclude functional communication. Multiple psychophysiological studies have associated cardiac deceleration and increased phasic electrodermal activity with self-realization of errors among able-bodied individuals. Thus, physiological measurements have potential utility at enhancing single-switch access, provided that such prototypical autonomic responses exist in persons with profound disabilities. Methods The present case series investigated the autonomic responses of three pediatric single-switch users with severe spastic quadriplegic cerebral palsy, in the context of a single-switch letter matching activity. Each participant exhibited distinct autonomic responses to activity engagement. Results Our analysis confirmed the presence of the autonomic response pattern of cardiac deceleration and increased phasic electrodermal activity following true positives, false positives and false negatives errors, but not subsequent to true negative outcomes. Conclusions These findings suggest that there may be merit in complementing single-switch input with autonomic measurements to improve augmentative and alternative communications for pediatric access technology users. PMID:24607065
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Leung, Brian; Chau, Tom
2014-03-08
The combination of single-switch access technology and scanning is the most promising means of augmentative and alternative communication for many children with severe physical disabilities. However, the physical impairment of the child and the technology's limited ability to interpret the child's intentions often lead to false positives and negatives (corresponding to accidental and missed selections, respectively) occurring at rates that frustrate the user and preclude functional communication. Multiple psychophysiological studies have associated cardiac deceleration and increased phasic electrodermal activity with self-realization of errors among able-bodied individuals. Thus, physiological measurements have potential utility at enhancing single-switch access, provided that such prototypical autonomic responses exist in persons with profound disabilities. The present case series investigated the autonomic responses of three pediatric single-switch users with severe spastic quadriplegic cerebral palsy, in the context of a single-switch letter matching activity. Each participant exhibited distinct autonomic responses to activity engagement. Our analysis confirmed the presence of the autonomic response pattern of cardiac deceleration and increased phasic electrodermal activity following true positives, false positives and false negatives errors, but not subsequent to true negative outcomes. These findings suggest that there may be merit in complementing single-switch input with autonomic measurements to improve augmentative and alternative communications for pediatric access technology users.
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Benning, Stephen D.; Patrick, Christopher J.; Blonigen, Daniel M.; Hicks, Brian M.; Iacono, William G.
2008-01-01
In three samples consisting of community and undergraduate men and women and incarcerated men, we examined the criterion validity of two distinct factors of psychopathy embodied in the Psychopathic Personality Inventory (PPI) as indexed by primary trait scales from the Multidimensional Personality Questionnaire (MPQ). Consistent with the PPI factors themselves, MPQ-estimated PPI-I related negatively with internalizing disorder symptoms and fearfulness and positively with thrill and adventure seeking, sociability, activity, and narcissism. MPQ-estimated PPI-II was associated negatively with socialization and positively with externalizing disorder symptoms, impulsivity, disinhibition and boredom susceptibility, and trait anxiety and negative emotionality. Additionally, PPI-I was selectively related to the interpersonal facet of Factor 1 of the Psychopathy Checklist—Revised (PCL-R), whereas PPI-II was related preferentially to Factor 2 of the PCL-R. PMID:15695739
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Lupton, S D; Brunton, L L; Kalberg, V A; Overell, R W
1991-06-01
The hygromycin phosphotransferase gene was fused in-frame with the herpes simplex virus type 1 thymidine kinase gene. The resulting fusion gene (termed HyTK) confers hygromycin B resistance for dominant positive selection and ganciclovir sensitivity for negative selection and provides a means by which these selectable phenotypes may be expressed and regulated as a single genetic entity.
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Lim, T K; Gough, A; Chin, N K; Kumarasinghe, G
2000-09-01
The AMPLICOR assay (Roche; Branchburg, NJ), a rapid direct amplification test for Mycobacterium tuberculosis, has only been licensed for use in smear-positive respiratory specimens. However, many patients with pulmonary tuberculosis (PTB) have smear-negative disease. The clinical utility of this test in patients with smear-negative PTB is unknown. To evaluate the effect of pretest probability of PTB estimated by chest physicians on the accuracy of the AMPLICOR assay in patients with smear-negative PTB. A prospective study of consecutive patients suspected of having smear-negative PTB. Two chest physicians estimated the pretest probability of active disease (high, intermediate, and low categories). Respiratory specimens were examined with radiometric broth medium cultures and with the AMPLICOR assay for M tuberculosis. The decision on a final diagnosis of PTB was blinded to the AMPLICOR results. Active PTB was diagnosed in 25 of 441 patients (5.7%). The AMPLICOR assay had an overall sensitivity of 44% and a specificity of 99%. Results of the assay were negative in seven patients with culture-negative PTB. The proportions of patients in the high, intermediate, and low pretest groups were 4.5%, 19.7%, and 75.7%, respectively. The incidence of PTB for each group was 95%, 3.4%, and 0.9%, respectively. The sensitivities of the AMPLICOR assay in the three groups of patients were 47%, 33%, and 33%, respectively, while the specificities were 100%, 98%, and 99%, respectively. In patients suspected of having smear-negative PTB, the following conclusions were drawn: (1) the incidence of active PTB was low; (2) pretest estimates accurately discriminated between patients with high and low risk of PTB; (3) the risk of PTB was overestimated in the intermediate group; and (4) the utility of the AMPLICOR assay in the intermediate-risk group may be limited by the overestimation of disease prevalence and low test sensitivity. Further studies are needed on the role of the AMPLICOR assay in better selected patients with an intermediate risk of having smear-negative PTB.
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Zink, Stephen I; Ohki, Stephen K; Stein, Barry; Zambuto, Domenic A; Rosenberg, Ronald J; Choi, Jenny J; Tubbs, Daniel S
2008-10-01
The purpose of our study was to compare contrast-enhanced MDCT and (99m)Tc-labeled RBC scanning for the evaluation of active lower gastrointestinal bleeding. Over 17 months, 55 patients (32 men, 23 women; age range, 21-92 years) were evaluated prospectively with contrast-enhanced MDCT using 100 mL of iopromide 300 mg I/mL. Technetium-99m-labeled RBC scans were obtained on 41 of 55 patients and select patients underwent angiography for attempted embolization. Each imaging technique was reviewed in a blinded fashion for sensitivity for detection of active bleeding as well as the active lower gastrointestinal bleeding location. Findings were positive on both examinations in eight patients and negative on both examinations in 20 patients. Findings were positive on contrast-enhanced MDCT and negative on (99m)Tc-labeled RBC in two patients; findings were negative on contrast-enhanced MDCT and positive on (99m)Tc-labeled RBC in 11 patients. Statistics showed significant disagreement, with simple agreement = 68.3%, kappa = 0.341, and p = 0.014. Sixteen of 60 (26.7%) contrast-enhanced MDCT scans were positive prospectively, with all accurately localizing the site of bleeding and identification of the underlying lesion in eight of 16 (50%). Nineteen of 41 (46.3%) (99m)Tc-labeled RBC scans were positive. Eighteen of 41 matched patients went on to angiography. In four of these 18 (22.2%) patients, the site of bleeding was confirmed by angiography, but in 14 of 18 (77.8%), the findings were negative. Contrast-enhanced MDCT and (99m)Tc-labeled RBC scanning show significant disagreement for evaluation of active lower gastrointestinal bleeding. Contrast-enhanced MDCT appears effective for detection and localization in cases of active lower gastrointestinal bleeding in which hemorrhage is active at the time of CT.
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Mutation in Fas Ligand Impairs Maturation of Thymocytes Bearing Moderate Affinity T Cell Receptors
Boursalian, Tamar E.; Fink, Pamela J.
2003-01-01
Fas ligand, best known as a death-inducer, is also a costimulatory molecule required for maximal proliferation of mature antigen-specific CD4+ and CD8+ T cells. We now extend the role of Fas ligand by showing that it can also influence thymocyte development. T cell maturation in some, but not all, strains of TCR transgenic mice is severely impaired in thymocytes expressing mutant Fas ligand incapable of interacting with Fas. Mutant Fas ligand inhibits neither negative selection nor death by neglect. Instead, it appears to modulate positive selection of thymocytes expressing both class I– and class II–restricted T cell receptors of moderate affinity for their positively selecting ligands. Fas ligand is therefore an inducer of death, a costimulator of peripheral T cell activation, and an accessory molecule in positive selection. PMID:12860933
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[Why are stereotypes about mentally ill so resistant? Lessons from social psychology].
Möller-Leimkühler, A M
2004-01-01
Prejudices and social stigma in mental illness have a long tradition and have hardly been modified by educational programmes on the long term. The question, why these negative social attitudes appear to be considerably resistant to change is analysed with reference to social psychological research on stereotypes. First, a short review of studies on public attitudes towards the mentally ill and media analyses will give evidence to the widespread stereotypical misconceptions and their reproduction by selected media information. Then the dynamics of social stereotyping will be explained in relation to cultural, cognitive and emotional factors focussing on the development and activation of stereotypes within the paradigm of information processing. It is supposed that stereotype activation facilitates the processing of consistent information as well as it inhibits the processing of inconsistent information. Implications for changing negative attitudes about the mentally ill are discussed.
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Sakaridis, I; Soultos, N; Dovas, C I; Papavergou, E; Ambrosiadis, I; Koidis, P
2012-02-01
This study was conducted to isolate psychrotrophic lactic acid bacteria (LAB) from chicken carcasses with inhibitory activity against strains of Salmonella spp. and Listeria monocytogenes. A total of 100 broiler samples were examined for the presence of LAB. Ninety-two LAB isolates that showed antimicrobial effects against Salmonella spp. and L. monocytogenes were further analysed to examine their LAB (Gram-positive, catalase negative, oxidase negative) and psychrotrophic characteristics (ability to grow at 7 °C). Fifty isolates were further selected and identified initially using standard biochemical tests in miniature (Micro-kits API CH 50) and then by sequencing of the 16s-23s rRNA gene boundary region (Intergenic Spacer Region). By molecular identification, these isolates were classified into 5 different LAB species: Lactobacillus salivarius, Lactobacillus reuteri, Lactobacillus johnsonii, Pediococcus acidilactici, and Lactobacillus paralimentarius. None of the isolates produced tyramine or histamine. Copyright © 2011 Elsevier Ltd. All rights reserved.
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Strekalova, Elena; Malin, Dmitry; Rajanala, Harisha; Cryns, Vincent L
2017-06-01
Despite robust antitumor activity in diverse preclinical models, TNF-related apoptosis-inducing ligand (TRAIL) receptor agonists have not demonstrated efficacy in clinical trials, underscoring the need to identify agents that enhance their activity. We postulated that the metabolic stress induced by the diabetes drug metformin would sensitize breast cancer cells to TRAIL receptor agonists. Human triple (estrogen receptor, progesterone receptor, and HER2)-negative breast cancer (TNBC) cell lines were treated with TRAIL receptor agonists (monoclonal antibodies or TRAIL peptide), metformin, or the combination. The effects on cell survival, caspase activation, and expression of TRAIL receptors and the antiapoptotic protein XIAP were determined. In addition, XIAP was silenced by RNAi in TNBC cells and the effects on sensitivity to TRAIL were determined. The antitumor effects of metformin, TRAIL, or the combination were evaluated in an orthotopic model of metastatic TNBC. Metformin sensitized diverse TNBC cells to TRAIL receptor agonists. Metformin selectively enhanced the sensitivity of transformed breast epithelial cells to TRAIL receptor agonist-induced caspase activation and apoptosis with little effect on untransformed breast epithelial cells. These effects of metformin were accompanied by robust reductions in the protein levels of XIAP, a negative regulator of TRAIL-induced apoptosis. Silencing XIAP in TNBC cells mimicked the TRAIL-sensitizing effects of metformin. Metformin also enhanced the antitumor effects of TRAIL in a metastatic murine TNBC model. Our findings indicate that metformin enhances the activity of TRAIL receptor agonists, thereby supporting the rationale for additional translational studies combining these agents.
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In vitro antibacterial activity of selected medicinal plants from lower Himalayas.
Zulqarnain; Rahim, Abdur; Ahmad, Khalid; Ullah, Faizan; Ullah, Hamid; Nishan, Umar
2015-03-01
The present studies cover antibacterial activity of the crude methanolic extracts of 11 medicinal plants viz. Adhatoda vasica, Bauhenia variegate, Bombax ceiba, Carrisa opaca, Caryopteris grata, Debregeasia salicifolia, Lantana camara, Melia azedarach, Phyllanthus emblica, Pinus roxburghii and Olea ferruginea collected from lower Himalayas against two Gram positive (Staphylococcus aureus, Micrococcus luteus) and two Gram negative (Escherichia coli, Pseudomonas aureginosa) bacterial strains. The extracts were applied at four different concentrations (120 mg/mL, 90mg/mL, 60mg/mL and 30mg/mL) in dimethyl sulfoxide (DMSO) by using agar well diffusion method. Antibacterial activities against Staphylococcus aureus and Micrococcus luteus were observed formethanolic extracts of all the above mentioned plants. Greater antibacterial activity against Pseudomonas aeruginosa was only exhibited by Phyllanthus emblica, Pinus roxburghii, Debregeasia salicifolia and Lantana camara. Escherichia coli was highly resistant to all the plant extracts at all concentrations. It is inferred that methanolic crude extracts of the above mentioned plantsexhibitantibacterial activities against pathogenic bacteria, which proved the ethnobotanical importance of the selected plants that indigenous people use for cure against various diseases.
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Gomez, M; Kioussis, D; Cantrell, D A
2001-11-01
The positive selection of CD4 or CD8 single-positive mature peripheral T lymphocytes and the deletion of self-reactive cells are crucial for central tolerance in the peripheral immune system. Previously, the guanine nucleotide binding protein Rac-1 has been shown to control pre-T cell development. The present report now describes the actions of Rac-1 in thymocyte selection. The study reveals that this molecule has the striking and unique ability to efficiently divert cells from positive selection into a pathway of negative selection and deletion. The ability of Rac-1 to switch thymocytes from a destiny of positive to negative selection identifies this molecule as a critical regulator of the developmental processes in T cells that are essential for immune homeostasis.
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Chen, Xiqun; Rzhetskaya, Margarita; Kareva, Tatyana; Bland, Ross; During, Matthew J.; Tank, A. William; Kholodilov, Nikolai; Burke, Robert E.
2009-01-01
There is extensive evidence that the mitogen-activated protein kinase (MAPK) signaling cascade mediates programmed cell death in neurons. However, current evidence that the mixed linage kinases (MLKs), upstream in this cascade, mediate cell death is based, in the in vivo context, entirely on pharmacological approaches. The compounds used in these studies have neither complete specificity nor selectivity among these kinases. Therefore, to better address the molecular specificity of the MLKs in mediating neuron death, we used dominant-negative constructs delivered by AAV (adenoassociated virus) vector transfer. We assessed effects in a neurotoxin model of parkinsonism, in which neuroprotection by pharmacologic MLK inhibition has been reported. We find that two dominant-negative forms of dual leucine zipper kinase (DLK) inhibit apoptosis and enhance long-term survival of dopamine neurons, but a dominant negative of MLK3 does not. Interestingly, the kinase-dead form of DLK not only blocks apoptosis but also has trophic effects on dopamine neurons. Although the MAPK cascade activates a number of downstream cell death mediators, we find that inhibition of DLK correlates closely with blockade of phosphorylation of c-jun and prevention of cell death. We conclude that DLK acts primarily through c-jun phosphorylation to mediate cell death in this model. PMID:18199767
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Production of β-Lactamase by Non-Streptomyces Actinomycetales
Schwartz, Jeffrey L.; Schwartz, Surya P.
1979-01-01
Supernatants and whole cells from fermentation broths of Micromonospora, Nocardia, Oerskovia, and other genera of the Actinomycetales were examined for the presence of β-lactamase activity by using the chromogenic cephalosporin 87/312. Nearly 60% of the 250 isolates examined produced detectable levels of β-lactamase. All enzyme preparations were active over a range of pH values from 6.5 to 8.2, with maximum activity occurring between 7.0 and 7.8. The preparations varied in their stability at 60°C. An examination of selected enzyme preparations revealed a similarity between substrate specificities of the non-Streptomyces Actinomycetales and gram-negative-bacterial β-lactamases. PMID:311614
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MA, JJ; Monsivais, D; Dyson, MT; Coon, JS; Malpani, S; Ono, M; Zhao, H; Xin, H; Pavone, ME; Kim, JJ; Chakravarti, D; Bulun, SE
2013-01-01
Endometrial cancer is the fourth most common malignancy among women and is a major cause of morbidity- contributing to approximately 8,200 annual deaths in the United States. Despite advances to the understanding of endometrial cancer, novel interventions for the disease are necessary given that many tumors become refractory to therapy. As a strategy to identify novel therapies for endometrial carcinoma, in this study we examined the contribution of the peroxisome proliferator-activated receptor β/δ (PPARβ/δ) to endometrial cancer cell proliferation and apoptosis. We found that when activated with the highly selective PPARβ/δ agonists, GW0742 and GW501516, PPARβ/δ inhibited the proliferation and markedly induced the apoptosis of three endometrial cancer cell lines. The specificity of the PPARβ/δ-induced effects on cell proliferation and apoptosis was demonstrated using PPARβ/δ-selective antagonists and PPARβ/δ siRNA in combination with PPARβ/δ-selective agonists. Furthermore, we showed that PPARβ/δ activation increased PTEN expression, which led to AKT and GSK3β dephosphorylation, and increased β-catenin phosphorylation associated with its degradation. Overall, our data suggest that the anti-tumorigenic effect of PPARβ/δ activation in endometrial cancer is mediated through the negative regulation of the AKT/GSK3β/β-catenin pathway. These findings warrant further investigation of PPARβ/δ as a therapeutic target in endometrial cancer. PMID:23943160
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Browning, Michael; Grol, Maud; Ly, Verena; Goodwin, Guy M; Holmes, Emily A; Harmer, Catherine J
2011-01-01
Selective serotonergic reuptake inhibitors (SSRIs) and cognitive therapies are effective in the treatment of anxiety and depression. Previous research suggests that both forms of treatments may work by altering cognitive biases in the processing of affective information. The current study assessed the effects of combining an SSRI with a cognitive intervention on measures of affective processing bias and resilience to external challenge. A total of 62 healthy participants were randomly assigned to receive either 7 days of citalopram (20 mg) or placebo capsules while also completing either an active or a control version of a computerized cognitive bias training task. After treatment, standard measures of affective processing bias were collected. Participants' resilience to external stress was also tested by measuring the increase in negative symptoms induced by a negative mood induction. Participants who received both citalopram and the active cognitive bias training task showed a smaller alteration in emotional memory and categorization bias than did those who received either active intervention singly. The degree to which memory for negative information was altered by citalopram predicted participants' resistance to the negative mood induction. These results suggest that co-administration of an SSRI and a cognitive training intervention can reduce the effectiveness of either treatment alone in terms of anxiety- and depression-relevant emotional processing. More generally, the findings suggest that pinpointing the cognitive actions of treatments may inform future development of combination strategies in mental health. PMID:21832988
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Bastian, Brock; Pe, Madeline Lee; Kuppens, Peter
2017-02-01
Social norms and values may be important predictors of how people engage with and regulate their negative emotional experiences. Previous research has shown that social expectancies (the perceived social pressure not to feel negative emotion (NE)) exacerbate feelings of sadness. In the current research, we examined whether social expectancies may be linked to how people process emotional information. Using a modified classical flanker task involving emotional rather than non-emotional stimuli, we found that, for those who experienced low levels of NE, social expectancies were linked to the selective avoidance of negative emotional information. Those who experienced high levels of NE did not show a selective avoidance of negative emotional information. The findings suggest that, for people who experience many NEs, social expectancies may lead to discrepancies between how they think they ought to feel and the kind of emotional information they pay attention to.
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Fathers’ Participation in Parenting and Maternal Parenting Stress: Variation by Relationship Status
Nomaguchi, Kei; Brown, Susan L.; Leyman, Tanya M.
2015-01-01
The growing diversity in mother-father relationship status has led to a debate over the role of fathers in parenting. Little is known, however, about how fathers’ participation in parenting is linked to maternal well-being across different mother-father relationship statuses. Using data from the Fragile Families and Child Wellbeing Study (N = 2,062), fixed-effects as well as random-effects regression models show that overall fathers’ engagement with children and sharing in child-related chores are negatively related to maternal parenting stress. Fathers’ cooperative coparenting is negatively related to maternal parenting stress only in the random-effects model, suggesting that the association is driven by selection factors. There is little variation in these associations by mother-father relationship status, once selection factors are controlled for. These findings extend support for the current cultural emphasis on benefits of fathers’ active participation in parenting for mothers and children even after the mother-father relationship dissolved. PMID:28479649
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Three Nightmare Traits in Leaders
de Vries, Reinout E.
2018-01-01
This review offers an integration of dark leadership styles with dark personality traits. The core of dark leadership consists of Three Nightmare Traits (TNT)—leader dishonesty, leader disagreeableness, and leader carelessness—that are conceptualized as contextualized personality traits aligned with respectively (low) honesty-humility, (low) agreeableness, and (low) conscientiousness. It is argued that the TNT, when combined with high extraversion and low emotionality, can have serious (“explosive”) negative consequences for employees and their organizations. A Situation-Trait-Outcome Activation (STOA) model is presented in which a description is offered of situations that are attractive to TNT leaders (situation activation), situations that activate TNT traits (trait activation), and the kinds of outcomes that may result from TNT behaviors (outcome activation). Subsequently, the TNT and STOA models are combined to offer a description of the organizational actions that may strengthen or weaken the TNT during six career stages: attraction, selection, socialization, production, promotion, and attrition. Except for mainly negative consequences of the TNT, possible positive consequences of TNT leadership are also explored, and an outline of a research program is offered that may provide answers to the most pressing questions in dark leadership research. PMID:29915552
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Garza-López, Edgar; Chávez, Julio César; Santana-Calvo, Carmen; López-González, Ignacio; Nishigaki, Takuya
2016-07-01
CatSper is a sperm-specific Ca(2+) channel that plays an essential role in the male fertility. However, its biophysical properties have been poorly characterized mainly due to its deficient heterologous expression. As other voltage-gated Ca(2+) channels (CaVs), CatSper possesses a conserved Ca(2+)-selective filter motif ([T/S]x[D/E]xW) in the pore region. Interestingly, CatSper conserves four aspartic acids (DDDD) as the negatively charged residues in this motif while high voltage-activated CaVs have four glutamic acids (EEEE) and low voltage-activated CaVs possess two glutamic acids and two aspartic acids (EEDD). Previous studies based on site-directed mutagenesis of L- and T-type channels showed that the number of D seems to have a negative correlation with their cadmium (Cd(2+)) sensitivity. These results suggest that CatSper (DDDD) would have low sensitivity to Cd(2+). To explore Cd(2+)-sensitivity and -permeability of CatSper, we performed two types of experiments: 1) Electrophysiological analysis of heterologously expressed human CaV3.1 channel and three pore mutants (DEDD, EDDD and DDDD), 2) Cd(2+) imaging of human spermatozoa with FluoZin-1. Electrophysiological studies showed a significant increase in Cd(2+) and manganese (Mn(2+)) currents through the CaV3.1 mutants as well as a reduction in the inhibitory effect of Cd(2+) on the Ca(2+) current. In fluorescence imaging with human sperm, we observed an increase in Cd(2+) influx potentiated by progesterone, a potent activator of CatSper. These results support our hypothesis, namely that Cd(2+)-sensitivity and -permeability are related to the absolute number of D in the Ca(2+)-selective filter independently to the type of the Cav channels. Copyright © 2016 Elsevier Ltd. All rights reserved.
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The effects of deoxynivalenol on gene expression in the murine thymus
DOE Office of Scientific and Technical Information (OSTI.GOV)
Kol, Sandra W.M. van; Department of Health Risk Analysis and Toxicology, Maastricht University; Netherlands Toxicogenomics Centre
Deoxynivalenol (DON) is a mycotoxin produced by several Fusarium species and is often detected in grains. Because of its high abundance, there has been a large interest in the effects of DON in animals and humans. DON is known to be immunosuppressive at high concentrations and immunostimulatory at low concentrations. The present study aimed to acquire insight into the modes of action of DON. For this, C57Bl6 mice were orally exposed to 5, 10, or 25 mg/kg bw DON for 3, 6, or 24 h and thymuses were subjected to genome-wide expression microarray analysis. Gene set enrichment analysis (GSEA) demonstratedmore » that DON downregulated genes involved in proliferation, mitochondria, protein synthesis, and ribosomal proteins. Furthermore, GSEA showed a selective downregulation of genes highly expressed at the early precursor thymocytes stage. This indicates that early precursor thymocytes, particularly at the double-positive CD4+CD8+ stage, are more vulnerable to DON than very early or late precursor thymocytes. There was a large overlap of genes upregulated by DON with genes previously reported to be either upregulated during T cell activation or upregulated during negative selection of thymocytes that recognize 'self-antigens'. This indicates that DON induces cellular events that also occur after activation of the T cell receptor, for example, release of calcium from the endoplasmatic reticulum. This T cell activation in the thymus then evokes negative selection and depletion of thymocytes, which provides a plausible explanation for the high sensitivity of the thymus for DON exposure. The expression patterns of four genes indicative for some of the processes that were affected after DON treatment were confirmed using real-time PCR. Immunocytological experiments with primary mouse thymocytes demonstrated the translocation of NFAT from the cytoplasm into the nucleus upon exposure top DON, thus providing further evidence for the involvement of T cell activation.« less
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Dideriksen, Jakob L.; Negro, Francesco
2015-01-01
Increasing joint stiffness by cocontraction of antagonist muscles and compensatory reflexes are neural strategies to minimize the impact of unexpected perturbations on movement. Combining these strategies, however, may compromise steadiness, as elements of the afferent input to motor pools innervating antagonist muscles are inherently negatively correlated. Consequently, a high afferent gain and active contractions of both muscles may imply negatively correlated neural drives to the muscles and thus an unstable limb position. This hypothesis was systematically explored with a novel computational model of the peripheral nervous system and the mechanics of one limb. Two populations of motor neurons received synaptic input from descending drive, spinal interneurons, and afferent feedback. Muscle force, simulated based on motor unit activity, determined limb movement that gave rise to afferent feedback from muscle spindles and Golgi tendon organs. The results indicated that optimal steadiness was achieved with low synaptic gain of the afferent feedback. High afferent gains during cocontraction implied increased levels of common drive in the motor neuron outputs, which were negatively correlated across the two populations, constraining instability of the limb. Increasing the force acting on the joint and the afferent gain both effectively minimized the impact of an external perturbation, and suboptimal adjustment of the afferent gain could be compensated by muscle cocontraction. These observations show that selection of the strategy for a given contraction implies a compromise between steadiness and effectiveness of compensations to perturbations. This indicates that a task-dependent selection of neural strategy for steadiness is necessary when acting in different environments. PMID:26203102
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Liu, Tzu-Ling; Chen, Nai-Feng; Cheng, Shih-Kuen
2017-02-01
Emotional items are often remembered more clearly than neutral items. However, whether stimuli embedded in an emotional context are more resistant to directed forgetting than those presented in a neutral context remains unclear. This question was tested by recording event-related potentials (ERPs) in an item-method directed forgetting paradigm involving neutral words that were embedded in neutral or negative contexts. During the study phase, participants were asked to associate a neutral word with a negative or neutral picture. A remember (R) or forget (F) cue was then designated to indicate whether the word was a to-be-remembered (TBR) or to-be-forgotten (TBF) word. In the test phase, participants were asked to identify all previously presented old words regardless of the R/F cues. The behavioral results indicated a significant interaction between the valence of the encoding contexts and the R/F cues. The hit rate was lower for the TBR words encoded in negative contexts relative to those encoded in neutral contexts. No such valence effect was observed in the hit rates of the TBF words. For the ERP data, the R cues elicited a P3b-like effect that has been linked to the selective rehearsal of the TBR items. This effect was more sustained in the negative encoding context than in the neutral context. The F cues elicited a frontal positivity that has been linked to the active inhibition of the TBF words; however, this positivity was not modulated by the valence of the encoding context. The sustained P3b-like effect for the R cues in the negative encoding context might reflect a compensative encoding for the TBR words caused by the attention-capturing negative contexts. Therefore, we argue that the emotional context affected the selective elaboration of the TBR words; however, we also argue that there was no supportive evidence of an emotional effect on the forgetting of TBF items. Copyright © 2016 Elsevier B.V. All rights reserved.
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Novel Molecular Strategies and Targets for Opioid Drug Discovery for the Treatment of Chronic Pain
Olson, Keith M.; Lei, Wei; Keresztes, Attila; LaVigne, Justin; Streicher, John M.
2017-01-01
Opioid drugs like morphine and fentanyl are the gold standard for treating moderate to severe acute and chronic pain. However, opioid drug use can be limited by serious side effects, including constipation, tolerance, respiratory suppression, and addiction. For more than 100 years, we have tried to develop opioids that decrease or eliminate these liabilities, with little success. Recent advances in understanding opioid receptor signal transduction have suggested new possibilities to activate the opioid receptors to cause analgesia, while reducing or eliminating unwanted side effects. These new approaches include designing functionally selective ligands, which activate desired signaling cascades while avoiding signaling cascades that are thought to provoke side effects. It may also be possible to directly modulate downstream signaling through the use of selective activators and inhibitors. Separate from downstream signal transduction, it has also been found that when the opioid system is stimulated, various negative feedback systems are upregulated to compensate, which can drive side effects. This has led to the development of multi-functional molecules that simultaneously activate the opioid receptor while blocking various negative feedback receptor systems including cholecystokinin and neurokinin-1. Other novel approaches include targeting heterodimers of the opioid and other receptor systems which may drive side effects, and making endogenous opioid peptides druggable, which may also reduce opioid mediated side effects. Taken together, these advances in our molecular understanding provide a path forward to break the barrier in producing an opioid with reduced or eliminated side effects, especially addiction, which may provide relief for millions of patients. PMID:28356897
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Sivakumar, K. K.; Rajasekharan, A.; Rao, R.; Narasimhan, B.
2013-01-01
In the present investigation, a series of 12 Mannich bases (QP1-12) and 5 Schiff bases (QSP1-5) of pyrazol-5(4H)-one moiety containing 3-(hydrazinyl)-2-phenylquinazolin-4(3H)-one has been synthesized and characterized by physicochemical as well as spectral means. The synthesized Mannich and Schiff bases were screened for their preliminary antimicrobial activity against Gram-positive and Gram-negative bacterial as well as fungal strains by the determination of zone of inhibition. Mannich bases (QP1-12) were found to be more potent antibacterial agents against Gram-positive bacteria, whereas Schiff bases (QSP1-5) were more potent against Gram-negative bacteria and fungi. Minimum inhibitory concentration result demonstrated that Mannich base compound (QP7) having ortho -OH and para -COOH group showed some improvement in antibacterial activity (minimum inhibitory concentration of 48.88×10−3 μM/ml) among the tested Gram-positive organisms and it also exhibit minimum inhibitory concentration of value of 12.22×10−3 μM/ml for Klebsiella pneumoniae. The antitubercular activity of synthesized compounds against Mycobacterium tuberculosis (H37Rv) was determined using microplate alamar blue assay. Compound QP11 showed appreciable antitubercular activity (minimum inhibitory concentration of 6.49×10−3 μM/ml) which was more active than the standard drugs, ethambutol (minimum inhibitory concentration of 7.60×10−3 μM/ml) and ciprofloxacin (9.4×10−3 μM/ml). Compounds QP11, QP9, QSP1, QSP2, and QSP5 have good selective index and may be selected as a lead compound for the development of novel antitubercular agents. PMID:24302802
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Selective antitumor activity of roscovitine in head and neck cancer
Biktasova, Asel; Bellinger, Gary; Yarbrough, Wendell G.; Issaeva, Natalia
2016-01-01
Radiation and chemotherapy that are commonly used to treat human cancers damage cellular DNA. DNA damage appears to be more toxic to cancer cells than normal cells, most likely due to deregulated checkpoint activation and/or deficiency in DNA repair pathways that are characteristics of many tumors. However, unwanted side effects arise as a result of DNA damage to normal cells during the treatment. Here, we show that roscovitine, a cyclin-dependent kinase (CDK) inhibitor that inhibits CDK-1, CDK-2, CDK-5, CDK-7, and CDK-9 due to competitive binding to the ATP site on the kinases, causes significant DNA damage followed by p53-dependent cell death in human papilloma virus (HPV)-positive, but not in HPV-negative, head and neck cancer cells. Since HPV positivity was a molecular marker for increased sensitivity of cells to roscovitine, we reasoned that systemic roscovitine administration would not be toxic to healthy HPV-negative tissue. Indeed, low roscovitine doses significantly inhibited the growth of HPV-associated xenografted tumors in mice without causing any detectable side effects. Given that inhibition of CDKs has been shown to inhibit replication of several viruses, we suggest that roscovitine treatment may represent a selective and safe targeted therapeutic option against HPV-positive head and neck cancer. PMID:27233076
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Cysewski, Piotr; Przybyłek, Maciej
2017-09-30
New theoretical screening procedure was proposed for appropriate selection of potential cocrystal formers possessing the ability of enhancing dissolution rates of drugs. The procedure relies on the training set comprising 102 positive and 17 negative cases of cocrystals found in the literature. Despite the fact that the only available data were of qualitative character, performed statistical analysis using binary classification allowed to formulate quantitative criterions. Among considered 3679 molecular descriptors the relative value of lipoaffinity index, expressed as the difference between values calculated for active compound and excipient, has been found as the most appropriate measure suited for discrimination of positive and negative cases. Assuming 5% precision, the applied classification criterion led to inclusion of 70% positive cases in the final prediction. Since lipoaffinity index is a molecular descriptor computed using only 2D information about a chemical structure, its estimation is straightforward and computationally inexpensive. The inclusion of an additional criterion quantifying the cocrystallization probability leads to the following conjunction criterions H mix <-0.18 and ΔLA>3.61, allowing for identification of dissolution rate enhancers. The screening procedure was applied for finding the most promising coformers of such drugs as Iloperidone, Ritonavir, Carbamazepine and Enthenzamide. Copyright © 2017 Elsevier B.V. All rights reserved.
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Tsukatani, Tadayuki; Suenaga, Hikaru; Higuchi, Tomoko; Shiga, Masanobu; Noguchi, Katsuya; Matsumoto, Kiyoshi
2011-01-01
Bacteria are fundamentally divided into two groups: Gram-positive and Gram-negative. Although the Gram stain and other techniques can be used to differentiate these groups, some issues exist with traditional approaches. In this study, we developed a method for differentiating Gram-positive and -negative bacteria using a colorimetric microbial viability assay based on the reduction of the tetrazolium salt {2-(2-methoxy-4-nitrophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfophenyl)-2H-tetrazolium, monosodium salt} (WST-8) via 2-methyl-1,4-napthoquinone with a selection medium. We optimized the composition of the selection medium to allow the growth of Gram-negative bacteria while inhibiting the growth of Gram-positive bacteria. When the colorimetric viability assay was carried out in a selection medium containing 0.5µg/ml crystal violet, 5.0 µg/ml daptomycin, and 5.0µg/ml vancomycin, the reduction in WST-8 by Gram-positive bacteria was inhibited. On the other hand, Gram-negative bacteria produced WST-8-formazan in the selection medium. The proposed method was also applied to determine the Gram staining characteristics of bacteria isolated from various foodstuffs. There was good agreement between the results obtained using the present method and those obtained using a conventional staining method. These results suggest that the WST-8 colorimetric assay with selection medium is a useful technique for accurately differentiating Gram-positive and -negative bacteria.
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BAPJ69-4A: a yeast two-hybrid strain for both positive and negative genetic selection.
Shaffer, Hally Anne; Rood, Michael Kenneth; Kashlan, Badar; Chang, Eileen I-ling; Doyle, Donald Francis; Azizi, Bahareh
2012-10-01
Genetic selection systems, such as the yeast two-hybrid system, are efficient methods to detect protein-protein and protein-ligand interactions. These systems have been further developed to assess negative interactions, such as inhibition, using the URA3 genetic selection marker. Previously, chemical complementation was used to assess positive selection in Saccharomyces cerevisiae. In this work, a new S. cerevisiae strain, called BAPJ69-4A, containing three selective markers ADE2, HIS3, and URA3 as well as the lacZ gene controlled by Gal4 response elements, was developed and characterized using the retinoid X receptor (RXR) and its ligand 9-cis retinoic acid (9cRA). Further characterization was performed using RXR variants and the synthetic ligand LG335. To assess the functionality of the strain, RXR was compared to the parent strain PJ69-4A in adenine, histidine, and uracil selective media. In positive selection, associating partners that lead to cell growth were observed in all media in the presence of ligand, whereas partners that did not associate due to the absence of ligand displayed no growth. Conversely, in negative selection, partners that did not associate in 5-FOA medium did not display cell death due to the lack of expression of the URA3 gene. The creation of the BAPJ69-4A yeast strain provides a high-throughput selection system, called negative chemical complementation, which can be used for both positive and negative selection, providing a fast, powerful tool for discovering novel ligand receptor pairs for applications in drug discovery and protein engineering. Copyright © 2012 Elsevier B.V. All rights reserved.
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Schellman, J A
1990-08-31
The properties of a simple model for solvation in mixed solvents are explored in this paper. The model is based on the supposition that solvent replacement is a simple one-for-one substitution reaction at macromolecular sites which are independent of one another. This leads to a new form for the binding polynomial in which all terms are associated with ligand interchange rather than ligand addition. The principal solvent acts as one of the ligands. Thermodynamic analysis then shows that thermodynamic binding (i.e., selective interaction) depends on the properties of K'-1, whereas stoichiometric binding (site occupation) depends on K'. K' is a 'practical' interchange equilibrium constant given by (f3/f1)K, where K is the true equilibrium constant for the interchange of components 3 and 1 on the site and f3 and f4 denote their respective activity coefficients on the mole fraction scale. Values of K' less than unity lead to negative selective interaction. It is selective interaction and not occupation number which determines the thermodynamic effects of solvation. When K' greater than 100 on the mole fraction scale or K' greater than 2 on the molality scale (in water), the differences between stoichiometric binding and selective interaction become less than 1%. The theory of this paper is therefore necessary only for very weak binding constants. When K'-1 is small, large concentrations of the added solvent component are required to produce a thermodynamic effect. Under these circumstances the isotherms for the selective interaction and for the excess (or transfer) free energy are strongly dependent on the behavior of the activity coefficients of both solvent components. Two classes of behavior are described depending on whether the components display positive or negative deviations from Raoult's law. Examples which are discussed are aqueous solutions of urea and guanidinium chloride for positive deviations and of sucrose and glucose for negative deviations. Examination of the few studies which have been reported in the literature shows that most of the qualitative features of the stabilization of proteins by sugars and their destabilization by urea and guanidinium chloride are faithfully represented with the model. This includes maxima in the free energy of stabilization and destabilization, decreased and zero selective interaction at high concentrations, etc. These phenomena had no prior explanation. Deficiencies in the model as a representation of solvation in aqueous solution are discussed in the appendix.
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[How children show positive and negative relationships on their drawings].
Gramel, Sabine
2005-01-01
This study analyses, whether pictures of children showing a positive relationship are significantly different from those showing a negative one with respect to several criteria. The study involved a random selection of 45 children aged 4;6 to 11;6 years. The children painted a picture with themselves and a person they liked and a picture of themselves with someone they disliked. For the most part, the children drew pictures of themselves with peers both with respect to positive as well as negative images. In an interview afterwards, the children specified the criteria in their drawings by which the quality of the particular relationship can be identified. Positive and negative relationship paintings differ in the character of activity described. The sun as an element in children's paintings is painted not more frequent on positive compared to negative pictures. The colour black is used more often in the drawings signifying negative relationships. While girls used more colour in negative relationship drawings, boys used more colour in the positive ones. There was no significant difference in the use of favourite colours and decorative elements between the two groups. Only in negative relationship drawings people were looking away from each other. Smiling individuals were more common in the positive relationship pictures and in pictures painted by the 6 to 8 year olds. A greater distance between the individuals emerged on negative relationship drawings of the girls.
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Definition and classification of negative motor signs in childhood.
Sanger, Terence D; Chen, Daofen; Delgado, Mauricio R; Gaebler-Spira, Deborah; Hallett, Mark; Mink, Jonathan W
2006-11-01
In this report we describe the outcome of a consensus meeting that occurred at the National Institutes of Health in Bethesda, Maryland, March 12 through 14, 2005. The meeting brought together 39 specialists from multiple clinical and research disciplines including developmental pediatrics, neurology, neurosurgery, orthopedic surgery, physical therapy, occupational therapy, physical medicine and rehabilitation, neurophysiology, muscle physiology, motor control, and biomechanics. The purpose of the meeting was to establish terminology and definitions for 4 aspects of motor disorders that occur in children: weakness, reduced selective motor control, ataxia, and deficits of praxis. The purpose of the definitions is to assist communication between clinicians, select homogeneous groups of children for clinical research trials, facilitate the development of rating scales to assess improvement or deterioration with time, and eventually to better match individual children with specific therapies. "Weakness" is defined as the inability to generate normal voluntary force in a muscle or normal voluntary torque about a joint. "Reduced selective motor control" is defined as the impaired ability to isolate the activation of muscles in a selected pattern in response to demands of a voluntary posture or movement. "Ataxia" is defined as an inability to generate a normal or expected voluntary movement trajectory that cannot be attributed to weakness or involuntary muscle activity about the affected joints. "Apraxia" is defined as an impairment in the ability to accomplish previously learned and performed complex motor actions that is not explained by ataxia, reduced selective motor control, weakness, or involuntary motor activity. "Developmental dyspraxia" is defined as a failure to have ever acquired the ability to perform age-appropriate complex motor actions that is not explained by the presence of inadequate demonstration or practice, ataxia, reduced selective motor control, weakness, or involuntary motor activity.
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Boyd, Michael J; Bandarage, Upul K; Bennett, Hamilton; Byrn, Randal R; Davies, Ioana; Gu, Wenxin; Jacobs, Marc; Ledeboer, Mark W; Ledford, Brian; Leeman, Joshua R; Perola, Emanuele; Wang, Tiansheng; Bennani, Youssef; Clark, Michael P; Charifson, Paul S
2015-05-01
VX-787 is a first in class, orally bioavailable compound that offers unparalleled potential for the treatment of pandemic and seasonal influenza. As a part of our routine SAR exploration, carboxylic acid isosteres of VX-787 were prepared and tested against influenza A. It was found that the negative charge is important for maintaining potency and selectivity relative to kinase targets. Neutral carboxylic acid replacements generally resulted in compounds that were significantly less potent and less selective relative to the charged species. Copyright © 2015 Elsevier Ltd. All rights reserved.
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Kinclova-Zimmermannova, Olga; Falson, Pierre; Cmunt, Denis; Sychrova, Hana
2015-04-24
Na(+)/H(+) antiporters may recognize all alkali-metal cations as substrates but may transport them selectively. Plasma-membrane Zygosaccharomyces rouxii Sod2-22 antiporter exports Na(+) and Li(+), but not K(+). The molecular basis of this selectivity is unknown. We combined protein structure modeling, site-directed mutagenesis, phenotype analysis and cation efflux measurements to localize and characterize the cation selectivity region. A three-dimensional model of the ZrSod2-22 transmembrane domain was generated based on the X-ray structure of the Escherichia coli NhaA antiporter and primary sequence alignments with homologous yeast antiporters. The model suggested a close proximity of Thr141, Ala179 and Val375 from transmembrane segments 4, 5 and 11, respectively, forming a hydrophobic hole in the putative cation pathway's core. A series of mutagenesis experiments verified the model and showed that structural modifications of the hole resulted in altered cation selectivity and transport activity. The triple ZrSod2-22 mutant T141S-A179T-V375I gained K(+) transport capacity. The point mutation A179T restricted the antiporter substrate specificity to Li(+) and reduced its transport activity, while serine at this position preserved the native cation selectivity. The negative effect of the A179T mutation can be eliminated by introducing a second mutation, T141S or T141A, in the preceding transmembrane domain. Our experimental results confirm that the three residues found through modeling play a central role in the determination of cation selectivity and transport activity in Z. rouxii Na(+)/H(+) antiporter and that the cation selectivity can be modulated by repositioning a single local methyl group. Copyright © 2015 Elsevier Ltd. All rights reserved.
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Nahon, Joya E; Groeneveldt, Christianne; Geerling, Janine J; Van Eck, Miranda; Hoekstra, Menno
2018-05-18
Agonists for the liver X receptor (LXR) are considered promising therapeutic moieties in cholesterol-driven diseases by promoting cellular cholesterol efflux pathways. However, current clinical application of these agents is hampered by the concomitant LXR-induced activation of a lipogenic transcriptional network, leading to hepatic steatosis. Recent studies have suggested that protein arginine methyltransferase 3 (PRMT3) may act as a selective co-activator of LXR activity. Here we verified the hypothesis that PRMT3 inhibition selectively disrupts the ability of LXR to stimulate lipogenesis, while maintaining the capacity of LXR to modulate macrophage cholesterol homeostasis. A combination of the LXR agonist T0901317 and palm oil was administered to C57BL/6 mice to maximally stimulate LXR and PRMT3 activity. PRMT3 activity was inhibited using the allosteric inhibitor SGC707. Treatment with the PRMT3 inhibitor SGC707 did not negatively influence the T0901317/palm oil induced upregulation of the cholesterol efflux genes ABCA1 and ABCG1 in peritoneal cells. In contrast, SGC707 treatment was associated with a significant decrease in the hepatic expression of the lipogenic gene FAS (-64%). A similar trend was observed for SCD1 and ACC expression (-43%; -56%) This obstruction of lipogenic gene transcription coincided with a significant 2.3-fold decrease in liver triglyceride content as compared to the T0901317 and palm oil treated control group. We have shown that inhibition of PRMT3 activity by SGC707 treatment selectively impairs LXR-driven transcription of hepatic lipogenic genes, while the positive effect of LXR stimulation on macrophage cholesterol efflux pathways is maintained. This article is protected by copyright. All rights reserved.
