The allocation of attention and working memory in visual crowding.

PubMed

Bacigalupo, Felix; Luck, Steven J

2015-06-01

When the distance between a visual target and nearby flankers falls below a critical distance, target discrimination declines precipitously. This is called "crowding." Many researchers have proposed that selective attention plays a role in crowding. However, although some research has examined the effects of directing attention toward versus away from the targets, no previous research has assessed how attentional allocation varies as a function of target-flanker distance in crowding. Here, we used ERPs to assess the operation of attention during crowding, focusing on the attention-related N2pc component. We used a typical crowding task in which participants were asked to report the category (vowel/consonant) of a lateralized target letter flanked by distractor letters at different distances. We tested the hypothesis that attention fails when the target-flanker distance becomes too small for attention to operate effectively. Consistent with this hypothesis, we found that N2pc amplitude was maximal at intermediate target-flanker distances and decreased substantially when crowding became severe. In addition, we examined the sustained posterior contralateral negativity (SPCN), which reflects the amount of information being maintained in working memory. Unlike the N2pc component, the SPCN increased in amplitude at small target-flanker distances, suggesting that observers stored information about the target and flankers in working memory when attention failed to select the target. Together, the N2pc and SPCN results suggest that attention and working memory play distinctive roles in crowding: Attention operates to minimize interference from the flankers at intermediate target-flanker distances, whereas working memory may be recruited when attention fails to select the target at small target-flanker distances.

Transient analysis mode participation for modal survey target mode selection using MSC/NASTRAN DMAP

NASA Technical Reports Server (NTRS)

Barnett, Alan R.; Ibrahim, Omar M.; Sullivan, Timothy L.; Goodnight, Thomas W.

1994-01-01

Many methods have been developed to aid analysts in identifying component modes which contribute significantly to component responses. These modes, typically targeted for dynamic model correlation via a modal survey, are known as target modes. Most methods used to identify target modes are based on component global dynamic behavior. It is sometimes unclear if these methods identify all modes contributing to responses important to the analyst. These responses are usually those in areas of hardware design concerns. One method used to check the completeness of target mode sets and identify modes contributing significantly to important component responses is mode participation. With this method, the participation of component modes in dynamic responses is quantified. Those modes which have high participation are likely modal survey target modes. Mode participation is most beneficial when it is used with responses from analyses simulating actual flight events. For spacecraft, these responses are generated via a structural dynamic coupled loads analysis. Using MSC/NASTRAN DMAP, a method has been developed for calculating mode participation based on transient coupled loads analysis results. The algorithm has been implemented to be compatible with an existing coupled loads methodology and has been used successfully to develop a set of modal survey target modes.

Emotion-induced blindness reflects competition at early and late processing stages: an ERP study.

PubMed

Kennedy, Briana L; Rawding, Jennifer; Most, Steven B; Hoffman, James E

2014-12-01

Emotion-induced blindness (EIB) refers to impaired awareness of items appearing soon after an irrelevant, emotionally arousing stimulus. Superficially, EIB appears to be similar to the attentional blink (AB), a failure to report a target that closely follows another relevant target. Previous studies of AB using event-related potentials suggest that the AB results from interference with selection (N2 component) and consolidation (P3b component) of the second target into working memory. The present study applied a similar analysis to EIB and, similarly, found that an irrelevant emotional distractor suppressed the N2 and P3b components associated with the following target at short lags. Emotional distractors also elicited a positive deflection that appeared to be similar to the PD component, which has been associated with attempts to suppress salient, irrelevant distractors (Kiss, Grubert, Petersen, & Eimer, 2012; Sawaki, Geng, & Luck, 2012; Sawaki & Luck, 2010). These results suggest that irrelevant emotional pictures gain access to working memory, even when observers are attempting to ignore them and, like the AB, prevent access of a closely following target.

Professional Orchestral Conductors' Use of Selected Teaching Behaviors in Rehearsal

ERIC Educational Resources Information Center

Whitaker, Jennifer A.

2017-01-01

This descriptive study examined professional conductors' use of rehearsal time in sequential pattern components, discussing task presentation targets, and using verbal imagery and modeling techniques. Commercially available videos of 15 professional conductors rehearsing prominent orchestras were scripted, coded, and timed for selected teaching…

Selective processing of multiple features in the human brain: effects of feature type and salience.

PubMed

McGinnis, E Menton; Keil, Andreas

2011-02-09

Identifying targets in a stream of items at a given constant spatial location relies on selection of aspects such as color, shape, or texture. Such attended (target) features of a stimulus elicit a negative-going event-related brain potential (ERP), termed Selection Negativity (SN), which has been used as an index of selective feature processing. In two experiments, participants viewed a series of Gabor patches in which targets were defined as a specific combination of color, orientation, and shape. Distracters were composed of different combinations of color, orientation, and shape of the target stimulus. This design allows comparisons of items with and without specific target features. Consistent with previous ERP research, SN deflections extended between 160-300 ms. Data from the subsequent P3 component (300-450 ms post-stimulus) were also examined, and were regarded as an index of target processing. In Experiment A, predominant effects of target color on SN and P3 amplitudes were found, along with smaller ERP differences in response to variations of orientation and shape. Manipulating color to be less salient while enhancing the saliency of the orientation of the Gabor patch (Experiment B) led to delayed color selection and enhanced orientation selection. Topographical analyses suggested that the location of SN on the scalp reliably varies with the nature of the to-be-attended feature. No interference of non-target features on the SN was observed. These results suggest that target feature selection operates by means of electrocortical facilitation of feature-specific sensory processes, and that selective electrocortical facilitation is more effective when stimulus saliency is heightened.

Target selection biases from recent experience transfer across effectors.

PubMed

Moher, Jeff; Song, Joo-Hyun

2016-02-01

Target selection is often biased by an observer's recent experiences. However, not much is known about whether these selection biases influence behavior across different effectors. For example, does looking at a red object make it easier to subsequently reach towards another red object? In the current study, we asked observers to find the uniquely colored target object on each trial. Randomly intermixed pre-trial cues indicated the mode of action: either an eye movement or a visually guided reach movement to the target. In Experiment 1, we found that priming of popout, reflected in faster responses following repetition of the target color on consecutive trials, occurred regardless of whether the effector was repeated from the previous trial or not. In Experiment 2, we examined whether an inhibitory selection bias away from a feature could transfer across effectors. While priming of popout reflects both enhancement of the repeated target features and suppression of the repeated distractor features, the distractor previewing effect isolates a purely inhibitory component of target selection in which a previewed color is presented in a homogenous display and subsequently inhibited. Much like priming of popout, intertrial suppression biases in the distractor previewing effect transferred across effectors. Together, these results suggest that biases for target selection driven by recent trial history transfer across effectors. This indicates that representations in memory that bias attention towards or away from specific features are largely independent from their associated actions.

The selective processing of emotional visual stimuli while detecting auditory targets: an ERP analysis.

PubMed

Schupp, Harald T; Stockburger, Jessica; Bublatzky, Florian; Junghöfer, Markus; Weike, Almut I; Hamm, Alfons O

2008-09-16

Event-related potential studies revealed an early posterior negativity (EPN) for emotional compared to neutral pictures. Exploring the emotion-attention relationship, a previous study observed that a primary visual discrimination task interfered with the emotional modulation of the EPN component. To specify the locus of interference, the present study assessed the fate of selective visual emotion processing while attention is directed towards the auditory modality. While simply viewing a rapid and continuous stream of pleasant, neutral, and unpleasant pictures in one experimental condition, processing demands of a concurrent auditory target discrimination task were systematically varied in three further experimental conditions. Participants successfully performed the auditory task as revealed by behavioral performance and selected event-related potential components. Replicating previous results, emotional pictures were associated with a larger posterior negativity compared to neutral pictures. Of main interest, increasing demands of the auditory task did not modulate the selective processing of emotional visual stimuli. With regard to the locus of interference, selective emotion processing as indexed by the EPN does not seem to reflect shared processing resources of visual and auditory modality.

Select Components and Finish System Design of a Window Air Conditioner with Propane

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

Shen, Bo; Abdelaziz, Omar

This report describes the technical targets for developing a high efficiency window air conditioner (WAC) using propane (R-290). The baseline unit selected for this activity is a GE R-410A WAC. We established collaboration with a Chinese rotary compressor manufacturer, to select an R-290 compressor. We first modelled and calibrated the WAC system model using R-410A. Next, we applied the calibrated system model to design the R-290 WAC, and decided the strategies to reduce the system charge below 260 grams and achieve the capacity and efficiency targets.

Dissecting patterns of preparatory activity in the frontal eye fields during pursuit target selection.

PubMed

Raghavan, Ramanujan T; Joshua, Mati

2017-10-01

We investigated the composition of preparatory activity of frontal eye field (FEF) neurons in monkeys performing a pursuit target selection task. In response to the orthogonal motion of a large and a small reward target, monkeys initiated pursuit biased toward the direction of large reward target motion. FEF neurons exhibited robust preparatory activity preceding movement initiation in this task. Preparatory activity consisted of two components, ramping activity that was constant across target selection conditions, and a flat offset in firing rates that signaled the target selection condition. Ramping activity accounted for 50% of the variance in the preparatory activity and was linked most strongly, on a trial-by-trial basis, to pursuit eye movement latency rather than to its direction or gain. The offset in firing rates that discriminated target selection conditions accounted for 25% of the variance in the preparatory activity and was commensurate with a winner-take-all representation, signaling the direction of large reward target motion rather than a representation that matched the parameters of the upcoming movement. These offer new insights into the role that the frontal eye fields play in target selection and pursuit control. They show that preparatory activity in the FEF signals more strongly when to move rather than where or how to move and suggest that structures outside the FEF augment its contributions to the target selection process. NEW & NOTEWORTHY We used the smooth eye movement pursuit system to link between patterns of preparatory activity in the frontal eye fields and movement during a target selection task. The dominant pattern was a ramping signal that did not discriminate between selection conditions and was linked, on trial-by-trial basis, to movement latency. A weaker pattern was composed of a constant signal that discriminated between selection conditions but was only weakly linked to the movement parameters. Copyright © 2017 the American Physiological Society.

The Neural Basis of Selective Attention

PubMed Central

Yantis, Steven

2009-01-01

Selective attention is an intrinsic component of perceptual representation in a visual system that is hierarchically organized. Modulatory signals originate in brain regions that represent behavioral goals; these signals specify which perceptual objects are to be represented by sensory neurons that are subject to contextual modulation. Attention can be deployed to spatial locations, features, or objects, and corresponding modulatory signals must be targeted within these domains. Open questions include how nonspatial perceptual domains are modulated by attention and how abstract goals are transformed into targeted modulatory signals. PMID:19444327

Qualitative differences in the guidance of attention during single-color and multiple-color visual search: behavioral and electrophysiological evidence.

PubMed

Grubert, Anna; Eimer, Martin

2013-10-01

To find out whether attentional target selection can be effectively guided by top-down task sets for multiple colors, we measured behavioral and ERP markers of attentional target selection in an experiment where participants had to identify color-defined target digits that were accompanied by a single gray distractor object in the opposite visual field. In the One Color task, target color was constant. In the Two Color task, targets could have one of two equally likely colors. Color-guided target selection was less efficient during multiple-color relative to single-color search, and this was reflected by slower response times and delayed N2pc components. Nontarget-color items that were presented in half of all trials captured attention and gained access to working memory when participants searched for two colors, but were excluded from attentional processing in the One Color task. Results demonstrate qualitative differences in the guidance of attentional target selection between single-color and multiple-color visual search. They suggest that top-down attentional control can be applied much more effectively when it is based on a single feature-specific attentional template. PsycINFO Database Record (c) 2013 APA, all rights reserved.

Identifying Educational Practices Supported by Rigorous Evidence: A Guide to the Selection of Evidence-Based Practices

ERIC Educational Resources Information Center

Regional Resource Center Program, 2014

2014-01-01

One component of the recently required State Systemic Improvement Plan (SSIP) for State Departments of Education calls for the selection and implementation of evidence-based practices (EBPs). This report provides six steps to guide the process of selecting evidence based practices (EBP): (1) Begin with the End in Mind--Determine Targeted Outcomes;…

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.

Age-related differences in the automatic processing of single letters: implications for selective attention.

PubMed

Daffner, Kirk R; Alperin, Brittany R; Mott, Katherine K; Holcomb, Phillip J

2014-01-22

Older adults exhibit diminished ability to inhibit the processing of visual stimuli that are supposed to be ignored. The extent to which age-related changes in early visual processing contribute to impairments in selective attention remains to be determined. Here, 103 adults, 18-85 years of age, completed a color selective attention task in which they were asked to attend to a specified color and respond to designated target letters. An optimal approach would be to initially filter according to color and then process letter forms in the attend color to identify targets. An asymmetric N170 ERP component (larger amplitude over left posterior hemisphere sites) was used as a marker of the early automatic processing of letter forms. Young and middle-aged adults did not generate an asymmetric N170 component. In contrast, young-old and old-old adults produced a larger N170 over the left hemisphere. Furthermore, older adults generated a larger N170 to letter than nonletter stimuli over the left, but not right hemisphere. More asymmetric N170 responses predicted greater allocation of late selection resources to target letters in the ignore color, as indexed by P3b amplitude. These results suggest that unlike their younger counterparts, older adults automatically process stimuli as letters early in the selection process, when it would be more efficient to attend to color only. The inability to ignore letters early in the processing stream helps explain the age-related increase in subsequent processing of target letter forms presented in the ignore color.

Characterization of anti-leukemia components from Indigo naturalis using comprehensive two-dimensional K562/cell membrane chromatography and in silico target identification.

PubMed

Wu, Xunxun; Chen, Xiaofei; Dan, Jia; Cao, Yan; Gao, Shouhong; Guo, Zhiying; Zerbe, Philipp; Chai, Yifeng; Diao, Yong; Zhang, Lei

2016-05-06

Traditional Chinese Medicine (TCM) has been developed for thousands of years and has formed an integrated theoretical system based on a large amount of clinical practice. However, essential ingredients in TCM herbs have not been fully identified, and their precise mechanisms and targets are not elucidated. In this study, a new strategy combining comprehensive two-dimensional K562/cell membrane chromatographic system and in silico target identification was established to characterize active components from Indigo naturalis, a famous TCM herb that has been widely used for the treatment of leukemia in China, and their targets. Three active components, indirubin, tryptanthrin and isorhamnetin, were successfully characterized and their anti-leukemia effects were validated by cell viability and cell apoptosis assays. Isorhamnetin, with undefined cancer related targets, was selected for in silico target identification. Proto-oncogene tyrosine-protein kinase (Src) was identified as its membrane target and the dissociation constant (Kd) between Src and isorhamnetin was 3.81 μM. Furthermore, anti-leukemia effects of isorhamnetin were mediated by Src through inducing G2/M cell cycle arrest. The results demonstrated that the integrated strategy could efficiently characterize active components in TCM and their targets, which may bring a new light for a better understanding of the complex mechanism of herbal medicines.

Characterization of anti-leukemia components from Indigo naturalis using comprehensive two-dimensional K562/cell membrane chromatography and in silico target identification

PubMed Central

Wu, Xunxun; Chen, Xiaofei; Dan, Jia; Cao, Yan; Gao, Shouhong; Guo, Zhiying; Zerbe, Philipp; Chai, Yifeng; Diao, Yong; Zhang, Lei

2016-01-01

Traditional Chinese Medicine (TCM) has been developed for thousands of years and has formed an integrated theoretical system based on a large amount of clinical practice. However, essential ingredients in TCM herbs have not been fully identified, and their precise mechanisms and targets are not elucidated. In this study, a new strategy combining comprehensive two-dimensional K562/cell membrane chromatographic system and in silico target identification was established to characterize active components from Indigo naturalis, a famous TCM herb that has been widely used for the treatment of leukemia in China, and their targets. Three active components, indirubin, tryptanthrin and isorhamnetin, were successfully characterized and their anti-leukemia effects were validated by cell viability and cell apoptosis assays. Isorhamnetin, with undefined cancer related targets, was selected for in silico target identification. Proto-oncogene tyrosine-protein kinase (Src) was identified as its membrane target and the dissociation constant (Kd) between Src and isorhamnetin was 3.81 μM. Furthermore, anti-leukemia effects of isorhamnetin were mediated by Src through inducing G2/M cell cycle arrest. The results demonstrated that the integrated strategy could efficiently characterize active components in TCM and their targets, which may bring a new light for a better understanding of the complex mechanism of herbal medicines. PMID:27150638

Detection of hydroxyapatite in calcified cardiovascular tissues.

PubMed

Lee, Jae Sam; Morrisett, Joel D; Tung, Ching-Hsuan

2012-10-01

The objective of this study is to develop a method for selective detection of the calcific (hydroxyapatite) component in human aortic smooth muscle cells in vitro and in calcified cardiovascular tissues ex vivo. This method uses a novel optical molecular imaging contrast dye, Cy-HABP-19, to target calcified cells and tissues. A peptide that mimics the binding affinity of osteocalcin was used to label hydroxyapatite in vitro and ex vivo. Morphological changes in vascular smooth muscle cells were evaluated at an early stage of the mineralization process induced by extrinsic stimuli, osteogenic factors and a magnetic suspension cell culture. Hydroxyapatite components were detected in monolayers of these cells in the presence of osteogenic factors and a magnetic suspension environment. Atherosclerotic plaque contains multiple components including lipidic, fibrotic, thrombotic, and calcific materials. Using optical imaging and the Cy-HABP-19 molecular imaging probe, we demonstrated that hydroxyapatite components could be selectively distinguished from various calcium salts in human aortic smooth muscle cells in vitro and in calcified cardiovascular tissues, carotid endarterectomy samples and aortic valves, ex vivo. Hydroxyapatite deposits in cardiovascular tissues were selectively detected in the early stage of the calcification process using our Cy-HABP-19 probe. This new probe makes it possible to study the earliest events associated with vascular hydroxyapatite deposition at the cellular and molecular levels. This target-selective molecular imaging probe approach holds high potential for revealing early pathophysiological changes, leading to progression, regression, or stabilization of cardiovascular diseases. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Detection of Hydroxyapatite in Calcified Cardiovascular Tissues

PubMed Central

Lee, Jae Sam; Morrisett, Joel D.; Tung, Ching-Hsuan

2012-01-01

Objective The objective of this study is to develop a method for selective detection of the calcific (hydroxyapatite) component in human aortic smooth muscle cells in vitro and in calcified cardiovascular tissues ex vivo. This method uses a novel optical molecular imaging contrast dye, Cy-HABP-19, to target calcified cells and tissues. Methods A peptide that mimics the binding affinity of osteocalcin was used to label hydroxyapatite in vitro and ex vivo. Morphological changes in vascular smooth muscle cells were evaluated at an early stage of the mineralization process induced by extrinsic stimuli, osteogenic factors and a magnetic suspension cell culture. Hydroxyapatite components were detected in monolayers of these cells in the presence of osteogenic factors and a magnetic suspension environment. Results Atherosclerotic plaque contains multiple components including lipidic, fibrotic, thrombotic, and calcific materials. Using optical imaging and the Cy-HABP-19 molecular imaging probe, we demonstrated that hydroxyapatite components could be selectively distinguished from various calcium salts in human aortic smooth muscle cells in vitro and in calcified cardiovascular tissues, carotid endarterectomy samples and aortic valves, ex vivo. Conclusion Hydroxyapatite deposits in cardiovascular tissues were selectively detected in the early stage of the calcification process using our Cy-HABP-19 probe. This new probe makes it possible to study the earliest events associated with vascular hydroxyapatite deposition at the cellular and molecular levels. This target-selective molecular imaging probe approach holds high potential for revealing early pathophysiological changes, leading to progression, regression, or stabilization of cardiovascular diseases. PMID:22877867

Auditory selective attention in adolescents with major depression: An event-related potential study.

PubMed

Greimel, E; Trinkl, M; Bartling, J; Bakos, S; Grossheinrich, N; Schulte-Körne, G

2015-02-01

Major depression (MD) is associated with deficits in selective attention. Previous studies in adults with MD using event-related potentials (ERPs) reported abnormalities in the neurophysiological correlates of auditory selective attention. However, it is yet unclear whether these findings can be generalized to MD in adolescence. Thus, the aim of the present ERP study was to explore the neural mechanisms of auditory selective attention in adolescents with MD. 24 male and female unmedicated adolescents with MD and 21 control subjects were included in the study. ERPs were collected during an auditory oddball paradigm. Depressive adolescents tended to show a longer N100 latency to target and non-target tones. Moreover, MD subjects showed a prolonged latency of the P200 component to targets. Across groups, longer P200 latency was associated with a decreased tendency of disinhibited behavior as assessed by a behavioral questionnaire. To be able to draw more precise conclusions about differences between the neural bases of selective attention in adolescents vs. adults with MD, future studies should include both age groups and apply the same experimental setting across all subjects. The study provides strong support for abnormalities in the neurophysiolgical bases of selective attention in adolecents with MD at early stages of auditory information processing. Absent group differences in later ERP components reflecting voluntary attentional processes stand in contrast to results reported in adults with MD and may suggest that adolescents with MD possess mechanisms to compensate for abnormalities in the early stages of selective attention. Copyright © 2014 Elsevier B.V. All rights reserved.

Genetically engineered and self-assembled oncolytic protein nanoparticles for targeted cancer therapy.

PubMed

Lee, Joong-Jae; Kang, Jung Ae; Ryu, Yiseul; Han, Sang-Soo; Nam, You Ree; Rho, Jong Kook; Choi, Dae Seong; Kang, Sun-Woong; Lee, Dong-Eun; Kim, Hak-Sung

2017-03-01

The integration of a targeted delivery with a tumour-selective agent has been considered an ideal platform for achieving high therapeutic efficacy and negligible side effects in cancer therapy. Here, we present engineered protein nanoparticles comprising a tumour-selective oncolytic protein and a targeting moiety as a new format for the targeted cancer therapy. Apoptin from chicken anaemia virus (CAV) was used as a tumour-selective apoptotic protein. An EGFR-specific repebody, which is composed of LRR (Leucine-rich repeat) modules, was employed to play a dual role as a tumour-targeting moiety and a fusion partner for producing apoptin nanoparticles in E. coli, respectively. The repebody was genetically fused to apoptin, and the resulting fusion protein was shown to self-assemble into supramolecular repebody-apoptin nanoparticles with high homogeneity and stability as a soluble form when expressed in E. coli. The repebody-apoptin nanoparticles showed a remarkable anti-tumour activity with negligible side effects in xenograft mice through a cooperative action of the two protein components with distinct functional roles. The repebody-apoptin nanoparticles can be developed as a systemic injectable and tumour-selective therapeutic protein for targeted cancer treatment. Copyright © 2016 Elsevier Ltd. All rights reserved.

Testing the concept of a modulation filter bank: the audibility of component modulation and detection of phase change in three-component modulators.

PubMed

Sek, Aleksander; Moore, Brian C J

2003-05-01

Two experiments were performed to test the concept that the auditory system contains a "modulation filter bank" (MFB). Experiment 1 examined the ability to "hear out" the modulation frequency of the central component of a three-component modulator applied to a 4-kHz sinusoidal carrier. On each trial, three modulated stimuli were presented. The modulator of the first stimulus contained three components. Within a run the frequencies of the outer two components were fixed and the frequency of the central ("target") component was drawn randomly from one of five values. The modulators of second and third stimuli contained one component. One had a frequency equal to that of the target and the other had a frequency randomly selected from one of the other possible values. Subjects indicated whether the target corresponded to the second or third stimulus. Scores were around 80% correct when the components in the three-component modulator were widely spaced and when the frequencies of the target and comparison differed sufficiently. Experiment 2 examined the ability to hear a change in the relative phase of the components in a three-component modulator with harmonically spaced components, using a 31FC task. The frequency of the central component, f(c), was either 50 or 100 Hz. Scores were 80%-90% correct when the component spacing was < or = 0.5 f(c), but decreased markedly for greater spacings. Performance was only slightly impaired by randomizing the overall modulation depth from one stimulus to the next. The results of both experiments are broadly consistent with what would be expected from a MFB with a Q value of 1 or slightly less.

Improved targeted immunization strategies based on two rounds of selection

NASA Astrophysics Data System (ADS)

Xia, Ling-Ling; Song, Yu-Rong; Li, Chan-Chan; Jiang, Guo-Ping

2018-04-01

In the case of high degree targeted immunization where the number of vaccine is limited, when more than one node associated with the same degree meets the requirement of high degree centrality, how can we choose a certain number of nodes from those nodes, so that the number of immunized nodes will not exceed the limit? In this paper, we introduce a new idea derived from the selection process of second-round exam to solve this problem and then propose three improved targeted immunization strategies. In these proposed strategies, the immunized nodes are selected through two rounds of selection, where we increase the quotas of first-round selection according the evaluation criterion of degree centrality and then consider another characteristic parameter of node, such as node's clustering coefficient, betweenness and closeness, to help choose targeted nodes in the second-round selection. To validate the effectiveness of the proposed strategies, we compare them with the degree immunizations including the high degree targeted and the high degree adaptive immunizations using two metrics: the size of the largest connected component of immunized network and the number of infected nodes. Simulation results demonstrate that the proposed strategies based on two rounds of sorting are effective for heterogeneous networks and their immunization effects are better than that of the degree immunizations.

Target Selection by the Frontal Cortex during Coordinated Saccadic and Smooth Pursuit Eye Movements

ERIC Educational Resources Information Center

Srihasam, Krishna; Bullock, Daniel; Grossberg, Stephen

2009-01-01

Oculomotor tracking of moving objects is an important component of visually based cognition and planning. Such tracking is achieved by a combination of saccades and smooth-pursuit eye movements. In particular, the saccadic and smooth-pursuit systems interact to often choose the same target, and to maximize its visibility through time. How do…

Functional Dissociation of Latency-Variable, Stimulus- and Response-Locked Target P3 Sub-components in Task-Switching.

PubMed

Brydges, Christopher R; Barceló, Francisco

2018-01-01

Cognitive control warrants efficient task performance in dynamic and changing environments through adjustments in executive attention, stimulus and response selection. The well-known P300 component of the human event-related potential (ERP) has long been proposed to index "context-updating"-critical for cognitive control-in simple target detection tasks. However, task switching ERP studies have revealed both target P3 (300-350 ms) and later sustained P3-like potentials (400-1,200 ms) to first targets ensuing transition cues, although it remains unclear whether these target P3-like potentials also reflect context updating operations. To address this question, we applied novel single-trial EEG analyses-residue iteration decomposition (RIDE)-in order to disentangle target P3 sub-components in a sample of 22 young adults while they either repeated or switched (updated) task rules. The rationale was to revise the context updating hypothesis of P300 elicitation in the light of new evidence suggesting that "the context" consists of not only the sensory units of stimulation, but also associated motor units, and intermediate low- and high-order sensorimotor units, all of which may need to be dynamically updated on a trial by trial basis. The results showed functionally distinct target P3-like potentials in stimulus-locked, response-locked, and intermediate RIDE component clusters overlying parietal and frontal regions, implying multiple functionally distinct, though temporarily overlapping context updating operations. These findings support a reformulated version of the context updating hypothesis, and reveal a rich family of distinct target P3-like sub-components during the reactive control of target detection in task-switching, plausibly indexing the complex and dynamic workings of frontoparietal cortical networks subserving cognitive control.

Functional Dissociation of Latency-Variable, Stimulus- and Response-Locked Target P3 Sub-components in Task-Switching

PubMed Central

Brydges, Christopher R.; Barceló, Francisco

2018-01-01

Cognitive control warrants efficient task performance in dynamic and changing environments through adjustments in executive attention, stimulus and response selection. The well-known P300 component of the human event-related potential (ERP) has long been proposed to index “context-updating”—critical for cognitive control—in simple target detection tasks. However, task switching ERP studies have revealed both target P3 (300–350 ms) and later sustained P3-like potentials (400–1,200 ms) to first targets ensuing transition cues, although it remains unclear whether these target P3-like potentials also reflect context updating operations. To address this question, we applied novel single-trial EEG analyses—residue iteration decomposition (RIDE)—in order to disentangle target P3 sub-components in a sample of 22 young adults while they either repeated or switched (updated) task rules. The rationale was to revise the context updating hypothesis of P300 elicitation in the light of new evidence suggesting that “the context” consists of not only the sensory units of stimulation, but also associated motor units, and intermediate low- and high-order sensorimotor units, all of which may need to be dynamically updated on a trial by trial basis. The results showed functionally distinct target P3-like potentials in stimulus-locked, response-locked, and intermediate RIDE component clusters overlying parietal and frontal regions, implying multiple functionally distinct, though temporarily overlapping context updating operations. These findings support a reformulated version of the context updating hypothesis, and reveal a rich family of distinct target P3-like sub-components during the reactive control of target detection in task-switching, plausibly indexing the complex and dynamic workings of frontoparietal cortical networks subserving cognitive control. PMID:29515383

Preferential Enhancement of Sensory and Motor Axon Regeneration by Combining Extracellular Matrix Components with Neurotrophic Factors

PubMed Central

Santos, Daniel; González-Pérez, Francisco; Giudetti, Guido; Micera, Silvestro; Udina, Esther; Del Valle, Jaume; Navarro, Xavier

2016-01-01

After peripheral nerve injury, motor and sensory axons are able to regenerate but inaccuracy of target reinnervation leads to poor functional recovery. Extracellular matrix (ECM) components and neurotrophic factors (NTFs) exert their effect on different neuronal populations creating a suitable environment to promote axonal growth. Here, we assessed in vitro and in vivo the selective effects of combining different ECM components with NTFs on motor and sensory axons regeneration and target reinnervation. Organotypic cultures with collagen, laminin and nerve growth factor (NGF)/neurotrophin-3 (NT3) or collagen, fibronectin and brain-derived neurotrophic factor (BDNF) selectively enhanced sensory neurite outgrowth of DRG neurons and motor neurite outgrowth from spinal cord slices respectively. For in vivo studies, the rat sciatic nerve was transected and repaired with a silicone tube filled with a collagen and laminin matrix with NGF/NT3 encapsulated in poly(lactic-co-glycolic acid) (PLGA) microspheres (MP) (LM + MP.NGF/NT3), or a collagen and fibronectin matrix with BDNF in PLGA MPs (FN + MP.BDNF). Retrograde labeling and functional tests showed that LM + MP.NGF/NT3 increased the number of regenerated sensory neurons and improved sensory functional recovery, whereas FN + MP.BDNF preferentially increased regenerated motoneurons and enhanced motor functional recovery. Therefore, combination of ECM molecules with NTFs may be a good approach to selectively enhance motor and sensory axons regeneration and promote appropriate target reinnervation. PMID:28036084

Laser selective microablation of sensitized intracellular components within auditory receptor cells

NASA Astrophysics Data System (ADS)

Harris, David M.; Evans, Burt N.; Santos-Sacchi, Joseph

1995-05-01

A laser system can be coupled to a light microscope for laser microbeam ablation and trapping of single cells in vitro. We have extended this technology by sensitization of target structures with vital dyes to provide selective ablation of specific subcellular components. Isolated auditory receptor cells (outer hair cells, OHCs) are known to elongate and contract in response to electrical, chemical and mechanical stimulation. Various intracellular structures are candidate components mediating motility of OHCs, but the exact mechanism(s) is currently unknown. In ongoing studies of OHC motility, we have used the microbeam for selective ablation of lateral wall components and of an axial cytoskeletal core that extends from the nucleus to the cell apex. Both the area beneath the subsurface cistemae of the lateral wall and the core are rich in mitochondria. OHCs isolated from guinea pig cochlea are suspended in L- 15 medium containing 2.0 (mu) M Rhodamine 123, a porphyrin with an affinity for mitochondria. A spark-pumped nitrogen laser pumping a dye cell (Coumarin 500) was aligned on the optical axis of a Nikon Optiphot-2 to produce a 3 ns, 0.5 - 10 micrometers spot (diameter above ablation threshold w/50X water immersion, N.A. 0.8), and energy at the target approximately equals 10 (mu) J/pulse. At short incubation times in Rh123 irradiation caused local blebbing or bulging of cytoplastic membrane and thus loss of the OHC's cylindrical shape. At longer Rh123 incubation times when the central axis of the cell was targeted we observed cytoplasmic clearing, immediate cell elongation (approximately equals 5%) and clumping of core material at nuclear and apical attachments. Experiments are underway to examine the significance of these preliminary observations.

Development of qualitative and quantitative analysis methods in pharmaceutical application with new selective signal excitation methods for 13 C solid-state nuclear magnetic resonance using 1 H T1rho relaxation time.

PubMed

Nasu, Mamiko; Nemoto, Takayuki; Mimura, Hisashi; Sako, Kazuhiro

2013-01-01

Most pharmaceutical drug substances and excipients in formulations exist in a crystalline or amorphous form, and an understanding of their state during manufacture and storage is critically important, particularly in formulated products. Carbon 13 solid-state nuclear magnetic resonance (NMR) spectroscopy is useful for studying the chemical and physical state of pharmaceutical solids in a formulated product. We developed two new selective signal excitation methods in (13) C solid-state NMR to extract the spectrum of a target component from such a mixture. These methods were based on equalization of the proton relaxation time in a single domain via rapid intraproton spin diffusion and the difference in proton spin-lattice relaxation time in the rotating frame ((1) H T1rho) of individual components in the mixture. Introduction of simple pulse sequences to one-dimensional experiments reduced data acquisition time and increased flexibility. We then demonstrated these methods in a commercially available drug and in a mixture of two saccharides, in which the (13) C signals of the target components were selectively excited, and showed them to be applicable to the quantitative analysis of individual components in solid mixtures, such as formulated products, polymorphic mixtures, or mixtures of crystalline and amorphous phases. Copyright © 2012 Wiley Periodicals, Inc.

Electrophysiological revelations of trial history effects in a color oddball search task.

PubMed

Shin, Eunsam; Chong, Sang Chul

2016-12-01

In visual oddball search tasks, viewing a no-target scene (i.e., no-target selection trial) leads to the facilitation or delay of the search time for a target in a subsequent trial. Presumably, this selection failure leads to biasing attentional set and prioritizing stimulus features unseen in the no-target scene. We observed attention-related ERP components and tracked the course of attentional biasing as a function of trial history. Participants were instructed to identify color oddballs (i.e., targets) shown in varied trial sequences. The number of no-target scenes preceding a target scene was increased from zero to two to reinforce attentional biasing, and colors presented in two successive no-target scenes were repeated or changed to systematically bias attention to specific colors. For the no-target scenes, the presentation of a second no-target scene resulted in an early selection of, and sustained attention to, the changed colors (mirrored in the frontal selection positivity, the anterior N2, and the P3b). For the target scenes, the N2pc indicated an earlier allocation of attention to the targets with unseen or remotely seen colors. Inhibitory control of attention, shown in the anterior N2, was greatest when the target scene was followed by repeated no-target scenes with repeated colors. Finally, search times and the P3b were influenced by both color previewing and its history. The current results demonstrate that attentional biasing can occur on a trial-by-trial basis and be influenced by both feature previewing and its history. © 2016 Society for Psychophysiological Research.

Managing Longleaf Pine Under The Selection System - Promises and Problems

Treesearch

Robert M. Farrar; William D. Boyer

1991-01-01

Abstract.Six- and ten-year results are reported on group-selection management of two small tracts of longleaf pine (Pinus palustris) in south Alabama. One stand is managed via volume control in the sawtimber component, the other is managed via a structure target, and both are prescription burned on a 3-year cycle. Information is...

Searching for the bull's eye: agents and targets of selection vary among geographically disparate cyanogenesis clines in white clover (Trifolium repens L.)

PubMed Central

Kooyers, N J; Olsen, K M

2013-01-01

The recurrent evolution of adaptive clines within a species can be used to elucidate the selective factors and genetic responses that underlie adaptation. White clover is polymorphic for cyanogenesis (HCN release with tissue damage), and climate-associated cyanogenesis clines have evolved throughout the native and introduced species range. This polymorphism arises through two independently segregating Mendelian polymorphisms for the presence/absence of two required components: cyanogenic glucosides and their hydrolyzing enzyme linamarase. Cyanogenesis is commonly thought to function in herbivore defense; however, the individual cyanogenic components may also serve other physiological functions. To test whether cyanogenesis clines have evolved in response to the same selective pressures acting on the same genetic targets, we examined cyanogenesis cline shape and its environmental correlates in three world regions: southern New Zealand, the central United States and the US Pacific Northwest. For some regional comparisons, cline shapes are remarkably similar despite large differences in the spatial scales over which clines occur (40–1600 km). However, we also find evidence for major differences in both the agents and targets of selection among the sampled clines. Variation in cyanogenesis frequency is best predicted using a combination of minimum winter temperature and aridity variables. Together, our results provide evidence that recurrent adaptive clines do not necessarily reflect shared adaptive processes. PMID:23900395

Masking reduces orientation selectivity in rat visual cortex

PubMed Central

Alwis, Dasuni S.; Richards, Katrina L.

2016-01-01

In visual masking the perception of a target stimulus is impaired by a preceding (forward) or succeeding (backward) mask stimulus. The illusion is of interest because it allows uncoupling of the physical stimulus, its neuronal representation, and its perception. To understand the neuronal correlates of masking, we examined how masks affected the neuronal responses to oriented target stimuli in the primary visual cortex (V1) of anesthetized rats (n = 37). Target stimuli were circular gratings with 12 orientations; mask stimuli were plaids created as a binarized sum of all possible target orientations. Spatially, masks were presented either overlapping or surrounding the target. Temporally, targets and masks were presented for 33 ms, but the stimulus onset asynchrony (SOA) of their relative appearance was varied. For the first time, we examine how spatially overlapping and center-surround masking affect orientation discriminability (rather than visibility) in V1. Regardless of the spatial or temporal arrangement of stimuli, the greatest reductions in firing rate and orientation selectivity occurred for the shortest SOAs. Interestingly, analyses conducted separately for transient and sustained target response components showed that changes in orientation selectivity do not always coincide with changes in firing rate. Given the near-instantaneous reductions observed in orientation selectivity even when target and mask do not spatially overlap, we suggest that monotonic visual masking is explained by a combination of neural integration and lateral inhibition. PMID:27535373

Improvements to the ShipIR/NTCS adaptive track gate algorithm and 3D flare particle model

NASA Astrophysics Data System (ADS)

Ramaswamy, Srinivasan; Vaitekunas, David A.; Gunter, Willem H.; February, Faith J.

2017-05-01

A key component in any image-based tracking system is the adaptive tracking algorithm used to segment the image into potential targets, rank-and-select the best candidate target, and gate the selected target to further improve tracker performance. Similarly, a key component in any soft-kill response to an incoming guided missile is the flare/chaff decoy used to distract or seduce the seeker homing system away from the naval platform. This paper describes the recent improvements to the naval threat countermeasure simulator (NTCS) of the NATO-standard ship signature model (ShipIR). Efforts to analyse and match the 3D flare particle model against actual IR measurements of the Chemring TALOS IR round resulted in further refinement of the 3D flare particle distribution. The changes in the flare model characteristics were significant enough to require an overhaul to the adaptive track gate (ATG) algorithm in the way it detects the presence of flare decoys and reacquires the target after flare separation. A series of test scenarios are used to demonstrate the impact of the new flare and ATG on IR tactics simulation.

Alterations to multisensory and unisensory integration by stimulus competition

PubMed Central

Rowland, Benjamin A.; Stanford, Terrence R.; Stein, Barry E.

2011-01-01

In environments containing sensory events at competing locations, selecting a target for orienting requires prioritization of stimulus values. Although the superior colliculus (SC) is causally linked to the stimulus selection process, the manner in which SC multisensory integration operates in a competitive stimulus environment is unknown. Here we examined how the activity of visual-auditory SC neurons is affected by placement of a competing target in the opposite hemifield, a stimulus configuration that would, in principle, promote interhemispheric competition for access to downstream motor circuitry. Competitive interactions between the targets were evident in how they altered unisensory and multisensory responses of individual neurons. Responses elicited by a cross-modal stimulus (multisensory responses) proved to be substantially more resistant to competitor-induced depression than were unisensory responses (evoked by the component modality-specific stimuli). Similarly, when a cross-modal stimulus served as the competitor, it exerted considerably more depression than did its individual component stimuli, in some cases producing more depression than predicted by their linear sum. These findings suggest that multisensory integration can help resolve competition among multiple targets by enhancing orientation to the location of cross-modal events while simultaneously suppressing orientation to events at alternate locations. PMID:21957224

Alterations to multisensory and unisensory integration by stimulus competition.

PubMed

Pluta, Scott R; Rowland, Benjamin A; Stanford, Terrence R; Stein, Barry E

2011-12-01

In environments containing sensory events at competing locations, selecting a target for orienting requires prioritization of stimulus values. Although the superior colliculus (SC) is causally linked to the stimulus selection process, the manner in which SC multisensory integration operates in a competitive stimulus environment is unknown. Here we examined how the activity of visual-auditory SC neurons is affected by placement of a competing target in the opposite hemifield, a stimulus configuration that would, in principle, promote interhemispheric competition for access to downstream motor circuitry. Competitive interactions between the targets were evident in how they altered unisensory and multisensory responses of individual neurons. Responses elicited by a cross-modal stimulus (multisensory responses) proved to be substantially more resistant to competitor-induced depression than were unisensory responses (evoked by the component modality-specific stimuli). Similarly, when a cross-modal stimulus served as the competitor, it exerted considerably more depression than did its individual component stimuli, in some cases producing more depression than predicted by their linear sum. These findings suggest that multisensory integration can help resolve competition among multiple targets by enhancing orientation to the location of cross-modal events while simultaneously suppressing orientation to events at alternate locations.

Antibody Drug Conjugates: Application of Quantitative Pharmacology in Modality Design and Target Selection.

PubMed

Sadekar, S; Figueroa, I; Tabrizi, M

2015-07-01

Antibody drug conjugates (ADCs) are a multi-component modality comprising of an antibody targeting a cell-specific antigen, a potent drug/payload, and a linker that can be processed within cellular compartments to release payload upon internalization. Numerous ADCs are being evaluated in both research and clinical settings within the academic and pharmaceutical industry due to their ability to selectively deliver potent payloads. Hence, there is a clear need to incorporate quantitative approaches during early stages of drug development for effective modality design and target selection. In this review, we describe a quantitative approach and framework for evaluation of the interplay between drug- and systems-dependent properties (i.e., target expression, density, localization, turnover, and affinity) in order to deliver a sufficient amount of a potent payload into the relevant target cells. As discussed, theoretical approaches with particular considerations given to various key properties for the target and modality suggest that delivery of the payload into particular effect cells to be more sensitive to antigen concentrations for targets with slow turnover rates as compared to those with faster internalization rates. Further assessments also suggest that increasing doses beyond the threshold of the target capacity (a function of target internalization and expression) may not impact the maximum amount of payload delivered to the intended effect cells. This article will explore the important application of quantitative sciences in selection of the target and design of ADC modalities.

Determination of target detection limits in hyperspectral data using band selection and dimensionality reduction

NASA Astrophysics Data System (ADS)

Gross, W.; Boehler, J.; Twizer, K.; Kedem, B.; Lenz, A.; Kneubuehler, M.; Wellig, P.; Oechslin, R.; Schilling, H.; Rotman, S.; Middelmann, W.

2016-10-01

Hyperspectral remote sensing data can be used for civil and military applications to robustly detect and classify target objects. High spectral resolution of hyperspectral data can compensate for the comparatively low spatial resolution, which allows for detection and classification of small targets, even below image resolution. Hyperspectral data sets are prone to considerable spectral redundancy, affecting and limiting data processing and algorithm performance. As a consequence, data reduction strategies become increasingly important, especially in view of near-real-time data analysis. The goal of this paper is to analyze different strategies for hyperspectral band selection algorithms and their effect on subpixel classification for different target and background materials. Airborne hyperspectral data is used in combination with linear target simulation procedures to create a representative amount of target-to-background ratios for evaluation of detection limits. Data from two different airborne hyperspectral sensors, AISA Eagle and Hawk, are used to evaluate transferability of band selection when using different sensors. The same target objects were recorded to compare the calculated detection limits. To determine subpixel classification results, pure pixels from the target materials are extracted and used to simulate mixed pixels with selected background materials. Target signatures are linearly combined with different background materials in varying ratios. The commonly used classification algorithms Adaptive Coherence Estimator (ACE) is used to compare the detection limit for the original data with several band selection and data reduction strategies. The evaluation of the classification results is done by assuming a fixed false alarm ratio and calculating the mean target-to-background ratio of correctly detected pixels. The results allow drawing conclusions about specific band combinations for certain target and background combinations. Additionally, generally useful wavelength ranges are determined and the optimal amount of principal components is analyzed.

Category-based attentional guidance can operate in parallel for multiple target objects.

PubMed

Jenkins, Michael; Grubert, Anna; Eimer, Martin

2018-05-01

The question whether the control of attention during visual search is always feature-based or can also be based on the category of objects remains unresolved. Here, we employed the N2pc component as an on-line marker for target selection processes to compare the efficiency of feature-based and category-based attentional guidance. Two successive displays containing pairs of real-world objects (line drawings of kitchen or clothing items) were separated by a 10 ms SOA. In Experiment 1, target objects were defined by their category. In Experiment 2, one specific visual object served as target (exemplar-based search). On different trials, targets appeared either in one or in both displays, and participants had to report the number of targets (one or two). Target N2pc components were larger and emerged earlier during exemplar-based search than during category-based search, demonstrating the superior efficiency of feature-based attentional guidance. On trials where target objects appeared in both displays, both targets elicited N2pc components that overlapped in time, suggesting that attention was allocated in parallel to these target objects. Critically, this was the case not only in the exemplar-based task, but also when targets were defined by their category. These results demonstrate that attention can be guided by object categories, and that this type of category-based attentional control can operate concurrently for multiple target objects. Copyright © 2018 Elsevier B.V. All rights reserved.

Concordance with dietary and lifestyle population goals for cancer prevention in Dutch, Scottish, Mexican, and Guatemalan population samples.

PubMed

Vossenaar, Marieke; Solomons, Noel W; Valdés-Ramos, Roxana; Anderson, Annie S

2010-01-01

We assessed concordance with selected population goal components of the 1997 World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) diet and lifestyle recommendations to decrease cancer risk across four population samples. This was a prospectively designed survey examining concordance with the population goals of the WCRF/AICR recommendations using target criteria across sites. Population samples were from the Netherlands, Scotland, Mexico, and Guatemala. A total of 3564 men and women aged 18 to 70 y were recruited in equal proportions by site and gender. None of the four pooled samples met the target population average criteria for body mass index or refined sugar intake. The Guatemalan sample had concordance with the largest number of recommended cancer-prevention goals (10 of 12 selected WCRF/AICR components). Successively, Mexican, Scottish, and Dutch samples were concordant with seven, four, and three selected components, respectively. A prospectively designed research instrument and exhaustive prior examination of operative criteria allow for the assessment of group-level concordance with cancer-prevention goals. To the extent that the study samples reflect the respective national situations, geographic variance in concordance exists, with conditions and behaviors in Guatemala bringing that nation into more general compliance with the 1997 WCRF/AICR goals.

Specific Visualization of Tumor Cells Using Upconversion Nanophosphors

PubMed Central

Grebenik, E. A.; Generalova, A. N.; Nechaev, A. V.; Khaydukov, E.V.; Mironova, K. E.; Stremovskiy, O. A.; Lebedenko, E.N.; Zvyagin, A. V.; Deyev, S. M.

2014-01-01

The development of targeted constructs on the basis of photoluminescent nanoparticles with a high photo- and chemical stability and absorption/emission spectra in the “transparency window” of biological tissues is an important focus area of present-day medical diagnostics. In this work, a targeted two-component construct on the basis of upconversion nanophosphors (UCNPs) and anti-tumor 4D5 scFv was developed for selective labeling of tumor cells overexpressing the HER2 tumor marker characteristic of a number of human malignant tumors. A high affinity barnase : barstar (Bn : Bs) protein pair, which exhibits high stability in a wide range of pH and temperatures, was exploited as a molecular adapter providing self-assembly of the two-component construct. High selectivity for the binding of the two-component 4D5 scFv-Bn : UCNP-Bs construct to human breast adenocarcinoma SK-BR-3 cells overexpressing HER2 was demonstrated. This approach provides an opportunity to produce similar constructs for the visualization of different specific markers in pathogenic tissues, including malignant tumors. PMID:25558394

Ligand-induced expansion of the S1' site in the anthrax toxin lethal factor

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

Maize, Kimberly M.; Kurbanov, Elbek K.; Johnson, Rodney L.

2016-07-05

The Bacillus anthracis lethal factor (LF) is one component of a tripartite exotoxin partly responsible for persistent anthrax cytotoxicity after initial bacterial infection. Inhibitors of the zinc metalloproteinase have been investigated as potential therapeutic agents, but LF is a challenging target because inhibitors lack sufficient selectivity or possess poor pharmaceutical properties. These structural studies reveal an alternate conformation of the enzyme, induced upon binding of specific inhibitors, that opens a previously unobserved deep pocket termed S1'* which might afford new opportunities to design selective inhibitors that target this subsite.

Phage display biopanning and isolation of target-unrelated peptides: in search of nonspecific binders hidden in a combinatorial library.

PubMed

Bakhshinejad, Babak; Zade, Hesam Motaleb; Shekarabi, Hosna Sadat Zahed; Neman, Sara

2016-12-01

Phage display is known as a powerful methodology for the identification of targeting ligands that specifically bind to a variety of targets. The high-throughput screening of phage display combinatorial peptide libraries is performed through the affinity selection method of biopanning. Although phage display selection has proven very successful in the discovery of numerous high-affinity target-binding peptides with potential application in drug discovery and delivery, the enrichment of false-positive target-unrelated peptides (TUPs) without any actual affinity towards the target remains a major problem of library screening. Selection-related TUPs may emerge because of binding to the components of the screening system rather than the target. Propagation-related TUPs may arise as a result of faster growth rate of some phage clones enabling them to outcompete slow-propagating clones. Amplification of the library between rounds of biopanning makes a significant contribution to the selection of phage clones with propagation advantage. Distinguishing nonspecific TUPs from true target binders is of particular importance for the translation of biopanning findings from basic research to clinical applications. Different experimental and in silico approaches are applied to assess the specificity of phage display-derived peptides towards the target. Bioinformatic tools are playing a rapidly growing role in the analysis of biopanning data and identification of target-irrelevant TUPs. Recent progress in the introduction of efficient strategies for TUP detection holds enormous promise for the discovery of clinically relevant cell- and tissue-homing peptides and paves the way for the development of novel targeted diagnostic and therapeutic platforms in pharmaceutical areas.

Ad-hoc and context-dependent adjustments of selective attention in conflict control: an ERP study with visual probes.

PubMed

Nigbur, R; Schneider, J; Sommer, W; Dimigen, O; Stürmer, B

2015-02-15

Cognitive conflict control in flanker tasks has often been described using the zoom-lens metaphor of selective attention. However, whether and how selective attention - in terms of suppression and enhancement - operates in this context has remained unclear. To examine the dynamic interplay of selective attention and cognitive control we used electrophysiological measures and presented task-irrelevant visual probe stimuli at foveal, parafoveal, and peripheral display positions. Target-flanker congruency varied either randomly from trial to trial (mixed-block) or block-wise (fixed-block) in order to induce reactive versus proactive control modes, respectively. Three EEG measures were used to capture ad-hoc adjustments within trials as well as effects of context-based predictions: the N1 component of the visual evoked potential (VEP) to probes, the VEP to targets, and the conflict-related midfrontal N2 component. Results from probe-VEPs indicate that enhanced processing of the foveal target rather than suppression of the peripheral flankers supports interference control. In incongruent mixed-block trials VEPs were larger to probes near the targets. In the fixed-blocks probe-VEPs were not modulated, but contrary to the mixed-block the preceding target-related VEP was affected by congruency. Results of the control-related N2 reveal largest amplitudes in the unpredictable context, which did not differentiate for stimulus and response incongruency. In contrast, in the predictable context, N2 amplitudes were reduced overall and differentiated between stimulus and response incongruency. Taken together these results imply that predictability alters interference control by a reconfiguration of stimulus processing. During unpredictable sequences participants adjust their attentional focus dynamically on a trial-by-trial basis as reflected in congruency-dependent probe-VEP-modulation. This reactive control mode also elicits larger N2 amplitudes. In contrast, when task demands are predictable, participants focus selective attention earlier as reflected in the target-related VEPs. This proactive control mode leads to smaller N2 amplitudes and absent probe effects. Copyright © 2014 Elsevier Inc. All rights reserved.

Manufacturing Methods and Technology Project Summary Reports

DTIC Science & Technology

1981-06-01

a tough urethane film. The basic principle is to pump two components to a spinning disc, mixing the components just prior to depositing in a well...and check out an electronic target scoring device using developed scientific principles without drastically modifying existing commercial...equipment. The scoring device selected and installed was an Accubar Model ATS-16D using the underlying physics principle of acoustic shock wave propagation

Event-related potentials during visual selective attention in children of alcoholics.

PubMed

van der Stelt, O; Gunning, W B; Snel, J; Kok, A

1998-12-01

Event-related potentials were recorded from 7- to 18-year-old children of alcoholics (COAs, n = 50) and age- and sex-matched control children (n = 50) while they performed a visual selective attention task. The task was to attend selectively to stimuli with a specified color (red or blue) in an attempt to detect the occurrence of target stimuli. COAs manifested a smaller P3b amplitude to attended-target stimuli over the parietal and occipital scalp than did the controls. A more specific analysis indicated that both the attentional relevance and the target properties of the eliciting stimulus determined the observed P3b amplitude differences between COAs and controls. In contrast, no significant group differences were observed in attention-related earlier occurring event-related potential components, referred to as frontal selection positivity, selection negativity, and N2b. These results represent neurophysiological evidence that COAs suffer from deficits at a late (semantic) level of visual selective information processing that are unlikely a consequence of deficits at earlier (sensory) levels of selective processing. The findings support the notion that a reduced visual P3b amplitude in COAs represents a high-level processing dysfunction indicating their increased vulnerability to alcoholism.

A novel approach to transforming a non-targeted metabolic profiling method to a pseudo-targeted method using the retention time locking gas chromatography/mass spectrometry-selected ions monitoring.

PubMed

Li, Yong; Ruan, Qiang; Li, Yanli; Ye, Guozhu; Lu, Xin; Lin, Xiaohui; Xu, Guowang

2012-09-14

Non-targeted metabolic profiling is the most widely used method for metabolomics. In this paper, a novel approach was established to transform a non-targeted metabolic profiling method to a pseudo-targeted method using the retention time locking gas chromatography/mass spectrometry-selected ion monitoring (RTL-GC/MS-SIM). To achieve this transformation, an algorithm based on the automated mass spectral deconvolution and identification system (AMDIS), GC/MS raw data and a bi-Gaussian chromatographic peak model was developed. The established GC/MS-SIM method was compared with GC/MS-full scan (the total ion current and extracted ion current, TIC and EIC) methods, it was found that for a typical tobacco leaf extract, 93% components had their relative standard deviations (RSDs) of relative peak areas less than 20% by the SIM method, while 88% by the EIC method and 81% by the TIC method. 47.3% components had their linear correlation coefficient higher than 0.99, compared with 5.0% by the EIC and 6.2% by TIC methods. Multivariate analysis showed the pooled quality control samples clustered more tightly using the developed method than using GC/MS-full scan methods, indicating a better data quality. With the analysis of the variance of the tobacco samples from three different planting regions, 167 differential components (p<0.05) were screened out using the RTL-GC/MS-SIM method, but 151 and 131 by the EIC and TIC methods, respectively. The results show that the developed method not only has a higher sensitivity, better linearity and data quality, but also does not need complicated peak alignment among different samples. It is especially suitable for the screening of differential components in the metabolic profiling investigation. Copyright © 2012 Elsevier B.V. All rights reserved.

Target-induced formation of neuraminidase inhibitors from in vitro virtual combinatorial libraries

PubMed Central

Hochgürtel, Matthias; Kroth, Heiko; Piecha, Dorothea; Hofmann, Michael W.; Nicolau, Claude; Krause, Sonja; Schaaf, Otmar; Sonnenmoser, Gabriele; Eliseev, Alexey V.

2002-01-01

Neuraminidase, a key enzyme responsible for influenza virus propagation, has been used as a template for selective synthesis of small subsets of its own inhibitors from theoretically highly diverse dynamic combinatorial libraries. We show that the library building blocks, aldehydes and amines, form significant amounts of the library components resulting from their coupling by reductive amination only in the presence of the enzyme. The target amplifies the best hits at least 120-fold. The dynamic libraries synthesized and screened in such an in vitro virtual mode form the components that possess high inhibitory activity, as confirmed by enzyme assays with independently synthesized individual compounds. PMID:11891312

[Development of an automatic vacuum liquid chromatographic device and its application in the separation of the components from Schisandra chinensis (Turz) Baill].