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Looking on the bright side: biased attention and the human serotonin transporter gene.
Fox, Elaine; Ridgewell, Anna; Ashwin, Chris
2009-05-22
Humans differ in terms of biased attention for emotional stimuli and these biases can confer differential resilience and vulnerability to emotional disorders. Selective processing of positive emotional information, for example, is associated with enhanced sociability and well-being while a bias for negative material is associated with neuroticism and anxiety. A tendency to selectively avoid negative material might also be associated with mental health and well-being. The neurobiological mechanisms underlying these cognitive phenotypes are currently unknown. Here we show for the first time that allelic variation in the promotor region of the serotonin transporter gene (5-HTTLPR) is associated with differential biases for positive and negative affective pictures. Individuals homozygous for the long allele (LL) showed a marked bias to selectively process positive affective material alongside selective avoidance of negative affective material. This potentially protective pattern was absent among individuals carrying the short allele (S or SL). Thus, allelic variation on a common genetic polymorphism was associated with the tendency to selectively process positive or negative information. The current study is important in demonstrating a genotype-related alteration in a well-established processing bias, which is a known risk factor in determining both resilience and vulnerability to emotional disorders.
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Reduced physical activity and risk of chronic disease: the biology behind the consequences.
Booth, Frank W; Laye, Matthew J; Lees, Simon J; Rector, R Scott; Thyfault, John P
2008-03-01
This review focuses on three preserved, ancient, biological mechanisms (physical activity, insulin sensitivity, and fat storage). Genes in humans and rodents were selected in an environment of high physical activity that favored an optimization of aerobic metabolic pathways to conserve energy for a potential, future food deficiency. Today machines and other technologies have replaced much of the physical activity that selected optimal gene expression for energy metabolism. Distressingly, the negative by-product of a lack of ancient physical activity levels in our modern civilization is an increased risk of chronic disease. We have been employing a rodent wheel-lock model to approximate the reduction in physical activity in humans from the level under which genes were selected to a lower level observed in modern daily functioning. Thus far, two major changes have been identified when rats undertaking daily, natural voluntary running on wheels experience an abrupt cessation of the running (wheel lock model). First, insulin sensitivity in the epitrochlearis muscle of rats falls to sedentary values after 2 days of the cessation of running, confirming the decline to sedentary values in whole-body insulin sensitivity when physically active humans stop high levels of daily exercise. Second, visceral fat increases within 1 week after rats cease daily running, confirming the plasticity of human visceral fat. This review focuses on the supporting data for the aforementioned two outcomes. Our primary goal is to better understand how a physically inactive lifestyle initiates maladaptations that cause chronic disease.
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Ding, Xu; Liang, Yaosi; Peng, Wan; Li, Ruozhu; Lin, Haoran; Zhang, Yong; Lu, Danqi
2018-01-01
TLR22, a typical member of the fish-specific TLRs, is a crucial sensor in virally triggered innate immune signalling retained from natural selection. To elucidate the role of the TLR22-specific signalling cascade mechanism, we provide evidence that the double-stranded (ds) RNA-sensor TLR22 positively regulates the ERK pathway and negatively regulates the JNK, p38 MAP kinase and NF-κB pathway. Here, we show that TLR22 restrains NF-κB activation and IFN (interferon) β and AP-1 (activator protein-1) promoter binding (impairing "primary response" genes (TNF and IL-1)), induces "secondary response" genes (IL-12 and IL-6) and mediates the irregular expression of inflammatory genes. Therefore, TLR22 promotes ERK phosphorylation but impairs the JNK and p38 MAP kinases and IκB phosphorylation. Additionally, TLR22 controls the excessive generation of reactive oxygen species (ROS) to avoid damaging the organism. The specific kinetics of TLR22 depends on its distinct cellular localization. We demonstrate that TLR22 is an intracellular receptor localized in the endosome, and the TLR22-TIR domain is the functional structure inducing the signalling cascade post-viral replication in the body. As mentioned above, our data reveal a novel mechanism whereby TLR22-induced positive adjustment and negative regulation evolved independently to avoid harmful and inappropriate inflammatory responses. Copyright © 2017. Published by Elsevier Ltd.
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Warner, Echo L; Ellington, Lee; Kirchhoff, Anne C; Cloyes, Kristin G
2018-04-01
Social media (SM) is a burgeoning source of social support for young adults (YAs). We explored the language used to communicate about YA cancer on Instagram and for indicators of social support (i.e., number of likes and comments). Instagram posts using #youngadultcancer were randomly selected (N = 50). Text and hashtags were collected, and posts were coded for gender (female and male), treatment status (active treatment and survivorship), type of user (individual and organization), and caregiver status (yes and no). Indicators of social support, valence (e.g., positive vs. negative terms), and lexical content (e.g., emotional terms and pronouns) were measured using Yoshikoder and Linguistic Inquiry Word Count and compared by gender, treatment status, type of user, and caregiver status. Survivors' posts had more likes compared to those in active treatment (mean: 54.5 vs. 32.3, p = 0.03). Individuals' posts had more comments than those of organizations (mean: 5.3 vs. 1.2, p = 0.01). More positive (30%) than negative (13%) terms were used by survivors (p < 0.01) and those in active treatment (20% vs. 9%, p = 0.04). Individuals' used more positive than negative language (p < 0.01), whereas organizations used equally positive and negative terms. Survivors used more emotional terms (79.6% vs. 34.9%, p < 0.01) and fewer pronouns (mean: 39.5 vs. 71.7, p = 0.01) than those in active treatment. Organizations (71.0%) used more emotional terms than individuals (55.9%, p = 0.03). We describe how Instagram users communicate about YA cancer and whether the language they use garners social support. Studying online language use may help YA patients, caregivers, and organizations use SM to gain social support.
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Alcohol use and negative consequences among active duty military personnel.
Mattiko, Mark J; Olmsted, Kristine L Rae; Brown, Janice M; Bray, Robert M
2011-06-01
An examination of alcohol use patterns in the active duty military to determine the relations of drinking levels and self-reported negative outcomes. A population-based cross-sectional study design using two-stage complex sampling methodology. Paper and pencil surveys were administered anonymously in groups at 64 U.S. military installations worldwide. Randomly selected active duty members (28,546) at major military installations representing the total active force, with the exception of recruits, cadets, and incarcerated personnel. Personnel were classified into five drinking levels ranging from abstainer to heavy drinker based on quantity and frequency of alcohol intake. Negative outcomes were measured as self-reported serious consequences of alcohol use and alcohol-related productivity loss. Risk for other alcohol related problems was assessed by the Alcohol Use Disorders Identification Test (AUDIT). Alcohol negative outcomes showed a curvilinear dose-response relationship with drinking levels. Higher levels of drinking were associated with higher rates of alcohol problems, but problem rates were notably higher for heavy drinkers. Heavy alcohol users showed nearly three times the rate of self-reported serious consequences and over twice the rate of self-reported productivity loss than moderate/heavy drinkers. Heavy drinkers also had the highest risk for alcohol problems on the AUDIT. One fifth of military personnel were heavy drinkers and were most likely aged 18 to 35. Prevention and clinical interventions should include a major focus on heavy drinkers. Commanders and peers should be trained in recognizing signs of heavy alcohol use and in approaching heavy alcohol users in a way that will foster positive attitudes as opposed to defensiveness and stigma. Published by Elsevier Ltd.
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Detecting Past Positive Selection through Ongoing Negative Selection
Bazykin, Georgii A.; Kondrashov, Alexey S.
2011-01-01
Detecting positive selection is a challenging task. We propose a method for detecting past positive selection through ongoing negative selection, based on comparison of the parameters of intraspecies polymorphism at functionally important and selectively neutral sites where a nucleotide substitution of the same kind occurred recently. Reduced occurrence of recently replaced ancestral alleles at functionally important sites indicates that negative selection currently acts against these alleles and, therefore, that their replacements were driven by positive selection. Application of this method to the Drosophila melanogaster lineage shows that the fraction of adaptive amino acid replacements remained approximately 0.5 for a long time. In the Homo sapiens lineage, however, this fraction drops from approximately 0.5 before the Ponginae–Homininae divergence to approximately 0 after it. The proposed method is based on essentially the same data as the McDonald–Kreitman test but is free from some of its limitations, which may open new opportunities, especially when many genotypes within a species are known. PMID:21859804
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Seebacher, Frank; James, Rob S
2008-03-01
Thermoregulation and thermal sensitivity of performance are thought to have coevolved so that performance is optimized within the selected body temperature range. However, locomotor performance in thermoregulating crocodiles (Crocodylus porosus) is plastic and maxima shift to different selected body temperatures in different thermal environments. Here we test the hypothesis that muscle metabolic and biomechanical parameters are optimized at the body temperatures selected in different thermal environments. Hence, we related indices of anaerobic (lactate dehydrogenase) and aerobic (cytochrome c oxidase) metabolic capacities and myofibrillar ATPase activity to the biomechanics of isometric and work loop caudofemoralis muscle function. Maximal isometric stress (force per muscle cross-sectional area) did not change with thermal acclimation, but muscle work loop power output increased with cold acclimation as a result of shorter activation and relaxation times. The thermal sensitivity of myofibrillar ATPase activity decreased with cold acclimation in caudofemoralis muscle. Neither aerobic nor anaerobic metabolic capacities were directly linked to changes in muscle performance during thermal acclimation, although there was a negative relationship between anaerobic capacity and isometric twitch stress in cold-acclimated animals. We conclude that by combining thermoregulation with plasticity in biomechanical function, crocodiles maximize performance in environments with highly variable thermal properties.
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Zarattini, Marco; De Bastiani, Morena; Bernacchia, Giovanni; Ferro, Sergio; De Battisti, Achille
2015-11-01
The use of highly polluting chemicals for plant and crop protection is one of the components of the negative environmental impact of agricultural activities. In the present paper, an environmentally friendly alternative to pesticide application has been studied, based on the so-called electrochemically activated solutions (ECAS). Experiments have been carried out, by applying ECAS having different contents of active ingredients, on tobacco plants at a laboratory scale and on apple trees at fruit garden scale. The results, accumulated during a couple of years, have shown that properly selected dilute solutions of chlorides, once activated by an electrochemical treatment, exhibit a very effective protecting action of plants, irrespective of their nature. Extension of the research has shown that the observed effect is the result of two distinct factors: the expected anti-microbial action of the electrochemically synthesized oxidants, and an unexpected priming of immune plant defenses, which is clearly due to the treatment with ECAS. Interestingly, the repetition of ECAS application triggers an even stronger activation of defense genes. No oxidative damages, due to the use of the activated solutions, could be detected.
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Brunati, Cristina; Thomsen, Thomas T; Gaspari, Eleonora; Maffioli, Sonia; Sosio, Margherita; Jabes, Daniela; Løbner-Olesen, Anders; Donadio, Stefano
2018-01-01
Abstract Objectives To characterize NAI-107 and related lantibiotics for their in vitro activity against Gram-negative pathogens, alone or in combination with polymyxin, and against non-dividing cells or biofilms of Staphylococcus aureus. NAI-107 was also evaluated for its propensity to select or induce self-resistance in Gram-positive bacteria. Methods We used MIC determinations and chequerboard experiments to establish the antibacterial activity of the examined compounds against target microorganisms. Time–kill assays were used to evaluate killing of exponential and stationary-phase cells. The effects on biofilms (growth inhibition and biofilm eradication) were evaluated using biofilm-coated pegs. The frequency of spontaneous resistant mutants was evaluated by either direct plating or by continuous sub-culturing at 0.5 × MIC levels, followed by population analysis profiles. Results The results showed that NAI-107 and its brominated variant are highly active against Neisseria gonorrhoeae and some other fastidious Gram-negative pathogens. Furthermore, all compounds strongly synergized with polymyxin against Acinetobacter baumannii, Escherichia coli, Klebsiella pneumoniae and Pseudomonas aeruginosa, and showed bactericidal activity. Surprisingly, NAI-107 alone was bactericidal against non-dividing A. baumannii cells. Against S. aureus, NAI-107 and related lantibiotics showed strong bactericidal activity against dividing and non-dividing cells. Activity was also observed against S. aureus biofilms. As expected for a lipid II binder, no significant resistance to NAI-107 was observed by direct plating or serial passages. Conclusions Overall, the results of the current work, along with previously published results on the efficacy of NAI-107 in experimental models of infection, indicate that this lantibiotic represents a promising option in addressing the serious threat of antibiotic resistance. PMID:29092042
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Brunati, Cristina; Thomsen, Thomas T; Gaspari, Eleonora; Maffioli, Sonia; Sosio, Margherita; Jabes, Daniela; Løbner-Olesen, Anders; Donadio, Stefano
2018-02-01
To characterize NAI-107 and related lantibiotics for their in vitro activity against Gram-negative pathogens, alone or in combination with polymyxin, and against non-dividing cells or biofilms of Staphylococcus aureus. NAI-107 was also evaluated for its propensity to select or induce self-resistance in Gram-positive bacteria. We used MIC determinations and chequerboard experiments to establish the antibacterial activity of the examined compounds against target microorganisms. Time-kill assays were used to evaluate killing of exponential and stationary-phase cells. The effects on biofilms (growth inhibition and biofilm eradication) were evaluated using biofilm-coated pegs. The frequency of spontaneous resistant mutants was evaluated by either direct plating or by continuous sub-culturing at 0.5 × MIC levels, followed by population analysis profiles. The results showed that NAI-107 and its brominated variant are highly active against Neisseria gonorrhoeae and some other fastidious Gram-negative pathogens. Furthermore, all compounds strongly synergized with polymyxin against Acinetobacter baumannii, Escherichia coli, Klebsiella pneumoniae and Pseudomonas aeruginosa, and showed bactericidal activity. Surprisingly, NAI-107 alone was bactericidal against non-dividing A. baumannii cells. Against S. aureus, NAI-107 and related lantibiotics showed strong bactericidal activity against dividing and non-dividing cells. Activity was also observed against S. aureus biofilms. As expected for a lipid II binder, no significant resistance to NAI-107 was observed by direct plating or serial passages. Overall, the results of the current work, along with previously published results on the efficacy of NAI-107 in experimental models of infection, indicate that this lantibiotic represents a promising option in addressing the serious threat of antibiotic resistance. © The Author 2017. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy.
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Blocking negative effects of senescence in human skin fibroblasts with a plant extract.
Lämmermann, Ingo; Terlecki-Zaniewicz, Lucia; Weinmüllner, Regina; Schosserer, Markus; Dellago, Hanna; de Matos Branco, André Dargen; Autheried, Dominik; Sevcnikar, Benjamin; Kleissl, Lisa; Berlin, Irina; Morizot, Frédérique; Lejeune, Francois; Fuzzati, Nicola; Forestier, Sandra; Toribio, Alix; Tromeur, Anaïs; Weinberg, Lionel; Higareda Almaraz, Juan Carlos; Scheideler, Marcel; Rietveld, Marion; El Ghalbzouri, Abdoel; Tschachler, Erwin; Gruber, Florian; Grillari, Johannes
2018-01-01
There is increasing evidence that senescent cells are a driving force behind many age-related pathologies and that their selective elimination increases the life- and healthspan of mice. Senescent cells negatively affect their surrounding tissue by losing their cell specific functionality and by secreting a pro-tumorigenic and pro-inflammatory mixture of growth hormones, chemokines, cytokines and proteases, termed the senescence-associated secretory phenotype (SASP). Here we identified an extract from the plant Solidago virgaurea subsp. alpestris , which exhibited weak senolytic activity, delayed the acquisition of a senescent phenotype and induced a papillary phenotype with improved functionality in human dermal fibroblasts. When administered to stress-induced premature senescent fibroblasts, this extract changed their global mRNA expression profile and particularly reduced the expression of various SASP components, thereby ameliorating the negative influence on nearby cells. Thus, the investigated plant extract represents a promising possibility to block age-related loss of tissue functionality.
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Network Architecture Predisposes an Enzyme to Either Pharmacologic or Genetic Targeting.
Jensen, Karin J; Moyer, Christian B; Janes, Kevin A
2016-02-24
Chemical inhibition and genetic knockdown of enzymes are not equivalent in cells, but network-level mechanisms that cause discrepancies between knockdown and inhibitor perturbations are not understood. Here we report that enzymes regulated by negative feedback are robust to knockdown but susceptible to inhibition. Using the Raf-MEK-ERK kinase cascade as a model system, we find that ERK activation is resistant to genetic knockdown of MEK but susceptible to a comparable degree of chemical MEK inhibition. We demonstrate that negative feedback from ERK to Raf causes this knockdown-versus-inhibitor discrepancy in vivo. Exhaustive mathematical modeling of three-tiered enzyme cascades suggests that this result is general: negative autoregulation or feedback favors inhibitor potency, whereas positive autoregulation or feedback favors knockdown potency. Our findings provide a rationale for selecting pharmacologic versus genetic perturbations in vivo and point out the dangers of using knockdown approaches in search of drug targets.
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Iwaki, Hiroyuki; Sasaki, Shigekazu; Matsushita, Akio; Ohba, Kenji; Matsunaga, Hideyuki; Misawa, Hiroko; Oki, Yutaka; Ishizuka, Keiko; Nakamura, Hirotoshi; Suda, Takafumi
2014-01-01
MYH7 (also referred to as cardiac myosin heavy chain β) gene expression is known to be repressed by thyroid hormone (T3). However, the molecular mechanism by which T3 inhibits the transcription of its target genes (negative regulation) remains to be clarified, whereas those of transcriptional activation by T3 (positive regulation) have been elucidated in detail. Two MCAT (muscle C, A, and T) sites and an A/T-rich region in the MYH7 gene have been shown to play a critical role in the expression of this gene and are known to be recognized by the TEAD/TEF family of transcription factors (TEADs). Using a reconstitution system with CV-1 cells, which has been utilized in the analysis of positive as well as negative regulation, we demonstrate that both T3 receptor (TR) β1 and α1 inhibit TEAD-dependent activation of the MYH7 promoter in a T3 dose-dependent manner. TRβ1 bound with GC-1, a TRβ-selective T3 analog, also repressed TEAD-induced activity. Although T3-dependent inhibition required the DNA-binding domain (DBD) of TRβ1, it remained after the putative negative T3-responsive elements were mutated. A co-immunoprecipitation study demonstrated the in vivo association of TRβ1 with TEAD-1, and the interaction surfaces were mapped to the DBD of the TRβ1 and TEA domains of TEAD-1, both of which are highly conserved among TRs and TEADs, respectively. The importance of TEADs in MYH7 expression was also validated with RNA interference using rat embryonic cardiomyocyte H9c2 cells. These results indicate that T3-bound TRs interfere with transactivation by TEADs via protein-protein interactions, resulting in the negative regulation of MYH7 promoter activity. PMID:24781449
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A mammalian pseudogene lncRNA at the interface of inflammation and anti-inflammatory therapeutics
Rapicavoli, Nicole A; Qu, Kun; Zhang, Jiajing; Mikhail, Megan; Laberge, Remi-Martin; Chang, Howard Y
2013-01-01
Pseudogenes are thought to be inactive gene sequences, but recent evidence of extensive pseudogene transcription raised the question of potential function. Here we discover and characterize the sets of mouse lncRNAs induced by inflammatory signaling via TNFα. TNFα regulates hundreds of lncRNAs, including 54 pseudogene lncRNAs, several of which show exquisitely selective expression in response to specific cytokines and microbial components in a NF-κB-dependent manner. Lethe, a pseudogene lncRNA, is selectively induced by proinflammatory cytokines via NF-κB or glucocorticoid receptor agonist, and functions in negative feedback signaling to NF-κB. Lethe interacts with NF-κB subunit RelA to inhibit RelA DNA binding and target gene activation. Lethe level decreases with organismal age, a physiological state associated with increased NF-κB activity. These findings suggest that expression of pseudogenes lncRNAs are actively regulated and constitute functional regulators of inflammatory signaling. DOI: http://dx.doi.org/10.7554/eLife.00762.001 PMID:23898399
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Structure-activity relationships between sterols and their thermal stability in oil matrix.
Hu, Yinzhou; Xu, Junli; Huang, Weisu; Zhao, Yajing; Li, Maiquan; Wang, Mengmeng; Zheng, Lufei; Lu, Baiyi
2018-08-30
Structure-activity relationships between 20 sterols and their thermal stabilities were studied in a model oil system. All sterol degradations were found to be consistent with a first-order kinetic model with determination of coefficient (R 2 ) higher than 0.9444. The number of double bonds in the sterol structure was negatively correlated with the thermal stability of sterol, whereas the length of the branch chain was positively correlated with the thermal stability of sterol. A quantitative structure-activity relationship (QSAR) model to predict thermal stability of sterol was developed by using partial least squares regression (PLSR) combined with genetic algorithm (GA). A regression model was built with R 2 of 0.806. Almost all sterol degradation constants can be predicted accurately with R 2 of cross-validation equals to 0.680. Four important variables were selected in optimal QSAR model and the selected variables were observed to be related with information indices, RDF descriptors, and 3D-MoRSE descriptors. Copyright © 2018 Elsevier Ltd. All rights reserved.
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The neural components of empathy: predicting daily prosocial behavior.
Morelli, Sylvia A; Rameson, Lian T; Lieberman, Matthew D
2014-01-01
Previous neuroimaging studies on empathy have not clearly identified neural systems that support the three components of empathy: affective congruence, perspective-taking, and prosocial motivation. These limitations stem from a focus on a single emotion per study, minimal variation in amount of social context provided, and lack of prosocial motivation assessment. In the current investigation, 32 participants completed a functional magnetic resonance imaging session assessing empathic responses to individuals experiencing painful, anxious, and happy events that varied in valence and amount of social context provided. They also completed a 14-day experience sampling survey that assessed real-world helping behaviors. The results demonstrate that empathy for positive and negative emotions selectively activates regions associated with positive and negative affect, respectively. In addition, the mirror system was more active during empathy for context-independent events (pain), whereas the mentalizing system was more active during empathy for context-dependent events (anxiety, happiness). Finally, the septal area, previously linked to prosocial motivation, was the only region that was commonly activated across empathy for pain, anxiety, and happiness. Septal activity during each of these empathic experiences was predictive of daily helping. These findings suggest that empathy has multiple input pathways, produces affect-congruent activations, and results in septally mediated prosocial motivation.
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Lying about the valence of affective pictures: an fMRI study.
Lee, Tatia M C; Lee, Tiffany M Y; Raine, Adrian; Chan, Chetwyn C H
2010-08-25
The neural correlates of lying about affective information were studied using a functional magnetic resonance imaging (fMRI) methodology. Specifically, 13 healthy right-handed Chinese men were instructed to lie about the valence, positive or negative, of pictures selected from the International Affective Picture System (IAPS) while their brain activity was scanned by a 3T Philip Achieva scanner. The key finding is that the neural activity associated with deception is valence-related. Comparing to telling the truth, deception about the valence of the affectively positive pictures was associated with activity in the inferior frontal, cingulate, inferior parietal, precuneus, and middle temporal regions. Lying about the valence of the affectively negative pictures, on the other hand, was associated with activity in the orbital and medial frontal regions. While a clear valence-related effect on deception was observed, common neural regions were also recruited for the process of deception about the valence of the affective pictures. These regions included the lateral prefrontal and inferior parietal regions. Activity in these regions has been widely reported in fMRI studies on deception using affectively-neutral stimuli. The findings of this study reveal the effect of valence on the neural activity associated with deception. Furthermore, the data also help to illustrate the complexity of the neural mechanisms underlying deception.
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The neural components of empathy: Predicting daily prosocial behavior
Rameson, Lian T.; Lieberman, Matthew D.
2014-01-01
Previous neuroimaging studies on empathy have not clearly identified neural systems that support the three components of empathy: affective congruence, perspective-taking, and prosocial motivation. These limitations stem from a focus on a single emotion per study, minimal variation in amount of social context provided, and lack of prosocial motivation assessment. In the current investigation, 32 participants completed a functional magnetic resonance imaging session assessing empathic responses to individuals experiencing painful, anxious, and happy events that varied in valence and amount of social context provided. They also completed a 14-day experience sampling survey that assessed real-world helping behaviors. The results demonstrate that empathy for positive and negative emotions selectively activates regions associated with positive and negative affect, respectively. In addition, the mirror system was more active during empathy for context-independent events (pain), whereas the mentalizing system was more active during empathy for context-dependent events (anxiety, happiness). Finally, the septal area, previously linked to prosocial motivation, was the only region that was commonly activated across empathy for pain, anxiety, and happiness. Septal activity during each of these empathic experiences was predictive of daily helping. These findings suggest that empathy has multiple input pathways, produces affect-congruent activations, and results in septally mediated prosocial motivation. PMID:22887480
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Frequency dependence limits divergent evolution by favouring rare immigrants over residents.
Bolnick, Daniel I; Stutz, William E
2017-06-08
Two distinct forms of natural selection promote adaptive biological diversity. Divergent selection occurs when different environments favour different phenotypes, leading to increased differences between populations. Negative frequency-dependent selection occurs when rare variants within a population are favoured over common ones, increasing diversity within populations. These two diversifying forces promote genetic variation at different spatial scales, and may act in opposition, but their relative effects remain unclear because they are rarely measured concurrently. Here we show that negative frequency-dependent selection within populations can favor rare immigrants over locally adapted residents. We reciprocally transplanted lake and stream ecotypes of threespine stickleback into lake and stream habitats, while manipulating the relative abundance of residents versus immigrants. We found negative frequency-dependence: survival was highest for the locally rare ecotype, rather than natives. Also, individuals with locally rare major histocompatibility complex (MHC) class IIb genotypes were infected by fewer parasites. This negative frequency-dependent selection will tend to favour rare immigrants over common residents, amplifying the effect of migration and undermining the efficacy of divergent natural selection to drive population differences. The only signal of divergent selection was a tendency for foreign fish to have higher parasite loads than residents, after controlling for MHC genotype rarity. Frequency-dependent ecological interactions have long been thought to promote speciation. Our results suggest a more nuanced view in which negative frequency dependence alters the fate of migrants to promote or constrain evolutionary divergence between populations.
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Rhomberg, Paul R.; Huband, Michael D.; Farrell, David J.
2016-01-01
Delafloxacin, an investigational anionic fluoroquinolone, is active against a broad range of Gram-positive and Gram-negative bacteria. In this study, 200 Streptococcus pneumoniae (plus 30 levofloxacin-resistant isolates), 200 Haemophilus influenzae, and 100 Moraxella catarrhalis isolates selected primarily from the United States (2014) were tested against delafloxacin and comparator agents. Delafloxacin was the most potent agent tested. MIC50 and MIC90 values against all S. pneumoniae isolates were 0.008 and 0.015 μg/ml. Delafloxacin susceptibility was not affected by β-lactamase status against H. influenzae and M. catarrhalis. PMID:27458220
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Using Quantile and Asymmetric Least Squares Regression for Optimal Risk Adjustment.
Lorenz, Normann
2017-06-01
In this paper, we analyze optimal risk adjustment for direct risk selection (DRS). Integrating insurers' activities for risk selection into a discrete choice model of individuals' health insurance choice shows that DRS has the structure of a contest. For the contest success function (csf) used in most of the contest literature (the Tullock-csf), optimal transfers for a risk adjustment scheme have to be determined by means of a restricted quantile regression, irrespective of whether insurers are primarily engaged in positive DRS (attracting low risks) or negative DRS (repelling high risks). This is at odds with the common practice of determining transfers by means of a least squares regression. However, this common practice can be rationalized for a new csf, but only if positive and negative DRSs are equally important; if they are not, optimal transfers have to be calculated by means of a restricted asymmetric least squares regression. Using data from German and Swiss health insurers, we find considerable differences between the three types of regressions. Optimal transfers therefore critically depend on which csf represents insurers' incentives for DRS and, if it is not the Tullock-csf, whether insurers are primarily engaged in positive or negative DRS. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.
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del Mar Alguacil, Maria; Torrecillas, Emma; Torres, Pilar; García-Orenes, Fuensanta; Roldán, Antonio
2012-01-01
The effects of irrigation with treated urban wastewater (WW) on the arbuscular mycorrhizal fungi (AMF) diversity and soil microbial activities were assayed on a long-term basis in a semiarid orange-tree orchard. After 43 years, the soil irrigated with fresh water (FW) had higher AMF diversity than soils irrigated with WW. Microbial activities were significantly higher in the soils irrigated with WW than in those irrigated with FW. Therefore, as no negative effects were observed on crop vitality and productivity, it seems that the ecosystem resilience gave rise to the selection of AMF species better able to thrive in soils with higher microbial activity and, thus, to higher soil fertility. PMID:23094075
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Lovewell, Thomas R J; McDonagh, Andrew J; Messenger, Andrew G; Azzouz, Mimoun; Tazi-Ahnini, Rachid
2015-01-01
The autoimmune regulator (AIRE) is expressed in the thymus, particularly in thymic medullary epithelial cells (mTECs), and is required for the ectopic expression of a diverse range of peripheral tissue antigens by mTECs, facilitating their ability to perform negative selection of auto-reactive immature T-cells. The expression profile of peripheral tissue antigens is affected not only by AIRE deficiency but also with variation of AIRE activity in the thymus. Therefore we screened 591bp upstream of the AIRE transcription start site including AIRE minimal promoter for single nucleotide polymorphism (SNPs) and identified two SNPs -655R (rs117557896) and -230Y (rs751032) respectively. To study the effect of these variations on AIRE promoter activity we generated a Flp-In host cell line which was stably transfected with a single copy of the reporter vector. Relative promoter activity was estimated by comparing the luciferase specific activity for lysates of the different reporter AIRE promoter-reporter gene constructs including AIRE-655G AIRE-230C, AIRE-655G AIRE-230T and AIRE-655A AIRE-230C. The analysis showed that the commonest haplotype AIRE-655G AIRE-230C has the highest luciferase specific activity (p<0.001). Whereas AIRE-655G AIRE-230T has a luciferase specific activity value that approaches null. Both AIRE promoter polymorphic sites have one allele that forms a CpG methylation site which we determined can be methylated in methylation assays using the M.SssI CpG methyltransferase. AIRE-230Y is in a conserved region of the promoter and is adjacent to a predicted WT1 transcription factor binding site, suggesting that AIRE-230Y affects AIRE expression by influencing the binding of biochemical factors to this region. Our findings show that AIRE-655GAIRE-230T haplotype could dramatically alter AIRE transcription and so have an effect on the process of negative selection and affect susceptibility to autoimmune conditions.
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2015-01-01
On the basis of recently reported abyssinone II and olympicin A, a series of chemically modified flavonoid phytochemicals were synthesized and evaluated against Mycobacterium tuberculosis and a panel of Gram-positive and -negative bacterial pathogens. Some of the synthesized compounds exhibited good antibacterial activities against Gram-positive pathogens including methicillin resistant Staphylococcus aureus with minimum inhibitory concentration as low as 0.39 μg/mL. SAR analysis revealed that the 2-hydrophobic substituent and the 4-hydrogen bond donor/acceptor of the 4-chromanone scaffold together with the hydroxy groups at 5- and 7-positions enhanced antibacterial activities; the 2′,4′-dihydroxylated A ring and the lipophilic substituted B ring of chalcone derivatives were pharmacophoric elements for antibacterial activities. Mode of action studies performed on selected compounds revealed that they dissipated the bacterial membrane potential, resulting in the inhibition of macromolecular biosynthesis; further studies showed that selected compounds inhibited DNA topoisomerase IV, suggesting complex mechanisms of actions for compounds in this series. PMID:25238443
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Self-Regulation as an Aid to Human Effectiveness and Biocybernetics Technology and Behavior
1976-01-01
feedback and two measures of information-processing capacity: short-term memory for digits and choice-reaction times. In this study, Beatty selected...Kamiya, like Beatty, found EEG activity unrelated to both memory for words and a simple reaction-time test. In another study, Kamiya (1972...creative intelligence, visual memory , mental arithmetic, digit memory span, and i,une tracking. The results were negative. Kamiya concluded that the self
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Leonetti, Francesco; Capaldi, Carmelida; Pisani, Leonardo; Nicolotti, Orazio; Muncipinto, Giovanni; Stefanachi, Angela; Cellamare, Saverio; Caccia, Carla; Carotti, Angelo
2007-10-04
Safinamide, (S)-N2-{4-[(3-fluorobenzyl)oxy]benzyl}alaninamide methanesulfonate, which is in phase III clinical trials as an anti-Parkinson drug, and a library of alkanamidic analogues were prepared through an expeditious solid-phase synthesis and evaluated for their monoamine oxidase B (MAO-B) and monoamine oxidase A (MAO-A) inhibitory activity and selectivity. (S)-3-Chlorobenzyloxyalaninamide (8) and (S)-3-chlorobenzyloxyserinamide (13) derivatives proved to be more potent MAO-B inhibitors than safinamide (IC50 = 33 and 43 nM, respectively, vs 98 nM) but with a lower MAO-B selectivity (SI = 3455 and 1967, respectively, vs 5918). The highest MAO-B inhibitory potency (IC50 = 17 nM) and a good selectivity (SI = 2941) were displayed by (R)-21, a tetrahydroisoquinoline analogue of safinamide. Structure-affinity relationships and docking simulations pointed out strong negative steric effects of alpha-aminoamide side chains and para substituents of the benzyloxy groups and favorable hydrophobic interactions of meta substituents. The significantly diverse MAO-B affinities of a number of R and S alpha-aminoamide enantiomers, including the two rigid analogues (21) of safinamide, indicated likely enantioselective interactions at the enzymatic binding sites.
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Molding the business end of neurotoxins by diversifying evolution.
Kozminsky-Atias, Adi; Zilberberg, Noam
2012-02-01
A diverse range of organisms utilize neurotoxins that target specific ion channels and modulate their activity. Typically, toxins are clustered into several multigene families, providing an organism with the upper hand in the never-ending predator-prey arms race. Several gene families, including those encoding certain neurotoxins, have been subject to diversifying selection forces, resulting in rapid gene evolution. Here we sought a spatial pattern in the distribution of both diversifying and purifying selection forces common to neurotoxin gene families. Utilizing the mechanistic empirical combination model, we analyzed various toxin families from different phyla affecting various receptors and relying on diverse modes of action. Through this approach, we were able to detect clear correlations between the pharmacological surface of a toxin and rapidly evolving domains, rich in positively selected residues. On the other hand, patches of negatively selected residues were restricted to the nontoxic face of the molecule and most likely help in stabilizing the tertiary structure of the toxin. We thus propose a mutual evolutionary strategy of venomous animals in which adaptive molecular evolution is directed toward the toxin active surface. Furthermore, we propose that the binding domains of unstudied toxins could be readily predicted using evolutionary considerations.
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Jabr, Mejdy M; Denke, Greg; Rawls, Eric; Lamm, Connie
2018-04-01
A number of studies have indicated that violent video gameplay is associated with higher levels of aggression and that desensitization and selective attention to violent content may contribute to this association. Utilizing an emotionally-charged rapid serial visual presentation (RSVP) task, the current study used two event-related potentials (ERPs) - the N1 and P3 - that have been associated with selective attention and desensitization as neurocognitive mechanisms potentially underlying the connection between gameplay and higher levels of aggression. Results indicated that video game players and non-players differed in N1 and P3 activation when engaged with emotionally-charged imagery. Additionally, P3 amplitudes moderated the association between video gameplay and aggression, indicating that players who display small P3 amplitudes also showed heightened levels of aggression. Follow-up moderational analyses revealed that individuals who play games for many hours and show more negative N1 amplitudes show smaller P3 activation. Together, our results suggest that selective attention to violent content and desensitization both play key roles in the association between video gameplay and aggression. Copyright © 2018 Elsevier Ltd. All rights reserved.
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Takahashi, Hidehiko; Kato, Motoichiro; Sassa, Takeshi; Shibuya, Tomohisa; Koeda, Michihiko; Yahata, Noriaki; Matsuura, Masato; Asai, Kunihiko; Suhara, Tetsuya; Okubo, Yoshiro
2010-01-01
Exercise and sports are increasingly being implemented in the management of schizophrenia. The process of action perception is as important as that of motor execution for learning and acquiring new skills. Recent studies have suggested that body-selective extrastriate body area (EBA) in the posterior temporal-occipital cortex is involved not only in static visual perception of body parts but also in the planning, imagination, and execution of actions. However, functional abnormality of the EBA in schizophrenia has yet to be investigated. Using functional magnetic resonance imaging (fMRI) with a task designed to activate the EBA by sports-related actions, we aimed to elucidate functional abnormality of the EBA during observation of sports-related actions in patients with schizophrenia. Twelve schizophrenia patients and 12 age-sex–matched control participants participated in the study. Using sports-related motions as visual stimuli, we examined brain activations during observation of context-congruent actions relative to context-incongruent actions by fMRI. Compared with controls, the patients with schizophrenia demonstrated diminished activation in the EBA during observation of sports-related context-congruent actions. Furthermore, the EBA activation in patients was negatively correlated with the severity of negative and general psychopathology symptoms measured by the Positive and Negative Syndrome Scale. Dysfunction of the EBA might reflect a difficulty in representing dynamic aspects of human actions and possibly lead to impairments of simulation, learning, and execution of actions in schizophrenia. PMID:18927345
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Ferguson, Scott B.; Anderson, Erik S.; Harshaw, Robyn B.; Thate, Tim; Craig, Nancy L.; Nelson, Hillary C. M.
2005-01-01
Hsf1p, the heat-shock transcription factor from Saccharomyces cerevisiae, has a low level of constitutive transcriptional activity and is kept in this state through negative regulation. In an effort to understand this negative regulation, we developed a novel genetic selection that detects altered expression from the HSP26 promoter. Using this reporter strain, we identified mutations and dosage compensators in the Ras/cAMP signaling pathway that decrease cAMP levels and increase expression from the HSP26 promoter. In yeast, low cAMP levels reduce the catalytic activity of the cAMP-dependent kinase PKA. Previous studies had proposed that the stress response transcription factors Msn2p/4p, but not Hsf1p, are repressed by PKA. However, we found that reduction or elimination of PKA activity strongly derepresses transcription of the small heat-shock genes HSP26 and HSP12, even in the absence of MSN2/4. In a strain deleted for MSN2/4 and the PKA catalytic subunits, expression of HSP12 and HSP26 depends on HSF1 expression. Our findings indicate that Hsf1p functions downstream of PKA and suggest that PKA might be involved in negative regulation of Hsf1p activity. These results represent a major change in our understanding of how PKA signaling influences the heat-shock response and heat-shock protein expression. PMID:15545649
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Eichmann, Mischa; Kugel, Harald; Suslow, Thomas
2008-12-01
Difficulties in identifying and differentiating one's emotions are a central characteristic of alexithymia. In the present study, automatic activation of the fusiform gyrus to facial emotion was investigated as a function of alexithymia as assessed by the 20-item Toronto Alexithymia Scale. During 3 Tesla fMRI scanning, pictures of faces bearing sad, happy, and neutral expressions masked by neutral faces were presented to 22 healthy adults who also responded to the Toronto Alexithymia Scale. The fusiform gyrus was selected as the region of interest, and voxel values of this region were extracted, summarized as means, and tested among the different conditions (sad, happy, and neutral faces). Masked sad facial emotions were associated with greater bilateral activation of the fusiform gyrus than masked neutral faces. The subscale, Difficulty Identifying Feelings, was negatively correlated with the neural response of the fusiform gyrus to masked sad faces. The correlation results suggest that automatic hyporesponsiveness of the fusiform gyrus to negative emotion stimuli may reflect problems in recognizing one's emotions in everyday life.
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Effects of overweight and leisure-time activities on aerobic fitness in urban and rural adolescents.
Albarwani, Sulayma; Al-Hashmi, Khamis; Al-Abri, Mohammed; Jaju, Deepali; Hassan, Mohammed O
2009-08-01
The aim of this research was to study the effects of overweight and leisure-time activities on maximal aerobic capacity (VO(2)max) in urban and rural Omani adolescents. A total of 529 (245 males, 284 females) adolescents, aged 15-16 years were randomly selected from segregated urban and rural schools. Maximal aerobic capacity was estimated using the multistage 20-meter shuttle-run test. The body mass index (BMI) of urban boys and girls was significantly higher than that of rural boys and girls. Urban boys and girls spent significantly less weekly hours on sports activities and significantly more weekly hours on TV/computer games than their rural counterpart. Urban boys and girls achieved significantly less VO(2)max than rural boys and girls (44.2 and 33.0 vs. 48.3 and 38.6 mL/kg/min, respectively). Maximal aerobic capacity was negatively correlated with BMI in urban boys. Overweight and inactivity had significant negative effects on cardiorespiratory fitness in urban boys and girls as compared to their rural counterparts. Weight gain in adolescence requires early intervention.
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Conformational study of melectin and antapin antimicrobial peptides in model membrane environments
NASA Astrophysics Data System (ADS)
Kocourková, Lucie; Novotná, Pavlína; Čujová, Sabína; Čeřovský, Václav; Urbanová, Marie; Setnička, Vladimír
2017-01-01
Antimicrobial peptides have long been considered as promising compounds against drug-resistant pathogens. In this work, we studied the secondary structure of antimicrobial peptides melectin and antapin using electronic (ECD) and vibrational circular dichroism (VCD) spectroscopies that are sensitive to peptide secondary structures. The results from quantitative ECD spectral evaluation by Dichroweb and CDNN program and from the qualitative evaluation of the VCD spectra were compared. The antimicrobial activity of the selected peptides depends on their ability to adopt an amphipathic α-helical conformation on the surface of the bacterial membrane. Hence, solutions of different zwitterionic and negatively charged liposomes and micelles were used to mimic the eukaryotic and bacterial biological membranes. The results show a significant content of α-helical conformation in the solutions of negatively charged liposomes mimicking the bacterial membrane, thus correlating with the antimicrobial activity of the studied peptides. On the other hand in the solutions of zwitterionic liposomes used as models of the eukaryotic membranes, the fraction of α-helical conformation was lower, which corresponds with their moderate hemolytic activity.
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High brilliance negative ion and neutral beam source
Compton, Robert N.
1991-01-01
A high brilliance mass selected (Z-selected) negative ion and neutral beam source having good energy resolution. The source is based upon laser resonance ionization of atoms or molecules in a small gaseous medium followed by charge exchange through an alkali oven. The source is capable of producing microampere beams of an extremely wide variety of negative ions, and milliampere beams when operated in the pulsed mode.
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Neural Correlates of Antidepressant Treatment Response in Adolescents with Major Depressive Disorder
Klimes-Dougan, Bonnie; Vu, Dung Pham; Westlund Schreiner, Melinda; Mueller, Bryon A.; Eberly, Lynn E.; Camchong, Jazmin; Westervelt, Ana; Lim, Kelvin O.
2016-01-01
Abstract Objective: The neural changes underlying response to antidepressant treatment in adolescents are unknown. Identification of neural change correlates of treatment response could (1) aid in understanding mechanisms of depression and its treatment and (2) serve as target biomarkers for future research. Method: Using functional magnetic resonance imaging, we examined changes in brain activation and functional connectivity in 13 unmedicated adolescents with major depressive disorder (MDD) before and after receiving treatment with a selective serotonin reuptake inhibitor medication for 8 weeks. Specifically, we examined brain activation during a negative emotion task and resting-state functional connectivity (RSFC), focusing on the amygdala to capture networks relevant to negative emotion. We conducted whole-brain analyses to identify how symptom improvement was related to change in brain activation during a negative emotion task or amygdala RSFC. Results: After treatment, clinical improvement was associated with decreased task activation in rostral and subgenual anterior cingulate cortex and increased activation in bilateral insula, bilateral middle frontal cortices, right parahippocampus, and left cerebellum. Analysis of change in amygdala RSFC showed that treatment response was associated with increased amygdala RSFC with right frontal cortex, but decreased amygdala RSFC with right precuneus and right posterior cingulate cortex. Conclusion: The findings represent a foothold for advancing understanding of pathophysiology of MDD in adolescents by revealing the critical neural circuitry changes that underlie a positive response to a standard treatment. Although preliminary, the present study provides a research platform for future work needed to confirm these biomarkers at a larger scale before using them in future target engagement studies of novel treatments. PMID:27159204
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Luo, W; Chen, M; Chen, A; Dong, W; Hou, X; Pu, B
2015-04-01
To isolate lactic acid bacteria (LAB) from pao cai, a Chinese traditional fermented vegetable, with outstanding inhibitory activity against Salmonella inoculated on fresh-cut apple, using a modelling method. Four kinds of pao cai were selected. A total of 122 isolates exhibited typical LAB characteristics: Gram-positive and catalase negative, among which 104 (85·24%) colonies showed antibacterial activity against Salmonella by the well diffusion assay. Four colonies showing maximum antibacterial radius against Salmonella were selected to co-inoculate with Salmonella on fresh-cut apple and stored at 10°C, further identified as three strains of Lactobacillus plantarum and one strain of Lactobacillus brevis by 16s rRNA gene sequence analysis. The modified Gompertz model was employed to analyse the growth of the micro-organisms on apple wedges. Two of the four selected strains showed antagonistic activity against Salmonella on fresh-cut apple, one of which, RD1, exhibited best inhibitory activity (Salmonella were greatly inhibited when co-inoculated with RD1 at 10°C at 168 h). No deterioration in odour or appearance of the apple piece was observed by the triangle test when fresh-cut apple was inoculated with RD1. The mathematical modelling method is essential to select LAB with outstanding inhibitory activity against Salmonella associated with fresh-cut apple. LAB RD1 holds promise for the preservation of fresh-cut apple. This study provided a new method on fresh-cut product preservation. Besides, to make the LAB isolating procedure a more correct one, this study first added the mathematical modelling method to the isolating procedure. © 2014 The Society for Applied Microbiology.