PubMed

Zhu, Jingbo; Liu, Baoyue; Shan, Shibo; Ding, Yanl; Kou, Zinong; Xiao, Wei

2015-08-01

In order to meet the needs of efficient purification of products from natural resources, this paper developed an automatic vacuum liquid chromatographic device (AUTO-VLC) and applied it to the component separation of petroleum ether extracts of Schisandra chinensis (Turcz) Baill. The device was comprised of a solvent system, a 10-position distribution valve, a 3-position changes valve, dynamic axis compress chromatographic columns with three diameters, and a 10-position fraction valve. The programmable logic controller (PLC) S7- 200 was adopted to realize the automatic control and monitoring of the mobile phase changing, column selection, separation time setting and fraction collection. The separation results showed that six fractions (S1-S6) of different chemical components from 100 g Schisandra chinensis (Turcz) Baill. petroleum ether phase were obtained by the AUTO-VLC with 150 mm diameter dynamic axis compress chromatographic column. A new method used for the VLC separation parameters screened by using multiple development TLC was developed and confirmed. The initial mobile phase of AUTO-VLC was selected by taking Rf of all the target compounds ranging from 0 to 0.45 for fist development on the TLC; gradient elution ratio was selected according to k value (the slope of the linear function of Rf value and development times on the TLC) and the resolution of target compounds; elution times (n) were calculated by the formula n ≈ ΔRf/k. A total of four compounds with the purity more than 85% and 13 other components were separated from S5 under the selected conditions for only 17 h. Therefore, the development of the automatic VLC and its method are significant to the automatic and systematic separation of traditional Chinese medicines.

Retirement investment theory explains patterns in songbird nest-site choice

USGS Publications Warehouse

Streby, Henry M.; Refsnider, Jeanine M.; Peterson, Sean M.; Andersen, David E.

2014-01-01

When opposing evolutionary selection pressures act on a behavioural trait, the result is often stabilizing selection for an intermediate optimal phenotype, with deviations from the predicted optimum attributed to tracking a moving target, development of behavioural syndromes or shifts in riskiness over an individual's lifetime. We investigated nest-site choice by female golden-winged warblers, and the selection pressures acting on that choice by two fitness components, nest success and fledgling survival. We observed strong and consistent opposing selection pressures on nest-site choice for maximizing these two fitness components, and an abrupt, within-season switch in the fitness component birds prioritize via nest-site choice, dependent on the time remaining for additional nesting attempts. We found that females consistently deviated from the predicted optimal behaviour when choosing nest sites because they can make multiple attempts at one fitness component, nest success, but only one attempt at the subsequent component, fledgling survival. Our results demonstrate a unique natural strategy for balancing opposing selection pressures to maximize total fitness. This time-dependent switch from high to low risk tolerance in nest-site choice maximizes songbird fitness in the same way a well-timed switch in human investor risk tolerance can maximize one's nest egg at retirement. Our results also provide strong evidence for the adaptive nature of songbird nest-site choice, which we suggest has been elusive primarily due to a lack of consideration for fledgling survival.

High-temperature, high-pressure bonding of nested tubular metallic components

DOEpatents

Quinby, T.C.

A tool is described for effecting high-temperature, high-compression bonding between the confronting faces of nested, tubular, metallic components. In a typical application, the tool is used to produce tubular target assemblies for irradiation in nuclear reactors or particle accelerators. The target assembly comprising a uranum foil and an aluninum-alloy substrate. The tool is composed of graphite. It comprises a tubular restraining member in which a mechanically expandable tubular core is mounted to form an annulus. The components to be bonded are mounted in nested relation in the annulus. The expandable core is formed of individually movable, axially elongated segments whose outer faces cooperatively define a cylindrical pressing surface and whose inner faces cooperatively define two opposed, inwardly tapered, axial bores. Tapered rams extend into the bores. The loaded tool is mounted in a conventional hot-press provided with evacuation means, heaters for maintaining its interior at bonding temperature, and hydraulic cylinders for maintaining a selected inwardly directed pressure on the tapered rams. With the hot-press evacuated and the loaded tool at the desired temperature, the cylinders are actuated to apply the selected pressure to the rams. The rams in turn expand the segmented core to maintain the nested components in compression against the restraining member. These conditions are maintained until the confronting faces of the nested components are joined in a continuous, uniform bond characterized by high thermal conductivity.

Acceptance and Commitment Therapy modules: Differential impact on treatment processes and outcomes.

PubMed

Villatte, Jennifer L; Vilardaga, Roger; Villatte, Matthieu; Plumb Vilardaga, Jennifer C; Atkins, David C; Hayes, Steven C

2016-02-01

A modular, transdiagnostic approach to treatment design and implementation may increase the public health impact of evidence-based psychosocial interventions. Such an approach relies on algorithms for selecting and implementing treatment components intended to have a specific therapeutic effect, yet there is little evidence for how components function independent of their treatment packages when employed in clinical service settings. This study aimed to demonstrate the specificity of treatment effects for two components of Acceptance and Commitment Therapy (ACT), a promising candidate for modularization. A randomized, nonconcurrent, multiple-baseline across participants design was used to examine component effects on treatment processes and outcomes in 15 adults seeking mental health treatment. The ACT OPEN module targeted acceptance and cognitive defusion; the ACT ENGAGED module targeted values-based activation and persistence. According to Tau-U analyses, both modules produced significant improvements in psychiatric symptoms, quality of life, and targeted therapeutic processes. ACT ENGAGED demonstrated greater improvements in quality of life and values-based activation. ACT OPEN showed greater improvements in symptom severity, acceptance, and defusion. Both modules improved awareness and non-reactivity, which were mutually targeted, though using distinct intervention procedures. Both interventions demonstrated high treatment acceptability, completion, and patient satisfaction. Treatment effects were maintained at 3-month follow up. ACT components should be considered for inclusion in a modular approach to implementing evidence-based psychosocial interventions for adults. Copyright © 2015 Elsevier Ltd. All rights reserved.

Exogenous attention can be counter-selective: onset cues disrupt sensitivity to color changes.

PubMed

Müller-Plath, Gisela; Klöckner, Nils

2014-03-01

In peripheral spatial cueing paradigms, exogenous attentional capture is commonly observed after salient onset cues or with cues contingent on target characteristics. We proposed that exogenously captured attention disrupts the selectivity to target features. We tested this by experimentally emulating the everyday observation that in a viewing situation in which the observer is monitoring a stationary display fort change to occur, the onset of a salient stimulus (onset cue) or a change in a stationary stimulus similar to the expected one (contingent cue) has a distracting effect. As predicted, we found that both types of cues reduced the target detection sensitivity but enhanced the bias to respond in a go-nogo-paradigm. With the onset cue, the sensitivity loss was more pronounced at the side of the cue, whereas the contingent cue affected both sides likewise. Moreover, the effects of the onset cue interacted with the task difficulty: the more selectivity a task required the more immune it was against disruption, but the more likely was a response. We concluded that onset capture disrupts selective attention by adding noise to the processing of the target location. The effects of contingent capture could be explained with cue-target confounding. Finally, we suggest a new model of attentional capture in which exogenous and endogenous components interact in a dynamic way.

Is that a belt or a snake? object attentional selection affects the early stages of visual sensory processing

PubMed Central

2012-01-01

Background There is at present crescent empirical evidence deriving from different lines of ERPs research that, unlike previously observed, the earliest sensory visual response, known as C1 component or P/N80, generated within the striate cortex, might be modulated by selective attention to visual stimulus features. Up to now, evidence of this modulation has been related to space location, and simple features such as spatial frequency, luminance, and texture. Additionally, neurophysiological conditions, such as emotion, vigilance, the reflexive or voluntary nature of input attentional selection, and workload have also been related to C1 modulations, although at least the workload status has received controversial indications. No information is instead available, at present, for objects attentional selection. Methods In this study object- and space-based attention mechanisms were conjointly investigated by presenting complex, familiar shapes of artefacts and animals, intermixed with distracters, in different tasks requiring the selection of a relevant target-category within a relevant spatial location, while ignoring the other shape categories within this location, and, overall, all the categories at an irrelevant location. EEG was recorded from 30 scalp electrode sites in 21 right-handed participants. Results and Conclusions ERP findings showed that visual processing was modulated by both shape- and location-relevance per se, beginning separately at the latency of the early phase of a precocious negativity (60-80 ms) at mesial scalp sites consistent with the C1 component, and a positivity at more lateral sites. The data also showed that the attentional modulation progressed conjointly at the latency of the subsequent P1 (100-120 ms) and N1 (120-180 ms), as well as later-latency components. These findings support the views that (1) V1 may be precociously modulated by direct top-down influences, and participates to object, besides simple features, attentional selection; (2) object spatial and non-spatial features selection might begin with an early, parallel detection of a target object in the visual field, followed by the progressive focusing of spatial attention onto the location of an actual target for its identification, somehow in line with neural mechanisms reported in the literature as "object-based space selection", or with those proposed for visual search. PMID:22300540

A matrix-assisted laser desorption/ionization mass spectroscopy method for the analysis of small molecules by integrating chemical labeling with the supramolecular chemistry of cucurbituril.

PubMed

Ding, Jun; Xiao, Hua-Ming; Liu, Simin; Wang, Chang; Liu, Xin; Feng, Yu-Qi

2018-10-05

Although several methods have realized the analysis of low molecular weight (LMW) compounds using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) by overcoming the problem of interference with MS signals in the low mass region derived from conventional organic matrices, this emerging field still requires strategies to address the issue of analyzing complex samples containing LMW components in addition to the LMW compounds of interest, and solve the problem of lack of universality. The present study proposes an integrated strategy that combines chemical labeling with the supramolecular chemistry of cucurbit [n]uril (CB [n]) for the MALDI MS analysis of LMW compounds in complex samples. In this strategy, the target LMW compounds are first labeled by introducing a series of bifunctional reagents that selectively react with the target analytes and also form stable inclusion complexes with CB [n]. Then, the labeled products act as guest molecules that readily and selectively form stable inclusion complexes with CB [n]. This strategy relocates the MS signals of the LMW compounds of interest from the low mass region suffering high interference to the high mass region where interference with low mass components is absent. Experimental results demonstrate that a wide range of LMW compounds, including carboxylic acids, aldehydes, amines, thiol, and cis-diols, can be successfully detected using the proposed strategy, and the limits of detection were in the range of 0.01-1.76 nmol/mL. In addition, the high selectivity of the labeling reagents for the target analytes in conjunction with the high selectivity of the binding between the labeled products and CB [n] ensures an absence of signal interference with the non-targeted LMW components of complex samples. Finally, the feasibility of the proposed strategy for complex sample analysis is demonstrated by the accurate and rapid quantitative analysis of aldehydes in saliva and herbal medicines. As such, this work not only provides an alternative method for the detection of various LMW compounds using MALDI MS, but also can be applied to the selective and high-throughput analysis of LMW analytes in complex samples. Copyright © 2018 Elsevier B.V. All rights reserved.

TRIM-directed selective autophagy regulates immune activation.

PubMed

Kimura, Tomonori; Jain, Ashish; Choi, Seong Won; Mandell, Michael A; Johansen, Terje; Deretic, Vojo

2017-05-04

Selectivity of autophagy is achieved by target recognition; however, the number of autophagy receptors identified so far is limited. In this study we demonstrate that a subset of tripartite motif (TRIM) proteins mediate selective autophagy of key regulators of inflammatory signaling. MEFV/TRIM20, and TRIM21 act as autophagic receptors recognizing their cognate targets and delivering them for autophagic degradation. MEFV recognizes the inflammasome components NLRP3, CASP1 and NLRP1, whereas TRIM21 specifically recognizes the activated, dimeric from of IRF3 inducing type I interferon gene expression. MEFV and TRIM21 have a second activity, whereby they act not only as receptors but also recruit and organize key components of autophagic machinery consisting of ULK1, BECN1, ATG16L1, and mammalian homologs of Atg8, with a preference for GABARAP. MEFV capacity to organize the autophagy apparatus is affected by common mutations causing familial Mediterranean fever. These findings reveal a general mode of action of TRIMs as autophagic receptor-regulators performing a highly-selective type of autophagy (precision autophagy), with MEFV specializing in the suppression of inflammasome and CASP1 activation engendering IL1B/interleukin-1β production and implicated in the form of cell death termed pyroptosis, whereas TRIM21 dampens type I interferon responses.

The effects of solar incidence angle over digital processing of LANDSAT data

NASA Technical Reports Server (NTRS)

Parada, N. D. J. (Principal Investigator); Novo, E. M. L. M.

1983-01-01

A technique to extract the topography modulation component from digital data is described. The enhancement process is based on the fact that the pixel contains two types of information: (1) reflectance variation due to the target; (2) reflectance variation due to the topography. In order to enhance the signal variation due to topography, the technique recommends the extraction from original LANDSAT data of the component resulting from target reflectance. Considering that the role of topographic modulation over the pixel information will vary with solar incidence angle, the results of this technique of digital processing will differ from one season to another, mainly in highly dissected topography. In this context, the effects of solar incidence angle over the topographic modulation technique were evaluated. Two sets of MSS/LANDSAT data, with solar elevation angles varying from 22 to 41 deg were selected to implement the digital processing at the Image-100 System. A secondary watershed (Rio Bocaina) draining into Rio Paraiba do Sul (Sao Paulo State) was selected as a test site. The results showed that the technique used was more appropriate to MSS data acquired under higher Sun elevation angles. Topographic modulation components applied to low Sun elevation angles lessens rather than enhances topography.

An Innovative Structural Mode Selection Methodology: Application for the X-33 Launch Vehicle Finite Element Model

NASA Technical Reports Server (NTRS)

Hidalgo, Homero, Jr.

2000-01-01

An innovative methodology for determining structural target mode selection and mode selection based on a specific criterion is presented. An effective approach to single out modes which interact with specific locations on a structure has been developed for the X-33 Launch Vehicle Finite Element Model (FEM). We presented Root-Sum-Square (RSS) displacement method computes resultant modal displacement for each mode at selected degrees of freedom (DOF) and sorts to locate modes with highest values. This method was used to determine modes, which most influenced specific locations/points on the X-33 flight vehicle such as avionics control components, aero-surface control actuators, propellant valve and engine points for use in flight control stability analysis and for flight POGO stability analysis. Additionally, the modal RSS method allows for primary or global target vehicle modes to also be identified in an accurate and efficient manner.

Retirement investment theory explains patterns in songbird nest-site choice

PubMed Central

Streby, Henry M.; Refsnider, Jeanine M.; Peterson, Sean M.; Andersen, David E.

2014-01-01

When opposing evolutionary selection pressures act on a behavioural trait, the result is often stabilizing selection for an intermediate optimal phenotype, with deviations from the predicted optimum attributed to tracking a moving target, development of behavioural syndromes or shifts in riskiness over an individual's lifetime. We investigated nest-site choice by female golden-winged warblers, and the selection pressures acting on that choice by two fitness components, nest success and fledgling survival. We observed strong and consistent opposing selection pressures on nest-site choice for maximizing these two fitness components, and an abrupt, within-season switch in the fitness component birds prioritize via nest-site choice, dependent on the time remaining for additional nesting attempts. We found that females consistently deviated from the predicted optimal behaviour when choosing nest sites because they can make multiple attempts at one fitness component, nest success, but only one attempt at the subsequent component, fledgling survival. Our results demonstrate a unique natural strategy for balancing opposing selection pressures to maximize total fitness. This time-dependent switch from high to low risk tolerance in nest-site choice maximizes songbird fitness in the same way a well-timed switch in human investor risk tolerance can maximize one's nest egg at retirement. Our results also provide strong evidence for the adaptive nature of songbird nest-site choice, which we suggest has been elusive primarily due to a lack of consideration for fledgling survival. PMID:24403320

Armour Materials for the ITER Plasma Facing Components

NASA Astrophysics Data System (ADS)

Barabash, V.; Federici, G.; Matera, R.; Raffray, A. R.; ITER Home Teams,

The selection of the armour materials for the Plasma Facing Components (PFCs) of the International Thermonuclear Experimental Reactor (ITER) is a trade-off between multiple requirements derived from the unique features of a burning fusion plasma environment. The factors that affect the selection come primarily from the requirements of plasma performance (e.g., minimise impurity contamination in the confined plasma), engineering integrity, component lifetime (e.g., withstand thermal stresses, acceptable erosion, etc.) and safety (minimise tritium and radioactive dust inventories). The current selection in ITER is to use beryllium on the first-wall, upper baffle and on the port limiter surfaces, carbon fibre composites near the strike points of the divertor vertical target and tungsten elsewhere in the divertor and lower baffle modules. This paper provides the background for this selection vis-à-vis the operating parameters expected during normal and off-normal conditions. The reasons for the selection of the specific grades of armour materials are also described. The effects of the neutron irradiation on the properties of Be, W and carbon fibre composites at the expected ITER conditions are briefly reviewed. Critical issues are discussed together with the necessary future R&D.

High-temperature, high-pressure bonding of nested tubular metallic components

DOEpatents

Quinby, Thomas C.

1980-01-01

This invention is a tool for effecting high-temperature, high-compression bonding between the confronting faces of nested, tubular, metallic components. In a typical application, the tool is used to produce tubular target assemblies for irradiation in nuclear reactors or particle accelerators, the target assembly comprising a uranium foil and an aluminum-alloy substrate. The tool preferably is composed throughout of graphite. It comprises a tubular restraining member in which a mechanically expandable tubular core is mounted to form an annulus with the member. The components to be bonded are mounted in nested relation in the annulus. The expandable core is formed of individually movable, axially elongated segments whose outer faces cooperatively define a cylindrical pressing surface and whose inner faces cooperatively define two opposed, inwardly tapered, axial bores. Tapered rams extend respectively into the bores. The loaded tool is mounted in a conventional hot-press provided with evacuation means, heaters for maintaining its interior at bonding temperature, and hydraulic cylinders for maintaining a selected inwardly directed pressure on the tapered rams. With the hot-press evacuated and the loaded tool at the desired temperature, the cylinders are actuated to apply the selected pressure to the rams. The rams in turn expand the segmented core to maintain the nested components in compression against the restraining member. These conditions are maintained until the confronting faces of the nested components are joined in a continuous, uniform bond characterized by high thermal conductivity.

Multistate and phase change selection in constitutional multivalent systems.

PubMed

Barboiu, Mihail

2012-01-01

Molecular architectures and materials can be constitutionally self-sorted in the presence of different biomolecular targets or external physical stimuli or chemical effectors, thus responding to an external selection pressure. The high selectivity and specificity of different bioreceptors or self-correlated internal interactions may be used to describe the complex constitutional behaviors through multistate component selection from a dynamic library. The self-selection may result in the dynamic amplification of self-optimized architectures during the phase change process. The sol-gel resolution of dynamic molecular/supramolecular libraries leads to higher self-organized constitutional hybrid materials, in which organic (supramolecular)/inorganic domains are reversibily connected.

Procrustean rotation in concert with principal component analysis of molecular dynamics trajectories: Quantifying global and local differences between conformational samples.

PubMed

Oblinsky, Daniel G; Vanschouwen, Bryan M B; Gordon, Heather L; Rothstein, Stuart M

2009-12-14

Given the principal component analysis (PCA) of a molecular dynamics (MD) conformational trajectory for a model protein, we perform orthogonal Procrustean rotation to "best fit" the PCA squared-loading matrix to that of a target matrix computed for a related but different molecular system. The sum of squared deviations of the elements of the rotated matrix from those of the target, known as the error of fit (EOF), provides a quantitative measure of the dissimilarity between the two conformational samples. To estimate precision of the EOF, we perform bootstrap resampling of the molecular conformations within the trajectories, generating a distribution of EOF values for the system and target. The average EOF per variable is determined and visualized to ascertain where, locally, system and target sample properties differ. We illustrate this approach by analyzing MD trajectories for the wild-type and four selected mutants of the beta1 domain of protein G.

Procrustean rotation in concert with principal component analysis of molecular dynamics trajectories: Quantifying global and local differences between conformational samples

NASA Astrophysics Data System (ADS)

Oblinsky, Daniel G.; VanSchouwen, Bryan M. B.; Gordon, Heather L.; Rothstein, Stuart M.

2009-12-01

Given the principal component analysis (PCA) of a molecular dynamics (MD) conformational trajectory for a model protein, we perform orthogonal Procrustean rotation to "best fit" the PCA squared-loading matrix to that of a target matrix computed for a related but different molecular system. The sum of squared deviations of the elements of the rotated matrix from those of the target, known as the error of fit (EOF), provides a quantitative measure of the dissimilarity between the two conformational samples. To estimate precision of the EOF, we perform bootstrap resampling of the molecular conformations within the trajectories, generating a distribution of EOF values for the system and target. The average EOF per variable is determined and visualized to ascertain where, locally, system and target sample properties differ. We illustrate this approach by analyzing MD trajectories for the wild-type and four selected mutants of the β1 domain of protein G.

Selection of a turbine cooling system applying multi-disciplinary design considerations.

PubMed

Glezer, B

2001-05-01

The presented paper describes a multi-disciplinary cooling selection approach applied to major gas turbine engine hot section components, including turbine nozzles, blades, discs, combustors and support structures, which maintain blade tip clearances. The paper demonstrates benefits of close interaction between participating disciplines starting from early phases of the hot section development. The approach targets advancements in engine performance and cost by optimizing the design process, often requiring compromises within individual disciplines.

Design and methods of the Midwest Stream Quality Assessment (MSQA), 2013

USGS Publications Warehouse

Garrett, Jessica D.; Frey, Jeffrey W.; Van Metre, Peter C.; Journey, Celeste A.; Nakagaki, Naomi; Button, Daniel T.; Nowell, Lisa H.

2017-10-18

During 2013, the U.S. Geological Survey (USGS) National Water-Quality Assessment Project (NAWQA), in collaboration with the USGS Columbia Environmental Research Center, the U.S. Environmental Protection Agency (EPA) National Rivers and Streams Assessment (NRSA), and the EPA Office of Pesticide Programs assessed stream quality across the Midwestern United States. This Midwest Stream Quality Assessment (MSQA) simultaneously characterized watershed and stream-reach water-quality stressors along with instream biological conditions, to better understand regional stressor-effects relations. The MSQA design focused on effects from the widespread agriculture in the region and urban development because of their importance as ecological stressors of particular concern to Midwest region resource managers.A combined random stratified selection and a targeted selection based on land-use data were used to identify and select sites representing gradients in agricultural intensity across the region. During a 14-week period from May through August 2013, 100 sites were selected and sampled 12 times for contaminants, nutrients, and sediment. This 14-week water-quality “index” period culminated with an ecological survey of habitat, periphyton, benthic macroinvertebrates, and fish at all sites. Sediment was collected during the ecological survey for analysis of sediment chemistry and toxicity testing. Of the 100 sites, 50 were selected for the MSQA random stratified group from 154 NRSA sites planned for the region, and the other 50 MSQA sites were selected as targeted sites to more evenly cover agricultural and urban stressor gradients in the study area. Of the 50 targeted sites, 12 were in urbanized watersheds and 21 represented “good” biological conditions or “least disturbed” conditions. The remaining 17 targeted sites were selected to improve coverage of the agricultural intensity gradient or because of historical data collection to provide temporal context for the study.This report provides a detailed description of the MSQA study components, including surveys of ecological conditions, routine water sampling, deployment of passive polar organic compound integrative samplers, and stream sediment sampling at all sites. Component studies that were completed to provide finer scale temporal data or more extensive analysis at selected sites, included continuous water-quality monitoring, daily pesticide sampling, laboratory and in-stream water toxicity testing efforts, and deployment of passive suspended-sediment samplers.

Color selectivity of the spatial congruency effect: evidence from the focused attention paradigm.

PubMed

Makovac, Elena; Gerbino, Walter

2014-01-01

The multisensory response enhancement (MRE), occurring when the response to a visual target integrated with a spatially congruent sound is stronger than the response to the visual target alone, is believed to be mediated by the superior colliculus (SC) (Stein & Meredith, 1993). Here, we used a focused attention paradigm to show that the spatial congruency effect occurs with red (SC-effective) but not blue (SC-ineffective) visual stimuli, when presented with spatially congruent sounds. To isolate the chromatic component of SC-ineffective targets and to demonstrate the selectivity of the spatial congruency effect we used the random luminance modulation technique (Experiment 1) and the tritanopic technique (Experiment 2). Our results indicate that the spatial congruency effect does not require the distribution of attention over different sensory modalities and provide correlational evidence that the SC mediates the effect.

Application of targeted quantitative proteomics analysis in human cerebrospinal fluid using a liquid chromatography matrix-assisted laser desorption/ionization time-of-flight tandem mass spectrometer (LC MALDI TOF/TOF) platform.

PubMed

Pan, Sheng; Rush, John; Peskind, Elaine R; Galasko, Douglas; Chung, Kathryn; Quinn, Joseph; Jankovic, Joseph; Leverenz, James B; Zabetian, Cyrus; Pan, Catherine; Wang, Yan; Oh, Jung Hun; Gao, Jean; Zhang, Jianpeng; Montine, Thomas; Zhang, Jing

2008-02-01

Targeted quantitative proteomics by mass spectrometry aims to selectively detect one or a panel of peptides/proteins in a complex sample and is particularly appealing for novel biomarker verification/validation because it does not require specific antibodies. Here, we demonstrated the application of targeted quantitative proteomics in searching, identifying, and quantifying selected peptides in human cerebrospinal spinal fluid (CSF) using a matrix-assisted laser desorption/ionization time-of-flight tandem mass spectrometer (MALDI TOF/TOF)-based platform. The approach involved two major components: the use of isotopic-labeled synthetic peptides as references for targeted identification and quantification and a highly selective mass spectrometric analysis based on the unique characteristics of the MALDI instrument. The platform provides high confidence for targeted peptide detection in a complex system and can potentially be developed into a high-throughput system. Using the liquid chromatography (LC) MALDI TOF/TOF platform and the complementary identification strategy, we were able to selectively identify and quantify a panel of targeted peptides in the whole proteome of CSF without prior depletion of abundant proteins. The effectiveness and robustness of the approach associated with different sample complexity, sample preparation strategies, as well as mass spectrometric quantification were evaluated. Other issues related to chromatography separation and the feasibility for high-throughput analysis were also discussed. Finally, we applied targeted quantitative proteomics to analyze a subset of previously identified candidate markers in CSF samples of patients with Parkinson's disease (PD) at different stages and Alzheimer's disease (AD) along with normal controls.

TINAGL1 and B3GALNT1 are potential therapy target genes to suppress metastasis in non-small cell lung cancer

PubMed Central

2014-01-01

Background Non-small cell lung cancer (NSCLC) remains lethal despite the development of numerous drug therapy technologies. About 85% to 90% of lung cancers are NSCLC and the 5-year survival rate is at best still below 50%. Thus, it is important to find drugable target genes for NSCLC to develop an effective therapy for NSCLC. Results Integrated analysis of publically available gene expression and promoter methylation patterns of two highly aggressive NSCLC cell lines generated by in vivo selection was performed. We selected eleven critical genes that may mediate metastasis using recently proposed principal component analysis based unsupervised feature extraction. The eleven selected genes were significantly related to cancer diagnosis. The tertiary protein structure of the selected genes was inferred by Full Automatic Modeling System, a profile-based protein structure inference software, to determine protein functions and to specify genes that could be potential drug targets. Conclusions We identified eleven potentially critical genes that may mediate NSCLC metastasis using bioinformatic analysis of publically available data sets. These genes are potential target genes for the therapy of NSCLC. Among the eleven genes, TINAGL1 and B3GALNT1 are possible candidates for drug compounds that inhibit their gene expression. PMID:25521548

Interim Calibration Report for the SMMR Simulator

NASA Technical Reports Server (NTRS)

Gloersen, P.; Cavalieri, D.

1979-01-01

The calibration data obtained during the fall 1978 Nimbus-G underflight mission with the scanning multichannel microwave radiometer (SMMR) simulator on board the NASA CV-990 aircraft were analyzed and an interim calibration algorithm was developed. Data selected for the analysis consisted of in flight sky, first-year sea ice, and open water observations, as well as ground based observations of fixed targets with varied temperatures of selected instrument components. For most of the SMMR channels, a good fit to the selected data set was obtained with the algorithm.

Detection of Chemical Precursors of Explosives

NASA Technical Reports Server (NTRS)

Li, Jing

2012-01-01

Certain selected chemicals associated with terrorist activities are too unstable to be prepared in final form. These chemicals are often prepared as precursor components, to be combined at a time immediately preceding the detonation. One example is a liquid explosive, which usually requires an oxidizer, an energy source, and a chemical or physical mechanism to combine the other components. Detection of the oxidizer (e.g. H2O2) or the energy source (e.g., nitromethane) is often possible, but must be performed in a short time interval (e.g., 5 15 seconds) and in an environment with a very small concentration (e.g.,1 100 ppm), because the target chemical(s) is carried in a sealed container. These needs are met by this invention, which provides a system and associated method for detecting one or more chemical precursors (components) of a multi-component explosive compound. Different carbon nanotubes (CNTs) are loaded (by doping, impregnation, coating, or other functionalization process) for detecting of different chemical substances that are the chemical precursors, respectively, if these precursors are present in a gas to which the CNTs are exposed. After exposure to the gas, a measured electrical parameter (e.g. voltage or current that correlate to impedance, conductivity, capacitance, inductance, etc.) changes with time and concentration in a predictable manner if a selected chemical precursor is present, and will approach an asymptotic value promptly after exposure to the precursor. The measured voltage or current are compared with one or more sequences of their reference values for one or more known target precursor molecules, and a most probable concentration value is estimated for each one, two, or more target molecules. An error value is computed, based on differences of voltage or current for the measured and reference values, using the most probable concentration values. Where the error value is less than a threshold, the system concludes that the target molecule is likely. Presence of one, two, or more target molecules in the gas can be sensed from a single set of measurements.

Lab-on-chip components for molecular detection

NASA Astrophysics Data System (ADS)

Adam, Tijjani; Dhahi, Th S.; Mohammed, Mohammed; Hashim, U.; Noriman, N. Z.; Dahham, Omar S.

2017-09-01

We successfully fabricated Lab on chip components and integrated for possible use in biomedical application. The sensor was fabricated by using conventional photolithography method integrated with PDMS micro channels for smooth delivery of sample to the sensing domain. The sensor was silanized and aminated with 3-Aminopropyl triethoxysilane (APTES) to functionalize the surface with biomolecules and create molecular binding chemistry. The resulting Si-O-Si- components were functionalized with oligonucleotides probe of HPV, which interacted with the single stranded HPV DNA target to create a field across on the device. The fabrication, immobilization and hybridization processes were characterized with current voltage (I-V) characterization (KEITHLEY, 6487). The sensor show selectivity for the HPV DNA target in a linear range from concentration 0.1 nM to 1 µM. This strategy presented a simple, rapid and sensitive platform for HPV detection and would become a powerful tool for pathogenic microorganisms screening in clinical diagnosis.

New genetic tools to improve citrus fruit quality and drive consumer demand

USDA-ARS?s Scientific Manuscript database

Chemical and genomic dissection of important components underlying fruit quality has led toward the development of new tools to make the creation and selection of citrus cultivars improved in quality attributes more targeted and efficient. The use of SNP platforms and other technologies have resulte...

Peptides for Specific Intracellular Delivery and Targeting of Nanoparticles: Implications for Developing Nanoparticle-Mediated Drug Delivery

DTIC Science & Technology

2010-01-01

for selective delivery of therapeutics and imaging agents to the tumour vasculature. Drug Resist. Update 8(6), 381–402 (2005). 89 Smith BR, Cheng Z...component can be realized. Select examples from the literature have already demonstrated the feasibility of generating hybrid NP–peptide constructs in...peptide-mediated delivery of NP-based imaging agents (fluorescence and magnetic resonance), drug-delivery vehicles, therapeutic proteins and nucleic

Gene Therapy in Heart Failure.

PubMed

Fargnoli, Anthony S; Katz, Michael G; Bridges, Charles R; Hajjar, Roger J

2017-01-01

Heart failure is a significant burden to the global healthcare system and represents an underserved market for new pharmacologic strategies, especially therapies which can address root cause myocyte dysfunction. Modern drugs, surgeries, and state-of-the-art interventions are costly and do not improve survival outcome measures. Gene therapy is an attractive strategy, whereby selected gene targets and their associated regulatory mechanisms can be permanently managed therapeutically in a single treatment. This in theory could be sustainable for the patient's life. Despite the promise, however, gene therapy has numerous challenges that must be addressed together as a treatment plan comprising these key elements: myocyte physiologic target validation, gene target manipulation strategy, vector selection for the correct level of manipulation, and carefully utilizing an efficient delivery route that can be implemented in the clinic to efficiently transfer the therapy within safety limits. This chapter summarizes the key developments in cardiac gene therapy from the perspective of understanding each of these components of the treatment plan. The latest pharmacologic gene targets, gene therapy vectors, delivery routes, and strategies are reviewed.

Fibrinogen signal transduction as a mediator and therapeutic target in inflammation: lessons from multiple sclerosis.

PubMed

Adams, R A; Schachtrup, C; Davalos, D; Tsigelny, I; Akassoglou, K

2007-01-01

The blood protein fibrinogen as a ligand for integrin and non-integrin receptors functions as the molecular nexus of coagulation, inflammation and immunity. Studies in animal models and in human disease have demonstrated that extravascular fibrinogen that is deposited in tissues upon vascular rupture is not merely a marker, but a mediator of diseases with an inflammatory component, such as rheumatoid arthritis, multiple sclerosis, sepsis, myocardial infarction and bacterial infection. The present article focuses on the recent discoveries of specific cellular targets and receptors for fibrinogen within tissues that have extended the role of fibrinogen from a coagulation factor to a regulator of inflammation and immunity. Fibrinogen has the potential for selective drug targeting that would target its proinflammatory properties without affecting its beneficial effects in hemostasis, since it interacts with different receptors to mediate blood coagulation and inflammation. Strategies to target receptors for fibrinogen and fibrin within the tissue microenvironment could reveal selective and disease-specific agents for therapeutic intervention in a variety of human diseases associated with fibrin deposition.

Assessing quality of life in diabetes: I. A practical guide to selecting the best instruments and using them wisely.

PubMed

Fisher, Lawrence; Tang, Tricia; Polonsky, William

2017-04-01

The rapid development of new medications and devices in diabetes research and clinical care has led to an increased need to assess their impact on health-related quality of life (HRQOL). Unfortunately, the lack of consensus definitions and guidelines has led to the use of HRQOL measures that are often imprecise and inappropriate. The goal of this report is to provide a practical structure to the definition and measurement of HRQOL in diabetes research and clinical care. Following a brief historical background to provide context, we define HRQOL and provide a three-step framework for scale selection: identify the specific, proximal intervention targets; decide how reaching these targets will affect HRQOL; and select appropriate measures based on sample diversity, the intervention and the targets using a 2×2 grid (generic vs. diabetes specific measures; global vs. component measures). Practical tips for scale selection include: gaining patient input to document important potential HRQOL effects, varying scale selection by patient characteristics, considering common HRQOL measurement problems, and considering the timing of HRQOL assessment. We emphasize the importance of a careful, planned evaluation of HRQOL in diabetes, rather than an "off the shelf" approach. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Regulators of G-protein signaling and their Gα substrates: promises and challenges in their use as drug discovery targets.

PubMed

Kimple, Adam J; Bosch, Dustin E; Giguère, Patrick M; Siderovski, David P

2011-09-01

Because G-protein coupled receptors (GPCRs) continue to represent excellent targets for the discovery and development of small-molecule therapeutics, it is posited that additional protein components of the signal transduction pathways emanating from activated GPCRs themselves are attractive as drug discovery targets. This review considers the drug discovery potential of two such components: members of the "regulators of G-protein signaling" (RGS protein) superfamily, as well as their substrates, the heterotrimeric G-protein α subunits. Highlighted are recent advances, stemming from mouse knockout studies and the use of "RGS-insensitivity" and fast-hydrolysis mutations to Gα, in our understanding of how RGS proteins selectively act in (patho)physiologic conditions controlled by GPCR signaling and how they act on the nucleotide cycling of heterotrimeric G-proteins in shaping the kinetics and sensitivity of GPCR signaling. Progress is documented regarding recent activities along the path to devising screening assays and chemical probes for the RGS protein target, not only in pursuits of inhibitors of RGS domain-mediated acceleration of Gα GTP hydrolysis but also to embrace the potential of finding allosteric activators of this RGS protein action. The review concludes in considering the Gα subunit itself as a drug target, as brought to focus by recent reports of activating mutations to GNAQ and GNA11 in ocular (uveal) melanoma. We consider the likelihood of several strategies for antagonizing the function of these oncogene alleles and their gene products, including the use of RGS proteins with Gα(q) selectivity.

Uncovering the Mechanisms of Chinese Herbal Medicine (MaZiRenWan) for Functional Constipation by Focused Network Pharmacology Approach.

PubMed

Huang, Tao; Ning, Ziwan; Hu, Dongdong; Zhang, Man; Zhao, Ling; Lin, Chengyuan; Zhong, Linda L D; Yang, Zhijun; Xu, Hongxi; Bian, Zhaoxiang

2018-01-01

MaZiRenWan (MZRW, also known as Hemp Seed Pill) is a Chinese Herbal Medicine which has been demonstrated to safely and effectively alleviate functional constipation (FC) in a randomized, placebo-controlled clinical study with 120 subjects. However, the underlying pharmacological actions of MZRW for FC, are still largely unknown. We systematically analyzed the bioactive compounds of MZRW and mechanism-of-action biological targets through a novel approach called "focused network pharmacology." Among the 97 compounds identified by UPLC-QTOF-MS/MS in MZRW extract, 34 were found in rat plasma, while 10 were found in rat feces. Hierarchical clustering analysis suggest that these compounds can be classified into component groups, in which compounds are highly similar to each other and most of them are from the same herb. Emodin, amygdalin, albiflorin, honokiol, and naringin were selected as representative compounds of corresponding component groups. All of them were shown to induce spontaneous contractions of rat colonic smooth muscle in vitro . Network analysis revealed that biological targets in acetylcholine-, estrogen-, prostaglandin-, cannabinoid-, and purine signaling pathways are able to explain the prokinetic effects of representative compounds and corresponding component groups. In conclusion, MZRW active components enhance colonic motility, possibly by acting on multiple targets and pathways.

Uncovering the Mechanisms of Chinese Herbal Medicine (MaZiRenWan) for Functional Constipation by Focused Network Pharmacology Approach

PubMed Central

Huang, Tao; Ning, Ziwan; Hu, Dongdong; Zhang, Man; Zhao, Ling; Lin, Chengyuan; Zhong, Linda L. D.; Yang, Zhijun; Xu, Hongxi; Bian, Zhaoxiang

2018-01-01

MaZiRenWan (MZRW, also known as Hemp Seed Pill) is a Chinese Herbal Medicine which has been demonstrated to safely and effectively alleviate functional constipation (FC) in a randomized, placebo-controlled clinical study with 120 subjects. However, the underlying pharmacological actions of MZRW for FC, are still largely unknown. We systematically analyzed the bioactive compounds of MZRW and mechanism-of-action biological targets through a novel approach called “focused network pharmacology.” Among the 97 compounds identified by UPLC-QTOF-MS/MS in MZRW extract, 34 were found in rat plasma, while 10 were found in rat feces. Hierarchical clustering analysis suggest that these compounds can be classified into component groups, in which compounds are highly similar to each other and most of them are from the same herb. Emodin, amygdalin, albiflorin, honokiol, and naringin were selected as representative compounds of corresponding component groups. All of them were shown to induce spontaneous contractions of rat colonic smooth muscle in vitro. Network analysis revealed that biological targets in acetylcholine-, estrogen-, prostaglandin-, cannabinoid-, and purine signaling pathways are able to explain the prokinetic effects of representative compounds and corresponding component groups. In conclusion, MZRW active components enhance colonic motility, possibly by acting on multiple targets and pathways. PMID:29632490

Studies in Multifunctional Drug Development: Preparation and Evaluation of 11beta-Substituted Estradiol-Drug Conjugates, Cell Membrane Targeting Imaging Agents, and Target Multifunctional Nanoparticles

NASA Astrophysics Data System (ADS)

Dao, KinhLuan Lenny D.

Cancer is the second leading cause of death after cardiovascular disease in the United State. Despite extensive research in development of antitumor drugs, most of these therapeutic entities often possess nonspecific toxicity, thus they can only be used to treat tumors in higher doses or more frequently. Because of the cytotoxicity and severe side effects, the drug therapeutic window normally is limited. Beside the toxicity issue, antitumor drug are also not selectively taken up by tumor cells, thus the necessitating concentrations that would eradicate the tumor can often not be used. In addition, tumor cells tend to develop resistance against the anticancer drugs after prolonged treatment. Therefore, alleviating the systemic cytotoxicity and side effects, improving in tumor selectivity, high potency, and therapeutic efficacy are still major obstacles in the area of anticancer drug development. A more promising approach for developing a selective agent for cancer is to conjugate a potent therapeutic drug, or an imaging agent with a targeting group, such as antibody or a high binding-specificity small molecule, that selectively recognize the overexpressed antigens or proteins on tumor cells. My research combines several approaches to describe this strategy via using different targeting molecules to different diseases, as well as different potent cytotoxic drugs for different therapies. Three studies related to the preparation and biological evaluation of new therapeutic agents, such as estradiol-drug hybrids, cell membrane targeted molecular imaging agents, and multifunctional NPs will be discussed. The preliminary results of these studies indicated that our new reagents achieved their initial objectives and can be further improved for optimized synthesis and in vivo experiments. The first study describes the method in which we employed a modular assembly approach to synthesize a novel 11beta-substituted steroidal anti-estrogen. The key intermediate was synthesized with an azido-tetraethylene glycol moiety that could be coupled to a complementary doxorubicin benzoyl hydrazone, functionalized with a propargyl tetraethylene glycol moiety. Huisgen [3+2] cycloaddition chemistry gave the final hybrid which was evaluated for receptor binding to demonstrate ER-affinity and for cytotoxicity in ER(+)-MCF-7 and ER(-)-MDA-MB-231 breast cancer cell lines. The anti-estrogen-doxorubicin hybrid demonstrated enhanced (>70-fold) selectivity for ER(+)-cells versus ER(-)-cells and enhanced efficacy compared to doxorubicin alone. The reversal of these effects by co-administration of estradiol demonstrated that the presence of the anti-estrogenic component was critical for selectivity and cytotoxicity in ER(+)-MCF-7 human breast cancer cells. The results suggest that this approach the basis for developing selective therapeutic agents for ER(+)-cancer cells with reduced effects on non-target tissues.1,2 The second study describes our use of 11beta-AE for targeting ER membrane targeting in hormone-dependent breast cancer, and of a urea-based prostate specific membrane antigen (PSMA) inhibitor for targeting PSMA membrane receptors in androgen-independent of prostate cancer. These derivatives were used to prepare a series of molecular imaging probes. We have successfully established our model compound, 11beta-AE radiolabeled with 18F-fluoro-OEG-azide, for in vivo imaging.3 The third study describes a strategy based on the design and synthesis of a multifunctional gold nanoparticulate (mfAuNPs) drug delivery system that can be used for prostate cancer therapy. We have utilized a convergent modular assembly approach to prepare individual components such as a) prostate specific membrane antigen (PSMA) ligands for targeting; b) pH-sensitive doxorubicin; and c) Re/99Tc chelating complex for radioimaging. The components can be assembled with a terminal lipoic acid or thiolated ethylene glycol oligomer for attachment to the Au surface. Initial in vitro studies with the PSMA-targeted mfAuNPs demonstrated significant selective uptake and localization properties in LnCaP and PC-3 prostate cancer cells.4 References: (1) Dao, K.-L.; Hanson, R. N.: Targeting the Estrogen Receptor using Steroid-Therapeutic Drug Conjugates (Hybrids). Bioconjugate Chemistry 2012. DOI: 10.1021/bc300378e. (2) Dao, K.-L.; Sawant, R. R.; Hendricks, J. A.; Ronga, V.; Torchilin, V. P.; Hanson, R. N.: Design, Synthesis, and Initial Biological Evaluation of a Steroidal Anti-Estrogen-Doxorubicin Bioconjugate for Targeting Estrogen Receptor-Positive Breast Cancer Cells. Bioconjugate Chemistry 2012, 23, 785-795. (3) Design, Synthesis, and in vivo PET imaging of radioligand 18F-11beta-substituted estradiol (18F-11betaAE) in breast cancer (manuscript in prep.) (4) Prostate Cancer-Specific Drug Delivery and Imaging Systems: Design, Synthesis, and Biological Evaluation of Multi-functional Gold Nanoparticles (manuscript in prep.)

Target oriented dimensionality reduction of hyperspectral data by Kernel Fukunaga-Koontz Transform

NASA Astrophysics Data System (ADS)

Binol, Hamidullah; Ochilov, Shuhrat; Alam, Mohammad S.; Bal, Abdullah

2017-02-01

Principal component analysis (PCA) is a popular technique in remote sensing for dimensionality reduction. While PCA is suitable for data compression, it is not necessarily an optimal technique for feature extraction, particularly when the features are exploited in supervised learning applications (Cheriyadat and Bruce, 2003) [1]. Preserving features belonging to the target is very crucial to the performance of target detection/recognition techniques. Fukunaga-Koontz Transform (FKT) based supervised band reduction technique can be used to provide this requirement. FKT achieves feature selection by transforming into a new space in where feature classes have complimentary eigenvectors. Analysis of these eigenvectors under two classes, target and background clutter, can be utilized for target oriented band reduction since each basis functions best represent target class while carrying least information of the background class. By selecting few eigenvectors which are the most relevant to the target class, dimension of hyperspectral data can be reduced and thus, it presents significant advantages for near real time target detection applications. The nonlinear properties of the data can be extracted by kernel approach which provides better target features. Thus, we propose constructing kernel FKT (KFKT) to present target oriented band reduction. The performance of the proposed KFKT based target oriented dimensionality reduction algorithm has been tested employing two real-world hyperspectral data and results have been reported consequently.

Hormones and the Evolution of Complex Traits: Insights from Artificial Selection on Behavior

PubMed Central

Garland, Theodore; Zhao, Meng; Saltzman, Wendy

2016-01-01

Although behavior may often be a fairly direct target of natural or sexual selection, it cannot evolve without changes in subordinate traits that cause or permit its expression. In principle, changes in endocrine function could be a common mechanism underlying behavioral evolution because they are well positioned to mediate integrated responses to behavioral selection. More specifically, hormones can influence both motivational (e.g., brain) and performance (e.g., muscles) components of behavior simultaneously and in a coordinated fashion. If the endocrine system is often “used” as a general mechanism to effect responses to selection, then correlated responses in other aspects of behavior, life history, and organismal performance (e.g., locomotor abilities) should commonly occur because any cell with appropriate receptors could be affected. Ways in which behavior coadapts with other aspects of the phenotype can be studied directly through artificial selection and experimental evolution. Several studies have targeted rodent behavior for selective breeding and reported changes in other aspects of behavior, life history, and lower-level effectors of these organismal traits, including endocrine function. One example involves selection for high levels of voluntary wheel running, one aspect of physical activity, in four replicate High Runner (HR) lines of mice. Circulating levels of several hormones (including insulin, testosterone, thyroxine, triiodothyronine) have been characterized, three of which—corticosterone, leptin, and adiponectin—differ between HR and control lines, depending on sex, age, and generation. Potential changes in circulating levels of other behaviorally and metabolically relevant hormones, as well as in other components of the endocrine system (e.g., receptors), have yet to be examined. Overall, results to date identify promising avenues for further studies on the endocrine basis of activity levels. PMID:27252193

Timing as a sexually selected trait: the right mate at the right moment.

PubMed

Hau, Michaela; Dominoni, Davide; Casagrande, Stefania; Buck, C Loren; Wagner, Gabriela; Hazlerigg, David; Greives, Timothy; Hut, Roelof A

2017-11-19

Sexual selection favours the expression of traits in one sex that attract members of the opposite sex for mating. The nature of sexually selected traits such as vocalization, colour and ornamentation, their fitness benefits as well as their costs have received ample attention in field and laboratory studies. However, sexually selected traits may not always be expressed: coloration and ornaments often follow a seasonal pattern and behaviours may be displayed only at specific times of the day. Despite the widely recognized differences in the daily and seasonal timing of traits and their consequences for reproductive success, the actions of sexual selection on the temporal organization of traits has received only scant attention. Drawing on selected examples from bird and mammal studies, here we summarize the current evidence for the daily and seasonal timing of traits. We highlight that molecular advances in chronobiology have opened exciting new opportunities for identifying the genetic targets that sexual selection may act on to shape the timing of trait expression. Furthermore, known genetic links between daily and seasonal timing mechanisms lead to the hypothesis that selection on one timescale may simultaneously also affect the other. We emphasize that studies on the timing of sexual displays of both males and females from wild populations will be invaluable for understanding the nature of sexual selection and its potential to act on differences within and between the sexes in timing. Molecular approaches will be important for pinpointing genetic components of biological rhythms that are targeted by sexual selection, and to clarify whether these represent core or peripheral components of endogenous clocks. Finally, we call for a renewed integration of the fields of evolution, behavioural ecology and chronobiology to tackle the exciting question of how sexual selection contributes to the evolution of biological clocks.This article is part of the themed issue 'Wild clocks: integrating chronobiology and ecology to understand timekeeping in free-living animals'. © 2017 The Author(s).

A philosophy for CNS radiotracer design.

PubMed

Van de Bittner, Genevieve C; Ricq, Emily L; Hooker, Jacob M

2014-10-21

Decades after its discovery, positron emission tomography (PET) remains the premier tool for imaging neurochemistry in living humans. Technological improvements in radiolabeling methods, camera design, and image analysis have kept PET in the forefront. In addition, the use of PET imaging has expanded because researchers have developed new radiotracers that visualize receptors, transporters, enzymes, and other molecular targets within the human brain. However, of the thousands of proteins in the central nervous system (CNS), researchers have successfully imaged fewer than 40 human proteins. To address the critical need for new radiotracers, this Account expounds on the decisions, strategies, and pitfalls of CNS radiotracer development based on our current experience in this area. We discuss the five key components of radiotracer development for human imaging: choosing a biomedical question, selection of a biological target, design of the radiotracer chemical structure, evaluation of candidate radiotracers, and analysis of preclinical imaging. It is particularly important to analyze the market of scientists or companies who might use a new radiotracer and carefully select a relevant biomedical question(s) for that audience. In the selection of a specific biological target, we emphasize how target localization and identity can constrain this process and discuss the optimal target density and affinity ratios needed for binding-based radiotracers. In addition, we discuss various PET test-retest variability requirements for monitoring changes in density, occupancy, or functionality for new radiotracers. In the synthesis of new radiotracer structures, high-throughput, modular syntheses have proved valuable, and these processes provide compounds with sites for late-stage radioisotope installation. As a result, researchers can manage the time constraints associated with the limited half-lives of isotopes. In order to evaluate brain uptake, a number of methods are available to predict bioavailability, blood-brain barrier (BBB) permeability, and the associated issues of nonspecific binding and metabolic stability. To evaluate the synthesized chemical library, researchers need to consider high-throughput affinity assays, the analysis of specific binding, and the importance of fast binding kinetics. Finally, we describe how we initially assess preclinical radiotracer imaging, using brain uptake, specific binding, and preliminary kinetic analysis to identify promising radiotracers that may be useful for human brain imaging. Although we discuss these five design components separately and linearly in this Account, in practice we develop new PET-based radiotracers using these design components nonlinearly and iteratively to develop new compounds in the most efficient way possible.

Fusion technologies for Laser Inertial Fusion Energy (LIFE)

NASA Astrophysics Data System (ADS)

Kramer, K. J.; Latkowski, J. F.; Abbott, R. P.; Anklam, T. P.; Dunne, A. M.; El-Dasher, B. S.; Flowers, D. L.; Fluss, M. J.; Lafuente, A.; Loosmore, G. A.; Morris, K. R.; Moses, E.; Reyes, S.

2013-11-01

The Laser Inertial Fusion-based Energy (LIFE) engine design builds upon on going progress at the National Ignition Facility (NIF) and offers a near-term pathway to commercial fusion. Fusion technologies that are critical to success are reflected in the design of the first wall, blanket and tritium separation subsystems. The present work describes the LIFE engine-related components and technologies. LIFE utilizes a thermally robust indirect-drive target and a chamber fill gas. Coolant selection and a large chamber solid-angle coverage provide ample tritium breeding margin and high blanket gain. Target material selection eliminates the need for aggressive chamber clearing, while enabling recycling. Demonstrated tritium separation and storage technologies limit the site tritium inventory to attractive levels. These key technologies, along with the maintenance and advanced materials qualification program have been integrated into the LIFE delivery plan. This describes the development of components and subsystems, through prototyping and integration into a First Of A Kind power plant. This work performed under the auspices of the U.S. Department of Energy by Lawrence Livermore National Laboratory under Contract DE-AC52-07NA27344.

Strategy to improve the quantitative LC-MS analysis of molecular ions resistant to gas-phase collision induced dissociation: application to disulfide-rich cyclic peptides.

PubMed

Ciccimaro, Eugene; Ranasinghe, Asoka; D'Arienzo, Celia; Xu, Carrie; Onorato, Joelle; Drexler, Dieter M; Josephs, Jonathan L; Poss, Michael; Olah, Timothy

2014-12-02

Due to observed collision induced dissociation (CID) fragmentation inefficiency, developing sensitive liquid chromatography tandem mass spectrometry (LC-MS/MS) assays for CID resistant compounds is especially challenging. As an alternative to traditional LC-MS/MS, we present here a methodology that preserves the intact analyte ion for quantification by selectively filtering ions while reducing chemical noise. Utilizing a quadrupole-Orbitrap MS, the target ion is selectively isolated while interfering matrix components undergo MS/MS fragmentation by CID, allowing noise-free detection of the analyte's surviving molecular ion. In this manner, CID affords additional selectivity during high resolution accurate mass analysis by elimination of isobaric interferences, a fundamentally different concept than the traditional approach of monitoring a target analyte's unique fragment following CID. This survivor-selected ion monitoring (survivor-SIM) approach has allowed sensitive and specific detection of disulfide-rich cyclic peptides extracted from plasma.

Flight service evaluation of an advanced composite empennage component on commercial transport aircraft. Phase 1: Engineering development

NASA Technical Reports Server (NTRS)

Ary, A.; Axtell, C.; Fogg, L.; Jackson, A.; James, A. M.; Mosesian, B.; Vanderwier, J.; Vanhamersveld, J.

1976-01-01

The empennage component selected for this program is the vertical fin box of the L-1011 aircraft. The box structure extends from the fuselage production joint to the tip rib and includes the front and rear spars. Various design options were evaluated to arrive at a configuration which would offer the highest potential for satisfying program objectives. The preferred configuration selected consists of a hat-stiffened cover with molded integrally stiffened spars, aluminum trussed composite ribs, and composite miniwich web ribs with integrally molded caps. Material screening tests were performed to select an advanced composite material system for the Advanced Composite Vertical Fin (ACFV) that would meet the program requirements from the standpoint of quality, reproducibility, and cost. Preliminary weight and cost analysis were made, targets established, and tracking plans developed. These include FAA certification, ancillary test program, quality control, and structural integrity control plans.

Controlling Cargo Trafficking in Multicomponent Membranes.

PubMed

Curk, Tine; Wirnsberger, Peter; Dobnikar, Jure; Frenkel, Daan; Šarić, Anđela

2018-04-27

Biological membranes typically contain a large number of different components dispersed in small concentrations in the main membrane phase, including proteins, sugars, and lipids of varying geometrical properties. Most of these components do not bind the cargo. Here, we show that such "inert" components can be crucial for the precise control of cross-membrane trafficking. Using a statistical mechanics model and molecular dynamics simulations, we demonstrate that the presence of inert membrane components of small isotropic curvatures dramatically influences cargo endocytosis, even if the total spontaneous curvature of such a membrane remains unchanged. Curved lipids, such as cholesterol, as well as asymmetrically included proteins and tethered sugars can, therefore, actively participate in the control of the membrane trafficking of nanoscopic cargo. We find that even a low-level expression of curved inert membrane components can determine the membrane selectivity toward the cargo size and can be used to selectively target membranes of certain compositions. Our results suggest a robust and general method of controlling cargo trafficking by adjusting the membrane composition without needing to alter the concentration of receptors or the average membrane curvature. This study indicates that cells can prepare for any trafficking event by incorporating curved inert components in either of the membrane leaflets.

Developing a multi-pollutant conceptual framework for the selection and targeting of interventions in water industry catchment management schemes.

PubMed

Bloodworth, J W; Holman, I P; Burgess, P J; Gillman, S; Frogbrook, Z; Brown, P

2015-09-15

In recent years water companies have started to adopt catchment management to reduce diffuse pollution in drinking water supply areas. The heterogeneity of catchments and the range of pollutants that must be removed to meet the EU Drinking Water Directive (98/83/EC) limits make it difficult to prioritise areas of a catchment for intervention. Thus conceptual frameworks are required that can disaggregate the components of pollutant risk and help water companies make decisions about where to target interventions in their catchments to maximum effect. This paper demonstrates the concept of generalising pollutants in the same framework by reviewing key pollutant processes within a source-mobilisation-delivery context. From this, criteria are developed (with input from water industry professionals involved in catchment management) which highlights the need for a new water industry specific conceptual framework. The new CaRPoW (Catchment Risk to Potable Water) framework uses the Source-Mobilisation-Delivery concept as modular components of risk that work at two scales, source and mobilisation at the field scale and delivery at the catchment scale. Disaggregating pollutant processes permits the main components of risk to be ascertained so that appropriate interventions can be selected. The generic structure also allows for the outputs from different pollutants to be compared so that potential multiple benefits can be identified. CaRPow provides a transferable framework that can be used by water companies to cost-effectively target interventions under current conditions or under scenarios of land use or climate change. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

Independent priming of location and color in identification of briefly presented letters.

PubMed

Ásgeirsson, Árni Gunnar; Kristjánsson, Árni; Bundesen, Claus

2014-01-01

Attention shifts are facilitated if the items to be attended remain the same across trials. Some researchers argue that this priming effect is perceptual, whereas others propose that priming is postperceptual, involving facilitated response selection. The experimental findings have not been consistent regarding the roles of variables such as task difficulty, response repetition, expectancies, and decision-making. Position priming, when repetition of a target position facilitates responses on a subsequent trial, is another source of disagreement among researchers. Experimental results have likewise been inconsistent as to whether position priming is dependent on the repetition of target features or has an independent effect on attention shifts. We attempted to isolate the perceptual components of priming by presenting brief (10-180 ms) search arrays to eight healthy observers. The task was to identify a color-singleton letter among distractors. All stimulus presentation contingencies were randomized, and responses were unspeeded, to avoid effects of observer expectation and postperceptual effects. Repeating target color and/or position strongly improved performance. The effects of color and position repetition were independent of one another and were stable across participants. The results argue for a strong perceptual component in priming, which biases selection toward recent target features and positions, showing that perceptual mechanisms are sufficient to produce priming in visual search and that such effects can be elicited with limited sensory evidence. The results are the first to demonstrate independent priming of color and position in the identification of briefly presented, postmasked stimuli.

Mechanical intermixing of components in (CoMoNi)-based systems and the formation of (CoMoNi)/WC nanocomposite layers on Ti sheets under ball collisions

NASA Astrophysics Data System (ADS)

Romankov, S.; Park, Y. C.; Shchetinin, I. V.

2017-11-01

Cobalt (Co), molybdenum (Mo), and nickel (Ni) components were simultaneously introduced onto titanium (Ti) surfaces from a composed target using ball collisions. Tungsten carbide (WC) balls were selected for processing as the source of a cemented carbide reinforcement phase. During processing, ball collisions continuously introduced components from the target and the grinding media onto the Ti surface and induced mechanical intermixing of the elements, resulting in formation of a complex nanocomposite structure onto the Ti surface. The as-fabricated microstructure consisted of uniformly dispersed WC particles embedded within an integrated metallic matrix composed of an amorphous phase with nanocrystalline grains. The phase composition of the alloyed layers, atomic reactions, and the matrix grain sizes depended on the combination of components introduced onto the Ti surface during milling. The as-fabricated layer exhibited a very high hardness compared to industrial metallic alloys and tool steel materials. This approach could be used for the manufacture of both cemented carbides and amorphous matrix composite layers.

Changes of Attention during Value-Based Reversal Learning Are Tracked by N2pc and Feedback-Related Negativity

PubMed Central

Oemisch, Mariann; Watson, Marcus R.; Womelsdorf, Thilo; Schubö, Anna

2017-01-01

Previously learned reward values can have a pronounced impact, behaviorally and neurophysiologically, on the allocation of selective attention. All else constant, stimuli previously associated with a high value gain stronger attentional prioritization than stimuli previously associated with a low value. The N2pc, an ERP component indicative of attentional target selection, has been shown to reflect aspects of this prioritization, by changes of mean amplitudes closely corresponding to selective enhancement of high value target processing and suppression of high value distractor processing. What has remained unclear so far is whether the N2pc also reflects the flexible and repeated behavioral adjustments needed in a volatile task environment, in which the values of stimuli are reversed often and unannounced. Using a value-based reversal learning task, we found evidence that the N2pc amplitude flexibly and reversibly tracks value-based choices during the learning of reward associated stimulus colors. Specifically, successful learning of current value-contingencies was associated with reduced N2pc amplitudes, and this effect was more apparent for distractor processing, compared with target processing. In addition, following a value reversal the feedback related negativity(FRN), an ERP component that reflects feedback processing, was amplified and co-occurred with increased N2pc amplitudes in trials following low-value feedback. Importantly, participants that showed the greatest adjustment in N2pc amplitudes based on feedback were also the most efficient learners. These results allow further insight into how changes in attentional prioritization in an uncertain and volatile environment support flexible adjustments of behavior. PMID:29163113

Changes of Attention during Value-Based Reversal Learning Are Tracked by N2pc and Feedback-Related Negativity.

PubMed

Oemisch, Mariann; Watson, Marcus R; Womelsdorf, Thilo; Schubö, Anna

2017-01-01

Previously learned reward values can have a pronounced impact, behaviorally and neurophysiologically, on the allocation of selective attention. All else constant, stimuli previously associated with a high value gain stronger attentional prioritization than stimuli previously associated with a low value. The N2pc, an ERP component indicative of attentional target selection, has been shown to reflect aspects of this prioritization, by changes of mean amplitudes closely corresponding to selective enhancement of high value target processing and suppression of high value distractor processing. What has remained unclear so far is whether the N2pc also reflects the flexible and repeated behavioral adjustments needed in a volatile task environment, in which the values of stimuli are reversed often and unannounced. Using a value-based reversal learning task, we found evidence that the N2pc amplitude flexibly and reversibly tracks value-based choices during the learning of reward associated stimulus colors. Specifically, successful learning of current value-contingencies was associated with reduced N2pc amplitudes, and this effect was more apparent for distractor processing, compared with target processing. In addition, following a value reversal the feedback related negativity(FRN), an ERP component that reflects feedback processing, was amplified and co-occurred with increased N2pc amplitudes in trials following low-value feedback. Importantly, participants that showed the greatest adjustment in N2pc amplitudes based on feedback were also the most efficient learners. These results allow further insight into how changes in attentional prioritization in an uncertain and volatile environment support flexible adjustments of behavior.

The effect of category learning on attentional modulation of visual cortex.

PubMed

Folstein, Jonathan R; Fuller, Kelly; Howard, Dorothy; DePatie, Thomas

2017-09-01

Learning about visual object categories causes changes in the way we perceive those objects. One likely mechanism by which this occurs is the application of attention to potentially relevant objects. Here we test the hypothesis that category membership influences the allocation of attention, allowing attention to be applied not only to object features, but to entire categories. Participants briefly learned to categorize a set of novel cartoon animals after which EEG was recorded while participants distinguished between a target and non-target category. A second identical EEG session was conducted after two sessions of categorization practice. The category structure and task design allowed parametric manipulation of number of target features while holding feature frequency and category membership constant. We found no evidence that category membership influenced attentional selection: a postero-lateral negative component, labeled the selection negativity/N250, increased over time and was sensitive to number of target features, not target categories. In contrast, the right hemisphere N170 was not sensitive to target features. The P300 appeared sensitive to category in the first session, but showed a graded sensitivity to number of target features in the second session, possibly suggesting a transition from rule-based to similarity based categorization. Copyright © 2017. Published by Elsevier Ltd.

An Adenovirus DNA Replication Factor, but Not Incoming Genome Complexes, Targets PML Nuclear Bodies.

PubMed

Komatsu, Tetsuro; Nagata, Kyosuke; Wodrich, Harald

2016-02-01

Promyelocytic leukemia protein nuclear bodies (PML-NBs) are subnuclear domains implicated in cellular antiviral responses. Despite the antiviral activity, several nuclear replicating DNA viruses use the domains as deposition sites for the incoming viral genomes and/or as sites for viral DNA replication, suggesting that PML-NBs are functionally relevant during early viral infection to establish productive replication. Although PML-NBs and their components have also been implicated in the adenoviral life cycle, it remains unclear whether incoming adenoviral genome complexes target PML-NBs. Here we show using immunofluorescence and live-cell imaging analyses that incoming adenovirus genome complexes neither localize at nor recruit components of PML-NBs during early phases of infection. We further show that the viral DNA binding protein (DBP), an early expressed viral gene and essential DNA replication factor, independently targets PML-NBs. We show that DBP oligomerization is required to selectively recruit the PML-NB components Sp100 and USP7. Depletion experiments suggest that the absence of one PML-NB component might not affect the recruitment of other components toward DBP oligomers. Thus, our findings suggest a model in which an adenoviral DNA replication factor, but not incoming viral genome complexes, targets and modulates PML-NBs to support a conducive state for viral DNA replication and argue against a generalized concept that PML-NBs target incoming viral genomes. The immediate fate upon nuclear delivery of genomes of incoming DNA viruses is largely unclear. Early reports suggested that incoming genomes of herpesviruses are targeted and repressed by PML-NBs immediately upon nuclear import. Genome localization and/or viral DNA replication has also been observed at PML-NBs for other DNA viruses. Thus, it was suggested that PML-NBs may immediately sense and target nuclear viral genomes and hence serve as sites for deposition of incoming viral genomes and/or subsequent viral DNA replication. Here we performed a detailed analyses of the spatiotemporal distribution of incoming adenoviral genome complexes and found, in contrast to the expectation, that an adenoviral DNA replication factor, but not incoming genomes, targets PML-NBs. Thus, our findings may explain why adenoviral genomes could be observed at PML-NBs in earlier reports but argue against a generalized role for PML-NBs in targeting invading viral genomes. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

Efficient Generation of Somatic Cell Nuclear Transfer-Competent Porcine Cells with Mutated Alleles at Multiple Target Loci by Using CRISPR/Cas9 Combined with Targeted Toxin-Based Selection System.

PubMed

Sato, Masahiro; Miyoshi, Kazuchika; Nakamura, Shingo; Ohtsuka, Masato; Sakurai, Takayuki; Watanabe, Satoshi; Kawaguchi, Hiroaki; Tanimoto, Akihide

2017-12-04

The recent advancement in genome editing such a CRISPR/Cas9 system has enabled isolation of cells with knocked multiple alleles through a one-step transfection. Somatic cell nuclear transfer (SCNT) has been frequently employed as one of the efficient tools for the production of genetically modified (GM) animals. To use GM cells as SCNT donor, efficient isolation of transfectants with mutations at multiple target loci is often required. The methods for the isolation of such GM cells largely rely on the use of drug selection-based approach using selectable genes; however, it is often difficult to isolate cells with mutations at multiple target loci. In this study, we used a novel approach for the efficient isolation of porcine cells with at least two target loci mutations by one-step introduction of CRISPR/Cas9-related components. A single guide (sg) RNA targeted to GGTA1 gene, involved in the synthesis of cell-surface α-Gal epitope (known as xenogenic antigen), is always a prerequisite. When the transfected cells were reacted with toxin-labeled BS-I-B₄ isolectin for 2 h at 37 C to eliminate α-Gal epitope-expressing cells, the surviving clones lacked α-Gal epitope expression and were highly expected to exhibit induced mutations at another target loci. Analysis of these α-Gal epitope-negative surviving cells demonstrated a 100% occurrence of genome editing at target loci. SCNT using these cells as donors resulted in the production of cloned blastocysts with the genotype similar to that of the donor cells used. Thus, this novel system will be useful for SCNT-mediated acquisition of GM cloned piglets, in which multiple target loci may be mutated.

Using Negotiated Joining to Construct and Fill Open-ended Roles in Elite Culinary Groups.

PubMed

Tan, Vaughn

2015-03-01

This qualitative study examines membership processes in groups operating in an uncertain environment that prevents them from fully predefining new members' roles. I describe how nine elite high-end, cutting-edge culinary groups in the U.S. and Europe, ranging from innovative restaurants to culinary R&D groups, use negotiated joining-a previously undocumented process-to systematically construct and fill these emergent, open-ended roles. I show that negotiated joining is a consistently patterned, iterative process that begins with a role that both aspirant and target group explicitly understand to be provisional. This provisional role is then jointly modified and constructed by the aspirant and target group through repeated iterations of proposition, validation through trial and evaluation, and selective integration of validated role components. The initially provisional role stabilizes and the aspirant achieves membership if enough role components are validated; otherwise the negotiated joining process is abandoned. Negotiated joining allows the aspirant and target group to learn if a mutually desirable role is likely and, if so, to construct such a role. In addition, the provisional roles in negotiated joining can support absorptive capacity by allowing novel role components to enter target groups through aspirants' efforts to construct stable roles for themselves, while the internal adjustment involved in integrating newly validated role components can have the unintended side effect of supporting adaptation by providing opportunities for the groups to use these novel role components to modify their role structure and goals to suit a changing and uncertain environment. Negotiated joining thus reveals role ambiguity's hitherto unexamined beneficial consequences and provides a foundation for a contingency theory of new-member acquisition.

Using Negotiated Joining to Construct and Fill Open-ended Roles in Elite Culinary Groups

PubMed Central

Tan, Vaughn

2015-01-01

This qualitative study examines membership processes in groups operating in an uncertain environment that prevents them from fully predefining new members’ roles. I describe how nine elite high-end, cutting-edge culinary groups in the U.S. and Europe, ranging from innovative restaurants to culinary R&D groups, use negotiated joining—a previously undocumented process—to systematically construct and fill these emergent, open-ended roles. I show that negotiated joining is a consistently patterned, iterative process that begins with a role that both aspirant and target group explicitly understand to be provisional. This provisional role is then jointly modified and constructed by the aspirant and target group through repeated iterations of proposition, validation through trial and evaluation, and selective integration of validated role components. The initially provisional role stabilizes and the aspirant achieves membership if enough role components are validated; otherwise the negotiated joining process is abandoned. Negotiated joining allows the aspirant and target group to learn if a mutually desirable role is likely and, if so, to construct such a role. In addition, the provisional roles in negotiated joining can support absorptive capacity by allowing novel role components to enter target groups through aspirants’ efforts to construct stable roles for themselves, while the internal adjustment involved in integrating newly validated role components can have the unintended side effect of supporting adaptation by providing opportunities for the groups to use these novel role components to modify their role structure and goals to suit a changing and uncertain environment. Negotiated joining thus reveals role ambiguity’s hitherto unexamined beneficial consequences and provides a foundation for a contingency theory of new-member acquisition. PMID:26273105

Phenotype-information-phenotype cycle for deconvolution of combinatorial antibody libraries selected against complex systems.

PubMed

Zhang, Hongkai; Torkamani, Ali; Jones, Teresa M; Ruiz, Diana I; Pons, Jaume; Lerner, Richard A

2011-08-16

Use of large combinatorial antibody libraries and next-generation sequencing of nucleic acids are two of the most powerful methods in modern molecular biology. The libraries are screened using the principles of evolutionary selection, albeit in real time, to enrich for members with a particular phenotype. This selective process necessarily results in the loss of information about less-fit molecules. On the other hand, sequencing of the library, by itself, gives information that is mostly unrelated to phenotype. If the two methods could be combined, the full potential of very large molecular libraries could be realized. Here we report the implementation of a phenotype-information-phenotype cycle that integrates information and gene recovery. After selection for phage-encoded antibodies that bind to targets expressed on the surface of Escherichia coli, the information content of the selected pool is obtained by pyrosequencing. Sequences that encode specific antibodies are identified by a bioinformatic analysis and recovered by a stringent affinity method that is uniquely suited for gene isolation from a highly degenerate collection of nucleic acids. This approach can be generalized for selection of antibodies against targets that are present as minor components of complex systems.

Fertilization selection on egg and jelly-coat size in the sand dollar Dendraster excentricus.

PubMed

Levitan, D R; Irvine, S D

2001-12-01

Organisms with external fertilization are often sperm limited, and in echinoids, larger eggs have a higher probability of fertilization than smaller eggs. This difference is thought to be a result of the more frequent sperm-egg collisions experienced by larger targets. Here we report how two components of egg target size, the egg cell and jelly coat, contributed to fertilization success in a selection experiment. We used a cross-sectional analysis of correlated characters to estimate the selection gradients on egg and jelly-coat size in five replicate male pairs of the sand dollar Dendraster excentricus. Results indicated that eggs with larger cells and jelly coats were preferentially fertilized under sperm limitation in the laboratory. The selection gradients were an average of 922% steeper for egg than for jelly-coat size. The standardized selection gradients for egg and jelly-coat size were similar. Our results suggest that fertilization selection can act on both egg-cell and jelly-coat size but that an increase in egg-cell volume is much more likely to increase fertilization success than an equal change in jelly-coat volume. The strengths of the selection gradients were inversely related to the correlation of egg traits across replicate egg clutches. This result suggests the importance of replication in studies of selection of correlated characters.

Development of a microprocessing-assisted cell-systematic evolution of ligands by exponential enrichment method for human umbilical vein endothelial cells

NASA Astrophysics Data System (ADS)

Terazono, Hideyuki; Kim, Hyonchol; Nomura, Fumimasa; Yasuda, Kenji

2016-06-01

We developed a microprocessing-assisted technique to select single-strand DNA aptamers that bind to unknown targets on the cell surface by modifying the conventional systematic evolution of ligands by exponential enrichment (cell-SELEX). Our technique involves 1) the specific selection of target-cell-surface-bound aptamers without leakage of intracellular components by trypsinization and 2) cloning of aptamers by microprocessing-assisted picking of single cells using magnetic beads. After cell-SELEX, the enriched aptamers were conjugated with magnetic beads. The aptamer-magnetic beads conjugates attached to target cells were collected individually by microassisted procedures using microneedles under a microscope. After that, the sequences of the collected magnetic-bead-bound aptamers were identified. As a result, a specific aptamer for the surface of target cells, e.g., human umbilical vein endothelial cells (HUVECs), was chosen and its specificity was examined using other cell types, e.g., HeLa cells. The results indicate that this microprocessing-assisted cell-SELEX method for identifying aptamers is applicable in biological research and clinical diagnostics.

Observations and light curve solutions of a selection of middle-contact W UMa binaries

NASA Astrophysics Data System (ADS)

Kjurkchieva, Diana Petrova; Popov, Velimir Angelov; Lyubenova Vasileva, Doroteya; Petrov, Nikola Ivanov

2018-04-01

Photometric observations in Sloan g‧ and i‧ bands of W UMa binaries NSVS 4340949, T-Dra0–00959, GSC 03950–00707, NSVS 4665041, NSVS 4803568, MM Peg, MM Com and NSVS 4751449 are presented. The light curve solutions revealed that the components of each target are of G and K spectral types. The binaries of the sample have middle-contact configurations whose fillout factors are within the range 0.2–0.4. The only exception is NSVS 4751449 which is in deeper contact (fillout factor of 0.55). It precisely obeys the relation between mass ratio and fillout factor for deep, low mass ratio overcontact binaries. One of the eclipses of almost all targets (except MM Peg) is an occultation and their photometric mass ratios and solutions could be accepted with confidence. We found that the target components have almost equal temperatures but differ considerably in size and mass. The components of the partially-eclipsed MM Peg have close parameters. Our solutions reveal that NSVS 4340949, T-Dra0–00959, NSVS 4803568 and MM Com are of W subtype while GSC 03950–00707, NSVS 4665041, MM Peg and NSVS 4751449 are of A subtype. This subclassification is well-determined for all totally-eclipsed binaries. The targets confirm the trends in which W-subtype systems have smaller periods and lower temperatures than A subtype binaries.

Progress Toward Efficient Laminar Flow Analysis and Design

NASA Technical Reports Server (NTRS)

Campbell, Richard L.; Campbell, Matthew L.; Streit, Thomas

2011-01-01

A multi-fidelity system of computer codes for the analysis and design of vehicles having extensive areas of laminar flow is under development at the NASA Langley Research Center. The overall approach consists of the loose coupling of a flow solver, a transition prediction method and a design module using shell scripts, along with interface modules to prepare the input for each method. This approach allows the user to select the flow solver and transition prediction module, as well as run mode for each code, based on the fidelity most compatible with the problem and available resources. The design module can be any method that designs to a specified target pressure distribution. In addition to the interface modules, two new components have been developed: 1) an efficient, empirical transition prediction module (MATTC) that provides n-factor growth distributions without requiring boundary layer information; and 2) an automated target pressure generation code (ATPG) that develops a target pressure distribution that meets a variety of flow and geometry constraints. The ATPG code also includes empirical estimates of several drag components to allow the optimization of the target pressure distribution. The current system has been developed for the design of subsonic and transonic airfoils and wings, but may be extendable to other speed ranges and components. Several analysis and design examples are included to demonstrate the current capabilities of the system.

Identification of (antioxidative) plants in herbal pharmaceutical preparations and dietary supplements.

PubMed

Deconinck, Eric; Custers, Deborah; De Beer, Jacques Omer

2015-01-01

The standard procedures for the identification, authentication, and quality control of medicinal plants and herbs are nowadays limited to pure herbal products. No guidelines or procedures, describing the detection or identification of a targeted plant or herb in pharmaceutical preparations or dietary supplements, can be found. In these products the targeted plant is often present together with other components of herbal or synthetic origin. This chapter describes a strategy for the fast development of a chromatographic fingerprint approach that allows the identification of a targeted plant in herbal preparations and dietary supplements. The strategy consists of a standard chromatographic gradient that is tested for the targeted plant with different extraction solvents and different mobile phases. From the results obtained, the optimal fingerprint is selected. Subsequently the samples are analyzed according to the selected methodological parameters, and the obtained fingerprints can be compared with the one obtained for the pure herbal product or a standard preparation. Calculation of the dissimilarity between these fingerprints will result in a probability of presence of the targeted plant. Optionally mass spectrometry can be used to improve specificity, to confirm identification, or to identify molecules with a potential medicinal or antioxidant activity.

Method and apparatus for noble gas atom detection with isotopic selectivity

DOEpatents

Hurst, G. Samuel; Payne, Marvin G.; Chen, Chung-Hsuan; Parks, James E.

1984-01-01

Apparatus and methods of operation are described for determining, with isotopic selectivity, the number of noble gas atoms in a sample. The analysis is conducted within an evacuated chamber which can be isolated by a valve from a vacuum pumping system capable of producing a pressure of 10.sup.-8 Torr. Provision is made to pass pulses of laser beams through the chamber, these pulses having wavelengths appropriate for the resonance ionization of atoms of the noble gas under analysis. A mass filter within the chamber selects ions of a specific isotope of the noble gas, and means are provided to accelerate these selected ions sufficiently for implantation into a target. Specific types of targets are discussed. An electron measuring device produces a signal relatable to the number of ions implanted into the target and thus to the number of atoms of the selected isotope of the noble gas removed from the gas sample. The measurement can be continued until a substantial fraction, or all, of the atoms in the sample have been counted. Furthermore, additional embodiments of the apparatus are described for bunching the atoms of a noble gas for more rapid analysis, and for changing the target for repetitive cycling of the gas in the chamber. The number of repetitions of the cyclic steps depend upon the concentration of the isotope of interest, the separative efficiency of the mass filter, etc. The cycles are continued until a desired selectivity is achieved. Also described are components and a method of operation for a pre-enrichment operation for use when an introduction of a total sample would elevate the pressure within the chamber to levels in excess of those for operation of the mass filter, specifically a quadrupole mass filter. Specific examples of three noble gas isotope analyses are described.

Development of a component design tool for metal hydride heat pumps

NASA Astrophysics Data System (ADS)

Waters, Essene L.

Given current demands for more efficient and environmentally friendly energy sources, hydrogen based energy systems are an increasingly popular field of interest. Within the field, metal hydrides have become a prominent focus of research due to their large hydrogen storage capacity and relative system simplicity and safety. Metal hydride heat pumps constitute one such application, in which heat and hydrogen are transferred to and from metal hydrides. While a significant amount of work has been done to study such systems, the scope of materials selection has been quite limited. Typical studies compare only a few metal hydride materials and provide limited justification for the choice of those few. In this work, a metal hydride component design tool has been developed to enable the targeted down-selection of an extensive database of metal hydrides to identify the most promising materials for use in metal hydride thermal systems. The material database contains over 300 metal hydrides with various physical and thermodynamic properties included for each material. Sub-models for equilibrium pressure, thermophysical data, and default properties are used to predict the behavior of each material within the given system. For a given thermal system, this tool can be used to identify optimal materials out of over 100,000 possible hydride combinations. The selection tool described herein has been applied to a stationary combined heat and power system containing a high-temperature proton exchange membrane (PEM) fuel cell, a hot water tank, and two metal hydride beds used as a heat pump. A variety of factors can be used to select materials including efficiency, maximum and minimum system pressures, pressure difference, coefficient of performance (COP), and COP sensitivity. The targeted down-selection of metal hydrides for this system focuses on the system's COP for each potential pair. The values of COP and COP sensitivity have been used to identify pairs of highest interest for use in this application. The metal hydride component design tool developed in this work selects between metal hydride materials on an unprecedented scale. It can be easily applied to other hydrogen-based thermal systems, making it a powerful and versatile tool.

Cognitive processes facilitated by contextual cueing: evidence from event-related brain potentials.

PubMed

Schankin, Andrea; Schubö, Anna

2009-05-01

Finding a target in repeated search displays is faster than finding the same target in novel ones (contextual cueing). It is assumed that the visual context (the arrangement of the distracting objects) is used to guide attention efficiently to the target location. Alternatively, other factors, e.g., facilitation in early visual processing or in response selection, may play a role as well. In a contextual cueing experiment, participant's electrophysiological brain activity was recorded. Participants identified the target faster and more accurately in repeatedly presented displays. In this condition, the N2pc, a component reflecting the allocation of visual-spatial attention, was enhanced, indicating that attention was allocated more efficiently to those targets. However, also response-related processes, reflected by the LRP, were facilitated, indicating that guidance of attention cannot account for the entire contextual cueing benefit.

Debris and shrapnel assessments for National Ignition Facility targets and diagnostics

NASA Astrophysics Data System (ADS)

Masters, N. D.; Fisher, A.; Kalantar, D.; Stölken, J.; Smith, C.; Vignes, R.; Burns, S.; Doeppner, T.; Kritcher, A.; Park, H.-S.

2016-05-01

High-energy laser experiments at the National Ignition Facility (NIF) can create debris and shrapnel capable of damaging laser optics and diagnostic instruments. The size, composition and location of target components and sacrificial shielding (e.g., disposable debris shields, or diagnostic filters) and the protection they provide is constrained by many factors, including: chamber and diagnostic geometries, experimental goals and material considerations. An assessment of the generation, nature and velocity of shrapnel and debris and their potential threats is necessary prior to fielding targets or diagnostics. These assessments may influence target and shielding design, filter configurations and diagnostic selection. This paper will outline the approach used to manage the debris and shrapnel risk associated with NIF targets and diagnostics and present some aspects of two such cases: the Material Strength Rayleigh- Taylor campaign and the Mono Angle Crystal Spectrometer (MACS).

Breaking into the epithelial apical–junctional complex — news from pathogen hackers

PubMed Central

Vogelmann, Roger; Amieva, Manuel R; Falkow, Stanley; Nelson, W James

2012-01-01

The epithelial apical–junctional complex is a key regulator of cellular functions. In addition, it is an important target for microbial pathogens that manipulate the cell to survive, proliferate and sometimes persist within a host. Out of a myriad of potential molecular targets, some bacterial and viral pathogens have selected a subset of protein targets at the apical–junctional complex of epithelial cells. Studying how microbes use these targets also teaches us about the inherent physiological properties of host molecules in the context of normal junctional structure and function. Thus, we have learned that three recently uncovered components of the apical–junctional complex of the Ig superfamily — junctional adhesion molecule, Nectin and the coxsackievirus and adenovirus receptor — are important regulators of junction structure and function and represent critical targets of microbial virulence gene products. PMID:15037310

Breaking into the epithelial apical-junctional complex--news from pathogen hackers.

PubMed

Vogelmann, Roger; Amieva, Manuel R; Falkow, Stanley; Nelson, W James

2004-02-01

The epithelial apical-junctional complex is a key regulator of cellular functions. In addition, it is an important target for microbial pathogens that manipulate the cell to survive, proliferate and sometimes persist within a host. Out of a myriad of potential molecular targets, some bacterial and viral pathogens have selected a subset of protein targets at the apical-junctional complex of epithelial cells. Studying how microbes use these targets also teaches us about the inherent physiological properties of host molecules in the context of normal junctional structure and function. Thus, we have learned that three recently uncovered components of the apical-junctional complex of the Ig superfamily--junctional adhesion molecule, Nectin and the coxsackievirus and adenovirus receptor--are important regulators of junction structure and function and represent critical targets of microbial virulence gene products.

Target contrast considerations in millimeter wave radiometry for airborne navigation

NASA Technical Reports Server (NTRS)

Mayer, A.

1971-01-01

Target signal requirements for aircraft navigation systems that use radiometric receivers which map thermally emitted power radiated by terrain or power radiated by ground-based beacons are discussed. For selected millimeter wavelength bands, microwaves suffer relatively little degradation by absorption or scattering on passage through the atmosphere, despite extreme weather variations. Interest centers on 8-millimeter waves because of component availability, portability (small size), high image resolution, and all-weather capability at this wavelength. The idea of radiometric airborne navigation is introduced. Elements of radiometry, terrain radiation, and atmospheric transmission characteristics are reviewed. Data pertaining to these elements at 8 mm wavelength are collected. Calculation of radiometric contrasts is discussed for some simple models of terrain targets.

Molecular target of synthetic antimicrobial oligomer in bacterial membranes

NASA Astrophysics Data System (ADS)

Yang, Lihua; Gordon, Vernita; Som, Abhigyan; Cronan, John; Tew, Gregory; Wong, Gerard

2008-03-01

Antimicrobial peptides comprises a key component of innate immunity for a wide range of multicellular organisms. It has been shown that natural antimicrobial peptides and their synthetic analogs have demonstrated broad-spectrum antimicrobial activity via permeating bacterial membranes selectively. Synthetic antimicrobials with tunable structure and toxicological profiles are ideal for investigations of selectivity mechanisms. We investigate interactions and self-assembly using a prototypical family of antimicrobials based on phenylene ethynylene. Results from synchrotron small angle x-ray scattering (SAXS) results and in vitro microbicidal assays on genetically modified `knock-out' bacteria will be presented.

Oncolytic Adenovirus: Strategies and Insights for Vector Design and Immuno-Oncolytic Applications

PubMed Central

Uusi-Kerttula, Hanni; Hulin-Curtis, Sarah; Davies, James; Parker, Alan L.

2015-01-01

Adenoviruses (Ad) are commonly used both experimentally and clinically, including oncolytic virotherapy applications. In the clinical area, efficacy is frequently hampered by the high rates of neutralizing immunity, estimated as high as 90% in some populations that promote vector clearance and limit bioavailability for tumor targeting following systemic delivery. Active tumor targeting is also hampered by the ubiquitous nature of the Ad5 receptor, hCAR, as well as the lack of highly tumor-selective targeting ligands and suitable targeting strategies. Furthermore, significant off-target interactions between the viral vector and cellular and proteinaceous components of the bloodstream have been documented that promote uptake into non-target cells and determine dose-limiting toxicities. Novel strategies are therefore needed to overcome the obstacles that prevent efficacious Ad deployment for wider clinical applications. The use of less seroprevalent Ad serotypes, non-human serotypes, capsid pseudotyping, chemical shielding and genetic masking by heterologous peptide incorporation are all potential strategies to achieve efficient vector escape from humoral immune recognition. Conversely, selective vector arming with immunostimulatory agents can be utilized to enhance their oncolytic potential by activation of cancer-specific immune responses against the malignant tissues. This review presents recent advantages and pitfalls occurring in the field of adenoviral oncolytic therapies. PMID:26610547

Scaling Impacts in Life Support Architecture and Technology Selection

NASA Technical Reports Server (NTRS)

Lange, Kevin

2016-01-01

For long-duration space missions outside of Earth orbit, reliability considerations will drive higher levels of redundancy and/or on-board spares for life support equipment. Component scaling will be a critical element in minimizing overall launch mass while maintaining an acceptable level of system reliability. Building on an earlier reliability study (AIAA 2012-3491), this paper considers the impact of alternative scaling approaches, including the design of technology assemblies and their individual components to maximum, nominal, survival, or other fractional requirements. The optimal level of life support system closure is evaluated for deep-space missions of varying duration using equivalent system mass (ESM) as the comparative basis. Reliability impacts are included in ESM by estimating the number of component spares required to meet a target system reliability. Common cause failures are included in the analysis. ISS and ISS-derived life support technologies are considered along with selected alternatives. This study focusses on minimizing launch mass, which may be enabling for deep-space missions.

Functional imaging correlates of impaired distractor suppression following sleep deprivation.

PubMed

Kong, Danyang; Soon, Chun Siong; Chee, Michael W L

2012-05-15

Sleep deprivation (SD) has been shown to affect selective attention but it is not known how two of its component processes: target enhancement and distractor suppression, are affected. To investigate, young volunteers either attended to houses or were obliged to ignore them (when attending to faces) while viewing superimposed face-house pictures. MR signal enhancement and suppression in the parahippocampal place area (PPA) were determined relative to a passive viewing control condition. Sleep deprivation was associated with lower PPA activation across conditions. Critically SD specifically impaired distractor suppression in selective attention, leaving target enhancement relatively preserved. These findings parallel some observations in cognitive aging. Additionally, following SD, attended houses were not significantly better recognized than ignored houses in a post-experiment test of recognition memory contrasting with the finding of superior recognition of attended houses in the well-rested state. These results provide evidence for co-encoding of distracting information with targets into memory when one is sleep deprived. Copyright © 2012 Elsevier Inc. All rights reserved.

The integration of nonsimultaneous frequency components into a single virtual pitch.

PubMed

Ciocca, V; Darwin, C J

1999-04-01

The integration of nonsimultaneous frequency components into a single virtual pitch was investigated by using a pitch matching task in which a mistuned 4th harmonic (mistuned component) produced pitch shifts in a harmonic series (12 equal-amplitude harmonics of a 155-Hz F0). In experiment 1, the mistuned component could either be simultaneous, stop as the target started (pre-target component), or start as the target stopped (post-target component). Pitch shifts produced by the pre-target components were significantly smaller than those obtained with simultaneous components; in the post-target condition, the size of pitch shifts did not decrease relative to the simultaneous condition. In experiment 2, a silent gap of 20, 40, 80, or 160 ms was introduced between the nonsimultaneous components and the target sound. In the pre-target condition, pitch shifts were reduced to zero for silent gaps of 80 ms or longer; by contrast, a gap of 160 ms was required to eliminate pitch shifts in the post-target condition. The third experiment tested the hypothesis that, when post-target components were presented, the processing of the pitch of the target tone started at the onset of the target, and ended at the gap duration at which pitch shifts decreased to zero. This hypothesis was confirmed by the finding that pitch shifts could not be observed when the target tone had a duration of 410 ms. Taken together, the results of these experiments show that nonsimultaneous components that occur after the onset of the target sound make a larger contribution to the virtual pitch of the target, and over a longer period, than components that precede the onset of the target sound.

High-performance thin-layer chromatography linked with (bio)assays and mass spectrometry - a suited method for discovery and quantification of bioactive components? Exemplarily shown for turmeric and milk thistle extracts.

PubMed

Taha, Mahmoud N; Krawinkel, Michael B; Morlock, Gertrud E

2015-05-15

Extraction parameters, chemical fingerprint, and the single compounds' activity levels were considered for the selection of active botanicals. For an initial survey, the total bioactivity (i.e., total reducing capacity, total flavonoids contents and free radical scavenging capacity) of 21 aqueous and 21 ethanolic plant extracts was investigated. Ethanolic extracts showed a higher yield and were further analyzed by HPTLC in detail to obtain fingerprints of single flavonoids and further bioactive components. Exemplarily shown for turmeric (Curcuma longa) and milk thistle (Silybum marianum), effect-directed analysis (EDA) was performed using three selected (bio)assays, the Aliivibrio fischeri bioassay, the Bacillus subtilis bioassay and the 2,2-diphenyl-1-picrylhydrazyl (DPPH*) assay. As a proof of principle, the bioactive components found in the extracts were confirmed by HPTLC-MS. Bioassays in combination with planar chromatography directly linked to the known, single effective compounds like curcumin and silibinin. However, also some unknown bioactive components were discovered and exemplarily characterized, which demonstrated the strength of this kind of EDA. HPTLC-UV/Vis/FLD-EDA-MS could become a useful tool for selection of active botanicals and for the activity profiling of the active ingredients therein. The flexibility in effect-directed detections allows a comprehensive survey of effective ingredients in samples. This streamlined methodology comprised a non-targeted, effect-directed screening first, followed by a highly targeted characterization of the discovered bioactive compounds. HPTLC-EDA-MS can also be recommended for bioactivity profiling of food on the food intake side, as not only effective phytochemicals, but also unknown bioactive degradation products during food processing or contamination products or residues or metabolites can be detected. Thus, an efficient survey on potential food intake effects on wellness could be obtained. Having performed both, sum parameter assays and HPTLC analysis, a comparison of both approaches was made and discussed. Copyright © 2015 Elsevier B.V. All rights reserved.

Targeting the Thioredoxin System for Cancer Therapy.

PubMed

Zhang, Junmin; Li, Xinming; Han, Xiao; Liu, Ruijuan; Fang, Jianguo

2017-09-01

Thioredoxin (Trx) and thioredoxin reductase (TrxR) are essential components of the Trx system which plays pivotal roles in regulating multiple cellular redox signaling pathways. In recent years TrxR/Trx have been increasingly recognized as an important modulator of tumor development, and hence targeting TrxR/Trx is a promising strategy for cancer treatment. In this review we first discuss the structural details of TrxR, the functions of the Trx system, and the rational of targeting TrxR/Trx for cancer treatment. We also highlight small-molecule TrxR/Trx inhibitors that have potential anticancer activity and review their mechanisms of action. Finally, we examine the challenges of developing TrxR/Trx inhibitors as anticancer agents and perspectives for selectively targeting TrxR/Trx. Copyright © 2017 Elsevier Ltd. All rights reserved.

Components Qualification for a Possible use in the Mu2e Calorimeter Waveform Digitizer

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

Di Falco, S.; Donati, S.; Morescalchi, L.

2017-03-30

The Mu2e experiment at Fermilab searches for the charged flavor violating conversion of a muon into an electron in the Coulomb field of a nucleus. The detector consists of a straw tube tracker and a CSI crystal electromagnetic calorimeter, both housed in a superconducting solenoid. Both the front-end and the digital electronics, located inside the cryostat, will be operated in vacuum under a 1 T magnetic field, having to sustain the high flux of neutrons and ionizing particles coming from the muons stopping target. These harsh experimental conditions make the design of the calorimeter waveform digitizer quite challenging. All themore » selected commercial devices must be tested individually and qualified for radiation hardness and operation in high magnetic field. At the moment the expected particles flux and spectra at the digitizers location are not completely simulated and we are using initial rough estimates to select the components for the first prototype. We are gaining experience in the qualification procedures using the selected components but the choice will be frozen only when dose and neutron flux simulations will be completed. The experimental results of the first qualification campaign are presented.« less

Selective Inactivation of Functional RNAs by Ribozyme-Catalyzed Covalent Modification.

PubMed

Poudyal, Raghav R; Benslimane, Malak; Lokugamage, Melissa P; Callaway, Mackenzie K; Staller, Seth; Burke, Donald H

2017-03-17

The diverse functions of RNA provide numerous opportunities for programming biological circuits. We describe a new strategy that uses ribozyme K28min to covalently tag a specific nucleobase within an RNA or DNA target strand to regulate and selectively inactivate those nucleic acids. K28min variants with appropriately reprogrammed internal guide sequences efficiently tagged multiple sites from an mRNA and from aptamer and ribozyme targets. Upon covalent modification by the corresponding K28min variant, an ATP-binding aptamer lost all affinity for ATP, and the fluorogenic Mango aptamer lost its ability to activate fluorescence of its dye ligand. Modifying a hammerhead ribozyme near the catalytic core led to loss of almost all of its substrate-cleaving activity, but modifying the same hammerhead ribozyme within a tertiary stabilizing element that reduces magnesium dependence only impaired substrate cleavage at low magnesium concentration. Thus, ribozyme-mediated covalent modification can be used both to selectively inactivate and to fine-tune the activities of targeted functional RNAs, analogous to the effects of post-translational modifications of proteins. Ribozyme-catalyzed covalent modification could therefore be developed to regulate nucleic acids components of synthetic and natural circuits.

A dissociation between selective attention and conscious awareness in the representation of temporal order information.

PubMed

Eimer, Martin; Grubert, Anna

2015-09-01

Previous electrophysiological studies have shown that attentional selection processes are highly sensitive to the temporal order of task-relevant visual events. When two successively presented colour-defined target stimuli are separated by a stimulus onset asynchrony (SOA) of only 10 ms, the onset latencies of N2pc components to these stimuli (which reflect their attentional selection) precisely match their objective temporal separation. We tested whether such small onset differences are accessible to conscious awareness by instructing participants to report the category (letter or digit) of the first of two target-colour items that were separated by an SOA of 10, 20, or 30 ms. Performance was at chance level for the 10 ms SOA, demonstrating that temporal order information which is available to attentional control processes cannot be utilized for conscious temporal order judgments. These results provide new evidence that selective attention and conscious awareness are functionally separable, and support the hypothesis that attention and awareness operate at different stages of cognitive processing. Copyright © 2015 Elsevier Inc. All rights reserved.

A quick responding quartz crystal microbalance sensor array based on molecular imprinted polyacrylic acids coating for selective identification of aldehydes in body odor.

PubMed

Jha, Sunil K; Hayashi, Kenshi

2015-03-01

In present work, a novel quartz crystal microbalance (QCM) sensor array has been developed for prompt identification of primary aldehydes in human body odor. Molecularly imprinted polymers (MIP) are prepared using the polyacrylic acid (PAA) polymer matrix and three organic acids (propenoic acid, hexanoic acid and octanoic acid) as template molecules, and utilized as QCM surface coating layer. The performance of MIP films is characterized by 4-element QCM sensor array (three coated with MIP layers and one with pure PAA for reference) dynamic and static responses to target aldehydes: hexanal, heptanal, and nonanal in single, binary, and tertiary mixtures at distinct concentrations. The target aldehydes were selected subsequent to characterization of body odor samples with solid phase-micro extraction gas chromatography mass spectrometer (SPME-GC-MS). The hexanoic acid and octanoic acid imprinted PAA exhibit fast response, and better sensitivity, selectivity and reproducibility than the propenoic acid, and non-imprinted PAA in array. The response time and recovery time for hexanoic acid imprinted PAA are obtained as 5 s and 12 s respectively to typical concentrations of binary and tertiary mixtures of aldehydes using the static response. Dynamic sensor array response matrix has been processed with principal component analysis (PCA) for visual, and support vector machine (SVM) classifier for quantitative identification of target odors. Aldehyde odors were identified successfully in principal component (PC) space. SVM classifier results maximum recognition rate 79% for three classes of binary odors and 83% including single, binary, and tertiary odor classes in 3-fold cross validation. Copyright © 2014 Elsevier B.V. All rights reserved.

A philosophy for CNS radiotracer design

DOE PAGES

Van de Bittner, Genevieve C.; Ricq, Emily L.; Hooker, Jacob M.

2014-10-01

Decades after its discovery, positron emission tomography (PET) remains the premier tool for imaging neurochemistry in living humans. Technological improvements in radiolabeling methods, camera design, and image analysis have kept PET in the forefront. In addition, the use of PET imaging has expanded because researchers have developed new radiotracers that visualize receptors, transporters, enzymes, and other molecular targets within the human brain. However, of the thousands of proteins in the central nervous system (CNS), researchers have successfully imaged fewer than 40 human proteins. To address the critical need for new radiotracers, this Account expounds on the decisions, strategies, and pitfallsmore » of CNS radiotracer development based on our current experience in this area. We discuss the five key components of radiotracer development for human imaging: choosing a biomedical question, selection of a biological target, design of the radiotracer chemical structure, evaluation of candidate radiotracers, and analysis of preclinical imaging. It is particularly important to analyze the market of scientists or companies who might use a new radiotracer and carefully select a relevant biomedical question(s) for that audience. In the selection of a specific biological target, we emphasize how target localization and identity can constrain this process and discuss the optimal target density and affinity ratios needed for binding-based radiotracers. In addition, we discuss various PET test–retest variability requirements for monitoring changes in density, occupancy, or functionality for new radiotracers. In the synthesis of new radiotracer structures, high-throughput, modular syntheses have proved valuable, and these processes provide compounds with sites for late-stage radioisotope installation. As a result, researchers can manage the time constraints associated with the limited half-lives of isotopes. In order to evaluate brain uptake, a number of methods are available to predict bioavailability, blood–brain barrier (BBB) permeability, and the associated issues of nonspecific binding and metabolic stability. To evaluate the synthesized chemical library, researchers need to consider high-throughput affinity assays, the analysis of specific binding, and the importance of fast binding kinetics. Lastly, we describe how we initially assess preclinical radiotracer imaging, using brain uptake, specific binding, and preliminary kinetic analysis to identify promising radiotracers that may be useful for human brain imaging. Although we discuss these five design components separately and linearly in this Account, in practice we develop new PET-based radiotracers using these design components nonlinearly and iteratively to develop new compounds in the most efficient way possible.« less

A Philosophy for CNS Radiotracer Design

PubMed Central

2015-01-01

Conspectus Decades after its discovery, positron emission tomography (PET) remains the premier tool for imaging neurochemistry in living humans. Technological improvements in radiolabeling methods, camera design, and image analysis have kept PET in the forefront. In addition, the use of PET imaging has expanded because researchers have developed new radiotracers that visualize receptors, transporters, enzymes, and other molecular targets within the human brain. However, of the thousands of proteins in the central nervous system (CNS), researchers have successfully imaged fewer than 40 human proteins. To address the critical need for new radiotracers, this Account expounds on the decisions, strategies, and pitfalls of CNS radiotracer development based on our current experience in this area. We discuss the five key components of radiotracer development for human imaging: choosing a biomedical question, selection of a biological target, design of the radiotracer chemical structure, evaluation of candidate radiotracers, and analysis of preclinical imaging. It is particularly important to analyze the market of scientists or companies who might use a new radiotracer and carefully select a relevant biomedical question(s) for that audience. In the selection of a specific biological target, we emphasize how target localization and identity can constrain this process and discuss the optimal target density and affinity ratios needed for binding-based radiotracers. In addition, we discuss various PET test–retest variability requirements for monitoring changes in density, occupancy, or functionality for new radiotracers. In the synthesis of new radiotracer structures, high-throughput, modular syntheses have proved valuable, and these processes provide compounds with sites for late-stage radioisotope installation. As a result, researchers can manage the time constraints associated with the limited half-lives of isotopes. In order to evaluate brain uptake, a number of methods are available to predict bioavailability, blood–brain barrier (BBB) permeability, and the associated issues of nonspecific binding and metabolic stability. To evaluate the synthesized chemical library, researchers need to consider high-throughput affinity assays, the analysis of specific binding, and the importance of fast binding kinetics. Finally, we describe how we initially assess preclinical radiotracer imaging, using brain uptake, specific binding, and preliminary kinetic analysis to identify promising radiotracers that may be useful for human brain imaging. Although we discuss these five design components separately and linearly in this Account, in practice we develop new PET-based radiotracers using these design components nonlinearly and iteratively to develop new compounds in the most efficient way possible. PMID:25272291

Rewarded visual items capture attention only in heterogeneous contexts.

PubMed

Feldmann-Wüstefeld, Tobias; Brandhofer, Ruben; Schubö, Anna

2016-07-01

Reward is known to affect visual search performance. Rewarding targets can increase search performance, whereas rewarding distractors can decrease search performance. We used subcomponents of the N2pc in the event-related EEG, the NT (target negativity) and ND /PD (distractor negativity/positivity), in a visual search task to disentangle target and distractor processing related to reward. The visual search task comprised homogeneous and heterogeneous contexts in which a target and a colored distractor were embedded. After each correct trial, participants were given a monetary reward that depended on the color of the distractor. We found longer response times for displays with high-reward distractors compared to displays with low-reward distractors, indicating reward-induced interference, however, only for heterogeneous contexts. The NT component, indicative of attention deployment to the target, showed that target selection was impaired by high-reward distractors, regardless of the context homogeneity. Processing of distractors was not affected by reward in homogeneous contexts. In heterogeneous contexts, however, high-reward distractors were more likely to capture attention (ND ) and required more effort to be suppressed (PD ) than low-reward distractors. In sum the results showed that, despite the fact that target selection is impaired by high-reward distractors in both homogeneous and heterogeneous background contexts, high-reward distractors capture attention only in scenarios that foster attentional capture. © 2016 Society for Psychophysiological Research.

Enhancing links between visual short term memory, visual attention and cognitive control processes through practice: An electrophysiological insight.

PubMed

Fuggetta, Giorgio; Duke, Philip A

2017-05-01

The operation of attention on visible objects involves a sequence of cognitive processes. The current study firstly aimed to elucidate the effects of practice on neural mechanisms underlying attentional processes as measured with both behavioural and electrophysiological measures. Secondly, it aimed to identify any pattern in the relationship between Event-Related Potential (ERP) components which play a role in the operation of attention in vision. Twenty-seven participants took part in two recording sessions one week apart, performing an experimental paradigm which combined a match-to-sample task with a memory-guided efficient visual-search task within one trial sequence. Overall, practice decreased behavioural response times, increased accuracy, and modulated several ERP components that represent cognitive and neural processing stages. This neuromodulation through practice was also associated with an enhanced link between behavioural measures and ERP components and with an enhanced cortico-cortical interaction of functionally interconnected ERP components. Principal component analysis (PCA) of the ERP amplitude data revealed three components, having different rostro-caudal topographic representations. The first component included both the centro-parietal and parieto-occipital mismatch triggered negativity - involved in integration of visual representations of the target with current task-relevant representations stored in visual working memory - loaded with second negative posterior-bilateral (N2pb) component, involved in categorising specific pop-out target features. The second component comprised the amplitude of bilateral anterior P2 - related to detection of a specific pop-out feature - loaded with bilateral anterior N2, related to detection of conflicting features, and fronto-central mismatch triggered negativity. The third component included the parieto-occipital N1 - related to early neural responses to the stimulus array - which loaded with the second negative posterior-contralateral (N2pc) component, mediating the process of orienting and focusing covert attention on peripheral target features. We discussed these three components as representing different neurocognitive systems modulated with practice within which the input selection process operates. Crown Copyright © 2017. Published by Elsevier B.V. All rights reserved.

Coupled parametric design of flow control and duct shape

NASA Technical Reports Server (NTRS)

Florea, Razvan (Inventor); Bertuccioli, Luca (Inventor)

2009-01-01

A method for designing gas turbine engine components using a coupled parametric analysis of part geometry and flow control is disclosed. Included are the steps of parametrically defining the geometry of the duct wall shape, parametrically defining one or more flow control actuators in the duct wall, measuring a plurality of performance parameters or metrics (e.g., flow characteristics) of the duct and comparing the results of the measurement with desired or target parameters, and selecting the optimal duct geometry and flow control for at least a portion of the duct, the selection process including evaluating the plurality of performance metrics in a pareto analysis. The use of this method in the design of inter-turbine transition ducts, serpentine ducts, inlets, diffusers, and similar components provides a design which reduces pressure losses and flow profile distortions.

Ibrutinib (PCI-32765) in chronic lymphocytic leukemia.

PubMed

Jain, Nitin; O'Brien, Susan

2013-08-01

B-cell receptor (BCR) signaling is essential for chronic lymphocytic leukemia (CLL) cell survival. Many kinases in the BCR signaling pathway are being studied as potential therapeutic targets. Ibrutinib (PCI-32765) is a novel first-in-class selective inhibitor of Bruton tyrosine kinase. Preclinical evidence suggests that ibrutinib inhibits CLL cell survival and proliferation and affects CLL cell migration and homing. Early clinical data in patients with CLL and non-Hodgkin lymphoma is encouraging. It is likely that ibrutinib and other drugs targeting the BCR pathway will become an integral component of CLL therapy. Copyright © 2013 Elsevier Inc. All rights reserved.

Hormones and the Evolution of Complex Traits: Insights from Artificial Selection on Behavior.

PubMed

Garland, Theodore; Zhao, Meng; Saltzman, Wendy

2016-08-01

Although behavior may often be a fairly direct target of natural or sexual selection, it cannot evolve without changes in subordinate traits that cause or permit its expression. In principle, changes in endocrine function could be a common mechanism underlying behavioral evolution because they are well positioned to mediate integrated responses to behavioral selection. More specifically, hormones can influence both motivational (e.g., brain) and performance (e.g., muscles) components of behavior simultaneously and in a coordinated fashion. If the endocrine system is often "used" as a general mechanism to effect responses to selection, then correlated responses in other aspects of behavior, life history, and organismal performance (e.g., locomotor abilities) should commonly occur because any cell with appropriate receptors could be affected. Ways in which behavior coadapts with other aspects of the phenotype can be studied directly through artificial selection and experimental evolution. Several studies have targeted rodent behavior for selective breeding and reported changes in other aspects of behavior, life history, and lower-level effectors of these organismal traits, including endocrine function. One example involves selection for high levels of voluntary wheel running, one aspect of physical activity, in four replicate High Runner (HR) lines of mice. Circulating levels of several hormones (including insulin, testosterone, thyroxine, triiodothyronine) have been characterized, three of which-corticosterone, leptin, and adiponectin-differ between HR and control lines, depending on sex, age, and generation. Potential changes in circulating levels of other behaviorally and metabolically relevant hormones, as well as in other components of the endocrine system (e.g., receptors), have yet to be examined. Overall, results to date identify promising avenues for further studies on the endocrine basis of activity levels. © The Author 2016. Published by Oxford University Press on behalf of the Society for Integrative and Comparative Biology. All rights reserved. For permissions please email: journals.permissions@oup.com.

P300-based brain-computer interface (BCI) event-related potentials (ERPs): People with amyotrophic lateral sclerosis (ALS) vs. age-matched controls.

PubMed

McCane, Lynn M; Heckman, Susan M; McFarland, Dennis J; Townsend, George; Mak, Joseph N; Sellers, Eric W; Zeitlin, Debra; Tenteromano, Laura M; Wolpaw, Jonathan R; Vaughan, Theresa M

2015-11-01

Brain-computer interfaces (BCIs) aimed at restoring communication to people with severe neuromuscular disabilities often use event-related potentials (ERPs) in scalp-recorded EEG activity. Up to the present, most research and development in this area has been done in the laboratory with young healthy control subjects. In order to facilitate the development of BCI most useful to people with disabilities, the present study set out to: (1) determine whether people with amyotrophic lateral sclerosis (ALS) and healthy, age-matched volunteers (HVs) differ in the speed and accuracy of their ERP-based BCI use; (2) compare the ERP characteristics of these two groups; and (3) identify ERP-related factors that might enable improvement in BCI performance for people with disabilities. Sixteen EEG channels were recorded while people with ALS or healthy age-matched volunteers (HVs) used a P300-based BCI. The subjects with ALS had little or no remaining useful motor control (mean ALS Functional Rating Scale-Revised 9.4 (±9.5SD) (range 0-25)). Each subject attended to a target item as the items in a 6×6 visual matrix flashed. The BCI used a stepwise linear discriminant function (SWLDA) to determine the item the user wished to select (i.e., the target item). Offline analyses assessed the latencies, amplitudes, and locations of ERPs to the target and non-target items for people with ALS and age-matched control subjects. BCI accuracy and communication rate did not differ significantly between ALS users and HVs. Although ERP morphology was similar for the two groups, their target ERPs differed significantly in the location and amplitude of the late positivity (P300), the amplitude of the early negativity (N200), and the latency of the late negativity (LN). The differences in target ERP components between people with ALS and age-matched HVs are consistent with the growing recognition that ALS may affect cortical function. The development of BCIs for use by this population may begin with studies in HVs but also needs to include studies in people with ALS. Their differences in ERP components may affect the selection of electrode montages, and might also affect the selection of presentation parameters (e.g., matrix design, stimulation rate). P300-based BCI performance in people severely disabled by ALS is similar to that of age-matched control subjects. At the same time, their ERP components differ to some degree from those of controls. Attention to these differences could contribute to the development of BCIs useful to those with ALS and possibly to others with severe neuromuscular disabilities. Copyright © 2015 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

Plasma-wall interactions in ITER

NASA Astrophysics Data System (ADS)

Parker, R.; Janeschitz, G.; Pacher, H. D.; Post, D.; Chiocchio, S.; Federici, G.; Ladd, P.; Iter Joint Central Team; Home Teams

1997-02-01

This paper reviews the status of the design of the divertor and first-wall/shield, the main in-vessel components for ITER. Under nominal ignited conditions, 300 MW of alpha power will be produced and must be removed from the divertor and first-wall. Additional power from auxiliary sources up to the level of 100 MW must also be removed in the case of driven burns. In the ignited case, about 100 MW will be radiated to the first wall as bremsstrahlung. Allowing the remaining power to be conducted to the divertor target plates would result in excessive heat fluxes. The power handling strategy is to radiate an additional 100-150 MW in the SOL and the divertor channel via a combination of radiation from hydrogen, and intrinsic and seeded impurities. Vertical targets have been adopted for the baseline divertor configuration. This geometry promotes partial detachment, as found in present experiments and in the results of modelling runs for ITER conditions, and power densities on the target plates can be ≤ 5 MW/ m2. Such regimes promote relatively high pressure (> 1 Pa) in the divertor and even with a low helium enrichment factor of 0.2, the required pumping speed to pump helium is ≤ 50 m3/ s. An important physics question is the quality of core confinement in these attractive divertor regimes. In addition to power and particle handling issues, the effects of disruptions play a major role in the design and performance of in-vessel components. Both centered disruptions and VDE's produce stresses in the first-wall/shield modules, backplate and the divertor wings and cassettes that are near or even somewhat in excess of allowables for normal operation. Also plasma-wall contact from disruptions, including at the divertor target, together with material properties are major factors determining component lifetime. Considering the potential for impurity contamination and minimizing tritium inventory as well as thermomechanical performance, the present material selection calls for carbon divertor targets near the strike point, tungsten on the rest of the target and on the baffle where the charge-exchange flux could be high, and beryllium elsewhere. All three materials and relevant joining techniques are being developed in the R&D program and the final selection for the first assembly will be made at the end of the EDA.