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Brödel, Andreas K; Jaramillo, Alfonso; Isalan, Mark
2017-09-01
Directed evolution is a powerful tool to improve the characteristics of biomolecules. Here we present a protocol for the intracellular evolution of proteins with distinct differences and advantages in comparison with established techniques. These include the ability to select for a particular function from a library of protein variants inside cells, minimizing undesired coevolution and propagation of nonfunctional library members, as well as allowing positive and negative selection logics using basally active promoters. A typical evolution experiment comprises the following stages: (i) preparation of a combinatorial M13 phagemid (PM) library expressing variants of the gene of interest (GOI) and preparation of the Escherichia coli host cells; (ii) multiple rounds of an intracellular selection process toward a desired activity; and (iii) the characterization of the evolved target proteins. The system has been developed for the selection of new orthogonal transcription factors (TFs) but is capable of evolving any gene-or gene circuit function-that can be linked to conditional M13 phage replication. Here we demonstrate our approach using as an example the directed evolution of the bacteriophage λ cI TF against two synthetic bidirectional promoters. The evolved TF variants enable simultaneous activation and repression against their engineered promoters and do not cross-react with the wild-type promoter, thus ensuring orthogonality. This protocol requires no special equipment, allowing synthetic biologists and general users to evolve improved biomolecules within ∼7 weeks.
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G protein-coupled estrogen receptor-selective ligands modulate endometrial tumor growth.
Petrie, Whitney K; Dennis, Megan K; Hu, Chelin; Dai, Donghai; Arterburn, Jeffrey B; Smith, Harriet O; Hathaway, Helen J; Prossnitz, Eric R
2013-01-01
Endometrial carcinoma is the most common cancer of the female reproductive tract. GPER/GPR30 is a 7-transmembrane spanning G protein-coupled receptor that has been identified as the third estrogen receptor, in addition to ERα and ERβ. High GPER expression is predictive of poor survival in endometrial and ovarian cancer, but despite this, the estrogen-mediated signaling pathways and specific estrogen receptors involved in endometrial cancer remain unclear. Here, employing ERα-negative Hec50 endometrial cancer cells, we demonstrate that GPER mediates estrogen-stimulated activation of ERK and PI3K via matrix metalloproteinase activation and subsequent transactivation of the EGFR and that ER-targeted therapeutic agents (4-hydroxytamoxifen, ICI182,780/fulvestrant, and Raloxifene), the phytoestrogen genistein, and the "ERα-selective" agonist propylpyrazole triol also function as GPER agonists. Furthermore, xenograft tumors of Hec50 cells yield enhanced growth with G-1 and estrogen, the latter being inhibited by GPER-selective pharmacologic antagonism with G36. These results have important implications with respect to the use of putatively ER-selective ligands and particularly for the widespread long-term use of "ER-targeted" therapeutics. Moreover, our findings shed light on the potential mechanisms of SERM/SERD side effects reported in many clinical studies. Finally, our results provide the first demonstration that pharmacological inhibition of GPER activity in vivo prevents estrogen-mediated tumor growth.
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Seamless Genome Editing in Rice via Gene Targeting and Precise Marker Elimination.
Nishizawa-Yokoi, Ayako; Saika, Hiroaki; Toki, Seiichi
2016-01-01
Positive-negative selection using hygromycin phosphotransferase (hpt) and diphtheria toxin A-fragment (DT-A) as positive and negative selection markers, respectively, allows enrichment of cells harboring target genes modified via gene targeting (GT). We have developed a successful GT system employing positive-negative selection and subsequent precise marker excision via the piggyBac transposon derived from the cabbage looper moth to introduce desired modifications into target genes in the rice genome. This approach could be applied to the precision genome editing of almost all endogenous genes throughout the genome, at least in rice.
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Liming effects on cadmium stabilization in upland soil affected by gold mining activity.
Hong, Chang Oh; Lee, Do Kyoung; Chung, Doug Young; Kim, Pil Joo
2007-05-01
To reduce cadmium (Cd) uptake of plants cultivated in heavy metal-contaminated soil, the best liming material was selected in the incubation test. The effect of the selected material was evaluated in the field. In the incubation experimentation, CaCO(3), Ca(OH)(2), CaSO(4).2H(2)O, and oyster shell meal were mixed with soil at rates corresponding to 0, 400, 800, 1600, 3200 mg Ca kg(-1). The limed soil was moistened to 70% of field moisture capacity, and incubated at 25 degrees C for 4 weeks. Ca(OH)(2) was found to be more efficient on reducing soil NH(4)OAc extractable Cd concentration, due to pH increase induced net negative charge. The selected Ca(OH)(2) was applied at rates 0, 2, 4, 8 Mg ha(-1) and then cultivated radish (Raphanus sativa L.) in the field. NH(4)OAc extractable Cd concentration of soil and plant Cd concentration decreased significantly with increasing Ca(OH)(2) rate, since alkaline-liming material markedly increased net negative charge of soil induced by pH increase, and decreased bioavailable Cd fractions (exchangeable + acidic and reducible Cd fraction) during radish cultivation. Cadmium uptake of radish could be reduced by about 50% by amending with about 5 Mg ha(-1) Ca(OH)(2) without adverse effect on radish yield and growth. The increase of net negative charge of soil by Ca(OH)(2) application may suppress Cd uptake and the competition between Ca(2+) and Cd(2+) may additionally affect the suppression of Cd uptake.
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Cos, P; Hermans, N; De Bruyne, T; Apers, S; Sindambiwe, J B; Vanden Berghe, D; Pieters, L; Vlietinck, A J
2002-02-01
A total of 45 Rwandan plant extracts, belonging to 37 different plant species out of 21 families, were investigated for their antibacterial, antifungal, and antiviral properties. The plants were selected on the base of their ethnomedicinal use against infections and autoimmune diseases. From all the plant extracts tested, only Clematis hirsuta (leaves) showed a pronounced antifungal activity against Candida albicans and the dermatophytes Trichophyton rubrum, Epidermophyton floccosum, and Microsporum canis. Seven plant extracts showed a high antiviral activity against the DNA-virus Herpes simplex type 1, while five and three plant extracts were highly active against the RNA-viruses Coxsackie and Polio, respectively. Only Macaranga kilimandscharica (leaves) showed an interesting anti-measles activity, whereas Eriosema montanum (leaves) and Entada abyssinica (leaves) were highly active against Semliki forest virus. Some plant extracts showed an antibacterial activity against Gram-positive bacteria and Mycobacterium fortuitum, but none of them were active against the Gram-negative bacteria tested.
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Reduced TCR signaling potential impairs negative selection but does not result in autoimmune disease
Hwang, SuJin; Song, Ki-Duk; Lesourne, Renaud; Lee, Jan; Pinkhasov, Julia; Li, LiQi; El-Khoury, Dalal
2012-01-01
Negative selection and regulatory T (T reg) cell development are two thymus-dependent processes necessary for the enforcement of self-tolerance, and both require high-affinity interactions between the T cell receptor (TCR) and self-ligands. However, it remains unclear if they are similarly impacted by alterations in TCR signaling potential. We generated a knock-in allele (6F) of the TCR ζ chain gene encoding a mutant protein lacking signaling capability whose expression is controlled by endogenous ζ regulatory sequences. Although negative selection was defective in 6F/6F mice, leading to the survival of autoreactive T cells, 6F/6F mice did not develop autoimmune disease. We found that 6F/6F mice generated increased numbers of thymus-derived T reg cells. We show that attenuation of TCR signaling potential selectively impacts downstream signaling responses and that this differential effect favors Foxp3 expression and T reg cell lineage commitment. These results identify a potential compensatory pathway for the enforcement of immune tolerance in response to defective negative selection caused by reduced TCR signaling capability. PMID:22945921
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Targeted σ factor turnover inserts negative control into a positive feedback loop
Donohue, Timothy J.
2009-01-01
Summary Since their classification as members of the σ70 super-family, Group IV alternative σ factors have been found to control gene expression in response to diverse environmental or stress signals. Activity of the Streptomyces coelicolor Group IV family member, σR (SigR), is increased by changes in the oxidation-reduction state of cytoplasmic disulphide bonds. Once released by its cognate anti-σ factor RsrA, σR activates expression of gene products that help cells reduce cytoplasmic disulphide bonds. In this issue of Molecular Microbiology, Kim and co-workers provide new insights into positive and negative control of σR activity. The authors show that a transcript derived from the inducible σR-dependent sigRrsrA p2 promoter operon encodes a σR protein of a higher molecular weight (termed σR′) than is found in uninduced cells. One major difference between σR′ and the smaller σR protein found in uninduced cells is the rapid proteolysis of σR′ by the ClpP1/P2 protease system. The genes for the ClpP1/ClpP2 protease subunits are themselves members of the σR regulon. The newly identified positive (σR′ synthesis) and negative control (selective σR′ turnover) aspects of this circuit are either found or predicted to exist in other related Group IV σ factor family members. PMID:19682265
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Affective traits link to reliable neural markers of incentive anticipation.
Wu, Charlene C; Samanez-Larkin, Gregory R; Katovich, Kiefer; Knutson, Brian
2014-01-01
While theorists have speculated that different affective traits are linked to reliable brain activity during anticipation of gains and losses, few have directly tested this prediction. We examined these associations in a community sample of healthy human adults (n=52) as they played a Monetary Incentive Delay task while undergoing functional magnetic resonance imaging (FMRI). Factor analysis of personality measures revealed that subjects independently varied in trait Positive Arousal and trait Negative Arousal. In a subsample (n=14) retested over 2.5years later, left nucleus accumbens (NAcc) activity during anticipation of large gains (+$5.00) and right anterior insula activity during anticipation of large losses (-$5.00) showed significant test-retest reliability (intraclass correlations>0.50, p's<0.01). In the full sample (n=52), trait Positive Arousal correlated with individual differences in left NAcc activity during anticipation of large gains, while trait Negative Arousal correlated with individual differences in right anterior insula activity during anticipation of large losses. Associations of affective traits with neural activity were not attributable to the influence of other potential confounds (including sex, age, wealth, and motion). Together, these results demonstrate selective links between distinct affective traits and reliably-elicited activity in neural circuits associated with anticipation of gain versus loss. The findings thus reveal neural markers for affective dimensions of healthy personality, and potentially for related psychiatric symptoms. © 2013. Published by Elsevier Inc. All rights reserved.
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Affective traits link to reliable neural markers of incentive anticipation
Wu, Charlene C.; Samanez-Larkin, Gregory R.; Katovich, Kiefer; Knutson, Brian
2013-01-01
While theorists have speculated that different affective traits are linked to reliable brain activity during anticipation of gains and losses, few have directly tested this prediction. We examined these associations in a community sample of healthy human adults (n = 52) as they played a Monetary Incentive Delay Task while undergoing functional magnetic resonance imaging (FMRI). Factor analysis of personality measures revealed that subjects independently varied in trait Positive Arousal and Negative Arousal. In a subsample (n = 14) retested over 2.5 years later, left nucleus accumbens (NAcc) activity during anticipation of large gains (+$5.00) and right anterior insula activity during anticipation of large losses (−$5.00) showed significant test-retest reliability (intraclass correlations > 0.50, p’s < 0.01). In the full sample (n = 52), trait Positive Arousal correlated with individual differences in left NAcc activity during anticipation of large gains, while trait Negative Arousal correlated with individual differences in right anterior insula activity during anticipation of large losses. Associations of affective traits with neural activity were not attributable to the influence of other potential confounds (including sex, age, wealth, and motion). Together, these results demonstrate selective links between distinct affective traits and reliably-elicited activity in neural circuits associated with anticipation of gain versus loss. The findings thus reveal neural markers for affective dimensions of healthy personality, and potentially for related psychiatric symptoms. PMID:24001457
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Exaggerated Health Benefits of Physical Fitness and Activity dueto Self-selection.
DOE Office of Scientific and Technical Information (OSTI.GOV)
Williams, Paul T.
Background: The predicted health benefits of becomingphysically active or fit will be exaggerated if health outcomes causefitness and activity rather than the converse in prospective andcross-sectional epidemiological studies. Objective: Assess whether therelationships of adiposity to fitness and activity are explained byadiposity prior to exercising. Design: Cross-sectional study of physicalfitness (running speed during 10km foot race) and physical activity(weekly running distance) to current BMI (BMIcurrent) and BMI at thestart of running (BMIstarting) in 44,370 male and 25,252 femaleparticipants of the National Runners' Health Study. Results: BMIstartingexplained all of the association between fitness and BMIcurrent in bothsexes, but less than a thirdmore » of the association between physical activityand BMIcurrent in men. In women, BMIstarting accounted for 58 percent ofthe association between BMIcurrent and activity levels. The 95thpercentile of BMIcurrent showed substantially greater declines withfitness and activity levels than the 5th percentile of BMIcurrent in men(i.e., the negative slope for 95th percentile was 2.6-fold greater thanthe 5th percentile for fitness and 3-fold greater for activity) and women(6-fold and 3.4-fold greater, respectively). At all percentiles, theregression slopes relating BMIstarting to fitness were comparable orgreater (more negative) than the slopes relating BMIcurrent to fitness,whereas the converse was true for activity. Conclusion: Self-selectionbias accounts for all of the association between fitness and adiposityand probably a portion of other health outcomes, but has less affect onassociations involving physical activity« less
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Depoortère, R; Auclair, A L; Bardin, L; Slot, L Bruins; Kleven, M S; Colpaert, F; Vacher, B; Newman-Tancredi, A
2007-01-01
Background and purpose: The D2/D3 receptor antagonist, D4 receptor partial agonist, and high efficacy 5-HT1A receptor agonist F15063 was shown to be highly efficacious and potent in rodent models of activity against positive symptoms of schizophrenia. However F15063 induced neither catalepsy nor the ‘serotonin syndrome'. Here, we evaluated its profile in rat models predictive of efficacy against negative symptoms/cognitive deficits of schizophrenia. Experimental approach: F15063, given i.p., was assessed in models of behavioural deficits induced by interference with the NMDA/glutamatergic (phencyclidine: PCP) or cholinergic (scopolamine) systems. Key results: Through 5-HT1A activation, F15063 partially alleviated (MED: 0.04 mg kg−1) PCP-induced social interaction deficit between two adult rats, without effect by itself, underlining its potential to combat negative symptoms. At doses above 0.16 mg kg−1, F15063 reduced interaction by itself. F15063 (0.16 mg kg−1) selectively re-established PCP-impaired ‘cognitive flexibility' in a reversal learning task, suggesting potential against adaptability deficits. F15063 (0.04–0.63 mg kg−1) also reversed scopolamine-induced amnesia in a juvenile-adult rat social recognition test, indicative of a pro-cholinergic influence. Activity in this latter test is consistent with its D4 partial agonism, as it was blocked by the D4 antagonist L745,870. Finally, F15063 up to 40 mg kg−1 did not disrupt basal prepulse inhibition of startle reflex in rats, a marker of sensorimotor gating. Conclusions and implications: The balance of D2/D3, D4 and 5-HT1A receptor interactions of F15063 yields a promising profile of activity in models of cognitive deficits and negative symptoms of schizophrenia. PMID:17375085
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Ali, Faleh Mohamed Hussain; Reka, Husein; Renwick, Matthew J; Roman, Gabriela D; Mossialos, Elias
2016-01-01
Aims Understanding type 2 diabetes mellitus is critical for designing effective diabetes prevention policies in Qatar and the Middle East. Methods Using the Qatar 2012 WHO STEPwise approach to surveillance survey, a subsample of 1224 Qatari participants aged 18–64 years was selected. Subjects had their fasting blood glucose levels tested, had not been diagnosed with or treated for diabetes, had a fasting time >12 hours and were not pregnant. We applied a hypothesized structural equation model (SEM) to assess sociodemographic, behavioral, anthropometric and metabolic variables affecting persons with type 2 diabetes mellitus. Results There is a direct effect of triglyceride levels (0.336) and body mass index (BMI) (0.164) on diabetes status. We also found that physical activity levels negatively affect BMI (−0.148) and positively affect high-density lipoprotein (HDL) (0.106); sociodemographic background negatively affects diet (−0.522) and BMI (−0.352); HDL positively affects total cholesterol (0.230) and has a negative effect on BMI (−0.108), triglycerides (−0.128) and waist circumference (−0.104). Diet has a positive effect on triglycerides (0.281) while family history of diabetes negatively affects total cholesterol (−0.104). BMI has a positive effect on waist circumference (0.788) and mediates the effects of physical activity over diabetes status (−0.028). BMI also mediates the effects that sociodemographic factors (−0.058) and physical activity (−0.024) have on diabetes status. BMI and HDL (−0.002) together mediate the effect of physical activity on diabetes status and similarly HDL and tryglycerides (−0.005) also mediate the effect of physical activity on diabetes status. Finally diet and tryglycerides mediate the effects that sociodemographic factors have on diabetes status (−0.049). Conclusions This study's main finding is that triglyceride levels and BMI are the main variables directly affecting diabetes status in the Qatari population. PMID:27752326
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Lam, Carol K L; Chari, Madhu; Rutter, Guy A; Lam, Tony K T
2011-01-01
Hypothalamic nutrient sensing regulates glucose production, but the neuronal circuits involved remain largely unknown. Recent studies underscore the importance of N-methyl-d-aspartate (NMDA) receptors in the dorsal vagal complex in glucose regulation. These studies raise the possibility that hypothalamic nutrient sensing activates a forebrain-hindbrain NMDA-dependent circuit to regulate glucose production. We implanted bilateral catheters targeting the mediobasal hypothalamus (MBH) (forebrain) and dorsal vagal complex (DVC) (hindbrain) and performed intravenous catheterizations to the same rat for infusion and sampling purposes. This model enabled concurrent selective activation of MBH nutrient sensing by either MBH delivery of lactate or an adenovirus expressing the dominant negative form of AMPK (Ad-DN AMPK α2 [D¹⁵⁷A]) and inhibition of DVC NMDA receptors by either DVC delivery of NMDA receptor blocker MK-801 or an adenovirus expressing the shRNA of NR1 subunit of NMDA receptors (Ad-shRNA NR1). Tracer-dilution methodology and the pancreatic euglycemic clamp technique were performed to assess changes in glucose kinetics in the same conscious, unrestrained rat in vivo. MBH lactate or Ad-DN AMPK with DVC saline increased glucose infusion required to maintain euglycemia due to an inhibition of glucose production during the clamps. However, DVC MK-801 negated the ability of MBH lactate or Ad-DN AMPK to increase glucose infusion or lower glucose production. Molecular knockdown of DVC NR1 of NMDA receptor via Ad-shRNA NR1 injection also negated MBH Ad-DN AMPK to lower glucose production. Molecular and pharmacological inhibition of DVC NMDA receptors negated hypothalamic nutrient sensing mechanisms activated by lactate metabolism or AMPK inhibition to lower glucose production. Thus, DVC NMDA receptor is required for hypothalamic nutrient sensing to lower glucose production and that hypothalamic nutrient sensing activates a forebrain-hindbrain circuit to lower glucose production.
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Liljavirta, J; Ekman, A; Knight, J S; Pernthaner, A; Iivanainen, A; Niku, M
2013-09-01
Due to a limited range of immunoglobulin (Ig) genes, cattle and several other domestic animals rely on postrecombinatorial amplification of the primary repertoire. We report that activation-induced cytidine deaminase (AID) is strongly expressed in the fetal bovine ileal Peyer's patch and spleen but not in fetal bone marrow. The numbers of IGHV (immunoglobulin heavy chain variable) mutations correlate with AID expression. The mutational profile in the fetuses is similar to postnatal and immunized calves, with targeting of complementarity-determining region (CDR) over framework region (FR), preference of replacement over silent mutations in CDRs but not in FRs, and targeting of the AID hotspot motif RGYW/WRCY. Statistical analysis indicates negative selection on FRs and positive selection on CDRs. Our results suggest that AID-mediated somatic hypermutation and selection take place in bovine fetuses, implying a role for AID in the diversification of the primary antibody repertoire in the absence of exogenous antigens.
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Ding, Shujing; Dudley, Ed; Plummer, Sue; Tang, Jiandong; Newton, Russell P; Brenton, A Gareth
2006-01-01
A reversed-phase high-performance liquid chromatography/electrospray ionisation mass spectrometry (RP-HPLC/ESI-MS) method was developed and validated for the simultaneous determination of ten major active components in Ginkgo biloba extract (bilobalide, ginkgolides A, B, C, quercetin, kaempferol, isorhamnetin, rutin hydrate, quercetin-3-beta-D-glucoside and quercitrin hydrate) which have not been previously reported to be quantified in a single analysis. The ten components exhibit baseline separation in 50 min by C18 chromatography using a water/1:1 (v/v) methanol/acetonitrile gradient. Quantitation was performed using negative ESI-MS in selected ion monitoring (SIM) mode. Good reproducibility and recovery were obtained by this method. The sensitivity of both UV and different mass spectrometry modes (full scan, selected ion monitoring (SIM), and selected reaction monitoring (SRM)) were compared and both quantitation with and without internal standard were evaluated. The analysis of Ginkgo biloba commercial products showed remarkable variations in the rutin and quercetin content as well as the terpene lactone contents although all the products satisfy the conventional quality control method. Copyright 2006 John Wiley & Sons, Ltd.
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Response of local vascular volumes to lower body negative pressure stress
NASA Technical Reports Server (NTRS)
Wolthuis, R. A.; Leblanc, A.; Carpentier, W. A.; Bergman, S. A., Jr.
1975-01-01
The present study involved an intravenous injection of radioactive iodinated serum albumin, equilibration of this isotope within the vascular space, and the continuous measurement of isotope activity over selected anatomical areas before, during and following multiple human LBNP tests. Both rate and magnitude of vascular pooling were distinctly different within each of five selected lower body anatomical areas. In the upper body, all areas except the abdomen showed depletions from their resting vascular volumes during LBNP. The presence of uniquely different pooling patterns in the lower body, the apparent stability of abdominal vascular volumes, and a possible decrease in cerebral blood volume during LBNP represent the major findings of this study.
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Chen, Yu-Fon; Shiau, Ai-Li; Chang, Sue-Joan; Fan, Nai-Shin; Wang, Chung-Teng; Wu, Chao-Liang; Jan, Jeng-Shiung
2017-06-01
Herein, we report the oncolytic activity of cationic, one-dimensional (1D) fibril assemblies formed from coil-sheet poly(L-lysine)-block-poly(L-threonine) (PLL-b-PLT) block copolypeptides for cancer therapy. The 1D fibril assemblies can efficiently interact with negatively charged cellular and mitochondrial membranes via electrostatic interactions, leading to necrosis via membrane lysis and apoptosis via the mitochondria-lytic effect. The concept is analogous to that of 1D drug carriers that exhibit enhanced cell penetration. In comparison to free PLL chains, PLL-b-PLT fibril assemblies exhibit selective cytotoxicity toward cancer cells, low hemolysis activity, enhanced membranolytic activity, and a different apoptosis pathway, which may be due to differences in the peptide-membrane interactions. Antitumor studies using a metastatic LL2 lung carcinoma model indicate that the fibril assemblies significantly inhibited tumor growth, improved survival in tumor-bearing mice and suppressed lung metastasis without obvious body weight loss. An additive efficacy was also observed for treatment with both PLL-b-PLT and cisplatin. These results support the feasibility of using 1D fibril assemblies as potential apoptotic anticancer therapeutics. We report that cationic, one-dimensional (1D) fibril assemblies formed by coil-sheet poly(L-lysine)-block-poly(L-threonine) (PLL-b-PLT) block copolypeptides exhibited potent anticancer activity by enhancing membranolysis. The 1D fibril assemblies can efficiently interact with negatively charged cellular and mitochondrial membranes via electrostatic interactions, leading to necrosis via membrane lysis and apoptosis via mitochondria-lytic effect. Moreover, the fibril assemblies exhibited low hemolytic activity and selective cytotoxicity toward cancer cell, which is advantageous as compared to PLL and most antimicrobial/anticancerous peptides. This study provides a new concept of using cationic, 1D fibril assemblies for cancer therapy. Copyright © 2017 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.
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Molecular Mechanisms of Innate Immune Inhibition by Non-Segmented Negative-Sense RNA Viruses
DOE Office of Scientific and Technical Information (OSTI.GOV)
Chatterjee, Srirupa; Basler, Christopher F.; Amarasinghe, Gaya K.
The host innate immune system serves as the first line of defense against viral infections. Germline-encoded pattern recognition receptors detect molecular patterns associated with pathogens and activate innate immune responses. Of particular relevance to viral infections are those pattern recognition receptors that activate type I interferon responses, which establish an antiviral state. The order Mononegavirales is composed of viruses that possess single-stranded, non-segmented negative-sense (NNS) RNA genomes and are important human pathogens that consistently antagonize signaling related to type I interferon responses. NNS viruses have limited encoding capacity compared to many DNA viruses, and as a likely consequence, most openmore » reading frames encode multifunctional viral proteins that interact with host factors in order to evade host cell defenses while promoting viral replication. In this review, we will discuss the molecular mechanisms of innate immune evasion by select NNS viruses. A greater understanding of these interactions will be critical in facilitating the development of effective therapeutics and viral countermeasures.« less
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Ben Cheikh, Ridha; Latiri, Imed; Dogui, Mohamed; Ben Saad, Helmi
2017-06-01
Most of the available literature related to aspects of sleep deprivation is primarily focused on memory and learning, and studies regarding its effects on selective attention and/or physical performance are scarce. Moreover, the available literature includes general population or people involved in team sports (e.g. volleyball). However, only few studies were performed on athletes involved in combat sports (e.g. karate). The aim of the present study was to determine the effects of a total one-night sleep deprivation (1NSD) on activation and inhibition processes of selective attention and on maximal isometric force in karate athletes. Twelve young karate athletes (mean age 16.9±0.8 years) were enrolled. The protocol consists of two successive sessions: a normal night's sleep (NNS) and a total 1NSD. After each night, athletes performed selective attention and muscle strength tests during the same following three times (T) of the day: T1NNS or T11NSD: 8-9 a.m.; T2NNS or T21NSD: 12 a.m.-1 p.m.; T3NNS or T31NSD: 4-5 p.m. Activation (simple [SRT] and choice reaction times [CRT]) and inhibition (negative priming) processes were evaluated using Superlab v. 4.5 software (Cedrus Corporation, San Pedro, CA, USA). Maximal force and maximal force time (MFT) of brachial biceps isometric contraction were evaluated (Ergo System®, Globus, Codognè, Italy). A non-parametric test was used to evaluate the sessions (NNS vs. SND for the same time period) and time (T1NNS vs. 1NSD) effects. All athletes completed all tests after a NNS. Twelve, eleven and four athletes completed all tests at T11NSD, T21NSD and T31NSD, respectively. As for sessions effects, no statistically significant difference was found. As for time effects, a significant increase in SRT at T21NSD vs. T1NNS (345±47 vs. 317±33 ms, respectively), a significant increase in MFT at T21NSD vs. T1NNS (2172±260 vs.1885±292 ms, respectively), and no significant changes in CRT and negative priming reaction time or MFT data were observed. 1NSD affects both activation processes of selective attention and maximal isometric strength, two key skills in combat sports.
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Anti-microbial principles of selected remedial plants from Southern India.
Tirupathi, Rao G; Suresh, Babu K; Ujwal, Kumar J; Sujana, P; Raoa, A Veerabhadr; Sreedhar, A S
2011-08-01
To examine the anti-bacterial activity of leaf extracts of Morus alba L. (Moraceae) and Piper betel L. (Piperaceae), and seed extracts of Bombax ceiba L. (Borabacaceae). We have partially purified plant extracts by solvent extraction method, and evaluated the effect of individual fractions on bacterial growth using Escherichia coli (E. coli), Pseudomonas aeruginosa (P. aeruginosa) and Staphylococcus aureus (S. aureus) bacterial strains. Compared with Morus and Bombax fractions, Piper fractions showed significant growth inhibition on all the three types of bacteria studied. The EtOAc-hexane fractions of Piper leaves exhibited significant anti-bacterial activity with minimum inhibitory concentrations (MIC) of 50 µg/mL culture against both gram-positive and gram-negative bacteria. The EtOAc-fractions I, II, and IV inhibited bacterial colony formation on soft agar in addition to growth inhibition. A combination treatment of piper fractions with ampicillin resulted in significant growth inhibition in E. coli and P. aeruginosa, and combination with anticancer drug geldanamycin (2µg/mL) showed selective growth inhibition against P. aeruginosa and S. aureus. Three major compounds, i.e., eugenol, 3-hexene-ol and stigmasterol, were primarily identified from Piper betel leaf extractions. Among the individual compounds, eugenol treatment showed improved growth inhibition compared with stigmasterol and 3-hexene-ol. We are reporting potential anti-bacterial compounds from Piper betel against both gram-positive and gram-negative bacteria either alone or in combination with drug treatment.
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Selective Imaging of Gram-Negative and Gram-Positive Microbiotas in the Mouse Gut.
Wang, Wei; Zhu, Yuntao; Chen, Xing
2017-08-01
The diverse gut microbial communities are crucial for host health. How the interactions between microbial communities and between host and microbes influence the host, however, is not well understood. To facilitate gut microbiota research, selective imaging of specific groups of microbiotas in the gut is of great utility but remains technically challenging. Here we present a chemical approach that enables selective imaging of Gram-negative and Gram-positive microbiotas in the mouse gut by exploiting their distinctive cell wall components. Cell-selective labeling is achieved by the combined use of metabolic labeling of Gram-negative bacterial lipopolysaccharides with a clickable azidosugar and direct labeling of Gram-positive bacteria with a vancomycin-derivatized fluorescent probe. We demonstrated this strategy by two-color fluorescence imaging of Gram-negative and Gram-positive gut microbiotas in the mouse intestines. This chemical method should be broadly applicable to different gut microbiota research fields and other bacterial communities studied in microbiology.
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Yohn, Samantha; Covey, Daniel; Foster, Daniel; Moehle, Mark; Galbraith, Jordan; Cheer, Joseph; Lindsley, Craig; Jeffrey Conn, P
2018-01-01
Abstract Background Clinical and preclinical studies suggest that selective activators of the muscarinic M4 receptor have exciting potential as a novel approach for treatment of schizophrenia. M4 reduces striatal dopamine (DA) though release of endocannabinoids (eCB), providing a mechanism for local effects on DA signaling in the striatum. M4 signals through Gαi/o and does not couple to Gαq/11 or induce calcium (Ca++) mobilization. This raises the possibility that M4-induced eCB release and inhibition of DA release may require co-activation of another receptor that activates Gαq/11. If so, this receptor could provide a novel target that may be more proximal to inhibition of DA release. Interestingly, the group 1 metabotropic glutamate (mGlu) receptors (mGlu1 and Glu5), couple to Gαq/11 and activate eCB signaling in multiple brain regions. Methods We tested the hypothesis that M4-induced reductions in DA release and subsequent antipsychotic-effect requires co-activation of group 1 mGlu receptors. The effect of M4 activation on electrically-evoked DA release in striatal slices was assessed using fast-scan cyclic voltammetry (FSCV) in the absence or presence of selective negative allosteric modulators (NAMs) of group 1 mGlu receptor subtypes. To evaluate the potential role of mGlu1, we determined the effects of a selective mGlu1 positive allosteric modulators (PAMs) on striatal DA release and antipsychotic-like activity in rodent models that are dependent on increased DA transmission. Since reductions in DA signaling, including D1 signaling have been implicated in reduced motivation, we also determined the effects of an mGlu1 PAM, M4 PAM, and the typical antipsychotic haloperidol on motivational responding in a progressive ratio (PR) schedule. Results We now present exciting new data in which we found that activation of mGlu1 through application of exogenous agonists or selective stimulation of thalamostriatal afferents induces a reduction of striatal DA release and that selective mGlu1 PAMs have robust antipsychotic-like effects in rodent models. Interestingly, our studies also suggest that mGlu1 activation is required for M4 PAM-induced inhibition of DA release and antipsychotic-like effects. However, in contrast to available antipsychotic agents, the present results and previous studies suggest that mGlu1 and M4 PAMs reduce DA signaling through local release of an eCB from striatal SPNs and activation of CB2 receptors on neighboring DA terminals to reduce DA release. While these studies suggest that the effects of M4 PAMs on DA release require activation of mGlu1, we have also found that these targets have important differences. Most notably, M4 PAMs also directly inhibits D1 signaling in D1-SPN terminals in the substatnia nigra pars reticulata (SNr). Unlike M4, mGlu1 does not directly inhibit DA D1 receptor signaling and does not induce behavioral changes that could be associated with negative symptoms. Discussion Our findings are especially interesting in light of recent findings that multiple loss of function single nucleotide polymorphisms (SNPs) in the human gene encoding mGlu1 (GRM1) are associated with schizophrenia, and points to GRM1/mGlu1 as a gene within the “druggable genome” that could be targeted for treatment of schizophrenia. Recent clinical imaging studies suggesting that symptoms in schizophrenia patients are associated with selective increases in striatal DA signaling and while extrastriatal regions display hypo-dopaminergic function; thus, mGlu1 and M4 PAMs may provide a mechanism for selective inhibition of DA release in striatal regions that are important for antipsychotic efficacy, without further disruptions in extrastriatal DA signaling.
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Door detection in images based on learning by components
NASA Astrophysics Data System (ADS)
Cicirelli, Grazia; D'Orazio, Tiziana; Ancona, Nicola
2001-10-01
In this paper we present a vision-based technique for detecting targets of the environment which has to be reached by an autonomous mobile robot during its navigational task. The targets the robot has to reach are the doors of our office building. Color and shape information are used as identifying features for detecting principal components of the door. In fact in images the door can appear of different dimensions depending on the attitude of the robot with respect to the door, therefore detection of the door is performed by detecting its most significant components in the image. Positive and negative examples, in form of image patterns, are manually selected from real images for training two neural classifiers in order to recognize the single components. Each classifier has been realized by a feed-forward neural network with one hidden layer and sigmoid activation function. Moreover for selecting negative examples, relevant for the problem at hand, a bootstrap technique has been used during the training process. Finally the detecting system has been applied to several test real images for evaluating its performance.
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New β-Lactamase Inhibitors: a Therapeutic Renaissance in an MDR World
Drawz, Sarah M.; Papp-Wallace, Krisztina M.
2014-01-01
As the incidence of Gram-negative bacterial infections for which few effective treatments remain increases, so does the contribution of drug-hydrolyzing β-lactamase enzymes to this serious clinical problem. This review highlights recent advances in β-lactamase inhibitors and focuses on agents with novel mechanisms of action against a wide range of enzymes. To this end, we review the β-lactamase inhibitors currently in clinical trials, select agents still in preclinical development, and older therapeutic approaches that are being revisited. Particular emphasis is placed on the activity of compounds at the forefront of the developmental pipeline, including the diazabicyclooctane inhibitors (avibactam and MK-7655) and the boronate RPX7009. With its novel reversible mechanism, avibactam stands to be the first new β-lactamase inhibitor brought into clinical use in the past 2 decades. Our discussion includes the importance of selecting the appropriate partner β-lactam and dosing regimens for these promising agents. This “renaissance” of β-lactamase inhibitors offers new hope in a world plagued by multidrug-resistant (MDR) Gram-negative bacteria. PMID:24379206
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Counterintuitive effects of negative social feedback on attention.
Anderson, Brian A
2017-04-01
Which stimuli we pay attention to is strongly influenced by learning. Stimuli previously associated with reward outcomes, such as money and food, and stimuli previously associated with aversive outcomes, such as monetary loss and electric shock, automatically capture attention. Social reward (happy expressions) can bias attention towards associated stimuli, but the role of negative social feedback in biasing attentional selection remains unexplored. On the one hand, negative social feedback often serves to discourage particular behaviours. If attentional selection can be curbed much like any other behavioural preference, we might expect stimuli associated with negative social feedback to be more readily ignored. On the other hand, if negative social feedback influences attention in the same way that other aversive outcomes do, such feedback might ironically bias attention towards the stimuli it is intended to discourage selection of. In the present study, participants first completed a training phase in which colour targets were associated with negative social feedback. Then, in a subsequent test phase, these same colour stimuli served as task-irrelevant distractors during a visual search task. The results strongly support the latter interpretation in that stimuli previously associated with negative social feedback impaired search performance.
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Elling, Ludger; Steinberg, Christian; Bröckelmann, Ann-Kathrin; Dobel, Christan; Bölte, Jens; Junghofer, Markus
2011-01-01
Background Acute stress is a stereotypical, but multimodal response to a present or imminent challenge overcharging an organism. Among the different branches of this multimodal response, the consequences of glucocorticoid secretion have been extensively investigated, mostly in connection with long-term memory (LTM). However, stress responses comprise other endocrine signaling and altered neuronal activity wholly independent of pituitary regulation. To date, knowledge of the impact of such “paracorticoidal” stress responses on higher cognitive functions is scarce. We investigated the impact of an ecological stressor on the ability to direct selective attention using event-related potentials in humans. Based on research in rodents, we assumed that a stress-induced imbalance of catecholaminergic transmission would impair this ability. Methodology/Principal Findings The stressor consisted of a single cold pressor test. Auditory negative difference (Nd) and mismatch negativity (MMN) were recorded in a tonal dichotic listening task. A time series of such tasks confirmed an increased distractibility occuring 4–7 minutes after onset of the stressor as reflected by an attenuated Nd. Salivary cortisol began to rise 8–11 minutes after onset when no further modulations in the event-related potentials (ERP) occurred, thus precluding a causal relationship. This effect may be attributed to a stress-induced activation of mesofrontal dopaminergic projections. It may also be attributed to an activation of noradrenergic projections. Known characteristics of the modulation of ERP by different stress-related ligands were used for further disambiguation of causality. The conjuncture of an attenuated Nd and an increased MMN might be interpreted as indicating a dopaminergic influence. The selective effect on the late portion of the Nd provides another tentative clue for this. Conclusions/Significance Prior studies have deliberately tracked the adrenocortical influence on cognition, as it has proven most influential with respect to LTM. However, current cortisol-optimized study designs would have failed to detect the present findings regarding attention. PMID:21483666
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Chappell, Amy S; Iyengar, Smriti; Lobo, Evelyn D; Prucka, William R
2014-06-01
This article reports results of 2 studies investigating LY545694 in pain due to osteoarthritis (OA) of the knee and diabetic peripheral neuropathic pain (DPNP). Study I randomized patients to either of 2 doses of LY545694 or to placebo, and study II randomized patients to either of 3 doses of LY545694, to pregabalin, or to placebo. No significant differences between LY545694 groups and placebo were observed on the primary (average pain severity) or secondary efficacy measures in either study. Notably, study I lacked an active control, and, in study II, pregabalin, did not separate from placebo. Treatment-emergent nausea, vomiting, and dizziness were significantly more frequent in the LY545694 groups in both trials (P⩽.05), and significantly more LY545694-treated patients discontinued because of adverse events (P<.001). Steady-state concentrations of LY545694 were comparable in patients in both studies but were lower than exposures required for efficacy in animal models of pain behavior. Because the active control did not separate from placebo in the DPNP study, the study was potentially failed, rather than negative. Without an active control, it is unknown whether the OA study was negative or failed. Consequently, efficacy of selective ionotropic glutamate receptor antagonism in chronic pain conditions may warrant further investigation. Future trials should consider different pain conditions, contain a positive control with larger patient numbers per arm, and be conducted within a single region. Copyright © 2014 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.
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Thomson, Caroline E; Bayer, Florian; Crouch, Nicholas; Farrell, Samantha; Heap, Elizabeth; Mittell, Elizabeth; Zurita-Cassinello, Mar; Hadfield, Jarrod D
2017-03-01
There is abundant evidence in many taxa for positive directional selection on body size, and yet little evidence for microevolutionary change. In many species, variation in body size is partly determined by the actions of parents, so a proposed explanation for stasis is the presence of a negative genetic correlation between direct and parental effects. Consequently, selecting genes for increased body size would result in a correlated decline in parental effects, reducing body size in the following generation. We show that these arguments implicitly assume that parental care is cost free, and that including a cost alters the predicted genetic architectures needed to explain stasis. Using a large cross-fostered population of blue tits, we estimate direct selection on parental effects for body mass, and show it is negative. Negative selection is consistent with a cost to parental care, mainly acting through a reduction in current fecundity rather than survival. Under these conditions, evolutionary stasis is possible for moderately negative genetic correlations between direct and parental effects. This is in contrast to the implausibly extreme correlations needed when care is assumed to be cost-free. Thus, we highlight the importance of accounting correctly for complete selection acting on traits across generations. © 2017 The Author(s). Evolution © 2017 The Society for the Study of Evolution.
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Negative frequency-dependent selection between Pasteuria penetrans and its host Meloidogyne arenaria
USDA-ARS?s Scientific Manuscript database
In negative frequency-dependant selection (NFDS), parasite genotypes capable of infecting the numerically dominant host genotype are favored, while host genotypes resistant to the dominant parasite genotype are favored, creating a cyclical pattern of resistant genotypes in the host population and, a...
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Flamm, Robert K; Rhomberg, Paul R; Huband, Michael D; Farrell, David J
2016-10-01
Delafloxacin, an investigational anionic fluoroquinolone, is active against a broad range of Gram-positive and Gram-negative bacteria. In this study, 200 Streptococcus pneumoniae (plus 30 levofloxacin-resistant isolates), 200 Haemophilus influenzae, and 100 Moraxella catarrhalis isolates selected primarily from the United States (2014) were tested against delafloxacin and comparator agents. Delafloxacin was the most potent agent tested. MIC50 and MIC90 values against all S. pneumoniae isolates were 0.008 and 0.015 μg/ml. Delafloxacin susceptibility was not affected by β-lactamase status against H. influenzae and M. catarrhalis. Copyright © 2016, American Society for Microbiology. All Rights Reserved.
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Martorell, Òscar; Barriga, Francisco M; Merlos-Suárez, Anna; Stephan-Otto Attolini, Camille; Casanova, Jordi; Batlle, Eduard; Sancho, Elena; Casali, Andreu
2014-11-01
Activating mutations in Wnt and EGFR/Ras signaling pathways are common in colorectal cancer (CRC). Remarkably, clonal co-activation of these pathways in the adult Drosophila midgut induces "tumor-like" overgrowths. Here, we show that, in these clones and in CRC cell lines, Dpp/TGF-β acts as a tumor suppressor. Moreover, we discover that the Iroquois/IRX-family-protein Mirror downregulates the transcription of core components of the Dpp pathway, reducing its tumor suppressor activity. We also show that this genetic interaction is conserved in human CRC cells, where the Iro/IRX proteins IRX3 and IRX5 diminish the response to TGF-β. IRX3 and IRX5 are upregulated in human adenomas, and their levels correlate inversely with the gene expression signature of response to TGF-β. In addition, Irx5 expression confers a growth advantage in the presence of TGF-β, but is selected against in its absence. Together, our results identify a set of Iro/IRX proteins as conserved negative regulators of Dpp/TGF-β activity. We propose that during the characteristic adenoma-to-carcinoma transition of human CRC, the activity of IRX proteins could reduce the sensitivity to the cytostatic effect of TGF-β, conferring a growth advantage to tumor cells prior to the acquisition of mutations in TGF-β pathway components. © 2014 The Authors.
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Moubayed, Nadine M S; Al Houri, Hadeel Jawad; Al Khulaifi, Manal M; Al Farraj, Dunia A
2017-01-01
The present study demonstrates the antibacterial activity of selected brown and green marine algae collected from Saudi Arabia Red Sea and Arabian Gulf. The methanolic and acetone extracts were tested against gram positive, gram negative bacteria and Candida albicans in an attempt to be used as an alternative to commonly used antibiotics. Both brown seaweed species Sargassum latifolium B and Sargassum platycarpum A methanolic extracts were found to be active against gram positive than gram negative; however, S. latifolium acetone extract gave the highest inhibitory activity against Salmonella sp. On the other hand, Cladophorasocialis organic extract demonstrated higher antibacterial activity than the fresh extract but both C. socialis extracts revealed decreased activity compared to Sargassum extracts. Cladophora methanolic extract showed an obvious effect on methicillin resistant Staphylococcus aureus (MRSA). The present work shows a comparable therapeutic potency of the tested seaweed members Sargassum and Cladophora extracts in treating human microbial pathogens to synthetic chemical antibiotics. A remarkable higher antioxidant DPPH free radical scavenging effect was recorded with Sargassum sp. compared to Cladophora sp. FTIR Infrared Spectrometer analysis together with the high performance liquid chromatography provided a detailed description of the possible functional constituents and the major chemical components present in marine macroalgae particularly in brown seaweeds to be mainly of phenolic nature to which the potent antimicrobial activity is being attributed.
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Study of in vitro antimicrobial and antiproliferative activities of selected Saharan plants.
Palici, Ionut F; Liktor-Busa, Erika; Zupkó, István; Touzard, Blaise; Chaieb, Mohamed; Urbán, Edit; Hohmann, Judit
2015-12-01
The aim of the present study was the evaluation of the antimicrobial and antiproliferative activities of selected Saharan species, which are applied in the traditional medicine but not studied thoroughly from chemical and pharmacological point of view. The studied plants, namely Anthyllis henoniana, Centropodia forskalii, Cornulaca monacantha, Ephedra alata var. alenda, Euphorbia guyoniana, Helianthemum confertum, Henophyton deserti, Moltkiopsis ciliata and Spartidium saharae were collected from remote areas of North Africa, especially from the Tunisian region of Sahara. After drying and applying the appropriate extraction methods, the plant extracts were tested in antimicrobial screening assay, performed on 19 Gram-positive and -negative strains of microbes. The inhibition zones produced by plant extracts were determined by disc-diffusion method. Remarkable antibacterial activities were exhibited by extracts of Ephedra alata var. alenda and Helianthemum confertum against B. subtilis, M. catarrhalis and methicillin-resistant and non-resistant S. aureus. Minimum inhibitory concentrations of these two species were also determined. Antiproliferative effects of the extracts were evaluated against 4 human adherent cell lines (HeLa, A431, A2780 and MCF7). Notable cell growth inhibition was found for extract of Helianthemum confertum and Euphorbia guyoniana. Our results provided data for selection of some plant species for further detailed pharmacological and phytochemical examinations.
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Activation of TRPV2 negatively regulates the differentiation of mouse brown adipocytes.
Sun, Wuping; Uchida, Kunitoshi; Takahashi, Nobuyuki; Iwata, Yuko; Wakabayashi, Shigeo; Goto, Tsuyoshi; Kawada, Teruo; Tominaga, Makoto
2016-09-01
Transient receptor potential vanilloid 2 (TRPV2) acts as a Ca(2+)-permeable non-selective cation channel that has been reported to be sensitive to temperature, mechanical force, and some chemicals. We recently showed that TRPV2 is critical for maintenance of the thermogenic function of brown adipose tissue in mice. However, the involvement of TRPV2 in the differentiation of brown adipocytes remains unexplored. We found that the expression of TRPV2 was dramatically increased during the differentiation of brown adipocytes. Non-selective TRPV2 agonists (2-aminoethoxydiphenyl borate and lysophosphatidylcholine) inhibited the differentiation of brown adipocytes in a dose-dependent manner during the early stage of differentiation of brown adipocytes. The inhibition was rescued by a TRPV2-selective antagonist, SKF96365 (SKF). Mechanical force, which activates TRPV2, also inhibited the differentiation of brown adipocytes in a strength-dependent manner, and the effect was reversed by SKF. In addition, the inhibition of adipocyte differentiation by either TRPV2 ligand or mechanical stimulation was significantly smaller in the cells from TRPV2KO mice. Moreover, calcineurin inhibitors, cyclosporine A and FK506, partially reversed TRPV2 activation-induced inhibition of brown adipocyte differentiation. Thus, we conclude that TRPV2 might be involved in the modulation of brown adipocyte differentiation partially via a calcineurin pathway.
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Jarcho, Johanna M.; Dahl, Ronald E.; Pine, Daniel S.; Ernst, Monique; Nelson, Eric E.
2015-01-01
Adolescence is the time of peak onset for many anxiety disorders, particularly Social Anxiety Disorder. Research using simulated social interactions consistently finds differential activation in several brain regions in anxious (vs non-anxious) youth, including amygdala, striatum and medial prefrontal cortex. However, few studies examined the anticipation of peer interactions, a key component in the etiology and maintenance of anxiety disorders. Youth completed the Chatroom Task while undergoing functional magnetic resonance imaging. Patterns of neural activation were assessed in anxious and non-anxious youth as they were cued to anticipate social feedback from peers. Anxious participants evidenced greater amygdala activation and rostral anterior cingulate (rACC)↔amygdala coupling than non-anxious participants during anticipation of feedback from peers they had previously rejected; anxious participants also evidenced less nucleus accumbens activation during anticipation of feedback from selected peers. Finally, anxiety interacted with age in rACC: in anxious participants, age was positively associated with activation to anticipated feedback from rejected peers and negatively for selected peers, whereas the opposite pattern emerged for non-anxious youth. Overall, anxious youth showed greater reactivity in anticipation of feedback from rejected peers and thus may ascribe greater salience to these potential interactions and increase the likelihood of avoidance behavior. PMID:25552568
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Wheeler, K P; Walker, J A; Barker, D M
1975-01-01
The dependence of the (Na-++K-+)-dependent ATPase (adenosine triphosphatase) (EC 3.6.1.3) on lipid has been examined in a number of different ways, with the use of various preparations from kidney tissue. The main findings were as follows. (1) The ATPase activities of the preparations examined were closely correlated with their total phospholipid content. (2) Extraction of the ATPase with deoxycholate or Lubrol W, combined with suitable salt-fractionation and washing procedures, removed phospholipid, cholesterol and enzymic activity in parallel; but activity was completely lost before all lipid had been removed. (3) The loss of activity could not be attributed to inhibition by residual detergent. (4) No selective removal of any particular phospholipid class by detergent could be detected. (5) Consistent reactivation of the Lubrol-extracted enzymes was obtained by adding dispersions of exogenous phospholipid, but only some, bearing a net negative charge, such as phosphatidylserine and phosphatidylglycerol, were effective. (6) The degree of reactivation was correlated with the amount of residual activity remaining after lipid depletion. (7) Partial purification of the ATPase, giving a 50-fold increase in specific activity, was not accompanied by selective enhancement of any particular class of phospholipid. We conclude that although the ATPase is dependent on phospholipid, only the reactivation results provide evidence for specificity. PMID:125082
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Towards functional selectivity for α6β3γ2 GABAA receptors: a series of novel pyrazoloquinolinones
Treven, Marco; Siebert, David C B; Holzinger, Raphael; Bampali, Konstantina; Fabjan, Jure; Varagic, Zdravko; Wimmer, Laurin; Steudle, Friederike; Scholze, Petra; Schnürch, Michael; Mihovilovic, Marko D
2017-01-01
Background and Purpose The GABAA receptors are ligand‐gated ion channels, which play an important role in neurotransmission. Their variety of binding sites serves as an appealing target for many clinically relevant drugs. Here, we explored the functional selectivity of modulatory effects at specific extracellular α+/β− interfaces, using a systematically varied series of pyrazoloquinolinones. Experimental Approach Recombinant GABAA receptors were expressed in Xenopus laevis oocytes and modulatory effects on GABA‐elicited currents by the newly synthesized and reference compounds were investigated by the two‐electrode voltage clamp method. Key Results We identified a new compound which, to the best of our knowledge, shows the highest functional selectivity for positive modulation at α6β3γ2 GABAA receptors with nearly no residual activity at the other αxβ3γ2 (x = 1–5) subtypes. This modulation was independent of affinity for α+/γ− interfaces. Furthermore, we demonstrated for the first time a compound that elicits a negative modulation at specific extracellular α+/β− interfaces. Conclusion and Implications These results constitute a major step towards a potential selective positive modulation of certain α6‐containing GABAA receptors, which might be useful to elicit their physiological role. Furthermore, these studies pave the way towards insights into molecular principles that drive positive versus negative allosteric modulation of specific GABAA receptor isoforms. PMID:29127702
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Clark, Imogen N; Baker, Felicity A; Taylor, Nicholas F
2016-01-01
Music listening during exercise is thought to increase physiological arousal and enhance subjective experience, and may support physical activity participation among older adults with cardiac disease. However, little is known about how music preferences, or perceptions of music during exercise, inform clinical practice with this population. Identify predominant musical characteristics of preferred music selected by older adults, and explore participants' music listening experiences during walking-based exercise following cardiac rehabilitation. Twenty-seven participants aged 60 years and older (21 men, 6 women; mean age = 67.3 years) selected music to support walking over a 6-month intervention period, and participated in post-intervention interviews. In this two-phase study, we first identified predominant characteristics of participant-selected music using the Structural Model of Music Analysis. Second, we used inductive thematic analysis to explore participant experiences. Predominant characteristics of participant-selected music included duple meter, consistent rhythm, major key, rounded melodic shape, legato articulation, predictable harmonies, variable volume, and episodes of tension with delayed resolution. There was no predominant tempo, with music selections ranging from slow through to medium and fast. Four themes emerged from thematic analysis of participant interviews: psycho-emotional responses, physical responses, influence on exercise behavior, and negative experiences. Findings are consistent with theory and research explaining influences from music listening on physiological arousal and subjective experience during exercise. Additionally, for older adults with cardiac disease, a holistic approach to music selection considering general well-being and adjustment issues, rather than just exercise performance, may improve long-term lifestyle changes and compliance with physical activity guidelines. © the American Music Therapy Association 2016. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
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Gao, Dong; Shao, Juan; Jin, Waishu; Xia, Xiujuan; Qu, Yan
2018-05-22
To investigate the correlations of serum cystatin C and high-sensitivity C-reactive protein (hs-CRP) with vascular endothelial cell injury in patients with active systemic lupus erythematosus (SLE). A total of 80 patients with SLE treated in our hospital from January 2016 to September 2017 were selected and randomly divided into stable-stage group (n=40) and active-stage group (n=40) using a random number table. The expressions of cystatin C and hs-CRPin stable and active stages were compared, and the inner diameters of brachial artery and levels of vascular endothelial growth factors in stable and active stages were also compared.The correlationsof expressions of cystatin C and hs-CRP in active stage with the inner diameter of brachial artery and vascular endothelial growth factor were analyzed. At the same time, the correlation between vascular endothelial growth factor and inner diameter of brachial artery in active stage was analyzed. The level of cystatin C in active stage was higher than that in stable stage (P<0.05), and the expression level of hs-CRP in active stage was also higher than that in stable stage (P<0.05). The inner diameter of brachial artery in active stage was smaller than that in stable stage (P<0.05), butthe level of vascular endothelial growth factor was higher than that in stable stage (P<0.05). The expressions of cystatin C and hs-CRP were negatively correlated with the inner diameter of brachial artery in active stage (P<0.05). The expressions of cystatin C and hs-CRP were positively correlated with vascular endothelial growth factor in active stage (P<0.05). Moreover, there was a negative correlation between vascular endothelial growth factor and inner diameter of brachial artery in active stage (P<0.05). Levels of cystatin C and hs-CRP are significantly increased in patients with active SLE, and the increase degrees are negatively correlated with the inner diameter of brachial artery under ultrasound, but positively correlated with the level of vascular endothelial growth factor in vivo.
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Vortex lattices and defect-mediated viscosity reduction in active liquids
NASA Astrophysics Data System (ADS)
Slomka, Jonasz; Dunkel, Jorn
2016-11-01
Generic pattern-formation and viscosity-reduction mechanisms in active fluids are investigated using a generalized Navier-Stokes model that captures the experimentally observed bulk vortex dynamics in microbial suspensions. We present exact analytical solutions including stress-free vortex lattices and introduce a computational framework that allows the efficient treatment of previously intractable higher-order shear boundary conditions. Large-scale parameter scans identify the conditions for spontaneous flow symmetry breaking, defect-mediated low-viscosity phases and negative-viscosity states amenable to energy harvesting in confined suspensions. The theory uses only generic assumptions about the symmetries and long-wavelength structure of active stress tensors, suggesting that inviscid phases may be achievable in a broad class of non-equilibrium fluids by tuning confinement geometry and pattern scale selection.
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Geometry-dependent viscosity reduction in sheared active fluids
NASA Astrophysics Data System (ADS)
Słomka, Jonasz; Dunkel, Jörn
2017-04-01
We investigate flow pattern formation and viscosity reduction mechanisms in active fluids by studying a generalized Navier-Stokes model that captures the experimentally observed bulk vortex dynamics in microbial suspensions. We present exact analytical solutions including stress-free vortex lattices and introduce a computational framework that allows the efficient treatment of higher-order shear boundary conditions. Large-scale parameter scans identify the conditions for spontaneous flow symmetry breaking, geometry-dependent viscosity reduction, and negative-viscosity states amenable to energy harvesting in confined suspensions. The theory uses only generic assumptions about the symmetries and long-wavelength structure of active stress tensors, suggesting that inviscid phases may be achievable in a broad class of nonequilibrium fluids by tuning confinement geometry and pattern scale selection.
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The impact of selection bias on vaccine effectiveness estimates from test-negative studies.
Jackson, Michael L; Phillips, C Hallie; Benoit, Joyce; Kiniry, Erika; Madziwa, Lawrence; Nelson, Jennifer C; Jackson, Lisa A
2018-01-29
Estimates of vaccine effectiveness (VE) from test-negative studies may be subject to selection bias. In the context of influenza VE, we used simulations to identify situations in which meaningful selection bias can occur. We also analyzed observational study data for evidence of selection bias. For the simulation study, we defined a hypothetical population whose members are at risk for acute respiratory illness (ARI) due to influenza and other pathogens. An unmeasured "healthcare seeking proclivity" affects both probability of vaccination and probability of seeking care for an ARI. We varied the direction and magnitude of these effects and identified situations where meaningful bias occurred. For the observational study, we reanalyzed data from the United States Influenza VE Network, an ongoing test-negative study. We compared "bias-naïve" VE estimates to bias-adjusted estimates, which used data from the source populations to correct for sampling bias. In the simulation study, an unmeasured care-seeking proclivity could create selection bias if persons with influenza ARI were more (or less) likely to seek care than persons with non-influenza ARI. However, selection bias was only meaningful when rates of care seeking between influenza ARI and non-influenza ARI were very different. In the observational study, the bias-naïve VE estimate of 55% (95% CI, 47--62%) was trivially different from the bias-adjusted VE estimate of 57% (95% CI, 49--63%). In combination, these studies suggest that while selection bias is possible in test-negative VE studies, this bias in unlikely to be meaningful under conditions likely to be encountered in practice. Researchers and public health officials can continue to rely on VE estimates from test-negative studies. Copyright © 2017 Elsevier Ltd. All rights reserved.
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Loprinzi, Paul D; Joyner, Chelsea
2017-06-13
Limited research has examined the interrelationships among cardiometabolic parameters, physical activity, and hearing function, which was this study's purpose. Data from the National Health and Nutrition Examination Survey (NHANES) 2003-2006 were used in the path analyses. Physical activity and hearing function were both objectively measured. Various cardiometabolic parameters were assessed from a blood sample. Adults 30-85 years (N = 1,070) constituted the analytic sample. Physical activity was negatively associated with triglycerides (β = -0.11, p < .05) and insulin (β = -0.27, p < .05); triglycerides (β = 0.01, p < .05), and insulin (β = 0.05, p < .05) were positively associated with high-frequency pure-tone average (HPTA). The direct path from physical activity to HPTA was nonsignificant (β = 0.01, p = .99). Physical activity was associated with select cardiovascular disease risk factors. Several cardiovascular disease risk factors were associated with hearing function.
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Avoidance-based human Pavlovian-to-instrumental transfer
Lewis, Andrea H.; Niznikiewicz, Michael A.; Delamater, Andrew R.; Delgado, Mauricio R.
2013-01-01
The Pavlovian-to-instrumental transfer (PIT) paradigm probes the influence of Pavlovian cues over instrumentally learned behavior. The paradigm has been used extensively to probe basic cognitive and motivational processes in studies of animal learning but, more recently, PIT and its underlying neural basis have been extended to investigations in humans. These initial neuroimaging studies of PIT have focused on the influence of appetitively conditioned stimuli on instrumental responses maintained by positive reinforcement, and highlight the involvement of the striatum. In the current study, we sought to understand the neural correlates of PIT in an aversive Pavlovian learning situation when instrumental responding was maintained through negative reinforcement. Participants exhibited specific PIT, wherein selective increases in instrumental responding to conditioned stimuli occurred when the stimulus signaled a specific aversive outcome whose omission negatively reinforced the instrumental response. Additionally, a general PIT effect was observed such that when a stimulus was associated with a different aversive outcome than was used to negatively reinforce instrumental behavior, the presence of that stimulus caused a non-selective increase in overall instrumental responding. Both specific and general PIT behavioral effects correlated with increased activation in corticostriatal circuitry, particularly in the striatum, a region involved in cognitive and motivational processes. These results suggest that avoidance-based PIT utilizes a similar neural mechanism to that seen with PIT in an appetitive context, which has implications for understanding mechanisms of drug-seeking behavior during addiction and relapse. PMID:24118624
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Health-related quality of life for patients with rheumatoid arthritis foot involvement.
Wickman, Amy M; Pinzur, Michael S; Kadanoff, Ruth; Juknelis, Dainius
2004-01-01
Rheumatoid arthritis is a common disabling form of arthritis that frequently affects the hands and feet. With time, the majority of affected individuals will become disabled. Sixty-nine consecutively selected mild to moderately affected individuals with rheumatoid arthritis provided demographic data and agreed to complete the Short Musculoskeletal Function Assessment (SFMA) instrument. Focus group subjects selectively used minimally adaptive nonprescription footwear. Control subjects had similar disease expression, but did not alter their choice of footwear due to their disease. Adult patients with rheumatoid arthritis demonstrate a significant negative impact on their quality of life with mild or moderate disease expression, as evidenced by poor scores in all six domains of the SFMA. Subjects who used even mildly adaptive nonprescription footwear demonstrated a statistically significant negative impact in mobility (p < .044) and functional index (p < .052) domains as compared with the control population having similar overall disease expression. Focus subjects also demonstrated a trend to less favorable scores in the arm and hand domain. Mean scores of the daily activity, emotional status, and bother index domains fared worse than population norms, but there was no statistical difference between subjects using, or not using, adaptive footwear. Individuals affected with mild to moderate rheumatoid arthritis are disabled as compared with the general population. There is a severe negative impact on mobility and functional capacity when the disease process begins to affect their feet.
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Song, Weizhong; Du, Yuzhe; Liu, Zhiqi; Luo, Ningguang; Turkov, Michael; Gordon, Dalia; Gurevitz, Michael; Goldin, Alan L; Dong, Ke
2011-05-06
Scorpion β-toxins bind to the extracellular regions of the voltage-sensing module of domain II and to the pore module of domain III in voltage-gated sodium channels and enhance channel activation by trapping and stabilizing the voltage sensor of domain II in its activated state. We investigated the interaction of a highly potent insect-selective scorpion depressant β-toxin, Lqh-dprIT(3), from Leiurus quinquestriatus hebraeus with insect sodium channels from Blattella germanica (BgNa(v)). Like other scorpion β-toxins, Lqh-dprIT(3) shifts the voltage dependence of activation of BgNa(v) channels expressed in Xenopus oocytes to more negative membrane potentials but only after strong depolarizing prepulses. Notably, among 10 BgNa(v) splice variants tested for their sensitivity to the toxin, only BgNa(v)1-1 was hypersensitive due to an L1285P substitution in IIIS1 resulting from a U-to-C RNA-editing event. Furthermore, charge reversal of a negatively charged residue (E1290K) at the extracellular end of IIIS1 and the two innermost positively charged residues (R4E and R5E) in IIIS4 also increased the channel sensitivity to Lqh-dprIT(3). Besides enhancement of toxin sensitivity, the R4E substitution caused an additional 20-mV negative shift in the voltage dependence of activation of toxin-modified channels, inducing a unique toxin-modified state. Our findings provide the first direct evidence for the involvement of the domain III voltage-sensing module in the action of scorpion β-toxins. This hypersensitivity most likely reflects an increase in IIS4 trapping via allosteric mechanisms, suggesting coupling between the voltage sensors in neighboring domains during channel activation.
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Are all judgments created equal? An fMRI study of semantic and episodic metamemory predictions.
Reggev, Niv; Zuckerman, Maya; Maril, Anat
2011-04-01
Metamemory refers to the ability of individuals to monitor and control their own memory performance. Although little theoretical consideration of the possible differences between the monitoring of episodic and of semantic knowledge has been published, results from patient and drug studies that used the "feeling of knowing" (FOK) paradigm show a selective impairment in the accuracy of episodic monitoring but not in its semantic counterpart. Similarly, neuroimaging studies provide indirect evidence for separate patterns of activation during episodic or semantic FOKs. However, the semantic-episodic distinction hypothesis has not been directly addressed. In the current event-related fMRI study, we used a within-subject, within-experiment comparison of the monitoring of semantic and episodic content. Whereas the common neural correlates of episodic and semantic FOKs observed in this study generally replicate the previous neuroimaging findings, several regions were found to be differentially associated with each task. Activity of the right inferior frontal gyrus was modulated by the semantic-episodic factor only during the negative predictions of retrieval, suggesting that negative predictions are based on partially distinct mechanisms during each task. A posterior midline network, known to be activated during episodic retrieval, was activated during episodic and not semantic monitoring, suggesting that episodic FOKs rely, to some extent, on common episodic retrieval processes. These findings suggest that theoretical accounts of the etiology and function of FOKs may benefit from incorporating the prediction directionality (positive/negative) and the memory domain (semantic/episodic) distinctions. Copyright © 2011 Elsevier Ltd. All rights reserved.
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Ji, E; Weickert, C S; Lenroot, R; Kindler, J; Skilleter, A J; Vercammen, A; White, C; Gur, R E; Weickert, T W
2016-05-03
Estrogen has been implicated in the development and course of schizophrenia with most evidence suggesting a neuroprotective effect. Treatment with raloxifene, a selective estrogen receptor modulator, can reduce symptom severity, improve cognition and normalize brain activity during learning in schizophrenia. People with schizophrenia are especially impaired in the identification of negative facial emotions. The present study was designed to determine the extent to which adjunctive raloxifene treatment would alter abnormal neural activity during angry facial emotion recognition in schizophrenia. Twenty people with schizophrenia (12 men, 8 women) participated in a 13-week, randomized, double-blind, placebo-controlled, crossover trial of adjunctive raloxifene treatment (120 mg per day orally) and performed a facial emotion recognition task during functional magnetic resonance imaging after each treatment phase. Two-sample t-tests in regions of interest selected a priori were performed to assess activation differences between raloxifene and placebo conditions during the recognition of angry faces. Adjunctive raloxifene significantly increased activation in the right hippocampus and left inferior frontal gyrus compared with the placebo condition (family-wise error, P<0.05). There was no significant difference in performance accuracy or reaction time between active and placebo conditions. To the best of our knowledge, this study provides the first evidence suggesting that adjunctive raloxifene treatment changes neural activity in brain regions associated with facial emotion recognition in schizophrenia. These findings support the hypothesis that estrogen plays a modifying role in schizophrenia and shows that adjunctive raloxifene treatment may reverse abnormal neural activity during facial emotion recognition, which is relevant to impaired social functioning in men and women with schizophrenia.
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Ory, Marcia G.; Lee, Shinduk; Han, Gang; Towne, Samuel D.; Quinn, Cindy; Neher, Taylor; Stevens, Alan; Smith, Matthew Lee
2018-01-01
Despite the well-recognized benefits of physical activity across the life course, older adults are more inactive than other age groups. The current study examines the effects of Texercise Select participation on self-reported sedentary, light, moderate, and vigorous physical activity. Secondarily, this study examined intervention effects on two potential facilitators of physical activity: (1) self-efficacy for being more physically active and (2) social support received for physical activity. This study used a non-equivalent group design with self-reported surveys administered at baseline, three-month (immediate post for cases) and six-month follow-ups for the intervention (n = 163) and a comparison group (n = 267). Multivariable mixed model analyses were conducted controlling for age, sex, race, ethnicity, education, comorbid conditions, and site. Among the intervention group, the program had significant immediate effects on most primary outcomes (p < 0.05) at three months. Furthermore, significant improvements were observed for all physical activity intensity levels at six months (p < 0.05). The reduction in sedentary behavior and increases in all physical activity intensity levels were significantly greater from baseline to three-month and baseline to six-month follow-ups among intervention group participants relative to those in the comparison group. This study confirms the effectiveness of Texercise Select to reduce sedentary behavior and improve physicality, supporting the intervention’s robustness as a scalable and sustainable evidence-based program. It also counters negative stereotypes that older adults are not interested in attending multi-modal lifestyle intervention programs nor able to make health behavior changes that can improve health and overall functioning. PMID:29385779
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Kabayama, Mai; Watanabe, Chie; Ryuno, Hirochika; Kamide, Kei
2017-12-01
Previous literature has found positive correlations between social capital and health in older adults, fewer studies have investigated the subdimension's effects of social capital on health. We aimed to determine the individual social capital subfactors in community-dwelling older adults in Japan, and to analyze the associations of these factors with physical and mental health. We sent a self-administered questionnaire assessing their perception of social group activity as the individual social capital, and mental and physical health (measured by the Medical Outcomes Study Short Form-36) to 4320 randomly selected older people. There were 1836 valid responses. We clarified that people who participated in any social activity group were in significantly better physical and mental health compared with the people who did not. By the factor analysis of the perception for the social group activity, we identified three components of the individual social capital aspect that we termed harmonious, hierarchic and diversity. Using multiple linear regression, we found the hierarchic aspect was significantly negatively associated with mental health, whereas the harmonious aspect was significantly positively associated with mental and physical health, and diversity was significantly positively associated with mental health. As the previous research literature on social capital has mainly emphasized its positive health consequences, the present findings provide a novel demonstration that some aspects of individual social capital can have negative associations with health outcomes in community-dwelling older people. For the practical application of promoting a healthier society, it is important to consider both the positive and negative sides of social capital. Geriatr Gerontol Int 2017; 17: 2427-2434. © 2017 Japan Geriatrics Society.
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Di Perri, Carol; Amico, Enrico; Heine, Lizette; Annen, Jitka; Martial, Charlotte; Larroque, Stephen Karl; Soddu, Andrea; Marinazzo, Daniele; Laureys, Steven
2018-01-01
Given that recent research has shown that functional connectivity is not a static phenomenon, we aim to investigate the dynamic properties of the default mode network's (DMN) connectivity in patients with disorders of consciousness. Resting-state fMRI volumes of a convenience sample of 17 patients in unresponsive wakefulness syndrome (UWS) and controls were reduced to a spatiotemporal point process by selecting critical time points in the posterior cingulate cortex (PCC). Spatial clustering was performed on the extracted PCC time frames to obtain 8 different co-activation patterns (CAPs). We investigated spatial connectivity patterns positively and negatively correlated with PCC using both CAPs and standard stationary method. We calculated CAPs occurrences and the total number of frames. Compared to controls, patients showed (i) decreased within-network positive correlations and between-network negative correlations, (ii) emergence of "pathological" within-network negative correlations and between-network positive correlations (better defined with CAPs), and (iii) "pathological" increases in within-network positive correlations and between-network negative correlations (only detectable using CAPs). Patients showed decreased occurrence of DMN-like CAPs (1-2) compared to controls. No between-group differences were observed in the total number of frames CONCLUSION: CAPs reveal at a more fine-grained level the multifaceted spatial connectivity reconfiguration following the DMN disruption in UWS patients, which is more complex than previously thought and suggests alternative anatomical substrates for consciousness. BOLD fluctuations do not seem to differ between patients and controls, suggesting that BOLD response represents an intrinsic feature of the signal, and therefore that spatial configuration is more important for consciousness than BOLD activation itself. Hum Brain Mapp 39:89-103, 2018. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.
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2013-01-01
Background The main objective of this study was the phytochemical characterization of four indigenous essential oils obtained from spices and their antibacterial activities against the multidrug resistant clinical and soil isolates prevalent in Pakistan, and ATCC reference strains. Methods Chemical composition of essential oils from four Pakistani spices cumin (Cuminum cyminum), cinnamon (Cinnamomum verum), cardamom (Amomum subulatum) and clove (Syzygium aromaticum) were analyzed on GC/MS. Their antibacterial activities were investigated by minimum inhibitory concentration (MIC) and Thin-Layer Chromatography-Bioautographic (TLC-Bioautographic) assays against pathogenic strains Salmonella typhi (D1 Vi-positive), Salmonella typhi (G7 Vi-negative), Salmonella paratyphi A, Escherichia coli (SS1), Staphylococcus aureus, Pseudomonas fluorescens and Bacillus licheniformis (ATCC 14580). The data were statistically analyzed by using Analysis of Variance (ANOVA) and Least Significant Difference (LSD) method to find out significant relationship of essential oils biological activities at p <0.05. Results Among all the tested essential oils, oil from the bark of C. verum showed best antibacterial activities against all selected bacterial strains in the MIC assay, especially with 2.9 mg/ml concentration against S. typhi G7 Vi-negative and P. fluorescens strains. TLC-bioautography confirmed the presence of biologically active anti-microbial components in all tested essential oils. P. fluorescens was found susceptible to C. verum essential oil while E. coli SS1 and S. aureus were resistant to C. verum and A. subulatum essential oils, respectively, as determined in bioautography assay. The GC/MS analysis revealed that essential oils of C. cyminum, C. verum, A. subulatum, and S. aromaticum contain 17.2% cuminaldehyde, 4.3% t-cinnamaldehyde, 5.2% eucalyptol and 0.73% eugenol, respectively. Conclusions Most of the essential oils included in this study possessed good antibacterial activities against selected multi drug resistant clinical and soil bacterial strains. Cinnamaldehyde was identified as the most active antimicrobial component present in the cinnamon essential oil which acted as a strong inhibitory agent in MIC assay against the tested bacteria. The results indicate that essential oils from Pakistani spices can be pursued against multidrug resistant bacteria. PMID:24119438
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Árnason, Einar
2015-01-01
Natural selection, the most important force in evolution, comes in three forms. Negative purifying selection removes deleterious variation and maintains adaptations. Positive directional selection fixes beneficial variants, producing new adaptations. Balancing selection maintains variation in a population. Important mechanisms of balancing selection include heterozygote advantage, frequency-dependent advantage of rarity, and local and fluctuating episodic selection. A rare pathogen gains an advantage because host defenses are predominantly effective against prevalent types. Similarly, a rare immune variant gives its host an advantage because the prevalent pathogens cannot escape the host’s apostatic defense. Due to the stochastic nature of evolution, neutral variation may accumulate on genealogical branches, but trans-species polymorphisms are rare under neutrality and are strong evidence for balancing selection. Balanced polymorphism maintains diversity at the major histocompatibility complex (MHC) in vertebrates. The Atlantic cod is missing genes for both MHC-II and CD4, vital parts of the adaptive immune system. Nevertheless, cod are healthy in their ecological niche, maintaining large populations that support major commercial fisheries. Innate immunity is of interest from an evolutionary perspective, particularly in taxa lacking adaptive immunity. Here, we analyze extensive amino acid and nucleotide polymorphisms of the cathelicidin gene family in Atlantic cod and closely related taxa. There are three major clusters, Cath1, Cath2, and Cath3, that we consider to be paralogous genes. There is extensive nucleotide and amino acid allelic variation between and within clusters. The major feature of the results is that the variation clusters by alleles and not by species in phylogenetic trees and discriminant analysis of principal components. Variation within the three groups shows trans-species polymorphism that is older than speciation and that is suggestive of balancing selection maintaining the variation. Using Bayesian and likelihood methods positive and negative selection is evident at sites in the conserved part of the genes and, to a larger extent, in the active part which also shows episodic diversifying selection, further supporting the argument for balancing selection. PMID:26038731
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Aripiprazole, A Drug that Displays Partial Agonism and Functional Selectivity.
Tuplin, Erin W; Holahan, Matthew R
2017-11-14
The treatment of schizophrenia is challenging due to the wide range of symptoms (positive, negative, cognitive) associated with the disease. Typical antipsychotics that antagonize D2 receptors are effective in treating positive symptoms, but extrapyramidal side-effects (EPS) are a common occurrence. Atypical antipsychotics targeting 5-HT2A and D2 receptors are more effective at treating cognitive and negative symptoms compared to typical antipsychotics, but these drugs also result in side-effects such as metabolic syndromes. To identify evidence in the literature that elucidates the pharmacological profile of aripiprazole.s. We searched PubMed for peer reviewed articles on aripiprazole and its clinical efficacy, side-effects, pharmacology, and effects in animal models of schizophrenia symptoms. Aripiprazole is a newer atypical antipsychotic that displays a unique pharmacological profile, including partial D2 agonism and functionally selective properties. Aripiprazole is effective at treating the positive symptoms of schizophrenia and has the potential to treat negative and cognitive symptoms at least as well as other atypical antipsychotics. The drug has a favorable side-effect profile and has a low propensity to result in EPS or metabolic syndromes. Animal models of schizophrenia have been used to determine the efficacy of aripiprazole in symptom management. In these instances, aripiprazole resulted in the reversal of deficits in extinction, pre-pulse inhibition, and social withdrawal. Because aripiprazole requires a greater than 90% occupancy rate at D2 receptors to be clinically active and does not produce EPS, this suggests a functionally selective effect on intracellular signaling pathways. A combination of factors such as dopamine system stabilization via partial agonism, functional selectivity at D2 receptors, and serotonin-dopamine system interaction may contribute to the ability of aripiprazole to successfully manage schizophrenia symptoms. This review examines these mechanisms of action to further clarify the pharmacological actions of aripiprazole. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.
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Ferenci, T; Lee, K S
1989-01-01
Maltoporin trimers constitute maltodextrin-selective channels in the outer membrane of Escherichia coli. To study the organization of the maltodextrin-binding site within trimers, dominance studies were undertaken with maltoporin variants of altered binding affinity. It has been established that amino acid substitutions at three dispersed regions of the maltoporin sequence (at residues 8, 82, and 360) resulted specifically in maltodextrin-binding defects and loss of maltodextrin channel selectivity; a substitution at residue 118 increased both binding affinity and maltodextrin transport. Strains heterodiploid for lamB were constructed in which these substitutions were encoded by chromosomal and plasmid-borne genes, and the relative level of maltoporin expression from these genes was estimated. Binding assays with bacteria forming maltoporin heterotrimers were performed in order to test for complementation between binding-negative alleles, negative dominance of negative over wild-type alleles, and possible dominance of negatives over the high-affinity allele. Double mutants with mutations affecting residues 8 and 118, 82 and 118, and 118 and 360 were constructed in vitro, and the dominance properties of the mutations in cis were also tested. There was no complementation between negatives and no negative dominance in heterotrimers. The high-affinity mutation was dominant over negatives in trans but not in cis. The affinity of binding sites in heterotrimer populations was characteristic of the high-affinity allele present and uninfluenced by the negative allele. These results are consistent with the presence of three discrete binding sites in a maltoporin trimer and suggest that the selectivity filter for maltodextrins is not at the interface between the three subunits. PMID:2521623
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NegGOA: negative GO annotations selection using ontology structure.
Fu, Guangyuan; Wang, Jun; Yang, Bo; Yu, Guoxian
2016-10-01
Predicting the biological functions of proteins is one of the key challenges in the post-genomic era. Computational models have demonstrated the utility of applying machine learning methods to predict protein function. Most prediction methods explicitly require a set of negative examples-proteins that are known not carrying out a particular function. However, Gene Ontology (GO) almost always only provides the knowledge that proteins carry out a particular function, and functional annotations of proteins are incomplete. GO structurally organizes more than tens of thousands GO terms and a protein is annotated with several (or dozens) of these terms. For these reasons, the negative examples of a protein can greatly help distinguishing true positive examples of the protein from such a large candidate GO space. In this paper, we present a novel approach (called NegGOA) to select negative examples. Specifically, NegGOA takes advantage of the ontology structure, available annotations and potentiality of additional annotations of a protein to choose negative examples of the protein. We compare NegGOA with other negative examples selection algorithms and find that NegGOA produces much fewer false negatives than them. We incorporate the selected negative examples into an efficient function prediction model to predict the functions of proteins in Yeast, Human, Mouse and Fly. NegGOA also demonstrates improved accuracy than these comparing algorithms across various evaluation metrics. In addition, NegGOA is less suffered from incomplete annotations of proteins than these comparing methods. The Matlab and R codes are available at https://sites.google.com/site/guoxian85/neggoa gxyu@swu.edu.cn Supplementary data are available at Bioinformatics online. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.
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Designing Superoxide-Generating Quantum Dots for Selective Light-Activated Nanotherapy
NASA Astrophysics Data System (ADS)
Goodman, Samuel M.; Levy, Max; Li, Fei-Fei; Ding, Yuchen; Courtney, Colleen M.; Chowdhury, Partha P.; Erbse, Annette; Chatterjee, Anushree; Nagpal, Prashant
2018-03-01
The rapid emergence of superbugs or multi-drug resistant (MDR) organisms has prompted a search for novel antibiotics, beyond traditional small-molecule therapies. Nanotherapeutics are being investigated as alternatives, and recently superoxide-generating quantum dots (QDs) have been shown as important candidates for selective light-activated therapy and potentiating existing antibiotics against MDR superbugs. Their therapeutic action is selective, can be tailored by simply changing their quantum-confined conduction-valence bands and their alignment with different redox half-reactions, and hence their ability to generate specific radical species in biological media. Here, we show the design of superoxide-generating QDs using optimal QD material and size well matched to superoxide redox potential, charged ligands to modulate their uptake in cells and selective redox interventions, and core/shell structures to improve their stability for therapeutic action. We show that cadmium telluride (CdTe) QDs with conduction band position at -0.5V with respect to Normal Hydrogen Electron (NHE) and visible 2.4 eV bandgap generate a large flux of selective superoxide radicals, thereby demonstrating the most effective light-activated therapy. Although the positively charged QDs demonstrate large cellular uptake, they bind indiscriminately to cell surfaces and cause non-selective cell death, while negatively charged and zwitterionic QD ligands reduce the uptake and allow selective therapeutic action via interaction with redox species. The stability of designed QDs in biologically-relevant media increases with the formation of core-shell QD structures, but an appropriate design of core-shell structures is needed to minimize any reduction in charge injection efficiency to adsorbed oxygen molecules (to form superoxide) and maintain similar quantitative generation of tailored redox species, as measured using electron paramagnetic resonance (EPR) spectroscopy and electrochemical impedance spectroscopy. Using these findings, we demonstrate the rational design of QDs as selective therapeutic kills more than 99% of priority class I pathogens, thus providing an effective therapy against MDR superbugs.
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Designing Superoxide-Generating Quantum Dots for Selective Light-Activated Nanotherapy.
Goodman, Samuel M; Levy, Max; Li, Fei-Fei; Ding, Yuchen; Courtney, Colleen M; Chowdhury, Partha P; Erbse, Annette; Chatterjee, Anushree; Nagpal, Prashant
2018-01-01
The rapid emergence of superbugs, or multi-drug resistant (MDR) organisms, has prompted a search for novel antibiotics, beyond traditional small-molecule therapies. Nanotherapeutics are being investigated as alternatives, and recently superoxide-generating quantum dots (QDs) have been shown as important candidates for selective light-activated therapy, while also potentiating existing antibiotics against MDR superbugs. Their therapeutic action is selective, can be tailored by simply changing their quantum-confined conduction-valence band (CB-VB) positions and alignment with different redox half-reactions-and hence their ability to generate specific radical species in biological media. Here, we show the design of superoxide-generating QDs using optimal QD material and size well-matched to superoxide redox potential, charged ligands to modulate their uptake in cells and selective redox interventions, and core/shell structures to improve their stability for therapeutic action. We show that cadmium telluride (CdTe) QDs with conduction band (CB) position at -0.5 V with respect to Normal Hydrogen Electron (NHE) and visible 2.4 eV bandgap generate a large flux of selective superoxide radicals, thereby demonstrating the effective light-activated therapy. Although the positively charged QDs demonstrate large cellular uptake, they bind indiscriminately to cell surfaces and cause non-selective cell death, while negatively charged and zwitterionic QD ligands reduce the uptake and allow selective therapeutic action via interaction with redox species. The stability of designed QDs in biologically-relevant media increases with the formation of core-shell QD structures, but an appropriate design of core-shell structures is needed to minimize any reduction in charge injection efficiency to adsorbed oxygen molecules (to form superoxide) and maintain similar quantitative generation of tailored redox species, as measured using electron paramagnetic resonance (EPR) spectroscopy and electrochemical impedance spectroscopy (EIS). Using these findings, we demonstrate the rational design of QDs as selective therapeutic to kill more than 99% of a priority class I pathogen, thus providing an effective therapy against MDR superbugs.
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Isolation of a New Herpesvirus from Human CD4+ T Cells
1990-01-01
of (PBLs) by negative selection using immunoadsorption with lymphocyte- infected with the RK virus exhibited a cytopathic goat anti -mouse...human herpesvirus 6 (HHV-6). is the causative min in 0.1 M cacodylate buffer, pH 7.2). stained with 1% agent of roseola infantum, a common childhood... herpesvirus 6?humn herp eviru8S/ -CD4+ human T cellsd latency ,T cell activation4~ virus laec 1 .1. ’~ Y ’ ") X)I- 19. ABSTRACT (Continue an peyerre if
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In vitro inhibition of bacterial growth by iron chelators.
Qiu, Di-Hong; Huang, Zhu-Liang; Zhou, Tao; Shen, Chen; Hider, Robert C
2011-01-01
The antimicrobial activity of the iron(III)-selective 3-hydroxypyridin-4-one chelators, CP251(1) and CP252(2), was evaluated in comparison with that of diethylenetriamine-penta acetic acid (3). CP251 was found to exhibit an inhibitory effect on the growth of both Gram-positive and Gram-negative bacteria. CP251 may find application in the treatment of external infections such as those associated with wounds. © 2010 Federation of European Microbiological Societies. Published by Blackwell Publishing Ltd. All rights reserved.
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What we talk about when we talk about access deficits
Mirman, Daniel; Britt, Allison E.
2014-01-01
Semantic impairments have been divided into storage deficits, in which the semantic representations themselves are damaged, and access deficits, in which the representations are intact but access to them is impaired. The behavioural phenomena that have been associated with access deficits include sensitivity to cueing, sensitivity to presentation rate, performance inconsistency, negative serial position effects, sensitivity to number and strength of competitors, semantic blocking effects, disordered selection between strong and weak competitors, correlation between semantic deficits and executive function deficits and reduced word frequency effects. Four general accounts have been proposed for different subsets of these phenomena: abnormal refractoriness, too much activation, impaired competitive selection and deficits of semantic control. A combination of abnormal refractoriness and impaired competitive selection can account for most of the behavioural phenomena, but there remain several open questions. In particular, it remains unclear whether access deficits represent a single syndrome, a syndrome with multiple subtypes or a variable collection of phenomena, whether the underlying deficit is domain-general or domain-specific, whether it is owing to disorders of inhibition, activation or selection, and the nature of the connection (if any) between access phenomena in aphasia and in neurologically intact controls. Computational models offer a promising approach to answering these questions. PMID:24324232
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NASA Astrophysics Data System (ADS)
Li, Jiqiu; Tan, Beiping; Mai, Kangsen
2011-09-01
It is a practical approach to select candidate probiotic bacterial stains on the basis of their special traits. Production of digestive enzyme was used as a trait to select a candidate probiotic bacterial strain in this study. In order to select a bacterium with the ability to degrade both starch and protein, an ideal bacterial strain STE was isolated from marine shrimp ( Litopenaeus vannamei) intestines by using multiple selective media. The selected isolate STE was identified on the basis of its morphological, physiological, and biochemical characteristics as well as molecular analyses. Results of degradation experiments confirmed the ability of the selected isolate to degrade both starch and casein. The isolate STE was aerobic, Gram-negative, rod-shaped, motile and non-spore-forming, and had catalase and oxidase activities but no glucose fermentation activity. Among the tested carbon/nitrogen sources, only Tween40, alanyl-glycine, aspartyl-glycine, and glycyl-l-glutamic acid were utilized by the isolate STE. Results of homology comparison analyses of the 16S rDNA sequences showed that the isolate STE had a high similarity to several Pseudoalteromonas species and, in the phylogenetic tree, grouped with P. ruthenica with maximum bootstrap support (100%). In conclusion, the isolate STE was characterized as a novel strain belonging to the genus Pseudoalteromonas. This study provides a further example of a probiotic bacterial strain with specific characteristics isolated from the host gastrointestinal tract.
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Bim is required for T-cell allogeneic responses and graft-versus-host disease in vivo
Yu, Yu; Yu, Jing; Iclozan, Cristina; Kaosaard, Kane; Anasetti, Claudio; Yu, Xue-Zhong
2012-01-01
Bim, a BH3-only Bcl-2-family protein, is essential for T-cell negative selection in the thymus as well as for the death of activated T cells in the periphery. The role of Bim has been extensively studied in T-cell responses to self-antigens and viral infections. Recent findings on Bim in autoimmunity triggered our interest in investigating whether Bim may play a role in another disease with inflammatory symptoms as graft-versus-host disease (GVHD). Here we report that Bim is required for optimal T-cell responses to alloantigens in vivo and for the development of GVHD. Using murine models of allogeneic bone marrow transplantation (BMT), we found that donor T cells deficient for Bim are impaired in the induction of GVHD primarily due to a significant defect in T cell activation and expansion in vivo. Upon TCR engagement, Bim-/- T cells exhibited selective defects in CD69 expression and phosphorylation of PLCγ1. Our studies uncover a novel aspect of Bim function in T-cell activation with important implications in understanding the mechanisms of T-cell activation and tolerance under allogeneic transplantation. PMID:22432091
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Sinicropi, Maria Stefania; Lappano, Rosamaria; Caruso, Anna; Santolla, Maria Francesca; Pisano, Assunta; Rosano, Camillo; Capasso, Anna; Panno, Antonella; Lancelot, Jean Charles; Rault, Sylvain; Saturnino, Carmela; Maggiolini, Marcello
2015-01-01
Estrogens control a wide number of aspects of human physiology and play a key role in multiple diseases, including cancer. Estrogens act by binding to and activating the cognate receptor (ER), however numerous studies have revealed that the G protein-coupled receptor named GPR30/GPER mediates also estrogen signals. As ER and GPER share the ability to bind to same compounds, the use of GPER-selective ligands has allowed a better understanding of the biological responses mediated by GPER. In the present study, we designed and synthesized two novel carbazole derivatives and then investigated their ability to interact with and activate the GPER-mediated transduction pathway in breast cancer cells. Both compounds did not activate the classical ER in MCF7 cells, whereas one of the two compounds synthesized triggered through GPER the rapid ERK activation in ER-negative SkBr3 cells, demonstrating a good affinity for GPER in docking studies. The characterization of this novel selective GPER agonist could represent a potential useful tool to provide further insights into the physiopathological role exerted by GPER.