Perceptual load, voluntary attention, and aging: an event-related potential study

PubMed Central

Wang, Yan; Fu, Shimin; Greenwood, Pamela; Luo, Yuejia; Parasuraman, Raja

2012-01-01

The locus of attentional selection is known to vary with perceptual load (Lavie et al., 2004). Under voluntary attention, perceptual load modulates selective visual processing at an early cortical stage, as reflected in the posterior P1 and N1 components of the event-related potentials (ERPs). Adult aging also affects both behavioral and ERP signs of attentional selection. However, it is not known whether perceptual load modulates this relationship. Accordingly, in the present study ERPs were recorded in a voluntary attention task. Young and old participants were asked to discriminate the direction of a target line embedded within a display of four lines that appeared in the left or right visual field. Participants responded faster and more accurately to valid relative to invalid trials and to low-load relative to high-load condition. Older participants responded more slowly and with lower accuracy than young participants in all conditions. The amplitudes of the posterior contralateral P1 and N1 components in valid trials were larger than that in invalid trials in all conditions. N1 amplitude was larger under the high load condition than that in the low load condition. Moreover, in the high perceptual load condition, the old group had a larger N1 than the young group at contralateral sites. The findings suggest that under voluntary attention, perceptual load and aging modulates attentional selection at an early but not the earliest stage, during the N1 (120–200ms) time range. Increased N1 amplitude in older adults may reflect increased demands on target discrimination in high perceptual load. PMID:22248536

Target-adaptive polarimetric synthetic aperture radar target discrimination using maximum average correlation height filters.

PubMed

Sadjadi, Firooz A; Mahalanobis, Abhijit

2006-05-01

We report the development of a technique for adaptive selection of polarization ellipse tilt and ellipticity angles such that the target separation from clutter is maximized. From the radar scattering matrix [S] and its complex components, in phase and quadrature phase, the elements of the Mueller matrix are obtained. Then, by means of polarization synthesis, the radar cross section of the radar scatters are obtained at different transmitting and receiving polarization states. By designing a maximum average correlation height filter, we derive a target versus clutter distance measure as a function of four transmit and receive polarization state angles. The results of applying this method on real synthetic aperture radar imagery indicate a set of four transmit and receive angles that lead to maximum target versus clutter discrimination. These optimum angles are different for different targets. Hence, by adaptive control of the state of polarization of polarimetric radar, one can noticeably improve the discrimination of targets from clutter.

Contextual cueing effects despite spatially cued target locations.

PubMed

Schankin, Andrea; Schubö, Anna

2010-07-01

Reaction times (RT) to targets are faster in repeated displays relative to novel ones when the spatial arrangement of the distracting items predicts the target location (contextual cueing). It is assumed that visual-spatial attention is guided more efficiently to the target resulting in reduced RTs. In the present experiment, contextual cueing even occurred when the target location was previously peripherally cued. Electrophysiologically, repeated displays elicited an enhanced N2pc component in both conditions and resulted in an earlier onset of the stimulus-locked lateralized readiness potential (s-LRP) in the cued condition and in an enhanced P3 in the uncued condition relative to novel displays. These results indicate that attentional guidance is less important than previously assumed but that other cognitive processes, such as attentional selection (N2pc) and response-related processes (s-LRP, P3) are facilitated by context familiarity.

Remanent Activation in the Mini-SHINE Experiments

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

Micklich, Bradley J.

2015-04-16

Argonne National Laboratory is assisting SHINE Medical Technologies in developing a domestic source of the medical isotope 99Mo through the fission of low-enrichment uranium in a uranyl sulfate solution. In Phase 2 of these experiments, electrons from a linear accelerator create neutrons by interacting in a depleted uranium target, and these neutrons are used to irradiate the solution. The resulting neutron and photon radiation activates the target, the solution vessels, and a shielded cell that surrounds the experimental apparatus. When the experimental campaign is complete, the target must be removed into a shielding cask, and the experimental components must bemore » disassembled. The radiation transport code MCNPX and the transmutation code CINDER were used to calculate the radionuclide inventories of the solution, the target assembly, and the shielded cell, and to determine the dose rates and shielding requirements for selected removal scenarios for the target assembly and the solution vessels.« less

Optimizing the Targeting of Mouse Parvovirus 1 to Murine Melanoma Selects for Recombinant Genomes and Novel Mutations in the Viral Capsid Gene

PubMed Central

Marr, Matthew; D’Abramo, Anthony; Agbandje-McKenna, Mavis; Cotmore, Susan; Tattersall, Peter

2018-01-01

Combining virus-enhanced immunogenicity with direct delivery of immunomodulatory molecules would represent a novel treatment modality for melanoma, and would require development of new viral vectors capable of targeting melanoma cells preferentially. Here we explore the use of rodent protoparvoviruses targeting cells of the murine melanoma model B16F10. An uncloned stock of mouse parvovirus 1 (MPV1) showed some efficacy, which was substantially enhanced following serial passage in the target cell. Molecular cloning of the genes of both starter and selected virus pools revealed considerable sequence diversity. Chimera analysis mapped the majority of the improved infectivity to the product of the major coat protein gene, VP2, in which linked blocks of amino acid changes and one or other of two apparently spontaneous mutations were selected. Intragenic chimeras showed that these represented separable components, both contributing to enhanced infection. Comparison of biochemical parameters of infection by clonal viruses indicated that the enhancement due to changes in VP2 operates after the virus has bound to the cell surface and penetrated into the cell. Construction of an in silico homology model for MPV1 allowed placement of these changes within the capsid shell, and revealed aspects of the capsid involved in infection initiation that had not been previously recognized. PMID:29385689

Essential medicines for breast cancer in low and middle income countries.

PubMed

Bazargani, Y T; de Boer, A; Schellens, J H M; Leufkens, H G M; Mantel-Teeuwisse, Aukje K

2015-08-18

Breast cancer is the most common type of cancer among women worldwide. In low and middle-income countries (LMICs), appropriate selection of medicines on national essential medicines lists (NEMLs) is a first step towards adequate access to treatment. We studied selection of systemic treatments for breast cancer on NEMLs and assessed its alignment with treatment guidelines for different types of early and advanced breast cancer. Furthermore, influence of country characteristics on the selection was investigated. NEMLs from 75 LMICs were studied for inclusion of all components of therapy in each stage of breast cancer according to international consensus guidelines. The results were then grouped by income level, WHO region and the NEMLs' release date. Non parametric tests were used for statistical analysis. Unlike HER2-targeted therapies (<10%), aromatase inhibitors (12%) and taxanes (28%); tamoxifen and first generation chemotherapeutic regimens (e.g., anthracycline-based regimens) were frequently found in the NEMLs (71-78%). Consequently, all components of treatment for "Luminal A" early breast cancer and non HER2 overexpressed advanced breast cancer were found on the NEMLs of over 70% of countries. However, 40% of the low income countries did not have all the components of therapy for any type of early breast cancer in their NEMLs, and adequate treatment of HER2 overexpressed breast cancer was hardly possible with the current selections. Recent NEMLs were more aligned with the guidelines (p < 0.05). Eastern Mediterranean and African regions less frequently incorporated all components of breast cancer treatment in their NEMLs. Alignment of selection with guidelines' recommendations was inconsistent for different types of early and advanced breast cancer in NEMLs. Regular updates and more attention to clinical guidelines is therefore recommended.

Drugging the Cancers Addicted to DNA Repair.

PubMed

Nickoloff, Jac A; Jones, Dennie; Lee, Suk-Hee; Williamson, Elizabeth A; Hromas, Robert

2017-11-01

Defects in DNA repair can result in oncogenic genomic instability. Cancers occurring from DNA repair defects were once thought to be limited to rare inherited mutations (such as BRCA1 or 2). It now appears that a clinically significant fraction of cancers have acquired DNA repair defects. DNA repair pathways operate in related networks, and cancers arising from loss of one DNA repair component typically become addicted to other repair pathways to survive and proliferate. Drug inhibition of the rescue repair pathway prevents the repair-deficient cancer cell from replicating, causing apoptosis (termed synthetic lethality). However, the selective pressure of inhibiting the rescue repair pathway can generate further mutations that confer resistance to the synthetic lethal drugs. Many such drugs currently in clinical use inhibit PARP1, a repair component to which cancers arising from inherited BRCA1 or 2 mutations become addicted. It is now clear that drugs inducing synthetic lethality may also be therapeutic in cancers with acquired DNA repair defects, which would markedly broaden their applicability beyond treatment of cancers with inherited DNA repair defects. Here we review how each DNA repair pathway can be attacked therapeutically and evaluate DNA repair components as potential drug targets to induce synthetic lethality. Clinical use of drugs targeting DNA repair will markedly increase when functional and genetic loss of repair components are consistently identified. In addition, future therapies will exploit artificial synthetic lethality, where complementary DNA repair pathways are targeted simultaneously in cancers without DNA repair defects. © The Author 2017. Published by Oxford University Press.

A Review of Culturally Targeted/Tailored Tobacco Prevention and Cessation Interventions for Minority Adolescents

PubMed Central

Singh, Nisha; Krishnan-Sarin, Suchitra

2012-01-01

Aim: Emerging racial/ethnic disparities in tobacco use behaviors and resulting long-term health outcomes highlight the importance of developing culturally tailored/targeted tobacco prevention and cessation interventions. This manuscript describes the efficacy and the components of prevention and cessation interventions developed for minority adolescents. Methods: Thirteen studies focused on culturally tailoring and targeting tobacco prevention/cessation interventions were selected and information on intervention design (type, number of sessions), setting (school or community), theoretical constructs, culture-specific components (surface/deep structures), and treatment outcomes were extracted. Results: Of the 13 studies, 5 focused on prevention, 4 on cessation, and 4 combined prevention and cessation, and most of the studies were primarily school-based, while a few used community locations. Although diverse minority groups were targeted, a majority of the studies (n = 6) worked with Hispanic adolescents. The most common theoretical construct examined was the Social Influence Model (n = 5). The overall findings indicated that culturally tailoring cessation interventions did not appear to improve tobacco quit rates among minority adolescents, but culturally tailored prevention interventions appeared to produce lower tobacco initiation rates among minority adolescents than control conditions. Conclusions: The results of review suggest that there is a critical need to develop better interventions to reduce tobacco use among minority adolescents and that developing a better understanding of cultural issues related to both cessation and initiation of tobacco use among minority populations is a key component of this endeavor. PMID:22614548

Proceedings of the 1983 Scientific Conference on Obscuration and Aerosol Research

DTIC Science & Technology

1984-07-01

Aerosol Measurement Spheroids Laser Pulses Target Signatures Optical Pulses Pulse Propagation Clouds Laser Radiation Transport Analysis...Schematic diagram of apparatus used to make ATR measurements . (a) Top view of components. Solid line is path of laser radiation, broken line is path of...fabricated to measure the extinction properties of these materials for CO2 laser radiation. The selection process and preparation of the

The development of a fear of falling interdisciplinary intervention program

PubMed Central

Gomez, Fernando; Curcio, Carmen-Lucia

2007-01-01

Objective: To describe the development process of a protocol for a fear of falling interdisciplinary intervention program based on the main factors associated with fear of falling. Design/methods: The process of developing a protocol consisted of defining the target population, selecting the initial assessment components, adapting the intervention program based on findings about fear of falling and restriction of activities in this population. Settings: University-affiliated outpatient vertigo, dizziness and falls clinic in coffee-growers zone of Colombian Andes Mountains. Results: An intervention program was developed based on three main falling conceptual models. A medical intervention, based on a biomedical and pathophysiological model, a physiotherapeutic intervention based on a postural control model and a psychological intervention based on a biological-behavioral model. Conclusion: This interdisciplinary fear of falling intervention program developed is based on particular characteristics of target population, with differences in the inclusion criteria and the program intervention components; with emphasis on medical (recurrent falls and dizziness evaluation and management), psychological (cognitive-behavioral therapy) and physiotherapeutic (balance and transfers training) components. PMID:18225468

Aptamer-incorporated hydrogels for visual detection, controlled drug release, and targeted cancer therapy

PubMed Central

Liu, Jun; Kang, Huaizhi; Donovan, Michael; Zhu, Zhi

2017-01-01

Hydrogels are water-retainable materials, made from cross-linked polymers, that can be tailored to applications in bioanalysis and biomedicine. As technology advances, an increasing number of molecules have been used as the components of hydrogel systems. However, the shortcomings of these systems have prompted researchers to find new materials that can be incorporated into them. Among all of these emerging materials, aptamers have recently attracted substantial attention because of their unique properties, for example biocompatibility, selective binding, and molecular recognition, all of which make them promising candidates for target-responsive hydrogel engineering. In this work, we will review how aptamers have been incorporated into hydrogel systems to enable colorimetric detection, controlled drug release, and targeted cancer therapy. PMID:22052153

The role of visual attention in multiple object tracking: evidence from ERPs.

PubMed

Doran, Matthew M; Hoffman, James E

2010-01-01

We examined the role of visual attention in the multiple object tracking (MOT) task by measuring the amplitude of the N1 component of the event-related potential (ERP) to probe flashes presented on targets, distractors, or empty background areas. We found evidence that visual attention enhances targets and suppresses distractors (Experiment 1 & 3). However, we also found that when tracking load was light (two targets and two distractors), accurate tracking could be carried out without any apparent contribution from the visual attention system (Experiment 2). Our results suggest that attentional selection during MOT is flexibly determined by task demands as well as tracking load and that visual attention may not always be necessary for accurate tracking.

The Control of Single-color and Multiple-color Visual Search by Attentional Templates in Working Memory and in Long-term Memory.

PubMed

Grubert, Anna; Carlisle, Nancy B; Eimer, Martin

2016-12-01

The question whether target selection in visual search can be effectively controlled by simultaneous attentional templates for multiple features is still under dispute. We investigated whether multiple-color attentional guidance is possible when target colors remain constant and can thus be represented in long-term memory but not when they change frequently and have to be held in working memory. Participants searched for one, two, or three possible target colors that were specified by cue displays at the start of each trial. In constant-color blocks, the same colors remained task-relevant throughout. In variable-color blocks, target colors changed between trials. The contralateral delay activity (CDA) to cue displays increased in amplitude as a function of color memory load in variable-color blocks, which indicates that cued target colors were held in working memory. In constant-color blocks, the CDA was much smaller, suggesting that color representations were primarily stored in long-term memory. N2pc components to targets were measured as a marker of attentional target selection. Target N2pcs were attenuated and delayed during multiple-color search, demonstrating less efficient attentional deployment to color-defined target objects relative to single-color search. Importantly, these costs were the same in constant-color and variable-color blocks. These results demonstrate that attentional guidance by multiple-feature as compared with single-feature templates is less efficient both when target features remain constant and can be represented in long-term memory and when they change across trials and therefore have to be maintained in working memory.

Multifunction Imaging and Spectroscopic Instrument

NASA Technical Reports Server (NTRS)

Mouroulis, Pantazis

2004-01-01

A proposed optoelectronic instrument would perform several different spectroscopic and imaging functions that, heretofore, have been performed by separate instruments. The functions would be reflectance, fluorescence, and Raman spectroscopies; variable-color confocal imaging at two different resolutions; and wide-field color imaging. The instrument was conceived for use in examination of minerals on remote planets. It could also be used on Earth to characterize material specimens. The conceptual design of the instrument emphasizes compactness and economy, to be achieved largely through sharing of components among subsystems that perform different imaging and spectrometric functions. The input optics for the various functions would be mounted in a single optical head. With the exception of a targeting lens, the input optics would all be aimed at the same spot on a specimen, thereby both (1) eliminating the need to reposition the specimen to perform different imaging and/or spectroscopic observations and (2) ensuring that data from such observations can be correlated with respect to known positions on the specimen. The figure schematically depicts the principal components and subsystems of the instrument. The targeting lens would collect light into a multimode optical fiber, which would guide the light through a fiber-selection switch to a reflection/ fluorescence spectrometer. The switch would have four positions, enabling selection of spectrometer input from the targeting lens, from either of one or two multimode optical fibers coming from a reflectance/fluorescence- microspectrometer optical head, or from a dark calibration position (no fiber). The switch would be the only moving part within the instrument.

Transforming Growth Factor-β Is an Upstream Regulator of Mammalian Target of Rapamycin Complex 2–Dependent Bladder Cancer Cell Migration and Invasion

PubMed Central

Gupta, Sounak; Hau, Andrew M.; Al-Ahmadie, Hikmat A.; Harwalkar, Jyoti; Shoskes, Aaron C.; Elson, Paul; Beach, Jordan R.; Hussey, George S.; Schiemann, William P.; Egelhoff, Thomas T.; Howe, Philip H.; Hansel, Donna E.

2017-01-01

Our prior work identified the mammalian target of rapamycin complex 2 (mTORC2) as a key regulator of bladder cancer cell migration and invasion, although upstream growth factor mediators of this pathway in bladder cancer have not been well delineated. We tested whether transforming growth factor (TGF)-β, which can function as a promotility factor in bladder cancer cells, could regulate mTORC2-dependent bladder cancer cell motility and invasion. In human bladder cancers, the highest levels of phosphorylated SMAD2, a TGF-β signaling intermediate, were present in high-grade invasive bladder cancers and associated with more frequent recurrence and decreased disease-specific survival. Increased expression of TGF-β isoforms, receptors, and signaling components was detected in invasive high-grade bladder cancer cells that expressed Vimentin and lacked E-cadherin. Application of TGF-β induced phosphorylation of the Ser473 residue of AKT, a selective target of mTORC2, in a SMAD2- and SMAD4-independent manner and increased bladder cancer cell migration in a modified scratch wound assay and invasion through Matrigel. Inhibition of TGF-β receptor I using SB431542 ablated TGF-β–induced migration and invasion. A similar effect was seen when Rictor, a key mTORC2 component, was selectively silenced. Our results suggest that TGF-β can induce bladder cancer cell invasion via mTORC2 signaling, which may be applicable in most bladder cancers. PMID:26988652

Strategy Developed for Selecting Optimal Sensors for Monitoring Engine Health

NASA Technical Reports Server (NTRS)

2004-01-01

Sensor indications during rocket engine operation are the primary means of assessing engine performance and health. Effective selection and location of sensors in the operating engine environment enables accurate real-time condition monitoring and rapid engine controller response to mitigate critical fault conditions. These capabilities are crucial to ensure crew safety and mission success. Effective sensor selection also facilitates postflight condition assessment, which contributes to efficient engine maintenance and reduced operating costs. Under the Next Generation Launch Technology program, the NASA Glenn Research Center, in partnership with Rocketdyne Propulsion and Power, has developed a model-based procedure for systematically selecting an optimal sensor suite for assessing rocket engine system health. This optimization process is termed the systematic sensor selection strategy. Engine health management (EHM) systems generally employ multiple diagnostic procedures including data validation, anomaly detection, fault-isolation, and information fusion. The effectiveness of each diagnostic component is affected by the quality, availability, and compatibility of sensor data. Therefore systematic sensor selection is an enabling technology for EHM. Information in three categories is required by the systematic sensor selection strategy. The first category consists of targeted engine fault information; including the description and estimated risk-reduction factor for each identified fault. Risk-reduction factors are used to define and rank the potential merit of timely fault diagnoses. The second category is composed of candidate sensor information; including type, location, and estimated variance in normal operation. The final category includes the definition of fault scenarios characteristic of each targeted engine fault. These scenarios are defined in terms of engine model hardware parameters. Values of these parameters define engine simulations that generate expected sensor values for targeted fault scenarios. Taken together, this information provides an efficient condensation of the engineering experience and engine flow physics needed for sensor selection. The systematic sensor selection strategy is composed of three primary algorithms. The core of the selection process is a genetic algorithm that iteratively improves a defined quality measure of selected sensor suites. A merit algorithm is employed to compute the quality measure for each test sensor suite presented by the selection process. The quality measure is based on the fidelity of fault detection and the level of fault source discrimination provided by the test sensor suite. An inverse engine model, whose function is to derive hardware performance parameters from sensor data, is an integral part of the merit algorithm. The final component is a statistical evaluation algorithm that characterizes the impact of interference effects, such as control-induced sensor variation and sensor noise, on the probability of fault detection and isolation for optimal and near-optimal sensor suites.

Modality-specificity of Selective Attention Networks.

PubMed

Stewart, Hannah J; Amitay, Sygal

2015-01-01

To establish the modality specificity and generality of selective attention networks. Forty-eight young adults completed a battery of four auditory and visual selective attention tests based upon the Attention Network framework: the visual and auditory Attention Network Tests (vANT, aANT), the Test of Everyday Attention (TEA), and the Test of Attention in Listening (TAiL). These provided independent measures for auditory and visual alerting, orienting, and conflict resolution networks. The measures were subjected to an exploratory factor analysis to assess underlying attention constructs. The analysis yielded a four-component solution. The first component comprised of a range of measures from the TEA and was labeled "general attention." The third component was labeled "auditory attention," as it only contained measures from the TAiL using pitch as the attended stimulus feature. The second and fourth components were labeled as "spatial orienting" and "spatial conflict," respectively-they were comprised of orienting and conflict resolution measures from the vANT, aANT, and TAiL attend-location task-all tasks based upon spatial judgments (e.g., the direction of a target arrow or sound location). These results do not support our a-priori hypothesis that attention networks are either modality specific or supramodal. Auditory attention separated into selectively attending to spatial and non-spatial features, with the auditory spatial attention loading onto the same factor as visual spatial attention, suggesting spatial attention is supramodal. However, since our study did not include a non-spatial measure of visual attention, further research will be required to ascertain whether non-spatial attention is modality-specific.

Self-initiated encoding facilitates object working memory in schizophrenia: implications for the etiology of working memory deficit.

PubMed

Kim, Jejoong; Park, Sohee; Shin, Yong-Wook; Jin Lee, Kyung; Kwon, Jun Soo

2006-02-15

Working memory (WM) deficit is present in a majority of patients with schizophrenia but it is unclear which components of WM are impaired. Past studies suggest that encoding may be compromised. One important determinant of encoding is the deployment of selective attention to the target stimulus. In addition, attention and encoding are modulated by motivational factors. In this study, we investigated the effects of self-initiated encoding (i.e., voluntary attention) on WM. 19 patients with schizophrenia and 19 matched control subjects participated in visual WM and control tasks. Encoding was manipulated by asking subjects to select from two face targets and memorize 1) one of the two identical faces (Non-preference condition), 2) one that is marked (Non-choice condition), and 3) one they prefer (Preference condition). WM accuracy for both location (spatial) and identity (object) was measured. Overall, patients with schizophrenia were less accurate and slower than the control subjects but the deficit was greater for object WM. However, patients were more accurate in object WM when they selected a preferred face as their target during encoding (preference condition) compared with the other two conditions. This effect was not significant for spatial WM. These results suggest that voluntary, self-initiated attention may facilitate object encoding especially if the selection of the target involves affective choice, and that attention may play different roles in encoding 'what' versus 'where' in WM. Since encoding affects all forms of memory, these results may have a more general implication for memory.

HomoTarget: a new algorithm for prediction of microRNA targets in Homo sapiens.

PubMed

Ahmadi, Hamed; Ahmadi, Ali; Azimzadeh-Jamalkandi, Sadegh; Shoorehdeli, Mahdi Aliyari; Salehzadeh-Yazdi, Ali; Bidkhori, Gholamreza; Masoudi-Nejad, Ali

2013-02-01

MiRNAs play an essential role in the networks of gene regulation by inhibiting the translation of target mRNAs. Several computational approaches have been proposed for the prediction of miRNA target-genes. Reports reveal a large fraction of under-predicted or falsely predicted target genes. Thus, there is an imperative need to develop a computational method by which the target mRNAs of existing miRNAs can be correctly identified. In this study, combined pattern recognition neural network (PRNN) and principle component analysis (PCA) architecture has been proposed in order to model the complicated relationship between miRNAs and their target mRNAs in humans. The results of several types of intelligent classifiers and our proposed model were compared, showing that our algorithm outperformed them with higher sensitivity and specificity. Using the recent release of the mirBase database to find potential targets of miRNAs, this model incorporated twelve structural, thermodynamic and positional features of miRNA:mRNA binding sites to select target candidates. Copyright © 2012 Elsevier Inc. All rights reserved.

Neural correlates of the spatial and expectancy components of endogenous and stimulus-driven orienting of attention in the Posner task.

PubMed

Doricchi, Fabrizio; Macci, Enrica; Silvetti, Massimo; Macaluso, Emiliano

2010-07-01

Voluntary orienting of visual attention is conventionally measured in tasks with predictive central cues followed by frequent valid targets at the cued location and by infrequent invalid targets at the uncued location. This implies that invalid targets entail both spatial reorienting of attention and breaching of the expected spatial congruency between cues and targets. Here, we used event-related functional magnetic resonance imaging (fMRI) to separate the neural correlates of the spatial and expectancy components of both endogenous orienting and stimulus-driven reorienting of attention. We found that during endogenous orienting with predictive cues, there was a significant deactivation of the right Temporal-Parietal Junction (TPJ). We also discovered that the lack of an equivalent deactivation with nonpredictive cues was matched to drop in attentional costs and preservation of attentional benefits. The right TPJ showed equivalent responses to invalid targets following predictive and nonpredictive cues. On the contrary, infrequent-unexpected invalid targets following predictive cues specifically activated the right Middle and Inferior Frontal Gyrus (MFG-IFG). Additional comparisons with spatially neutral trials demonstrated that, independently of cue predictiveness, valid targets activate the left TPJ, whereas invalid targets activate both the left and right TPJs. These findings show that the selective right TPJ activation that is found in the comparison between invalid and valid trials results from the reciprocal cancelling of the different activations that in the left TPJ are related to the processing of valid and invalid targets. We propose that left and right TPJs provide "matching and mismatching to attentional template" signals. These signals enable reorienting of attention and play a crucial role in the updating of the statistical contingency between cues and targets.

Integrating CFD, CAA, and Experiments Towards Benchmark Datasets for Airframe Noise Problems

NASA Technical Reports Server (NTRS)

Choudhari, Meelan M.; Yamamoto, Kazuomi

2012-01-01

Airframe noise corresponds to the acoustic radiation due to turbulent flow in the vicinity of airframe components such as high-lift devices and landing gears. The combination of geometric complexity, high Reynolds number turbulence, multiple regions of separation, and a strong coupling with adjacent physical components makes the problem of airframe noise highly challenging. Since 2010, the American Institute of Aeronautics and Astronautics has organized an ongoing series of workshops devoted to Benchmark Problems for Airframe Noise Computations (BANC). The BANC workshops are aimed at enabling a systematic progress in the understanding and high-fidelity predictions of airframe noise via collaborative investigations that integrate state of the art computational fluid dynamics, computational aeroacoustics, and in depth, holistic, and multifacility measurements targeting a selected set of canonical yet realistic configurations. This paper provides a brief summary of the BANC effort, including its technical objectives, strategy, and selective outcomes thus far.

Determinants of Propranolol's Selective Effect on Loss Aversion.

PubMed

Sokol-Hessner, Peter; Lackovic, Sandra F; Tobe, Russell H; Camerer, Colin F; Leventhal, Bennett L; Phelps, Elizabeth A

2015-07-01

Research on emotion and decision making has suggested that arousal mediates risky decisions, but several distinct and often confounded processes drive such choices. We used econometric modeling to separate and quantify the unique contributions of loss aversion, risk attitudes, and choice consistency to risky decision making. We administered the beta-blocker propranolol in a double-blind, placebo-controlled within-subjects study, targeting the neurohormonal basis of physiological arousal. Matching our intervention's pharmacological specificity with a quantitative model delineating decision-making components allowed us to identify the causal relationships between arousal and decision making that do and do not exist. Propranolol selectively reduced loss aversion in a baseline- and dose-dependent manner (i.e., as a function of initial loss aversion and body mass index), and did not affect risk attitudes or choice consistency. These findings provide evidence for a specific, modulatory, and causal relationship between precise components of emotion and risky decision making. © The Author(s) 2015.

The perception of visual images encoded in musical form: a study in cross-modality information transfer.

PubMed Central

Cronly-Dillon, J; Persaud, K; Gregory, R P

1999-01-01

This study demonstrates the ability of blind (previously sighted) and blindfolded (sighted) subjects in reconstructing and identifying a number of visual targets transformed into equivalent musical representations. Visual images are deconstructed through a process which selectively segregates different features of the image into separate packages. These are then encoded in sound and presented as a polyphonic musical melody which resembles a Baroque fugue with many voices, allowing subjects to analyse the component voices selectively in combination, or separately in sequence, in a manner which allows a subject to patch together and bind the different features of the object mentally into a mental percept of a single recognizable entity. The visual targets used in this study included a variety of geometrical figures, simple high-contrast line drawings of man-made objects, natural and urban scenes, etc., translated into sound and presented to the subject in polyphonic musical form. PMID:10643086

Single-molecule fluorescence measurements reveal the reaction mechanisms of the core RISC, composed of human Argonaute 2 and a guide RNA.

PubMed

Jo, Myung Hyun; Song, Ji-Joon; Hohng, Sungchul

2015-12-01

In eukaryotes, small RNAs play important roles in both gene regulation and resistance to viral infection. Argonaute proteins have been identified as a key component of the effector complexes of various RNA-silencing pathways, but the mechanistic roles of Argonaute proteins in these pathways are not clearly understood. To address this question, we performed single-molecule fluorescence experiments using an RNA-induced silencing complex (core-RISC) composed of a small RNA and human Argonaute 2. We found that target binding of core-RISC starts at the seed region of the guide RNA. After target binding, four distinct reactions followed: target cleavage, transient binding, stable binding, and Argonaute unloading. Target cleavage required extensive sequence complementarity and accelerated core-RISC dissociation for recycling. In contrast, the stable binding of core-RISC to target RNAs required seed-match only, suggesting a potential explanation for the seed-match rule of microRNA (miRNA) target selection.

A category-specific top-down attentional set can affect the neural responses outside the current focus of attention.

PubMed

Jiang, Yunpeng; Wu, Xia; Gao, Xiaorong

2017-10-17

A top-down set can guide attention to enhance the processing of task-relevant objects. Many studies have found that the top-down set can be tuned to a category level. However, it is unclear whether the category-specific top-down set involving a central search task can exist outside the current area of attentional focus. To directly probe the neural responses inside and outside the current focus of attention, we recorded continuous EEG to measure the contralateral ERP components for central targets and the steady-state visual evoked potential (SSVEP) oscillations associated with a flickering checkerboard placed on the visual periphery. The relationship of color categories between targets and non-targets was manipulated to investigate the effect of category-specific top-down set. Results showed that when the color categories of targets and non-targets in the central search arrays were the same, larger SSVEP oscillations were evoked by target color peripheral checkerboards relative to the non-target color ones outside the current attentional focus. However, when the color categories of targets and non-targets were different, the peripheral checkerboards in two different colors of the same category evoked similar SSVEP oscillations, indicating the effects of category-specific top-down set. These results firstly demonstrate that the category-specific top-down set can affect the neural responses of peripheral distractors. The results could support the idea of a global selection account and challenge the attentional window account in selective attention. Copyright © 2017. Published by Elsevier B.V.

Selective effects of acute alcohol intake on the prospective and retrospective components of a prospective-memory task with emotional targets.

PubMed

Walter, Nora T; Bayen, Ute J

2016-01-01

Prospective memory involves remembering to do something in the future and has a prospective component (remembering that something must be done) and a retrospective component (remembering what must be done and when it must be done). Initial studies reported an impairment in prospective-memory performance due to acute alcohol consumption. Retrospective-memory studies demonstrated that alcohol effects vary depending on the emotionality of the information that needs to be learned. The aim of the present study was to investigate possible differential effects of a mild acute alcohol dose (0.4 g/kg) on the prospective and retrospective components of prospective memory depending on cue valence. Seventy-five participants were allocated to an alcohol or placebo group and performed a prospective-memory task in which prospective-memory cue valence was manipulated (negative, neutral, positive). The multinomial model of event-based prospective memory (Smith and Bayen 2004) was used to measure alcohol and valence effects on the two prospective-memory components separately. Overall, no main effect of alcohol or valence on prospective-memory performance occurred. However, model-based analyses demonstrated a significantly higher retrospective component for positive compared with negative cues in the placebo group. In the alcohol group, the prospective component was weaker for negative than for neutral cues and the retrospective component was stronger for positive than for neutral cues. Group comparisons showed that the alcohol group had a significantly lower prospective component for negative cues and a lower retrospective component for neutral cues. This is the first study to demonstrate selective alcohol effects on prospective-memory components depending on prospective-memory cue valence.

Suicide Gene-Engineered Stromal Cells Reveal a Dynamic Regulation of Cancer Metastasis

NASA Astrophysics Data System (ADS)

Shen, Keyue; Luk, Samantha; Elman, Jessica; Murray, Ryan; Mukundan, Shilpaa; Parekkadan, Biju

2016-02-01

Cancer-associated fibroblasts (CAFs) are a major cancer-promoting component in the tumor microenvironment (TME). The dynamic role of human CAFs in cancer progression has been ill-defined because human CAFs lack a unique marker needed for a cell-specific, promoter-driven knockout model. Here, we developed an engineered human CAF cell line with an inducible suicide gene to enable selective in vivo elimination of human CAFs at different stages of xenograft tumor development, effectively circumventing the challenge of targeting a cell-specific marker. Suicide-engineered CAFs were highly sensitive to apoptosis induction in vitro and in vivo by the addition of a simple small molecule inducer. Selection of timepoints for targeted CAF apoptosis in vivo during the progression of a human breast cancer xenograft model was guided by a bi-phasic host cytokine response that peaked at early timepoints after tumor implantation. Remarkably, we observed that the selective apoptosis of CAFs at these early timepoints did not affect primary tumor growth, but instead increased the presence of tumor-associated macrophages and the metastatic spread of breast cancer cells to the lung and bone. The study revealed a dynamic relationship between CAFs and cancer metastasis that has counter-intuitive ramifications for CAF-targeted therapy.

Electrophysiological evidence for attentional guidance by the contents of working memory.

PubMed

Kumar, Sanjay; Soto, David; Humphreys, Glyn W

2009-07-01

The deployment of visual attention can be strongly modulated by stimuli matching the contents of working memory (WM), even when WM contents are detrimental to performance and salient bottom-up cues define the critical target [D. Soto et al. (2006)Vision Research, 46, 1010-1018]. Here we investigated the electrophysiological correlates of this early guidance of attention by WM in humans. Observers were presented with a prime to either identify or hold in memory. Subsequently, they had to search for a target line amongst different distractor lines. Each line was embedded within one of four objects and one of the distractor objects could match the stimulus held in WM. Behavioural data showed that performance was more strongly affected by the prime when it was held in memory than when it was merely identified. An electrophysiological measure of the efficiency of target selection (the N2pc) was also affected by the match between the item in WM and the location of the target in the search task. The N2pc was enhanced when the target fell in the same visual field as the re-presented (invalid) prime, compared with when the prime did not reappear in the search display (on neutral trials) and when the prime was contralateral to the target. Merely identifying the prime produced no effect on the N2pc component. The evidence suggests that WM modulates competitive interactions between the items in the visual field to determine the efficiency of target selection.

Masked Proportional Routing

NASA Technical Reports Server (NTRS)

Wolpert, David H. (Inventor)

2003-01-01

Distributed approach for determining a path connecting adjacent network nodes, for probabilistically or deterministically transporting an entity, with entity characteristic mu from a source node to a destination node. Each node i is directly connected to an arbitrary number J(mu) of nodes, labeled or numbered j=jl, j2, .... jJ(mu). In a deterministic version, a J(mu)-component baseline proportion vector p(i;mu) is associated with node i. A J(mu)-component applied proportion vector p*(i;mu) is determined from p(i;mu) to preclude an entity visiting a node more than once. Third and fourth J(mu)-component vectors, with components iteratively determined by Target(i;n(mu);mu),=alpha(mu).Target(i;n(mu)-1;mu)j+beta(mu).p* (i;mu)j and Actual(i;n(mu);+a(mu)j. Actual(i;n(mu)-l;mu)j+beta(mu).Sent(i;j'(mu);n(mu)-1;mu)j, are computed, where n(mu) is an entity sequence index and alpha(mu) and beta(mu) are selected numbers. In one embodiment, at each node i, the node j=j'(mu) with the largest vector component difference, Target(i;n(mu);mu)j'- Actual (i;n(mu);mu)j'. is chosen for the next link for entity transport, except in special gap circumstances, where the same link is optionally used for transporting consecutively arriving entities. The network nodes may be computer-controlled routers that switch collections of packets, frames, cells or other information units. Alternatively, the nodes may be waypoints for movement of physical items in a network or for transformation of a physical item. The nodes may be states of an entity undergoing state transitions, where allowed transitions are specified by the network and/or the destination node.

Medical Surveillance Monthly Report (MSMR). Volume 22, Number 3, March 2015

DTIC Science & Technology

2015-03-01

1 1 Incidence and prevalence of diagnoses of eye disorders of refraction and accommodation, active component service members, U.S. Armed Forces...example, high rates of infection are oft en accompanied by decreased case reporting (underreporting bias).4 Syndromic sur- veillance eff orts are, in...Centers for Disease Control and Prevention [CDC] Stage Selected symptoms Acute, localized Erythema migrans ("target lesion") Prodromal syndrome

Screening of patients with bronchopulmonary diseases using methods of infrared laser photoacoustic spectroscopy and principal component analysis

NASA Astrophysics Data System (ADS)

Kistenev, Yury V.; Karapuzikov, Alexander I.; Kostyukova, Nadezhda Yu.; Starikova, Marina K.; Boyko, Andrey A.; Bukreeva, Ekaterina B.; Bulanova, Anna A.; Kolker, Dmitry B.; Kuzmin, Dmitry A.; Zenov, Konstantin G.; Karapuzikov, Alexey A.

2015-06-01

A human exhaled air analysis by means of infrared (IR) laser photoacoustic spectroscopy is presented. Eleven healthy nonsmoking volunteers (control group) and seven patients with chronic obstructive pulmonary disease (COPD, target group) were involved in the study. The principal component analysis method was used to select the most informative ranges of the absorption spectra of patients' exhaled air in terms of the separation of the studied groups. It is shown that the data of the profiles of exhaled air absorption spectrum in the informative ranges allow identifying COPD patients in comparison to the control group.

High resolution spectrograph. [for LST

NASA Technical Reports Server (NTRS)

Peacock, K.

1975-01-01

The high resolution spectrograph (HRS) is designed to be used with the Large Space Telescope (LST) for the study of spectra of point and extended targets in the spectral range 110 to 410 nm. It has spectral resolutions of 1,000; 30,000; and 100,000 and has a field of view as large as 10 arc sec. The spectral range and resolution are selectable using interchangeable optical components and an echelle spectrograph is used to display a cross dispersed spectrum on the photocathode of either of 2 SEC orthicon image tubes. Provisions are included for wavelength calibration, target identification and acquisition and thermal control. The system considerations of the instrument are described.

Identification and Development of 2,3-Dihydropyrrolo[1,2-a]quinazolin-5(1H)-one Inhibitors Targeting Bromodomains within the Switch/Sucrose Nonfermenting Complex

PubMed Central

2016-01-01

Bromodomain containing proteins PB1, SMARCA4, and SMARCA2 are important components of SWI/SNF chromatin remodeling complexes. We identified bromodomain inhibitors that target these proteins and display unusual binding modes involving water displacement from the KAc binding site. The best compound binds the fifth bromodomain of PB1 with a KD of 124 nM, SMARCA2B and SMARCA4 with KD values of 262 and 417 nM, respectively, and displays excellent selectivity over bromodomains other than PB1, SMARCA2, and SMARCA4. PMID:27119626

The Polerovirus silencing suppressor P0 targets ARGONAUTE proteins for degradation.

PubMed

Baumberger, Nicolas; Tsai, Ching-Hsui; Lie, Miranda; Havecker, Ericka; Baulcombe, David C

2007-09-18

Plant and animal viruses encode suppressor proteins of an adaptive immunity mechanism in which viral double-stranded RNA is processed into 21-25 nt short interfering (si)RNAs. The siRNAs guide ARGONAUTE (AGO) proteins so that they target viral RNA. Most viral suppressors bind long dsRNA or siRNAs and thereby prevent production of siRNA or binding of siRNA to AGO. The one exception is the 2b suppressor of Cucumoviruses that binds to and inhibits AGO1. Here we describe a novel suppressor mechanism in which a Polerovirus-encoded F box protein (P0) targets the PAZ motif and its adjacent upstream sequence in AGO1 and mediates its degradation. F box proteins are components of E3 ubiquitin ligase complexes that add polyubiquitin tracts on selected lysine residues and thereby mark a protein for proteasome-mediated degradation. With P0, however, the targeted degradation of AGO is insensitive to inhibition of the proteasome, indicating that the proteasome is not involved. We also show that P0 does not block a mobile signal of silencing, indicating that the signal molecule does not have AGO protein components. The ability of P0 to block silencing without affecting signal movement may contribute to the phloem restriction of viruses in the Polerovirus group.

Overview of field gamma spectrometries based on Si-photomultiplier

NASA Astrophysics Data System (ADS)

Denisov, Viktor; Korotaev, Valery; Titov, Aleksandr; Blokhina, Anastasia; Kleshchenok, Maksim

2017-05-01

Design of optical-electronic devices and systems involves the selection of such technical patterns that under given initial requirements and conditions are optimal according to certain criteria. The original characteristic of the OES for any purpose, defining its most important feature ability is a threshold detection. Based on this property, will be achieved the required functional quality of the device or system. Therefore, the original criteria and optimization methods have to subordinate to the idea of a better detectability. Generally reduces to the problem of optimal selection of the expected (predetermined) signals in the predetermined observation conditions. Thus the main purpose of optimization of the system when calculating its detectability is the choice of circuits and components that provide the most effective selection of a target.

Evodiamine selectively targets cancer stem-like cells through the p53-p21-Rb pathway

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

Han, Seula; Woo, Jong Kyu; Jung, Yuchae

In spite of the recent improvements, the resistance to chemotherapy/radiotherapy followed by relapse is the main hurdle for the successful treatment of breast cancer, a leading cause of death in women. A small population of breast cancer cells that have stem-like characteristics (cancer stem-like cells; CSLC) may contribute to this resistance and relapse. Here, we report on a component of a traditional Chinese medicine, evodiamine, which selectively targets CSLC of breast cancer cell lines MCF7 and MDAMB 231 at a concentration that does show a little or no cytotoxic effect on bulk cancer cells. While evodiamine caused the accumulation of bulkmore » cancer cells at the G2/M phase, it did not hold CSLC in a specific cell cycle phase but instead, selectively killed CSLC. This was not due to the culture of CSLC in suspension or without FBS. A proteomic analysis and western blotting revealed that evodiamine changed the expression of cell cycle regulating molecules more efficiently in CSLC cells than in bulk cancer cells. Surprisingly, evodiamine selectively activated p53 and p21 and decreased inactive Rb, the master molecules in G1/S checkpoint. These data collectively suggest a novel mechanism involving CSLC-specific targeting by evodiamine and its possible use to the therapy of breast cancer. - Highlights: • Evodiamine selectively kills breast cancer stem like cells at G1 phase. • Evodiamine utilizes different mechanism of cell cycle modulation in CSLC and in bulk cancer cells. • Evodiamine activate the p53, p21 and Rb pathway.« less

The Competitive Influences of Perceptual Load and Working Memory Guidance on Selective Attention.

PubMed

Tan, Jinfeng; Zhao, Yuanfang; Wang, Lijun; Tian, Xia; Cui, Yan; Yang, Qian; Pan, Weigang; Zhao, Xiaoyue; Chen, Antao

2015-01-01

The perceptual load theory in selective attention literature proposes that the interference from task-irrelevant distractor is eliminated when perceptual capacity is fully consumed by task-relevant information. However, the biased competition model suggests that the contents of working memory (WM) can guide attentional selection automatically, even when this guidance is detrimental to visual search. An intriguing but unsolved question is what will happen when selective attention is influenced by both perceptual load and WM guidance. To study this issue, behavioral performances and event-related potentials (ERPs) were recorded when participants were presented with a cue to either identify or hold in memory and had to perform a visual search task subsequently, under conditions of low or high perceptual load. Behavioural data showed that high perceptual load eliminated the attentional capture by WM. The ERP results revealed an obvious WM guidance effect in P1 component with invalid trials eliciting larger P1 than neutral trials, regardless of the level of perceptual load. The interaction between perceptual load and WM guidance was significant for the posterior N1 component. The memory guidance effect on N1 was eliminated by high perceptual load. Standardized Low Resolution Electrical Tomography Analysis (sLORETA) showed that the WM guidance effect and the perceptual load effect on attention can be localized into the occipital area and parietal lobe, respectively. Merely identifying the cue produced no effect on the P1 or N1 component. These results suggest that in selective attention, the information held in WM could capture attention at the early stage of visual processing in the occipital cortex. Interestingly, this initial capture of attention by WM could be modulated by the level of perceptual load and the parietal lobe mediates target selection at the discrimination stage.

The Competitive Influences of Perceptual Load and Working Memory Guidance on Selective Attention

PubMed Central

Tan, Jinfeng; Zhao, Yuanfang; Wang, Lijun; Tian, Xia; Cui, Yan; Yang, Qian; Pan, Weigang; Zhao, Xiaoyue; Chen, Antao

2015-01-01

The perceptual load theory in selective attention literature proposes that the interference from task-irrelevant distractor is eliminated when perceptual capacity is fully consumed by task-relevant information. However, the biased competition model suggests that the contents of working memory (WM) can guide attentional selection automatically, even when this guidance is detrimental to visual search. An intriguing but unsolved question is what will happen when selective attention is influenced by both perceptual load and WM guidance. To study this issue, behavioral performances and event-related potentials (ERPs) were recorded when participants were presented with a cue to either identify or hold in memory and had to perform a visual search task subsequently, under conditions of low or high perceptual load. Behavioural data showed that high perceptual load eliminated the attentional capture by WM. The ERP results revealed an obvious WM guidance effect in P1 component with invalid trials eliciting larger P1 than neutral trials, regardless of the level of perceptual load. The interaction between perceptual load and WM guidance was significant for the posterior N1 component. The memory guidance effect on N1 was eliminated by high perceptual load. Standardized Low Resolution Electrical Tomography Analysis (sLORETA) showed that the WM guidance effect and the perceptual load effect on attention can be localized into the occipital area and parietal lobe, respectively. Merely identifying the cue produced no effect on the P1 or N1 component. These results suggest that in selective attention, the information held in WM could capture attention at the early stage of visual processing in the occipital cortex. Interestingly, this initial capture of attention by WM could be modulated by the level of perceptual load and the parietal lobe mediates target selection at the discrimination stage. PMID:26098079

Targeting Human Central Nervous System Protein Kinases: An Isoform Selective p38αMAPK Inhibitor That Attenuates Disease Progression in Alzheimer’s Disease Mouse Models

PubMed Central

2015-01-01

The first kinase inhibitor drug approval in 2001 initiated a remarkable decade of tyrosine kinase inhibitor drugs for oncology indications, but a void exists for serine/threonine protein kinase inhibitor drugs and central nervous system indications. Stress kinases are of special interest in neurological and neuropsychiatric disorders due to their involvement in synaptic dysfunction and complex disease susceptibility. Clinical and preclinical evidence implicates the stress related kinase p38αMAPK as a potential neurotherapeutic target, but isoform selective p38αMAPK inhibitor candidates are lacking and the mixed kinase inhibitor drugs that are promising in peripheral tissue disease indications have limitations for neurologic indications. Therefore, pursuit of the neurotherapeutic hypothesis requires kinase isoform selective inhibitors with appropriate neuropharmacology features. Synaptic dysfunction disorders offer a potential for enhanced pharmacological efficacy due to stress-induced activation of p38αMAPK in both neurons and glia, the interacting cellular components of the synaptic pathophysiological axis, to be modulated. We report a novel isoform selective p38αMAPK inhibitor, MW01-18-150SRM (=MW150), that is efficacious in suppression of hippocampal-dependent associative and spatial memory deficits in two distinct synaptic dysfunction mouse models. A synthetic scheme for biocompatible product and positive outcomes from pharmacological screens are presented. The high-resolution crystallographic structure of the p38αMAPK/MW150 complex documents active site binding, reveals a potential low energy conformation of the bound inhibitor, and suggests a structural explanation for MW150’s exquisite target selectivity. As far as we are aware, MW150 is without precedent as an isoform selective p38MAPK inhibitor or as a kinase inhibitor capable of modulating in vivo stress related behavior. PMID:25676389

Characterization of the pharmacokinetics of gasoline using PBPK modeling with a complex mixtures chemical lumping approach.

PubMed

Dennison, James E; Andersen, Melvin E; Yang, Raymond S H

2003-09-01

Gasoline consists of a few toxicologically significant components and a large number of other hydrocarbons in a complex mixture. By using an integrated, physiologically based pharmacokinetic (PBPK) modeling and lumping approach, we have developed a method for characterizing the pharmacokinetics (PKs) of gasoline in rats. The PBPK model tracks selected target components (benzene, toluene, ethylbenzene, o-xylene [BTEX], and n-hexane) and a lumped chemical group representing all nontarget components, with competitive metabolic inhibition between all target compounds and the lumped chemical. PK data was acquired by performing gas uptake PK studies with male F344 rats in a closed chamber. Chamber air samples were analyzed every 10-20 min by gas chromatography/flame ionization detection and all nontarget chemicals were co-integrated. A four-compartment PBPK model with metabolic interactions was constructed using the BTEX, n-hexane, and lumped chemical data. Target chemical kinetic parameters were refined by studies with either the single chemical alone or with all five chemicals together. o-Xylene, at high concentrations, decreased alveolar ventilation, consistent with respiratory irritation. A six-chemical interaction model with the lumped chemical group was used to estimate lumped chemical partitioning and metabolic parameters for a winter blend of gasoline with methyl t-butyl ether and a summer blend without any oxygenate. Computer simulation results from this model matched well with experimental data from single chemical, five-chemical mixture, and the two blends of gasoline. The PBPK model analysis indicated that metabolism of individual components was inhibited up to 27% during the 6-h gas uptake experiments of gasoline exposures.

Ecosystem-based fisheries management requires a change to the selective fishing philosophy

PubMed Central

Zhou, Shijie; Smith, Anthony D. M.; Punt, André E.; Richardson, Anthony J.; Gibbs, Mark; Fulton, Elizabeth A.; Pascoe, Sean; Bulman, Catherine; Bayliss, Peter; Sainsbury, Keith

2010-01-01

Globally, many fish species are overexploited, and many stocks have collapsed. This crisis, along with increasing concerns over flow-on effects on ecosystems, has caused a reevaluation of traditional fisheries management practices, and a new ecosystem-based fisheries management (EBFM) paradigm has emerged. As part of this approach, selective fishing is widely encouraged in the belief that nonselective fishing has many adverse impacts. In particular, incidental bycatch is seen as wasteful and a negative feature of fishing, and methods to reduce bycatch are implemented in many fisheries. However, recent advances in fishery science and ecology suggest that a selective approach may also result in undesirable impacts both to fisheries and marine ecosystems. Selective fishing applies one or more of the “6-S” selections: species, stock, size, sex, season, and space. However, selective fishing alters biodiversity, which in turn changes ecosystem functioning and may affect fisheries production, hindering rather than helping achieve the goals of EBFM. We argue here that a “balanced exploitation” approach might alleviate many of the ecological effects of fishing by avoiding intensive removal of particular components of the ecosystem, while still supporting sustainable fisheries. This concept may require reducing exploitation rates on certain target species or groups to protect vulnerable components of the ecosystem. Benefits to society could be maintained or even increased because a greater proportion of the entire suite of harvested species is used. PMID:20435916

Ecosystem-based fisheries management requires a change to the selective fishing philosophy.

PubMed

Zhou, Shijie; Smith, Anthony D M; Punt, André E; Richardson, Anthony J; Gibbs, Mark; Fulton, Elizabeth A; Pascoe, Sean; Bulman, Catherine; Bayliss, Peter; Sainsbury, Keith

2010-05-25

Globally, many fish species are overexploited, and many stocks have collapsed. This crisis, along with increasing concerns over flow-on effects on ecosystems, has caused a reevaluation of traditional fisheries management practices, and a new ecosystem-based fisheries management (EBFM) paradigm has emerged. As part of this approach, selective fishing is widely encouraged in the belief that nonselective fishing has many adverse impacts. In particular, incidental bycatch is seen as wasteful and a negative feature of fishing, and methods to reduce bycatch are implemented in many fisheries. However, recent advances in fishery science and ecology suggest that a selective approach may also result in undesirable impacts both to fisheries and marine ecosystems. Selective fishing applies one or more of the "6-S" selections: species, stock, size, sex, season, and space. However, selective fishing alters biodiversity, which in turn changes ecosystem functioning and may affect fisheries production, hindering rather than helping achieve the goals of EBFM. We argue here that a "balanced exploitation" approach might alleviate many of the ecological effects of fishing by avoiding intensive removal of particular components of the ecosystem, while still supporting sustainable fisheries. This concept may require reducing exploitation rates on certain target species or groups to protect vulnerable components of the ecosystem. Benefits to society could be maintained or even increased because a greater proportion of the entire suite of harvested species is used.

Targeted sequencing for high-resolution evolutionary analyses following genome duplication in salmonid fish: Proof of concept for key components of the insulin-like growth factor axis.

PubMed

Lappin, Fiona M; Shaw, Rebecca L; Macqueen, Daniel J

2016-12-01

High-throughput sequencing has revolutionised comparative and evolutionary genome biology. It has now become relatively commonplace to generate multiple genomes and/or transcriptomes to characterize the evolution of large taxonomic groups of interest. Nevertheless, such efforts may be unsuited to some research questions or remain beyond the scope of some research groups. Here we show that targeted high-throughput sequencing offers a viable alternative to study genome evolution across a vertebrate family of great scientific interest. Specifically, we exploited sequence capture and Illumina sequencing to characterize the evolution of key components from the insulin-like growth (IGF) signalling axis of salmonid fish at unprecedented phylogenetic resolution. The IGF axis represents a central governor of vertebrate growth and its core components were expanded by whole genome duplication in the salmonid ancestor ~95Ma. Using RNA baits synthesised to genes encoding the complete family of IGF binding proteins (IGFBP) and an IGF hormone (IGF2), we captured, sequenced and assembled orthologous and paralogous exons from species representing all ten salmonid genera. This approach generated 299 novel sequences, most as complete or near-complete protein-coding sequences. Phylogenetic analyses confirmed congruent evolutionary histories for all nineteen recognized salmonid IGFBP family members and identified novel salmonid-specific IGF2 paralogues. Moreover, we reconstructed the evolution of duplicated IGF axis paralogues across a replete salmonid phylogeny, revealing complex historic selection regimes - both ancestral to salmonids and lineage-restricted - that frequently involved asymmetric paralogue divergence under positive and/or relaxed purifying selection. Our findings add to an emerging literature highlighting diverse applications for targeted sequencing in comparative-evolutionary genomics. We also set out a viable approach to obtain large sets of nuclear genes for any member of the salmonid family, which should enable insights into the evolutionary role of whole genome duplication before additional nuclear genome sequences become available. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

A network analysis of the Chinese medicine Lianhua-Qingwen formula to identify its main effective components.

PubMed

Wang, Chun-Hua; Zhong, Yi; Zhang, Yan; Liu, Jin-Ping; Wang, Yue-Fei; Jia, Wei-Na; Wang, Guo-Cai; Li, Zheng; Zhu, Yan; Gao, Xiu-Mei

2016-02-01

Chinese medicine is known to treat complex diseases with multiple components and multiple targets. However, the main effective components and their related key targets and functions remain to be identified. Herein, a network analysis method was developed to identify the main effective components and key targets of a Chinese medicine, Lianhua-Qingwen Formula (LQF). The LQF is commonly used for the prevention and treatment of viral influenza in China. It is composed of 11 herbs, gypsum and menthol with 61 compounds being identified in our previous work. In this paper, these 61 candidate compounds were used to find their related targets and construct the predicted-target (PT) network. An influenza-related protein-protein interaction (PPI) network was constructed and integrated with the PT network. Then the compound-effective target (CET) network and compound-ineffective target network (CIT) were extracted, respectively. A novel approach was developed to identify effective components by comparing CET and CIT networks. As a result, 15 main effective components were identified along with 61 corresponding targets. 7 of these main effective components were further experimentally validated to have antivirus efficacy in vitro. The main effective component-target (MECT) network was further constructed with main effective components and their key targets. Gene Ontology (GO) analysis of the MECT network predicted key functions such as NO production being modulated by the LQF. Interestingly, five effective components were experimentally tested and exhibited inhibitory effects on NO production in the LPS induced RAW 264.7 cell. In summary, we have developed a novel approach to identify the main effective components in a Chinese medicine LQF and experimentally validated some of the predictions.

Selection, Characterization and Interaction Studies of a DNA Aptamer for the Detection of Bifidobacterium bifidum

PubMed Central

Hu, Lujun; Wang, Linlin; Lu, Wenwei; Zhao, Jianxin; Zhang, Hao; Chen, Wei

2017-01-01

A whole-bacterium-based SELEX (Systematic Evolution of Ligands by Exponential Enrichment) procedure was adopted in this study for the selection of an ssDNA aptamer that binds to Bifidobacterium bifidum. After 12 rounds of selection targeted against B. bifidum, 30 sequences were obtained and divided into seven families according to primary sequence homology and similarity of secondary structure. Four FAM (fluorescein amidite) labeled aptamer sequences from different families were selected for further characterization by flow cytometric analysis. The results reveal that the aptamer sequence CCFM641-5 demonstrated high-affinity and specificity for B. bifidum compared with the other sequences tested, and the estimated Kd value was 10.69 ± 0.89 nM. Additionally, sequence truncation experiments of the aptamer CCFM641-5 led to the conclusion that the 5′-primer and 3′-primer binding sites were essential for aptamer-target binding. In addition, the possible component of the target B. bifidum, bound by the aptamer CCFM641-5, was identified as a membrane protein by treatment with proteinase. Furthermore, to prove the potential application of the aptamer CCFM641-5, a colorimetric bioassay of the sandwich-type structure was used to detect B. bifidum. The assay had a linear range of 104 to 107 cfu/mL (R2 = 0.9834). Therefore, the colorimetric bioassay appears to be a promising method for the detection of B. bifidum based on the aptamer CCFM641-5. PMID:28441340

Modality-specificity of Selective Attention Networks

PubMed Central

Stewart, Hannah J.; Amitay, Sygal

2015-01-01

Objective: To establish the modality specificity and generality of selective attention networks. Method: Forty-eight young adults completed a battery of four auditory and visual selective attention tests based upon the Attention Network framework: the visual and auditory Attention Network Tests (vANT, aANT), the Test of Everyday Attention (TEA), and the Test of Attention in Listening (TAiL). These provided independent measures for auditory and visual alerting, orienting, and conflict resolution networks. The measures were subjected to an exploratory factor analysis to assess underlying attention constructs. Results: The analysis yielded a four-component solution. The first component comprised of a range of measures from the TEA and was labeled “general attention.” The third component was labeled “auditory attention,” as it only contained measures from the TAiL using pitch as the attended stimulus feature. The second and fourth components were labeled as “spatial orienting” and “spatial conflict,” respectively—they were comprised of orienting and conflict resolution measures from the vANT, aANT, and TAiL attend-location task—all tasks based upon spatial judgments (e.g., the direction of a target arrow or sound location). Conclusions: These results do not support our a-priori hypothesis that attention networks are either modality specific or supramodal. Auditory attention separated into selectively attending to spatial and non-spatial features, with the auditory spatial attention loading onto the same factor as visual spatial attention, suggesting spatial attention is supramodal. However, since our study did not include a non-spatial measure of visual attention, further research will be required to ascertain whether non-spatial attention is modality-specific. PMID:26635709

Adaptive fusion of infrared and visible images in dynamic scene

NASA Astrophysics Data System (ADS)

Yang, Guang; Yin, Yafeng; Man, Hong; Desai, Sachi

2011-11-01

Multiple modalities sensor fusion has been widely employed in various surveillance and military applications. A variety of image fusion techniques including PCA, wavelet, curvelet and HSV has been proposed in recent years to improve human visual perception for object detection. One of the main challenges for visible and infrared image fusion is to automatically determine an optimal fusion strategy for different input scenes along with an acceptable computational cost. This paper, we propose a fast and adaptive feature selection based image fusion method to obtain high a contrast image from visible and infrared sensors for targets detection. At first, fuzzy c-means clustering is applied on the infrared image to highlight possible hotspot regions, which will be considered as potential targets' locations. After that, the region surrounding the target area is segmented as the background regions. Then image fusion is locally applied on the selected target and background regions by computing different linear combination of color components from registered visible and infrared images. After obtaining different fused images, histogram distributions are computed on these local fusion images as the fusion feature set. The variance ratio which is based on Linear Discriminative Analysis (LDA) measure is employed to sort the feature set and the most discriminative one is selected for the whole image fusion. As the feature selection is performed over time, the process will dynamically determine the most suitable feature for the image fusion in different scenes. Experiment is conducted on the OSU Color-Thermal database, and TNO Human Factor dataset. The fusion results indicate that our proposed method achieved a competitive performance compared with other fusion algorithms at a relatively low computational cost.

In silico and ex vivo approaches indicate immune pressure on capsid and non-capsid regions of coxsackie B viruses in the human system.

PubMed

Kundu, Rhiannon; Knight, Robin; Dunga, Meenakshi; Peakman, Mark

2018-01-01

Coxsackie B Virus (CBV) infection has been linked to the aetiology of type 1 diabetes (T1D) and vaccination has been proposed as prophylaxis for disease prevention. Serum neutralising antibodies and the presence of viral protein and RNA in tissues have been common tools to examine this potential disease relationship, whilst the role of anti-CBV cytotoxic T cell responses and their targets have not been studied. To address this knowledge gap, we augmented conventional HLA-binding predictive algorithm-based epitope discovery by cross-referencing epitopes with sites of positive natural selection within the CBV3 viral genome, identified using mixed effects models of evolution. Eight epitopes for the common MHC class I allele HLA-A*0201 occur at sites that appear to be positively selected. Furthermore, such epitopes span the viral genome, indicating that effective anti-viral responses may not be restricted to the capsid region. To assess the spectrum of IFNy responses in non-diabetic subjects and recently diagnosed type 1 diabetes (T1D) patients, we stimulated PBMC ex vivo with pools of synthetic peptides based on component-restricted sequences identified in silico. We found responders were more likely to recognize multiple rather than a single CBV peptide pool, indicating that the natural course of infection results in multiple targets for effector memory responses, rather than immunodominant epitopes or viral components. The finding that anti-CBV CD8 T cell immunity is broadly targeted has implications for vaccination strategies and studies on the pathogenesis of CBV-linked diseases.

Transforming Growth Factor-β Is an Upstream Regulator of Mammalian Target of Rapamycin Complex 2-Dependent Bladder Cancer Cell Migration and Invasion.

PubMed

Gupta, Sounak; Hau, Andrew M; Al-Ahmadie, Hikmat A; Harwalkar, Jyoti; Shoskes, Aaron C; Elson, Paul; Beach, Jordan R; Hussey, George S; Schiemann, William P; Egelhoff, Thomas T; Howe, Philip H; Hansel, Donna E

2016-05-01

Our prior work identified the mammalian target of rapamycin complex 2 (mTORC2) as a key regulator of bladder cancer cell migration and invasion, although upstream growth factor mediators of this pathway in bladder cancer have not been well delineated. We tested whether transforming growth factor (TGF)-β, which can function as a promotility factor in bladder cancer cells, could regulate mTORC2-dependent bladder cancer cell motility and invasion. In human bladder cancers, the highest levels of phosphorylated SMAD2, a TGF-β signaling intermediate, were present in high-grade invasive bladder cancers and associated with more frequent recurrence and decreased disease-specific survival. Increased expression of TGF-β isoforms, receptors, and signaling components was detected in invasive high-grade bladder cancer cells that expressed Vimentin and lacked E-cadherin. Application of TGF-β induced phosphorylation of the Ser473 residue of AKT, a selective target of mTORC2, in a SMAD2- and SMAD4-independent manner and increased bladder cancer cell migration in a modified scratch wound assay and invasion through Matrigel. Inhibition of TGF-β receptor I using SB431542 ablated TGF-β-induced migration and invasion. A similar effect was seen when Rictor, a key mTORC2 component, was selectively silenced. Our results suggest that TGF-β can induce bladder cancer cell invasion via mTORC2 signaling, which may be applicable in most bladder cancers. Copyright © 2016. Published by Elsevier Inc.

Design, Synthesis, and Structure–Activity Relationship of a Novel Series of GluN2C-Selective Potentiators

PubMed Central

2015-01-01

NMDA receptors are tetrameric complexes composed of GluN1 and GluN2A–D subunits that mediate a slow Ca2+-permeable component of excitatory synaptic transmission. NMDA receptors have been implicated in a wide range of neurological diseases and thus represent an important therapeutic target. We herein describe a novel series of pyrrolidinones that selectively potentiate only NMDA receptors that contain the GluN2C subunit. The most active analogues tested were over 100-fold selective for recombinant GluN2C-containing receptors over GluN2A/B/D-containing NMDA receptors as well as AMPA and kainate receptors. This series represents the first class of allosteric potentiators that are selective for diheteromeric GluN2C-containing NMDA receptors. PMID:24512267

Applying Quantitative Approaches to the Formative Evaluation of Antismoking Campaign Messages

PubMed Central

Parvanta, Sarah; Gibson, Laura; Forquer, Heather; Shapiro-Luft, Dina; Dean, Lorraine; Freres, Derek; Lerman, Caryn; Mallya, Giridhar; Moldovan-Johnson, Mihaela; Tan, Andy; Cappella, Joseph; Hornik, Robert

2014-01-01

This article shares an in-depth summary of a formative evaluation that used quantitative data to inform the development and selection of promotional ads for the antismoking communication component of a social marketing campaign. A foundational survey provided cross-sectional data to identify beliefs about quitting smoking that campaign messages should target, as well as beliefs to avoid. Pretesting draft ads against quantitative indicators of message effectiveness further facilitated the selection and rejection of final campaign ads. Finally, we consider lessons learned from the process of balancing quantitative methods and judgment to make formative decisions about more and less promising persuasive messages for campaigns. PMID:24817829

Optical modeling of agricultural fields and rough-textured rock and mineral surfaces

NASA Technical Reports Server (NTRS)

Suits, G. H.; Vincent, R. K.; Horwitz, H. M.; Erickson, J. D.

1973-01-01

Review was made of past models for describing the reflectance and/or emittance properties of agricultural/forestry and geological targets in an effort to select the best theoretical models. An extension of the six parameter Allen-Gayle-Richardson model was chosen as the agricultural plant canopy model. The model is used to predict the bidirectional reflectance of a field crop from known laboratory spectra of crop components and approximate plant geometry. The selected geological model is based on Mie theory and radiative transfer equations, and will assess the effect of textural variations of the spectral emittance of natural rock surfaces.

Method of synthesizing a low density material

DOEpatents

Lorensen, L.E.; Monaco, S.B.

1987-02-27

A novel method of synthesizing a polymeric material of low density of the order of 50mg/cc or less. Such a low density material has applications in many areas including laser target fabrication. The method comprises preparing a polymer blend of two incompatible polymers as a major and a minor phase by mixing them and extruding the mixture, and then selectively extracting the major component, to yield a fine, low density structure.

Observability of Plant Metabolic Networks Is Reflected in the Correlation of Metabolic Profiles.

PubMed

Schwahn, Kevin; Küken, Anika; Kliebenstein, Daniel J; Fernie, Alisdair R; Nikoloski, Zoran

2016-10-01

Understanding whether the functionality of a biological system can be characterized by measuring few selected components is key to targeted phenotyping techniques in systems biology. Methods from observability theory have proven useful in identifying sensor components that have to be measured to obtain information about the entire system. Yet, the extent to which the data profiles reflect the role of components in the observability of the system remains unexplored. Here we first identify the sensor metabolites in the model plant Arabidopsis (Arabidopsis thaliana) by employing state-of-the-art genome-scale metabolic networks. By using metabolic data profiles from a set of seven environmental perturbations as well as from natural variability, we demonstrate that the data profiles of sensor metabolites are more correlated than those of nonsensor metabolites. This pattern was confirmed with in silico generated metabolic profiles from a medium-size kinetic model of plant central carbon metabolism. Altogether, due to the small number of identified sensors, our study implies that targeted metabolite analyses may provide the vast majority of relevant information about plant metabolic systems. © 2016 American Society of Plant Biologists. All Rights Reserved.

Secreted Phospholipases A₂ from Animal Venoms in Pain and Analgesia.

PubMed

Zambelli, Vanessa O; Picolo, Gisele; Fernandes, Carlos A H; Fontes, Marcos R M; Cury, Yara

2017-12-19

Animal venoms comprise a complex mixture of components that affect several biological systems. Based on the high selectivity for their molecular targets, these components are also a rich source of potential therapeutic agents. Among the main components of animal venoms are the secreted phospholipases A₂ (sPLA₂s). These PLA₂ belong to distinct PLA₂s groups. For example, snake venom sPLA₂s from Elapidae and Viperidae families, the most important families when considering envenomation, belong, respectively, to the IA and IIA/IIB groups, whereas bee venom PLA₂ belongs to group III of sPLA₂s. It is well known that PLA₂, due to its hydrolytic activity on phospholipids, takes part in many pathophysiological processes, including inflammation and pain. Therefore, secreted PLA₂s obtained from animal venoms have been widely used as tools to (a) modulate inflammation and pain, uncovering molecular targets that are implicated in the control of inflammatory (including painful) and neurodegenerative diseases; (b) shed light on the pathophysiology of inflammation and pain observed in human envenomation by poisonous animals; and, (c) characterize molecular mechanisms involved in inflammatory diseases. The present review summarizes the knowledge on the nociceptive and antinociceptive actions of sPLA₂s from animal venoms, particularly snake venoms.

Contrast performance modeling of broadband reflective imaging systems with hypothetical tunable filter fore-optics

NASA Astrophysics Data System (ADS)

Hodgkin, Van A.

2015-05-01

Most mass-produced, commercially available and fielded military reflective imaging systems operate across broad swaths of the visible, near infrared (NIR), and shortwave infrared (SWIR) wavebands without any spectral selectivity within those wavebands. In applications that employ these systems, it is not uncommon to be imaging a scene in which the image contrasts between the objects of interest, i.e., the targets, and the objects of little or no interest, i.e., the backgrounds, are sufficiently low to make target discrimination difficult or uncertain. This can occur even when the spectral distribution of the target and background reflectivity across the given waveband differ significantly from each other, because the fundamental components of broadband image contrast are the spectral integrals of the target and background signatures. Spectral integration by the detectors tends to smooth out any differences. Hyperspectral imaging is one approach to preserving, and thus highlighting, spectral differences across the scene, even when the waveband integrated signatures would be about the same, but it is an expensive, complex, noncompact, and untimely solution. This paper documents a study of how the capability to selectively customize the spectral width and center wavelength with a hypothetical tunable fore-optic filter would allow a broadband reflective imaging sensor to optimize image contrast as a function of scene content and ambient illumination.

A hybrid deconvolution approach for estimation of in vivo non-displaceable binding for brain PET targets without a reference region

PubMed Central

Mann, J. John; Ogden, R. Todd

2017-01-01

Background and aim Estimation of a PET tracer’s non-displaceable distribution volume (VND) is required for quantification of specific binding to its target of interest. VND is generally assumed to be comparable brain-wide and is determined either from a reference region devoid of the target, often not available for many tracers and targets, or by imaging each subject before and after blocking the target with another molecule that has high affinity for the target, which is cumbersome and involves additional radiation exposure. Here we propose, and validate for the tracers [11C]DASB and [11C]CUMI-101, a new data-driven hybrid deconvolution approach (HYDECA) that determines VND at the individual level without requiring either a reference region or a blocking study. Methods HYDECA requires the tracer metabolite-corrected concentration curve in blood plasma and uses a singular value decomposition to estimate the impulse response function across several brain regions from measured time activity curves. HYDECA decomposes each region’s impulse response function into the sum of a parametric non-displaceable component, which is a function of VND, assumed common across regions, and a nonparametric specific component. These two components differentially contribute to each impulse response function. Different regions show different contributions of the two components, and HYDECA examines data across regions to find a suitable common VND. HYDECA implementation requires determination of two tuning parameters, and we propose two strategies for objectively selecting these parameters for a given tracer: using data from blocking studies, and realistic simulations of the tracer. Using available test-retest data, we compare HYDECA estimates of VND and binding potentials to those obtained based on VND estimated using a purported reference region. Results For [11C]DASB and [11C]CUMI-101, we find that regardless of the strategy used to optimize the tuning parameters, HYDECA provides considerably less biased estimates of VND than those obtained, as is commonly done, using a non-ideal reference region. HYDECA test-retest reproducibility is comparable to that obtained using a VND determined from a non-ideal reference region, when considering the binding potentials BPP and BPND. Conclusions HYDECA can provide subject-specific estimates of VND without requiring a blocking study for tracers and targets for which a valid reference region does not exist. PMID:28459878

Distribution of toxic alkaloids in tissues from three herbal medicine Aconitum species using laser micro-dissection, UHPLC-QTOF MS and LC-MS/MS techniques.

PubMed

Jaiswal, Yogini; Liang, Zhitao; Ho, Alan; Wong, LaiLai; Yong, Peng; Chen, Hubiao; Zhao, Zhongzhen

2014-11-01

Aconite poisoning continues to be a major type of poisoning caused by herbal drugs in many countries. Nevertheless, despite its toxic characteristics, aconite is used because of its valuable therapeutic benefits. The aim of the present study was to determine the distribution of toxic alkaloids in tissues of aconite roots through chemical profiling. Three species were studied, all being used in traditional Chinese Medicine (TCM) and traditional Indian medicine (Ayurveda), namely: Aconitum carmichaelii, Aconitum kusnezoffii and Aconitum heterophyllum. Laser micro-dissection was used for isolation of target microscopic tissues, such as the metaderm, cortex, xylem, pith, and phloem, with ultra-high performance liquid chromatography equipped with quadrupole time-of-flight mass spectrometry (UHPLC-QTOF MS) employed for detection of metabolites. Using a multi-targeted approach through auto and targeted LC-MS/MS, 48 known compounds were identified and the presence of aconitine, mesaconitine and hypaconitine that are the biomarkers of this plant was confirmed in the tissues. These results suggest that the three selected toxic alkaloids were exclusively found in A. carmichaelii and A. kusnezoffii. The most toxic components were found in large A. carmichaelii roots with more lateral root projections, and specifically in the metaderm, cork and vascular bundle tissues. The results from metabolite profiling were correlated with morphological features to predict the tissue specific distribution of toxic components and toxicity differences among the selected species. By careful exclusion of tissues having toxic diester diterpenoid alkaloids, the beneficial effects of aconite can still be retained and the frequency of toxicity occurrences can be greatly reduced. Knowledge of tissue-specific metabolite distribution can guide users and herbal drug manufacturers in prudent selection of relatively safer and therapeutically more effective parts of the root. The information provided from this study can contribute towards improved and effective management of therapeutically important, nonetheless, toxic drug such as Aconite. Copyright © 2014 Elsevier Ltd. All rights reserved.

Pricing of new vaccines

PubMed Central

McGlone, Sarah M

2010-01-01

New vaccine pricing is a complicated process that could have substantial long-standing scientific, medical and public health ramifications. Pricing can have a considerable impact on new vaccine adoption and, thereby, either culminate or thwart years of research and development and public health efforts. Typically, pricing strategy consists of the following eleven components: (1) Conduct a target population analysis; (2) Map potential competitors and alternatives; (3) Construct a vaccine target product profile (TPP) and compare it to projected or actual TPPs of competing vaccines; (4) Quantify the incremental value of the new vaccine's characteristics; (5) Determine vaccine positioning in the marketplace; (6) Estimate the vaccine price-demand curve; (7) Calculate vaccine costs (including those of manufacturing, distribution, and research and development); (8) Account for various legal, regulatory, third party payer and competitor factors; (9) Consider the overall product portfolio; (10) Set pricing objectives; (11) Select pricing and pricing structure. While the biomedical literature contains some studies that have addressed these components, there is still considerable room for more extensive evaluation of this important area. PMID:20861678

Pricing of new vaccines.

PubMed

Lee, Bruce Y; McGlone, Sarah M

2010-08-01

New vaccine pricing is a complicated process that could have substantial long-standing scientific, medical, and public health ramifications. Pricing can have a considerable impact on new vaccine adoption and, thereby, either culminate or thwart years of research and development and public health efforts. Typically, pricing strategy consists of the following ten components: 1. Conduct a target population analysis; 2. Map potential competitors and alternatives; 3. Construct a vaccine target product profile (TPP) and compare it to projected or actual TPPs of competing vaccines; 4. Quantify the incremental value of the new vaccine's characteristics; 5. Determine vaccine positioning in the marketplace; 6. Estimate the vaccine price-demand curve; 7. Calculate vaccine costs (including those of manufacturing, distribution, and research and development); 8. Account for various legal, regulatory, third party payer, and competitor factors; 9. Consider the overall product portfolio; 10. Set pricing objectives; 11. Select pricing and pricing structure. While the biomedical literature contains some studies that have addressed these components, there is still considerable room for more extensive evaluation of this important area.

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

Hornemann, Andrea, E-mail: andrea.hornemann@ptb.de; Hoehl, Arne, E-mail: arne.hoehl@ptb.de; Ulm, Gerhard, E-mail: gerhard.ulm@ptb.de

Bio-diagnostic assays of high complexity rely on nanoscaled assay recognition elements that can provide unique selectivity and design-enhanced sensitivity features. High throughput performance requires the simultaneous detection of various analytes combined with appropriate bioassay components. Nanoparticle induced sensitivity enhancement, and subsequent multiplexed capability Surface-Enhanced InfraRed Absorption (SEIRA) assay formats are fitting well these purposes. SEIRA constitutes an ideal platform to isolate the vibrational signatures of targeted bioassay and active molecules. The potential of several targeted biolabels, here fluorophore-labeled antibody conjugates, chemisorbed onto low-cost biocompatible gold nano-aggregates substrates have been explored for their use in assay platforms. Dried films were analyzedmore » by synchrotron radiation based FTIR/SEIRA spectro-microscopy and the resulting complex hyperspectral datasets were submitted to automated statistical analysis, namely Principal Components Analysis (PCA). The relationships between molecular fingerprints were put in evidence to highlight their spectral discrimination capabilities. We demonstrate that robust spectral encoding via SEIRA fingerprints opens up new opportunities for fast, reliable and multiplexed high-end screening not only in biodiagnostics but also in vitro biochemical imaging.« less

An ICA-based method for the identification of optimal FMRI features and components using combined group-discriminative techniques

PubMed Central

Sui, Jing; Adali, Tülay; Pearlson, Godfrey D.; Calhoun, Vince D.

2013-01-01

Extraction of relevant features from multitask functional MRI (fMRI) data in order to identify potential biomarkers for disease, is an attractive goal. In this paper, we introduce a novel feature-based framework, which is sensitive and accurate in detecting group differences (e.g. controls vs. patients) by proposing three key ideas. First, we integrate two goal-directed techniques: coefficient-constrained independent component analysis (CC-ICA) and principal component analysis with reference (PCA-R), both of which improve sensitivity to group differences. Secondly, an automated artifact-removal method is developed for selecting components of interest derived from CC-ICA, with an average accuracy of 91%. Finally, we propose a strategy for optimal feature/component selection, aiming to identify optimal group-discriminative brain networks as well as the tasks within which these circuits are engaged. The group-discriminating performance is evaluated on 15 fMRI feature combinations (5 single features and 10 joint features) collected from 28 healthy control subjects and 25 schizophrenia patients. Results show that a feature from a sensorimotor task and a joint feature from a Sternberg working memory (probe) task and an auditory oddball (target) task are the top two feature combinations distinguishing groups. We identified three optimal features that best separate patients from controls, including brain networks consisting of temporal lobe, default mode and occipital lobe circuits, which when grouped together provide improved capability in classifying group membership. The proposed framework provides a general approach for selecting optimal brain networks which may serve as potential biomarkers of several brain diseases and thus has wide applicability in the neuroimaging research community. PMID:19457398

Hole-y Debris Disks, Batman! Where are the planets?

NASA Astrophysics Data System (ADS)

Bailey, V.; Meshkat, T.; Hinz, P.; Kenworthy, M.; Su, K. Y. L.

2014-03-01

Giant planets at wide separations are rare and direct imaging surveys are resource-intensive, so a cheaper marker for the presence of giant planets is desirable. One intriguing possibility is to use the effect of planets on their host stars' debris disks. Theoretical studies indicate giant planets can gravitationally carve sharp boundaries and gaps in their disks; this has been seen for HR 8799, β Pic, and tentatively for HD 95086 (Su et al. 2009, Lagrange et al. 2010, Moor et al. 2013). If more broadly demonstrated, this link could help guide target selection for next generation direct imaging surveys. Using Spitzer MIPS/IRS spectral energy distributions (SEDs), we identify several dozen systems with two-component and/or large inner cavity disks (aka Hole-y Debris Disks). With LBT/LBTI, VLT/NaCo, GeminiS/NICI, MMT/Clio and Magellan/Clio, we survey a subset these SEDselected targets (~20). In contrast to previous disk-selected planet surveys (e.g.: Janson et al. 2013, Wahhaj et al. 2013) we image primarily in the thermal IR (L'-band), where planet-to-star contrast is more favorable and background contaminants less numerous. Thus far, two of our survey targets host planet-mass companions, both of which were discovered in L'-band after they were unrecognized or undetectable in H-band. For each system in our sample set, we will investigate whether the known companions and/or companions below our detection threshold could be responsible for the disk architecture. Ultimately, we will increase our effective sample size by incorporating detection limits from surveys that have independently targeted some of our systems of interest. In this way we will refine the conditions under which disk SED-based target selection is likely to be useful and valid.

SapTrap, a Toolkit for High-Throughput CRISPR/Cas9 Gene Modification in Caenorhabditis elegans.

PubMed

Schwartz, Matthew L; Jorgensen, Erik M

2016-04-01

In principle, clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 allows genetic tags to be inserted at any locus. However, throughput is limited by the laborious construction of repair templates and guide RNA constructs and by the identification of modified strains. We have developed a reagent toolkit and plasmid assembly pipeline, called "SapTrap," that streamlines the production of targeting vectors for tag insertion, as well as the selection of modified Caenorhabditis elegans strains. SapTrap is a high-efficiency modular plasmid assembly pipeline that produces single plasmid targeting vectors, each of which encodes both a guide RNA transcript and a repair template for a particular tagging event. The plasmid is generated in a single tube by cutting modular components with the restriction enzyme SapI, which are then "trapped" in a fixed order by ligation to generate the targeting vector. A library of donor plasmids supplies a variety of protein tags, a selectable marker, and regulatory sequences that allow cell-specific tagging at either the N or the C termini. All site-specific sequences, such as guide RNA targeting sequences and homology arms, are supplied as annealed synthetic oligonucleotides, eliminating the need for PCR or molecular cloning during plasmid assembly. Each tag includes an embedded Cbr-unc-119 selectable marker that is positioned to allow concurrent expression of both the tag and the marker. We demonstrate that SapTrap targeting vectors direct insertion of 3- to 4-kb tags at six different loci in 10-37% of injected animals. Thus SapTrap vectors introduce the possibility for high-throughput generation of CRISPR/Cas9 genome modifications. Copyright © 2016 by the Genetics Society of America.

Many Routes to an Antibody Heavy-Chain CDR3: Necessary, Yet Insufficient, for Specific Binding

DOE PAGES

D'Angelo, Sara; Ferrara, Fortunato; Naranjo, Leslie; ...

2018-03-08

Because of its great potential for diversity, the immunoglobulin heavy-chain complementarity-determining region 3 (HCDR3) is taken as an antibody molecule’s most important component in conferring binding activity and specificity. For this reason, HCDR3s have been used as unique identifiers to investigate adaptive immune responses in vivo and to characterize in vitro selection outputs where display systems were employed. Here, we show that many different HCDR3s can be identified within a target-specific antibody population after in vitro selection. For each identified HCDR3, a number of different antibodies bearing differences elsewhere can be found. In such selected populations, all antibodies with themore » same HCDR3 recognize the target, albeit at different affinities. In contrast, within unselected populations, the majority of antibodies with the same HCDR3 sequence do not bind the target. In one HCDR3 examined in depth, all target-specific antibodies were derived from the same VDJ rearrangement, while non-binding antibodies with the same HCDR3 were derived from many different V and D gene rearrangements. Careful examination of previously published in vivo datasets reveals that HCDR3s shared between, and within, different individuals can also originate from rearrangements of different V and D genes, with up to 26 different rearrangements yielding the same identical HCDR3 sequence. On the basis of these observations, we conclude that the same HCDR3 can be generated by many different rearrangements, but that specific target binding is an outcome of unique rearrangements and VL pairing: the HCDR3 is necessary, albeit insufficient, for specific antibody binding.« less

Many Routes to an Antibody Heavy-Chain CDR3: Necessary, Yet Insufficient, for Specific Binding

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

D'Angelo, Sara; Ferrara, Fortunato; Naranjo, Leslie

Because of its great potential for diversity, the immunoglobulin heavy-chain complementarity-determining region 3 (HCDR3) is taken as an antibody molecule’s most important component in conferring binding activity and specificity. For this reason, HCDR3s have been used as unique identifiers to investigate adaptive immune responses in vivo and to characterize in vitro selection outputs where display systems were employed. Here, we show that many different HCDR3s can be identified within a target-specific antibody population after in vitro selection. For each identified HCDR3, a number of different antibodies bearing differences elsewhere can be found. In such selected populations, all antibodies with themore » same HCDR3 recognize the target, albeit at different affinities. In contrast, within unselected populations, the majority of antibodies with the same HCDR3 sequence do not bind the target. In one HCDR3 examined in depth, all target-specific antibodies were derived from the same VDJ rearrangement, while non-binding antibodies with the same HCDR3 were derived from many different V and D gene rearrangements. Careful examination of previously published in vivo datasets reveals that HCDR3s shared between, and within, different individuals can also originate from rearrangements of different V and D genes, with up to 26 different rearrangements yielding the same identical HCDR3 sequence. On the basis of these observations, we conclude that the same HCDR3 can be generated by many different rearrangements, but that specific target binding is an outcome of unique rearrangements and VL pairing: the HCDR3 is necessary, albeit insufficient, for specific antibody binding.« less

Drug discovery in the next millennium.

PubMed

Ohlstein, E H; Ruffolo, R R; Elliott, J D

2000-01-01

Selection and validation of novel molecular targets have become of paramount importance in light of the plethora of new potential therapeutic drug targets that have emerged from human gene sequencing. In response to this revolution within the pharmaceutical industry, the development of high-throughput methods in both biology and chemistry has been necessitated. This review addresses these technological advances as well as several new areas that have been created by necessity to deal with this new paradigm, such as bioinformatics, cheminformatics, and functional genomics. With many of these key components of future drug discovery now in place, it is possible to map out a critical path for this process that will be used into the new millennium.

Do emotion-induced blindness and the attentional blink share underlying mechanisms? An event-related potential study of emotionally-arousing words.

PubMed

MacLeod, Jeffrey; Stewart, Brandie M; Newman, Aaron J; Arnell, Karen M

2017-06-01

When two targets are presented within approximately 500 ms of each other in the context of rapid serial visual presentation (RSVP), participants' ability to report the second target is reduced compared to when the targets are presented further apart in time. This phenomenon is known as the attentional blink (AB). The AB is increased in magnitude when the first target is emotionally arousing. Emotionally arousing stimuli can also capture attention and create an AB-like effect even when these stimuli are presented as to-be-ignored distractor items in a single-target RSVP task. This phenomenon is known as emotion-induced blindness (EIB). The phenomenological similarity in the behavioral results associated with the AB with an emotional T1 and EIB suggest that these effects may result from similar underlying mechanisms - a hypothesis that we tested using event-related electrical brain potentials (ERPs). Behavioral results replicated those reported previously, demonstrating an enhanced AB following an emotionally arousing target and a clear EIB effect. In both paradigms highly arousing taboo/sexual words resulted in an increased early posterior negativity (EPN) component that has been suggested to represent early semantic activation and selection for further processing in working memory. In both paradigms taboo/sexual words also produced an increased late positive potential (LPP) component that has been suggested to represent consolidation of a stimulus in working memory. Therefore, ERP results provide evidence that the EIB and emotion-enhanced AB effects share a common underlying mechanism.

An experimental sample of the field gamma-spectrometer based on solid state Si-photomultiplier

NASA Astrophysics Data System (ADS)

Denisov, Viktor; Korotaev, Valery; Titov, Aleksandr; Blokhina, Anastasia; Kleshchenok, Maksim

2017-05-01

Design of optical-electronic devices and systems involves the selection of such technical patterns that under given initial requirements and conditions are optimal according to certain criteria. The original characteristic of the OES for any purpose, defining its most important feature ability is a threshold detection. Based on this property, will be achieved the required functional quality of the device or system. Therefore, the original criteria and optimization methods have to subordinate to the idea of a better detectability. Generally reduces to the problem of optimal selection of the expected (predetermined) signals in the predetermined observation conditions. Thus the main purpose of optimization of the system when calculating its detectability is the choice of circuits and components that provide the most effective selection of a target.

Study for identification of Beneficial Uses of Space (BUS). Volume 2: Technical report. Book 1: Sections 1 through 4. [with emphasis on space manufacturing and product development

NASA Technical Reports Server (NTRS)

1973-01-01

Consolidated information is presented for the study whose purpose was to identify products, processes, and services to be produced in future spacecraft environments for direct utilization on earth. Discussion of methodology for selecting from among potential space processing approaches, definition of requirements for experiments and tests needed to acquire sufficient knowledge for proof testing of selected processes, formulation of research and development schedules to achieve proof testing, and documentation of the decision processes involved in the programs are presented. Technology and programmatics are reported for the following select studies: (1) surface acoustic wave components; (2) transparent oxides; (3) high purity tungsten X-ray targets; and (4) high specificity isoenzymes.

Components of reward-driven attentional capture.

PubMed

Sha, Li Z; Jiang, Yuhong V

2016-02-01

Recent research reported that task-irrelevant colors captured attention if these colors previously served as search targets and received high monetary reward. We showed that both monetary reward and value-independent mechanisms influenced selective attention. Participants searched for two potential target colors among distractor colors in the training phase. Subsequently, they searched for a shape singleton in a testing phase. Experiment 1 found that participants were slower in the testing phase if a distractor of a previous target color was present rather than absent. Such slowing was observed even when no monetary reward was used during training. Experiment 2 associated monetary rewards with the target colors during the training phase. Participants were faster finding the target associated with higher monetary reward. However, reward training did not yield value-dependent attentional capture in the testing phase. Attentional capture by the previous target colors was not significantly greater for the previously high-reward color than the previously low or no-reward color. These findings revealed both the power and limitations of monetary reward on attention. Although monetary reward can increase attentional priority for the high-reward target during training, subsequent attentional capture effects may not be reward-based, but reflect, in part, attentional capture by previous targets.

Acute Stress and Perceptual Load Consume the Same Attentional Resources: A Behavioral-ERP Study

PubMed Central

Tiferet-Dweck, Chen; Hensel, Michael; Kirschbaum, Clemens; Tzelgov, Joseph; Friedman, Alon; Salti, Moti

2016-01-01

Stress and perceptual load affect selective attention in a paradoxical manner. They can facilitate selectivity or disrupt it. This EEG study was designed to examine the reciprocal relations between stress, load and attention. Two groups of subjects, one that performed the Trier Social Stress Test (TSST), and a control group, were asked to respond to a target letter under low and high perceptual load in the absence or presence of a distractor. In the control group, the distractor increased response times (RTs) for high and low load. In the TSST group, distractor increased RTs under low load only. ERPs showed that distractor’s presentation attenuated early visual P1 component and shortened its latency. In the TSST group, distractor reduced P1 component under high load but did not affect its latency. Source localization demonstrated reduced activation in V1 in response to distractors presence in the P1 time window for the TSST group compared to the control group. A behavioral replication revealed that in the TSST group distractors were less perceived under high load. Taken together, our results show that stress and perceptual load affect selectivity through the early stages of visual processing and might increase selectivity in a manner that would block conscious perception of irrelevant stimuli. PMID:27196027

Functional Expression of P-glycoprotein and Organic Anion Transporting Polypeptides at the Blood-Brain Barrier: Understanding Transport Mechanisms for Improved CNS Drug Delivery?

PubMed

Abdullahi, Wazir; Davis, Thomas P; Ronaldson, Patrick T

2017-07-01

Drug delivery to the central nervous system (CNS) is greatly limited by the blood-brain barrier (BBB). Physical and biochemical properties of the BBB have rendered treatment of CNS diseases, including those with a hypoxia/reoxygenation (H/R) component, extremely difficult. Targeting endogenous BBB transporters from the ATP-binding cassette (ABC) superfamily (i.e., P-glycoprotein (P-gp)) or from the solute carrier (SLC) family (i.e., organic anion transporting polypeptides (OATPs in humans; Oatps in rodents)) has been suggested as a strategy that can improve delivery of drugs to the brain. With respect to P-gp, direct pharmacological inhibition using small molecules or selective regulation by targeting intracellular signaling pathways has been explored. These approaches have been largely unsuccessful due to toxicity issues and unpredictable pharmacokinetics. Therefore, our laboratory has proposed that optimization of CNS drug delivery, particularly for treatment of diseases with an H/R component, can be achieved by targeting Oatp isoforms at the BBB. As the major drug transporting Oatp isoform, Oatp1a4 has demonstrated blood-to-brain transport of substrate drugs with neuroprotective properties. Furthermore, our laboratory has shown that targeting Oatp1a4 regulation (i.e., TGF-β signaling mediated via the ALK-1 and ALK-5 transmembrane receptors) represents an opportunity to control Oatp1a4 functional expression for the purpose of delivering therapeutics to the CNS. In this review, we will discuss limitations of targeting P-gp-mediated transport activity and the advantages of targeting Oatp-mediated transport. Through this discussion, we will also provide critical information on novel approaches to improve CNS drug delivery by targeting endogenous uptake transporters expressed at the BBB.

ARL Summer Student Research Symposium. Volume 1: Select Papers

DTIC Science & Technology

2012-08-01

deploying Android smart phones and tablets on the battlefield, which may be a target for malware. In our research, we attempt to improve static...network. (a) The T1 and MRI images are (b) segmented into different material components. The segmented geometry is then used to create (c) a finite element...towards finding a method to detect mTBI non-invasively. One method in particular includes the use of a magnetic resonance image ( MRI )-based imaging

Facial Dermatitis and Rosacea.

PubMed

Fowler, Joseph F

2016-06-01

Rosacea is a chronic skin disorder associated with flushing, erythema, dryness, burning and stinging, and inflammatory papules and pustules. New treatments available or in development target the inflammatory and erythematous components of the disease. These agents include the selective α2 receptor agonist brimonidine, the topical agents ivermectin cream 1% and azelaic acid foam 15%, and use of tetracyclinetype antibiotics, which affect the cathelicidin pathway. Semin Cutan Med Surg 35(supp6):S107-S109. 2016 published by Frontline Medical Communications.

Evaporative Mass Transfer Behavior of a Complex Immiscible Liquid

PubMed Central

McColl, Colleen M.; Johnson, Gwynn R.; Brusseau, Mark L.

2010-01-01

A series of laboratory experiments was conducted with a multiple-component immiscible liquid, collected from the Picillo Farm Superfund Site in Rhode Island, to examine liquid-vapor mass-transfer behavior. The immiscible liquid, which comprises solvents, oils, pesticides, PCBs, paint sludges, explosives, and other compounds, was characterized using gas chromatography and gas chromatography/mass spectrometry to determine mole fractions of selected constituents. Batch experiments were conducted to evaluate equilibrium phase-partitioning behavior. Two sets of air-stripping column studies were conducted to examine the mass-transfer dynamics of five selected target compounds present in the immiscible-liquid mixture. One set of column experiments was designed to represent a system with free-phase immiscible liquid present; the other was designed to represent a system with a residual phase of immiscible liquid. Initial elution behavior of all target components generally appeared to be ideal for both systems, as the initial vapor-phase concentrations were similar to vapor-phase concentrations measured for the batch experiment and those estimated using Raoult’s law (incorporating the immiscible-liquid composition data). Later-stage removal of 1,2-dichlorobenzene appeared to be rate limited for the columns containing free-phase immiscible liquid and no porous medium. Conversely, evaporative mass transfer appeared to be ideal throughout the experiment conducted with immiscible liquid distributed relatively uniformly as a residual phase within a sandy porous medium. PMID:18614196

Evaporative mass transfer behavior of a complex immiscible liquid.

PubMed

McColl, Colleen M; Johnson, Gwynn R; Brusseau, Mark L

2008-09-01

A series of laboratory experiments was conducted with a multiple-component immiscible liquid, collected from the Picillo Farm Superfund Site in Rhode Island, to examine liquid-vapor mass-transfer behavior. The immiscible liquid, which comprises solvents, oils, pesticides, PCBs, paint sludges, explosives, and other compounds, was characterized using gas chromatography and gas chromatography/mass spectrometry to determine mole fractions of selected constituents. Batch experiments were conducted to evaluate equilibrium phase-partitioning behavior. Two sets of air-stripping column studies were conducted to examine the mass-transfer dynamics of five selected target compounds present in the immiscible-liquid mixture. One set of column experiments was designed to represent a system with free-phase immiscible liquid present; the other was designed to represent a system with a residual phase of immiscible liquid. Initial elution behavior of all target components generally appeared to be ideal for both systems, as the initial vapor-phase concentrations were similar to vapor-phase concentrations measured for the batch experiment and those estimated using Raoult's law (incorporating the immiscible-liquid composition data). Later-stage removal of 1,2-dichlorobenzene appeared to be rate limited for the columns containing free-phase immiscible liquid and no porous medium. Conversely, evaporative mass transfer appeared to be ideal throughout the experiment conducted with immiscible liquid distributed relatively uniformly as a residual phase within a sandy porous medium.

Application of principal component analysis in the pollution assessment with heavy metals of vegetable food chain in the old mining areas

PubMed Central

2012-01-01

Background The aim of the paper is to assess by the principal components analysis (PCA) the heavy metal contamination of soil and vegetables widely used as food for people who live in areas contaminated by heavy metals (HMs) due to long-lasting mining activities. This chemometric technique allowed us to select the best model for determining the risk of HMs on the food chain as well as on people's health. Results Many PCA models were computed with different variables: heavy metals contents and some agro-chemical parameters which characterize the soil samples from contaminated and uncontaminated areas, HMs contents of different types of vegetables grown and consumed in these areas, and the complex parameter target hazard quotients (THQ). Results were discussed in terms of principal component analysis. Conclusion There were two major benefits in processing the data PCA: firstly, it helped in optimizing the number and type of data that are best in rendering the HMs contamination of the soil and vegetables. Secondly, it was valuable for selecting the vegetable species which present the highest/minimum risk of a negative impact on the food chain and human health. PMID:23234365

Utilizing chemo-mechanically functionalized oscillating fins to ``catch and release'' nanoparticles in binary flow

NASA Astrophysics Data System (ADS)

Liu, Ya; Ma, Yongting; Bhattacharya, Amitabh; Kuksenok, Olga; He, Ximin; Aizenberg, Joanna; Balazs, Anna

2013-11-01

In biomimetics, designing an effective ``catch and release'' device for the selective removal of target species from the surrounding solution is critical for developing autonomous sensors and sorters. Using computational simulation, we model an array of oscillating fins that are tethered on the floor of a microchannel and immersed in a binary-fluid stream. During the oscillation, the fins with the specific chemical wetting reach the upper fluid when they are upright and are entirely within the lower stream when they are tilted. We introduce specific adhesive interactions between the fins and particulates in the solution and determine conditions where the oscillating fins can selectively bind (``catch'') target nanoparticles within the upper fluid stream and then release these particles into the lower stream. We isolate the effects of chemical wetting on the fins (e.g., wetting contact angle between fins and fluid) and mechanical parameters (e.g., frequency of fins' oscillations) that lead to the efficient extraction of target species from the upper stream and placement into the lower fluid. Our understanding provides fundamental insights into the system's complex dynamics and mechanism for detection, separation, and purification of multi-component mixtures.

Utilizing Chemo-mechanically Functionalized Oscillating Fins to ``Catch and Release'' Nanoparticles in Binary Flow

NASA Astrophysics Data System (ADS)

Liu, Ya; Kuksenok, Olga; Bhattacharya, Amitabh; Ma, Yongting; He, Ximin; Aizenberg4, Joanna; Balazs, Anna

2014-03-01

In biomimetics, designing an effective ``catch and release'' device for the selective removal of target species from the surrounding solution is critical for developing autonomous sensors and sorters. Using computer simulations, we model an array of oscillating fins that are tethered on the floor of a microchannel and immersed in a mixture of binary fluid stream and binary nanoparticles. During the oscillation, the fins with the specific chemical wetting reach the upper fluid when they are upright and are entirely immersed within the lower stream when they are tilted. We introduce specific interaction between the fins and particulates in the solution and determine conditions where the oscillating fins can selectively ?catch? target nanoparticles within the upper fluid stream and then release these particles into the lower stream. We isolate the effects of wetting contact angle between fins and fluid and the mode of fins' oscillations that lead to the efficient extraction of target species from the upper stream and their placement into the lower fluid. These studies provide fundamental insights into the system's complex dynamics and mechanism for detection, separation, and purification of multi-component mixtures.

Structured Post-IQ Domain Governs Selectivity of Myosin X for Fascin-Actin Bundles*

PubMed Central

Nagy, Stanislav; Rock, Ronald S.

2010-01-01

Without guidance cues, cytoskeletal motors would traffic components to the wrong destination with disastrous consequences for the cell. Recently, we identified a motor protein, myosin X, that identifies bundled actin filaments for transport. These bundles direct myosin X to a unique destination, the tips of cellular filopodia. Because the structural and kinetic features that drive bundle selection are unknown, we employed a domain-swapping approach with the nonselective myosin V to identify the selectivity module of myosin X. We found a surprising role of the myosin X tail region (post-IQ) in supporting long runs on bundles. Moreover, the myosin X head is adapted for initiating processive runs on bundles. We found that the tail is structured and biases the orientation of the two myosin X heads because a targeted insertion that introduces flexibility in the tail abolishes selectivity. Together, these results suggest how myosin motors may manage to read cellular addresses. PMID:20538587

Alternating evolutionary pressure in a genetic algorithm facilitates protein model selection

PubMed Central

Offman, Marc N; Tournier, Alexander L; Bates, Paul A

2008-01-01

Background Automatic protein modelling pipelines are becoming ever more accurate; this has come hand in hand with an increasingly complicated interplay between all components involved. Nevertheless, there are still potential improvements to be made in template selection, refinement and protein model selection. Results In the context of an automatic modelling pipeline, we analysed each step separately, revealing several non-intuitive trends and explored a new strategy for protein conformation sampling using Genetic Algorithms (GA). We apply the concept of alternating evolutionary pressure (AEP), i.e. intermediate rounds within the GA runs where unrestrained, linear growth of the model populations is allowed. Conclusion This approach improves the overall performance of the GA by allowing models to overcome local energy barriers. AEP enabled the selection of the best models in 40% of all targets; compared to 25% for a normal GA. PMID:18673557

Novel N-allyl/propargyl tetrahydroquinolines: Synthesis via Three-component Cationic Imino Diels-Alder Reaction, Binding Prediction, and Evaluation as Cholinesterase Inhibitors.

PubMed

Rodríguez, Yeray A; Gutiérrez, Margarita; Ramírez, David; Alzate-Morales, Jans; Bernal, Cristian C; Güiza, Fausto M; Romero Bohórquez, Arnold R

2016-10-01

New N-allyl/propargyl 4-substituted 1,2,3,4-tetrahydroquinolines derivatives were efficiently synthesized using acid-catalyzed three components cationic imino Diels-Alder reaction (70-95%). All compounds were tested in vitro as dual acetylcholinesterase and butyryl-cholinesterase inhibitors and their potential binding modes, and affinity, were predicted by molecular docking and binding free energy calculations (∆G) respectively. The compound 4af (IC50 = 72 μm) presented the most effective inhibition against acetylcholinesterase despite its poor selectivity (SI = 2), while the best inhibitory activity on butyryl-cholinesterase was exhibited by compound 4ae (IC50 = 25.58 μm) with considerable selectivity (SI = 0.15). Molecular docking studies indicated that the most active compounds fit in the reported acetylcholinesterase and butyryl-cholinesterase active sites. Moreover, our computational data indicated a high correlation between the calculated ∆G and the experimental activity values in both targets. © 2016 The Authors Chemical Biology & Drug Design Published by John Wiley & Sons Ltd.

Double differential light charged particle emission cross sections for some structural fusion materials

NASA Astrophysics Data System (ADS)

Sarpün, Ismail Hakki; n, Abdullah Aydı; Tel, Eyyup

2017-09-01

In fusion reactors, neutron induced radioactivity strongly depends on the irradiated material. So, a proper selection of structural materials will have been limited the radioactive inventory in a fusion reactor. First-wall and blanket components have high radioactivity concentration due to being the most flux-exposed structures. The main objective of fusion structural material research is the development and selection of materials for reactor components with good thermo-mechanical and physical properties, coupled with low-activation characteristics. Double differential light charged particle emission cross section, which is a fundamental data to determine nuclear heating and material damages in structural fusion material research, for some elements target nuclei have been calculated by the TALYS 1.8 nuclear reaction code at 14-15 MeV neutron incident energy and compared with available experimental data in EXFOR library. Direct, compound and pre-equilibrium reaction contribution have been theoretically calculated and dominant contribution have been determined for each emission of proton, deuteron and alpha particle.

Determinants of propranolol’s selective effect on loss aversion

PubMed Central

Sokol-Hessner, Peter; Lackovic, Sandra F.; Tobe, Russell H.; Camerer, Colin F.; Leventhal, Bennett L.; Phelps, Elizabeth A.

2015-01-01

Research on emotion and decision-making has suggested that arousal mediates risky decisions (e.g., Bechara et al., 1997), but several distinct and often confounded processes drive such choices. Here, we used econometric modeling to separate and quantify the unique contributions of loss aversion, risk sensitivity and choice consistency to risky decision-making. We administered the beta-blocker propranolol in a double-blind, placebo-controlled within-subjects study, targeting the neurohormonal basis of physiological arousal. Matching our intervention’s pharmacological specificity with a quantitative model delineating decision-making components allowed us to identify the causal relationships between arousal and decision-making that do and do not exist. Propranolol selectively reduced loss aversion in a baseline- and dose-dependent manner (i.e. as a function of initial loss aversion and body-mass index), and did not affect risk sensitivity or choice consistency. These findings provide evidence for a specific, modulatory, and causal relationship between precise components of both emotion and risky decision-making. PMID:26063441

Selective Small Molecule Compounds Increase BMP-2 Responsiveness by Inhibiting Smurf1-mediated Smad1/5 Degradation

PubMed Central

Cao, Yu; Wang, Cheng; Zhang, Xueli; Xing, Guichun; Lu, Kefeng; Gu, Yongqing; He, Fuchu; Zhang, Lingqiang

2014-01-01

The ubiquitin ligase Smad ubiquitination regulatory factor-1 (Smurf1) negatively regulates bone morphogenetic protein (BMP) pathway by ubiquitinating certain signal components for degradation. Thus, it can be an eligible pharmacological target for increasing BMP signal responsiveness. We established a strategy to discover small molecule compounds that block the WW1 domain of Smurf1 from interacting with Smad1/5 by structure based virtual screening, molecular experimental examination and cytological efficacy evaluation. Our selected hits could reserve the protein level of Smad1/5 from degradation by interrupting Smurf1-Smad1/5 interaction and inhibiting Smurf1 mediated ubiquitination of Smad1/5. Further, these compounds increased BMP-2 signal responsiveness and the expression of certain downstream genes, enhanced the osteoblastic activity of myoblasts and osteoblasts. Our work indicates targeting Smurf1 for inhibition could be an accessible strategy to discover BMP-sensitizers that might be applied in future clinical treatments of bone disorders such as osteopenia. PMID:24828823

A pathway of targeted autophagy is induced by DNA damage in budding yeast

PubMed Central

Eapen, Vinay V.; Waterman, David P.; Bernard, Amélie; Schiffmann, Nathan; Sayas, Enrich; Kamber, Roarke; Lemos, Brenda; Memisoglu, Gonen; Ang, Jessie; Mazella, Allison; Chuartzman, Silvia G.; Loewith, Robbie J.; Schuldiner, Maya; Denic, Vladimir; Klionsky, Daniel J.; Haber, James E.

2017-01-01

Autophagy plays a central role in the DNA damage response (DDR) by controlling the levels of various DNA repair and checkpoint proteins; however, how the DDR communicates with the autophagy pathway remains unknown. Using budding yeast, we demonstrate that global genotoxic damage or even a single unrepaired double-strand break (DSB) initiates a previously undescribed and selective pathway of autophagy that we term genotoxin-induced targeted autophagy (GTA). GTA requires the action primarily of Mec1/ATR and Rad53/CHEK2 checkpoint kinases, in part via transcriptional up-regulation of central autophagy proteins. GTA is distinct from starvation-induced autophagy. GTA requires Atg11, a central component of the selective autophagy machinery, but is different from previously described autophagy pathways. By screening a collection of ∼6,000 yeast mutants, we identified genes that control GTA but do not significantly affect rapamycin-induced autophagy. Overall, our findings establish a pathway of autophagy specific to the DNA damage response. PMID:28154131

A pathway of targeted autophagy is induced by DNA damage in budding yeast.

PubMed

Eapen, Vinay V; Waterman, David P; Bernard, Amélie; Schiffmann, Nathan; Sayas, Enrich; Kamber, Roarke; Lemos, Brenda; Memisoglu, Gonen; Ang, Jessie; Mazella, Allison; Chuartzman, Silvia G; Loewith, Robbie J; Schuldiner, Maya; Denic, Vladimir; Klionsky, Daniel J; Haber, James E

2017-02-14

Autophagy plays a central role in the DNA damage response (DDR) by controlling the levels of various DNA repair and checkpoint proteins; however, how the DDR communicates with the autophagy pathway remains unknown. Using budding yeast, we demonstrate that global genotoxic damage or even a single unrepaired double-strand break (DSB) initiates a previously undescribed and selective pathway of autophagy that we term genotoxin-induced targeted autophagy (GTA). GTA requires the action primarily of Mec1/ATR and Rad53/CHEK2 checkpoint kinases, in part via transcriptional up-regulation of central autophagy proteins. GTA is distinct from starvation-induced autophagy. GTA requires Atg11, a central component of the selective autophagy machinery, but is different from previously described autophagy pathways. By screening a collection of ∼6,000 yeast mutants, we identified genes that control GTA but do not significantly affect rapamycin-induced autophagy. Overall, our findings establish a pathway of autophagy specific to the DNA damage response.

Characterization and Validation of Transiting Planets in the TESS SPOC Pipeline

NASA Astrophysics Data System (ADS)

Twicken, Joseph D.; Caldwell, Douglas A.; Davies, Misty; Jenkins, Jon Michael; Li, Jie; Morris, Robert L.; Rose, Mark; Smith, Jeffrey C.; Tenenbaum, Peter; Ting, Eric; Wohler, Bill

2018-06-01

Light curves for Transiting Exoplanet Survey Satellite (TESS) target stars will be extracted and searched for transiting planet signatures in the Science Processing Operations Center (SPOC) Science Pipeline at NASA Ames Research Center. Targets for which the transiting planet detection threshold is exceeded will be processed in the Data Validation (DV) component of the Pipeline. The primary functions of DV are to (1) characterize planets identified in the transiting planet search, (2) search for additional transiting planet signatures in light curves after modeled transit signatures have been removed, and (3) perform a comprehensive suite of diagnostic tests to aid in discrimination between true transiting planets and false positive detections. DV data products include extensive reports by target, one-page summaries by planet candidate, and tabulated transit model fit and diagnostic test results. DV products may be employed by humans and automated systems to vet planet candidates identified in the Pipeline. TESS will launch in 2018 and survey the full sky for transiting exoplanets over a period of two years. The SPOC pipeline was ported from the Kepler Science Operations Center (SOC) codebase and extended for TESS after the mission was selected for flight in the NASA Astrophysics Explorer program. We describe the Data Validation component of the SPOC Pipeline. The diagnostic tests exploit the flux (i.e., light curve) and pixel time series associated with each target to support the determination of the origin of each purported transiting planet signature. We also highlight the differences between the DV components for Kepler and TESS. Candidate planet detections and data products will be delivered to the Mikulski Archive for Space Telescopes (MAST); the MAST URL is archive.stsci.edu/tess. Funding for the TESS Mission has been provided by the NASA Science Mission Directorate.

Genetic algorithm in the structural design of Cooke triplet lenses

NASA Astrophysics Data System (ADS)

Hazra, Lakshminarayan; Banerjee, Saswatee

1999-08-01

This paper is in tune with our efforts to develop a systematic method for multicomponent lens design. Our aim is to find a suitable starting point in the final configuration space, so that popular local search methods like damped least squares (DLS) may directly lead to a useful solution. For 'ab initio' design problems, a thin lens layout specifying the powers of the individual components and the intercomponent separations are worked out analytically. Requirements of central aberration targets for the individual components in order to satisfy the prespecified primary aberration targets for the overall system are then determined by nonlinear optimization. The next step involves structural design of the individual components by optimization techniques. This general method may be adapted for the design of triplets and their derivatives. However, for the thin lens design of a Cooke triplet composed of three airspaced singlets, the two steps of optimization mentioned above may be combined into a single optimization procedure. The optimum configuration for each of the single set, catering to the required Gaussian specification and primary aberration targets for the Cooke triplet, are determined by an application of genetic algorithm (GA). Our implementation of this algorithm is based on simulations of some complex tools of natural evolution, like selection, crossover and mutation. Our version of GA may or may not converge to a unique optimum, depending on some of the algorithm specific parameter values. With our algorithm, practically useful solutions are always available, although convergence to a global optimum can not be guaranteed. This is perfectly in keeping with our need to allow 'floating' of aberration targets in the subproblem level. Some numerical results dealing with our preliminary investigations on this problem are presented.

Locally Bayesian Learning with Applications to Retrospective Revaluation and Highlighting

ERIC Educational Resources Information Center

Kruschke, John K.

2006-01-01

A scheme is described for locally Bayesian parameter updating in models structured as successions of component functions. The essential idea is to back-propagate the target data to interior modules, such that an interior component's target is the input to the next component that maximizes the probability of the next component's target. Each layer…

GEPSI: A Gene Expression Profile Similarity-Based Identification Method of Bioactive Components in Traditional Chinese Medicine Formula.