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The role of the JAK/STAT signal pathway in rheumatoid arthritis
Malemud, Charles J.
2018-01-01
Proinflammatory cytokine activation of the Janus kinase/signal transducers and activators of transcription (JAK/STAT) signal transduction pathway is a critical event in the pathogenesis and progression of rheumatoid arthritis. Under normal conditions, JAK/STAT signaling reflects the influence of negative regulators of JAK/STAT, exemplified by the suppressor of cytokine signaling and protein inhibitor of activated STAT. However, in rheumatoid arthritis (RA) both of these regulators are dysfunctional. Thus, continuous activation of JAK/STAT signaling in RA synovial joints results in the elevated level of matrix metalloproteinase gene expression, increased frequency of apoptotic chondrocytes and most prominently ‘apoptosis resistance’ in the inflamed synovial tissue. Tofacitinib, a JAK small molecule inhibitor, with selectivity for JAK2/JAK3 was approved by the United States Food and Drug Administration (US FDA) for the therapy of RA. Importantly, tofacitinib has demonstrated significant clinical efficacy for RA in the post-US FDA-approval surveillance period. Of note, the success of tofacitinib has spurred the development of JAK1, JAK2 and other JAK3-selective small molecule inhibitors, some of which have also entered the clinical setting, whereas other JAK inhibitors are currently being evaluated in RA clinical trials. PMID:29942363
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[Aminoglycoside levels in bronchial secretions].
Mombelli, G
1985-01-19
Aminoglycosides are of limited clinical efficacy in gram-negative bacillary pneumonia, although they are commonly employed to treat this infection. This poor efficacy has been related in part to host factors (abnormalities in the lung, immunocompromise) and in part to pharmacologic factors. In particular, aminoglycoside levels in bronchial secretions are often borderline or inadequate in relation to the minimal inhibitory concentrations for most gram-negative strains. The low aminoglycoside concentrations result from poor penetrance into the respiratory tract or from local inactivation of these drugs, but basically reflect their low therapeutic-to-toxic ratio. The endotracheal injection of aminoglycosides resulted in high bactericidal activity within the bronchial lumen and in increased clinical efficacy, without increasing systemic toxicity. In view of the potential dangers of topical antibiotics, however, endotracheal treatment should be confined to selected patients.
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Kawahara, Takashi; Aljarah, Ali Kadhim; Shareef, Hasanain Khaleel; Inoue, Satoshi; Ide, Hiroki; Patterson, John D; Kashiwagi, Eiji; Han, Bin; Li, Yi; Zheng, Yichun; Miyamoto, Hiroshi
2016-06-01
Biological significance of ELK1, a transcriptional factor whose phosphorylation is necessary for c-fos proto-oncogene activation, in prostate cancer remains far from fully understood. In this study, we aim to investigate the role of ELK1 in tumor growth as well as the efficacy of a selective α1A-adrenergic blocker, silodosin, in ELK1 activity in prostate cancer cells. We first immunohistochemically determined the levels of phospho-ELK1 (p-ELK1) expression in radical prostatectomy specimens. We then assessed the effects of ELK1 knockdown via short hairpin RNA and silodosin on cell proliferation, migration, and invasion in prostate cancer lines. The levels of p-ELK1 expression were significantly higher in carcinoma than in benign (P < 0.001) or high-grade prostatic intraepithelial neoplasia (HGPIN) (P = 0.002) as well as in HGPIN than in benign (P < 0.001). Kaplan-Meier and log-rank tests revealed that moderate-strong positivity of p-ELK1 in carcinomas tended to correlate with biochemical recurrence after radical prostatectomy (P = 0.098). In PC3 and DU145 expressing ELK1 (mRNA/protein) but no androgen receptor (AR), ELK1 silencing resulted in considerable decreases in the expression of c-fos as well as in cell migration/invasion and matrix metalloproteinase-2 expression, but not in cell viability. Silodosin treatment reduced the expression/activity of ELK1 in these cells as well as the viability of AR-positive LNCaP and C4-2 cells and the migration of both AR-positive and AR-negative cells, but not the viability of AR-negative or ELK1-negative cells. Interestingly, silodosin significantly increased sensitivity to gemcitabine, but not to cisplatin or docetaxel, even in AR-negative cells. ELK1 is likely to be activated in prostate cancer cells and promote tumor progression. Furthermore, silodosin that inactivates ELK1 in prostate cancer cells not only inhibits their growth but also enhances the cytotoxic activity of gemcitabine. Thus, ELK1 inhibition has the potential of being a therapeutic approach for prostate cancer. © 2016 Wiley Periodicals, Inc.
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Grossman, Zvi; Singer, Alfred
1996-01-01
Immature CD4+CD8+ thymocytes expressing T-cell antigen receptors (TCR) are selected by TCR-mediated recognition of peptides associated with major histocompatibility complex molecules on thymic stromal cells. Selection ensures reactivity of the mature cells to foreign antigens and tolerance to self. Although much has been learned about the factors that determine whether a thymocyte with a given specificity will be positively or negatively selected, selection as an aspect of the developmental process as a whole is less well-understood. Here we invoke a model in which thymocytes tune their response characteristics individually and dynamically in the course of development. Cellular development and selection are driven by receptor-mediated metabolic perturbations. Perturbation is a measure of the net intracellular change induced by external stimulation. It results from the integration of several signals and countersignals over time and therefore depends on the environment and the maturation stage of the cell. Individual cell adaptation limits the range of perturbations. Such adaptation renders thymocytes less sensitive to the level of stimulation per se, but responsive to environmental changes in that level. This formulation begins to explain the mechanisms that link developmental and selection events to each other. PMID:8962126
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Narahara, Hiroki; Sakai, Eri; Katayama, Masafumi; Ohtomo, Yukiko; Yamamoto, Kanako; Takemoto, Miki; Aso, Hisashi; Ohwada, Shyuichi; Mohri, Yasuaki; Nishimori, Katsuhiko; Isogai, Emiko; Yamaguchi, Takahiro; Fukuda, Tomokazu
2012-05-01
Genetic improvement of resistance to infectious diseases is a challenging goal in animal breeding. Infection resistance involves multiple immunological characteristics, including natural and acquired immunity. In the present study, we developed an experimental model based on genetic selection, to improve immunological phenotypes. We selectively established three mouse lines based on phagocytic activity, antibody production and the combination of these two phenotypes. We analyzed the immunological characteristics of these lines using a lipopolysaccharide (LPS), which is one of the main components of Gram-negative bacteria. An intense immunological reaction was induced in each of the three mouse lines. Severe loss of body weight and liver damage were observed, and a high level of cytokine messenger RNA was detected in the liver tissue. The mouse line established using a combination of the two selection standards showed unique characteristics relative to the mouse lines selected on the basis of a single phenotype. Our results indicate that genetic selection and breeding is effective, even for immunological phenotypes with a relatively low heritability. Thus, it may be possible to improve resistance to infectious diseases by means of genetic selection. © 2011 The Authors. Animal Science Journal © 2011 Japanese Society of Animal Science.
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de Ridder, D J; Verliefde, A R D; Heijman, S G J; Verberk, J Q J C; Rietveld, L C; van der Aa, L T J; Amy, G L; van Dijk, J C
2011-01-01
Natural organic matter (NOM) can influence pharmaceutical adsorption onto granular activated carbon (GAC) by direct adsorption competition and pore blocking. However, in the literature there is limited information on which of these mechanisms is more important and how this is related to NOM and pharmaceutical properties. Adsorption batch experiments were carried out in ultrapure, waste- and surface water and fresh and NOM preloaded GAC was used. Twenty-one pharmaceuticals were selected with varying hydrophobicity and with neutral, negative or positive charge. The influence of NOM competition and pore blocking could not be separated. However, while reduction in surface area was similar for both preloaded GACs, up to 50% lower pharmaceutical removal was observed on wastewater preloaded GAC. This was attributed to higher hydrophobicity of wastewater NOM, indicating that NOM competition may influence pharmaceutical removal more than pore blocking. Preloaded GAC was negatively charged, which influenced removal of charged pharmaceuticals significantly. At a GAC dose of 6.7 mg/L, negatively charged pharmaceuticals were removed for 0-58%, while removal of positively charged pharmaceuticals was between 32-98%. Charge effects were more pronounced in ultrapure water, as it contained no ions to shield the surface charge. Solutes with higher log D could compete better with NOM, resulting in higher removal.
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Sample Selection for Training Cascade Detectors.
Vállez, Noelia; Deniz, Oscar; Bueno, Gloria
2015-01-01
Automatic detection systems usually require large and representative training datasets in order to obtain good detection and false positive rates. Training datasets are such that the positive set has few samples and/or the negative set should represent anything except the object of interest. In this respect, the negative set typically contains orders of magnitude more images than the positive set. However, imbalanced training databases lead to biased classifiers. In this paper, we focus our attention on a negative sample selection method to properly balance the training data for cascade detectors. The method is based on the selection of the most informative false positive samples generated in one stage to feed the next stage. The results show that the proposed cascade detector with sample selection obtains on average better partial AUC and smaller standard deviation than the other compared cascade detectors.
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Okamura, Toshihiro; Maeda, Kouki; Onodera, Wataru; Kadowaki, Hiroshi; Kojima-Shibata, Chihiro; Suzuki, Eisaku; Uenishi, Hirohide; Satoh, Masahiro; Suzuki, Keiichi
2016-09-01
Five generations of Landrace pigs selected for average daily gain, backfat thickness, Mycoplasmal pneumonia of swine (MPS) lesion score, and plasma cortisol levels, was executed to decrease the MPS lesion score. Genetic parameters and correlated genetic responses for respiratory disease and peripheral blood immune traits were estimated in 1395 Landrace pigs. We estimated the negative genetic correlation of MPS lesion score with phagocytic activity (PA) at 7 weeks of age (-0.67). The breeding values of PA at 7 weeks of age and 105 kg body weight and the correlated selection response of the ratio of granular leukocytes to lymphocytes at 105 kg body weight were significantly increased, and sheep red blood cell-specific antibody production (AP) was significantly decreased in a selection-dependent manner. Increasing of natural immunological indicators (e.g. PA) and decreasing of humoral immunological indicator (e.g. AP) were observed due to genetically decreasing MPS lesion score. © 2015 Japanese Society of Animal Science.
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Morton, Nicholas M.; Beltram, Jasmina; Carter, Roderick N.; Michailidou, Zoi; Gorjanc, Gregor; Fadden, Clare Mc; Barrios-Llerena, Martin E.; Rodriguez-Cuenca, Sergio; Gibbins, Matthew T. G.; Aird, Rhona E.; Moreno-Navarrete, José Maria; Munger, Steven C.; Svenson, Karen L.; Gastaldello, Annalisa; Ramage, Lynne; Naredo, Gregorio; Zeyda, Maximilian; Wang, Zhao V.; Howie, Alexander F.; Saari, Aila; Sipilä, Petra; Stulnig, Thomas M.; Gudnason, Vilmundur; Kenyon, Christopher J.; Seckl, Jonathan R.; Walker, Brian R.; Webster, Scott P.; Dunbar, Donald R.; Churchill, Gary A.; Vidal-Puig, Antonio; Fernandez-Real, José Manuel; Emilsson, Valur; Horvat, Simon
2017-01-01
Discovery of genetic mechanisms for resistance to obesity and diabetes may illuminate new therapeutic strategies for the treatment of this global health challenge. We used the polygenic Lean mouse model, selected for low adiposity over 60 generations, to identify thiosulfate sulfurtransferase (Tst, Rhodanese) as a candidate obesity-resistance gene with selectively increased adipocyte expression. Elevated adipose Tst expression correlated with indices of metabolic health across diverse mouse strains. Transgenic overexpression of Tst in adipocytes protected mice from diet-induced obesity and insulin-resistant diabetes. Tst gene deficiency markedly exacerbated diabetes whereas pharmacological TST activation ameliorated diabetes in mice in vivo. Mechanistically, TST selectively augmented mitochondrial function combined with degradation of reactive oxygen species and sulfide. In humans, adipose TST mRNA correlated positively with adipose insulin sensitivity and negatively with fat mass. Genetic identification of Tst as a beneficial regulator of adipocyte mitochondrial function may have therapeutic significance for type 2 diabetes. PMID:27270587
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Helicobacter pylori-negative gastritis: prevalence and risk factors.
Nordenstedt, Helena; Graham, David Y; Kramer, Jennifer R; Rugge, Massimo; Verstovsek, Gordana; Fitzgerald, Stephanie; Alsarraj, Abeer; Shaib, Yasser; Velez, Maria E; Abraham, Neena; Anand, Bhupinderjit; Cole, Rhonda; El-Serag, Hashem B
2013-01-01
Recent studies using histology alone in select patients have suggested that Helicobacter pylori-negative gastritis may be common. The objective of this study was to investigate the prevalence of H. pylori among individuals with histologic gastritis. Subjects between 40 and 80 years underwent elective esophagogastroduodenoscopy at a VA Medical Center. Gastric biopsies were mapped from seven prespecified sites (two antrum, four corpus, and one cardia) and graded by two gastrointestinal pathologists, using the Updated Sydney System. H. pylori-negative required four criteria: negative triple staining at all seven gastric sites, negative H. pylori culture, negative IgG H. pylori serology, and no previous treatment for H. pylori. Data regarding tobacco smoking, alcohol drinking, nonsteroidal anti-inflammatory drug, and proton pump inhibitor (PPI) use were obtained by questionnaire. Of the 491 individuals enrolled, 40.7% (200) had gastritis of at least grade 2 in at least one biopsy site or grade 1 in at least two sites. Forty-one (20.5%) had H. pylori-negative gastritis; most (30 or 73.2%) had chronic gastritis, five (12.2%) had active gastritis, and six (14.6%) had both. H. pylori-negative gastritis was approximately equally distributed in the antrum, corpus, and both antrum and corpus. Past and current PPI use was more frequent in H. pylori-negative vs. H. pylori-positive gastritis (68.2% and 53.8%; P=0.06). We used multiple methods to define non-H. pylori gastritis and found it in 21% of patients with histologic gastritis. While PPI use is a potential risk factor, the cause or implications of this entity are not known.
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Helicobacter pylori-Negative Gastritis: Prevalence and Risk Factors
Nordenstedt, Helena; Graham, David Y.; Kramer, Jennifer R.; Rugge, Massimo; Verstovsek, Gordana; Fitzgerald, Stephanie; Alsarraj, Abeer; Shaib, Yasser; Velez, Maria E.; Abraham, Neena; Anand, Bhupinderjit; Cole, Rhonda; El-Serag, Hashem B.
2014-01-01
OBJECTIVES Recent studies using histology alone in select patients have suggested that Helicobacter pylori-negative gastritis may be common. The objective of this study was to investigate the prevalence of H. pylori among individuals with histologic gastritis. METHODS Subjects between 40 and 80 years underwent elective esophagogastroduodenoscopy at a VA Medical Center. Gastric biopsies were mapped from seven prespecified sites (two antrum, four corpus, and one cardia) and graded by two gastrointestinal pathologists, using the Updated Sydney System. H. pylori-negative required four criteria: negative triple staining at all seven gastric sites, negative H. pylori culture, negative IgG H. pylori serology, and no previous treatment for H. pylori. Data regarding tobacco smoking, alcohol drinking, nonsteroidal anti-inflammatory drug, and proton pump inhibitor (PPI) use were obtained by questionnaire. RESULTS Of the 491 individuals enrolled, 40.7% (200) had gastritis of at least grade 2 in at least one biopsy site or grade 1 in at least two sites. Forty-one (20.5%) had H. pylori-negative gastritis; most (30 or 73.2%) had chronic gastritis, five (12.2%) had active gastritis, and six (14.6%) had both. H. pylori-negative gastritis was approximately equally distributed in the antrum, corpus, and both antrum and corpus. Past and current PPI use was more frequent in H. pylori-negative vs. H. pylori-positive gastritis (68.2% and 53.8%; P = 0.06). CONCLUSIONS We used multiple methods to define non-H. pylori gastritis and found it in 21% of patients with histologic gastritis. While PPI use is a potential risk factor, the cause or implications of this entity are not known. PMID:23147524
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tDCS over the left prefrontal cortex enhances cognitive control for positive affective stimuli.
Vanderhasselt, Marie-Anne; De Raedt, Rudi; Brunoni, Andre R; Campanhã, Camila; Baeken, Chris; Remue, Jonathan; Boggio, Paulo S
2013-01-01
Transcranial Direct Current Stimulation (tDCS) is a neuromodulation technique with promising results for enhancing cognitive information processes. So far, however, research has mainly focused on the effects of tDCS on cognitive control operations for non-emotional material. Therefore, our aim was to investigate the effects on cognitive control considering negative versus positive material. For this sham-controlled, within-subjects study, we selected a homogeneous sample of twenty-five healthy participants. By using behavioral measures and event related potentials (ERP) as indexes, we aimed to investigate whether a single session of anodal tDCS of the left dorsolateral prefrontal cortex (DLPFC) would have specific effects in enhancing cognitive control for positive and negative valenced stimuli. After tDCS over the left DLPFC (and not sham control stimulation), we observed more negative N450 amplitudes along with faster reaction times when inhibiting a habitual response to happy compared to sad facial expressions. Gender did not influence the effects of tDCS on cognitive control for emotional information. In line with the Valence Theory of side-lateralized activity, this stimulation protocol might have led to a left dominant (relative to right) prefrontal cortical activity, resulting in augmented cognitive control specifically for positive relative to negative stimuli. To verify that tDCS induces effects that are in line with all aspects of the well known Valence Theory, future research should investigate the effects of tDCS over the left vs. right DLPFC on cognitive control for emotional information.
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NASA Astrophysics Data System (ADS)
Wang, Huan; Qiu, Xueqing; Liu, Weifeng; Yang, Dongjie
2017-12-01
In this work, a novel lignin-based carbon/ZnO (LC/ZnO) hybrid composite with excellent photocatalytic performance was prepared through a convenient and environment friendly method using alkali lignin (AL) as carbon source. The morphological, microstructure and optical properties of the as-prepared LC/ZnO hybrid composite was characterized with scanning electron microscope (SEM), X-ray diffraction (XRD), Raman and UV-vis. The resulting LC/ZnO hybrid is composed of highly dispersed ZnO nanoparticles embedded on a lignin-based carbon nanosheet, showing excellent photogenerated electrons and holes separation and migration efficiency. The photocatalytic activity of LC/ZnO was much higher than the pure ZnO. The LC/ZnO hybrid composite showed different photocatalytic mechanism for degradation of negative methyl orange (MO) and positive Rhodamine B (RhB). It showed that h+ was the main photocatalytic active group during the degradation of MO, ·O2- and ·OH were the photocatalytic active groups during degradation of RhB. This reported photocatalyst with selective degradation of positive and negative organic dyes may have a great application prospect for photoelectric conversion and catalytic materials. Results of this work were of practical importance for high-valued utilization of lignin for carbon materials.
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Effect of plasma-induced surface charging on catalytic processes: application to CO2 activation
NASA Astrophysics Data System (ADS)
Bal, Kristof M.; Huygh, Stijn; Bogaerts, Annemie; Neyts, Erik C.
2018-02-01
Understanding the nature and effect of the multitude of plasma-surface interactions in plasma catalysis is a crucial requirement for further process development and improvement. A particularly intriguing and rather unique property of a plasma-catalytic setup is the ability of the plasma to modify the electronic structure, and hence chemical properties, of the catalyst through charging, i.e. the absorption of excess electrons. In this work, we develop a quantum chemical model based on density functional theory to study excess negative surface charges in a heterogeneous catalyst exposed to a plasma. This method is specifically applied to investigate plasma-catalytic CO2 activation on supported M/Al2O3 (M = Ti, Ni, Cu) single atom catalysts. We find that (1) the presence of a negative surface charge dramatically improves the reductive power of the catalyst, strongly promoting the splitting of CO2 to CO and oxygen, and (2) the relative activity of the investigated transition metals is also changed upon charging, suggesting that controlled surface charging is a powerful additional parameter to tune catalyst activity and selectivity. These results strongly point to plasma-induced surface charging of the catalyst as an important factor contributing to the plasma-catalyst synergistic effects frequently reported for plasma catalysis.
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Choices between positive and negative reinforcement during treatment for escape-maintained behavior.
DeLeon, I G; Neidert, P L; Anders, B M; Rodriguez-Catter, V
2001-01-01
Positive reinforcement was more effective than negative reinforcement in promoting compliance and reducing escape-maintained problem behavior for a child with autism. Escape extinction was then added while the child was given a choice between positive or negative reinforcement for compliance and the reinforcement schedule was thinned. When the reinforcement requirement reached 10 consecutive tasks, the treatment effects became inconsistent and reinforcer selection shifted from a strong preference for positive reinforcement to an unstable selection pattern.
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ERIC Educational Resources Information Center
Magno, Carlo
2010-01-01
The present study investigated the composition of negative affect and its function as inhibitory to thought processes such as self-regulation. Negative affect in the present study were composed of anxiety, worry, thought suppression, and fear of negative evaluation. These four factors were selected based on the criteria of negative affect by…
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Mei, Suyu; Zhu, Hao
2015-01-26
Protein-protein interaction (PPI) prediction is generally treated as a problem of binary classification wherein negative data sampling is still an open problem to be addressed. The commonly used random sampling is prone to yield less representative negative data with considerable false negatives. Meanwhile rational constraints are seldom exerted on model selection to reduce the risk of false positive predictions for most of the existing computational methods. In this work, we propose a novel negative data sampling method based on one-class SVM (support vector machine, SVM) to predict proteome-wide protein interactions between HTLV retrovirus and Homo sapiens, wherein one-class SVM is used to choose reliable and representative negative data, and two-class SVM is used to yield proteome-wide outcomes as predictive feedback for rational model selection. Computational results suggest that one-class SVM is more suited to be used as negative data sampling method than two-class PPI predictor, and the predictive feedback constrained model selection helps to yield a rational predictive model that reduces the risk of false positive predictions. Some predictions have been validated by the recent literature. Lastly, gene ontology based clustering of the predicted PPI networks is conducted to provide valuable cues for the pathogenesis of HTLV retrovirus.
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Invasion strategy and abiotic activity triggers for non-native gobiids of the River Rhine
Hartmann, Frank; Brinker, Alexander
2017-01-01
The 24 hour activity patterns of three non-native gobiids (round goby Neogobius melanostomus, Western tubenose goby Proterorhinus semilunaris and bighead goby Ponticola kessleri) were assessed over 46 consecutive months between 2011 and 2014 from their occurrence in the cooling water intake of a nuclear power plant on the River Rhine, Germany. In total, 117717 gobiids were identified and classified. The occurrence of all three species varied strongly between sampling years, and species-specific activity triggers were identified. The activity of juveniles of all three gobiids species was positively temperature dependent while adult tubenose goby activity appeared to be negatively temperature dependent. Increasing fluvial discharge in the adjoining main river stimulated the activity of juvenile round goby but inhibited activity of adult tubenose goby. Except for adult bighead goby, activity was also structured by time of day, but with no uniform mean. Meteorological factors such as precipitation, air pressure and duration of sunshine hours had little or no influence on gobiid activity. On selected rare occasions, mainly at night, all three species exhibited pulsed swarming behaviour, with thousands of individuals recorded in the intake water. Round goby swarms exhibited both the highest intensity and the largest swarming individuals, suggesting a potential competitive advantage over tubenose and bighead goby. Electric fishing surveys in natural river stretches corroborated this observation. Negative effects on the native fish fauna were apparent only for the bullhead, Cottus gobio. The activity triggers identified offer a unique insight into the invasion mechanisms of these ecosystem-changing non-native gobiids. PMID:28915248
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Risk Factors for Anthroponotic Cutaneous Leishmaniasis at the Household Level in Kabul, Afghanistan
Reithinger, Richard; Mohsen, Mohammad; Leslie, Toby
2010-01-01
Background Kabul, Afghanistan, is the largest focus of anthroponotic cutaneous leishmaniasis (ACL) in the world. ACL is a protozoan disease transmitted to humans by the bite of phlebotomine sand flies. Although not fatal, ACL can lead to considerable stigmatization of affected populations. Methods Using data from a standardized survey of 872 households in 4 wards of Kabul, Afghanistan, univariate and multivariate logistic regression analyses tested associations between presence of active ACL and ACL scars with 15 household-level variables. Findings Univariate analyses showed that active ACL was positively associated with household member's age, ACL prevalence, and brick wall type, but negatively associated with household number of rooms, bednet use, and proportion of windows with screens. Multivariate analysis showed a positive association between active ACL and household member's age, ACL prevalence, and brick wall type, and a negative association with household proportion of windows with screens. Conclusion Household-level charateristics were shown to be risk factors for ACL. Monitoring a selected number of household characteristics could assist in rapid assessments of household-level variation in risk of ACL. ACL prevention and control programs should consider improving house construction, including smoothing of walls and screening of windows. PMID:20351787
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Combined ICA-LORETA analysis of mismatch negativity.
Marco-Pallarés, J; Grau, C; Ruffini, G
2005-04-01
A major challenge for neuroscience is to map accurately the spatiotemporal patterns of activity of the large neuronal populations that are believed to underlie computing in the human brain. To study a specific example, we selected the mismatch negativity (MMN) brain wave (an event-related potential, ERP) because it gives an electrophysiological index of a "primitive intelligence" capable of detecting changes, even abstract ones, in a regular auditory pattern. ERPs have a temporal resolution of milliseconds but appear to result from mixed neuronal contributions whose spatial location is not fully understood. Thus, it is important to separate these sources in space and time. To tackle this problem, a two-step approach was designed combining the independent component analysis (ICA) and low-resolution tomography (LORETA) algorithms. Here we implement this approach to analyze the subsecond spatiotemporal dynamics of MMN cerebral sources using trial-by-trial experimental data. We show evidence that a cerebral computation mechanism underlies MMN. This mechanism is mediated by the orchestrated activity of several spatially distributed brain sources located in the temporal, frontal, and parietal areas, which activate at distinct time intervals and are grouped in six main statistically independent components.
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Lynch, Luiz Felipe; Lynch, Maria Isabel; Ferreira, Rodrigo Santana do Nascimento; Vasconcelos, Mirelle Souza Leão; Melo, Narjara; Ferreira, Silvana; Malagueño, Elizabeth
2011-08-01
Ocular toxoplasmosis can result in recurrent uveitis. Studies have shown that a correlation between active ocular toxoplasmosis and the presence of anti-Toxoplasma gondii secretory IgA (SIgA) in tears. This study compares anti-T. gondii SIgA levels in patients' tears during the acute and inactive phases of toxoplasmic uveitis. Twenty-nine positive tear specific SIgA for T. gondii patients with acute toxoplasmic uveitis were selected and were followed-up for at least two years, when the anti-T. gondii SIgA tears levels were determined. Specific SIgA for T. gondii was negative in 22 patients (75.86%) and positive in seven patients (24.13%) of whom six (85.7%) were followed over three years. Average SIgA levels during the acute phase are 1.54 and decrease significantly to 0.72 (p = 0.0001) during the inactive phase of disease. Because anti-T. gondii SIgA in the tear is negative in 75.86% of patients after the acute phase of infection, T. gondii SIgA levels may be used as a complementary diagnostic marker for active ocular toxoplasmosis.
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Pshenichnyuk, Stanislav A; Elkin, Yury N; Kulesh, Nadezda I; Lazneva, Eleonora F; Komolov, Alexei S
2015-07-14
The antioxidant isoflavone retusin efficiently attaches low-energy electrons in vacuo, generating fragment species via dissociative electron attachment (DEA), as has been shown by DEA spectroscopy. According to in silico results obtained by means of density functional theory, retusin is able to attach solvated electrons and could be decomposed under reductive conditions in vivo, for instance, near the mitochondrial electron transport chain, analogous to gas-phase DEA. The most intense decay channels of retusin temporary negative ions were found to be associated with the elimination of H atoms and H2 molecules. Doubly dehydrogenated fragment anions were predicted to possess a quinone structure. It is thought that molecular hydrogen, known for its selective antioxidant properties, can be efficiently generated via electron attachment to retusin in mitochondria and may be responsible for its antioxidant activity. The second abundant species, i.e., quinone bearing an excess negative charge, can serve as an electron carrier and can return the captured electron back to the respiration cycle. The number of OH substituents and their relative positions are crucial for the present molecular mechanism, which can explain the radical scavenging activity of polyphenolic compounds.
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A bivalent cationic dye enabling selective photo-inactivation against Gram-negative bacteria.
Li, Ke; Zhang, Yang-Yang; Jiang, Guo-Yu; Hou, Yuan-Jun; Zhang, Bao-Wen; Zhou, Qian-Xiong; Wang, Xue-Song
2015-05-07
A piperazine-modified Crystal Violet was found to be able to selectively inactivate Gram-negative bacteria upon visible light irradiation but left Gram-positive bacteria less damaged, which can serve as a blueprint for the development of novel narrow-spectrum agents to replenish the current arsenal of photodynamic antimicrobial chemotherapy (PACT).
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Evolution of genetic architecture under directional selection.
Hansen, Thomas F; Alvarez-Castro, José M; Carter, Ashley J R; Hermisson, Joachim; Wagner, Günter P
2006-08-01
We investigate the multilinear epistatic model under mutation-limited directional selection. We confirm previous results that only directional epistasis, in which genes on average reinforce or diminish each other's effects, contribute to the initial evolution of mutational effects. Thus, either canalization or decanalization can occur under directional selection, depending on whether positive or negative epistasis is prevalent. We then focus on the evolution of the epistatic coefficients themselves. In the absence of higher-order epistasis, positive pairwise epistasis will tend to weaken relative to additive effects, while negative pairwise epistasis will tend to become strengthened. Positive third-order epistasis will counteract these effects, while negative third-order epistasis will reinforce them. More generally, gene interactions of all orders have an inherent tendency for negative changes under directional selection, which can only be modified by higher-order directional epistasis. We identify three types of nonadditive quasi-equilibrium architectures that, although not strictly stable, can be maintained for an extended time: (1) nondirectional epistatic architectures; (2) canalized architectures with strong epistasis; and (3) near-additive architectures in which additive effects keep increasing relative to epistasis.
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Neural correlates of the encoding of multimodal contextual features
Gottlieb, Lauren J.; Wong, Jenny; de Chastelaine, Marianne; Rugg, Michael D.
2012-01-01
Functional magnetic resonance imaging (fMRI) was employed to identify neural regions engaged during the encoding of contextual features belonging to different modalities. Subjects studied objects that were presented to the left or right of fixation. Each object was paired with its name, spoken in either a male or a female voice. The test requirement was to discriminate studied from unstudied pictures and, for each picture judged old, to retrieve its study location and the gender of the voice that spoke its name. Study trials associated with accurate rather than inaccurate location memory demonstrated enhanced activity in the fusiform and parahippocampal cortex and the hippocampus and reduced activity (a negative subsequent memory effect) in the medial occipital cortex. Successful encoding of voice information was associated with enhanced study activity in the right middle superior temporal sulcus and activity reduction in the right superior frontal cortex. These findings support the proposal that encoding of a contextual feature is associated with enhanced activity in regions engaged during its online processing. In addition, they indicate that negative subsequent memory effects can also demonstrate feature-selectivity. Relative to other classes of study trials, trials for which both contextual features were later retrieved demonstrated enhanced activity in the lateral occipital complex and reduced activity in the temporo-parietal junction. These findings suggest that multifeatural encoding was facilitated when the study item was processed efficiently and study processing was not interrupted by redirection of attention toward extraneous events. PMID:23166292
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Abler, Birgit; Hofer, Christian; Walter, Henrik; Erk, Susanne; Hoffmann, Holger; Traue, Harald C; Kessler, Henrik
2010-08-30
The response-focused emotion regulation style 'Expressive suppression' has been associated with symptoms of lower psychological well-being and increased function magnetic resonance imaging (fMRI) activation of the sublenticular extended amygdala (SLEA) in patients with major depression. Extending prior studies on active emotion regulation, we were interested in effects of habitual emotion regulation on neurobiology. Thirty subjects with either relatively high or low suppression scores as assessed with the Emotion Regulation Questionnaire without symptoms of clinical depression participated in the study. They were instructed to expect and then perceive emotionally unpleasant, pleasant or neutral stimuli selected from the International Affective Picture System that were announced by a congruent cue during fMRI. In the subjects with high suppression scores, decreased activation of the orbital medial prefrontal cortex (oMFC) when expecting negative pictures and increased activation of the SLEA upon presentation of neutral stimuli were found. Subclinical depression ratings independently of suppression scores in the healthy subjects were positively correlated with brain activation in the SLEA when expecting negative pictures. SLEA hyperactivity may represent an emotional responsivity that involves less successful habitual emotion regulation and a tendency to depressed mood in healthy subjects, as shown in patients with major depression. Decreased anticipatory oMFC activation may parallel a lack of antecedent emotion regulation in subjects with high suppression scores, representing another neurobiological predictor of lower mental well-being. Copyright 2010 Elsevier Ireland Ltd. All rights reserved.
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Ramalho, José S; Anders, Ross; Jaissle, Gesine B; Seeliger, Mathias W; Huxley, Clare; Seabra, Miguel C
2002-01-01
Background Transgenic mice have proven to be a powerful system to study normal and pathological gene functions. Here we describe an attempt to generate a transgenic mouse model for choroideremia (CHM), a slow-onset X-linked retinal degeneration caused by mutations in the Rab Escort Protein-1 (REP1) gene. REP1 is part of the Rab geranylgeranylation machinery, a modification that is essential for Rab function in membrane traffic. The loss of REP1 in CHM patients may trigger retinal degeneration through its effects on Rab proteins. We have previously reported that Rab27a is the Rab most affected in CHM lymphoblasts and hypothesised that the selective dysfunction of Rab27a (and possibly a few other Rab GTPases) plays an essential role in the retinal degenerative process. Results To investigate this hypothesis, we generated several lines of dominant-negative, constitutively-active and wild-type Rab27a (and Rab27b) transgenic mice whose expression was driven either by the pigment cell-specific tyrosinase promoter or the ubiquitous β-actin promoter. High levels of mRNA and protein were observed in transgenic lines expressing wild-type or constitutively active Rab27a and Rab27b. However, only modest levels of transgenic protein were expressed. Pulse-chase experiments suggest that the dominant-negative proteins, but not the constitutively-active or wild type proteins, are rapidly degraded. Consistently, no significant phenotype was observed in our transgenic lines. Coat-colour was normal, indicating normal Rab27a activity. Retinal function as determined by fundoscopy, angiography, electroretinography and histology was also normal. Conclusions We suggest that the instability of the dominant-negative mutant Rab27 proteins in vivo precludes the use of this approach to generate mouse models of disease caused by Rab27 GTPases. PMID:12401133
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Smadja-Lamère, Nicolas; Shum, Michael; Déléris, Paul; Roux, Philippe P.; Abe, Jun-Ichi; Marette, André
2013-01-01
We previously demonstrated that the mTORC1/S6K1 pathway is activated by insulin and nutrient overload (e.g. amino acids (AA)), which leads to the inhibition of the PI3K/Akt pathway via the inhibitory serine phosphorylation of IRS-1, notably on serine 1101 (Ser-1101). However, even in the absence of AA, insulin can still promote IRS-1 Ser-1101 phosphorylation by other kinases that remain to be fully characterized. Here, we describe a new negative regulator of IRS-1, the p90 ribosomal S6 kinase (RSK). Computational analyses revealed that Ser-1101 within IRS-1 falls into the consensus motif of RSK. Moreover, recombinant RSK phosphorylated IRS-1 C-terminal fragment on Ser-1101, which was prevented by mutations of this site or when a kinase-inactive mutant of RSK was used. Using antibodies directed toward the phosphorylation sites located in the activation segment of RSK (Ser-221 or Ser-380), we found that insulin activates RSK in L6 myocytes in the absence of AA overload. Inhibition of RSK using either the pharmacological inhibitor BI-D1870 or after adenoviral expression of a dominant negative RSK1 mutant (RSK1-DN) showed that RSK selectively phosphorylates IRS-1 on Ser-1101. Accordingly, expression of the RSK1-DN mutant in L6 myocytes and FAO hepatic cells improved insulin action on glucose uptake and glucose production, respectively. Furthermore, RSK1 inhibition prevented insulin resistance in L6 myocytes chronically exposed to high glucose and high insulin. These results show that RSK is a novel regulator of insulin signaling and glucose metabolism and a potential mediator of insulin resistance, notably through the negative phosphorylation of IRS-1 on Ser-1101. PMID:24036112
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Diouf, Barthélémy; Collazos, Alejandra; Labesse, Gilles; Macari, Françoise; Choquet, Armelle; Clair, Philippe; Gauthier-Rouvière, Cécile; Guérineau, Nathalie C.; Jay, Philippe; Hollande, Frédéric; Joubert, Dominique
2009-01-01
In the pituitary gland, activated protein kinase C (PKC) isoforms accumulate either selectively at the cell-cell contact (α and ϵ) or at the entire plasma membrane (β1 and δ). The molecular mechanisms underlying these various subcellular locations are not known. Here, we demonstrate the existence within PKCϵ of a cell-cell contact targeting sequence (3CTS) that, upon stimulation, is capable of targeting PKCδ, chimerin-α1, and the PKCϵ C1 domain to the cell-cell contact. We show that this selective targeting of PKCϵ is lost upon overexpression of 3CTS fused to a (R-Ahx-R)4 (where Ahx is 6-aminohexanoic acid) vectorization peptide, reflecting a dominant-negative effect of the overexpressed 3CTS on targeting selectivity. 3CTS contains a putative amphipathic α-helix, a 14-3-3-binding site, and the Glu-374 amino acid, involved in targeting selectivity. We show that the integrity of the α-helix is important for translocation but that 14-3-3 is not involved in targeting selectivity. However, PKCϵ translocation is increased when PKCϵ/14-3-3 interaction is abolished, suggesting that phorbol 12-myristate 13-acetate activation may initiate two sets of PKCϵ functions, those depending on 14-3-3 and those depending on translocation to cell-cell contacts. Thus, 3CTS is involved in the modulation of translocation via its 14-3-3-binding site, in cytoplasmic desequestration via the α-helix, and in selective PKCϵ targeting at the cell-cell contact via Glu-374. PMID:19429675
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Selective in vivo metabolic cell-labeling-mediated cancer targeting
Wang, Hua; Wang, Ruibo; Cai, Kaimin; He, Hua; Liu, Yang; Yen, Jonathan; Wang, Zhiyu; Xu, Ming; Sun, Yiwen; Zhou, Xin; Yin, Qian; Tang, Li; Dobrucki, Iwona T; Dobrucki, Lawrence W; Chaney, Eric J; Boppart, Stephen A; Fan, Timothy M; Lezmi, Stéphane; Chen, Xuesi; Yin, Lichen; Cheng, Jianjun
2017-01-01
Distinguishing cancer cells from normal cells through surface receptors is vital for cancer diagnosis and targeted therapy. Metabolic glycoengineering of unnatural sugars provides a powerful tool to manually introduce chemical receptors onto the cell surface; however, cancer-selective labeling still remains a great challenge. Herein we report the design of sugars that can selectively label cancer cells both in vitro and in vivo. Specifically, we inhibit the cell-labeling activity of tetraacetyl-N-azidoacetylmannosamine (Ac4ManAz) by converting its anomeric acetyl group to a caged ether bond that can be selectively cleaved by cancer-overexpressed enzymes and thus enables the overexpression of azido groups on the surface of cancer cells. Histone deacetylase and cathepsin L-responsive acetylated azidomannosamine, one such enzymatically activatable Ac4ManAz analog developed, mediated cancer-selective labeling in vivo, which enhanced tumor accumulation of a dibenzocyclooctyne–doxorubicin conjugate via click chemistry and enabled targeted therapy against LS174T colon cancer, MDA-MB-231 triple-negative breast cancer and 4T1 metastatic breast cancer in mice. PMID:28192414
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The negative priming paradigm: An update and implications for selective attention.
Frings, Christian; Schneider, Katja Kerstin; Fox, Elaine
2015-12-01
Negative Priming (NP) is an influential paradigm in cognitive psychology that was originally developed to measure attentional selection. Yet, up to the mid-1990s, a large number of experimental reports questioned whether the NP effect is based on attentional inhibition and/or episodic retrieval processes. In this review, we summarize findings since the mid-1990s and discuss new and old theoretical approaches to Negative Priming. We conclude that more than one process contributes to NP and that future research should analyze the conditions under which a particular process contributes to NP. Moreover, we argue that the paradigm--although it does not measure a single cognitive process alone--is still a useful tool for understanding selection in cognition. In fact, it might be a virtue of the paradigm that several cognitive processes work here together as selection in nonexperimental contexts is surely a multidimensional process. From this perspective, research on NP is relevant for all research fields analyzing selection. We therefore close our review by discussing the implications of the new evidence on NP for theories of selective attention.
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Structure-activity studies and therapeutic potential of host defense peptides of human thrombin.
Kasetty, Gopinath; Papareddy, Praveen; Kalle, Martina; Rydengård, Victoria; Mörgelin, Matthias; Albiger, Barbara; Malmsten, Martin; Schmidtchen, Artur
2011-06-01
Peptides of the C-terminal region of human thrombin are released upon proteolysis and identified in human wounds. In this study, we wanted to investigate minimal determinants, as well as structural features, governing the antimicrobial and immunomodulating activity of this peptide region. Sequential amino acid deletions of the peptide GKYGFYTHVFRLKKWIQKVIDQFGE (GKY25), as well as substitutions at strategic and structurally relevant positions, were followed by analyses of antimicrobial activity against the Gram-negative bacteria Escherichia coli and Pseudomonas aeruginosa, the Gram-positive bacterium Staphylococcus aureus, and the fungus Candida albicans. Furthermore, peptide effects on lipopolysaccharide (LPS)-, lipoteichoic acid-, or zymosan-induced macrophage activation were studied. The thrombin-derived peptides displayed length- and sequence-dependent antimicrobial as well as immunomodulating effects. A peptide length of at least 20 amino acids was required for effective anti-inflammatory effects in macrophage models, as well as optimal antimicrobial activity as judged by MIC assays. However, shorter (>12 amino acids) variants also displayed significant antimicrobial effects. A central K14 residue was important for optimal antimicrobial activity. Finally, one peptide variant, GKYGFYTHVFRLKKWIQKVI (GKY20) exhibiting improved selectivity, i.e., low toxicity and a preserved antimicrobial as well as anti-inflammatory effect, showed efficiency in mouse models of LPS shock and P. aeruginosa sepsis. The work defines structure-activity relationships of C-terminal host defense peptides of thrombin and delineates a strategy for selecting peptide epitopes of therapeutic interest.
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Boosting Natural Killer Cell-Based Immunotherapy with Anticancer Drugs: a Perspective.
Cifaldi, Loredana; Locatelli, Franco; Marasco, Emiliano; Moretta, Lorenzo; Pistoia, Vito
2017-12-01
Natural killer (NK) cells efficiently recognize and kill tumor cells through several mechanisms including the expression of ligands for NK cell-activating receptors on target cells. Different clinical trials indicate that NK cell-based immunotherapy represents a promising antitumor treatment. However, tumors develop immune-evasion strategies, including downregulation of ligands for NK cell-activating receptors, that can negatively affect antitumor activity of NK cells, which either reside endogenously, or are adoptively transferred. Thus, restoration of the expression of NK cell-activating ligands on tumor cells represents a strategic therapeutic goal. As discussed here, various anticancer drugs can fulfill this task via different mechanisms. We envision that the combination of selected chemotherapeutic agents with NK cell adoptive transfer may represent a novel strategy for cancer immunotherapy. Copyright © 2017 Elsevier Ltd. All rights reserved.
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Antibacterial Activity of Mother Tinctures of Cholistan Desert Plants in Pakistan
Ahmad, M.; Ghafoor, Nazia; Aamir, M. N.
2012-01-01
The mother tinctures of desert were screened for antibacterial activity against bacterial strains of Gram-positive and Gram-negative bacteria. Mother tinctures were prepared by maceration process and antibacterial activity of different plants was evaluated and compared by measuring their zones of inhibition. The results indicated that Boerrhavia diffusa mother tincture had excellent activity only against Escherichia coli. Mother tincture of Chorozophora plicata showed highly effective results against Staphylococcus aureus, Escherichia coli and Pseudomonas aeruginosa whereas Echinops echinatus mother tincture showed highly effectiveness only against Salmonella typhi. Heliotropium europaeum mother tincture exhibited highly effective results against Bacillus subtilis in all concentrations. Tamrix aphylla presented maximum activity only against Bacillus subtilis in all three concentrations. Among the selected species Heliotropium europaeum, Chorozophora plicata and Tamrix aphylla were more effective plants against many microorganisms. However, Boerrhavia diffusa and Echinops echinatus were less effective plants against tested pathogenic bacteria. PMID:23716878
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Negative mood increases selective attention to food cues and subjective appetite.