PubMed

Zhang, Baixia; He, Shuaibing; Lv, Chenyang; Zhang, Yanling; Wang, Yun

2018-01-01

The identification of bioactive components in traditional Chinese medicine (TCM) is an important part of the TCM material foundation research. Recently, molecular docking technology has been extensively used for the identification of TCM bioactive components. However, target proteins that are used in molecular docking may not be the actual TCM target. For this reason, the bioactive components would likely be omitted or incorrect. To address this problem, this study proposed the GEPSI method that identified the target proteins of TCM based on the similarity of gene expression profiles. The similarity of the gene expression profiles affected by TCM and small molecular drugs was calculated. The pharmacological action of TCM may be similar to that of small molecule drugs that have a high similarity score. Indeed, the target proteins of the small molecule drugs could be considered TCM targets. Thus, we identified the bioactive components of a TCM by molecular docking and verified the reliability of this method by a literature investigation. Using the target proteins that TCM actually affected as targets, the identification of the bioactive components was more accurate. This study provides a fast and effective method for the identification of TCM bioactive components.

GEPSI: A Gene Expression Profile Similarity-Based Identification Method of Bioactive Components in Traditional Chinese Medicine Formula

PubMed Central

Zhang, Baixia; He, Shuaibing; Lv, Chenyang; Zhang, Yanling

2018-01-01

The identification of bioactive components in traditional Chinese medicine (TCM) is an important part of the TCM material foundation research. Recently, molecular docking technology has been extensively used for the identification of TCM bioactive components. However, target proteins that are used in molecular docking may not be the actual TCM target. For this reason, the bioactive components would likely be omitted or incorrect. To address this problem, this study proposed the GEPSI method that identified the target proteins of TCM based on the similarity of gene expression profiles. The similarity of the gene expression profiles affected by TCM and small molecular drugs was calculated. The pharmacological action of TCM may be similar to that of small molecule drugs that have a high similarity score. Indeed, the target proteins of the small molecule drugs could be considered TCM targets. Thus, we identified the bioactive components of a TCM by molecular docking and verified the reliability of this method by a literature investigation. Using the target proteins that TCM actually affected as targets, the identification of the bioactive components was more accurate. This study provides a fast and effective method for the identification of TCM bioactive components. PMID:29692857

The effects of combined caffeine and glucose drinks on attention in the human brain.

PubMed

Rao, Anling; Hu, Henglong; Nobre, Anna Christina

2005-06-01

The objective of this research was to measure the effects of energising drinks containing caffeine and glucose, upon mental activity during sustained selective attention. Non-invasive electrophysiological brain recordings were made during a behavioural study of selective attention in which participants received either energising or placebo drinks. We tested specifically whether energising drinks have significant effects upon behavioural measures of performance during a task requiring sustained visual selective attention, as well as on accompanying components of the event-related potential (ERPs) related to information processing in the brain. Forty healthy volunteers were blindly assigned to receive either the energising drink or a similar-tasting placebo drink. The behavioural task involved identifying predefined target stimulus among rapidly presented streams of peripheral visual stimuli, and making speeded motor responses to this stimulus. During task performance, accuracy, reaction times and ongoing brain activity were stored for analysis. The energising drink enhanced behavioural performance both in terms of accuracy and speed of reactions. The energising drink also had significant effects upon the event-related potentials. Effects started from the enhancement of the earliest components (Cl/P1), reflecting early visual cortical processing in the energising-drink group relative to the placebo group over the contralateral scalp. The later N1, N2 and P3 components related to decision-making and responses were also modulated by the energising drink. Energising drinks containing caffeine and glucose can enhance behavioural performance during demanding tasks requiring selective attention. The behavioural benefits are coupled to direct effects upon neural information processing.

Designing highly active siRNAs for therapeutic applications.

PubMed

Walton, S Patrick; Wu, Ming; Gredell, Joseph A; Chan, Christina

2010-12-01

The discovery of RNA interference (RNAi) generated considerable interest in developing short interfering RNAs (siRNAs) for understanding basic biology and as the active agents in a new variety of therapeutics. Early studies showed that selecting an active siRNA was not as straightforward as simply picking a sequence on the target mRNA and synthesizing the siRNA complementary to that sequence. As interest in applying RNAi has increased, the methods for identifying active siRNA sequences have evolved from focusing on the simplicity of synthesis and purification, to identifying preferred target sequences and secondary structures, to predicting the thermodynamic stability of the siRNA. As more specific details of the RNAi mechanism have been defined, these have been incorporated into more complex siRNA selection algorithms, increasing the reliability of selecting active siRNAs against a single target. Ultimately, design of the best siRNA therapeutics will require design of the siRNA itself, in addition to design of the vehicle and other components necessary for it to function in vivo. In this minireview, we summarize the evolution of siRNA selection techniques with a particular focus on one issue of current importance to the field, how best to identify those siRNA sequences likely to have high activity. Approaches to designing active siRNAs through chemical and structural modifications will also be highlighted. As the understanding of how to control the activity and specificity of siRNAs improves, the potential utility of siRNAs as human therapeutics will concomitantly grow. © 2010 The Authors Journal compilation © 2010 FEBS.

Peptide- and Amine-Modified Glucan Particles for the Delivery of Therapeutic siRNA

PubMed Central

Aouadi, Myriam; Vangala, Pranitha; Tencerova, Michaela; Amano, Shinya U.; Nicoloro, Sarah M.; Yawe, Joseph C.; Czech, Michael P.

2016-01-01

Translation of siRNA technology into the clinic is limited by the need for improved delivery systems that target specific cell types. Macrophages are particularly attractive targets for RNAi therapy because they promote pathogenic inflammatory responses in a number of important human diseases. We previously demonstrated that a multi-component formulation of β-1,3-D-glucan-encapsulated siRNA particles (GeRPs) can specifically and potently silence genes in mouse macrophages. A major advance would be to simplify the GeRP system by reducing the number of delivery components, thus enabling more facile manufacturing and future commercialization. Here we report the synthesis and evaluation of a simplified glucan-based particle (GP) capable of delivering siRNA in vivo to selectively silence macrophage genes. Covalent attachment of small-molecule amines and short peptides containing weak bases to GPs facilitated electrostatic interaction of the particles with siRNA and aided in the endosomal release of siRNA by the proton-sponge effect. Modified GPs were non-toxic and were efficiently internalized by macrophages in vitro. When injected intraperitoneally (i.p.), several of the new peptide-modified GPs were found to efficiently deliver siRNA to peritoneal macrophages in lean, healthy mice. In an animal model of obesity-induced inflammation, i.p. administration of one of the peptide-modified GPs (GP-EP14) bound to siRNA selectively reduced the expression of target inflammatory cytokines in the visceral adipose tissue macrophages. Decreasing adipose tissue inflammation resulted in an improvement of glucose metabolism in these metabolically challenged animals. Thus, modified GPs represent a promising new simplified system for the efficient delivery of therapeutic siRNAs specifically to phagocytic cells in vivo for modulation of inflammation responses. PMID:26815386

Fabrication of light water reactor tritium targets

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

Pilger, J.P.

1991-11-01

The mission of the Fabrication Development Task of the Tritium Target Development Project is: to produce a documented technology basis, including specifications and procedures for target rod fabrication; to demonstrate that light water tritium targets can be manufactured at a rate consistent with tritium production requirements; and to develop quality control methods to evaluate target rod components and assemblies, and establish correlations between evaluated characteristics and target rod performance. Many of the target rod components: cladding tubes, end caps, plenum springs, etc., have similar counterparts in LWR fuel rods. High production rate manufacture and inspection of these components has beenmore » adequately demonstrated by nuclear fuel rod manufacturers. This summary describes the more non-conventional manufacturing processes and inspection techniques developed to fabricate target rod components whose manufacturability at required production rates had not been previously demonstrated.« less

Cell Membrane-formed Nanovesicles for Disease-Targeted Delivery

PubMed Central

Gao, Jin; Chu, Dafeng; Wang, Zhenjia

2016-01-01

Vascular inflammation is underlying components of most diseases. To target inflamed vasculature, nanoparticles are commonly engineered by conjugating antibody to the nanoparticle surface, but this bottom-up approach could affect nanoparticle targeting and therapeutic efficacy in complex, physiologically related systems. During vascular inflammation endothelium via the NF-κB pathway instantly upregulates intercellular adhesion molecule 1 (ICAM-1) which binds integrin β2 on neutrophil membrane. Inspired by this interaction, we created a nanovesicle-based drug delivery system using nitrogen cavitation which rapidly disrupts activated neutrophils to make cell membrane nanovesicles. Studies using intravital microscopy of live mouse cremaster venules showed that these vesicles can selectively bind inflamed vasculature because they possess intact targeting molecules of integrin β2. Administering of nanovesicles loaded with TPCA-1 (a NF-κB inhibitor) markedly mitigated mouse acute lung inflammation. Our studies reveal a new top-down strategy for directly employing a diseased tissue to produce biofunctional nanovesicle-based drug delivery systems potentially applied to treat various diseases. PMID:26778696

Evaluation of Waveform Structure Features on Time Domain Target Recognition under Cross Polarization

NASA Astrophysics Data System (ADS)

Selver, M. A.; Seçmen, M.; Zoral, E. Y.

2016-08-01

Classification of aircraft targets from scattered electromagnetic waves is a challenging application, which suffers from aspect angle dependency. In order to eliminate the adverse effects of aspect angle, various strategies were developed including the techniques that rely on extraction of several features and design of suitable classification systems to process them. Recently, a hierarchical method, which uses features that take advantage of waveform structure of the scattered signals, is introduced and shown to have effective results. However, this approach has been applied to the special cases that consider only a single planar component of electric field that cause no-cross polarization at the observation point. In this study, two small scale aircraft models, Boeing-747 and DC-10, are selected as the targets and various polarizations are used to analyse the cross-polarization effects on system performance of the aforementioned method. The results reveal the advantages and the shortcomings of using waveform structures in time-domain target identification.

Variable Selection through Correlation Sifting

NASA Astrophysics Data System (ADS)

Huang, Jim C.; Jojic, Nebojsa

Many applications of computational biology require a variable selection procedure to sift through a large number of input variables and select some smaller number that influence a target variable of interest. For example, in virology, only some small number of viral protein fragments influence the nature of the immune response during viral infection. Due to the large number of variables to be considered, a brute-force search for the subset of variables is in general intractable. To approximate this, methods based on ℓ1-regularized linear regression have been proposed and have been found to be particularly successful. It is well understood however that such methods fail to choose the correct subset of variables if these are highly correlated with other "decoy" variables. We present a method for sifting through sets of highly correlated variables which leads to higher accuracy in selecting the correct variables. The main innovation is a filtering step that reduces correlations among variables to be selected, making the ℓ1-regularization effective for datasets on which many methods for variable selection fail. The filtering step changes both the values of the predictor variables and output values by projections onto components obtained through a computationally-inexpensive principal components analysis. In this paper we demonstrate the usefulness of our method on synthetic datasets and on novel applications in virology. These include HIV viral load analysis based on patients' HIV sequences and immune types, as well as the analysis of seasonal variation in influenza death rates based on the regions of the influenza genome that undergo diversifying selection in the previous season.

Systematic bioinformatics and experimental validation of yeast complexes reduces the rate of attrition during structural investigations.

PubMed

Brooks, Mark A; Gewartowski, Kamil; Mitsiki, Eirini; Létoquart, Juliette; Pache, Roland A; Billier, Ysaline; Bertero, Michela; Corréa, Margot; Czarnocki-Cieciura, Mariusz; Dadlez, Michal; Henriot, Véronique; Lazar, Noureddine; Delbos, Lila; Lebert, Dorothée; Piwowarski, Jan; Rochaix, Pascal; Böttcher, Bettina; Serrano, Luis; Séraphin, Bertrand; van Tilbeurgh, Herman; Aloy, Patrick; Perrakis, Anastassis; Dziembowski, Andrzej

2010-09-08

For high-throughput structural studies of protein complexes of composition inferred from proteomics data, it is crucial that candidate complexes are selected accurately. Herein, we exemplify a procedure that combines a bioinformatics tool for complex selection with in vivo validation, to deliver structural results in a medium-throughout manner. We have selected a set of 20 yeast complexes, which were predicted to be feasible by either an automated bioinformatics algorithm, by manual inspection of primary data, or by literature searches. These complexes were validated with two straightforward and efficient biochemical assays, and heterologous expression technologies of complex components were then used to produce the complexes to assess their feasibility experimentally. Approximately one-half of the selected complexes were useful for structural studies, and we detail one particular success story. Our results underscore the importance of accurate target selection and validation in avoiding transient, unstable, or simply nonexistent complexes from the outset. Copyright © 2010 Elsevier Ltd. All rights reserved.

Breaking the cipher: ant eavesdropping on the variational trail pheromone of its termite prey

PubMed Central

Wen, Xiao-Lan

2017-01-01

Predators may eavesdrop on their prey using innate signals of varying nature. In regards to social prey, most of the prey signals are derived from social communication and may therefore be highly complex. The most efficient predators select signals that provide the highest benefits. Here, we showed the use of eusocial prey signals by the termite-raiding ant Odontoponera transversa. O. transversa selected the trail pheromone of termites as kairomone in several species of fungus-growing termites (Termitidae: Macrotermitinae: Odontotermes yunnanensis, Macrotermes yunnanensis, Ancistrotermes dimorphus). The most commonly predated termite, O. yunnanensis, was able to regulate the trail pheromone component ratios during its foraging activity. The ratio of the two trail pheromone compounds was correlated with the number of termites in the foraging party. (3Z)-Dodec-3-en-1-ol (DOE) was the dominant trail pheromone component in the initial foraging stages when fewer termites were present. Once a trail was established, (3Z,6Z)-dodeca-3,6-dien-1-ol (DDE) became the major recruitment component in the trail pheromone and enabled mass recruitment of nest-mates to the food source. Although the ants could perceive both components, they revealed stronger behavioural responses to the recruitment component, DDE, than to the common major component, DOE. In other words, the ants use the trail pheromone information as an indication of suitable prey abundance, and regulate their behavioural responses based on the changing trail pheromone component. The eavesdropping behaviour in ants therefore leads to an arms race between predator and prey where the species specific production of trail pheromones in termites is targeted by predatory ant species. PMID:28446695

Breaking the cipher: ant eavesdropping on the variational trail pheromone of its termite prey.

PubMed

Wen, Xiao-Lan; Wen, Ping; Dahlsjö, Cecilia A L; Sillam-Dussès, David; Šobotník, Jan

2017-04-26

Predators may eavesdrop on their prey using innate signals of varying nature. In regards to social prey, most of the prey signals are derived from social communication and may therefore be highly complex. The most efficient predators select signals that provide the highest benefits. Here, we showed the use of eusocial prey signals by the termite-raiding ant Odontoponera transversa O. transversa selected the trail pheromone of termites as kairomone in several species of fungus-growing termites (Termitidae: Macrotermitinae: Odontotermes yunnanensis , Macrotermes yunnanensis , Ancistrotermes dimorphus ). The most commonly predated termite, O. yunnanensis, was able to regulate the trail pheromone component ratios during its foraging activity. The ratio of the two trail pheromone compounds was correlated with the number of termites in the foraging party. (3 Z )-Dodec-3-en-1-ol (DOE) was the dominant trail pheromone component in the initial foraging stages when fewer termites were present. Once a trail was established, (3 Z,6Z )-dodeca-3,6-dien-1-ol (DDE) became the major recruitment component in the trail pheromone and enabled mass recruitment of nest-mates to the food source. Although the ants could perceive both components, they revealed stronger behavioural responses to the recruitment component, DDE, than to the common major component, DOE. In other words, the ants use the trail pheromone information as an indication of suitable prey abundance, and regulate their behavioural responses based on the changing trail pheromone component. The eavesdropping behaviour in ants therefore leads to an arms race between predator and prey where the species specific production of trail pheromones in termites is targeted by predatory ant species. © 2017 The Author(s).

Multi-targeted priming for genome-wide gene expression assays.

PubMed

Adomas, Aleksandra B; Lopez-Giraldez, Francesc; Clark, Travis A; Wang, Zheng; Townsend, Jeffrey P

2010-08-17

Complementary approaches to assaying global gene expression are needed to assess gene expression in regions that are poorly assayed by current methodologies. A key component of nearly all gene expression assays is the reverse transcription of transcribed sequences that has traditionally been performed by priming the poly-A tails on many of the transcribed genes in eukaryotes with oligo-dT, or by priming RNA indiscriminately with random hexamers. We designed an algorithm to find common sequence motifs that were present within most protein-coding genes of Saccharomyces cerevisiae and of Neurospora crassa, but that were not present within their ribosomal RNA or transfer RNA genes. We then experimentally tested whether degenerately priming these motifs with multi-targeted primers improved the accuracy and completeness of transcriptomic assays. We discovered two multi-targeted primers that would prime a preponderance of genes in the genomes of Saccharomyces cerevisiae and Neurospora crassa while avoiding priming ribosomal RNA or transfer RNA. Examining the response of Saccharomyces cerevisiae to nitrogen deficiency and profiling Neurospora crassa early sexual development, we demonstrated that using multi-targeted primers in reverse transcription led to superior performance of microarray profiling and next-generation RNA tag sequencing. Priming with multi-targeted primers in addition to oligo-dT resulted in higher sensitivity, a larger number of well-measured genes and greater power to detect differences in gene expression. Our results provide the most complete and detailed expression profiles of the yeast nitrogen starvation response and N. crassa early sexual development to date. Furthermore, our multi-targeting priming methodology for genome-wide gene expression assays provides selective targeting of multiple sequences and counter-selection against undesirable sequences, facilitating a more complete and precise assay of the transcribed sequences within the genome.

Accelerator tube construction and characterization for a tandem-electrostatic-quadrupole for accelerator-based boron neutron capture therapy.

PubMed

Cartelli, D; Vento, V Thatar; Castell, W; Di Paolo, H; Kesque, J M; Bergueiro, J; Valda, A A; Erhardt, J; Kreiner, A J

2011-12-01

The accelerator tubes are essential components of the accelerator. Their function is to transport and accelerate a very intense proton or deuteron beam through the machine, from the ion source to the neutron production target, without significant losses. In this contribution, we discuss materials selected for the tube construction, the procedures used for their assembly and the testing performed to meet the stringent requirements to which it is subjected. Copyright © 2011 Elsevier Ltd. All rights reserved.

The selective recognition of antibody IgY for digestive system cancers.

PubMed

Yang, J; Jin, Z; Yu, Q; Yang, T; Wang, H; Liu, L

1997-01-01

Biological methods for cancer therapies are very important. A small and efficient target carrier is the key component for anti-cancer drugs. In our laboratory, the antibody IgY was extracted from egg yolk of a SPF hen. The SPF hen was immunized with an antigene of P110 protein which was purified from human stomach cancer MGC-803 cells. Results indicated that the antibody IgY can specifically recognize gastrointestinal system cancers. It may become an important carrier for antitumorigenic drugs.

VizieR Online Data Catalog: Spitzer obs. of warm dust in 83 debris disks (Ballering+, 2017)

NASA Astrophysics Data System (ADS)

Ballering, N. P.; Rieke, G. H.; Su, K. Y. L.; Gaspar, A.

2018-04-01

For our sample, we used the systems with a warm component found by Ballering+ (2013, J/ApJ/775/55), where "warm" was defined as warmer than 130K. All of these systems have data available from the Multiband Imaging Photometer for Spitzer (MIPS) at 24 and 70um and from the Spitzer Infrared Spectrograph (IRS). The selected 83 targets used for our analysis are listed in Table 1. (5 data files).

Fusion-based multi-target tracking and localization for intelligent surveillance systems

NASA Astrophysics Data System (ADS)

Rababaah, Haroun; Shirkhodaie, Amir

2008-04-01

In this paper, we have presented two approaches addressing visual target tracking and localization in complex urban environment. The two techniques presented in this paper are: fusion-based multi-target visual tracking, and multi-target localization via camera calibration. For multi-target tracking, the data fusion concepts of hypothesis generation/evaluation/selection, target-to-target registration, and association are employed. An association matrix is implemented using RGB histograms for associated tracking of multi-targets of interests. Motion segmentation of targets of interest (TOI) from the background was achieved by a Gaussian Mixture Model. Foreground segmentation, on other hand, was achieved by the Connected Components Analysis (CCA) technique. The tracking of individual targets was estimated by fusing two sources of information, the centroid with the spatial gating, and the RGB histogram association matrix. The localization problem is addressed through an effective camera calibration technique using edge modeling for grid mapping (EMGM). A two-stage image pixel to world coordinates mapping technique is introduced that performs coarse and fine location estimation of moving TOIs. In coarse estimation, an approximate neighborhood of the target position is estimated based on nearest 4-neighbor method, and in fine estimation, we use Euclidean interpolation to localize the position within the estimated four neighbors. Both techniques were tested and shown reliable results for tracking and localization of Targets of interests in complex urban environment.

Comprehensive GMO detection using real-time PCR array: single-laboratory validation.

PubMed

Mano, Junichi; Harada, Mioko; Takabatake, Reona; Furui, Satoshi; Kitta, Kazumi; Nakamura, Kosuke; Akiyama, Hiroshi; Teshima, Reiko; Noritake, Hiromichi; Hatano, Shuko; Futo, Satoshi; Minegishi, Yasutaka; Iizuka, Tayoshi

2012-01-01

We have developed a real-time PCR array method to comprehensively detect genetically modified (GM) organisms. In the method, genomic DNA extracted from an agricultural product is analyzed using various qualitative real-time PCR assays on a 96-well PCR plate, targeting for individual GM events, recombinant DNA (r-DNA) segments, taxon-specific DNAs, and donor organisms of the respective r-DNAs. In this article, we report the single-laboratory validation of both DNA extraction methods and component PCR assays constituting the real-time PCR array. We selected some DNA extraction methods for specified plant matrixes, i.e., maize flour, soybean flour, and ground canola seeds, then evaluated the DNA quantity, DNA fragmentation, and PCR inhibition of the resultant DNA extracts. For the component PCR assays, we evaluated the specificity and LOD. All DNA extraction methods and component PCR assays satisfied the criteria set on the basis of previous reports.

Titration-based screening for evaluation of natural product extracts: identification of an aspulvinone family of luciferase inhibitors

PubMed Central

Cruz, Patricia G.; Auld, Douglas S.; Schultz, Pamela J.; Lovell, Scott; Battaile, Kevin P.; MacArthur, Ryan; Shen, Min; Tamayo-Castillo, Giselle; Inglese, James; Sherman, David H.

2011-01-01

The chemical diversity of nature has tremendous potential for discovery of new molecular probes and medicinal agents. However, sensitivity of HTS assays to interfering components of crude extracts derived from plants, macro- and microorganisms has curtailed their use in lead discovery efforts. Here we describe a process for leveraging the concentration-response curves (CRCs) obtained from quantitative HTS to improve the initial selection of “actives” from a library of partially fractionated natural product extracts derived from marine actinomycetes and fungi. By using pharmacological activity, the first-pass CRC paradigm aims to improve the probability that labor-intensive subsequent steps of re-culturing, extraction and bioassay-guided isolation of active component(s) target the most promising strains and growth conditions. We illustrate how this process identified a family of fungal metabolites as potent inhibitors of firefly luciferase, subsequently resolved in molecular detail by x-ray crystallography. PMID:22118678

Titration-based screening for evaluation of natural product extracts: identification of an aspulvinone family of luciferase inhibitors

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

Cruz, P.G.; Auld, D.S.; Schultz, P.J.

2011-11-28

The chemical diversity of nature has tremendous potential for the discovery of molecular probes and medicinal agents. However, sensitivity of HTS assays to interfering components of crude extracts derived from plants, and macro- and microorganisms has curtailed their use in lead discovery. Here, we describe a process for leveraging the concentration-response curves obtained from quantitative HTS to improve the initial selection of actives from a library of partially fractionated natural product extracts derived from marine actinomycetes and fungi. By using pharmacological activity, the first-pass CRC paradigm improves the probability that labor-intensive subsequent steps of reculturing, extraction, and bioassay-guided isolation ofmore » active component(s) target the most promising strains and growth conditions. We illustrate how this process identified a family of fungal metabolites as potent inhibitors of firefly luciferase, subsequently resolved in molecular detail by X-ray crystallography.« less

Big Sky and Greenhorn Drilling Area on Mount Sharp

NASA Image and Video Library

2015-12-17

This view from the Mast Camera (Mastcam) on NASA's Curiosity Mars rover covers an area in "Bridger Basin" that includes the locations where the rover drilled a target called "Big Sky" on the mission's Sol 1119 (Sept. 29, 2015) and a target called "Greenhorn" on Sol 1137 (Oct. 18, 2015). The scene combines portions of several observations taken from sols 1112 to 1126 (Sept. 22 to Oct. 6, 2015) while Curiosity was stationed at Big Sky drilling site. The Big Sky drill hole is visible in the lower part of the scene. The Greenhorn target, in a pale fracture zone near the center of the image, had not yet been drilled when the component images were taken. Researchers selected this pair of drilling sites to investigate the nature of silica enrichment in the fracture zones of the area. http://photojournal.jpl.nasa.gov/catalog/PIA20270

Biological Matrix Effects in Quantitative Tandem Mass Spectrometry-Based Analytical Methods: Advancing Biomonitoring

PubMed Central

Panuwet, Parinya; Hunter, Ronald E.; D’Souza, Priya E.; Chen, Xianyu; Radford, Samantha A.; Cohen, Jordan R.; Marder, M. Elizabeth; Kartavenka, Kostya; Ryan, P. Barry; Barr, Dana Boyd

2015-01-01

The ability to quantify levels of target analytes in biological samples accurately and precisely, in biomonitoring, involves the use of highly sensitive and selective instrumentation such as tandem mass spectrometers and a thorough understanding of highly variable matrix effects. Typically, matrix effects are caused by co-eluting matrix components that alter the ionization of target analytes as well as the chromatographic response of target analytes, leading to reduced or increased sensitivity of the analysis. Thus, before the desired accuracy and precision standards of laboratory data are achieved, these effects must be characterized and controlled. Here we present our review and observations of matrix effects encountered during the validation and implementation of tandem mass spectrometry-based analytical methods. We also provide systematic, comprehensive laboratory strategies needed to control challenges posed by matrix effects in order to ensure delivery of the most accurate data for biomonitoring studies assessing exposure to environmental toxicants. PMID:25562585

Network immunization under limited budget using graph spectra

NASA Astrophysics Data System (ADS)

Zahedi, R.; Khansari, M.

2016-03-01

In this paper, we propose a new algorithm that minimizes the worst expected growth of an epidemic by reducing the size of the largest connected component (LCC) of the underlying contact network. The proposed algorithm is applicable to any level of available resources and, despite the greedy approaches of most immunization strategies, selects nodes simultaneously. In each iteration, the proposed method partitions the LCC into two groups. These are the best candidates for communities in that component, and the available resources are sufficient to separate them. Using Laplacian spectral partitioning, the proposed method performs community detection inference with a time complexity that rivals that of the best previous methods. Experiments show that our method outperforms targeted immunization approaches in both real and synthetic networks.

Inhibition of the ubiquitin-proteasome system by natural products for cancer therapy.

PubMed

Tsukamoto, Sachiko; Yokosawa, Hideyoshi

2010-08-01

The ubiquitin-proteasome system plays a critical role in selective protein degradation and regulates almost all cellular events such as cell cycle progression, signal transduction, cell death, immune responses, metabolism, protein quality control, development, and neuronal function. The recent approval of bortezomib, a synthetic proteasome inhibitor, for the treatment of relapsed multiple myeloma has opened the way to the discovery of drugs targeting the proteasome and ubiquitinating and deubiquitinating enzymes as well as the delivery system. To date, various synthetic and natural products have been reported to inhibit the components of the ubiquitin-proteasome system. Here, we review natural products targeting the ubiquitin-proteasome system as well as synthetic compounds with potent inhibitory effects. Georg Thieme Verlag KG Stuttgart-New York.

Experimental design to generate strong shear layers in a high-energy-density plasma

NASA Astrophysics Data System (ADS)

Harding, E. C.; Drake, R. P.; Aglitskiy, Y.; Gillespie, R. S.; Grosskopf, M. J.; Weaver, J. L.; Velikovich, A. L.; Visco, A.; Ditmar, J. R.

2010-06-01

The development of a new experimental system for generating a strong shear flow in a high-energy-density plasma is described in detail. The targets were designed with the goal of producing a diagnosable Kelvin-Helmholtz (KH) instability, which plays an important role in the transition turbulence but remains relatively unexplored in the high-energy-density regime. To generate the shear flow the Nike laser was used to drive a flow of Al plasma over a low-density foam surface with an initial perturbation. The interaction of the Al and foam was captured with a spherical crystal imager using 1.86 keV X-rays. The selection of the individual targets components is discussed and results are presented.

Cathepsin-Mediated Cleavage of Peptides from Peptide Amphiphiles Leads to Enhanced Intracellular Peptide Accumulation

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

Acar, Handan; Samaeekia, Ravand; Schnorenberg, Mathew R.

Peptides synthesized in the likeness of their native interaction domain(s) are natural choices to target protein protein interactions (PPIs) due to their fidelity of orthostatic contact points between binding partners. Despite therapeutic promise, intracellular delivery of biofunctional peptides at concentrations necessary for efficacy remains a formidable challenge. Peptide amphiphiles (PAs) provide a facile method of intracellular delivery and stabilization of bioactive peptides. PAs consisting of biofunctional peptide headgroups linked to hydrophobic alkyl lipid-like tails prevent peptide hydrolysis and proteolysis in circulation, and PA monomers are internalized via endocytosis. However, endocytotic sequestration and steric hindrance from the lipid tail are twomore » major mechanisms that limit PA efficacy to target intracellular PPIs. To address these problems, we have constructed a PA platform consisting of cathepsin-B cleavable PAs in which a selective p53-based inhibitory peptide is cleaved from its lipid tail within endosomes, allowing for intracellular peptide accumulation and extracellular recycling of the lipid moiety. We monitor for cleavage and follow individual PA components in real time using a resonance energy transfer (FRET)-based tracking system. Using this platform, components in real time using a Forster we provide a better understanding and quantification of cellular internalization, trafficking, and endosomal cleavage of PAs and of the ultimate fates of each component.« less

The Emerging Role of Insulin and Insulin-Like Growth Factor Signaling in Cancer Stem Cells

PubMed Central

Malaguarnera, Roberta; Belfiore, Antonino

2014-01-01

Cancer cells frequently exploit the IGF signaling, a fundamental pathway mediating development, cell growth, and survival. As a consequence, several components of the IGF signaling are deregulated in cancer and sustain cancer progression. However, specific targeting of IGF-IR in humans has resulted efficacious only in small subsets of cancers, making researches wondering whether IGF system targeting is still worth pursuing in the clinical setting. Although no definite answer is yet available, it has become increasingly clear that other components of the IGF signaling pathway, such as IR-A, may substitute for the lack of IGF-IR, and induce cancer resistance and/or clonal selection. Moreover, accumulating evidence now indicates that IGF signaling is a central player in the induction/maintenance of epithelial mesenchymal transition (EMT) and cell stemness, two strictly related programs, which play a key role in metastatic spread and resistance to cancer treatments. Here we review the evidences indicating that IGF signaling enhances the expression of transcription factors implicated in the EMT program and has extensive cross-talk with specific pathways involved in cell pluripotency and stemness maintenance. In turn, EMT and cell stemness activate positive feed-back mechanisms causing up-regulation of various IGF signaling components. These findings may have novel translational implications. PMID:24550888

The development and implementation of the Chronic Care Management Programme in Counties Manukau.

PubMed

Wellingham, John; Tracey, Jocelyn; Rea, Harold; Gribben, Barry

2003-02-21

To develop an effective and efficient process for the seamless delivery of care for targeted patients with specific chronic diseases. To reduce inexplicable variation and maximise use of available resources by implementing evidence-based care processes. To develop a programme that is acceptable and applicable to the Counties Manukau region. A model for the management of people with chronic diseases was developed. Model components and potential interventions were piloted. For each disease project, a return on investment was calculated and external evaluation was undertaken. The initial model was subsequently modified and individual disease projects aligned to it. The final Chronic Care Management model, agreed in September 2001, described a single common process. Key components were the targeting of high risk patients, organisation of cost effective interventions into a system of care, and an integrated care server acting as a data warehouse with a rules engine, providing flags and reminders. Return on investment analysis suggested potential savings for each disease component from $277 to $980 per person per annum. For selected chronic diseases, introduction of an integrated chronic care management programme, based on internationally accepted best practice processes and interventions can make significant savings, reducing morbidity and improving the efficiency of health delivery in the Counties Manukau region.

Secreted Phospholipases A2 from Animal Venoms in Pain and Analgesia

PubMed Central

Zambelli, Vanessa O.; Picolo, Gisele; Fernandes, Carlos A. H.

2017-01-01

Animal venoms comprise a complex mixture of components that affect several biological systems. Based on the high selectivity for their molecular targets, these components are also a rich source of potential therapeutic agents. Among the main components of animal venoms are the secreted phospholipases A2 (sPLA2s). These PLA2 belong to distinct PLA2s groups. For example, snake venom sPLA2s from Elapidae and Viperidae families, the most important families when considering envenomation, belong, respectively, to the IA and IIA/IIB groups, whereas bee venom PLA2 belongs to group III of sPLA2s. It is well known that PLA2, due to its hydrolytic activity on phospholipids, takes part in many pathophysiological processes, including inflammation and pain. Therefore, secreted PLA2s obtained from animal venoms have been widely used as tools to (a) modulate inflammation and pain, uncovering molecular targets that are implicated in the control of inflammatory (including painful) and neurodegenerative diseases; (b) shed light on the pathophysiology of inflammation and pain observed in human envenomation by poisonous animals; and, (c) characterize molecular mechanisms involved in inflammatory diseases. The present review summarizes the knowledge on the nociceptive and antinociceptive actions of sPLA2s from animal venoms, particularly snake venoms. PMID:29311537

A comparison of robust principal component analysis techniques for buried object detection in downward looking GPR sensor data

NASA Astrophysics Data System (ADS)

Pinar, Anthony; Havens, Timothy C.; Rice, Joseph; Masarik, Matthew; Burns, Joseph; Thelen, Brian

2016-05-01

Explosive hazards are a deadly threat in modern conflicts; hence, detecting them before they cause injury or death is of paramount importance. One method of buried explosive hazard discovery relies on data collected from ground penetrating radar (GPR) sensors. Threat detection with downward looking GPR is challenging due to large returns from non-target objects and clutter. This leads to a large number of false alarms (FAs), and since the responses of clutter and targets can form very similar signatures, classifier design is not trivial. One approach to combat these issues uses robust principal component analysis (RPCA) to enhance target signatures while suppressing clutter and background responses, though there are many versions of RPCA. This work applies some of these RPCA techniques to GPR sensor data and evaluates their merit using the peak signal-to-clutter ratio (SCR) of the RPCA-processed B-scans. Experimental results on government furnished data show that while some of the RPCA methods yield similar results, there are indeed some methods that outperform others. Furthermore, we show that the computation time required by the different RPCA methods varies widely, and the selection of tuning parameters in the RPCA algorithms has a major effect on the peak SCR.

Comparative Normal/Failing Rat Myocardium Cell Membrane Chromatographic Analysis System for Screening Specific Components That Counteract Doxorubicin-Induced Heart Failure from Acontium carmichaeli

PubMed Central

2015-01-01

Cell membrane chromatography (CMC) derived from pathological tissues is ideal for screening specific components acting on specific diseases from complex medicines owing to the maximum simulation of in vivo drug-receptor interactions. However, there are no pathological tissue-derived CMC models that have ever been developed, as well as no visualized affinity comparison of potential active components between normal and pathological CMC columns. In this study, a novel comparative normal/failing rat myocardium CMC analysis system based on online column selection and comprehensive two-dimensional (2D) chromatography/monolithic column/time-of-flight mass spectrometry was developed for parallel comparison of the chromatographic behaviors on both normal and pathological CMC columns, as well as rapid screening of the specific therapeutic agents that counteract doxorubicin (DOX)-induced heart failure from Acontium carmichaeli (Fuzi). In total, 16 potential active alkaloid components with similar structures in Fuzi were retained on both normal and failing myocardium CMC models. Most of them had obvious decreases of affinities on failing myocardium CMC compared with normal CMC model except for four components, talatizamine (TALA), 14-acetyl-TALA, hetisine, and 14-benzoylneoline. One compound TALA with the highest affinity was isolated for further in vitro pharmacodynamic validation and target identification to validate the screen results. Voltage-dependent K+ channel was confirmed as a binding target of TALA and 14-acetyl-TALA with high affinities. The online high throughput comparative CMC analysis method is suitable for screening specific active components from herbal medicines by increasing the specificity of screened results and can also be applied to other biological chromatography models. PMID:24731167

Attentional sets influence perceptual load effects, but not dilution effects.

PubMed

Benoni, Hanna; Zivony, Alon; Tsal, Yehoshua

2014-01-01

Perceptual load theory [Lavie, N. (1995). Perceptual load as a necessary condition for selective attention. Journal of Experimental Psychology: Human Perception and Performance, 21, 451-468.; Lavie, N., & Tsal, Y. (1994) Perceptual load as a major determinant of the locus of selection in visual attention. Perception & Psychophysics, 56, 183-197.] proposes that interference from distractors can only be avoided in situations of high perceptual load. This theory has been supported by blocked design manipulations separating low load (when the target appears alone) and high load (when the target is embedded among neutral letters). Tsal and Benoni [(2010a). Diluting the burden of load: Perceptual load effects are simply dilution effects. Journal of Experimental Psychology: Human Perception and Performance, 36, 1645-1656.; Benoni, H., & Tsal, Y. (2010). Where have we gone wrong? Perceptual load does not affect selective attention. Vision Research, 50, 1292-1298.] have recently shown that these manipulations confound perceptual load with "dilution" (the mere presence of additional heterogeneous items in high-load situations). Theeuwes, Kramer, and Belopolsky [(2004). Attentional set interacts with perceptual load in visual search. Psychonomic Bulletin & Review, 11, 697-702.] independently questioned load theory by suggesting that attentional sets might also affect distractor interference. When high load and low load were intermixed, and participants could not prepare for the presentation that followed, both the low-load and high-load trials showed distractor interference. This result may also challenge the dilution account, which proposes a stimulus-driven mechanism. In the current study, we presented subjects with both fixed and mixed blocks, including a mix of dilution trials with low-load trials and with high-load trials. We thus separated the effect of dilution from load and tested the influence of attentional sets on each component. The results revealed that whereas perceptual load effects are influenced by attentional sets, the dilution component is not. This strengthens the notion that dilution is a stimulus-driven mechanism, which enables effective selectivity.

Neuronal metabolomics by ion mobility mass spectrometry: cocaine effects on glucose and selected biogenic amine metabolites in the frontal cortex, striatum, and thalamus of the rat.

PubMed

Kaplan, Kimberly A; Chiu, Veronica M; Lukus, Peter A; Zhang, Xing; Siems, William F; Schenk, James O; Hill, Herbert H

2013-02-01

We report results of studies of global and targeted neuronal metabolomes by ambient pressure ion mobility mass spectrometry. The rat frontal cortex, striatum, and thalamus were sampled from control nontreated rats and those treated with acute cocaine or pargyline. Quantitative evaluations were made by standard additions or isotopic dilution. The mass detection limit was ~100 pmol varying with the analyte. Targeted metabolites of dopamine, serotonin, and glucose followed the rank order of distribution expected between the anatomical areas. Data was evaluated by principal component analysis on 764 common metabolites (identified by m/z and reduced mobility). Differences between anatomical areas and treatment groups were observed for 53 % of these metabolites using principal component analysis. Global and targeted metabolic differences were observed between the three anatomical areas with contralateral differences between some areas. Following drug treatments, global and targeted metabolomes were found to shift relative to controls and still maintained anatomical differences. Pargyline reduced 3,4-dihydroxyphenylacetic acid below detection limits, and 5-HIAA varied between anatomical regions. Notable findings were: (1) global metabolomes were different between anatomical areas and were altered by acute cocaine providing a broad but targeted window of discovery for metabolic changes produced by drugs of abuse; (2) quantitative analysis was demonstrated using isotope dilution and standard addition; (3) cocaine changed glucose and biogenic amine metabolism in the anatomical areas tested; and (4) the largest effect of cocaine was on the glycolysis metabolome in the thalamus confirming inferences from previous positron emission tomography studies using 2-deoxyglucose.

Preparation and guest-uptake protocol for a porous complex useful for 'crystal-free' crystallography.

PubMed

Inokuma, Yasuhide; Yoshioka, Shota; Ariyoshi, Junko; Arai, Tatsuhiko; Fujita, Makoto

2014-02-01

We recently reported a new method for single-crystal X-ray diffraction (SCD) analysis that does not require the crystallization of the target compound. In this 'crystal-free' crystallography, a tiny crystal of a porous complex is soaked in the solution of the target guest. The guest molecules are absorbed and oriented in the crystal pores and can be analyzed by X-ray diffraction. We describe here a detailed synthetic protocol for the preparation of uniform single crystals of the porous host complex and for the subsequent guest uptake. The protocol describes our most versatile porous complex, which is prepared from commercially available ZnI2 and 2,4,6-tri(4-pyridyl)-1,3,5-triazine. The host complex has large pores with a cross-section of 8 × 5 Å(2). Single crystals of the complex are grown from layered solutions of the two components. The pores of the as-synthesized complex are filled with nitrobenzene, which is replaced with the inert solvent cyclohexane. This solvent exchange is essential for the rapid and effective inclusion of target compounds. The most crucial and delicate step is the selection of high-quality single crystals from the mixture of crystals of various shapes and sizes. We suggest using the facial indices of the single crystals as a criterion for crystal selection. Single-crystal samples for X-ray analysis can be prepared by immersing the selected crystals in a cyclohexane/dichloromethane solution of target compound. After a very slow evaporation of the solvent, typically over 2 d, the final crystal can be picked and directly subjected to SCD analysis. The protocol can be completed within ∼16 d.

Landslide susceptibility mapping in three selected target zones in Afghanistan

NASA Astrophysics Data System (ADS)

Schwanghart, Wolfgang; Seegers, Joe; Zeilinger, Gerold

2015-04-01

In May 2014, a large and mobile landslide destroyed the village Ab Barek, a village in Badakshan Province, Afghanistan. The landslide caused several hundred fatalities and once again demonstrated the vulnerability of Afghanistan's population to extreme natural events following more than 30 years of civil war and violent conflict. Increasing the capacity of Afghanistan's population by strengthening the disaster preparedness and management of responsible government authorities and institutions is thus a major component of international cooperation and development strategies. Afghanistan is characterized by high relief and widely varying rock types that largely determine the spatial distribution as well as emplacement modes of mass movements. The major aim of our study is to characterize this variability by conducting a landslide susceptibility analysis in three selected target zones: Greater Kabul Area, Badakhshan Province and Takhar Province. We expand on an existing landslide database by mapping landforms diagnostic for landslides (e.g. head scarps, normal faults and tension cracks), and historical landslide scars and landslide deposits by visual interpretation of high-resolution satellite imagery. We conduct magnitude frequency analysis within subregional physiogeographic classes based on geological maps, climatological and topographic data to identify regional parameters influencing landslide magnitude and frequency. In addition, we prepare a landslide susceptibility map for each area using the Weight-of-Evidence model. Preliminary results show that the three selected target zones vastly differ in modes of landsliding. Low magnitude but frequent rockfall events are a major hazard in the Greater Kabul Area threatening buildings and infrastructure encroaching steep terrain in the city's outskirts. Mass movements in loess covered areas of Badakshan are characterized by medium to large magnitudes. This spatial variability of characteristic landslide magnitudes and modes of emplacement necessitates different strategies to assess, mitigate, and prepare for landslides in the three different target zones.

A SURVEY OF THE HIGH ORDER MULTIPLICITY OF NEARBY SOLAR-TYPE BINARY STARS WITH Robo-AO

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

Riddle, Reed L.; Bui, Khanh; Dekany, Richard G.

2015-01-20

We conducted a survey of nearby binary systems composed of main sequence stars of spectral types F and G in order to improve our understanding of the hierarchical nature of multiple star systems. Using Robo-AO, the first robotic adaptive optics instrument, we collected high angular resolution images with deep and well-defined detection limits in the Sloan Digital Sky Survey i' band. A total of 695 components belonging to 595 systems were observed. We prioritized observations of faint secondary components with separations over 10'' to quantify the still poorly constrained frequency of their subsystems. Of the 214 secondaries observed, 39 containmore » such subsystems; 19 of those were discovered with Robo-AO. The selection-corrected frequency of secondary subsystems with periods from 10{sup 3.5} to 10{sup 5} days is 0.12 ± 0.03, the same as the frequency of such companions to the primary. Half of the secondary pairs belong to quadruple systems where the primary is also a close pair, showing that the presence of subsystems in both components of the outer binary is correlated. The relatively large abundance of 2+2 quadruple systems is a new finding, and will require more exploration of the formation mechanism of multiple star systems. We also targeted close binaries with periods less than 100 yr, searching for their distant tertiary components, and discovered 17 certain and 2 potential new triples. In a subsample of 241 close binaries, 71 have additional outer companions. The overall frequency of tertiary components is not enhanced, compared to all (non-binary) targets, but in the range of outer periods from 10{sup 6} to 10{sup 7.5} days (separations on the order of 500 AU), the frequency of tertiary components is 0.16 ± 0.03, exceeding the frequency of similar systems among all targets (0.09) by almost a factor of two. Measurements of binary stars with Robo-AO allowed us to compute first orbits for 9 pairs and to improve orbits of another 11 pairs.« less

In silico approaches and proportional odds model towards identifying selective ADAM17 inhibitors from anti-inflammatory natural molecules.

PubMed

Borah, Pallab Kumar; Chakraborty, Sourav; Jha, Anupam N; Rajkhowa, Sanchaita; Duary, Raj Kumar

2016-11-01

ADAM metallopeptidase domain 17 (ADAM17) is an attractive target for the development of new anti-inflammatory drugs. We aimed to identify selective inhibitors of ADAM17 against matrix metalloproteinase enzymes (MMP-1, MMP-2, MMP-3, MMP-7, MMP-8, MMP-9, MMP-13, and MMP-16) which have substantial structural similarity. Target proteins were docked with 29 anti-inflammatory natural molecule ligands and a known selective inhibitor IK682. The ligands were screened based on Lipinski rules, interaction with the ADAM17 active site cavity, and then ranked using the proportional odds model multinomial logistic regression. Silymarin was the most selective inhibitor of ADAM17 exhibiting H-bonding with Glu 406, Gly 349, Glu 398, Asn 447, Tyr 433, and Lys 432. Molecular dynamics simulations were carried out for 10ns. The root mean square deviation (RMSD), root mean squared fluctuations (RMSF), radius of gyration (Rg), solvent accessible surface area (SASA), and H-bonding indicated the induced metastability. A comparison of the principal component analysis revealed that the silymarin complex also explored lesser region compared to IK682 complex. A control study on ADAM17 protein (2OI0) is included. These observations present silymarin (widely present in plants such as milk thistle (Silybum maianum), wild artichokes (Cynara cardunculus), turmeric (Curcuma longa) roots, coriander (Coriandrum sativum) seeds, etc.) as a promising natural template for development of ADAM17 selective drugs. Copyright © 2016 Elsevier Inc. All rights reserved.

Coarsening of protein clusters on subcellular drops exhibits strong and sudden size selectivity

NASA Astrophysics Data System (ADS)

Brown, Aidan; Rutenberg, Andrew

2015-03-01

Autophagy is an important process for the degradation of cellular components, with receptor proteins targeting substrates to downstream autophagy machinery. An important question is how receptor protein interactions lead to their selective accumulation on autophagy substrates. Receptor proteins have recently been observed in clusters, raising the possibility that clustering could affect autophagy selectivity. We investigate the clustering dynamics of the autophagy receptor protein NBR1. In addition to standard receptor protein domains, NBR1 has a ``J'' domain that anchors it to membranes, and a coiled-coil domain that enhances self-interaction. We model coarsening clusters of NBR1 on the surfaces of a polydisperse collection of drops, representing organelles. Despite the disconnected nature of the drop surfaces, we recover dynamical scaling of cluster sizes. Significantly, we find that at a well-defined time after coarsening begins, clusters evaporate from smaller drops and grow on larger drops. Thus, coarsening-driven size selection will localize protein clusters to larger substrates, leaving smaller substrates without clusters. This provides a possible physical mechanism for autophagy selectivity, and can explain reports of size selection during peroxisome degradation.

A literature review of learning collaboratives in mental health care: used but untested.

PubMed

Nadeem, Erum; Olin, S Serene; Hill, Laura Campbell; Hoagwood, Kimberly Eaton; Horwitz, Sarah McCue

2014-09-01

Policy makers have increasingly turned to learning collaboratives (LCs) as a strategy for improving usual care through the dissemination of evidence-based practices. The purpose of this review was to characterize the state of the evidence for use of LCs in mental health care. A systematic search of major academic databases for peer-reviewed articles on LCs in mental health care generated 421 unique articles across a range of disciplines; 28 mental health articles were selected for full-text review, and 20 articles representing 16 distinct studies met criteria for final inclusion. Articles were coded to identify the LC components reported, the focus of the research, and key findings. Most of the articles included assessments of provider- or patient-level variables at baseline and post-LC. Only one study included a comparison condition. LC targets ranged widely, from use of a depression screening tool to implementation of evidence-based treatments. Fourteen crosscutting LC components (for example, in-person learning sessions, phone meetings, data reporting, leadership involvement, and training in quality improvement methods) were identified. The LCs reviewed reported including, on average, seven components, most commonly in-person learning sessions, plan-do-study-act cycles, multidisciplinary quality improvement teams, and data collection for quality improvement. LCs are being used widely in mental health care, although there is minimal evidence of their effectiveness and unclear reporting in regard to specific components. Rigorous observational and controlled research studies on the impact of LCs on targeted provider- and patient-level outcomes are greatly needed.

Study design and implementation for population pharmacokinetics of Chinese medicine: An expert consensus.

PubMed

Jiang, Jun-jie; Zhang, Wen; Xie, Yan-ming; Wang, Jian-nong; He, Fu-yuan; Xiong, Xin

2016-02-01

Although many population pharmacokinetics (PPK) researches have been conducted on chemical drugs, few have been in the field of Chinese medicine (CM). Each ingredient in CMs possesses different pharmacokinetic characteristics, therefore, it is important to develop methods of PPK studies on them to identify the differences in CM drug safety and efficacy among the population subgroups and to conduct quantitative studies on the determinants of CM drug concentrations. To develop an expert consensus on study design and implementation for PPK of CM, in August 2013, 6 experts in the field of PPK, CMs pharmacology, and statistics discussed problems on the PPK research protocol of CMs, and a consensus was reached. The medicines with toxicity and narrow therapeutic windows and with wide range of target population or with frequent adverse reactions were selected. The compositions with definite therapeutic effects were selected as indices, and specific time points and sample sizes were designed according to standard PPK design methods. Target components were tested through various chromatography methods. Total quantity statistical moment analysis was used to estimate PPK parameters of each component and PPK models reflecting the trend of CMs (which assists in reasonable adjustments on clinical dosage). This consensus specifies the study design and implementation process of PPK. It provides guidance for the following: post-marketing clinical studies, in vivo investigations related to the metabolism in different populations, and development and clinical adjustment of dosages of CMs.

What top-down task sets do for us: an ERP study on the benefits of advance preparation in visual search.

PubMed

Eimer, Martin; Kiss, Monika; Nicholas, Susan

2011-12-01

When target-defining features are specified in advance, attentional target selection in visual search is controlled by preparatory top-down task sets. We used ERP measures to study voluntary target selection in the absence of such feature-specific task sets, and to compare it to selection that is guided by advance knowledge about target features. Visual search arrays contained two different color singleton digits, and participants had to select one of these as target and report its parity. Target color was either known in advance (fixed color task) or had to be selected anew on each trial (free color-choice task). ERP correlates of spatially selective attentional target selection (N2pc) and working memory processing (SPCN) demonstrated rapid target selection and efficient exclusion of color singleton distractors from focal attention and working memory in the fixed color task. In the free color-choice task, spatially selective processing also emerged rapidly, but selection efficiency was reduced, with nontarget singleton digits capturing attention and gaining access to working memory. Results demonstrate the benefits of top-down task sets: Feature-specific advance preparation accelerates target selection, rapidly resolves attentional competition, and prevents irrelevant events from attracting attention and entering working memory.

Neuroelectrical signs of selective attention to color in boys with attention-deficit hyperactivity disorder.

PubMed

van der Stelt, O; van der Molen, M; Boudewijn Gunning, W; Kok, A

2001-10-01

In order to gain insight into the functional and macroanatomical loci of visual selective processing deficits that may be basic to attention-deficit hyperactivity disorder (ADHD), the present study examined multi-channel event-related potentials (ERPs) recorded from 7- to 11-year-old boys clinically diagnosed as having ADHD (n=24) and age-matched healthy control boys (n=24) while they performed a visual (color) selective attention task. The spatio-temporal dynamics of several ERP components related to attention to color were characterized using topographic profile analysis, topographic mapping of the ERP and associated scalp current density distributions, and spatio-temporal source potential modeling. Boys with ADHD showed a lower target hit rate, a higher false-alarm rate, and a lower perceptual sensitivity than controls. Also, whereas color attention induced in the ERPs from controls a characteristic early frontally maximal selection positivity (FSP), ADHD boys displayed little or no FSP. Similarly, ADHD boys manifested P3b amplitude decrements that were partially lateralized (i.e., maximal at left temporal scalp locations) as well as affected by maturation. These results indicate that ADHD boys suffer from deficits at both relatively early (sensory) and late (semantic) levels of visual selective information processing. The data also support the hypothesis that the visual selective processing deficits observed in the ADHD boys originate from deficits in the strength of activation of a neural network comprising prefrontal and occipito-temporal brain regions. This network seems to be actively engaged during attention to color and may contain the major intracerebral generating sources of the associated scalp-recorded ERP components.

Targeting gene expression selectively in cancer cells by using the progression-elevated gene-3 promoter.

PubMed

Su, Zhao-Zhong; Sarkar, Devanand; Emdad, Luni; Duigou, Gregory J; Young, Charles S H; Ware, Joy; Randolph, Aaron; Valerie, Kristoffer; Fisher, Paul B

2005-01-25

One impediment to effective cancer-specific gene therapy is the rarity of regulatory sequences targeting gene expression selectively in tumor cells. Although many tissue-specific promoters are recognized, few cancer-selective gene promoters are available. Progression-elevated gene-3 (PEG-3) is a rodent gene identified by subtraction hybridization that displays elevated expression as a function of transformation by diversely acting oncogenes, DNA damage, and cancer cell progression. The promoter of PEG-3, PEG-Prom, displays robust expression in a broad spectrum of human cancer cell lines with marginal expression in normal cellular counterparts. Whereas GFP expression, when under the control of a CMV promoter, is detected in both normal and cancer cells, when GFP is expressed under the control of the PEG-Prom, cancer-selective expression is evident. Mutational analysis identifies the AP-1 and PEA-3 transcription factors as primary mediators of selective, cancer-specific expression of the PEG-Prom. Synthesis of apoptosis-inducing genes, under the control of the CMV promoter, inhibits the growth of both normal and cancer cells, whereas PEG-Prom-mediated expression of these genes kills only cancer cells and spares normal cells. The efficacy of the PEG-Prom as part of a cancer gene therapeutic regimen is further documented by in vivo experiments in which PEG-Prom-controlled expression of an apoptosis-inducing gene completely inhibited prostate cancer xenograft growth in nude mice. These compelling observations indicate that the PEG-Prom, with its cancer-specific expression, provides a means of selectively delivering genes to cancer cells, thereby providing a crucial component in developing effective cancer gene therapies.

Drug target identification using network analysis: Taking active components in Sini decoction as an example

NASA Astrophysics Data System (ADS)

Chen, Si; Jiang, Hailong; Cao, Yan; Wang, Yun; Hu, Ziheng; Zhu, Zhenyu; Chai, Yifeng

2016-04-01

Identifying the molecular targets for the beneficial effects of active small-molecule compounds simultaneously is an important and currently unmet challenge. In this study, we firstly proposed network analysis by integrating data from network pharmacology and metabolomics to identify targets of active components in sini decoction (SND) simultaneously against heart failure. To begin with, 48 potential active components in SND against heart failure were predicted by serum pharmacochemistry, text mining and similarity match. Then, we employed network pharmacology including text mining and molecular docking to identify the potential targets of these components. The key enriched processes, pathways and related diseases of these target proteins were analyzed by STRING database. At last, network analysis was conducted to identify most possible targets of components in SND. Among the 25 targets predicted by network analysis, tumor necrosis factor α (TNF-α) was firstly experimentally validated in molecular and cellular level. Results indicated that hypaconitine, mesaconitine, higenamine and quercetin in SND can directly bind to TNF-α, reduce the TNF-α-mediated cytotoxicity on L929 cells and exert anti-myocardial cell apoptosis effects. We envisage that network analysis will also be useful in target identification of a bioactive compound.

Drug target identification using network analysis: Taking active components in Sini decoction as an example

PubMed Central

Chen, Si; Jiang, Hailong; Cao, Yan; Wang, Yun; Hu, Ziheng; Zhu, Zhenyu; Chai, Yifeng

2016-01-01

Identifying the molecular targets for the beneficial effects of active small-molecule compounds simultaneously is an important and currently unmet challenge. In this study, we firstly proposed network analysis by integrating data from network pharmacology and metabolomics to identify targets of active components in sini decoction (SND) simultaneously against heart failure. To begin with, 48 potential active components in SND against heart failure were predicted by serum pharmacochemistry, text mining and similarity match. Then, we employed network pharmacology including text mining and molecular docking to identify the potential targets of these components. The key enriched processes, pathways and related diseases of these target proteins were analyzed by STRING database. At last, network analysis was conducted to identify most possible targets of components in SND. Among the 25 targets predicted by network analysis, tumor necrosis factor α (TNF-α) was firstly experimentally validated in molecular and cellular level. Results indicated that hypaconitine, mesaconitine, higenamine and quercetin in SND can directly bind to TNF-α, reduce the TNF-α-mediated cytotoxicity on L929 cells and exert anti-myocardial cell apoptosis effects. We envisage that network analysis will also be useful in target identification of a bioactive compound. PMID:27095146

Dual targeting of gene delivery by genetic modification of adenovirus serotype 5 fibers and cell-selective transcriptional control.

PubMed

Work, L M; Ritchie, N; Nicklin, S A; Reynolds, P N; Baker, A H

2004-08-01

Adenovirus (Ad)-mediated gene delivery is a promising approach for genetic manipulation of the vasculature and is being used in both preclinical models and clinical trials. However, safety concerns relating to infection of nontarget tissue and the poor infectivity of vascular cells compared to other cell types necessitates Ad vector refinement. Here, we combine a transductional targeting approach to improve vascular cell infectivity through RGD peptide insertion into adenovirus fibers, combined with transcriptional targeting to endothelial cells using a approximately 1 kb fragment of the fms-like tyrosine kinase receptor-1 (FLT-1) promoter. Single- and double-modified vectors were characterized in human cell lines that either support or have silenced FLT-1 expression. In rat hepatocytes and endothelial cells, the double modification substantially shifted transduction profiles toward vascular endothelial cells. Furthermore, in intact aortae derived from spontaneously hypertensive rats that display enhanced alphav integrin expression on dysfunctional endothelium, enhanced levels of transduction were observed using the double-modified vector but not in aortae derived from normotensive control rats. Our data indicate that Ad-mediated transduction can be beneficially modified in vitro and in vivo by combining fiber modification and a cell-selective promoter within a single-component vector system.

Non-psychotropic analgesic drugs from the endocannabinoid system: "magic bullet" or "multiple-target" strategies?

PubMed

Starowicz, Katarzyna; Di Marzo, Vincenzo

2013-09-15

The exploitation of preparations of Cannabis sativa to combat pain seems to date back to time immemorial, although their psychotropic effects, which are at the bases of their recreational use and limit their therapeutic use, are at least as ancient. Indeed, it has always been different to tease apart the unwanted central effects from the therapeutic benefits of Δ⁹-tetrahydrocannabinol (THC), the main psychotropic component of cannabis. The discovery of the cannabinoid receptors and of their endogenous ligands, the endocannabinoids, which, unlike THC, play a pro-homeostatic function in a tissue- and time-selective manner, offered the opportunity to develop new analgesics from synthetic inhibitors of endocannabinoid inactivation. The advantages of this approach over direct activation of cannabinoid receptors as a therapeutic strategy against neuropathic and inflammatory pain are discussed here along with its potential complications. These latter have been such that clinical success has been achieved so far more rapidly with naturally occurring THC or endocannabinoid structural analogues acting at a plethora of cannabinoid-related and -unrelated molecular targets, than with selective inhibitors of endocannabinoid enzymatic hydrolysis, thus leading to revisit the potential usefulness of "multi-target" versus "magic bullet" compounds as new analgesics. © 2013 Elsevier B.V. All rights reserved.

The role of the electrolyte in the selective dissolution of metal alloys

NASA Astrophysics Data System (ADS)

Policastro, Steven A.

Dealloying plays an important role in several corrosion processes, including pitting corrosion through the formation of local cathodes from the selective dissolution of intermetallic particles and stress-corrosion cracking in which it is responsible for injecting cracks from the surface into the undealloyed bulk material. Additionally, directed dealloying in the laboratory to form nanoporous structures has been the subject of much recent study because of the unique structural properties that the porous layer provides. In order to better understand the physical reasons for dealloying as well as understand the parameters that influence the evolution of the microstructure, several models have been proposed. Current theoretical descriptions of dealloying have been very successful in explaining some features of selective dissolution but additional behaviors can be included into the model to improve understanding of the dealloying process. In the present work, the effects of electrolyte component interactions, temperature, alloy cohesive energies, and applied potential on the development of nanoporosity via the selective dissolution of the less-noble component from binary and ternary alloys are considered. Both a kinetic Monte-Carlo (KMC) model of the behavior of the metal atoms and the electrolyte ions at the metal-solution interface and a phase-yield model of ligament coarsening are developed. By adding these additional parameters into the KMC model, a rich set of behaviors is observed in the simulation results. From the simulation results, it is suggested that selectively dissolving a binary alloy in a very aggressive electrolyte that targeted the LN atoms could provide a porous microstructure that retained a higher concentration of the LN atoms in its ligaments and thus retain more of the mechanical properties of the bulk alloy. In addition, by adding even a small fraction of a third, noble component to form a ternary alloy the dissolution kinetics of the least noble component can be dramatically altered, providing a means of controlling dealloying depth. Some molecular dynamics calculations are used to justify the assumptions of metal atom motion in the KMC model. A recently developed parameter-space exploration technique, COERCE, is employed to optimize the process of obtaining meaningful parameter values from the KMC simulation.

Neuropharmacology beyond reductionism - A likely prospect.

PubMed

Margineanu, Doru Georg

2016-03-01

Neuropharmacology had several major past successes, but the last few decades did not witness any leap forward in the drug treatment of brain disorders. Moreover, current drugs used in neurology and psychiatry alleviate the symptoms, while hardly curing any cause of disease, basically because the etiology of most neuro-psychic syndromes is but poorly known. This review argues that this largely derives from the unbalanced prevalence in neuroscience of the analytic reductionist approach, focused on the cellular and molecular level, while the understanding of integrated brain activities remains flimsier. The decline of drug discovery output in the last decades, quite obvious in neuropharmacology, coincided with the advent of the single target-focused search of potent ligands selective for a well-defined protein, deemed critical in a given pathology. However, all the widespread neuro-psychic troubles are multi-mechanistic and polygenic, their complex etiology making unsuited the single-target drug discovery. An evolving approach, based on systems biology considers that a disease expresses a disturbance of the network of interactions underlying organismic functions, rather than alteration of single molecular components. Accordingly, systems pharmacology seeks to restore a disturbed network via multi-targeted drugs. This review notices that neuropharmacology in fact relies on drugs which are multi-target, this feature having occurred just because those drugs were selected by phenotypic screening in vivo, or emerged from serendipitous clinical observations. The novel systems pharmacology aims, however, to devise ab initio multi-target drugs that will appropriately act on multiple molecular entities. Though this is a task much more complex than the single-target strategy, major informatics resources and computational tools for the systemic approach of drug discovery are already set forth and their rapid progress forecasts promising outcomes for neuropharmacology. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Component-based target recognition inspired by human vision

NASA Astrophysics Data System (ADS)

Zheng, Yufeng; Agyepong, Kwabena

2009-05-01

In contrast with machine vision, human can recognize an object from complex background with great flexibility. For example, given the task of finding and circling all cars (no further information) in a picture, you may build a virtual image in mind from the task (or target) description before looking at the picture. Specifically, the virtual car image may be composed of the key components such as driver cabin and wheels. In this paper, we propose a component-based target recognition method by simulating the human recognition process. The component templates (equivalent to the virtual image in mind) of the target (car) are manually decomposed from the target feature image. Meanwhile, the edges of the testing image can be extracted by using a difference of Gaussian (DOG) model that simulates the spatiotemporal response in visual process. A phase correlation matching algorithm is then applied to match the templates with the testing edge image. If all key component templates are matched with the examining object, then this object is recognized as the target. Besides the recognition accuracy, we will also investigate if this method works with part targets (half cars). In our experiments, several natural pictures taken on streets were used to test the proposed method. The preliminary results show that the component-based recognition method is very promising.

Genetic address book for retinal cell types.

PubMed

Siegert, Sandra; Scherf, Brigitte Gross; Del Punta, Karina; Didkovsky, Nick; Heintz, Nathaniel; Roska, Botond

2009-09-01

The mammalian brain is assembled from thousands of neuronal cell types that are organized in distinct circuits to perform behaviorally relevant computations. Transgenic mouse lines with selectively marked cell types would facilitate our ability to dissect functional components of complex circuits. We carried out a screen for cell type-specific green fluorescent protein expression in the retina using BAC transgenic mice from the GENSAT project. Among others, we identified mouse lines in which the inhibitory cell types of the night vision and directional selective circuit were selectively labeled. We quantified the stratification patterns to predict potential synaptic connectivity between marked cells of different lines and found that some of the lines enabled targeted recordings and imaging of cell types from developing or mature retinal circuits. Our results suggest the potential use of a stratification-based screening approach for characterizing neuronal circuitry in other layered brain structures, such as the neocortex.

A time domain frequency-selective multivariate Granger causality approach.

PubMed

Leistritz, Lutz; Witte, Herbert

2016-08-01

The investigation of effective connectivity is one of the major topics in computational neuroscience to understand the interaction between spatially distributed neuronal units of the brain. Thus, a wide variety of methods has been developed during the last decades to investigate functional and effective connectivity in multivariate systems. Their spectrum ranges from model-based to model-free approaches with a clear separation into time and frequency range methods. We present in this simulation study a novel time domain approach based on Granger's principle of predictability, which allows frequency-selective considerations of directed interactions. It is based on a comparison of prediction errors of multivariate autoregressive models fitted to systematically modified time series. These modifications are based on signal decompositions, which enable a targeted cancellation of specific signal components with specific spectral properties. Depending on the embedded signal decomposition method, a frequency-selective or data-driven signal-adaptive Granger Causality Index may be derived.

Optical phase measuring sensors for automated rendezvous and capture

NASA Technical Reports Server (NTRS)

Metheny, Wayne; Malin, Mark

1991-01-01

A technique is described for sensing relative spatial orientations of approach and target vehicles, using optical phase mensuration (in the interferometric sense, as opposed to LIDAR), in place of the more conventional intensity, image, or transit time measurements. This approach permits the parameters to be measured with great accuracy with relatively simple, small sensors having no moving components. A suite of sensors operating on this principle can produce all desired data using either active detection on the target or passive retroreflection to the detectors on the approach vehicle. These optical phase measurements can be applied to determine bearing angle (location of the target vehicle in the approach vehicle coordinates), range, and attitude (orientation of the target vehicle with respect to the line-of-sight). The first two quantities require the approach vehicle to project a modulated interference pattern into space. The bearing angle is determined for a selected point on the target by measuring the phase of the interference pattern at that point using either a detector on the target or a retroreflector on the target and a detector at the transmitter. The range is found by measuring differential bearing angles to predetermined relative instrumentation sites. Two interferometers, a coarse and a fine ranger are required to resolve the 2pi ambiguity.

Selective visual scaling of time-scale processes facilitates broadband learning of isometric force frequency tracking.

PubMed

King, Adam C; Newell, Karl M

2015-10-01

The experiment investigated the effect of selectively augmenting faster time scales of visual feedback information on the learning and transfer of continuous isometric force tracking tasks to test the generality of the self-organization of 1/f properties of force output. Three experimental groups tracked an irregular target pattern either under a standard fixed gain condition or with selectively enhancement in the visual feedback display of intermediate (4-8 Hz) or high (8-12 Hz) frequency components of the force output. All groups reduced tracking error over practice, with the error lowest in the intermediate scaling condition followed by the high scaling and fixed gain conditions, respectively. Selective visual scaling induced persistent changes across the frequency spectrum, with the strongest effect in the intermediate scaling condition and positive transfer to novel feedback displays. The findings reveal an interdependence of the timescales in the learning and transfer of isometric force output frequency structures consistent with 1/f process models of the time scales of motor output variability.

Technological progress as a driver of innovation in infant foods.

PubMed

Ferruzzi, Mario G; Neilson, Andrew P

2010-01-01

Advances in nutrition and food sciences are interrelated components of the innovative framework for infant formula and foods. While nutrition science continues to define the composition and functionality of human milk as a reference, food ingredient, formulation and processing technologies facilitate the design and delivery of nutritional and functional concepts to infant products. Expanding knowledge of both nutritive and non-nutritive components of human milk and their functionality guides selection and development of novel ingredient, formulation and processing methods to generate enhanced infant products targeting benefits including healthy growth, development as well as protection of health through the life cycle. In this chapter, identification and application of select novel ingredients/technologies will be discussed in the context of how these technological advancements have stimulated innovation in infant foods. Special focus will be given to advancements in protein technologies, as well as bioactive long-chain polyunsaturated fatty acids, prebiotics, probiotics that have allowed infant formula composition, and more critically functionality, to more closely align with that of human milk. Copyright © 2010 S. Karger AG, Basel.

The mm-wave compact component of an AGN

NASA Astrophysics Data System (ADS)

Behar, Ehud; Vogel, Stuart; Baldi, Ranieri D.; Smith, Krista L.; Mushotzky, Richard F.

2018-07-01

mm-wave emission from active galactic nuclei (AGNs) may hold the key to understanding the physical origin of their radio cores. The correlation between radio/mm and X-ray luminosity may suggest a similar physical origin of the two sources. Since synchrotron self-absorption decreases with frequency, mm-waves probe smaller length-scales than cm-waves. We report on 100 GHz (3 mm) observations with the Combined Array for Research in Millimeter-wave Astronomy of 26 AGNs selected from the hard X-ray Swift/Burst Alert Telescope survey. 20/26 targets were detected at 100 GHz down to the 1 mJy (3σ) sensitivity, which corresponds to optically thick synchrotron source sizes of 10-4-10-3 pc. Most sources show a 100 GHz flux excess with respect to the spectral slope extrapolated from low frequencies. This mm spectral component likely originates from smaller scales than the few-GHz emission. The measured mm sources lie roughly around the Lmm (100 GHz) ˜10-4LX (2-10 keV) relation, similar to a few previously published X-ray selected sources, and hinting perhaps at a common coronal origin.

The mm-wave compact component of AGN

NASA Astrophysics Data System (ADS)

Behar, Ehud; Vogel, Stuart; Baldi, Ranieri D.; Smith, Krista L.; Mushotzky, Richard F.

2018-05-01

mm-wave emission from Active Galactic Nuclei (AGN) may hold the key to understanding the physical origin of their radio cores. The correlation between radio/mm and X-ray luminosity may suggest a similar physical origin of the two sources. Since synchrotron self absorption decreases with frequency, mm-waves probe smaller length scales than cm-waves. We report on 100 GHz (3 mm) observations with CARMA of 26 AGNs selected from the hard X-ray Swift/BAT survey. 20/26 targets were detected at 100 GHz down to the 1 mJy (3σ) sensitivity, which corresponds to optically thick synchrotron source sizes of 10-4 - 10-3 pc. Most sources show a 100 GHz flux excess with respect to the spectral slope extrapolated from low frequencies. This mm spectral component likely originates from smaller scales than the few-GHz emission. The measured mm sources lie roughly around the Lmm (100 GHz) ˜10-4LX (2-10 keV) relation, similar to a few previously published X-ray selected sources, and hinting perhaps at a common coronal origin.

Multi-Domain Transfer Learning for Early Diagnosis of Alzheimer's Disease.

PubMed

Cheng, Bo; Liu, Mingxia; Shen, Dinggang; Li, Zuoyong; Zhang, Daoqiang

2017-04-01

Recently, transfer learning has been successfully applied in early diagnosis of Alzheimer's Disease (AD) based on multi-domain data. However, most of existing methods only use data from a single auxiliary domain, and thus cannot utilize the intrinsic useful correlation information from multiple domains. Accordingly, in this paper, we consider the joint learning of tasks in multi-auxiliary domains and the target domain, and propose a novel Multi-Domain Transfer Learning (MDTL) framework for early diagnosis of AD. Specifically, the proposed MDTL framework consists of two key components: 1) a multi-domain transfer feature selection (MDTFS) model that selects the most informative feature subset from multi-domain data, and 2) a multi-domain transfer classification (MDTC) model that can identify disease status for early AD detection. We evaluate our method on 807 subjects from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database using baseline magnetic resonance imaging (MRI) data. The experimental results show that the proposed MDTL method can effectively utilize multi-auxiliary domain data for improving the learning performance in the target domain, compared with several state-of-the-art methods.

SPRAT: Spectrograph for the Rapid Acquisition of Transients

NASA Astrophysics Data System (ADS)

Piascik, A. S.; Steele, Iain A.; Bates, Stuart D.; Mottram, Christopher J.; Smith, R. J.; Barnsley, R. M.; Bolton, B.

2014-07-01

We describe the development of a low cost, low resolution (R ~ 350), high throughput, long slit spectrograph covering visible (4000-8000) wavelengths. The spectrograph has been developed for fully robotic operation with the Liverpool Telescope (La Palma). The primary aim is to provide rapid spectral classification of faint (V ˜ 20) transient objects detected by projects such as Gaia, iPTF (intermediate Palomar Transient Factory), LOFAR, and a variety of high energy satellites. The design employs a volume phase holographic (VPH) transmission grating as the dispersive element combined with a prism pair (grism) in a linear optical path. One of two peak spectral sensitivities are selectable by rotating the grism. The VPH and prism combination and entrance slit are deployable, and when removed from the beam allow the collimator/camera pair to re-image the target field onto the detector. This mode of operation provides automatic acquisition of the target onto the slit prior to spectrographic observation through World Coordinate System fitting. The selection and characterisation of optical components to maximise photon throughput is described together with performance predictions.

Multi-Domain Transfer Learning for Early Diagnosis of Alzheimer’s Disease

PubMed Central

Cheng, Bo; Liu, Mingxia; Li, Zuoyong

2017-01-01

Recently, transfer learning has been successfully applied in early diagnosis of Alzheimer’s Disease (AD) based on multi-domain data. However, most of existing methods only use data from a single auxiliary domain, and thus cannot utilize the intrinsic useful correlation information from multiple domains. Accordingly, in this paper, we consider the joint learning of tasks in multi-auxiliary domains and the target domain, and propose a novel Multi-Domain Transfer Learning (MDTL) framework for early diagnosis of AD. Specifically, the proposed MDTL framework consists of two key components: 1) a multi-domain transfer feature selection (MDTFS) model that selects the most informative feature subset from multi-domain data, and 2) a multidomain transfer classification (MDTC) model that can identify disease status for early AD detection. We evaluate our method on 807 subjects from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database using baseline magnetic resonance imaging (MRI) data. The experimental results show that the proposed MDTL method can effectively utilize multi-auxiliary domain data for improving the learning performance in the target domain, compared with several state-of-the-art methods. PMID:27928657

Binding mode and potency of N-indolyloxopyridinyl-4-aminopropanyl-based inhibitors targeting Trypanosoma cruzi CYP51

DOE PAGES

Vieira, Debora F.; Choi, Jun Yong; Calvet, Claudia M.; ...

2014-11-13

Chagas disease is a chronic infection in humans caused by Trypanosoma cruzi and manifested in progressive cardiomyopathy and/or gastrointestinal dysfunction. Limited therapeutic options to prevent and treat Chagas disease put 8 million people infected with T. cruzi worldwide at risk. CYP51, involved in the biosynthesis of the membrane sterol component in eukaryotes, is a promising drug target in T. cruzi. We report the structure–activity relationships (SAR) of an N-arylpiperazine series of N-indolyloxopyridinyl-4-aminopropanyl-based inhibitors designed to probe the impact of substituents in the terminal N-phenyl ring on binding mode, selectivity and potency. Depending on the substituents at C-4, two distinct ringmore » binding modes, buried and solvent-exposed, have been observed by X-ray structure analysis (resolution of 1.95–2.48 Å). Lastly, the 5-chloro-substituted analogs 9 and 10 with no substituent at C-4 demonstrated improved selectivity and potency, suppressing ≥99.8% parasitemia in mice when administered orally at 25 mg/kg, b.i.d., for 4 days.« less

Construction of a versatile SNP array for pyramiding useful genes of rice.

PubMed

Kurokawa, Yusuke; Noda, Tomonori; Yamagata, Yoshiyuki; Angeles-Shim, Rosalyn; Sunohara, Hidehiko; Uehara, Kanako; Furuta, Tomoyuki; Nagai, Keisuke; Jena, Kshirod Kumar; Yasui, Hideshi; Yoshimura, Atsushi; Ashikari, Motoyuki; Doi, Kazuyuki

2016-01-01

DNA marker-assisted selection (MAS) has become an indispensable component of breeding. Single nucleotide polymorphisms (SNP) are the most frequent polymorphism in the rice genome. However, SNP markers are not readily employed in MAS because of limitations in genotyping platforms. Here the authors report a Golden Gate SNP array that targets specific genes controlling yield-related traits and biotic stress resistance in rice. As a first step, the SNP genotypes were surveyed in 31 parental varieties using the Affymetrix Rice 44K SNP microarray. The haplotype information for 16 target genes was then converted to the Golden Gate platform with 143-plex markers. Haplotypes for the 14 useful allele are unique and can discriminate among all other varieties. The genotyping consistency between the Affymetrix microarray and the Golden Gate array was 92.8%, and the accuracy of the Golden Gate array was confirmed in 3 F2 segregating populations. The concept of the haplotype-based selection by using the constructed SNP array was proofed. Copyright © 2015 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.

Top-down dimensional weight set determines the capture of visual attention: evidence from the PCN component.

PubMed

Töllner, Thomas; Müller, Hermann J; Zehetleitner, Michael

2012-07-01

Visual search for feature singletons is slowed when a task-irrelevant, but more salient distracter singleton is concurrently presented. While there is a consensus that this distracter interference effect can be influenced by internal system settings, it remains controversial at what stage of processing this influence starts to affect visual coding. Advocates of the "stimulus-driven" view maintain that the initial sweep of visual processing is entirely driven by physical stimulus attributes and that top-down settings can bias visual processing only after selection of the most salient item. By contrast, opponents argue that top-down expectancies can alter the initial selection priority, so that focal attention is "not automatically" shifted to the location exhibiting the highest feature contrast. To precisely trace the allocation of focal attention, we analyzed the Posterior-Contralateral-Negativity (PCN) in a task in which the likelihood (expectancy) with which a distracter occurred was systematically varied. Our results show that both high (vs. low) distracter expectancy and experiencing a distracter on the previous trial speed up the timing of the target-elicited PCN. Importantly, there was no distracter-elicited PCN, indicating that participants did not shift attention to the distracter before selecting the target. This pattern unambiguously demonstrates that preattentive vision is top-down modifiable.

Non-targeted 1H NMR fingerprinting and multivariate statistical analyses for the characterisation of the geographical origin of Italian sweet cherries.

PubMed

Longobardi, F; Ventrella, A; Bianco, A; Catucci, L; Cafagna, I; Gallo, V; Mastrorilli, P; Agostiano, A

2013-12-01

In this study, non-targeted (1)H NMR fingerprinting was used in combination with multivariate statistical techniques for the classification of Italian sweet cherries based on their different geographical origins (Emilia Romagna and Puglia). As classification techniques, Soft Independent Modelling of Class Analogy (SIMCA), Partial Least Squares Discriminant Analysis (PLS-DA), and Linear Discriminant Analysis (LDA) were carried out and the results were compared. For LDA, before performing a refined selection of the number/combination of variables, two different strategies for a preliminary reduction of the variable number were tested. The best average recognition and CV prediction abilities (both 100.0%) were obtained for all the LDA models, although PLS-DA also showed remarkable performances (94.6%). All the statistical models were validated by observing the prediction abilities with respect to an external set of cherry samples. The best result (94.9%) was obtained with LDA by performing a best subset selection procedure on a set of 30 principal components previously selected by a stepwise decorrelation. The metabolites that mostly contributed to the classification performances of such LDA model, were found to be malate, glucose, fructose, glutamine and succinate. Copyright © 2013 Elsevier Ltd. All rights reserved.

A chemical screen in diverse breast cancer cell lines reveals genetic enhancers and suppressors of sensitivity to PI3K isotype-selective inhibition

PubMed Central

Torbett, Neil E; Luna, Antonio; Knight, Zachary A.; Houk, Andrew; Moasser, Mark; Weiss, William; Shokat, Kevan M.; Stokoe, David

2011-01-01

Synopsis The Phosphoinositide-3-kinase (PI3K) pathway regulates cell proliferation, survival and migration and is consequently of great interest for targeted cancer therapy. Using a panel of small molecule PI3K isoform-selective inhibitors in a diverse set of breast cancer cell lines, we demonstrate that the biochemical and biological responses were highly variable and dependent on the genetic alterations present. p110α inhibitors were generally effective in inhibiting the phosphorylation of Akt and S6, two downstream components of PI3K signaling, in most cell lines examined. In contrast, 110β selective inhibitors only reduced Akt phosphorylation in PTEN mutant cell lines, and was associated with a lesser decrease in S6 phosphorylation. PI3K inhibitors reduced cell viability by causing a cell cycle arrest in the G1 phase of the cell cycle, with multi-targeted inhibitors causing the most potent effects. Cells expressing mutant Ras were resistant to the cell cycle effects of PI3K inhibition, which could be reversed using inhibitors of Ras signaling pathways. Taken together our data indicates that these compounds, alone or in suitable combinations, may be useful as breast cancer therapeutics, when used in appropriate genetic contexts. PMID:18498248

Optical Radiation from Shock-Compressed Materials. Ph.D. Thesis

NASA Technical Reports Server (NTRS)

Svendsen, Robert F., Jr.

1987-01-01

Recent observations of shock-induced radiation from oxides, silicates, and metals of geophysical interest constrain the shock-compressed temperature of these materials. The relationships between the temperature inferred from the observed radiation and the temperature of the shock-compressed film or foil and/or window were investigated. Changes of the temperature field in each target component away from that of their respective shock-compressed states occur because of: shock-impedance mismatch between target components; thermal mismatch between target components; surface roughness at target interfaces; and conduction within and between target components. In particular, conduction may affect the temperature of the film/foil window interface on the time scale of the experiments, and so control the intensity and history of the dominant thermal radiation sources in the target. This type of model was used to interpret the radiation emitted by a variety of shock-compressed materials and interfaces.

Contributions of depth filter components to protein adsorption in bioprocessing.

PubMed

Khanal, Ohnmar; Singh, Nripen; Traylor, Steven J; Xu, Xuankuo; Ghose, Sanchayita; Li, Zheng J; Lenhoff, Abraham M

2018-04-16

Depth filtration is widely used in downstream bioprocessing to remove particulate contaminants via depth straining and is therefore applied to harvest clarification and other processing steps. However, depth filtration also removes proteins via adsorption, which can contribute variously to impurity clearance and to reduction in product yield. The adsorption may occur on the different components of the depth filter, that is, filter aid, binder, and cellulose filter. We measured adsorption of several model proteins and therapeutic proteins onto filter aids, cellulose, and commercial depth filters at pH 5-8 and ionic strengths <50 mM and correlated the adsorption data to bulk measured properties such as surface area, morphology, surface charge density, and composition. We also explored the role of each depth filter component in the adsorption of proteins with different net charges, using confocal microscopy. Our findings show that a complete depth filter's maximum adsorptive capacity for proteins can be estimated by its protein monolayer coverage values, which are of order mg/m 2 , depending on the protein size. Furthermore, the extent of adsorption of different proteins appears to depend on the nature of the resin binder and its extent of coating over the depth filter surface, particularly in masking the cation-exchanger-like capacity of the siliceous filter aids. In addition to guiding improved depth filter selection, the findings can be leveraged in inspiring a more intentional selection of components and design of depth filter construction for particular impurity removal targets. © 2018 Wiley Periodicals, Inc.

Should the United States Marine Corps Refine Its System of Active Component Enlisted Recruitment in Order to Target the Needs of Select Marine Corps Reserve Units?

DTIC Science & Technology

2012-03-23

1K.pdf ( accessed January 3, 2012). 6 Charts built by the author using data extracted the Marine Corps Total Force System database. Information...Washington D.C., February 2012. http://www.defense.gov/news/Fact_Sheet_Budget.pdf ( accessed February 17, 2012). 10 Department of Defense. 11...www.defense.gov/news/newsarticle.aspx?id=66698 ( accessed January 8, 2012) 12 Amos. 13 David Cloud, and Christi Parsons. "President Obama Calls for

Author name recognition in degraded journal images

NASA Astrophysics Data System (ADS)

de Bodard de la Jacopière, Aliette; Likforman-Sulem, Laurence

2006-01-01

A method for extracting names in degraded documents is presented in this article. The documents targeted are images of photocopied scientific journals from various scientific domains. Due to the degradation, there is poor OCR recognition, and pieces of other articles appear on the sides of the image. The proposed approach relies on the combination of a low-level textual analysis and an image-based analysis. The textual analysis extracts robust typographic features, while the image analysis selects image regions of interest through anchor components. We report results on the University of Washington benchmark database.

One-Electron Reduction of Penicillins in Relation to the Oxidative Stress Phenomenon

PubMed Central

Szabó, László; Tóth, Tünde; Takács, Erzsébet; Wojnárovits, László

2015-01-01

Certain bactericidal antibiotics target mitochondrial components and, due to the leakage of electrons from the electron transport chain, one-electron reduction might occur that can lead to intermediates passing the electron to suitable acceptors. This study aimed at investigating the one-electron reduction mechanism of selected penicillin derivatives using pulse radiolysis techniques. Penicillins can accommodate the electron on each of their carbonyl carbon. Ketyl radicals are thus produced, which are reducing agents with possibility to interact with suitable biomolecules. A detailed mechanism of the reduction is reported. PMID:26690427

Activation Levels, Handling, and Storage of Activated Components in the Target Hall at FRIB

NASA Astrophysics Data System (ADS)

Georgobiani, D.; Bennett, R.; Bollen, G.; Kostin, M.; Ronningen, R.

2018-06-01

The Facility for Rare Isotope Beams (FRIB) is a major new scientific user facility under construction in the United States for nuclear science research with beams of rare isotopes. 400 kW beam operations with heavy ions ranging from oxygen to uranium will create a high radiation environment for many components, particularly for the beam line components located in the target hall, where approximately 100 kW of beam power are dissipated in the target and another 300 kW are dissipated in the beam dump. Detailed studies of the component activation, their remote handling, storage, and transport, have been performed to ensure safe operation levels in this environment. Levels of activation are calculated for the beam line components within the FRIB target hall.

Active suppression after involuntary capture of attention.

PubMed

Sawaki, Risa; Luck, Steven J

2013-04-01

After attention has been involuntarily captured by a distractor, how is it reoriented toward a target? One possibility is that attention to the distractor passively fades over time, allowing the target to become attended. Another possibility is that the captured location is actively suppressed so that attention can be directed toward the target location. The present study investigated this issue with event-related potentials (ERPs), focusing on the N2pc component (a neural measure of attentional deployment) and the Pd component (a neural measure of attentional suppression). Observers identified a color-defined target in a search array, which was preceded by a task-irrelevant cue array. When the cue array contained an item that matched the target color, this item captured attention (as measured both behaviorally and with the N2pc component). This capture of attention was followed by active suppression (indexed by the Pd component), and this was then followed by a reorienting of attention toward the target in the search array (indexed by the N2pc component). These findings indicate that the involuntary capture of attention by a distractor is followed by an active suppression process that presumably facilitates the subsequent voluntary orienting of attention to the target.

Evaluation design for a complex intervention program targeting loneliness in non-institutionalized elderly Dutch people.

PubMed

de Vlaming, Rianne; Haveman-Nies, Annemien; Van't Veer, Pieter; de Groot, Lisette Cpgm

2010-09-13

The aim of this paper is to provide the rationale for an evaluation design for a complex intervention program targeting loneliness among non-institutionalized elderly people in a Dutch community. Complex public health interventions characteristically use the combined approach of intervening on the individual and on the environmental level. It is assumed that the components of a complex intervention interact with and reinforce each other. Furthermore, implementation is highly context-specific and its impact is influenced by external factors. Although the entire community is exposed to the intervention components, each individual is exposed to different components with a different intensity. A logic model of change is used to develop the evaluation design. The model describes what outcomes may logically be expected at different points in time at the individual level. In order to address the complexity of a real-life setting, the evaluation design of the loneliness intervention comprises two types of evaluation studies. The first uses a quasi-experimental pre-test post-test design to evaluate the effectiveness of the overall intervention. A control community comparable to the intervention community was selected, with baseline measurements in 2008 and follow-up measurements scheduled for 2010. This study focuses on changes in the prevalence of loneliness and in the determinants of loneliness within individuals in the general elderly population. Complementarily, the second study is designed to evaluate the individual intervention components and focuses on delivery, reach, acceptance, and short-term outcomes. Different means of project records and surveys among participants are used to collect these data. Combining these two evaluation strategies has the potential to assess the effectiveness of the overall complex intervention and the contribution of the individual intervention components thereto.

Evaluation design for a complex intervention program targeting loneliness in non-institutionalized elderly Dutch people

PubMed Central

2010-01-01

Background The aim of this paper is to provide the rationale for an evaluation design for a complex intervention program targeting loneliness among non-institutionalized elderly people in a Dutch community. Complex public health interventions characteristically use the combined approach of intervening on the individual and on the environmental level. It is assumed that the components of a complex intervention interact with and reinforce each other. Furthermore, implementation is highly context-specific and its impact is influenced by external factors. Although the entire community is exposed to the intervention components, each individual is exposed to different components with a different intensity. Methods/Design A logic model of change is used to develop the evaluation design. The model describes what outcomes may logically be expected at different points in time at the individual level. In order to address the complexity of a real-life setting, the evaluation design of the loneliness intervention comprises two types of evaluation studies. The first uses a quasi-experimental pre-test post-test design to evaluate the effectiveness of the overall intervention. A control community comparable to the intervention community was selected, with baseline measurements in 2008 and follow-up measurements scheduled for 2010. This study focuses on changes in the prevalence of loneliness and in the determinants of loneliness within individuals in the general elderly population. Complementarily, the second study is designed to evaluate the individual intervention components and focuses on delivery, reach, acceptance, and short-term outcomes. Different means of project records and surveys among participants are used to collect these data. Discussion Combining these two evaluation strategies has the potential to assess the effectiveness of the overall complex intervention and the contribution of the individual intervention components thereto. PMID:20836840

Nanoplatforms for constructing new approaches to cancer treatment, imaging, and drug delivery: what should be the policy?

PubMed

Kateb, Babak; Chiu, Katherine; Black, Keith L; Yamamoto, Vicky; Khalsa, Bhavraj; Ljubimova, Julia Y; Ding, Hui; Patil, Rameshwar; Portilla-Arias, Jose Antonio; Modo, Mike; Moore, David F; Farahani, Keyvan; Okun, Michael S; Prakash, Neal; Neman, Josh; Ahdoot, Daniel; Grundfest, Warren; Nikzad, Shouleh; Heiss, John D

2011-01-01

Nanotechnology is the design and assembly of submicroscopic devices called nanoparticles, which are 1-100 nm in diameter. Nanomedicine is the application of nanotechnology for the diagnosis and treatment of human disease. Disease-specific receptors on the surface of cells provide useful targets for nanoparticles. Because nanoparticles can be engineered from components that (1) recognize disease at the cellular level, (2) are visible on imaging studies, and (3) deliver therapeutic compounds, nanotechnology is well suited for the diagnosis and treatment of a variety of diseases. Nanotechnology will enable earlier detection and treatment of diseases that are best treated in their initial stages, such as cancer. Advances in nanotechnology will also spur the discovery of new methods for delivery of therapeutic compounds, including genes and proteins, to diseased tissue. A myriad of nanostructured drugs with effective site-targeting can be developed by combining a diverse selection of targeting, diagnostic, and therapeutic components. Incorporating immune target specificity with nanostructures introduces a new type of treatment modality, nano-immunochemotherapy, for patients with cancer. In this review, we will discuss the development and potential applications of nanoscale platforms in medical diagnosis and treatment. To impact the care of patients with neurological diseases, advances in nanotechnology will require accelerated translation to the fields of brain mapping, CNS imaging, and nanoneurosurgery. Advances in nanoplatform, nano-imaging, and nano-drug delivery will drive the future development of nanomedicine, personalized medicine, and targeted therapy. We believe that the formation of a science, technology, medicine law-healthcare policy (STML) hub/center, which encourages collaboration among universities, medical centers, US government, industry, patient advocacy groups, charitable foundations, and philanthropists, could significantly facilitate such advancements and contribute to the translation of nanotechnology across medical disciplines. Copyright © 2010 Elsevier Inc. All rights reserved.

Nanoplatforms for constructing new approaches to cancer treatment, imaging, and drug delivery: What should be the policy?

PubMed Central

Kateb, Babak; Chiu, Katherine; Black, Keith L.; Yamamoto, Vicky; Khalsa, Bhavraj; Ljubimova, Julia Y.; Ding, Hui; Patil, Rameshwar; Portilla-Arias, Jose Antonio; Modo, Mike; Moore, David F.; Farahani, Keyvan; Okun, Michael S.; Prakash, Neal; Neman, Josh; Ahdoot, Daniel; Grundfest, Warren; Nikzad, Shouleh; Heiss, John D.

2012-01-01

Nanotechnology is the design and assembly of submicroscopic devices called nanoparticles, which are 1–100 nm in diameter. Nanomedicine is the application of nanotechnology for the diagnosis and treatment of human disease. Disease-specific receptors on the surface of cells provide useful targets for nanoparticles. Because nanoparticles can be engineered from components that (1) recognize disease at the cellular level, (2) are visible on imaging studies, and (3) deliver therapeutic compounds, nanotechnology is well suited for the diagnosis and treatment of a variety of diseases. Nanotechnology will enable earlier detection and treatment of diseases that are best treated in their initial stages, such as cancer. Advances in nanotechnology will also spur the discovery of new methods for delivery of therapeutic compounds, including genes and proteins, to diseased tissue. A myriad of nanostructured drugs with effective site-targeting can be developed by combining a diverse selection of targeting, diagnostic, and therapeutic components. Incorporating immune target specificity with nanostructures introduces a new type of treatment modality, nano-immunochemotherapy, for patients with cancer. In this review, we will discuss the development and potential applications of nanoscale platforms in medical diagnosis and treatment. To impact the care of patients with neurological diseases, advances in nanotechnology will require accelerated translation to the fields of brain mapping, CNS imaging, and nanoneurosurgery. Advances in nanoplatform, nano-imaging, and nano-drug delivery will drive the future development of nanomedicine, personalized medicine, and targeted therapy. We believe that the formation of a science, technology, medicine law–healthcare policy (STML) hub/center, which encourages collaboration among universities, medical centers, US government, industry, patient advocacy groups, charitable foundations, and philanthropists, could significantly facilitate such advancements and contribute to the translation of nanotechnology across medical disciplines. PMID:20149882

Independent representation of parts and the relations between them: evidence from integrative agnosia.

PubMed

Behrmann, Marlene; Peterson, Mary A; Moscovitch, Morris; Suzuki, Satoru

2006-10-01

Whether objects are represented as a collection of parts whose relations are coded independently remains a topic of ongoing discussion among theorists in the domain of shape perception. S. M., an individual with integrative agnosia, and neurologically intact ("normal") individuals learned initially to identify 4 target objects constructed of 2 simple volumetric parts. At test, the targets were mixed with distractors, some of which could be discriminated from the targets on the basis of a mismatching part, whereas the rest could be discriminated only on the basis of the altered spatial arrangements of parts. S. M. learned to identify the target objects, although at a rate slower than that of the normal participants. At test, he correctly rejected distractors on the basis of mismatching parts but was profoundly impaired at rejecting distractors made of the same local components but with mismatching spatial arrangements. These results suggest that encoding the spatial arrangements of parts of an object requires a mechanism that is different from that required for encoding the shape of individual parts, with the former selectively compromised in integrative agnosia. Copyright 2006 APA.

Novel on-demand droplet generation for selective fluid sample extraction

PubMed Central

Lin, Robert; Fisher, Jeffery S.; Simon, Melinda G.; Lee, Abraham P.

2012-01-01

A novel microfluidic device enabling selective generation of droplets and encapsulation of targets is presented. Unlike conventional methods, the presented mechanism generates droplets with unique selectivity by utilizing a K-junction design. The K-junction is a modified version of the classic T-junction with an added leg that serves as the exit channel for waste. The dispersed phase fluid enters from one diagonal of the K and exits the other diagonal while the continuous phase travels in the straight leg of the K. The intersection forms an interface that allows the dispersed phase to be controllably injected through actuation of an elastomer membrane located above the inlet channel near the interface. We have characterized two critical components in controlling the droplet size—membrane actuation pressure and timing as well as identified the region of fluid in which the droplet will be formed. This scheme will have applications in fluid sampling processes and selective encapsulation of materials. Selective encapsulation of a single cell from the dispersed phase fluid is demonstrated as an example of functionality of this design. PMID:22655015

76 FR 19173 - Self-Regulatory Organizations; the Options Clearing Corporation; Order Granting Approval of...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-04-06

... Lawson, Senior Special Counsel, Division of Trading and Markets (``Division''), Commission, dated May 20... return--of two index components (the target component and the benchmark component). The index is calculated by measuring the total return of the target component relative to the total return of the...

76 FR 12942 - Proposed Information Collection; Comment Request; Defining Target Levels for Ecosystem Components...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-03-09

... Collection; Comment Request; Defining Target Levels for Ecosystem Components: A Socio-Ecological Approach... numerous species, and a mean level of species placement within a predator/prey chain or food web can serve...-based Management, when target levels for indicators exist. Because targets are an expression of the...

Identification of New Signaling Components in the Sensory Epithelium of Human Saccule

PubMed Central

Degerman, Eva; Rauch, Uwe; Göransson, Olga; Lindberg, Sven; Hultgårdh, Anna; Magnusson, Måns

2011-01-01

Objective: To locate components and target proteins of relevance for the cAMP and cGMP signaling networks including cAMP and cGMP phosphodiesterases (PDEs), salt-inducible kinases (SIKs), subunits of Na+, K+-ATPases, and aquaporins (AQPs) in the human saccule. Methods: The human saccule was dissected out during the removal of vestibular schwannoma via the translabyrinthine approach and immediately fixed. Immunohistochemistry was performed using PDE, SIK, Na+, K+-ATPase, and AQP antibodies. Results: PDEs selective for cAMP (PDE4A, PDE4D, and PDE8A) and cGMP (PDE9A) as well a dual specificity PDE (PDE10A) were detected in the sensory epithelium of the saccule. Furthermore, AQP2, 4, and 9, SIK1 and the α-1 subunit of the Na+, K+-ATPase were detected. Conclusion: cAMP and cGMP are important regulators of ion and water homeostasis in the inner ear. The identification of PDEs and SIK1 in the vestibular system offers new treatment targets for endolymphatic hydrops. Exactly how the PDEs are connected to SIK1 and the SIK1 substrate Na+, K+-ATPase and to AQPs 2, 4, 9 remains to be elucidated. The dissection of the signaling networks utilizing these components and evaluating their roles will add new basic knowledge regarding inner ear physiology. PMID:21886636

Targeting bacterial secretion systems: benefits of disarmament in the microcosm.

PubMed

Baron, Christian; Coombes, Brian

2007-03-01

Secretion systems are used by many bacterial pathogens for the delivery of virulence factors to the extracellular space or directly into host cells. They are attractive targets for the development of novel anti-virulence drugs as their inactivation would lead to pathogen attenuation or avirulence, followed by clearance of the bacteria by the immune system. This review will present the state of knowledge on the assembly and function of type II, type III and type IV secretion systems in Gram-negative bacteria focusing on insights provided by structural analyses of several key components. The suitability of transcription factors regulating the expression of secretion system components and of ATPases, lytic transglycosylases and protein assembly factors as drug targets will be discussed. Recent progress using innovative in vivo as well as in vitro screening strategies led to a first set of secretion system inhibitors with potential for further development as anti-infectives. The discovery of such inhibitors offers exciting and innovative opportunities to further develop these anti-virulence drugs into monotherapy or in combination with classical antibiotics. Bacterial growth per se would not be inhibited by such drugs so that the selection for mutations causing resistance could be reduced. Secretion system inhibitors may therefore avoid many of the problems associated with classical antibiotics and may constitute a valuable addition to our arsenal for the treatment of bacterial infections.

Measurement of the intrinsic electron neutrino component in the T2K neutrino beam with the ND280 detector

NASA Astrophysics Data System (ADS)

Abe, K.; Adam, J.; Aihara, H.; Akiri, T.; Andreopoulos, C.; Aoki, S.; Ariga, A.; Ariga, T.; Assylbekov, S.; Autiero, D.; Barbi, M.; Barker, G. J.; Barr, G.; Bass, M.; Batkiewicz, M.; Bay, F.; Bentham, S. W.; Berardi, V.; Berger, B. E.; Berkman, S.; Bertram, I.; Bhadra, S.; Blaszczyk, F. d. M.; Blondel, A.; Bojechko, C.; Bordoni, S.; Boyd, S. B.; Brailsford, D.; Bravar, A.; Bronner, C.; Buchanan, N.; Calland, R. G.; Caravaca Rodríguez, J.; Cartwright, S. L.; Castillo, R.; Catanesi, M. G.; Cervera, A.; Cherdack, D.; Christodoulou, G.; Clifton, A.; Coleman, J.; Coleman, S. J.; Collazuol, G.; Connolly, K.; Cremonesi, L.; Dabrowska, A.; Danko, I.; Das, R.; Davis, S.; de Perio, P.; De Rosa, G.; Dealtry, T.; Dennis, S. R.; Densham, C.; Di Lodovico, F.; Di Luise, S.; Drapier, O.; Duboyski, T.; Duffy, K.; Dufour, F.; Dumarchez, J.; Dytman, S.; Dziewiecki, M.; Emery, S.; Ereditato, A.; Escudero, L.; Finch, A. J.; Floetotto, L.; Friend, M.; Fujii, Y.; Fukuda, Y.; Furmanski, A. P.; Galymov, V.; Giffin, S.; Giganti, C.; Gilje, K.; Goeldi, D.; Golan, T.; Gomez-Cadenas, J. J.; Gonin, M.; Grant, N.; Gudin, D.; Hadley, D. R.; Haesler, A.; Haigh, M. D.; Hamilton, P.; Hansen, D.; Hara, T.; Hartz, M.; Hasegawa, T.; Hastings, N. C.; Hayato, Y.; Hearty, C.; Helmer, R. L.; Hierholzer, M.; Hignight, J.; Hillairet, A.; Himmel, A.; Hiraki, T.; Hirota, S.; Holeczek, J.; Horikawa, S.; Huang, K.; Ichikawa, A. K.; Ieki, K.; Ieva, M.; Ikeda, M.; Imber, J.; Insler, J.; Irvine, T. J.; Ishida, T.; Ishii, T.; Ives, S. J.; Iwai, E.; Iyogi, K.; Izmaylov, A.; Jacob, A.; Jamieson, B.; Johnson, R. A.; Jo, J. H.; Jonsson, P.; Jung, C. K.; Kabirnezhad, M.; Kaboth, A. C.; Kajita, T.; Kakuno, H.; Kameda, J.; Kanazawa, Y.; Karlen, D.; Karpikov, I.; Kearns, E.; Khabibullin, M.; Khotjantsev, A.; Kielczewska, D.; Kikawa, T.; Kilinski, A.; Kim, J.; Kisiel, J.; Kitching, P.; Kobayashi, T.; Koch, L.; Kolaceke, A.; Konaka, A.; Kormos, L. L.; Korzenev, A.; Koseki, K.; Koshio, Y.; Kreslo, I.; Kropp, W.; Kubo, H.; Kudenko, Y.; Kumaratunga, S.; Kurjata, R.; Kutter, T.; Lagoda, J.; Laihem, K.; Lamont, I.; Larkin, E.; Laveder, M.; Lawe, M.; Lazos, M.; Lee, K. P.; Lindner, T.; Lister, C.; Litchfield, R. P.; Longhin, A.; Ludovici, L.; Macaire, M.; Magaletti, L.; Mahn, K.; Malek, M.; Manly, S.; Marino, A. D.; Marteau, J.; Martin, J. F.; Maruyama, T.; Marzec, J.; Mathie, E. L.; Matveev, V.; Mavrokoridis, K.; Mazzucato, E.; McCarthy, M.; McCauley, N.; McFarland, K. S.; McGrew, C.; Metelko, C.; Mezzetto, M.; Mijakowski, P.; Miller, C. A.; Minamino, A.; Mineev, O.; Mine, S.; Missert, A.; Miura, M.; Monfregola, L.; Moriyama, S.; Mueller, Th. A.; Murakami, A.; Murdoch, M.; Murphy, S.; Myslik, J.; Nagasaki, T.; Nakadaira, T.; Nakahata, M.; Nakai, T.; Nakamura, K.; Nakayama, S.; Nakaya, T.; Nakayoshi, K.; Naples, D.; Nielsen, C.; Nirkko, M.; Nishikawa, K.; Nishimura, Y.; O'Keeffe, H. M.; Ohta, R.; Okumura, K.; Okusawa, T.; Oryszczak, W.; Oser, S. M.; Owen, R. A.; Oyama, Y.; Palladino, V.; Palomino, J.; Paolone, V.; Payne, D.; Perevozchikov, O.; Perkin, J. D.; Petrov, Y.; Pickard, L.; Pinzon Guerra, E. S.; Pistillo, C.; Plonski, P.; Poplawska, E.; Popov, B.; Posiadala, M.; Poutissou, J.-M.; Poutissou, R.; Przewlocki, P.; Quilain, B.; Radicioni, E.; Ratoff, P. N.; Ravonel, M.; Rayner, M. A. M.; Redij, A.; Reeves, M.; Reinherz-Aronis, E.; Retiere, F.; Robert, A.; Rodrigues, P. A.; Rojas, P.; Rondio, E.; Roth, S.; Rubbia, A.; Ruterbories, D.; Sacco, R.; Sakashita, K.; Sánchez, F.; Sato, F.; Scantamburlo, E.; Scholberg, K.; Schoppmann, S.; Schwehr, J.; Scott, M.; Seiya, Y.; Sekiguchi, T.; Sekiya, H.; Sgalaberna, D.; Shiozawa, M.; Short, S.; Shustrov, Y.; Sinclair, P.; Smith, B.; Smith, R. J.; Smy, M.; Sobczyk, J. T.; Sobel, H.; Sorel, M.; Southwell, L.; Stamoulis, P.; Steinmann, J.; Still, B.; Suda, Y.; Suzuki, A.; Suzuki, K.; Suzuki, S. Y.; Suzuki, Y.; Szeglowski, T.; Tacik, R.; Tada, M.; Takahashi, S.; Takeda, A.; Takeuchi, Y.; Tanaka, H. K.; Tanaka, H. A.; Tanaka, M. M.; Terhorst, D.; Terri, R.; Thompson, L. F.; Thorley, A.; Tobayama, S.; Toki, W.; Tomura, T.; Totsuka, Y.; Touramanis, C.; Tsukamoto, T.; Tzanov, M.; Uchida, Y.; Ueno, K.; Vacheret, A.; Vagins, M.; Vasseur, G.; Wachala, T.; Waldron, A. V.; Walter, C. W.; Wark, D.; Wascko, M. O.; Weber, A.; Wendell, R.; Wilkes, R. J.; Wilking, M. J.; Wilkinson, C.; Williamson, Z.; Wilson, J. R.; Wilson, R. J.; Wongjirad, T.; Yamada, Y.; Yamamoto, K.; Yanagisawa, C.; Yen, S.; Yershov, N.; Yokoyama, M.; Yuan, T.; Yu, M.; Zalewska, A.; Zalipska, J.; Zambelli, L.; Zaremba, K.; Ziembicki, M.; Zimmerman, E. D.; Zito, M.; Żmuda, J.; T2K Collaboration

2014-05-01

The T2K experiment has reported the first observation of the appearance of electron neutrinos in a muon neutrino beam. The main and irreducible background to the appearance signal comes from the presence in the neutrino beam of a small intrinsic component of electron neutrinos originating from muon and kaon decays. In T2K, this component is expected to represent 1.2% of the total neutrino flux. A measurement of this component using the near detector (ND280), located 280 m from the target, is presented. The charged current interactions of electron neutrinos are selected by combining the particle identification capabilities of both the time projection chambers and electromagnetic calorimeters of ND280. The measured ratio between the observed electron neutrino beam component and the prediction is 1.01±0.10 providing a direct confirmation of the neutrino fluxes and neutrino cross section modeling used for T2K neutrino oscillation analyses. Electron neutrinos coming from muons and kaons decay are also separately measured, resulting in a ratio with respect to the prediction of 0.68±0.30 and 1.10±0.14, respectively.

Target and Tissue Selectivity Prediction by Integrated Mechanistic Pharmacokinetic-Target Binding and Quantitative Structure Activity Modeling.

PubMed

Vlot, Anna H C; de Witte, Wilhelmus E A; Danhof, Meindert; van der Graaf, Piet H; van Westen, Gerard J P; de Lange, Elizabeth C M

2017-12-04

Selectivity is an important attribute of effective and safe drugs, and prediction of in vivo target and tissue selectivity would likely improve drug development success rates. However, a lack of understanding of the underlying (pharmacological) mechanisms and availability of directly applicable predictive methods complicates the prediction of selectivity. We explore the value of combining physiologically based pharmacokinetic (PBPK) modeling with quantitative structure-activity relationship (QSAR) modeling to predict the influence of the target dissociation constant (K D ) and the target dissociation rate constant on target and tissue selectivity. The K D values of CB1 ligands in the ChEMBL database are predicted by QSAR random forest (RF) modeling for the CB1 receptor and known off-targets (TRPV1, mGlu5, 5-HT1a). Of these CB1 ligands, rimonabant, CP-55940, and Δ 8 -tetrahydrocanabinol, one of the active ingredients of cannabis, were selected for simulations of target occupancy for CB1, TRPV1, mGlu5, and 5-HT1a in three brain regions, to illustrate the principles of the combined PBPK-QSAR modeling. Our combined PBPK and target binding modeling demonstrated that the optimal values of the K D and k off for target and tissue selectivity were dependent on target concentration and tissue distribution kinetics. Interestingly, if the target concentration is high and the perfusion of the target site is low, the optimal K D value is often not the lowest K D value, suggesting that optimization towards high drug-target affinity can decrease the benefit-risk ratio. The presented integrative structure-pharmacokinetic-pharmacodynamic modeling provides an improved understanding of tissue and target selectivity.

A Network Pharmacology Approach to Determine the Active Components and Potential Targets of Curculigo Orchioides in the Treatment of Osteoporosis.

PubMed

Wang, Nani; Zhao, Guizhi; Zhang, Yang; Wang, Xuping; Zhao, Lisha; Xu, Pingcui; Shou, Dan

2017-10-27

BACKGROUND Osteoporosis is a complex bone disorder with a genetic predisposition, and is a cause of health problems worldwide. In China, Curculigo orchioides (CO) has been widely used as a herbal medicine in the prevention and treatment of osteoporosis. However, research on the mechanism of action of CO is still lacking. The aim of this study was to identify the absorbable components, potential targets, and associated treatment pathways of CO using a network pharmacology approach. MATERIAL AND METHODS We explored the chemical components of CO and used the five main principles of drug absorption to identify absorbable components. Targets for the therapeutic actions of CO were obtained from the PharmMapper server database. Pathway enrichment analysis was performed using the Comparative Toxicogenomics Database (CTD). Cytoscape was used to visualize the multiple components-multiple target-multiple pathways-multiple disease network for CO. RESULTS We identified 77 chemical components of CO, of which 32 components could be absorbed in the blood. These potential active components of CO regulated 83 targets and affected 58 pathways. Data analysis showed that the genes for estrogen receptor alpha (ESR1) and beta (ESR2), and the gene for 11 beta-hydroxysteroid dehydrogenase type 1, or cortisone reductase (HSD11B1) were the main targets of CO. Endocrine regulatory factors and factors regulating calcium reabsorption, steroid hormone biosynthesis, and metabolic pathways were related to these main targets and to ten corresponding compounds. CONCLUSIONS The network pharmacology approach used in our study has attempted to explain the mechanisms for the effects of CO in the prevention and treatment of osteoporosis, and provides an alternative approach to the investigation of the effects of this complex compound.

Constitutional dynamic chemistry: bridge from supramolecular chemistry to adaptive chemistry.

PubMed

Lehn, Jean-Marie

2012-01-01

Supramolecular chemistry aims at implementing highly complex chemical systems from molecular components held together by non-covalent intermolecular forces and effecting molecular recognition, catalysis and transport processes. A further step consists in the investigation of chemical systems undergoing self-organization, i.e. systems capable of spontaneously generating well-defined functional supramolecular architectures by self-assembly from their components, thus behaving as programmed chemical systems. Supramolecular chemistry is intrinsically a dynamic chemistry in view of the lability of the interactions connecting the molecular components of a supramolecular entity and the resulting ability of supramolecular species to exchange their constituents. The same holds for molecular chemistry when the molecular entity contains covalent bonds that may form and break reversibility, so as to allow a continuous change in constitution by reorganization and exchange of building blocks. These features define a Constitutional Dynamic Chemistry (CDC) on both the molecular and supramolecular levels.CDC introduces a paradigm shift with respect to constitutionally static chemistry. The latter relies on design for the generation of a target entity, whereas CDC takes advantage of dynamic diversity to allow variation and selection. The implementation of selection in chemistry introduces a fundamental change in outlook. Whereas self-organization by design strives to achieve full control over the output molecular or supramolecular entity by explicit programming, self-organization with selection operates on dynamic constitutional diversity in response to either internal or external factors to achieve adaptation.The merging of the features: -information and programmability, -dynamics and reversibility, -constitution and structural diversity, points to the emergence of adaptive and evolutive chemistry, towards a chemistry of complex matter.