Hepworth, Rebecca; Mogg, Karin; Brignell, Catherine; Bradley, Brendan P
2010-02-01
Following negative reinforcement and affect-regulation models of dysfunctional appetitive motivation, this study examined the effect of negative mood on objective and subjective cognitive indices of motivation for food; i.e., attentional bias for food cues and self-reported hunger/urge to eat, respectively. The study extended previous research on the effect of mood on food motivation by using (i) an experimental mood manipulation, (ii) an established index of attentional bias from the visual-probe task and (iii) pictorial food cues, which have greater ecological validity than word stimuli. Young female adults (n=80) were randomly allocated to a neutral or negative mood induction procedure. Attentional biases were assessed at two cue exposure durations (500 and 2000ms). Results showed that negative mood increased both attentional bias for food cues and subjective appetite. Attentional bias and subjective appetite were positively inter-correlated, suggesting a common mechanism, i.e. activation of the food-reward system. Attentional bias was also associated with trait eating style, such as external and restrained eating. Thus, current mood and trait eating style each influenced motivation for food (as reflected by subjective appetite and attentional bias). Findings relate to models of cognitive mechanisms underlying normal and dysfunctional appetitive motivation and eating behaviour. 2009 Elsevier Ltd. All rights reserved.
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Yang, C-A; Lin, J-A; Chang, C-W; Wu, K-H; Yeh, S-P; Ho, C-M; Chang, J-G
2016-10-01
To evaluate the clinical significance of GP. Mur antigen-negative blood selection for transfusion in patients with anti-'Mi a ' records. The GP. Mur RBC phenotype is prevalent (7·3%) in Taiwan. Antibodies against GP. Mur (anti-'Mi a ') are identified in 1·24% of our population, and anti-'Mi a ' screening using GP. Mur RBC has been routine for Taiwan's blood banks. However, due to the lack of commercial antibodies, only cross-matching was used to prevent transfusion of GP. Mur-positive blood to patients with anti-'Mi a ' in most hospitals. There is still a risk of GP. Mur-positive RBC exposure and subsequent anti-'Mi a '-related transfusion reactions. Since February 2014, GP. Mur antigen-negative RBCs identified by reaction with anti-'Mi a '-positive serum were selected for blood recipients with anti-'Mi a ' records. The transfusion reactions between January 2013 and January 2014 were compared with those that occurred between February 2014 and July 2015. The transfusion reaction rate was significantly higher in anti-'Mi a '-positive blood recipients compared to total subjects receiving an RBC transfusion before GP. Mur-negative donor RBC selection. After antigen-negative RBC selection, the transfusion reaction frequency in subjects with anti-'Mi a ' became similar to total blood recipients. IgG form anti-'Mi a ' antibodies were present in all cases of probable anti-'Mi a '-related transfusion reactions. The time required for anti-'Mi a ' boosting after transfusion was around 4-21 days. Selection of GP. Mur-negative RBC for transfusion to patients with anti-'Mi a ' records could decrease the rate of transfusion reaction and antibody boosting. This procedure should be incorporated into blood bank routines in areas where anti-'Mi a ' is prevalent. © 2016 British Blood Transfusion Society.
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Ito, Takehito; Kimura, Yasuyuki; Seki, Chie; Ichise, Masanori; Yokokawa, Keita; Kawamura, Kazunori; Takahashi, Hidehiko; Higuchi, Makoto; Zhang, Ming-Rong; Suhara, Tetsuya; Yamada, Makiko
2018-06-14
The histamine H 3 receptor is regarded as a drug target for cognitive impairments in psychiatric disorders. H 3 receptors are expressed in neocortical areas, including the prefrontal cortex, the key region of cognitive functions such as working memory. However, the role of prefrontal H 3 receptors in working memory has not yet been clarified. Therefore, using functional magnetic resonance imaging (fMRI) and positron emission tomography (PET) techniques, we aimed to investigate the association between the neural activity of working memory and the density of H 3 receptors in the prefrontal cortex. Ten healthy volunteers underwent both fMRI and PET scans. The N-back task was used to assess the neural activities related to working memory. H 3 receptor density was measured with the selective PET radioligand [ 11 C] TASP457. The neural activity of the right dorsolateral prefrontal cortex during the performance of the N-back task was negatively correlated with the density of H 3 receptors in this region. Higher neural activity of working memory was associated with lower H 3 receptor density in the right dorsolateral prefrontal cortex. This finding elucidates the role of H 3 receptors in working memory and indicates the potential of H 3 receptors as a therapeutic target for the cognitive impairments associated with neuropsychiatric disorders.
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Amyere, Mustapha; Payrastre, Bernard; Krause, Ulrike; Smissen, Patrick Van Der; Veithen, Alex; Courtoy, Pierre J.
2000-01-01
Macropinocytosis results from the closure of lamellipodia generated by membrane ruffling, thereby reflecting cortical actin dynamics. Both transformation of Rat-1 fibroblasts by v-Src or K-Ras and stable transfection for expression of dominant-positive, wild-type phosphoinositide 3-kinase (PI3K) regulatory subunit p85α constitutively led to stress fiber disruption, cortical actin recruitment, extensive ruffling, and macropinosome formation, as measured by a selective acceleration of fluid-phase endocytosis. These alterations closely correlated with activation of PI3K and phosphatidylinositol-specific phospholipase C (PI-PLC), as assayed by 3-phosphoinositide synthesis in situ and in vitro and inositol 1,4,5 trisphosphate steady-state levels, respectively; they were abolished by stable transfection of v-Src–transformed cells for dominant-negative truncated p85α expression and by pharmacological inhibitors of PI3K and PI-PLC, indicating a requirement for both enzymes. Whereas PI3K activation resisted PI-PLC inhibition, PI-PLC activation was abolished by a PI3K inhibitor and dominant-negative transfection, thus placing PI-PLC downstream of PI3K. Together, these data suggest that permanent sequential activation of both PI3K and PI-PLC is necessary for the dramatic reorganization of the actin cytoskeleton in oncogene-transformed fibroblasts, resulting in constitutive ruffling and macropinocytosis. PMID:11029048
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Osawa, Masaki
2018-01-01
It is difficult to target and kill cancer cells. One possible approach is to mutate bacteria to enhance their binding to cancer cells. In the present study, Gram-negative Escherichia coli and Gram-positive Bacillus subtilis were randomly mutated, and then were positively and negatively selected for binding cancer vs normal cells. With repetitive mutation and selection both bacteria successfully evolved to increase affinity to the pancreatic cancer cell line (Mia PaCa-2) but not normal cells (HPDE: immortalized human pancreatic ductal epithelial cells). The mutant E. coli and B. subtilis strains bound to Mia PaCa-2 cells about 10 and 25 times more than to HPDE cells. The selected E. coli strain had mutations in biofilm-related genes and the regulatory region for a type I pilus gene. Consistent with type I pili involvement, mannose could inhibit the binding to cells. The results suggest that weak but specific binding is involved in the initial step of adhesion. To test their ability to kill Mia PaCa-2 cells, hemolysin was expressed in the mutant strain. The hemolysin released from the mutant strain was active and could kill Mia PaCa-2 cells. In the case of B. subtilis, the initial binding to the cells was a weak interaction of the leading pole of the motile bacteria. The frequency of this interaction to Mia PaCa-2 cells dramatically increased in the evolved mutant strain. This mutant strain could also specifically invade beneath Mia PaCa-2 cells and settle there. This type of mutation/selection strategy may be applicable to other combinations of cancer cells and bacterial species.
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Lovewell, Thomas R. J.; McDonagh, Andrew J.; Messenger, Andrew G.; Azzouz, Mimoun; Tazi-Ahnini, Rachid
2015-01-01
Background The autoimmune regulator (AIRE) is expressed in the thymus, particularly in thymic medullary epithelial cells (mTECs), and is required for the ectopic expression of a diverse range of peripheral tissue antigens by mTECs, facilitating their ability to perform negative selection of auto-reactive immature T-cells. The expression profile of peripheral tissue antigens is affected not only by AIRE deficiency but also with variation of AIRE activity in the thymus. Method and Results Therefore we screened 591bp upstream of the AIRE transcription start site including AIRE minimal promoter for single nucleotide polymorphism (SNPs) and identified two SNPs -655R (rs117557896) and -230Y (rs751032) respectively. To study the effect of these variations on AIRE promoter activity we generated a Flp-In host cell line which was stably transfected with a single copy of the reporter vector. Relative promoter activity was estimated by comparing the luciferase specific activity for lysates of the different reporter AIRE promoter-reporter gene constructs including AIRE-655G AIRE-230C, AIRE-655G AIRE-230T and AIRE-655A AIRE-230C. The analysis showed that the commonest haplotype AIRE-655G AIRE-230C has the highest luciferase specific activity (p<0.001). Whereas AIRE-655G AIRE-230T has a luciferase specific activity value that approaches null. Both AIRE promoter polymorphic sites have one allele that forms a CpG methylation site which we determined can be methylated in methylation assays using the M.SssI CpG methyltransferase. Conclusion AIRE-230Y is in a conserved region of the promoter and is adjacent to a predicted WT1 transcription factor binding site, suggesting that AIRE-230Y affects AIRE expression by influencing the binding of biochemical factors to this region. Our findings show that AIRE-655GAIRE-230T haplotype could dramatically alter AIRE transcription and so have an effect on the process of negative selection and affect susceptibility to autoimmune conditions. PMID:25978041
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Sun, Zhengming; Wang, Xiaoqing; Ling, Ming; Wang, Wei; Chang, Yanhai; Yang, Guang; Dong, Xianghui; Wu, Shixun; Wu, Xueyuan; Yang, Bo; Chen, Ming
2017-04-18
The purpose of this study was to test effects of negative pressure on tendon-bone healing after reconstruction of anterior cruciate ligament (ACL) in rabbits. Hind legs of 24 New Zealand White rabbits were randomly selected as negative pressure group and the contralateral hind legs as control. Reconstruction of the ACL was done. Joints of the negative pressure side were placed with drainage tubes connecting the micro-negative pressure aspirator. Control side was placed with ordinary drainage tubes. Drainage tubes on both sides were removed at the same time 5 days after operation. After 6 weeks, joint fluid was drawn to detect the expression levels of interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α); at the same time, femur-ligament-tibia complex was obtained to determine tendon graft tension and to observe the histomorphology, blood vessels of the tendon-bone interface, and expression of vascular endothelial growth factor (VEGF). The maximum load breakage of tendon graft was significantly greater in the negative pressure group than in the control group (P < 0.05). Histological studies of the tendon-bone interface found that there was more new bone formation containing chondroid cells and aligned connective tissue in the negative pressure group than in the control group. Expression of VEGF was higher in the negative pressure group than in the control group (P < 0.01). Content of IL-1β and TNF-α in synovial fluid is lower in the negative pressure group than in the control group (P < 0.01). Intermittent negative pressure plays an active role in tendon-bone healing and creeping substitution of ACL reconstruction in the rabbits.
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42 CFR 431.978 - Eligibility sampling plan and procedures.
Code of Federal Regulations, 2012 CFR
2012-10-01
..., for example, by making adjustments to the plan when necessary due to fluctuations in the universe. (2... active and negative universes; or (ii) If the active case universe or negative case universe of Medicaid... active cases and negative cases, respectively. (iii) If the active case universe or negative case...
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42 CFR 431.978 - Eligibility sampling plan and procedures.
Code of Federal Regulations, 2010 CFR
2010-10-01
..., for example, by making adjustments to the plan when necessary due to fluctuations in the universe. (2... active and negative universes; or (ii) If the active case universe or negative case universe of Medicaid... active cases and negative cases, respectively. (iii) If the active case universe or negative case...
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42 CFR 431.978 - Eligibility sampling plan and procedures.
Code of Federal Regulations, 2011 CFR
2011-10-01
..., for example, by making adjustments to the plan when necessary due to fluctuations in the universe. (2... active and negative universes; or (ii) If the active case universe or negative case universe of Medicaid... active cases and negative cases, respectively. (iii) If the active case universe or negative case...
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42 CFR 431.978 - Eligibility sampling plan and procedures.
Code of Federal Regulations, 2013 CFR
2013-10-01
..., for example, by making adjustments to the plan when necessary due to fluctuations in the universe. (2... active and negative universes; or (ii) If the active case universe or negative case universe of Medicaid... active cases and negative cases, respectively. (iii) If the active case universe or negative case...
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42 CFR 431.978 - Eligibility sampling plan and procedures.
Code of Federal Regulations, 2014 CFR
2014-10-01
..., for example, by making adjustments to the plan when necessary due to fluctuations in the universe. (2... active and negative universes; or (ii) If the active case universe or negative case universe of Medicaid... active cases and negative cases, respectively. (iii) If the active case universe or negative case...
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Effects of cytosine methylation on transcription factor binding sites
2014-01-01
Background DNA methylation in promoters is closely linked to downstream gene repression. However, whether DNA methylation is a cause or a consequence of gene repression remains an open question. If it is a cause, then DNA methylation may affect the affinity of transcription factors (TFs) for their binding sites (TFBSs). If it is a consequence, then gene repression caused by chromatin modification may be stabilized by DNA methylation. Until now, these two possibilities have been supported only by non-systematic evidence and they have not been tested on a wide range of TFs. An average promoter methylation is usually used in studies, whereas recent results suggested that methylation of individual cytosines can also be important. Results We found that the methylation profiles of 16.6% of cytosines and the expression profiles of neighboring transcriptional start sites (TSSs) were significantly negatively correlated. We called the CpGs corresponding to such cytosines “traffic lights”. We observed a strong selection against CpG “traffic lights” within TFBSs. The negative selection was stronger for transcriptional repressors as compared with transcriptional activators or multifunctional TFs as well as for core TFBS positions as compared with flanking TFBS positions. Conclusions Our results indicate that direct and selective methylation of certain TFBS that prevents TF binding is restricted to special cases and cannot be considered as a general regulatory mechanism of transcription. PMID:24669864
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FoxO1-negative cells are cancer stem-like cells in pancreatic ductal adenocarcinoma.
Song, Weifeng; Li, Qi; Wang, Lei; Huang, Weiyi; Wang, Liwei
2015-06-11
Flow cytometry assays using aldehyde dehydrogenase (ALDH) activity or CD133 positivity to isolate cancer stem cells (CSCs) are widely applied but have limitations. Thus, characterization of CSC makers for a specific cancer is potentially important. We have previously shown that miR-21 regulates cancer cell growth via FoxO1 in pancreatic ductal adenocarcinoma (PDAC). Here, we areported evidence of FoxO1-negative PDAC cells as CSCs in PDAC. Both ALDH-high and CD133-high cell fractions isolated from PDAC of the patients expressed high levels of miR-21 and null FoxO1. Cultured PDAC cells were virally transduced with GFP under FoxO1 promoter. GFP (FoxO1)-null PDAC cells expressed high levels of miR-21, and grew more quickly than FoxO1-positive PDAC cells. Moreover, the fold increases in growth of FoxO1-negative vs FoxO1-positive cells were greater than CD133-high vs CD133-low cells, or ALDH-high vs ALDH-low cells. Further, FoxO1-negative cells formed tumor spheres in culture and developed tumors after serial adoptive transplantation into NOD/SCID mice, while the FoxO1-positive cells did not. Finally, selective elimination of FoxO1-negative cells completely inhibited the growth of PDAC cells. Together, these data suggest that FoxO1-negative cells as CSCs in PDAC, and targeting FoxO1-negative cells in PDAC may provide better therapeutic outcome.
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Selective killing of tumors deficient in methylthioadenosine phosphorylase: a novel strategy.
Lubin, Martin; Lubin, Adam
2009-05-29
The gene for methylthioadenosine phosphorylase (MTAP) lies on 9p21, close to the gene CDKN2A that encodes the tumor suppressor proteins p16 and p14ARF. MTAP and CDKN2A are homozygously co-deleted, with a frequency of 35 to 70%, in lung and pancreatic cancer, glioblastoma, osteosarcoma, soft-tissue sarcoma, mesothelioma, and T-cell acute lymphoblastic leukemia. In normal cells, but not in tumor cells lacking MTAP, MTAP cleaves the natural substrate, 5'-deoxy-5'-methylthioadenosine (MTA), to adenine and 5-methylthioribose-1-phosphate (MTR-1-P), which are then converted to adenine nucleotides and methionine. This distinct difference between normal MTAP-positive cells and tumor MTAP-negative cells led to several proposals for therapy. We offer a novel strategy in which both MTA and a toxic adenine analog, such as 2,6-diaminopurine (DAP), 6-methylpurine (MeP), or 2-fluoroadenine (F-Ade), are administered. In MTAP-positive cells, abundant adenine, generated from supplied MTA, competitively blocks the conversion of an analog, by adenine phosphoribosyltransferase (APRT), to its active nucleotide form. In MTAP-negative tumor cells, the supplied MTA cannot generate adenine; hence conversion of the analog is not blocked. We show that this combination treatment--adenine analog plus MTA--kills MTAP-negative A549 lung tumor cells, while MTAP-positive human fibroblasts (HF) are protected. In co-cultures of the breast tumor cell line, MCF-7, and HF cells, MCF-7 is inhibited or killed, while HF cells proliferate robustly. 5-Fluorouracil (5-FU) and 6-thioguanine (6-TG) may also be used with our strategy. Though neither analog is activated by APRT, in MTAP-positive cells, adenine produced from supplied MTA blocks conversion of 5-FU and 6-TG to their toxic nucleotide forms by competing for 5-phosphoribosyl-1-pyrophosphate (PRPP). The combination of MTA with 5-FU or 6-TG, in the treatment of MTAP-negative tumors, may produce a significantly improved therapeutic index. We describe a selective strategy to kill tumor cells lacking MTAP.
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Taner, Timucin; Park, Walter D; Stegall, Mark D
2017-05-01
Kidney allografts transplanted simultaneously with liver allografts from the same donor are known to be immunologically privileged. This is especially evident in recipients with high levels of donor-specific anti-HLA antibodies. Here we investigated the mechanisms of liver's protective impact using gene expression in the kidney allograft. Select solitary kidney transplant or simultaneous liver-kidney transplant recipients were retrospectively reviewed and separated into four groups: 16 cross-match negative kidney transplants, 15 cross-match positive kidney transplants, 12 cross-match negative simultaneous liver-kidney transplants, and nine cross-match-positive simultaneous liver-kidney transplants. Surveillance biopsies of cross-match-positive kidney transplants had increased expression of genes associated with donor-specific antigens, inflammation, and endothelial cell activation compared to cross-match-negative kidney transplants. These changes were not found in cross-match-positive simultaneous liver-kidney transplant biopsies when compared to cross-match-negative simultaneous liver-kidney transplants. In addition, simultaneously transplanting a liver markedly increased renal expression of genes associated with tissue integrity/metabolism, regardless of the cross-match status. While the expression of inflammatory gene sets in cross-match-positive simultaneous liver-kidney transplants was not completely reduced to the level of cross-match-negative kidney transplants, the downstream effects of donor-specific anti-HLA antibodies were blocked. Thus, simultaneous liver-kidney transplants can have a profound impact on the kidney allograft, not only by decreasing inflammation and avoiding endothelial cell activation in cross-match-positive recipients, but also by increasing processes associated with tissue integrity/metabolism by unknown mechanisms. Copyright © 2017 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.
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Light, Sharee N; Moran, Zachary D; Swander, Lena; Le, Van; Cage, Brandi; Burghy, Cory; Westbrook, Cecilia; Greishar, Larry; Davidson, Richard J
2015-01-01
The relation between empathy subtypes and prosocial behavior was investigated in a sample of healthy adults. "Empathic concern" and "empathic happiness", defined as negative and positive vicarious emotion (respectively) combined with an other-oriented feeling of "goodwill" (i.e. a thought to do good to others/see others happy), were elicited in 68 adult participants who watched video clips extracted from the television show Extreme Makeover: Home Edition. Prosocial behavior was quantified via performance on a non-monetary altruistic decision-making task involving book selection and donation. Empathic concern and empathic happiness were measured via self-report (immediately following each video clip) and via facial electromyography recorded from corrugator (active during frowning) and zygomatic (active during smiling) facial regions. Facial electromyographic signs of (a) empathic concern (i.e. frowning) during sad video clips, and (b) empathic happiness (i.e. smiling) during happy video clips, predicted increased prosocial behavior in the form of increased goodwill-themed book selection/donation. Copyright © 2014 Elsevier B.V. All rights reserved.
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Light, Sharee N.; Moran, Zachary D.; Swander, Lena; Le, Van; Cage, Brandi; Burghy, Cory; Westbrook, Cecilia; Greishar, Larry; Davidson, Richard J.
2016-01-01
The relation between empathy subtypes and prosocial behavior was investigated in a sample of healthy adults. "Empathic concern" and "empathic happiness," defined as negative and positive vicarious emotion (respectively) combined with an other-oriented feeling of “goodwill” (i.e. a thought to do good to others/see others happy), were elicited in 68 adult participants who watched video clips extracted from the television show Extreme Makeover: Home Edition. Prosocial behavior was quantified via performance on a non-monetary altruistic decision-making task involving book selection and donation. Empathic concern and empathic happiness were measured via self-report (immediately following each video clip) and via facial electromyography recorded from corrugator (active during frowning) and zygomatic (active during smiling) facial regions. Facial electromyographic signs of (a) empathic concern (i.e. frowning) during sad video clips, and (b) empathic happiness (i.e. smiling) during happy video clips, predicted increased prosocial behavior in the form of increased goodwill-themed book selection/donation. PMID:25486408
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Craven, Galen T; Nitzan, Abraham
2018-01-28
Statistical properties of Brownian motion that arise by analyzing, separately, trajectories over which the system energy increases (upside) or decreases (downside) with respect to a threshold energy level are derived. This selective analysis is applied to examine transport properties of a nonequilibrium Brownian process that is coupled to multiple thermal sources characterized by different temperatures. Distributions, moments, and correlation functions of a free particle that occur during upside and downside events are investigated for energy activation and energy relaxation processes and also for positive and negative energy fluctuations from the average energy. The presented results are sufficiently general and can be applied without modification to the standard Brownian motion. This article focuses on the mathematical basis of this selective analysis. In subsequent articles in this series, we apply this general formalism to processes in which heat transfer between thermal reservoirs is mediated by activated rate processes that take place in a system bridging them.
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NASA Astrophysics Data System (ADS)
Craven, Galen T.; Nitzan, Abraham
2018-01-01
Statistical properties of Brownian motion that arise by analyzing, separately, trajectories over which the system energy increases (upside) or decreases (downside) with respect to a threshold energy level are derived. This selective analysis is applied to examine transport properties of a nonequilibrium Brownian process that is coupled to multiple thermal sources characterized by different temperatures. Distributions, moments, and correlation functions of a free particle that occur during upside and downside events are investigated for energy activation and energy relaxation processes and also for positive and negative energy fluctuations from the average energy. The presented results are sufficiently general and can be applied without modification to the standard Brownian motion. This article focuses on the mathematical basis of this selective analysis. In subsequent articles in this series, we apply this general formalism to processes in which heat transfer between thermal reservoirs is mediated by activated rate processes that take place in a system bridging them.
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Smid, H G; Jakob, A; Heinze, H J
1999-03-01
What cognitive processes underlie event-related brain potential (ERP) effects related to visual multidimensional selective attention and how are these processes organized? We recorded ERPs when participants attended to one conjunction of color, global shape and local shape and ignored other conjunctions of these attributes in three discriminability conditions. Attending to color and shape produced three ERP effects: frontal selection positivity (FSP), central negativity (N2b), and posterior selection negativity (SN). The results suggested that the processes underlying SN and N2b perform independent within-dimension selections, whereas the process underlying the FSP performs hierarchical between-dimension selections. At posterior electrodes, manipulation of discriminability changed the ERPs to the relevant but not to the irrelevant stimuli, suggesting that the SN does not concern the selection process itself but rather a cognitive process initiated after selection is finished. Other findings suggested that selection of multiple visual attributes occurs in parallel.
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Yogo, Norihiro; Shihadeh, Katherine; Young, Heather; Calcaterra, Susan; Knepper, Bryan C; Burman, William J; Mehler, Philip S; Jenkins, Timothy C
2017-01-01
Objective For most common infections requiring hospitalization, antibiotic treatment is completed after hospital discharge. Post-discharge therapy is often unnecessarily broad-spectrum and prolonged. We developed an intervention to improve antibiotic selection and shorten treatment durations. Design Single center, quasi-experimental retrospective cohort study. Methods Patients prescribed oral antibiotics at hospital discharge before (July 2012 – June 2013) and after (October 2014 – February 2015) an intervention consisting of: 1) institutional guidance for oral step-down antibiotic selection and duration of therapy, and 2) pharmacy audit of discharge prescriptions with real-time prescribing recommendations to providers. The primary outcomes were total prescribed duration of therapy and use of antibiotics with broad gram-negative activity (fluoroquinolones or amoxicillin-clavulanate). Results 300 cases from the pre-intervention period and 200 from the intervention period were included. Compared with the pre-intervention period, use of antibiotics with broad gramnegative activity decreased during the intervention (51% vs 40%, p = 0.02), particularly fluoroquinolones (38% vs 25%, p = 0.002). The difference in total duration of therapy did not reach statistical significance (10 days [interquartile range (IQR) 7–13] vs 9 [IQR 6–13], p = 0.13); however, the duration prescribed at discharge declined from 6 days (IQR 4–10) to 5 (IQR 3–7) (p = 0.003). During the intervention, there was a non-significant increase in the overall appropriateness of discharge prescriptions (52% vs 66%, p = 0.15). Conclusions A multifaceted intervention to optimize antibiotic prescribing at hospital discharge was associated with less frequent use of antibiotics with broad gram-negative activity and shorter post-hospital treatment durations. PMID:28260538
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Effectiveness of a social inclusion program in people with non-affective psychosis.
Mazzi, Fausto; Baccari, Flavia; Mungai, Francesco; Ciambellini, Manuela; Brescancin, Lisa; Starace, Fabrizio
2018-06-07
People with psychotic illness suffer from reduced quality of life and often from an insufficient level of social inclusion. These variables are associated with several negative outcomes, such as higher neuro-cognitive deficits, negative symptoms, internalised stigma, increased cardiovascular risk and, most importantly, excess mortality. To date, only a minority of social interventions in psychosis have been investigated. Since 2011, the Department of Mental Health and Substance Abuse in Modena introduced the "Social Point" program, which provides social inclusion interventions to promote active social participation for patients suffering from severe mental illness. The aim of this study was to assess whether a social inclusion intervention is associated with better outcomes in terms of personal and social recovery, with particular reference to the areas of social functioning and activity, and subjective dimensions such as self-esteem, self-stigma and perceived quality of life. A cross-sectional design was adopted to compare 30 subjects, selected at the completion of "Social Point" program, with a group of subjects, matched for socio-demographic and clinical features, selected from a wait list for "Social Point". All subjects were evaluated by means of instruments assessing: level of disability, level of functioning, severity of psychopathology, self-esteem, internalised stigma and quality of life. Overall, the results of the study suggest that social inclusion interventions may be effective in people suffering from non-affective psychosis. A dose-effect relationship was also found between higher number of activities per patient and better outcomes within both social and psychopathological domains. However, due to the cross-sectional design of the study no definitive causality can be inferred. Psychosocial interventions promoting social inclusion are likely to represent an effective approach to improve personal and social recovery.
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Anti-microbial principles of selected remedial plants from Southern India
Tirupathi, Rao G; Suresh, Babu K; Ujwal, Kumar J; Sujana, P; Raoa, A Veerabhadr; Sreedhar, AS
2011-01-01
Objective To examine the anti-bacterial activity of leaf extracts of Morus alba L. (Moraceae) and Piper betel L. (Piperaceae), and seed extracts of Bombax ceiba L. (Borabacaceae). Methods We have partially purified plant extracts by solvent extraction method, and evaluated the effect of individual fractions on bacterial growth using Escherichia coli (E. coli), Pseudomonas aeruginosa (P. aeruginosa) and Staphylococcus aureus (S. aureus) bacterial strains. Results Compared with Morus and Bombax fractions, Piper fractions showed significant growth inhibition on all the three types of bacteria studied. The EtOAc-hexane fractions of Piper leaves exhibited significant anti-bacterial activity with minimum inhibitory concentrations (MIC) of 50 µg/mL culture against both gram-positive and gram-negative bacteria. The EtOAc-fractions I, II, and IV inhibited bacterial colony formation on soft agar in addition to growth inhibition. A combination treatment of piper fractions with ampicillin resulted in significant growth inhibition in E. coli and P. aeruginosa, and combination with anticancer drug geldanamycin (2µg/mL) showed selective growth inhibition against P. aeruginosa and S. aureus. Three major compounds, i.e., eugenol, 3-hexene-ol and stigmasterol, were primarily identified from Piper betel leaf extractions. Among the individual compounds, eugenol treatment showed improved growth inhibition compared with stigmasterol and 3-hexene-ol. Conclusions We are reporting potential anti-bacterial compounds from Piper betel against both gram-positive and gram-negative bacteria either alone or in combination with drug treatment. PMID:23569779
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Medical home characteristics and the pediatric patient experience.
Burnet, Deborah; Gunter, Kathryn E; Nocon, Robert S; Gao, Yue; Jin, Janel; Fairchild, Paige; Chin, Marshall H
2014-11-01
The patient-centered medical home (PCMH) has roots in pediatrics, yet we know little about the experience of pediatric patients in PCMH settings. To examine the association between clinic PCMH characteristics and pediatric patient experience as reported by parents. We assessed the cross-sectional correlation between clinic PCMH characteristics and pediatric patient experience in 24 clinics randomly selected from the Safety Net Medical Home Initiative, a 5-state PCMH demonstration project. PCMH characteristics were measured with surveys of randomly selected providers and staff; surveys generated 0 (worst) to 100 (best) scores for 5 subscales, and a total score. Patient experience was measured through surveying parents of pediatric patients. Questions from the Consumer Assessment of Healthcare Providers and Systems-Clinician and Group instrument produced 4 patient experience measures: timeliness, physician communication, staff helpfulness, and overall rating. To investigate the relationship between PCMH characteristics and patient experience, we used generalized estimating equations with an exchangeable correlation structure. We included 440 parents and 214 providers and staff in the analysis. Total PCMH score was not associated with parents' assessment of patient experience; however, PCMH subscales were associated with patient experience in different directions. In particular, quality improvement activities undertaken by clinics were strongly associated with positive ratings of patient experience, whereas patient care management activities were associated with more negative reports of patient experience. Future work should bolster features of the PCMH that work well for patients while investigating which PCMH features negatively impact patient experience, to yield a better patient experience overall.
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Flux of a Ratchet Model and Applications to Processive Motor Proteins
NASA Astrophysics Data System (ADS)
Li, Jing-Hui
2015-10-01
In this paper, we investigate the stationary probability current (or flux) of a Brownian ratchet model as a function of the flipping rate of the fluctuating potential barrier. It is shown that, with suitably selecting the parameters' values of the ratchet system, we can get the negative resonant activation, the positive resonant activation, the double resonant activation, and the current reversal, for the stationary probability current versus the flipping rate. The appearance of these phenomena is the result of the cooperative effects of the potential's dichotomous fluctuations and the internal thermal fluctuations on the evolution of the flux versus the flipping rate of the fluctuating potential barrier. In addition, some applications of our results to the motor proteins are discussed. Supported by K.C. Wong Magna Fund in Ningbo University in China
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An efficient platform for genetic selection and screening of gene switches in Escherichia coli
Muranaka, Norihito; Sharma, Vandana; Nomura, Yoko; Yokobayashi, Yohei
2009-01-01
Engineered gene switches and circuits that can sense various biochemical and physical signals, perform computation, and produce predictable outputs are expected to greatly advance our ability to program complex cellular behaviors. However, rational design of gene switches and circuits that function in living cells is challenging due to the complex intracellular milieu. Consequently, most successful designs of gene switches and circuits have relied, to some extent, on high-throughput screening and/or selection from combinatorial libraries of gene switch and circuit variants. In this study, we describe a generic and efficient platform for selection and screening of gene switches and circuits in Escherichia coli from large libraries. The single-gene dual selection marker tetA was translationally fused to green fluorescent protein (gfpuv) via a flexible peptide linker and used as a dual selection and screening marker for laboratory evolution of gene switches. Single-cycle (sequential positive and negative selections) enrichment efficiencies of >7000 were observed in mock selections of model libraries containing functional riboswitches in liquid culture. The technique was applied to optimize various parameters affecting the selection outcome, and to isolate novel thiamine pyrophosphate riboswitches from a complex library. Artificial riboswitches with excellent characteristics were isolated that exhibit up to 58-fold activation as measured by fluorescent reporter gene assay. PMID:19190095
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Ethnopharmacological study of plants from Pondoland used against diarrhoea.
Madikizela, B; Ndhlala, A R; Finnie, J F; Van Staden, J
2012-05-07
Waterborne diseases such as diarrhoea are common world wide, including in Bizana, South Africa where the majority of rural dwellers depend largely on water from unprotected sources. The people from Bizana use medicinal plants as their first line of health care to cure and prevent diarrhoea. To record and document plants used for the treatment of diarrhoea in Bizana, to evaluate antibacterial and anti-inflammatory activities of selected plant extracts as well as to perform genotoxicity testing of evaluated plants. An ethnobotanical approach was used to select plants used for treating diarrhoea in Bizana for pharmacological assays using questionnaires. Nine plants were selected for bioassays based on their frequency index and the fact that they have never been evaluated against diarrhoea causing-microorganisms. The petroleum ether (PE), dichloromethane (DCM), 70% ethanol (EtOH), and water extracts were evaluated for antibacterial (Gram-positive Staphylococcus aureus, Gram-negative Escherichia coli and Shigella flexneri) activity using the microdilution technique, their ability to inhibit COX-1 and COX-2 enzymes. Genotoxicity was evaluated using the Salmonella microsome assay. This study revealed that 34 plant species belonging to 27 families are used for the treatment of diarrhoea in Bizana. The extracts showed good inhibitory activity with MIC values ranging from 0.39 to 12.5mg/ml. The best activity was exhibited by DCM extracts of Rapanea melanophloeos, and EtOH extracts of Ficus craterostoma and Maesa lanceolata with MIC values of 0.098mg/ml. The inhibitory activity against COX-1 enzyme was higher than COX-2, with 19 plant extracts for the former and 7 for the latter. All the tested plant extracts were not mutagenic at all concentrations tested against all tester strains of bacteria. In view of the fact that the plants were selected based on their ethnobotanical usage for treating diarrhoea, the activities reported here goes a long way in validating the plants for traditional use. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.
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Haltigan, John D; Leerkes, Esther M; Supple, Andrew J; Calkins, Susan D
2014-01-01
The current study examined associations between attachment state of mind measured prenatally (N = 259) and maternal behavior in the reunion episode of the still-face procedure when infants were six months of age both as a main effect and in conjunction with infant negative affect. Using a dimensional approach to adult attachment measurement, dismissing and preoccupied states of mind were negatively associated with maternal sensitivity, and each correlated with distinct parenting behaviors. Positive associations were found between dismissing states of mind and maternal monitoring and preoccupied states of mind and maternal withdraw. Maternal preoccupation moderated associations between infant negative affect and maternal intrusive, withdrawn, and monitoring behaviors, supporting the notion that maternal attachment influences parenting behavior via a modulatory process in which infant distress cues are selectively filtered and responded to. Analyses using a traditional AAI scale and classification approach also provided evidence for distinct parenting behavior correlates of insecure adult attachment representations. The importance of measuring global and stylistic differences in maternal behavior in contexts which allow for the activation of the entire range of infant affective states is discussed.
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Haltigan, John D.; Leerkes, Esther M.; Supple, Andrew J.; Calkins, Susan D.
2013-01-01
The current study examined associations between attachment state of mind measured prenatally (N = 259) and maternal behavior in the reunion episode of the still-face procedure when infants were six months of age both as a main effect and in conjunction with infant negative affect. Using a dimensional approach to adult attachment measurement, dismissing and preoccupied states of mind were negatively associated with maternal sensitivity, and each correlated with distinct parenting behaviors. Positive associations were found between dismissing states of mind and maternal monitoring and preoccupied states of mind and maternal withdraw. Maternal preoccupation moderated associations between infant negative affect and maternal intrusive, withdrawn, and monitoring behaviors, supporting the notion that maternal attachment influences parenting behavior via a modulatory process in which infant distress cues are selectively filtered and responded to. Analyses using a traditional AAI scale and classification approach also provided evidence for distinct parenting behavior correlates of insecure adult attachment representations. The importance of measuring global and stylistic differences in maternal behavior in contexts which allow for the activation of the entire range of infant affective states is discussed. PMID:24329015
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Neural oscillatory deficits in schizophrenia predict behavioral and neurocognitive impairments
Martínez, Antígona; Gaspar, Pablo A.; Hillyard, Steven A.; Bickel, Stephan; Lakatos, Peter; Dias, Elisa C.; Javitt, Daniel C.
2015-01-01
Paying attention to visual stimuli is typically accompanied by event-related desynchronizations (ERD) of ongoing alpha (7–14 Hz) activity in visual cortex. The present study used time-frequency based analyses to investigate the role of impaired alpha ERD in visual processing deficits in schizophrenia (Sz). Subjects viewed sinusoidal gratings of high (HSF) and low (LSF) spatial frequency (SF) designed to test functioning of the parvo- vs. magnocellular pathways, respectively. Patients with Sz and healthy controls paid attention selectively to either the LSF or HSF gratings which were presented in random order. Event-related brain potentials (ERPs) were recorded to all stimuli. As in our previous study, it was found that Sz patients were selectively impaired at detecting LSF target stimuli and that ERP amplitudes to LSF stimuli were diminished, both for the early sensory-evoked components and for the attend minus unattend difference component (the Selection Negativity), which is generally regarded as a specific index of feature-selective attention. In the time-frequency domain, the differential ERP deficits to LSF stimuli were echoed in a virtually absent theta-band phase locked response to both unattended and attended LSF stimuli (along with relatively intact theta-band activity for HSF stimuli). In contrast to the theta-band evoked responses which were tightly stimulus locked, stimulus-induced desynchronizations of ongoing alpha activity were not tightly stimulus locked and were apparent only in induced power analyses. Sz patients were significantly impaired in the attention-related modulation of ongoing alpha activity for both HSF and LSF stimuli. These deficits correlated with patients’ behavioral deficits in visual information processing as well as with visually based neurocognitive deficits. These findings suggest an additional, pathway-independent, mechanism by which deficits in early visual processing contribute to overall cognitive impairment in Sz. PMID:26190988
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Shinde, Ranajit Nivrutti; Kumar, G Siva; Eqbal, Shahbaz; Sobhia, M Elizabeth
2018-01-01
Protein tyrosine phosphatase 1B (PTP1B) is a validated therapeutic target for Type 2 diabetes due to its specific role as a negative regulator of insulin signaling pathways. Discovery of active site directed PTP1B inhibitors is very challenging due to highly conserved nature of the active site and multiple charge requirements of the ligands, which makes them non-selective and non-permeable. Identification of the PTP1B allosteric site has opened up new avenues for discovering potent and selective ligands for therapeutic intervention. Interactions made by potent allosteric inhibitor in the presence of PTP1B were studied using Molecular Dynamics (MD). Computationally optimized models were used to build separate pharmacophore models of PTP1B and TCPTP, respectively. Based on the nature of interactions the target residues offered, a receptor based pharmacophore was developed. The pharmacophore considering conformational flexibility of the residues was used for the development of pharmacophore hypothesis to identify potentially active inhibitors by screening large compound databases. Two pharmacophore were successively used in the virtual screening protocol to identify potential selective and permeable inhibitors of PTP1B. Allosteric inhibition mechanism of these molecules was established using molecular docking and MD methods. The geometrical criteria values confirmed their ability to stabilize PTP1B in an open conformation. 23 molecules that were identified as potential inhibitors were screened for PTP1B inhibitory activity. After screening, 10 molecules which have good permeability values were identified as potential inhibitors of PTP1B. This study confirms that selective and permeable inhibitors can be identified by targeting allosteric site of PTP1B.
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Nguyen, Thao T; Parat, Marie-Odile; Shaw, Paul N; Hewavitharana, Amitha K; Hodson, Mark P
2016-01-01
Carica papaya leaf decoction, an Australian Aboriginal remedy, has been used widely for its healing capabilities against cancer, with numerous anecdotal reports. In this study we investigated its in vitro cytotoxicity on human squamous cell carcinoma cells followed by metabolomic profiling of Carica papaya leaf decoction and leaf juice/brewed leaf juice to determine the effects imparted by the long heating process typical of the Aboriginal remedy preparation. MTT assay results showed that in comparison with the decoction, the leaf juice not only exhibited a stronger cytotoxic effect on SCC25 cancer cells, but also produced a significant cancer-selective effect as shown by tests on non-cancerous human keratinocyte HaCaT cells. Furthermore, evidence from testing brewed leaf juice on these two cell lines suggested that the brewing process markedly reduced the selective effect of Carica papaya leaf on SCC25 cancer cells. To tentatively identify the compounds that contribute to the distinct selective anticancer activity of leaf juice, an untargeted metabolomic approach employing Ultra High Performance Liquid Chromatography-Quadrupole Time of Flight-Mass Spectrometry followed by multivariate data analysis was applied. Some 90 and 104 peaks in positive and negative mode respectively were selected as discriminatory features from the chemical profile of leaf juice and >1500 putative compound IDs were obtained via database searching. Direct comparison of chromatographic and tandem mass spectral data to available reference compounds confirmed one feature as a match with its proposed authentic standard, namely pheophorbide A. However, despite pheophorbide A exhibiting cytotoxic activity on SCC25 cancer cells, it did not prove to be the compound contributing principally to the selective activity of leaf juice. With promising results suggesting stronger and more selective anticancer effects when compared to the Aboriginal remedy, Carica papaya leaf juice warrants further study to explore its activity on other cancer cell lines, as well as investigation to confirm the identity of compounds contributing to its selective effect, particularly those compounds altered by the long heating process applied during the traditional Aboriginal remedy preparation.
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Nguyen, Thao T.; Parat, Marie-Odile; Shaw, Paul N.; Hewavitharana, Amitha K.; Hodson, Mark P.
2016-01-01
Carica papaya leaf decoction, an Australian Aboriginal remedy, has been used widely for its healing capabilities against cancer, with numerous anecdotal reports. In this study we investigated its in vitro cytotoxicity on human squamous cell carcinoma cells followed by metabolomic profiling of Carica papaya leaf decoction and leaf juice/brewed leaf juice to determine the effects imparted by the long heating process typical of the Aboriginal remedy preparation. MTT assay results showed that in comparison with the decoction, the leaf juice not only exhibited a stronger cytotoxic effect on SCC25 cancer cells, but also produced a significant cancer-selective effect as shown by tests on non-cancerous human keratinocyte HaCaT cells. Furthermore, evidence from testing brewed leaf juice on these two cell lines suggested that the brewing process markedly reduced the selective effect of Carica papaya leaf on SCC25 cancer cells. To tentatively identify the compounds that contribute to the distinct selective anticancer activity of leaf juice, an untargeted metabolomic approach employing Ultra High Performance Liquid Chromatography-Quadrupole Time of Flight-Mass Spectrometry followed by multivariate data analysis was applied. Some 90 and 104 peaks in positive and negative mode respectively were selected as discriminatory features from the chemical profile of leaf juice and >1500 putative compound IDs were obtained via database searching. Direct comparison of chromatographic and tandem mass spectral data to available reference compounds confirmed one feature as a match with its proposed authentic standard, namely pheophorbide A. However, despite pheophorbide A exhibiting cytotoxic activity on SCC25 cancer cells, it did not prove to be the compound contributing principally to the selective activity of leaf juice. With promising results suggesting stronger and more selective anticancer effects when compared to the Aboriginal remedy, Carica papaya leaf juice warrants further study to explore its activity on other cancer cell lines, as well as investigation to confirm the identity of compounds contributing to its selective effect, particularly those compounds altered by the long heating process applied during the traditional Aboriginal remedy preparation. PMID:26829042
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First-Line Cetuximab Monotherapy in KRAS/NRAS/BRAF Mutation-Negative Colorectal Cancer Patients.
Moiseyenko, Vladimir M; Moiseyenko, Fedor V; Yanus, Grigoriy A; Kuligina, Ekatherina Sh; Sokolenko, Anna P; Bizin, Ilya V; Kudriavtsev, Alexey A; Aleksakhina, Svetlana N; Volkov, Nikita M; Chubenko, Vyacheslav A; Kozyreva, Kseniya S; Kramchaninov, Mikhail M; Zhuravlev, Alexandr S; Shelekhova, Kseniya V; Pashkov, Denis V; Ivantsov, Alexandr O; Venina, Aigul R; Sokolova, Tatyana N; Preobrazhenskaya, Elena V; Mitiushkina, Natalia V; Togo, Alexandr V; Iyevleva, Aglaya G; Imyanitov, Evgeny N
2018-06-01
Colorectal carcinomas (CRCs) are sensitive to treatment by anti-epidermal growth factor receptor (EGFR) antibodies only if they do not carry activating mutations in down-stream EGFR targets (KRAS/NRAS/BRAF). Most clinical trials for chemo-naive CRC patients involved combination of targeted agents and chemotherapy, while single-agent cetuximab or panitumumab studies included either heavily pretreated patients or subjects who were not selected on the basis of molecular tests. We hypothesized that anti-EGFR therapy would have significant efficacy in chemo-naive patients with KRAS/NRAS/BRAF mutation-negative CRC. Nineteen patients were prospectively included in the study. Two (11%) patients experienced partial response (PR) and 11 (58%) subjects showed stable disease (SD). Median time to progression approached 6.1 months (range 1.6-15.0 months). Cetuximab efficacy did not correlate with RNA expression of EGFR and insulin-like growth factor 2 (IGF2). Only one tumor carried PIK3CA mutation, and this CRC responded to cetuximab. Exome analysis of patients with progressive disease (PD) revealed 1 CRC with high-level microsatellite instability and 1 instance of HER2 oncogene amplification; 3 of 4 remaining patients with PD had allergic reactions to cetuximab, while none of the subjects with PR or SD had this complication. Comparison with 19 retrospective KRAS/NRAS/BRAF mutation-negative patients receiving first-line fluoropyrimidines revealed no advantages or disadvantages of cetuximab therapy. Cetuximab demonstrates only modest efficacy when given as a first-line monotherapy to KRAS/NRAS/BRAF mutation-negative CRC patients. It is of question, why meticulous patient selection, which was undertaken in the current study, did not result in the improvement of outcomes of single-agent cetuximab treatment.
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Selection Shapes Transcriptional Logic and Regulatory Specialization in Genetic Networks.
Fogelmark, Karl; Peterson, Carsten; Troein, Carl
2016-01-01
Living organisms need to regulate their gene expression in response to environmental signals and internal cues. This is a computational task where genes act as logic gates that connect to form transcriptional networks, which are shaped at all scales by evolution. Large-scale mutations such as gene duplications and deletions add and remove network components, whereas smaller mutations alter the connections between them. Selection determines what mutations are accepted, but its importance for shaping the resulting networks has been debated. To investigate the effects of selection in the shaping of transcriptional networks, we derive transcriptional logic from a combinatorially powerful yet tractable model of the binding between DNA and transcription factors. By evolving the resulting networks based on their ability to function as either a simple decision system or a circadian clock, we obtain information on the regulation and logic rules encoded in functional transcriptional networks. Comparisons are made between networks evolved for different functions, as well as with structurally equivalent but non-functional (neutrally evolved) networks, and predictions are validated against the transcriptional network of E. coli. We find that the logic rules governing gene expression depend on the function performed by the network. Unlike the decision systems, the circadian clocks show strong cooperative binding and negative regulation, which achieves tight temporal control of gene expression. Furthermore, we find that transcription factors act preferentially as either activators or repressors, both when binding multiple sites for a single target gene and globally in the transcriptional networks. This separation into positive and negative regulators requires gene duplications, which highlights the interplay between mutation and selection in shaping the transcriptional networks.
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Davies-Thompson, Jodie; Johnston, Samantha; Tashakkor, Yashar; Pancaroglu, Raika; Barton, Jason J S
2016-08-01
Visual words and faces activate similar networks but with complementary hemispheric asymmetries, faces being lateralized to the right and words to the left. A recent theory proposes that this reflects developmental competition between visual word and face processing. We investigated whether this results in an inverse correlation between the degree of lateralization of visual word and face activation in the fusiform gyri. 26 literate right-handed healthy adults underwent functional MRI with face and word localizers. We derived lateralization indices for cluster size and peak responses for word and face activity in left and right fusiform gyri, and correlated these across subjects. A secondary analysis examined all face- and word-selective voxels in the inferior occipitotemporal cortex. No negative correlations were found. There were positive correlations for the peak MR response between word and face activity within the left hemisphere, and between word activity in the left visual word form area and face activity in the right fusiform face area. The face lateralization index was positively rather than negatively correlated with the word index. In summary, we do not find a complementary relationship between visual word and face lateralization across subjects. The significance of the positive correlations is unclear: some may reflect the influences of general factors such as attention, but others may point to other factors that influence lateralization of function. Copyright © 2016 Elsevier B.V. All rights reserved.
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Nargotra, Amit; Sharma, Sujata; Koul, Jawahir Lal; Sangwan, Pyare Lal; Khan, Inshad Ali; Kumar, Ashwani; Taneja, Subhash Chander; Koul, Surrinder
2009-10-01
Quantitative structure activity relationship (QSAR) analysis of piperine analogs as inhibitors of efflux pump NorA from Staphylococcus aureus has been performed in order to obtain a highly accurate model enabling prediction of inhibition of S. aureus NorA of new chemical entities from natural sources as well as synthetic ones. Algorithm based on genetic function approximation method of variable selection in Cerius2 was used to generate the model. Among several types of descriptors viz., topological, spatial, thermodynamic, information content and E-state indices that were considered in generating the QSAR model, three descriptors such as partial negative surface area of the compounds, area of the molecular shadow in the XZ plane and heat of formation of the molecules resulted in a statistically significant model with r(2)=0.962 and cross-validation parameter q(2)=0.917. The validation of the QSAR models was done by cross-validation, leave-25%-out and external test set prediction. The theoretical approach indicates that the increase in the exposed partial negative surface area increases the inhibitory activity of the compound against NorA whereas the area of the molecular shadow in the XZ plane is inversely proportional to the inhibitory activity. This model also explains the relationship of the heat of formation of the compound with the inhibitory activity. The model is not only able to predict the activity of new compounds but also explains the important regions in the molecules in quantitative manner.
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Echeverría, Javier; Opazo, Julia; Mendoza, Leonora; Urzúa, Alejandro; Wilkens, Marcela
2017-04-10
In this study, we tested eight naturally-occurring flavonoids-three flavanones and five flavones-for their possible antibacterial properties against four Gram-positive and four Gram-negative bacteria. Flavonoids are known for their antimicrobial properties, and due their structural diversity; these plant-derived compounds are a good model to study potential novel antibacterial mechanisms. The lipophilicity and the interaction of antibacterial compounds with the cell membrane define the success or failure to access its target. Therefore, through the determination of partition coefficients in a non-polar/aqueous phase, lipophilicity estimation and the quantification of the antibacterial activity of different flavonoids, flavanones, and flavones, a relationship between these parameters was assessed. Active flavonoids presented diffusion coefficients between 9.4 × 10 -10 and 12.3 × 10 -10 m²/s and lipophilicity range between 2.0 to 3.3. Active flavonoids against Gram-negative bacteria showed a narrower range of lipophilicity values, compared to active flavonoids against Gram-positive bacteria, which showed a wide range of lipophilicity and cell lysis. Galangin was the most active flavonoid, whose structural features are the presence of two hydroxyl groups located strategically on ring A and the absence of polar groups on ring B. Methylation of one hydroxyl group decreases the activity in 3- O -methylgalangin, and methylation of both hydroxyl groups caused inactivation, as shown for 3,7- O -dimethylgalangin. In conclusion, the amphipathic features of flavonoids play a crucial role in the antibacterial activity. In these compounds, hydrophilic and hydrophobic moieties must be present and could be predicted by lipophilicity analysis.
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Mode Selection Rules for a Two-Delay System with Positive and Negative Feedback Loops
NASA Astrophysics Data System (ADS)
Takahashi, Kin'ya; Kobayashi, Taizo
2018-04-01
The mode selection rules for a two-delay system, which has negative feedback with a short delay time t1 and positive feedback with a long delay time t2, are studied numerically and theoretically. We find two types of mode selection rules depending on the strength of the negative feedback. When the strength of the negative feedback |α1| (α1 < 0) is sufficiently small compared with that of the positive feedback α2 (> 0), 2m + 1-th harmonic oscillation is well sustained in a neighborhood of t1/t2 = even/odd, i.e., relevant condition. In a neighborhood of the irrelevant condition given by t1/t2 = odd/even or t1/t2 = odd/odd, higher harmonic oscillations are observed. However, if |α1| is slightly less than α2, a different mode selection rule works, where the condition t1/t2 = odd/even is relevant and the conditions t1/t2 = odd/odd and t1/t2 = even/odd are irrelevant. These mode selection rules are different from the mode selection rule of the normal two-delay system with two positive feedback loops, where t1/t2 = odd/odd is relevant and the others are irrelevant. The two types of mode selection rules are induced by individually different mechanisms controlling the Hopf bifurcation, i.e., the Hopf bifurcation controlled by the "boosted bifurcation process" and by the "anomalous bifurcation process", which occur for |α1| below and above the threshold value αth, respectively.
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Johannesson, K; Butlin, R K
2017-01-01
It is intriguing that conspicuous colour morphs of a prey species may be maintained at low frequencies alongside cryptic morphs. Negative frequency-dependent selection by predators using search images ('apostatic selection') is often suggested without rejecting alternative explanations. Using a maximum likelihood approach we fitted predictions from models of genetic drift, migration, constant selection, heterozygote advantage or negative frequency-dependent selection to time-series data of colour frequencies in isolated populations of a marine snail (Littorina saxatilis), re-established with perturbed colour morph frequencies and followed for >20 generations. Snails of conspicuous colours (white, red, banded) are naturally rare in the study area (usually <10%) but frequencies were manipulated to levels of ~50% (one colour per population) in 8 populations at the start of the experiment in 1992. In 2013, frequencies had declined to ~15-45%. Drift alone could not explain these changes. Migration could not be rejected in any population, but required rates much higher than those recorded. Directional selection was rejected in three populations in favour of balancing selection. Heterozygote advantage and negative frequency-dependent selection could not be distinguished statistically, although overall the results favoured the latter. Populations varied idiosyncratically as mild or variable colour selection (3-11%) interacted with demographic stochasticity, and the overall conclusion was that multiple mechanisms may contribute to maintaining the polymorphisms.
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Spielberg, Jeffrey M; Jarcho, Johanna M; Dahl, Ronald E; Pine, Daniel S; Ernst, Monique; Nelson, Eric E
2015-08-01
Adolescence is the time of peak onset for many anxiety disorders, particularly Social Anxiety Disorder. Research using simulated social interactions consistently finds differential activation in several brain regions in anxious (vs non-anxious) youth, including amygdala, striatum and medial prefrontal cortex. However, few studies examined the anticipation of peer interactions, a key component in the etiology and maintenance of anxiety disorders. Youth completed the Chatroom Task while undergoing functional magnetic resonance imaging. Patterns of neural activation were assessed in anxious and non-anxious youth as they were cued to anticipate social feedback from peers. Anxious participants evidenced greater amygdala activation and rostral anterior cingulate (rACC)↔amygdala coupling than non-anxious participants during anticipation of feedback from peers they had previously rejected; anxious participants also evidenced less nucleus accumbens activation during anticipation of feedback from selected peers. Finally, anxiety interacted with age in rACC: in anxious participants, age was positively associated with activation to anticipated feedback from rejected peers and negatively for selected peers, whereas the opposite pattern emerged for non-anxious youth. Overall, anxious youth showed greater reactivity in anticipation of feedback from rejected peers and thus may ascribe greater salience to these potential interactions and increase the likelihood of avoidance behavior. © The Author (2014). Published by Oxford University Press. For Permissions, please email: journals.permissions@oup.com.
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[New antibiotics - standstill or progress].
Rademacher, J; Welte, T
2017-04-01
The development of resistance to antibiotics has been ignored for a long time. But nowadays, increasing resistance is an important topic. For a decade no new antibiotics had been developed and it is not possible to quickly close this gap of new resistance and no new drugs. This work presents six new antibiotics (ceftaroline, ceftobiprole, solithromycin, tedizolid, ceftolozane/tazobactam, ceftazidime/avibactam). In part, only expert opinions are given due to lack of study results.The two 5th generation cephalosporins ceftaroline and ceftobiprole have beside their equivalent efficacy to ceftriaxone (ceftaroline) and cefipim (ceftobiprole) high activity against MRSA. The fluoroketolide solithromycin should help against macrolide-resistant pathogens and has been shown to be noninferior to the fluorochinolones. The oxazolidinone tedizolid is effective against linezolid-resistant MRSA. The two cephalosporins ceftolozane/tazobactam and ceftazidime/avibactam are not only effective against gram-negative pathogens, but they have a very broad spectrum. Due to the efficacy against extended-spectrum β‑lactamases, they can relieve the selection pressure of the carbapenems. We benefit from all new antibiotics which can take the selection pressure from other often used antibiotics. The increasing number of resistant gram-negative pathogens worldwide is alarming. Thus, focusing on the development of new drugs is extremely important.
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Kudo, Noriko; Nakagome, Kazuyuki; Kasai, Kiyoto; Araki, Tsuyoshi; Fukuda, Masato; Kato, Nobumasa; Iwanami, Akira
2004-01-01
Corollary discharge is a brain electrical activity associated with self-monitoring, which distinguishes self from others in thoughts or behaviors. Corollary discharge can be non-invasively assessed using event-related potential (ERP) recordings in humans. Previous studies have revealed that the amplitude of the N100 component elicited during an "odd-ball" task is reduced while a healthy subject is vocalizing, which may index the effect of corollary discharge on auditory ERPs. In this study, we attempted to assess the effect of vocalization on ERP components including N100, mismatch negativity (MMN), negative difference wave (Nd), and P300 during a selective attention task in 22 healthy adults. We also evaluated the possible contribution of gender to these effects. N100 amplitudes elicited by unattended standard stimuli were reduced under the vocalization condition compared with those under the baseline condition. However, there were no significant effects of vocalization on MMN, Nd or P300. Moreover, there was no significant effect of gender to the corollary discharge. These results suggest that the effect of corollary discharge on auditory ERPs is limited to the perceptual stage of information processing in healthy men and women.
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Wu, Sheng-Tang; Sun, Guang-Huan; Cha, Tai-Lung; Kao, Chien-Chang; Chang, Sun-Yran; Kuo, Sheng-Chu; Way, Tzong-Der
2016-08-15
Triple-negative breast cancer (TNBC) lacks specific therapeutic target and limits to chemotherapy and is essential to develop novel therapeutic regimens. Increasing studies indicated that tamoxifen, a selective estrogen receptor modulators (SERMs), has anti-tumor therapeutic effect in estrogen receptor α (ERα)-negative tumor. Here, we determined whether autophagy was activated by tamoxifen in TNBC cells. Moreover, CSC-3436 displayed strong and selective growth inhibition on cancer cells. Next, we investigated the anti-proliferation effect of combination of CSC-3436 plus tamoxifen on cell death in TNBC cells. Our study found that tamoxifen induces autophagy in TNBC cells. Endoplasmic reticulum stress and AMPK/mTOR contributed tamoxifen-induced autophagy. Interestingly, in combination treatment with CSC-3436 enhanced the anti-proliferative effect of tamoxifen. We found that CSC-3436 switched tamoxifen-induced autophagy to apoptosis via cleavage of ATG-5. Moreover, AMPK/mTOR pathway may involve in CSC-3436 switched tamoxifen-induced autophagy to apoptosis. The combination of tamoxifen and CSC-3436 produced stronger tumor growth inhibition compared with CSC-3436 or tamoxifen alone treatments in vivo. These data indicated that CSC-3436 combined with tamoxifen may be a potential approach for treatment TNBC.
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Zolfagharian, Hossein; Mohajeri, Mohammad; Babaie, Mahdi
2016-09-01
Mellitine, a major component of bee venom (BV, Apis mellifera ), is more active against gram positive than gram negative bacteria. Moreover, BV has been reported to have multiple effects, including antibacterial, antivirus, and anti-inflammation effects, in various types of cells. In addition, wasp venom has been reported to have antibacterial properties. The aim of this study was to evaluate the antibacterial activity of BV against selected gram positive and gram negative bacterial strains of medical importance. This investigation was set up to evaluate the antibacterial activity of BV against six grams positive and gram negative bacteria, including Staphylococcus aureus ( S. aureus ), Salmonella typhimurium , Escherichia coli ( E. coli ) O157:H7, Pseudomonas aeruginosa , Burkholderia mallei and Burkholderia pseudomallei. Three concentrations of crude BV and standard antibiotic (gentamicin) disks as positive controls were tested by using the disc diffusion method. BV was found to have a significant antibacterial effect against E. coli , S. aureus , and Salmonella typhyimurium in all three concentrations tested. However, BV had no noticeable effect on other tested bacteria for any of the three doses tested. The results of the current study indicate that BV inhibits the growth and survival of bacterial strains and that BV can be used as a complementary antimicrobial agent against pathogenic bacteria. BV lacked the effective proteins necessary for it to exhibit antibacterial activity for some specific strains while being very effective against other specific strains. Thus, one may conclude, that Apis mellifera venom may have a specific mechanism that allows it to have an antibacterial effect on certain susceptible bacteria, but that mechanism is not well understood.
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Fankam, Aimé G; Kuiate, Jules R; Kuete, Victor
2015-06-30
Bacterial resistance to antibiotics is becoming a serious problem worldwide. The discovery of new and effective antimicrobials and/or resistance modulators is necessary to tackle the spread of resistance or to reverse the multi-drug resistance. We investigated the antibacterial and antibiotic-resistance modifying activities of the methanol extracts from Allanblackia gabonensis, Gladiolus quartinianus and Combretum molle against 29 Gram-negative bacteria including multi-drug resistant (MDR) phenotypes. The broth microdilution method was used to determine the minimal inhibitory concentrations (MIC) and minimal bactericidal concentrations (MBC) of the samples meanwhile the standard phytochemical methods were used for the preliminary phytochemical screening of the plant extracts. Phytochemical analysis showed the presence of alkaloids, flavonoids, phenols and tannins in all studied extracts. Other chemical classes of secondary metabolites were selectively presents. Extracts from A. gabonensis and C. molle displayed a broad spectrum of activity with MICs varying from 16 to 1024 μg/mL against about 72.41% of the tested bacteria. The extract from the fruits of A. gabonensis had the best activity, with MIC values below 100 μg/mL on 37.9% of tested bacteria. Percentages of antibiotic-modulating effects ranging from 67 to 100% were observed against tested MDR bacteria when combining the leaves extract from C. molle (at MIC/2 and MIC/4) with chloramphenicol, kanamycin, streptomycin and tetracycline. The overall results of the present study provide information for the possible use of the studied plant, especially Allanblackia gabonensis and Combretum molle in the control of Gram-negative bacterial infections including MDR species as antibacterials as well as resistance modulators.
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G Protein-Coupled Estrogen Receptor-Selective Ligands Modulate Endometrial Tumor Growth
Petrie, Whitney K.; Dennis, Megan K.; Dai, Donghai; Arterburn, Jeffrey B.; Smith, Harriet O.; Hathaway, Helen J.; Prossnitz, Eric R.
2013-01-01
Endometrial carcinoma is the most common cancer of the female reproductive tract. GPER/GPR30 is a 7-transmembrane spanning G protein-coupled receptor that has been identified as the third estrogen receptor, in addition to ERα and ERβ. High GPER expression is predictive of poor survival in endometrial and ovarian cancer, but despite this, the estrogen-mediated signaling pathways and specific estrogen receptors involved in endometrial cancer remain unclear. Here, employing ERα-negative Hec50 endometrial cancer cells, we demonstrate that GPER mediates estrogen-stimulated activation of ERK and PI3K via matrix metalloproteinase activation and subsequent transactivation of the EGFR and that ER-targeted therapeutic agents (4-hydroxytamoxifen, ICI182,780/fulvestrant, and Raloxifene), the phytoestrogen genistein, and the “ERα-selective” agonist propylpyrazole triol also function as GPER agonists. Furthermore, xenograft tumors of Hec50 cells yield enhanced growth with G-1 and estrogen, the latter being inhibited by GPER-selective pharmacologic antagonism with G36. These results have important implications with respect to the use of putatively ER-selective ligands and particularly for the widespread long-term use of “ER-targeted” therapeutics. Moreover, our findings shed light on the potential mechanisms of SERM/SERD side effects reported in many clinical studies. Finally, our results provide the first demonstration that pharmacological inhibition of GPER activity in vivo prevents estrogen-mediated tumor growth. PMID:24379833
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Pasupuleti, Mukesh; Walse, Björn; Svensson, Bo; Malmsten, Martin; Schmidtchen, Artur
2008-09-02
The anaphylatoxin C3a and its inactivated derivative C3adesArg, generated during complement activation, exert direct antimicrobial effects, mediated via its C-terminal region [Nordahl et al. (2004) Proc. Natl. Acad. Sci. U.S.A. 101, 16879-16884]. During evolution, this region of C3a displays subtle changes in net charge, while preserving a moderate but variable amphipathicity [Pasupuleti et al. (2007) J. Biol. Chem. 282, 2520-2528]. In this study, we mimic these evolutionary changes, employing a design approach utilizing selected amino acid substitutions at strategic and structurally relevant positions in the original human C3a peptide CNYITELRRQHARASHLGLA, followed by structure-activity studies incorporating sequence-dependent QSAR models as tools for generation of C3a peptide variants with enhanced effects. While the native peptide and related amphipathic analogues of moderate positive net charge were active against the Gram-negative Escherichia coli, activity against the Gram-positive Staphylococcus aureus was primarily observed for peptides characterized by a combination of a relatively high net charge (+6-7) and a propensity to adopt an alpha-helical conformation with amphipathic character. Such increased helicity and charge also conferred activity against the fungus Candida albicans. A central histidine residue (H11), evolutionarily conserved among vertebrates, conferred high selectivity toward microbes, while substitutions with leucine rendered the peptides hemolytic. Selected C3a analogues retained their specificity against staphylococci in the presence of human plasma, while showing low cytotoxicity. The work illustrates structure-activity relationships underlying the function and specificity of antimicrobial C3a and related analogues and provides insights into the forces that drive evolution of antimicrobial peptides.
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Echo Chambers: Emotional Contagion and Group Polarization on Facebook
NASA Astrophysics Data System (ADS)
Del Vicario, Michela; Vivaldo, Gianna; Bessi, Alessandro; Zollo, Fabiana; Scala, Antonio; Caldarelli, Guido; Quattrociocchi, Walter
2016-12-01
Recent findings showed that users on Facebook tend to select information that adhere to their system of beliefs and to form polarized groups - i.e., echo chambers. Such a tendency dominates information cascades and might affect public debates on social relevant issues. In this work we explore the structural evolution of communities of interest by accounting for users emotions and engagement. Focusing on the Facebook pages reporting on scientific and conspiracy content, we characterize the evolution of the size of the two communities by fitting daily resolution data with three growth models - i.e. the Gompertz model, the Logistic model, and the Log-logistic model. Although all the models appropriately describe the data structure, the Logistic one shows the best fit. Then, we explore the interplay between emotional state and engagement of users in the group dynamics. Our findings show that communities’ emotional behavior is affected by the users’ involvement inside the echo chamber. Indeed, to an higher involvement corresponds a more negative approach. Moreover, we observe that, on average, more active users show a faster shift towards the negativity than less active ones.
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Tantak, Mukund P.; Wang, Jing; Singh, Rajnish Prakash; Kumar, Anil; Shah, Kavita; Kumar, Dalip
2015-01-01
A new series of 2-(3′-indolyl)-N-arylthiazole-4-carboxamides 17a-p has been designed and synthesized. Initial reaction of readily available thioamides 15 with bromopyruvic acid under refluxing conditions produced different thiazole carboxylic acids 16 which upon coupling with arylamines by using EDCI.HCl and HOBt afforded diverse arylthiazole-4-carboxamides 17a-p in 78-87% yields. Antibacterial activity evaluation against Gram-positive and Gram-negative bacterial strains led to compounds 17i-k and 17o as potent and selectively (Gram-negative) antibacterial agents. The cytotoxicity of thiazole carboxamides 17a-p was also evaluated on a panel of human cancer cell lines. Among the tested derivatives, compounds 17i (IC50 = 8.64 μM; HEK293T) and 17l (IC50 = 3.41 μM; HeLa) were identified as the most potent analogues of the series. Preliminary mechanism of action studies of thiazole carboxamide 17i suggested that its cytotoxicity against HeLa cells involves the induction of cell death by apoptosis. PMID:26298501
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Multiple types of motives don't multiply the motivation of West Point cadets.
Wrzesniewski, Amy; Schwartz, Barry; Cong, Xiangyu; Kane, Michael; Omar, Audrey; Kolditz, Thomas
2014-07-29
Although people often assume that multiple motives for doing something will be more powerful and effective than a single motive, research suggests that different types of motives for the same action sometimes compete. More specifically, research suggests that instrumental motives, which are extrinsic to the activities at hand, can weaken internal motives, which are intrinsic to the activities at hand. We tested whether holding both instrumental and internal motives yields negative outcomes in a field context in which various motives occur naturally and long-term educational and career outcomes are at stake. We assessed the impact of the motives of over 10,000 West Point cadets over the period of a decade on whether they would become commissioned officers, extend their officer service beyond the minimum required period, and be selected for early career promotions. For each outcome, motivation internal to military service itself predicted positive outcomes; a relationship that was negatively affected when instrumental motives were also in evidence. These results suggest that holding multiple motives damages persistence and performance in educational and occupational contexts over long periods of time.
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Multiple types of motives don't multiply the motivation of West Point cadets
Wrzesniewski, Amy; Schwartz, Barry; Cong, Xiangyu; Kane, Michael; Omar, Audrey; Kolditz, Thomas
2014-01-01
Although people often assume that multiple motives for doing something will be more powerful and effective than a single motive, research suggests that different types of motives for the same action sometimes compete. More specifically, research suggests that instrumental motives, which are extrinsic to the activities at hand, can weaken internal motives, which are intrinsic to the activities at hand. We tested whether holding both instrumental and internal motives yields negative outcomes in a field context in which various motives occur naturally and long-term educational and career outcomes are at stake. We assessed the impact of the motives of over 10,000 West Point cadets over the period of a decade on whether they would become commissioned officers, extend their officer service beyond the minimum required period, and be selected for early career promotions. For each outcome, motivation internal to military service itself predicted positive outcomes; a relationship that was negatively affected when instrumental motives were also in evidence. These results suggest that holding multiple motives damages persistence and performance in educational and occupational contexts over long periods of time. PMID:24982165
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Echo Chambers: Emotional Contagion and Group Polarization on Facebook.
Del Vicario, Michela; Vivaldo, Gianna; Bessi, Alessandro; Zollo, Fabiana; Scala, Antonio; Caldarelli, Guido; Quattrociocchi, Walter
2016-12-01
Recent findings showed that users on Facebook tend to select information that adhere to their system of beliefs and to form polarized groups - i.e., echo chambers. Such a tendency dominates information cascades and might affect public debates on social relevant issues. In this work we explore the structural evolution of communities of interest by accounting for users emotions and engagement. Focusing on the Facebook pages reporting on scientific and conspiracy content, we characterize the evolution of the size of the two communities by fitting daily resolution data with three growth models - i.e. the Gompertz model, the Logistic model, and the Log-logistic model. Although all the models appropriately describe the data structure, the Logistic one shows the best fit. Then, we explore the interplay between emotional state and engagement of users in the group dynamics. Our findings show that communities' emotional behavior is affected by the users' involvement inside the echo chamber. Indeed, to an higher involvement corresponds a more negative approach. Moreover, we observe that, on average, more active users show a faster shift towards the negativity than less active ones.
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Kemmler, Wolfgang; Kohl, Matthias; Bebenek, Michael; von Stengel, Simon
2015-03-01
Early adulthood is related to changes in lifestyle that negatively affect body weight and health. The aim of the study was to determine the effect of exercise changes on the development of weight and body composition in college students.Sixty-one randomly selected dental (ZMS) and 53 sport students (SLS) were accompanied over 5 years. Body mass, fat and lean body mass (LBM) were determined via DXA-technique. Exercise and physical activity were assessed by questionnaires and interviews.All exercise indices significantly increased in the SLS and significantly decreased in the ZMS. Physical activity slightly increased in both groups. Both cohorts comparably gained body mass, however, the increase in the SLS group can be attributed to LBM-changes with minor changes of fat-mass (2.4 % ± 3.3 % vs. 0.1 ± 1.0 %) whereas ZMS gained fat and LBM in a proportion of 2:1.Maintenance/increase of exercise compensate the negative effects of lifestyle changes on body composition during young adulthood.
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Ma, Yujun; Wang, Enguo; Yuan, Tian; Zhao, Guo Xiang
2016-08-01
As the reading process is inseparable from working memory, inhibition, and other higher cognitive processes, the deep cognitive processing defects that are associated with dyslexia may be due to defective distraction inhibition systems. In this study, we used event-related potential technology to explore the source of negative priming effects in children with developmental dyslexia and in a group of healthy children for comparison. We found that the changes in the average response times in the negative priming and control conditions were consistent across the two groups, while the negative priming effects differed significantly between the groups. The magnitude of the negative priming effect was significantly different between the two groups, with the magnitude being significantly higher in the control group than it was in the developmental dyslexia group. These results indicate that there are deficits in distraction inhibition in children with developmental dyslexia. In terms of the time course of processing, inhibition deficits in the dyslexia group appeared during early-stage cognition selection and lasted through the response selection phase. Regarding the cerebral cortex locations, early-stage cognition selection was mainly located in the parietal region, while late-stage response selection was mainly located in the frontal and central regions. The results of our study may help further our understanding of the intrinsic causes of developmental dyslexia. Copyright © 2016 Elsevier Ltd. All rights reserved.
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Kahlous, Nour Aldin; Bawarish, Muhammad Al Mohdi; Sarhan, Muhammad Arabi; Küpper, Manfred; Hasaba, Ali; Rajab, Mazen
2017-04-01
Discovering of new and effective antibiotics is a major issue facing scientists today. Luckily, the development of computer science offers new methods to overcome this issue. In this study, a set of computer software was used to predict the antibacterial activity of nonantibiotic Food and Drug Administration (FDA)-approved drugs, and to explain their action by possible binding to well-known bacterial protein targets, along with testing their antibacterial activity against Gram-positive and Gram-negative bacteria. A three-dimensional virtual screening method that relies on chemical and shape similarity was applied using rapid overlay of chemical structures (ROCS) software to select candidate compounds from the FDA-approved drugs database that share similarity with 17 known antibiotics. Then, to check their antibacterial activity, disk diffusion test was applied on Staphylococcus aureus and Escherichia coli. Finally, a protein docking method was applied using HYBRID software to predict the binding of the active candidate to the target receptor of its similar antibiotic. Of the 1,991 drugs that were screened, 34 had been selected and among them 10 drugs showed antibacterial activity, whereby drotaverine and metoclopramide activities were without precedent reports. Furthermore, the docking process predicted that diclofenac, drotaverine, (S)-flurbiprofen, (S)-ibuprofen, and indomethacin could bind to the protein target of their similar antibiotics. Nevertheless, their antibacterial activities are weak compared with those of their similar antibiotics, which can be potentiated further by performing chemical modifications on their structure.
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Correa, Hebelin; Aristizabal, Fabio; Duque, Carmenza; Kerr, Russell
2011-01-01
To expand the potential of pseudopterosins and seco-pseudopterosins isolated from the octocoral Pseudopterogorgia elisabethae of San Andrés and Providencia islands (southwest Caribbean Sea), we report the anti-microbial profile against four pathogenic microorganisms (Staphylococcus aureus, Enterococcus faecalis, Pseudomonas aeruginosa and Candida albicans) and report a more complete cytotoxic profile against five human cells lines (HeLa, PC-3, HCT116, MCF-7 and BJ) for the compounds PsG, PsP, PsQ, PsS, PsT, PsU, 3-O-acetyl-PsU, seco-PsJ, seco-PsK and IMNGD. For the cytotoxic profiles, all compounds evaluated showed moderate and non-selective activity against both tumor and normal cell lines, where PsQ and PsG were the most active compounds (GI50 values between 5.8 μM to 12.0 μM). With respect to their anti-microbial activity the compounds showed good and selective activity against the Gram-positive bacteria, while they did not show activity against the Gram-negative bacterium or yeast. PsU, PsQ, PsS, seco-PsK and PsG were the most active compounds (IC50 2.9–4.5 μM) against S. aureus and PsG, PsU and seco-PsK showed good activity (IC50 3.1–3.8 μM) against E. faecalis, comparable to the reference drug vancomycin (4.2 μM). PMID:21556163
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Cao, Xia; Rui, Lewei; Pennington, Paul R; Chlan-Fourney, Jennifer; Jiang, Zhongjian; Wei, Zelan; Li, Xin-Min; Edmondson, Dale E; Mousseau, Darrell D
2009-10-01
The p38 mitogen-activated protein kinase (MAPK) cascade as well as the enzyme monoamine oxidase-A (MAO-A) have both been associated with oxidative stress. We observed that the specific inhibition of the p38(MAPK) protein [using either a chemical inhibitor or a dominant-negative p38(MAPK) clone] selectively induces MAO-A activity and MAO-A-sensitive toxicity in several neuronal cell lines, including primary cortical neurons. Over-expression of a constitutively active p38(MAPK) results in the phosphorylation of the MAO-A protein and inhibition of MAO-A activity. The MAO-A(Ser209Glu) phosphomimic - bearing a targeted substitution within a putative p38(MAPK) consensus motif - is neither active nor neurotoxic. In contrast, the MAO-A(Ser209Ala) variant (mimics dephosphorylation) does not associate with p38(MAPK), and is both very active and very toxic. Substitution of the homologous serine in the MAO-B isoform, i.e. Ser200, with either Glu or Ala does not affect the catalytic activity of the corresponding over-expressed proteins. These combined in vitro data strongly suggest a direct p38(MAPK)-dependent inhibition of MAO-A function. Based on published observations, this endogenous means of selectively regulating MAO-A function could provide for an adaptive response to oxidative stress associated with disorders as diverse as depression, reperfusion/ischemia, and the early stages of Alzheimer's disease.
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A Cross-National Investigation of Student Intentions to Pursue a Sales Career
ERIC Educational Resources Information Center
Karakaya, Fahri; Quigley, Charles; Bingham, Frank
2011-01-01
Previous studies related to student selection of a sales career indicate that their perception of sales as a career is generally negative. Numerous reasons have been offered for this negative view, including negative perceptions of attributes associated with sales jobs and salespeople. This study examines the perceptions of negative and positive…
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Persson, Camilla; Sävenhed, Catrine; Bourdeau, Annie; Tremblay, Michel L.; Markova, Boyka; Böhmer, Frank D.; Haj, Fawaz G.; Neel, Benjamin G.; Elson, Ari; Heldin, Carl-Henrik; Rönnstrand, Lars; Östman, Arne; Hellberg, Carina
2004-01-01
The platelet-derived growth factor (PDGF) β receptor mediates mitogenic and chemotactic signals. Like other tyrosine kinase receptors, the PDGF β receptor is negatively regulated by protein tyrosine phosphatases (PTPs). To explore whether T-cell PTP (TC-PTP) negatively regulates the PDGF β receptor, we compared PDGF β receptor tyrosine phosphorylation in wild-type and TC-PTP knockout (ko) mouse embryos. PDGF β receptors were hyperphosphorylated in TC-PTP ko embryos. Fivefold-higher ligand-induced receptor phosphorylation was observed in TC-PTP ko mouse embryo fibroblasts (MEFs) as well. Reexpression of TC-PTP partly abolished this difference. As determined with site-specific phosphotyrosine antibodies, the extent of hyperphosphorylation varied among different autophosphorylation sites. The phospholipase Cγ1 binding site Y1021, previously implicated in chemotaxis, displayed the largest increase in phosphorylation. The increase in Y1021 phosphorylation was accompanied by increased phospholipase Cγ1 activity and migratory hyperresponsiveness to PDGF. PDGF β receptor tyrosine phosphorylation in PTP-1B ko MEFs but not in PTPɛ ko MEFs was also higher than that in control cells. This increase occurred with a site distribution different from that seen after TC-PTP depletion. PDGF-induced migration was not increased in PTP-1B ko cells. In summary, our findings identify TC-PTP as a previously unrecognized negative regulator of PDGF β receptor signaling and support the general notion that PTPs display site selectivity in their action on tyrosine kinase receptors. PMID:14966296
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mTORC1 Is a Local, Postsynaptic Voltage Sensor Regulated by Positive and Negative Feedback Pathways
Niere, Farr; Raab-Graham, Kimberly F.
2017-01-01
The mammalian/mechanistic target of rapamycin complex 1 (mTORC1) serves as a regulator of mRNA translation. Recent studies suggest that mTORC1 may also serve as a local, voltage sensor in the postsynaptic region of neurons. Considering biochemical, bioinformatics and imaging data, we hypothesize that the activity state of mTORC1 dynamically regulates local membrane potential by promoting and repressing protein synthesis of select mRNAs. Our hypothesis suggests that mTORC1 uses positive and negative feedback pathways, in a branch-specific manner, to maintain neuronal excitability within an optimal range. In some dendritic branches, mTORC1 activity oscillates between the “On” and “Off” states. We define this as negative feedback. In contrast, positive feedback is defined as the pathway that leads to a prolonged depolarized or hyperpolarized resting membrane potential, whereby mTORC1 activity is constitutively on or off, respectively. We propose that inactivation of mTORC1 increases the expression of voltage-gated potassium alpha (Kv1.1 and 1.2) and beta (Kvβ2) subunits, ensuring that the membrane resets to its resting membrane potential after experiencing increased synaptic activity. In turn, reduced mTORC1 activity increases the protein expression of syntaxin-1A and promotes the surface expression of the ionotropic glutamate receptor N-methyl-D-aspartate (NMDA)-type subunit 1 (GluN1) that facilitates increased calcium entry to turn mTORC1 back on. Under conditions such as learning and memory, mTORC1 activity is required to be high for longer periods of time. Thus, the arm of the pathway that promotes syntaxin-1A and Kv1 protein synthesis will be repressed. Moreover, dendritic branches that have low mTORC1 activity with increased Kv expression would balance dendrites with constitutively high mTORC1 activity, allowing for the neuron to maintain its overall activity level within an ideal operating range. Finally, such a model suggests that recruitment of more positive feedback dendritic branches within a neuron is likely to lead to neurodegenerative disorders. PMID:28611595
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2016-01-01
Serum paraoxonase 1 (PON1) is a native lactonase capable of promiscuously hydrolyzing a broad range of substrates, including organophosphates, esters, and carbonates. Structurally, PON1 is a six-bladed β-propeller with a flexible loop (residues 70–81) covering the active site. This loop contains a functionally critical Tyr at position 71. We have performed detailed experimental and computational analyses of the role of selected Y71 variants in the active site stability and catalytic activity in order to probe the role of Y71 in PON1’s lactonase and organophosphatase activities. We demonstrate that the impact of Y71 substitutions on PON1’s lactonase activity is minimal, whereas the kcat for the paraoxonase activity is negatively perturbed by up to 100-fold, suggesting greater mutational robustness of the native activity. Additionally, while these substitutions modulate PON1’s active site shape, volume, and loop flexibility, their largest effect is in altering the solvent accessibility of the active site by expanding the active site volume, allowing additional water molecules to enter. This effect is markedly more pronounced in the organophosphatase activity than the lactonase activity. Finally, a detailed comparison of PON1 to other organophosphatases demonstrates that either a similar “gating loop” or a highly buried solvent-excluding active site is a common feature of these enzymes. We therefore posit that modulating the active site hydrophobicity is a key element in facilitating the evolution of organophosphatase activity. This provides a concrete feature that can be utilized in the rational design of next-generation organophosphate hydrolases that are capable of selecting a specific reaction from a pool of viable substrates. PMID:28026940
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Blaha-Nelson, David; Krüger, Dennis M; Szeler, Klaudia; Ben-David, Moshe; Kamerlin, Shina Caroline Lynn
2017-01-25
Serum paraoxonase 1 (PON1) is a native lactonase capable of promiscuously hydrolyzing a broad range of substrates, including organophosphates, esters, and carbonates. Structurally, PON1 is a six-bladed β-propeller with a flexible loop (residues 70-81) covering the active site. This loop contains a functionally critical Tyr at position 71. We have performed detailed experimental and computational analyses of the role of selected Y71 variants in the active site stability and catalytic activity in order to probe the role of Y71 in PON1's lactonase and organophosphatase activities. We demonstrate that the impact of Y71 substitutions on PON1's lactonase activity is minimal, whereas the k cat for the paraoxonase activity is negatively perturbed by up to 100-fold, suggesting greater mutational robustness of the native activity. Additionally, while these substitutions modulate PON1's active site shape, volume, and loop flexibility, their largest effect is in altering the solvent accessibility of the active site by expanding the active site volume, allowing additional water molecules to enter. This effect is markedly more pronounced in the organophosphatase activity than the lactonase activity. Finally, a detailed comparison of PON1 to other organophosphatases demonstrates that either a similar "gating loop" or a highly buried solvent-excluding active site is a common feature of these enzymes. We therefore posit that modulating the active site hydrophobicity is a key element in facilitating the evolution of organophosphatase activity. This provides a concrete feature that can be utilized in the rational design of next-generation organophosphate hydrolases that are capable of selecting a specific reaction from a pool of viable substrates.
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Boone-Heinonen, Janne; Guilkey, David K; Evenson, Kelly R; Gordon-Larsen, Penny
2010-10-04
Built environment research is dominated by cross-sectional designs, which are particularly vulnerable to residential self-selection bias resulting from health-related attitudes, neighborhood preferences, or other unmeasured characteristics related to both neighborhood choice and health-related outcomes. We used cohort data from the National Longitudinal Study of Adolescent Health (United States; Wave I, 1994-95; Wave III, 2001-02; n = 12,701) and a time-varying geographic information system. Longitudinal relationships between moderate to vigorous physical activity (MVPA) bouts and built and socioeconomic environment measures (landcover diversity, pay and public physical activity facilities per 10,000 population, street connectivity, median household income, and crime rate) from adolescence to young adulthood were estimated using random effects models (biased by unmeasured confounders) and fixed effects models (within-person estimator, which adjusts for unmeasured confounders that are stable over time). Random effects models yielded null associations except for negative crime-MVPA associations [coefficient (95% CI): -0.056 (-0.083, -0.029) in males, -0.061 (-0.090, -0.033) in females]. After controlling for measured and time invariant unmeasured characteristics using within-person estimators, MVPA was higher with greater physical activity pay facilities in males [coefficient (95% CI): 0.024 (0.006, 0.042)], and lower with higher crime rates in males [coefficient (95% CI): -0.107 (-0.140, -0.075)] and females [coefficient (95% CI): -0.046 (-0.083, -0.009)]. Other associations were null or in the counter-intuitive direction. Comparison of within-person estimates to estimates unadjusted for unmeasured characteristics suggest that residential self-selection can bias associations toward the null, as opposed to its typical characterization as a positive confounder. Differential environment-MVPA associations by residential relocation suggest that studies examining changes following residential relocation may be vulnerable to selection bias. The authors discuss complexities of adjusting for residential self-selection and residential relocation, particularly during the adolescent to young adult transition.
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Correa, Hebelin; Zorro, Pamela; Arevalo-Ferro, Catalina; Puyana, Monica; Duque, Carmenza
2012-09-01
The gorgonian Pseudopterogorgia elisabethae collected at Providencia Island (Colombia) has an unfouled surface, free of obvious algal and invertebrate growth. This gorgonian produces significant amounts of the glycosilated diterpenes pseudopterosins and seco-pseudopterosins (Ps and seco-Ps). Our previous experiments have shown activity of these compounds against eukaryotic (human cancer cell lines and Candida albicans) and prokaryotic cells (Staphylococcus aureus and Enterococcus faecalis). However, the potential role of pseudopterosins on the regulation of the fouling process is still under study. We evaluated the activity of these compounds against bacteria isolated from heavily fouled marine surfaces as an indicator of antifouling activity. Additionally, we assessed their activity against bacteria isolated from P. elisabethae to determine whether potentially they play a role in preventing surface bacterial colonization, thus impairing presumptively the establishment of further successional stages of fouling communities. Results showed that Ps and seco-Ps seem to modulate bacterial growth (controlling Gram-positive bacterial growth and inducing Gram-negative bacterial associations). We thus hypothesized that Ps and seco-Ps may play a role in controlling microbial fouling communities on the surface of this gorgonian. By using bTEFAP and FISH we showed that the most abundant bacteria present in the microbial communities associated with P. elisabethae are Gram-negative bacteria, with Proteobacteria and Gammaproteobacteria the most representative. To evaluate whether Ps and seco-Ps have a direct effect on the structure of the bacterial community associated with P. elisabethae, we tested these compounds against culturable bacteria associated with the surface of P. elisabethae, finding remarkable selectivity against Gram-positive bacteria. The evidence presented here suggests that Ps and seco-Ps might have a role in the selection of organisms associated with the gorgonian surface and in the regulation of the associated bacterial community composition.
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Curcumin Quantum Dots Mediated Degradation of Bacterial Biofilms.
Singh, Ashish K; Prakash, Pradyot; Singh, Ranjana; Nandy, Nabarun; Firdaus, Zeba; Bansal, Monika; Singh, Ranjan K; Srivastava, Anchal; Roy, Jagat K; Mishra, Brahmeshwar; Singh, Rakesh K
2017-01-01
Bacterial biofilm has been reported to be associated with more than 80% of bacterial infections. Curcumin, a hydrophobic polyphenol compound, has anti-quorum sensing activity apart from having antimicrobial action. However, its use is limited by its poor aqueous solubility and rapid degradation. In this study, we attempted to prepare quantum dots of the drug curcumin in order to achieve enhanced solubility and stability and investigated for its antimicrobial and antibiofilm activity. We utilized a newer two-step bottom up wet milling approach to prepare Curcumin Quantum Dots (CurQDs) using acetone as a primary solvent. Minimum inhibitory concentration against select Gram-positive and Gram-negative bacteria was performed. The antibiofilm assay was performed at first using 96-well tissue culture plate and subsequently validated by Confocal Laser Scanning Microscopy. Further, biofilm matrix protein was isolated using formaldehyde sludge and TCA/Acetone precipitation method. Protein extracted was incubated with varying concentration of CurQDs for 4 h and was subjected to SDS-PAGE. Molecular docking study was performed to observe interaction between curcumin and phenol soluble modulins as well as curli proteins. The biophysical evidences obtained from TEM, SEM, UV-VIS, fluorescence, Raman spectroscopy, and zeta potential analysis confirmed the formation of curcumin quantum dots with increased stability and solubility. The MICs of curcumin quantum dots, as observed against both select gram positive and negative bacterial isolates, was observed to be significantly lower than native curcumin particles. On TCP assay, Curcumin observed to be having antibiofilm as well as biofilm degrading activity. Results of SDS-PAGE and molecular docking have shown interaction between biofilm matrix proteins and curcumin. The results indicate that aqueous solubility and stability of Curcumin can be achieved by preparing its quantum dots. The study also demonstrates that by sizing down the particle size has not only enhanced its antimicrobial properties but it has also shown its antibiofilm activities. Further, study is needed to elucidate the exact nature of interaction between curcumin and biofilm matrix proteins.
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Ferreira, Isabel C. F. R.; Barros, Lillian; Carvalho, Ana Maria; Soares, Graça; Henriques, Mariana
2014-01-01
The present work aims to assess the antibacterial potential of phenolic extracts, recovered from plants obtained on the North East of Portugal, and of their phenolic compounds (ellagic, caffeic, and gallic acids, quercetin, kaempferol, and rutin), against bacteria commonly found on skin infections. The disk diffusion and the susceptibility assays were used to identify the most active extracts and phenolic compounds. The effect of selected phenolic compounds on animal cells was assessed by determination of cellular metabolic activity. Gallic acid had a higher activity, against gram-positive (S. epidermidis and S. aureus) and gram-negative bacteria (K. pneumoniae) at lower concentrations, than the other compounds. The caffeic acid, also, showed good antibacterial activity against the 3 bacteria used. The gallic acid was effective against the 3 bacteria without causing harm to the animal cells. Gallic and caffeic acid showed a promising applicability as antibacterial agents for the treatment of infected wounds. PMID:24804249
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Mobin, Lubna; Saeed, Syed Asad; Ali, Rashida; Saeed, Syed Ghufran; Ahmed, Rahil
2017-09-26
Crude seed coat extracts from Abrus precatorius and Caesalpinia crista were purified into four different fractions namely phenolic acids, flavonols, flavanols and anthocyanin which were then examined for their polyphenol contents and antimicrobial potentials. The fractions derived from seed coat of A. precatorius were found more potent with high phenolic and flavonoid contents as compared to C. crista fractions. The significant antibacterial activity was observed against all strain tested by the fractions of both samples apart from anthocyanin fraction. It was interesting to note that the phenolic acid fractions of both samples was found more active against gram-negative bacteria, while gram-positive bacteria were found to be more sensitive towards flavonol fractions. The phenolic acid and flavonol fractions being potent antibacterial were selected to demonstrate the antifungal capacity of two samples. Among them, phenolic acid fraction of both samples was found active towards all the fungal strain.
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Caro, Irma; Mateo, Javier; Sandoval, María H; Soto, Sergio; García-Armesto, María R; Castro, José M
2013-06-01
The aim of this work was to identify and characterize lactobacilli strains from Mexican Oaxaca cheese. Twenty-seven lactobacilli isolated from Oaxaca cheese were identified at species level by 16S rRNA sequencing. Selected isolates were further characterized by ribotyping. Isolates were screened, among others, by acidifying capacity, antibiotic resistance, and activity against pathogens. Lactobacillus plantarum was predominant in Oaxaca cheese. The intraspecies variability of Lb. plantarum isolates was great. Multiple antibiotic resistances were observed. Eight isolates showed antimicrobial activity against the pathogenic species tested. Four Lb. plantarum strains showing low antibiotic resistance index, antimicrobial activity against enterotoxigenic Staphylococcus aureus and Listeria innocua stains, amine-negative decarboxylase activity, and resistance to NaCl and bile salt solutions, could be preselected to complete studies focused on designing a culture for use in pasteurized-milk Oaxaca cheese manufacturing. Copyright © 2013 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.
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Context-specific control and the Stroop negative priming effect.
Milliken, Bruce; Thomson, David R; Bleile, Karmen; MacLellan, Ellen; Giammarco, Maria
2012-01-01
The present study highlights the utility of context-specific learning for different probe types in accounting for the commonly observed dependence of negative priming on probe selection. Using a Stroop priming procedure, Experiments 1a and 1b offered a demonstration that Stroop priming effects can differ qualitatively for selection and no-selection probes when probe selection is manipulated between subjects, but not when it is manipulated randomly from trial to trial within subject (see also Moore, 1994). In Experiments 2 and 3, selection and no-selection probes served as two contexts that varied randomly from trial to trial, but for which proportion repeated was manipulated separately. A context-specific proportion repeated effect was observed in Experiment 2, characterized by modest quantitative shifts in the repetition effects as a function of the context-specific proportion repeated manipulation. However, with a longer intertrial interval in Experiment 3, a context-specific proportion repeated manipulation that focused on the no-selection probes changed the repetition effect qualitatively, from negative priming when the proportion repeated was .25 to positive priming when the proportion repeated was .75. The results are discussed with reference to the role of rapid, context-specific learning processes in the integration of prior experiences with current perception and action.
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Penas, Cristina; Sánchez, Mateo I.; Guerra-Varela, Jorge; Sanchez-Piñón, Laura; Vázquez, M. Eugenio; Mascareñas, José L.
2016-01-01
We have synthesized oligoarginine conjugates of selected DNA-binding agents (a bisbenzamidine, acridine and thiazole orange) and demonstrated that the DNA binding and cell internalization properties of such conjugates can be inhibited by appending a negatively charged oligoglutamic tail through a photolabile linker. Irradiation with UV light releases the parent octaarginine conjugates, thus restoring their cell internalization and biological activity. Preliminary assays using zebrafish embryos demonstrates the potential of this prodrug strategy for controlling in vivo cytotoxicity. PMID:26534774
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Detecting negative selection on recurrent mutations using gene genealogy
2013-01-01
Background Whether or not a mutant allele in a population is under selection is an important issue in population genetics, and various neutrality tests have been invented so far to detect selection. However, detection of negative selection has been notoriously difficult, partly because negatively selected alleles are usually rare in the population and have little impact on either population dynamics or the shape of the gene genealogy. Recently, through studies of genetic disorders and genome-wide analyses, many structural variations were shown to occur recurrently in the population. Such “recurrent mutations” might be revealed as deleterious by exploiting the signal of negative selection in the gene genealogy enhanced by their recurrence. Results Motivated by the above idea, we devised two new test statistics. One is the total number of mutants at a recurrently mutating locus among sampled sequences, which is tested conditionally on the number of forward mutations mapped on the sequence genealogy. The other is the size of the most common class of identical-by-descent mutants in the sample, again tested conditionally on the number of forward mutations mapped on the sequence genealogy. To examine the performance of these two tests, we simulated recurrently mutated loci each flanked by sites with neutral single nucleotide polymorphisms (SNPs), with no recombination. Using neutral recurrent mutations as null models, we attempted to detect deleterious recurrent mutations. Our analyses demonstrated high powers of our new tests under constant population size, as well as their moderate power to detect selection in expanding populations. We also devised a new maximum parsimony algorithm that, given the states of the sampled sequences at a recurrently mutating locus and an incompletely resolved genealogy, enumerates mutation histories with a minimum number of mutations while partially resolving genealogical relationships when necessary. Conclusions With their considerably high powers to detect negative selection, our new neutrality tests may open new venues for dealing with the population genetics of recurrent mutations as well as help identifying some types of genetic disorders that may have escaped identification by currently existing methods. PMID:23651527
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Hu, Jiangyuan; Ferguson, Larissa; Adler, Kerry; Farah, Carole A; Hastings, Margaret H; Sossin, Wayne S; Schacher, Samuel
2017-07-10
Generalization of fear responses to non-threatening stimuli is a feature of anxiety disorders. It has been challenging to target maladaptive generalized memories without affecting adaptive memories. Synapse-specific long-term plasticity underlying memory involves the targeting of plasticity-related proteins (PRPs) to activated synapses. If distinct tags and PRPs are used for different forms of plasticity, one could selectively remove distinct forms of memory. Using a stimulation paradigm in which associative long-term facilitation (LTF) occurs at one input and non-associative LTF at another input to the same postsynaptic neuron in an Aplysia sensorimotor preparation, we found that each form of LTF is reversed by inhibiting distinct isoforms of protein kinase M (PKM), putative PRPs, in the postsynaptic neuron. A dominant-negative (dn) atypical PKM selectively reversed associative LTF, while a dn classical PKM selectively reversed non-associative LTF. Although both PKMs are formed from calpain-mediated cleavage of protein kinase C (PKC) isoforms, each form of LTF is sensitive to a distinct dn calpain expressed in the postsynaptic neuron. Associative LTF is blocked by dn classical calpain, whereas non-associative LTF is blocked by dn small optic lobe (SOL) calpain. Interfering with a putative synaptic tag, the adaptor protein KIBRA, which protects the atypical PKM from degradation, selectively erases associative LTF. Thus, the activity of distinct PRPs and tags in a postsynaptic neuron contribute to the maintenance of different forms of synaptic plasticity at separate inputs, allowing for selective reversal of synaptic plasticity and providing a cellular basis for developing therapeutic strategies for selectively reversing maladaptive memories. Copyright © 2017 Elsevier Ltd. All rights reserved.
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Smith, Evelyn; Rieger, Elizabeth
2010-05-01
The aim of the present study was to investigate the effect of inducing body dissatisfaction on selective attention toward negative shape and weight-related information. A total of 54 female undergraduate university students were randomly allocated to one of three induction conditions: body dissatisfaction, negative mood, and neutral. Subsequently, participants' attentional bias toward negative shape/weight words was measured using a dot probe task. Contrary to the hypotheses, participants in the body dissatisfaction condition did not demonstrate an increase in attention toward negative shape/weight words compared with the negative mood and neutral conditions. Indeed, it was the negative mood induction that resulted in significantly increased attention toward negative shape/weight words relative to the body dissatisfaction condition. The finding that the negative mood (rather than the body dissatisfaction) induction triggered an attentional bias toward shape- and weight-related information is discussed in terms of the anxiety literature given the nature of the mood induction utilized. This finding might help to account for the high comorbidity between eating disorders and anxiety disorders and suggests the possible relevance of attentional training interventions designed for anxiety disorders in the treatment of eating disorders. 2009 by Wiley Periodicals, Inc.
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Attentional biases and memory for emotional stimuli in men and male rhesus monkeys.
Lacreuse, Agnès; Schatz, Kelly; Strazzullo, Sarah; King, Hanna M; Ready, Rebecca
2013-11-01
We examined attentional biases for social and non-social emotional stimuli in young adult men and compared the results to those of male rhesus monkeys (Macaca mulatta) previously tested in a similar dot-probe task (King et al. in Psychoneuroendocrinology 37(3):396-409, 2012). Recognition memory for these stimuli was also analyzed in each species, using a recognition memory task in humans and a delayed non-matching-to-sample task in monkeys. We found that both humans and monkeys displayed a similar pattern of attentional biases toward threatening facial expressions of conspecifics. The bias was significant in monkeys and of marginal significance in humans. In addition, humans, but not monkeys, exhibited an attentional bias away from negative non-social images. Attentional biases for social and non-social threat differed significantly, with both species showing a pattern of vigilance toward negative social images and avoidance of negative non-social images. Positive stimuli did not elicit significant attentional biases for either species. In humans, emotional content facilitated the recognition of non-social images, but no effect of emotion was found for the recognition of social images. Recognition accuracy was not affected by emotion in monkeys, but response times were faster for negative relative to positive images. Altogether, these results suggest shared mechanisms of social attention in humans and monkeys, with both species showing a pattern of selective attention toward threatening faces of conspecifics. These data are consistent with the view that selective vigilance to social threat is the result of evolutionary constraints. Yet, selective attention to threat was weaker in humans than in monkeys, suggesting that regulatory mechanisms enable non-anxious humans to reduce sensitivity to social threat in this paradigm, likely through enhanced prefrontal control and reduced amygdala activation. In addition, the findings emphasize important differences in attentional biases to social versus non-social threat in both species. Differences in the impact of emotional stimuli on recognition memory between monkeys and humans will require further study, as methodological differences in the recognition tasks may have affected the results.
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Cushing, Kevin; Undvall, Eva; Ceder, Yvonne; Lilja, Hans; Laurell, Thomas
2018-02-13
Cancer cells display acoustic properties enabling acoustophoretic separation from white blood cells (WBCs) with 2-3 log suppression of the WBC background. However, a subset of WBCs has overlapping acoustic properties with cancer cells, which is why label-free acoustophoretic cancer cell isolation needs additional purification prior to analysis. This paper reports for the first time a proof of concept for continuous flow acoustophoretic negative selection of WBCs from cancer cells using negative acoustic contrast elastomeric particles (EPs) activated with CD45-antibodies that specifically bind to WBCs. The EP/WBC complexes align at the acoustic pressure anti-nodes along the channel walls while unbound cancer cells focus to the pressure node in the channel center, enabling continuous flow based depletion of WBC background in a cancer cell product. The method does not provide a single process solution for the CTC separation challenge, but provides an elegant part to a multi-step process by further reducing the WBC background in cancer cell separation products derived from an initial step of label-free acoustophoresis. We report the recorded performance of the negative selection immuno-acoustophoretic WBC depletion and cancer cell recovery. To eliminate the negative impact of the separation due to the known problems of aggregation of negative acoustic contrast particles along the sidewalls of the acoustophoresis channel and to enable continuous separation of EP/WBC complexes from cancer cells, a new acoustic actuation method has been implemented where the ultrasound frequency is scanned (1.991MHz ± 100 kHz, scan rate 200 kHz ms -1 ). Using this frequency scanning strategy EP/WBC complexes were acoustophoretically separated from mixtures of WBCs spiked with breast and prostate cancer cells (DU145 and MCF-7). An 86-fold (MCF-7) and 52-fold (DU145) reduction of WBCs in the cancer cell fractions were recorded with separation efficiencies of 98.6% (MCF-7) and 99.7% (DU145) and cancer cell recoveries of 89.8% (MCF-7) and 85.0% (DU145). Copyright © 2017 Elsevier B.V. All rights reserved.
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The Longitudinal Course of Gross Motor Activity in Schizophrenia – Within and between Episodes
Walther, Sebastian; Stegmayer, Katharina; Horn, Helge; Rampa, Luca; Razavi, Nadja; Müller, Thomas J.; Strik, Werner
2015-01-01
Schizophrenia is associated with heterogeneous course of positive and negative symptoms. In addition, reduced motor activity as measured by wrist actigraphy has been reported. However, longitudinal studies of spontaneous motor activity are missing. We aimed to explore whether activity levels were stable within and between psychotic episodes. Furthermore, we investigated the association with the course of negative symptoms. In 45 medicated patients, we investigated motor behavior within a psychotic episode. In addition, we followed 18 medicated patients across 2 episodes. Wrist actigraphy and psychopathological ratings were applied. Within an episode symptoms changed but activity levels did not vary systematically. Activity at baseline predicted the course of negative symptoms. Between two episodes activity recordings were much more stable. Again, activity at the index episode predicted the outcome of negative symptoms. In sum, spontaneous motor activity shares trait and state characteristics, the latter are associated with negative symptom course. Actigraphy may therefore become an important ambulatory instrument to monitor negative symptoms and treatment outcome in schizophrenia. PMID:25698981
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Contact activation: a revision.
Schmaier, A H
1997-07-01
In conclusion, a revised view of the contact system has been presented. This system has little to do with the initiation of hemostasis. Like lupus anticoagulants, deficiencies of contact proteins give prolonged APTTs but may be risk factors for thrombosis. BK from kininogens is a potent modulator of vascular biology inducing vasodilation, tissue plasminogen activator release, and prostacyclin liberation. Kininogens, themselves, are selective inhibitors of alpha-thrombin-induced platelet activation preventing alpha-thrombin from cleaving the cloned thrombin receptor after arginine41. Kininogens' alpha-thrombin inhibitory activity exists in intact kininogens, BK, and all of BK's breakdown products. HK also is the pivotal protein for contact protein assembly on endothelium. It is the receptor for prekallikrein which when bound to HK becomes activated to kallikrein by an endothelial cell enzyme system independent of activated forms of plasma factor XII. Prekallikrein activation on endothelial cells results in kinetically favorable single chain urokinase and plasminogen activation. Thus the "physiologic, negatively charged surface" for contact system activation is really the assembly of these proteins on cell membranes and activation by membrane-associated enzymes.
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Simonov, P V
1997-01-01
At the 23rd International Congress of Physiology Sciences (Tokyo, 1965) the results of experiment led us to the conclusion that emotions were determined by the actual need and estimation of probability (possibility) of its satisfaction. Low probability of need satisfaction leads to negative emotions actively minimized by the subject. Increased probability of satisfaction, as compared to the earlier forecast, generates positive emotions which the subject tries to maximize, that is, to enhance, to prolong, to repeat. We named our concept the Need-Informational Theory of Emotions. According to this theory, motivation, emotion, and estimation of probability have different neuromorphological substrates. Activation through the hypothalamic motivatiogenic structures of the frontal parts of the neocortex orients the behavior to signals with a high probability of their reinforcement. At the same time the hippocampus is necessary for reactions to signals of low probability events, which are typical for the emotionally excited brain. By comparison of motivational excitation with available stimuli or their engrams, the amygdala selects a dominant motivation, destined to be satisfied in the first instance. In the cases of classical conditioning and escape reaction the reinforcement was related to involvement of the negative emotion's hypothalamic neurons, while in the course of avoidance reaction the positive emotion's neurons were involved. The role of the left and right frontal neocortex in the appearance or positive or negative emotions depends on these informational (cognitive) functions.
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[The brain mechanisms of emotions].
Simonov, P V
1997-01-01
At the 23rd International Congress of Physiological Sciences (Tokyo, 1965) the results of experiment brought us to a conclusion that emotions were determined by the actual need and estimation of probability (possibility) of its satisfaction. Low probability of need satisfaction leads to negative emotions actively minimized by the subject. Increased probability of satisfaction, as compared to the earlier forecast, generates positive emotions which the subject tries to maximize, that is to enhance, to prolong, to repeat. We named our concept the Need-Informational Theory of Emotions. According to this theory, motivation, emotion and estimation of probability have different neuromorphological substrate. Activating by motivatiogenic structures of the hypothalamus the frontal parts of neocortex orients the behavior to signals with a high probability of their reinforcement. At the same time the hippocampus is necessary for reactions to signals of low probability events, which is typical for emotionally excited brain. By comparison of motivational excitation with available stimuli or their engrams the amygdala selects a dominant motivation, destined to be satisfied in the first instance. In the cases of classical conditioning and escape reaction the reinforcement was related to involvement of the negative emotion's hypothalamic neurons while in the course of avoidance reaction the positive emotion's neurons being involved. The role of the left and right frontal neocortex in the appearance of positive or negative emotions depends on this informational (cognitive) functions.
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Yennu, Amarnath; Tian, Fenghua; Smith-Osborne, Alexa; J Gatchel, Robert; Woon, Fu Lye; Liu, Hanli
2016-07-25
Studies on posttraumatic stress disorder (PTSD) showing attentional deficits have implicated abnormal activities in the frontal lobe. In this study, we utilized multichannel functional near-infrared spectroscopy (fNIRS) to investigate selective attention-related hemodynamic activity in the prefrontal cortex among 15 combat-exposed war-zone veterans with PTSD and 13 age- and gender-matched healthy controls. While performing the incongruent Stroop task, healthy controls showed significant activations in the left lateral prefrontal cortex (LPFC) compared to baseline readings. This observation is consistent with previously reported results. In comparison, subjects with PTSD failed to activate left LPFC during the same Stroop task. Our observations may implicate that subjects with PTSD experienced difficulty in overcoming Stroop interference. We also observed significant negative correlation between task reaction times and hemodynamic responses from left LPFC during the incongruent Stroop task in the PTSD group. Regarding the methodology used in this study, we have learned that an appropriate design of Stroop paradigms is important for meeting an optimal cognitive load which can lead to better brain image contrasts in response to Stroop interference between healthy versus PTSD subjects. Overall, the feasibility of fNIRS for studying and mapping neural correlates of selective attention and interference in subjects with PTSD is reported.
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Yennu, Amarnath; Tian, Fenghua; Smith-Osborne, Alexa; J. Gatchel, Robert; Woon, Fu Lye; Liu, Hanli
2016-01-01
Studies on posttraumatic stress disorder (PTSD) showing attentional deficits have implicated abnormal activities in the frontal lobe. In this study, we utilized multichannel functional near-infrared spectroscopy (fNIRS) to investigate selective attention-related hemodynamic activity in the prefrontal cortex among 15 combat-exposed war-zone veterans with PTSD and 13 age- and gender-matched healthy controls. While performing the incongruent Stroop task, healthy controls showed significant activations in the left lateral prefrontal cortex (LPFC) compared to baseline readings. This observation is consistent with previously reported results. In comparison, subjects with PTSD failed to activate left LPFC during the same Stroop task. Our observations may implicate that subjects with PTSD experienced difficulty in overcoming Stroop interference. We also observed significant negative correlation between task reaction times and hemodynamic responses from left LPFC during the incongruent Stroop task in the PTSD group. Regarding the methodology used in this study, we have learned that an appropriate design of Stroop paradigms is important for meeting an optimal cognitive load which can lead to better brain image contrasts in response to Stroop interference between healthy versus PTSD subjects. Overall, the feasibility of fNIRS for studying and mapping neural correlates of selective attention and interference in subjects with PTSD is reported. PMID:27452397
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Tamilvanan, Thangaraju; Hopper, Waheeta
2014-01-01
Yersinia pestis, a Gram negative bacillus, spreads via lymphatic to lymph nodes and to all organs through the bloodstream, causing plague. Yersinia outer protein H (YopH) is one of the important effector proteins, which paralyzes lymphocytes and macrophages by dephosphorylating critical tyrosine kinases and signal transduction molecules. The purpose of the study is to generate a three-dimensional (3D) pharmacophore model by using diverse sets of YopH inhibitors, which would be useful for designing of potential antitoxin. In this study, we have selected 60 biologically active inhibitors of YopH to perform Ligand based pharmacophore study to elucidate the important structural features responsible for biological activity. Pharmacophore model demonstrated the importance of two acceptors, one hydrophobic and two aromatic features toward the biological activity. Based on these features, different databases were screened to identify novel compounds and these ligands were subjected for docking, ADME properties and Binding energy prediction. Post docking validation was performed using molecular dynamics simulation for selected ligands to calculate the Root Mean Square Deviation (RMSD) and Root Mean Square Fluctuation (RMSF). The ligands, ASN03270114, Mol_252138, Mol_31073 and ZINC04237078 may act as inhibitors against YopH of Y. pestis.
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Changing investment in activities and interests in elders' lives: theory and measurement.
Adams, Kathryn Betts
2004-01-01
Socioemotional selectivity and gerotranscendence, newer theories with roots in the disengagement theory of aging, provided the theoretical framework for a new measure of perceived change in investment in a variety of pursuits. The 30-item Change in Activity and Interest Index (CAII) was given to a sample of 327 outpatients aged 65-94. Items with at least 30% decreased investment responses included Entertaining in my home, Concern with others' opinions, Shopping and buying things, and Attending social events with new people. Principal Components Analysis of the index with dichotomous recoding (less vs. more or same investment) resulted in four factors: Active Instrumental (AI), Social Intellectual (SI), Spiritual Concerns (SC), and Transcendence (TR). Support for socioemotional selectivity and gerotranscendence is evident in the reported increase of importance of SI pursuits, with concurrent decrease in importance of AI activities among these respondents. Zero-order correlations of component scores with study variables suggest that AI and SI are more clearly related to older age, functional impairment, and negative affect than are SC and TR. The CAII appears to tap several dimensions of change in interests; the index gives geriatric mental health practitioners and researchers a tool to measure an aspect of social development that has been neglected in gerontology.
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NASA Astrophysics Data System (ADS)
Yennu, Amarnath; Tian, Fenghua; Smith-Osborne, Alexa; J. Gatchel, Robert; Woon, Fu Lye; Liu, Hanli
2016-07-01
Studies on posttraumatic stress disorder (PTSD) showing attentional deficits have implicated abnormal activities in the frontal lobe. In this study, we utilized multichannel functional near-infrared spectroscopy (fNIRS) to investigate selective attention-related hemodynamic activity in the prefrontal cortex among 15 combat-exposed war-zone veterans with PTSD and 13 age- and gender-matched healthy controls. While performing the incongruent Stroop task, healthy controls showed significant activations in the left lateral prefrontal cortex (LPFC) compared to baseline readings. This observation is consistent with previously reported results. In comparison, subjects with PTSD failed to activate left LPFC during the same Stroop task. Our observations may implicate that subjects with PTSD experienced difficulty in overcoming Stroop interference. We also observed significant negative correlation between task reaction times and hemodynamic responses from left LPFC during the incongruent Stroop task in the PTSD group. Regarding the methodology used in this study, we have learned that an appropriate design of Stroop paradigms is important for meeting an optimal cognitive load which can lead to better brain image contrasts in response to Stroop interference between healthy versus PTSD subjects. Overall, the feasibility of fNIRS for studying and mapping neural correlates of selective attention and interference in subjects with PTSD is reported.
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Mishra, Biswajit; Leishangthem, Geeta Devi; Gill, Kamaldeep; Singh, Abhay K; Das, Swagata; Singh, Kusum; Xess, Immaculata; Dinda, Amit; Kapil, Arti; Patro, Ishan K; Dey, Sharmistha
2013-02-01
Lactoferrin (LF) is believed to contribute to the host's defense against microbial infections. This work focuses on the antibacterial and antifungal activities of a designed peptide, L10 (WFRKQLKW) by modifying the first eight N-terminal residues of bovine LF by selective homologous substitution of amino acids on the basis of hydrophobicity, L10 has shown potent antibacterial and antifungal properties against clinically isolated extended spectrum beta lactamases (ESBL), producing gram-negative bacteria as well as Candida strains with minimal inhibitory concentrations (MIC) ranging from 1 to 8 μg/mL and 6.5 μg/mL, respectively. The peptide was found to be least hemolytic at a concentration of 800 μg/mL. Interaction with lipopolysaccharide (LPS) and lipid A (LA) suggests that the peptide targets the membrane of gram-negative bacteria. The membrane interactive nature of the peptide, both antibacterial and antifungal, was further confirmed by visual observations employing electron microscopy. Further analyses, by means of propidium iodide based flow cytometry, also supported the membrane permeabilization of Candida cells. The peptide was also found to possess anti-inflammatory properties, by virtue of its ability to inhibit cyclooxygenase-2 (COX-2). L10 therefore emerges as a potential therapeutic remedial solution for infections caused by ESBL positive, gram-negative bacteria and multidrug-resistant (MDR) fungal strains, on account of its multifunctional activities. This study may open up new approach to develop and design novel antimicrobials. Copyright © 2012 Elsevier B.V. All rights reserved.
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Automatic assessment of functional health decline in older adults based on smart home data.
Alberdi Aramendi, Ane; Weakley, Alyssa; Aztiria Goenaga, Asier; Schmitter-Edgecombe, Maureen; Cook, Diane J
2018-05-01
In the context of an aging population, tools to help elderly to live independently must be developed. The goal of this paper is to evaluate the possibility of using unobtrusively collected activity-aware smart home behavioral data to automatically detect one of the most common consequences of aging: functional health decline. After gathering the longitudinal smart home data of 29 older adults for an average of >2 years, we automatically labeled the data with corresponding activity classes and extracted time-series statistics containing 10 behavioral features. Using this data, we created regression models to predict absolute and standardized functional health scores, as well as classification models to detect reliable absolute change and positive and negative fluctuations in everyday functioning. Functional health was assessed every six months by means of the Instrumental Activities of Daily Living-Compensation (IADL-C) scale. Results show that total IADL-C score and subscores can be predicted by means of activity-aware smart home data, as well as a reliable change in these scores. Positive and negative fluctuations in everyday functioning are harder to detect using in-home behavioral data, yet changes in social skills have shown to be predictable. Future work must focus on improving the sensitivity of the presented models and performing an in-depth feature selection to improve overall accuracy. Copyright © 2018 Elsevier Inc. All rights reserved.
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Besserer, Arnaud; Burnotte, Emeline; Bienert, Gerd Patrick; Chevalier, Adrien S.; Errachid, Abdelmounaim; Grefen, Christopher; Blatt, Michael R.; Chaumont, François
2012-01-01
Plasma membrane intrinsic proteins (PIPs) are aquaporins facilitating the diffusion of water through the cell membrane. We previously showed that the traffic of the maize (Zea mays) PIP2;5 to the plasma membrane is dependent on the endoplasmic reticulum diacidic export motif. Here, we report that the post-Golgi traffic and water channel activity of PIP2;5 are regulated by the SNARE (for soluble N-ethylmaleimide-sensitive factor protein attachment protein receptor) SYP121, a plasma membrane resident syntaxin involved in vesicle traffic, signaling, and regulation of K+ channels. We demonstrate that the expression of the dominant-negative SYP121-Sp2 fragment in maize mesophyll protoplasts or epidermal cells leads to a decrease in the delivery of PIP2;5 to the plasma membrane. Protoplast and oocyte swelling assays showed that PIP2;5 water channel activity is negatively affected by SYP121-Sp2. A combination of in vitro (copurification assays) and in vivo (bimolecular fluorescence complementation, Förster resonance energy transfer, and yeast split-ubiquitin) approaches allowed us to demonstrate that SYP121 and PIP2;5 physically interact. Together with previous data demonstrating the role of SYP121 in regulating K+ channel trafficking and activity, these results suggest that SYP121 SNARE contributes to the regulation of the cell osmotic homeostasis. PMID:22942383
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Besserer, Arnaud; Burnotte, Emeline; Bienert, Gerd Patrick; Chevalier, Adrien S; Errachid, Abdelmounaim; Grefen, Christopher; Blatt, Michael R; Chaumont, François
2012-08-01
Plasma membrane intrinsic proteins (PIPs) are aquaporins facilitating the diffusion of water through the cell membrane. We previously showed that the traffic of the maize (Zea mays) PIP2;5 to the plasma membrane is dependent on the endoplasmic reticulum diacidic export motif. Here, we report that the post-Golgi traffic and water channel activity of PIP2;5 are regulated by the SNARE (for soluble N-ethylmaleimide-sensitive factor protein attachment protein receptor) SYP121, a plasma membrane resident syntaxin involved in vesicle traffic, signaling, and regulation of K(+) channels. We demonstrate that the expression of the dominant-negative SYP121-Sp2 fragment in maize mesophyll protoplasts or epidermal cells leads to a decrease in the delivery of PIP2;5 to the plasma membrane. Protoplast and oocyte swelling assays showed that PIP2;5 water channel activity is negatively affected by SYP121-Sp2. A combination of in vitro (copurification assays) and in vivo (bimolecular fluorescence complementation, Förster resonance energy transfer, and yeast split-ubiquitin) approaches allowed us to demonstrate that SYP121 and PIP2;5 physically interact. Together with previous data demonstrating the role of SYP121 in regulating K(+) channel trafficking and activity, these results suggest that SYP121 SNARE contributes to the regulation of the cell osmotic homeostasis.
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Fuentes, Lida Q.; Reyes, Carlos E.; Sarmiento, José M.; Villanueva, Carolina I.; Figueroa, Carlos D.; Navarro, Javier; González, Carlos B.
2008-01-01
Activation of V1a receptor triggers the expression of growth-related immediate-early genes (IEGs), including c-Fos and Egr-1. Here we found that pre-treatment of rat vascular smooth muscle A-10 cell line with the EGF receptor inhibitor AG1478 or the over-expression of an EGFR dominant negative mutant (HEBCD533) blocked the vasopressin-induced expression of IEGs, suggesting that activation of these early genes mediated by V1a receptor is via transactivation of the EGF receptor. Importantly, the inhibition of the metalloproteinases, which catalyzed the shedding of the EGF receptor agonist HB-EGF, selectively blocked the vasopressin-induced expression c-Fos. On the other hand, the inhibition of c-Src selectively blocked the vasopressin-induced expression of Egr-1. Interestingly, in contrast to the expression of c-Fos, the expression of Egr-1 was mediated via the Ras/MEK/MAPK-dependent signalling pathway. Vasopressin-triggered expression of both genes required the release of intracellular calcium, activation of PKC and β-arrestin 2. These findings demonstrated that vasopressin up-regulated the expression of c-Fos and Erg-1 via transactivation of two distinct EGF receptor-dependent signalling pathways. PMID:18571897
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Chen, Wangsheng; Luo, Jing; Qin, Linbo; Han, Jun
2015-12-01
In this paper, the selective autocatalytic reduction of NO by NH3 combined with multi-metal oxides in the hot sintered ore was studied, and the catalytic activity of the hot sintered ore was investigated as a function of temperature, NH3/NO ratio, O2 content, H2O and SO2. The experimental results indicated that the hot sintered ore, when combined with NH3, had a maximum denitration efficiency of 37.67% at 450 °C, 3000 h(-1) gas hourly space velocity (GHSV) and a NH3/NO ratio of 0.4/1. Additionally, it was found that O2 played an important role in removing NOx. However, high O2 content had a negative effect on NO reduction. H2O was found to promote the denitration efficiency in the absence of SO2, while SO2 inhibited the catalytic activity of the sintered ore. In the presence of H2O and SO2, the catalytic activity of the sintered ore was dramatically suppressed. Copyright © 2015 Elsevier Ltd. All rights reserved.
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de Vries-Hospers, H G; Sleijfer, D T; Mulder, N H; van der Waaij, D; Neiweg, H O; van Saene, H K
1981-01-01
We describe the bacteriological results of a controlled clinical trial of selective decontamination of the digestive tract as a method of infection prevention in granulocytopenic patients. Selective elimination of Enterobacteriaceae and Pseudomonadaceae species was accomplished by the oral administration of nalidixic acid, co-trimoxazole, or polymyxin. Yeasts were eliminated selectively by amphotericin B or nystatin treatment. The drugs used in this study were chosen because of their capacities to selectively eliminate gram-negative rods and yeast without affecting the anaerobic part of the gut flora which is responsible for colonization resistance. Compared with the control group, the selectively decontaminated patients had significantly fewer (P less than 0.0005) gram-negative rods or yeasts or both in their throat swab cultures and in their feces. This reduction may explain the clinical effectiveness of selective decontamination. PMID:7027923
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Hirani, Rena; Tohidi-Esfahani, Ibrahim; Mondy, Phillip; Irving, David O
2018-03-01
Supply of cytomegalovirus (CMV)-seronegative blood products in Australia is an ongoing challenge. Requests for CMV-negative products are increasing with prediction that the demand will exceed supply by 2019. Clinical information evaluating how these products are being utilized by health providers within Australia is limited. This study aimed to identify indications for use of CMV-negative blood products and gather data to support possible practice change. All CMV-negative products issued to three tertiary Australian hospitals from May 1, 2016, to May 31, 2016, were identified (n = 1219). This equated to 1044 red blood cell units and 175 platelet units. Data were collected on the fate of each unit. Information collected included the indication and urgency of transfusion, reason for discard, product age, and recipient CMV immunoglobulin G status. Of the units issued during the audit period, 32 (2.6%) were discarded by the hospitals. Transfusion data were collected on 411 units. Of these, 136 (33.1%) were transfused to CMV-positive recipients, in most cases for hematology indications, and 67 units (16.3%) were transfused to CMV-negative requiring recipients. A total of 144 (35%) CMV-negative units were selected based on their irradiation status. Other reasons for the selection of CMV-negative units included product close to expiry (n = 134, 32.6%) or specific patient phenotype requirements (n = 31, 7.5%). In this study, the majority of CMV-negative blood products were not used for CMV-negative requiring recipients. Alterations to inventory management would be advantageous to ensure continued supply for CMV-negative requiring recipients. © 2017 AABB.
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Using Negative Reinforcement to Increase Self-Feeding in a Child with Food Selectivity
ERIC Educational Resources Information Center
Vaz, Petula C. M.; Volkert, Valerie M.; Piazza, Cathleen C.
2011-01-01
We examined the effects of a negative reinforcement-based treatment on the self-feeding of 1 child with food selectivity by type and texture. Self-feeding increased when the child could choose to either self-feed 1 bite of a target food or be fed 1 bite of the target food and 5 bites of another food. Possible mechanisms that underlie the…
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Kernel Extended Real-Valued Negative Selection Algorithm (KERNSA)
2013-06-01
are discarded, which is similar to how T-cells function in the BIS. An unlabeled, future sample is considered non -self if any detectors match it. This...Affinity Performs Best With Each type of Dataset 65 5.1.4 More Kernel Functions . . . . . . . . . . . . . . . . . . . . . . . . 65 5.1.5 Automate the...13 2.5 The Negative Selection Algorithm (NSA). . . . . . . . . . . . . . . . . . . . . 16 2.6 Illustration of self and non -self
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Cut! that’s a wrap: regulating negative emotion by ending emotion-eliciting situations
Vujovic, Lara; Opitz, Philipp C.; Birk, Jeffrey L.; Urry, Heather L.
2014-01-01
Little is known about the potentially powerful set of emotion regulation (ER) processes that target emotion-eliciting situations. We thus studied the decision to end emotion-eliciting situations in the laboratory. We hypothesized that people would try to end negative situations more frequently than neutral situations to regulate distress. In addition, motivated by the selection, optimization, and compensation with ER framework, we hypothesized that failed attempts to end the situation would prompt either (a) greater negative emotion or (b) compensatory use of a different ER process, attentional deployment (AD). Fifty-eight participants (18–26 years old, 67% women) viewed negative and neutral pictures and pressed a key whenever they wished to stop viewing them. After key press, the picture disappeared (“success”) or stayed (“failure”) on screen. To index emotion, we measured corrugator and electrodermal activity, heart rate, and self-reported arousal. To index overt AD, we measured eye gaze. As their reason for ending the situation, participants more frequently reported being upset by high- than low-arousal negative pictures; they more frequently reported being bored by low- than high-arousal neutral pictures. Nevertheless, participants’ negative emotional responding did not increase in the context of ER failure nor did they use overt AD as a compensatory ER strategy. We conclude that situation-targeted ER processes are used to regulate emotional responses to high-arousal negative and low-arousal neutral situations; ER processes other than overt AD may be used to compensate for ER failure in this context. PMID:24592251
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MD-2-mediated Ionic Interactions between Lipid A and TLR4 Are Essential for Receptor Activation*
Meng, Jianmin; Lien, Egil; Golenbock, Douglas T.
2010-01-01
Lipopolysaccharide (LPS) activates innate immune responses through TLR4·MD-2. LPS binds to the MD-2 hydrophobic pocket and bridges the dimerization of two TLR4·MD-2 complexes to activate intracellular signaling. However, exactly how lipid A, the endotoxic moiety of LPS, activates myeloid lineage cells remains unknown. Lipid IVA, a tetra-acylated lipid A precursor, has been used widely as a model for lipid A activation. For unknown reasons, lipid IVA activates proinflammatory responses in rodent cells but inhibits the activity of LPS in human cells. Using stable TLR4-expressing cell lines and purified monomeric MD-2, as well as MD-2-deficient bone marrow-derived macrophages, we found that both mouse TLR4 and mouse MD-2 are required for lipid IVA activation. Computational studies suggested that unique ionic interactions exist between lipid IVA and TLR4 at the dimerization interface in the mouse complex only. The negatively charged 4′-phosphate on lipid IVA interacts with two positively charged residues on the opposing mouse, but not human, TLR4 (Lys367 and Arg434) at the dimerization interface. When replaced with their negatively charged human counterparts Glu369 and Gln436, mouse TLR4 was no longer responsive to lipid IVA. In contrast, human TLR4 gained lipid IVA responsiveness when ionic interactions were enabled by charge reversal at the dimerization interface, defining the basis of lipid IVA species specificity. Thus, using lipid IVA as a selective lipid A agonist, we successfully decoupled and coupled two sequential events required for intracellular signaling: receptor engagement and dimerization, underscoring the functional role of ionic interactions in receptor activation. PMID:20018893
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Running free: embracing a healthy lifestyle through distance running.
Shipway, Richard; Holloway, Immy
2010-11-01
Sport and leisure activity contribute to both health and quality of life. There is a dearth of qualitative studies on the lived experiences of active people, so the aim of this paper is to develop a deeper understanding of the experiences of one particular group of active leisure participants, distance runners, and to highlight the associated health and well-being benefits that result from participating in this increasingly popular form of active leisure. In doing so, this paper will briefly explore the potential opportunities and implications for sport and leisure policy and provision, and highlight examples of how distance running could positively contribute towards government objectives linked to tackling obesity levels, healthy living and physical well-being. It is suggested that similar benefits also exist across other forms of physical activity, exercise and sport. Qualitative methods of enquiry were adopted to understand the nature of the social world of long distance runners through interviews and observations, which were thematically analyzed. One of the key themes emerging from the data was the desire to embrace a healthy lifestyle, which then led to the emergence of four main sub-themes. The first was linked to the importance of seeking self-esteem and confirmation through running; second, an investigation of a selection of negative aspects associated with exercise addiction; third, the need to exercise among sport and leisure participants; and finally, an understanding of the concept of the 'running body'. Cautionary notes also identified negative aspects associated with exercise and physical activity. The findings highlight the potential role that distance running can play as an easily accessible and enjoyable leisure activity, one that can help facilitate increased participation in exercise and physical activity as an integral part of an active and healthy lifestyle.
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Bentin, S; Mouchetant-Rostaing, Y; Giard, M H; Echallier, J F; Pernier, J
1999-05-01
The aim of the present study was to examine the time course and scalp distribution of electrophysiological manifestations of the visual word recognition mechanism. Event-related potentials (ERPs) elicited by visually presented lists of words were recorded while subjects were involved in a series of oddball tasks. The distinction between the designated target and nontarget stimuli was manipulated to induce a different level of processing in each session (visual, phonological/phonetic, phonological/lexical, and semantic). The ERPs of main interest in this study were those elicited by nontarget stimuli. In the visual task the targets were twice as big as the nontargets. Words, pseudowords, strings of consonants, strings of alphanumeric symbols, and strings of forms elicited a sharp negative peak at 170 msec (N170); their distribution was limited to the occipito-temporal sites. For the left hemisphere electrode sites, the N170 was larger for orthographic than for nonorthographic stimuli and vice versa for the right hemisphere. The ERPs elicited by all orthographic stimuli formed a clearly distinct cluster that was different from the ERPs elicited by nonorthographic stimuli. In the phonological/phonetic decision task the targets were words and pseudowords rhyming with the French word vitrail, whereas the nontargets were words, pseudowords, and strings of consonants that did not rhyme with vitrail. The most conspicuous potential was a negative peak at 320 msec, which was similarly elicited by pronounceable stimuli but not by nonpronounceable stimuli. The N320 was bilaterally distributed over the middle temporal lobe and was significantly larger over the left than over the right hemisphere. In the phonological/lexical processing task we compared the ERPs elicited by strings of consonants (among which words were selected), pseudowords (among which words were selected), and by words (among which pseudowords were selected). The most conspicuous potential in these tasks was a negative potential peaking at 350 msec (N350) elicited by phonologically legal but not by phonologically illegal stimuli. The distribution of the N350 was similar to that of the N320, but it was broader and including temporo-parietal areas that were not activated in the "rhyme" task. Finally, in the semantic task the targets were abstract words, and the nontargets were concrete words, pseudowords, and strings of consonants. The negative potential in this task peaked at 450 msec. Unlike the lexical decision, the negative peak in this task significantly distinguished not only between phonologically legal and illegal words but also between meaningful (words) and meaningless (pseudowords) phonologically legal structures. The distribution of the N450 included the areas activated in the lexical decision task but also areas in the fronto-central regions. The present data corroborated the functional neuroanatomy of word recognition systems suggested by other neuroimaging methods and described their timecourse, supporting a cascade-type process that involves different but interconnected neural modules, each responsible for a different level of processing word-related information.
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Signatures of negative selection in the genetic architecture of human complex traits.
Zeng, Jian; de Vlaming, Ronald; Wu, Yang; Robinson, Matthew R; Lloyd-Jones, Luke R; Yengo, Loic; Yap, Chloe X; Xue, Angli; Sidorenko, Julia; McRae, Allan F; Powell, Joseph E; Montgomery, Grant W; Metspalu, Andres; Esko, Tonu; Gibson, Greg; Wray, Naomi R; Visscher, Peter M; Yang, Jian
2018-05-01
We develop a Bayesian mixed linear model that simultaneously estimates single-nucleotide polymorphism (SNP)-based heritability, polygenicity (proportion of SNPs with nonzero effects), and the relationship between SNP effect size and minor allele frequency for complex traits in conventionally unrelated individuals using genome-wide SNP data. We apply the method to 28 complex traits in the UK Biobank data (N = 126,752) and show that on average, 6% of SNPs have nonzero effects, which in total explain 22% of phenotypic variance. We detect significant (P < 0.05/28) signatures of natural selection in the genetic architecture of 23 traits, including reproductive, cardiovascular, and anthropometric traits, as well as educational attainment. The significant estimates of the relationship between effect size and minor allele frequency in complex traits are consistent with a model of negative (or purifying) selection, as confirmed by forward simulation. We conclude that negative selection acts pervasively on the genetic variants associated with human complex traits.