Genetic events in the progression of adenoid cystic carcinoma of the breast to high-grade triple-negative breast cancer.

PubMed

Fusco, Nicola; Geyer, Felipe C; De Filippo, Maria R; Martelotto, Luciano G; Ng, Charlotte K Y; Piscuoglio, Salvatore; Guerini-Rocco, Elena; Schultheis, Anne M; Fuhrmann, Laetitia; Wang, Lu; Jungbluth, Achim A; Burke, Kathleen A; Lim, Raymond S; Vincent-Salomon, Anne; Bamba, Masamichi; Moritani, Suzuko; Badve, Sunil S; Ichihara, Shu; Ellis, Ian O; Reis-Filho, Jorge S; Weigelt, Britta

2016-11-01

Adenoid cystic carcinoma of the breast is a rare histological type of triple-negative breast cancer with an indolent clinical behavior, often driven by the MYB-NFIB fusion gene. Here we sought to define the repertoire of somatic genetic alterations in two adenoid cystic carcinomas associated with high-grade triple-negative breast cancer. The different components of each case were subjected to copy number profiling and massively parallel sequencing targeting all exons and selected regulatory and intronic regions of 488 genes. Reverse transcription PCR and fluorescence in situ hybridization were employed to investigate the presence of the MYB-NFIB translocation. The MYB-NFIB fusion gene was detected in both adenoid cystic carcinomas and their associated high-grade triple-negative breast cancer components. Although the distinct components of both cases displayed similar patterns of gene copy number alterations, massively parallel sequencing analysis revealed intratumor genetic heterogeneity. In case 1, progression from the trabecular adenoid cystic carcinoma to the high-grade triple-negative breast cancer was found to involve clonal shifts with enrichment of mutations affecting EP300, NOTCH1, ERBB2 and FGFR1 in the high-grade triple-negative breast cancer. In case 2, a clonal KMT2C mutation was present in the cribriform adenoid cystic carcinoma, solid adenoid cystic carcinoma and high-grade triple-negative breast cancer components, whereas a mutation affecting MYB was present only in the solid and high-grade triple-negative breast cancer areas and additional three mutations targeting STAG2, KDM6A and CDK12 were restricted to the high-grade triple-negative breast cancer. In conclusion, adenoid cystic carcinomas of the breast with high-grade transformation are underpinned by the MYB-NFIB fusion gene and, akin to other forms of cancer, may be constituted by a mosaic of cancer cell clones at diagnosis. The progression from adenoid cystic carcinoma to high-grade triple-negative breast cancer of no special type may involve the selection of neoplastic clones and/or the acquisition of additional genetic alterations.

Genetic events in the progression of adenoid cystic carcinoma of the breast to high-grade triple-negative breast cancer

PubMed Central

Fusco, Nicola; Geyer, Felipe C; De Filippo, Maria R; Martelotto, Luciano G; Ng, Charlotte K Y; Piscuoglio, Salvatore; Guerini-Rocco, Elena; Schultheis, Anne M; Fuhrmann, Laetitia; Wang, Lu; Jungbluth, Achim A; Burke, Kathleen A; Lim, Raymond S; Vincent-Salomon, Anne; Bamba, Masamichi; Moritani, Suzuko; Badve, Sunil S; Ichihara, Shu; Ellis, Ian O; Reis-Filho, Jorge S; Weigelt, Britta

2016-01-01

Adenoid cystic carcinoma of the breast is a rare histologic type of triple-negative breast cancer with an indolent clinical behavior, often driven by the MYB-NFIB fusion gene. Here we sought to define the repertoire of somatic genetic alterations in two adenoid cystic carcinomas associated with high-grade triple-negative breast cancer. The different components of each case were subjected to copy number profiling and massively parallel sequencing targeting all exons and selected regulatory and intronic regions of 488 genes. Reverse transcription PCR and fluorescence in situ hybridization were employed to investigate the presence of the MYB-NFIB translocation. The MYB-NFIB fusion gene was detected in both adenoid cystic carcinomas and their associated high-grade triple-negative breast cancer components. Whilst the distinct components of both cases displayed similar patterns of gene copy number alterations, massively parallel sequencing analysis revealed intra-tumor genetic heterogeneity. In case 1, progression from the trabecular adenoid cystic carcinoma to the high-grade triple-negative breast cancer was found to involve clonal shifts with enrichment of mutations affecting EP300, NOTCH1, ERBB2 and FGFR1 in the high-grade triple-negative breast cancer. In case 2, a clonal KMT2C mutation was present in the cribriform adenoid cystic carcinoma, solid adenoid cystic carcinoma and high-grade triple-negative breast cancer components, whereas a mutation affecting MYB was present only in the solid and high-grade triple-negative breast cancer areas and additional three mutations targeting STAG2, KDM6A and CDK12 were restricted to the high-grade triple-negative breast cancer. In conclusion, adenoid cystic carcinomas of the breast with high-grade transformation are underpinned by MYB-NFIB fusion gene, and, akin to other forms of cancer, may be constituted by a mosaic of cancer cell clones at diagnosis. The progression from adenoid cystic carcinoma to high-grade triple-negative breast cancer of no special type may involve the selection of neoplastic clones and/ or the acquisition of additional genetic alterations. PMID:27491809

Phenotypic selection to increase floral scent emission, but not flower size or colour in bee-pollinated Penstemon digitalis.

PubMed

Parachnowitsch, Amy L; Raguso, Robert A; Kessler, André

2012-08-01

Fragrance is a putatively important character in the evolution of flowering plants, but natural selection on scent is rarely studied and thus poorly understood. We characterized floral scent composition and emission in a common garden of Penstemon digitalis from three nearby source populations. We measured phenotypic selection on scent as well as floral traits more frequently examined, such as floral phenology, display size, corolla pigment, and inflorescence height. Scent differed among populations in a common garden, underscoring the potential for scent to be shaped by differential selection pressures. Phenotypic selection on flower number and display size was strong. However, selection favoured scent rather than flower size or colour, suggesting that smelling stronger benefits reproductive success in P. digitalis. Linalool was a direct target of selection and its high frequency in floral-scent bouquets suggests that further studies of both pollinator- and antagonist-mediated selection on this compound would further our understanding of scent evolution. Our results indicate that chemical dimensions of floral display are just as likely as other components to experience selective pressure in a nonspecialized flowering herb. Therefore, studies that integrate visual and chemical floral traits should better reflect the true nature of floral evolutionary ecology. © 2012 The Authors. New Phytologist © 2012 New Phytologist Trust.

Identifying the control structure of multijoint coordination during pistol shooting.

PubMed

Scholz, J P; Schöner, G; Latash, M L

2000-12-01

The question of degrees of freedom in the control of multijoint movement is posed as the problem of discovering how the motor control system constrains the many possible combinations of joint postures to stabilize task-dependent essential variables. Success at a task can be achieved, in principle, by always adopting a particular joint combination. In contrast, we propose a more selective control strategy: variations of the joint configuration that leave the values of essential task variables unchanged are predicted to be less controlled (i.e., stabilized to a lesser degree) than joint configuration changes that shift the values of the task variables. Our experimental task involved shooting with a laser pistol at a target under four conditions. The seven joint angles of the arm were obtained from the recorded positions of markers on the limb segments. The joint configurations observed at each point in normalized time were analyzed with respect to trial-to-trial variability. Different hypotheses about relevant task variables were used to define sets of joint configurations ("uncontrolled manifolds" or UCMs) that, if realized, would leave essential task variables unchanged. The variability of joint configurations was decomposed into components lying parallel to those sets and components lying in their complement. The orientation of the gun's barrel relative to a vector pointing from the gun to the target was the task variable most successful at showing a difference between the two components of joint variability. This variable determines success at the task. Throughout the movement, not only while the gun was pointing at the target, fluctuations of joint configuration that affected this variable were much reduced compared with fluctuations that did not affect this variable. The UCM principle applied to relative gun orientation thus captures the structure of the motor control system across different parts of joint configuration space as the movement evolves in time. This suggests a specific control strategy in which changes of joint configuration that are irrelevant to success at the task are selectively released from control. By contrast, constraints representing an invariant spatial position of the gun or of the arm's center of mass structured joint configuration variability in the early and mid-portion of the movement trajectory, but not at the time of shooting. This specific control strategy is not trivial, because a target can be hit successfully also by controlling irrelevant directions in joint space equally to relevant ones. The results indicate that the method can be successfully used to determine the structure of coordination in joint space that underlies the control of the essential variables for a given task.

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

Johnson, Francis

A team led by GE Global Research developed new magnetic refrigerant materials needed to enhance the commercialization potential of residential appliances such as refrigerators and air conditioners based on the magnetocaloric effect (a nonvapor compression cooling cycle). The new magnetic refrigerant materials have potentially better performance at lower cost than existing materials, increasing technology readiness level. The performance target of the new magnetocaloric material was to reduce the magnetic field needed to achieve 4 °C adiabatic temperature change from 1.5 Tesla to 0.75 Tesla. Such a reduction in field minimizes the cost of the magnet assembly needed for a magneticmore » refrigerator. Such a reduction in magnet assembly cost is crucial to achieving commercialization of magnetic refrigerator technology. This project was organized as an iterative alloy development effort with a parallel material modeling task being performed at George Washington University. Four families of novel magnetocaloric alloys were identified, screened, and assessed for their performance potential in a magnetic refrigeration cycle. Compositions from three of the alloy families were manufactured into regenerator components. At the beginning of the project a previously studied magnetocaloric alloy was selected for manufacturing into the first regenerator component. Each of the regenerators was tested in magnetic refrigerator prototypes at a subcontractor at at GE Appliances. The property targets for operating temperature range, operating temperature control, magnetic field sensitivity, and corrosion resistance were met. The targets for adiabatic temperature change and thermal hysteresis were not met. The high thermal hysteresis also prevented the regenerator components from displaying measurable cooling power when tested in prototype magnetic refrigerators. Magnetic refrigerant alloy compositions that were predicted to have low hysteresis were not attainable with conventional alloy processing methods. Preliminary experiments with rapid solidification methods showed a path towards attaining low hysteresis compositions should this alloy development effort be continued.« less

Clast Selection and Metallographic Cooling Rates: Initial Results on Type 1A and 2A Mesosiderites

NASA Technical Reports Server (NTRS)

Baecker, B.; Cohen, B. A.; Rubin, A. E.; Frasl, B.; Corrigan, C. M.

2017-01-01

We initiated a comprehensive study on selected clasts and metal of mesosiderites using SEM, electron microprobe and the complete suite of noble gases. Here we report initial results on the petrography of selected clasts and metallographic cooling rates using the central Ni method used in sev-eral publications. We focus on the approach of selecting grains in least recrystallized mesosiderites. Hence, especially (lithic) clasts in type 1A, 1B, 2A and 2B are the first choice. They provide highest primitive-ness and least annealing/metamorphism. All grains selected should be in close proximity to each other. Lithic clasts in mesosiderites are of high interest be-cause of their igneous texture and similarity to eucrites and howardite petrography. We find pyrox-enes (px) and plagioclase (plag) attached to each other which implies a common formation history. It will be interesting to see differences and similarities in their noble gas inventory (CRE ages, trapped components and closure temperature). In addition, we will investi-gate variations of the lithic clasts toward similar grains in the thick sections which are not igneous. Plag grains are the best bases for noble gas measurements con-cerning He to Ar and Ar-Ar dating since it delivers im-portant target elements. We focus on plag grains in close contact to olivine (olv) / px grains to assess weth-er both grains show noble gas patterns being similar or different. Phosphate grains are suitable for Kr and Xe measurements since they yield REE abundances (tar-get elements).

Fast data transmission in dynamic data acquisition system for plasma diagnostics

NASA Astrophysics Data System (ADS)

Byszuk, Adrian; Poźniak, Krzysztof; Zabołotny, Wojciech M.; Kasprowicz, Grzegorz; Wojeński, Andrzej; Cieszewski, Radosław; Juszczyk, Bartłomiej; Kolasiński, Piotr; Zienkiewicz, Paweł; Chernyshova, Maryna; Czarski, Tomasz

2014-11-01

This paper describes architecture of a new data acquisition system (DAQ) targeted mainly at plasma diagnostic experiments. Modular architecture, in combination with selected hardware components, allows for straightforward reconfiguration of the whole system, both offline and online. Main emphasis will be put into the implementation of data transmission subsystem in said system. One of the biggest advantages of described system is modular architecture with well defined boundaries between main components: analog frontend (AFE), digital backplane and acquisition/control software. Usage of a FPGA chips allows for a high flexibility in design of analog frontends, including ADC <--> FPGA interface. Data transmission between backplane boards and user software was accomplished with the use of industry-standard PCI Express (PCIe) technology. PCIe implementation includes both FPGA firmware and Linux device driver. High flexibility of PCIe connections was accomplished due to use of configurable PCIe switch. Whenever it's possible, described DAQ system tries to make use of standard off-the-shelf (OTF) components, including typical x86 CPU & motherboard (acting as PCIe controller) and cabling.

The role of probiotics on each component of the metabolic syndrome and other cardiovascular risks.

PubMed

Miglioranza Scavuzzi, Bruna; Miglioranza, Lucia Helena da Silva; Henrique, Fernanda Carla; Pitelli Paroschi, Thanise; Lozovoy, Marcell Alysson Batisti; Simão, Andréa Name Colado; Dichi, Isaias

2015-01-01

Probiotics are defined as live microorganisms that when administered in adequate amounts confer health benefits to the host. The consumption of probiotics has gained increasing recognition from the scientific community due to the promising effects on metabolic health through gut microbiota modulation. This article presents a review of scientific studies investigating probiotic species and their effects on different risk factors of the metabolic syndrome (MetS). This article also presents a summary of the major mechanisms involved with gut microbiota and the components of the MetS and raises the key issues to be considered by scientists in search of probiotics species for treatment of patients suffering from this metabolic disorder. Probiotics may confer numerous health benefits to the host through positive gut microbiota modulation. The strain selection is the most important factor for determining health effects. Further studies may consider gut microbiota as a novel target for prevention and management of MetS components and other cardiovascular risks.

On-rail solution for autonomous inspections in electrical substations

NASA Astrophysics Data System (ADS)

Silva, Bruno P. A.; Ferreira, Rafael A. M.; Gomes, Selson C.; Calado, Flavio A. R.; Andrade, Roberto M.; Porto, Matheus P.

2018-05-01

This work presents an alternative solution for autonomous inspections in electrical substations. The autonomous system is a robot that moves on rails, collects infrared and visible images of selected targets, also processes the data and predicts the components lifetime. The robot moves on rails to overcome difficulties found in not paved substations commonly encountered in Brazil. We take advantage of using rails to convey the data by them, minimizing the electromagnetic interference, and at the same time transmitting electrical energy to feed the autonomous system. As part of the quality control process, we compared thermographic inspections made by the robot with inspections made by a trained thermographer using a scientific camera Flir® SC660. The results have shown that the robot achieved satisfactory results, identifying components and measuring temperature accurately. The embodied routine considers the weather changes along the day, providing a standard result of the components thermal response, also gives the uncertainty of temperature measurement, contributing to the quality in the decision making process.

Differential Regulation of CYP3A4 and CYP3A5 and Its Implication in Drug Discovery

PubMed Central

Lolodi, Ogheneochukome; Wang, Yue-Ming; Wright, William C.; Chen, Taosheng

2017-01-01

Cancer cells use several mechanisms to resist the cytotoxic effects of drugs, resulting in tumor progression and invasion. One such mechanism capitalizes on the body’s natural defense against xenobiotics by increasing the rate of xenobiotic efflux and metabolic inactivation. Xenobiotic metabolism typically involves conversion of parent molecules to more soluble and easily excreted derivatives in reactions catalyzed by Phase I and Phase II drug metabolizing enzymes. Recent reports indicate that components of the xenobiotic response system are upregulated in some diseases, including many cancers. Such components include the pregnane X receptor (PXR) and the cytochrome P450 (CYP) 3A4 and 3A5 enzymes. The CYP3A enzymes are a subset of the numerous enzymes that are transcriptionally activated following the interaction of PXR and many ligands. Intense research is ongoing to understand the functional ramifications of aberrant expression of these components in diseased states with the goal of designing novel drugs that can selectively target them. PMID:28558634

Novel, Biocompatible, Disease Modifying Nanomedicine of VIP for Rheumatoid Arthritis

PubMed Central

Sethi, Varun; Rubinstein, Israel; Kuzmis, Antonina; Kastrissios, Helen; Artwohl, James; Onyuksel, Hayat

2013-01-01

Despite advances in rheumatoid arthritis (RA) treatment, efficacious and safe disease-modifying therapy still represents an unmet medical need. Here we describe an innovative strategy to treat RA by targeting low doses of vasoactive intestinal peptide (VIP) self-associated with sterically stabilized micelles (SSMs). This spontaneous interaction of VIP with SSM protects the peptide from degradation or inactivation in biological fluids and prolongs circulation half-life. Treatment with targeted low doses of nano-sized SSM-VIP but not free VIP in buffer significantly reduced incidence and severity of arthritis in an experimental model, completely abrogating joint swelling and destruction of cartilage and bone. In addition, SSM associated VIP unlike free VIP had no side-effects on the systemic functions due to selective targeting to inflamed joints. Finally, low doses of VIP in SSM successfully downregulated both inflammatory and autoimmune components of RA. Collectively, our data clearly indicate that VIP-SSM should be developed to be used as a novel nanomedicine for the treatment of RA. PMID:23211088

Changing resident test ordering behavior: a multilevel intervention to decrease laboratory utilization at an academic medical center.

PubMed

Vidyarthi, Arpana R; Hamill, Timothy; Green, Adrienne L; Rosenbluth, Glenn; Baron, Robert B

2015-01-01

Hospital laboratory test volume is increasing, and overutilization contributes to errors and costs. Efforts to reduce laboratory utilization have targeted aspects of ordering behavior, but few have utilized a multilevel collaborative approach. The study team partnered with residents to reduce unnecessary laboratory tests and associated costs through multilevel interventions across the academic medical center. The study team selected laboratory tests for intervention based on cost, volume, and ordering frequency (complete blood count [CBC] and CBC with differential, common electrolytes, blood enzymes, and liver function tests). Interventions were designed collaboratively with residents and targeted components of ordering behavior, including system changes, teaching, social marketing, academic detailing, financial incentives, and audit/feedback. Laboratory ordering was reduced by 8% cumulatively over 3 years, saving $2 019 000. By involving residents at every stage of the intervention and targeting multiple levels simultaneously, laboratory utilization was reduced and cost savings were sustained over 3 years. © 2014 by the American College of Medical Quality.

The control system of the polarized internal target of ANKE at COSY

NASA Astrophysics Data System (ADS)

Kleines, H.; Sarkadi, J.; Zwoll, K.; Engels, R.; Grigoryev, K.; Mikirtychyants, M.; Nekipelov, M.; Rathmann, F.; Seyfarth, H.; Kravtsov, P.; Vasilyev, A.

2006-05-01

The polarized internal target for the ANKE experiment at the Cooler Synchrotron COSY of the Forschungszentrum Jülich utilizes a polarized atomic beam source to feed a storage cell with polarized hydrogen or deuterium atoms. The nuclear polarization is measured with a Lamb-shift polarimeter. For common control of the two systems, industrial equipment was selected providing reliable, long-term support and remote control of the target as well as measurement and optimization of its operating parameters. The interlock system has been implemented on the basis of SIEMENS SIMATIC S7-300 family of programmable logic controllers. In order to unify the interfacing to the control computer, all front-end equipment is connected via the PROFIBUS DP fieldbus. The process control software was implemented using the Windows-based WinCC toolkit from SIEMENS. The variety of components, to be controlled, and the logical structure of the control and interlock system are described. Finally, a number of applications derived from the present development to other, new installations are briefly mentioned.

Performance Characterization of the Production Facility Prototype Helium Flow System

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

Woloshun, Keith Albert; Dale, Gregory E.; Dalmas, Dale Allen

2015-12-16

The roots blower in use at ANL for in-beam experiments and also at LANL for flow tests was sized for 12 mm diameter disks and significantly less beam heating. Currently, the disks are 29 mm in diameter, with a 12 mm FWHM Gaussian beam spot at 42 MeV and 2.86 μA on each side of the target, 5.72 μA total. The target design itself is reported elsewhere. With the increased beam heating, the helium flow requirement increased so that a larger blower was need for a mass flow rate of 400 g/s at 2.76 MPa (400 psig). An Aerzen GMmore » 12.4 blower was selected, and is currently being installed at the LANL facility for target and component flow testing. This report describes this blower/motor/pressure vessel package and the status of the facility preparations. Blower performance (mass flow rate as a function of loop pressure drop) was measured at 4 blower speeds. Results are reported below.« less

Molecular-targeted antitumor agents. 19. Furospongolide from a marine Lendenfeldia sp. sponge inhibits hypoxia-inducible factor-1 activation in breast tumor cells.

PubMed

Liu, Yang; Liu, Rui; Mao, Shui-Chun; Morgan, J Brian; Jekabsons, Mika B; Zhou, Yu-Dong; Nagle, Dale G

2008-11-01

A natural product chemistry-based approach was employed to discover small-molecule inhibitors of the important tumor-selective molecular target hypoxia-inducible factor-1 (HIF-1). Bioassay-guided isolation of an active lipid extract of a Saipan collection of the marine sponge Lendenfeldia sp. afforded the terpene-derived furanolipid furospongolide as the primary inhibitor of hypoxia-induced HIF-1 activation (IC(50) 2.9 μM, T47D breast tumor cells). The active component of the extract also contained one new cytotoxic scalarane sesterterpene and two previously reported scalaranes. Furospongolide blocked the induction of the downstream HIF-1 target secreted vascular endothelial growth factor (VEGF) and was shown to suppress HIF-1 activation by inhibiting the hypoxic induction of HIF-1α protein. Mechanistic studies indicate that furospongolide inhibits HIF-1 activity primarily by suppressing tumor cell respiration via the blockade of NADH-ubiquinone oxidoreductase (complex I)-mediated mitochondrial electron transfer.

Inspection with Robotic Microscopic Imaging

NASA Technical Reports Server (NTRS)

Pedersen, Liam; Deans, Matthew; Kunz, Clay; Sargent, Randy; Chen, Alan; Mungas, Greg

2005-01-01

Future Mars rover missions will require more advanced onboard autonomy for increased scientific productivity and reduced mission operations cost. One such form of autonomy can be achieved by targeting precise science measurements to be made in a single command uplink cycle. In this paper we present an overview of our solution to the subproblems of navigating a rover into place for microscopic imaging, mapping an instrument target point selected by an operator using far away science camera images to close up hazard camera images, verifying the safety of placing a contact instrument on a sample or finding nearby safe points, and analyzing the data that comes back from the rover. The system developed includes portions used in the Multiple Target Single Cycle Instrument Placement demonstration at NASA Ames in October 2004, and portions of the MI Toolkit delivered to the Athena Microscopic Imager Instrument Team for the MER mission still operating on Mars today. Some of the component technologies are also under consideration for MSL mission infusion.

Human centromedian-parafascicular complex signals sensory cues for goal-oriented behavior selection.

PubMed

Schepers, Inga M; Beck, Anne-Kathrin; Bräuer, Susann; Schwabe, Kerstin; Abdallat, Mahmoud; Sandmann, Pascale; Dengler, Reinhard; Rieger, Jochem W; Krauss, Joachim K

2017-05-15

Experimental research has shown that the centromedian-parafascicular complex (CM-Pf) of the intralaminar thalamus is activated in attentional orienting and processing of behaviorally relevant stimuli. These observations resulted in the hypothesis that the CM-Pf plays a pivotal role in goal-oriented behavior selection. We here set out to test this hypothesis with electrophysiological recordings from patients with electrodes implanted in CM-Pf for deep brain stimulation (DBS) treatment of chronic neuropathic pain. Six patients participated in (1) an auditory three-class oddball experiment, which required a button press to target tones, but not to standard and deviant tones and in (2) a multi-speaker experiment with a target word that required attention selection and a target image that required response selection. Subjects showed transient neural responses (8-15Hz) to the target tone and the target word. Two subjects additionally showed transient neural responses (15-25Hz) to the target image. All sensory target stimuli were related to an internal goal and required a behavior selection (attention selection, response selection). In group analyses, neural responses were greater to target tones than deviant and standard tones and to target words than other task-relevant words that did not require attention selection. The transient neural responses occurred after the target stimuli but prior to the overt behavioral response. Our results demonstrate that in human subjects the CM-Pf is involved in signaling sensory inputs related to goal-oriented selection of behavior. Copyright © 2017 Elsevier Inc. All rights reserved.

Low-frequency repetitive transcranial magnetic stimulation (rTMS) affects event-related potential measures of novelty processing in autism.

PubMed

Sokhadze, Estate; Baruth, Joshua; Tasman, Allan; Mansoor, Mehreen; Ramaswamy, Rajesh; Sears, Lonnie; Mathai, Grace; El-Baz, Ayman; Casanova, Manuel F

2010-06-01

In our previous study on individuals with autism spectrum disorder (ASD) (Sokhadze et al., Appl Psychophysiol Biofeedback 34:37-51, 2009a) we reported abnormalities in the attention-orienting frontal event-related potentials (ERP) and the sustained-attention centro-parietal ERPs in a visual oddball experiment. These results suggest that individuals with autism over-process information needed for the successful differentiation of target and novel stimuli. In the present study we examine the effects of low-frequency, repetitive Transcranial Magnetic Stimulation (rTMS) on novelty processing as well as behavior and social functioning in 13 individuals with ASD. Our hypothesis was that low-frequency rTMS application to dorsolateral prefrontal cortex (DLFPC) would result in an alteration of the cortical excitatory/inhibitory balance through the activation of inhibitory GABAergic double bouquet interneurons. We expected to find post-TMS differences in amplitude and latency of early and late ERP components. The results of our current study validate the use of low-frequency rTMS as a modulatory tool that altered the disrupted ratio of cortical excitation to inhibition in autism. After rTMS the parieto-occipital P50 amplitude decreased to novel distracters but not to targets; also the amplitude and latency to targets increased for the frontal P50 while decreasing to non-target stimuli. Low-frequency rTMS minimized early cortical responses to irrelevant stimuli and increased responses to relevant stimuli. Improved selectivity in early cortical responses lead to better stimulus differentiation at later-stage responses as was made evident by our P3b and P3a component findings. These results indicate a significant change in early, middle-latency and late ERP components at the frontal, centro-parietal, and parieto-occipital regions of interest in response to target and distracter stimuli as a result of rTMS treatment. Overall, our preliminary results show that rTMS may prove to be an important research tool or treatment modality in addressing the stimulus hypersensitivity characteristic of autism spectrum disorders.

Targeted versus statistical approaches to selecting parameters for modelling sediment provenance

NASA Astrophysics Data System (ADS)

Laceby, J. Patrick

2017-04-01

One effective field-based approach to modelling sediment provenance is the source fingerprinting technique. Arguably, one of the most important steps for this approach is selecting the appropriate suite of parameters or fingerprints used to model source contributions. Accordingly, approaches to selecting parameters for sediment source fingerprinting will be reviewed. Thereafter, opportunities and limitations of these approaches and some future research directions will be presented. For properties to be effective tracers of sediment, they must discriminate between sources whilst behaving conservatively. Conservative behavior is characterized by constancy in sediment properties, where the properties of sediment sources remain constant, or at the very least, any variation in these properties should occur in a predictable and measurable way. Therefore, properties selected for sediment source fingerprinting should remain constant through sediment detachment, transportation and deposition processes, or vary in a predictable and measurable way. One approach to select conservative properties for sediment source fingerprinting is to identify targeted tracers, such as caesium-137, that provide specific source information (e.g. surface versus subsurface origins). A second approach is to use statistical tests to select an optimal suite of conservative properties capable of modelling sediment provenance. In general, statistical approaches use a combination of a discrimination (e.g. Kruskal Wallis H-test, Mann-Whitney U-test) and parameter selection statistics (e.g. Discriminant Function Analysis or Principle Component Analysis). The challenge is that modelling sediment provenance is often not straightforward and there is increasing debate in the literature surrounding the most appropriate approach to selecting elements for modelling. Moving forward, it would be beneficial if researchers test their results with multiple modelling approaches, artificial mixtures, and multiple lines of evidence to provide secondary support to their initial modelling results. Indeed, element selection can greatly impact modelling results and having multiple lines of evidence will help provide confidence when modelling sediment provenance.

Visuospatial Asymmetries Arise from Differences in the Onset Time of Perceptual Evidence Accumulation.

PubMed

Newman, Daniel P; Loughnane, Gerard M; Kelly, Simon P; O'Connell, Redmond G; Bellgrove, Mark A

2017-03-22

Healthy subjects tend to exhibit a bias of visual attention whereby left hemifield stimuli are processed more quickly and accurately than stimuli appearing in the right hemifield. It has long been held that this phenomenon arises from the dominant role of the right cerebral hemisphere in regulating attention. However, methods that would enable more precise understanding of the mechanisms underpinning visuospatial bias have remained elusive. We sought to finely trace the temporal evolution of spatial biases by leveraging a novel bilateral dot motion detection paradigm. In combination with electroencephalography, this paradigm enables researchers to isolate discrete neural signals reflecting the key neural processes needed for making these detection decisions. These include signals for spatial attention, early target selection, evidence accumulation, and motor preparation. Using this method, we established that three key neural markers accounted for unique between-subject variation in visuospatial bias: hemispheric asymmetry in posterior α power measured before target onset, which is related to the distribution of preparatory attention across the visual field; asymmetry in the peak latency of the early N2c target-selection signal; and, finally, asymmetry in the onset time of the subsequent neural evidence-accumulation process with earlier onsets for left hemifield targets. Our development of a single paradigm to dissociate distinct processing components that track the temporal evolution of spatial biases not only advances our understanding of the neural mechanisms underpinning normal visuospatial attention bias, but may also in the future aid differential diagnoses in disorders of spatial attention. SIGNIFICANCE STATEMENT The significance of this research is twofold. First, it shows that individual differences in how humans direct their attention between left and right space reflects physiological differences in how early the brain starts to accumulate evidence for the existence of a visual target. Second, the novel methods developed here may have particular relevance to disorders of attention, such as unilateral spatial neglect. In the case of spatial neglect, pathological inattention to left space could have multiple underlying causes, including biased attention, impaired decision formation, or a motor deficit related to one side of space. Our development of a single paradigm to dissociate each of these components may aid in supporting more precise differential diagnosis in such heterogeneous disorders. Copyright © 2017 the authors 0270-6474/17/373378-08$15.00/0.

FIRESTORM: a collaborative network suite application for rapid sensor data processing and precise decisive responses

NASA Astrophysics Data System (ADS)

Kaniyantethu, Shaji

2011-06-01

This paper discusses the many features and composed technologies in Firestorm™ - a Distributed Collaborative Fires and Effects software. Modern response management systems capitalize on the capabilities of a plethora of sensors and its output for situational awareness. Firestorm utilizes a unique networked lethality approach by integrating unmanned air and ground vehicles to provide target handoff and sharing of data between humans and sensors. The system employs Bayesian networks for track management of sensor data, and distributed auction algorithms for allocating targets and delivering the right effect without information overload to the Warfighter. Firestorm Networked Effects Component provides joint weapon-target pairing, attack guidance, target selection standards, and other fires and effects components. Moreover, the open and modular architecture allows for easy integration with new data sources. Versatility and adaptability of the application enable it to devise and dispense a suitable response to a wide variety of scenarios. Recently, this application was used for detecting and countering a vehicle intruder with the help of radio frequency spotter sensor, command driven cameras, remote weapon system, portable vehicle arresting barrier, and an unmanned aerial vehicle - which confirmed the presence of the intruder, as well as provided lethal/non-lethal response and battle damage assessment. The completed demonstrations have proved Firestorm's™ validity and feasibility to predict, detect, neutralize, and protect key assets and/or area against a variety of possible threats. The sensors and responding assets can be deployed with numerous configurations to cover the various terrain and environmental conditions, and can be integrated to a number of platforms.

Validating An Analytic Completeness Model for Kepler Target Stars Based on Flux-level Transit Injection Experiments

NASA Astrophysics Data System (ADS)

Catanzarite, Joseph; Burke, Christopher J.; Li, Jie; Seader, Shawn; Haas, Michael R.; Batalha, Natalie; Henze, Christopher; Christiansen, Jessie; Kepler Project, NASA Advanced Supercomputing Division

2016-06-01

The Kepler Mission is developing an Analytic Completeness Model (ACM) to estimate detection completeness contours as a function of exoplanet radius and period for each target star. Accurate completeness contours are necessary for robust estimation of exoplanet occurrence rates.The main components of the ACM for a target star are: detection efficiency as a function of SNR, the window function (WF) and the one-sigma depth function (OSDF). (Ref. Burke et al. 2015). The WF captures the falloff in transit detection probability at long periods that is determined by the observation window (the duration over which the target star has been observed). The OSDF is the transit depth (in parts per million) that yields SNR of unity for the full transit train. It is a function of period, and accounts for the time-varying properties of the noise and for missing or deweighted data.We are performing flux-level transit injection (FLTI) experiments on selected Kepler target stars with the goal of refining and validating the ACM. “Flux-level” injection machinery inserts exoplanet transit signatures directly into the flux time series, as opposed to “pixel-level” injection, which inserts transit signatures into the individual pixels using the pixel response function. See Jie Li's poster: ID #2493668, "Flux-level transit injection experiments with the NASA Pleiades Supercomputer" for details, including performance statistics.Since FLTI is affordable for only a small subset of the Kepler targets, the ACM is designed to apply to most Kepler target stars. We validate this model using “deep” FLTI experiments, with ~500,000 injection realizations on each of a small number of targets and “shallow” FLTI experiments with ~2000 injection realizations on each of many targets. From the results of these experiments, we identify anomalous targets, model their behavior and refine the ACM accordingly.In this presentation, we discuss progress in validating and refining the ACM, and we compare our detection efficiency curves with those derived from the associated pixel-level transit injection experiments.Kepler was selected as the 10th mission of the Discovery Program. Funding for this mission is provided by NASA, Science Mission Directorate.

Insights into the structural/conformational requirements of cytotoxic oxadiazoles as potential chemotherapeutic target binding agents

NASA Astrophysics Data System (ADS)

Alikhani, Radin; Razzaghi-Asl, Nima; Ramazani, Ali; Hosseinzadeh, Zahra

2018-07-01

A few novel previously synthesized 2,5-disubstituted 1,3,4-oxadiazoles with cytotoxic activity (1-17) were subjected to combined docking/quantum mechanical studies against chemotherapeutic targets. Selected macromolecular targets were those that were previously known to be inhibited by 1,3,4-oxadiazoles. Within this work, favorable binding modes/affinities of the oxadiazoles toward validated cancer targets were elucidated. Some oxadiazole structures exhibited ΔGbs comparable to or stronger than crystallographic ligands that were previously demonstrated to inhibit such targets. On the basis of obtained results, a general structure activity/binding relationship (SAR/SBR) was developed and a few 2,5-disubstituted 1,3,4-oxadiazole structures were proposed and virtually validated as potential cytotoxic candidates. To get more insight into structure binding relationship of candidate molecules within best correlated targets, docked conformation of the best in silico in vitro correlated oxadiazole structure was analyzed in terms of intermolecular binding energy components by functional B3LYP in association with split valence basis set using polarization functions (Def2-SVP). We believe that such modeling studies may be complementary to our previous results on the synthesis and cytotoxicity assessment of novel 1,3,4-oxadiazole derivatives through extending the scope of privileged structures toward designing new potential anti-tumor compounds.

Intracellular Delivery System for Antibody–Peptide Drug Conjugates

PubMed Central

Berguig, Geoffrey Y; Convertine, Anthony J; Frayo, Shani; Kern, Hanna B; Procko, Erik; Roy, Debashish; Srinivasan, Selvi; Margineantu, Daciana H; Booth, Garrett; Palanca-Wessels, Maria Corinna; Baker, David; Hockenbery, David; Press, Oliver W; Stayton, Patrick S

2015-01-01

Antibodies armed with biologic drugs could greatly expand the therapeutic potential of antibody–drug conjugates for cancer therapy, broadening their application to disease targets currently limited by intracellular delivery barriers. Additional selectivity and new therapeutic approaches could be realized with intracellular protein drugs that more specifically target dysregulated pathways in hematologic cancers and other malignancies. A multifunctional polymeric delivery system for enhanced cytosolic delivery of protein drugs has been developed that incorporates endosomal-releasing activity, antibody targeting, and a biocompatible long-chain ethylene glycol component for optimized safety, pharmacokinetics, and tumor biodistribution. The pH-responsive polymeric micelle carrier, with an internalizing anti-CD22 monoclonal targeting antibody, effectively delivered a proapoptotic Bcl-2 interacting mediator (BIM) peptide drug that suppressed tumor growth for the duration of treatment and prolonged survival in a xenograft mouse model of human B-cell lymphoma. Antitumor drug activity was correlated with a mechanistic induction of the Bcl-2 pathway biomarker cleaved caspase-3 and a marked decrease in the Ki-67 proliferation biomarker. Broadening the intracellular target space by more effective delivery of protein/peptide drugs could expand the repertoire of antibody–drug conjugates to currently undruggable disease-specific targets and permit tailored drug strategies to stratified subpopulations and personalized medicines. PMID:25669432

Infrared maritime target detection using the high order statistic filtering in fractional Fourier domain

NASA Astrophysics Data System (ADS)

Zhou, Anran; Xie, Weixin; Pei, Jihong

2018-06-01

Accurate detection of maritime targets in infrared imagery under various sea clutter conditions is always a challenging task. The fractional Fourier transform (FRFT) is the extension of the Fourier transform in the fractional order, and has richer spatial-frequency information. By combining it with the high order statistic filtering, a new ship detection method is proposed. First, the proper range of angle parameter is determined to make it easier for the ship components and background to be separated. Second, a new high order statistic curve (HOSC) at each fractional frequency point is designed. It is proved that maximal peak interval in HOSC reflects the target information, while the points outside the interval reflect the background. And the value of HOSC relative to the ship is much bigger than that to the sea clutter. Then, search the curve's maximal target peak interval and extract the interval by bandpass filtering in fractional Fourier domain. The value outside the peak interval of HOSC decreases rapidly to 0, so the background is effectively suppressed. Finally, the detection result is obtained by the double threshold segmenting and the target region selection method. The results show the proposed method is excellent for maritime targets detection with high clutters.

Nuclease Target Site Selection for Maximizing On-target Activity and Minimizing Off-target Effects in Genome Editing

PubMed Central

Lee, Ciaran M; Cradick, Thomas J; Fine, Eli J; Bao, Gang

2016-01-01

The rapid advancement in targeted genome editing using engineered nucleases such as ZFNs, TALENs, and CRISPR/Cas9 systems has resulted in a suite of powerful methods that allows researchers to target any genomic locus of interest. A complementary set of design tools has been developed to aid researchers with nuclease design, target site selection, and experimental validation. Here, we review the various tools available for target selection in designing engineered nucleases, and for quantifying nuclease activity and specificity, including web-based search tools and experimental methods. We also elucidate challenges in target selection, especially in predicting off-target effects, and discuss future directions in precision genome editing and its applications. PMID:26750397

Literature evidence in open targets - a target validation platform.

PubMed

Kafkas, Şenay; Dunham, Ian; McEntyre, Johanna

2017-06-06

We present the Europe PMC literature component of Open Targets - a target validation platform that integrates various evidence to aid drug target identification and validation. The component identifies target-disease associations in documents and ranks the documents based on their confidence from the Europe PMC literature database, by using rules utilising expert-provided heuristic information. The confidence score of a given document represents how valuable the document is in the scope of target validation for a given target-disease association by taking into account the credibility of the association based on the properties of the text. The component serves the platform regularly with the up-to-date data since December, 2015. Currently, there are a total number of 1168365 distinct target-disease associations text mined from >26 million PubMed abstracts and >1.2 million Open Access full text articles. Our comparative analyses on the current available evidence data in the platform revealed that 850179 of these associations are exclusively identified by literature mining. This component helps the platform's users by providing the most relevant literature hits for a given target and disease. The text mining evidence along with the other types of evidence can be explored visually through https://www.targetvalidation.org and all the evidence data is available for download in json format from https://www.targetvalidation.org/downloads/data .

An electrophysiological insight into visual attention mechanisms underlying schizotypy.

PubMed

Fuggetta, Giorgio; Bennett, Matthew A; Duke, Philip A

2015-07-01

A theoretical framework has been put forward to understand attention deficits in schizophrenia (Luck SJ & Gold JM. Biological Psychiatry. 2008; 64:34-39). We adopted this framework to evaluate any deficits in attentional processes in schizotypy. Sixteen low schizotypal (LoS) and 16 high schizotypal (HiS) individuals performed a novel paradigm combining a match-to-sample task, with inhibition of return (using spatially uninformative cues) and memory-guided efficient visual-search within one trial sequence. Behavioural measures and event-related potentials (ERPs) were recorded. Behaviourally, HiS individuals exhibited a spatial cueing effect while LoS individuals showed the more typical inhibition of return effect. These results suggest HiS individuals have a relative deficit in rule selection - the endogenous control process involved in disengaging attention from the uninformative location cue. ERP results showed that the late-phase of N2pc evoked by the target stimulus had greater peak latency and amplitude in HiS individuals. This suggests a relative deficit in the implementation of selection - the process of focusing attention onto target features that enhances relevant/suppresses irrelevant inputs. This is a different conclusion than when the same theoretical framework has been applied to schizophrenia, which argues little or no deficit in implementation of selection amongst patients. Also, HiS individuals exhibited earlier onset and greater amplitude of the mismatch-triggered negativity component. In summary, our results indicate deficits of both control and implementation of selection in HiS individuals. Copyright © 2015 Elsevier B.V. All rights reserved.

Methods for designing interventions to change healthcare professionals' behaviour: a systematic review.

PubMed

Colquhoun, Heather L; Squires, Janet E; Kolehmainen, Niina; Fraser, Cynthia; Grimshaw, Jeremy M

2017-03-04

Systematic reviews consistently indicate that interventions to change healthcare professional (HCP) behaviour are haphazardly designed and poorly specified. Clarity about methods for designing and specifying interventions is needed. The objective of this review was to identify published methods for designing interventions to change HCP behaviour. A search of MEDLINE, Embase, and PsycINFO was conducted from 1996 to April 2015. Using inclusion/exclusion criteria, a broad screen of abstracts by one rater was followed by a strict screen of full text for all potentially relevant papers by three raters. An inductive approach was first applied to the included studies to identify commonalities and differences between the descriptions of methods across the papers. Based on this process and knowledge of related literatures, we developed a data extraction framework that included, e.g. level of change (e.g. individual versus organization); context of development; a brief description of the method; tasks included in the method (e.g. barrier identification, component selection, use of theory). 3966 titles and abstracts and 64 full-text papers were screened to yield 15 papers included in the review, each outlining one design method. All of the papers reported methods developed within a specific context. Thirteen papers included barrier identification and 13 included linking barriers to intervention components; although not the same 13 papers. Thirteen papers targeted individual HCPs with only one paper targeting change across individual, organization, and system levels. The use of theory and user engagement were included in 13/15 and 13/15 papers, respectively. There is an agreement across methods of four tasks that need to be completed when designing individual-level interventions: identifying barriers, selecting intervention components, using theory, and engaging end-users. Methods also consist of further additional tasks. Examples of methods for designing the organisation and system-level interventions were limited. Further analysis of design tasks could facilitate the development of detailed guidelines for designing interventions.

Design of spray dried insulin microparticles to bypass deposition in the extrathoracic region and maximize total lung dose.

PubMed

Ung, Keith T; Rao, Nagaraja; Weers, Jeffry G; Huang, Daniel; Chan, Hak-Kim

2016-09-25

Inhaled drugs all too often deliver only a fraction of the emitted dose to the target lung site due to deposition in the extrathoracic region (i.e., mouth and throat), which can lead to increased variation in lung exposure, and in some instances increases in local and systemic side effects. For aerosol medications, improved targeting to the lungs may be achieved by tailoring the micromeritic properties of the particles (e.g., size, density, rugosity) to minimize deposition in the mouth-throat and maximize the total lung dose. This study evaluated a co-solvent spray drying approach to modulate particle morphology and dose delivery characteristics of engineered powder formulations of insulin microparticles. The binary co-solvent system studied included water as the primary solvent mixed with an organic co-solvent, e.g., ethanol. Factors such as the relative rate of evaporation of each component of a binary co-solvent mixture, and insulin solubility in each component were considered in selecting feedstock compositions. A water-ethanol co-solvent mixture with a composition range considered suitable for modulating particle shell formation during drying was selected for experimental investigation. An Alberta Idealized Throat model was used to evaluate the in vitro total lung dose of a series of spray dried insulin formulations engineered with different bulk powder properties and delivered with two prototype inhalers that fluidize and disperse powder using different principles. The in vitro total lung dose of insulin microparticles was improved and favored for powders with low bulk density and small primary particle size, with reduction of deposition in the extrathoracic region. The results demonstrated that a total lung dose >95% of the delivered dose can be achieved with engineered particles, indicating a high degree of lung targeting, almost completely bypassing deposition in the mouth-throat. Copyright © 2016 Elsevier B.V. All rights reserved.

A Genome-Wide Metabolic QTL Analysis in Europeans Implicates Two Loci Shaped by Recent Positive Selection

PubMed Central

Nicholson, George; Rantalainen, Mattias; Li, Jia V.; Maher, Anthony D.; Malmodin, Daniel; Ahmadi, Kourosh R.; Faber, Johan H.; Barrett, Amy; Min, Josine L.; Rayner, N. William; Toft, Henrik; Krestyaninova, Maria; Viksna, Juris; Neogi, Sudeshna Guha; Dumas, Marc-Emmanuel; Sarkans, Ugis; Donnelly, Peter; Illig, Thomas; Adamski, Jerzy; Suhre, Karsten; Allen, Maxine; Zondervan, Krina T.; Spector, Tim D.; Nicholson, Jeremy K.; Lindon, John C.

2011-01-01

We have performed a metabolite quantitative trait locus (mQTL) study of the 1H nuclear magnetic resonance spectroscopy (1H NMR) metabolome in humans, building on recent targeted knowledge of genetic drivers of metabolic regulation. Urine and plasma samples were collected from two cohorts of individuals of European descent, with one cohort comprised of female twins donating samples longitudinally. Sample metabolite concentrations were quantified by 1H NMR and tested for association with genome-wide single-nucleotide polymorphisms (SNPs). Four metabolites' concentrations exhibited significant, replicable association with SNP variation (8.6×10−11

Virtual ligand screening of the National Cancer Institute (NCI) compound library leads to the allosteric inhibitory scaffolds of the West Nile Virus NS3 proteinase.

PubMed

Shiryaev, Sergey A; Cheltsov, Anton V; Gawlik, Katarzyna; Ratnikov, Boris I; Strongin, Alex Y

2011-02-01

Viruses of the genus Flavivirus are responsible for significant human disease and mortality. The N-terminal domain of the flaviviral nonstructural (NS)3 protein codes for the serine, chymotrypsin-fold proteinase (NS3pro). The presence of the nonstructural (NS)2B cofactor, which is encoded by the upstream gene in the flaviviral genome, is necessary for NS3pro to exhibit its proteolytic activity. The two-component NS2B-NS3pro functional activity is essential for the viral polyprotein processing and replication. Both the structure and the function of NS2B-NS3pro are conserved in the Flavivirus family. Because of its essential function in the posttranslational processing of the viral polyprotein precursor, NS2B-NS3pro is a promising target for anti-flavivirus drugs. To identify selective inhibitors with the reduced cross-reactivity and off-target effects, we focused our strategy on the allosteric inhibitors capable of targeting the NS2B-NS3pro interface rather than the NS3pro active site. Using virtual ligand screening of the diverse, ∼275,000-compound library and the catalytic domain of the two-component West Nile virus (WNV) NS2B-NS3pro as a receptor, we identified a limited subset of the novel inhibitory scaffolds. Several of the discovered compounds performed as allosteric inhibitors and exhibited a nanomolar range potency in the in vitro cleavage assays. The inhibitors were also potent in cell-based assays employing the sub-genomic, luciferase-tagged WNV and Dengue viral replicons. The selectivity of the inhibitors was confirmed using the in vitro cleavage assays with furin, a human serine proteinase, the substrate preferences of which are similar to those of WNV NS2B-NS3pro. Conceptually, the similar in silico drug discovery strategy may be readily employed for the identification of inhibitors of other flaviviruses.

Cramer-Rao Lower Bound Evaluation for Linear Frequency Modulation Based Active Radar Networks Operating in a Rice Fading Environment.

PubMed

Shi, Chenguang; Salous, Sana; Wang, Fei; Zhou, Jianjiang

2016-12-06

This paper investigates the joint target parameter (delay and Doppler) estimation performance of linear frequency modulation (LFM)-based radar networks in a Rice fading environment. The active radar networks are composed of multiple radar transmitters and multichannel receivers placed on moving platforms. First, the log-likelihood function of the received signal for a Rician target is derived, where the received signal scattered off the target comprises of dominant scatterer (DS) component and weak isotropic scatterers (WIS) components. Then, the analytically closed-form expressions of the Cramer-Rao lower bounds (CRLBs) on the Cartesian coordinates of target position and velocity are calculated, which can be adopted as a performance metric to access the target parameter estimation accuracy for LFM-based radar network systems in a Rice fading environment. It is found that the cumulative Fisher information matrix (FIM) is a linear combination of both DS component and WIS components, and it also demonstrates that the joint CRLB is a function of signal-to-noise ratio (SNR), target's radar cross section (RCS) and transmitted waveform parameters, as well as the relative geometry between the target and the radar network architectures. Finally, numerical results are provided to indicate that the joint target parameter estimation performance of active radar networks can be significantly improved with the exploitation of DS component.

Intelligibility for Binaural Speech with Discarded Low-SNR Speech Components.

PubMed

Schoenmaker, Esther; van de Par, Steven

2016-01-01

Speech intelligibility in multitalker settings improves when the target speaker is spatially separated from the interfering speakers. A factor that may contribute to this improvement is the improved detectability of target-speech components due to binaural interaction in analogy to the Binaural Masking Level Difference (BMLD). This would allow listeners to hear target speech components within specific time-frequency intervals that have a negative SNR, similar to the improvement in the detectability of a tone in noise when these contain disparate interaural difference cues. To investigate whether these negative-SNR target-speech components indeed contribute to speech intelligibility, a stimulus manipulation was performed where all target components were removed when local SNRs were smaller than a certain criterion value. It can be expected that for sufficiently high criterion values target speech components will be removed that do contribute to speech intelligibility. For spatially separated speakers, assuming that a BMLD-like detection advantage contributes to intelligibility, degradation in intelligibility is expected already at criterion values below 0 dB SNR. However, for collocated speakers it is expected that higher criterion values can be applied without impairing speech intelligibility. Results show that degradation of intelligibility for separated speakers is only seen for criterion values of 0 dB and above, indicating a negligible contribution of a BMLD-like detection advantage in multitalker settings. These results show that the spatial benefit is related to a spatial separation of speech components at positive local SNRs rather than to a BMLD-like detection improvement for speech components at negative local SNRs.

Application of the Intervention Mapping protocol to develop Keys, a family child care home intervention to prevent early childhood obesity.

PubMed

Mann, Courtney M; Ward, Dianne S; Vaughn, Amber; Benjamin Neelon, Sara E; Long Vidal, Lenita J; Omar, Sakinah; Namenek Brouwer, Rebecca J; Østbye, Truls

2015-12-10

Many families rely on child care outside the home, making these settings important influences on child development. Nearly 1.5 million children in the U.S. spend time in family child care homes (FCCHs), where providers care for children in their own residences. There is some evidence that children in FCCHs are heavier than those cared for in centers. However, few interventions have targeted FCCHs for obesity prevention. This paper will describe the application of the Intervention Mapping (IM) framework to the development of a childhood obesity prevention intervention for FCCHs Following the IM protocol, six steps were completed in the planning and development of an intervention targeting FCCHs: needs assessment, formulation of change objectives matrices, selection of theory-based methods and strategies, creation of intervention components and materials, adoption and implementation planning, and evaluation planning Application of the IM process resulted in the creation of the Keys to Healthy Family Child Care Homes program (Keys), which includes three modules: Healthy You, Healthy Home, and Healthy Business. Delivery of each module includes a workshop, educational binder and tool-kit resources, and four coaching contacts. Social Cognitive Theory and Self-Determination Theory helped guide development of change objective matrices, selection of behavior change strategies, and identification of outcome measures. The Keys program is currently being evaluated through a cluster-randomized controlled trial The IM process, while time-consuming, enabled rigorous and systematic development of intervention components that are directly tied to behavior change theory and may increase the potential for behavior change within the FCCHs.

The LSST Scheduler from design to construction

NASA Astrophysics Data System (ADS)

Delgado, Francisco; Reuter, Michael A.

2016-07-01

The Large Synoptic Survey Telescope (LSST) will be a highly robotic facility, demanding a very high efficiency during its operation. To achieve this, the LSST Scheduler has been envisioned as an autonomous software component of the Observatory Control System (OCS), that selects the sequence of targets in real time. The Scheduler will drive the survey using optimization of a dynamic cost function of more than 200 parameters. Multiple science programs produce thousands of candidate targets for each observation, and multiple telemetry measurements are received to evaluate the external and the internal conditions of the observatory. The design of the LSST Scheduler started early in the project supported by Model Based Systems Engineering, detailed prototyping and scientific validation of the survey capabilities required. In order to build such a critical component, an agile development path in incremental releases is presented, integrated to the development plan of the Operations Simulator (OpSim) to allow constant testing, integration and validation in a simulated OCS environment. The final product is a Scheduler that is also capable of running 2000 times faster than real time in simulation mode for survey studies and scientific validation during commissioning and operations.

Transient Distraction and Attentional Control during a Sustained Selective Attention Task.

PubMed

Demeter, Elise; Woldorff, Marty G

2016-07-01

Distracting stimuli in the environment can pull our attention away from our goal-directed tasks. fMRI studies have implicated regions in right frontal cortex as being particularly important for processing distractors [e.g., de Fockert, J. W., & Theeuwes, J. Role of frontal cortex in attentional capture by singleton distractors. Brain and Cognition, 80, 367-373, 2012; Demeter, E., Hernandez-Garcia, L., Sarter, M., & Lustig, C. Challenges to attention: A continuous arterial spin labeling (ASL) study of the effects of distraction on sustained attention. Neuroimage, 54, 1518-1529, 2011]. Less is known, however, about the timing and sequence of how right frontal or other brain regions respond selectively to distractors and how distractors impinge upon the cascade of processes related to detecting and processing behaviorally relevant target stimuli. Here we used EEG and ERPs to investigate the neural consequences of a perceptually salient but task-irrelevant distractor on the detection of rare target stimuli embedded in a rapid, serial visual presentation (RSVP) stream. We found that distractors that occur during the presentation of a target interfere behaviorally with detection of those targets, reflected by reduced detection rates, and that these missed targets show a reduced amplitude of the long-latency, detection-related P3 component. We also found that distractors elicited a right-lateralized frontal negativity beginning at 100 msec, whose amplitude negatively correlated across participants with their distraction-related behavioral impairment. Finally, we also quantified the instantaneous amplitude of the steady-state visual evoked potentials elicited by the RSVP stream and found that the occurrence of a distractor resulted in a transient amplitude decrement of the steady-state visual evoked potential, presumably reflecting the pull of attention away from the RSVP stream when distracting stimuli occur in the environment.

Targeting mitochondria by Zn(II)N-alkylpyridylporphyrins: the impact of compound sub-mitochondrial partition on cell respiration and overall photodynamic efficacy.

PubMed

Odeh, Ahmad M; Craik, James D; Ezzeddine, Rima; Tovmasyan, Artak; Batinic-Haberle, Ines; Benov, Ludmil T

2014-01-01

Mitochondria play a key role in aerobic ATP production and redox control. They harness crucial metabolic pathways and control cell death mechanisms, properties that make these organelles essential for survival of most eukaryotic cells. Cancer cells have altered cell death pathways and typically show a shift towards anaerobic glycolysis for energy production, factors which point to mitochondria as potential culprits in cancer development. Targeting mitochondria is an attractive approach to tumor control, but design of pharmaceutical agents based on rational approaches is still not well established. The aim of this study was to investigate which structural features of specially designed Zn(II)N-alkylpyridylporphyrins would direct them to mitochondria and to particular mitochondrial targets. Since Zn(II)N-alkylpyridylporphyrins can act as highly efficient photosensitizers, their localization can be confirmed by photodamage to particular mitochondrial components. Using cultured LS174T adenocarcinoma cells, we found that subcellular distribution of Zn-porphyrins is directed by the nature of the substituents attached to the meso pyridyl nitrogens at the porphyrin ring. Increasing the length of the aliphatic chain from one carbon (methyl) to six carbons (hexyl) increased mitochondrial uptake of the compounds. Such modifications also affected sub-mitochondrial distribution of the Zn-porphyrins. The amphiphilic hexyl derivative (ZnTnHex-2-PyP) localized in the vicinity of cytochrome c oxidase complex, causing its inactivation during illumination. Photoinactivation of critical cellular targets explains the superior efficiency of the hexyl derivative in causing mitochondrial photodamage, and suppressing cellular respiration and survival. Design of potent photosensitizers and redox-active scavengers of free radicals should take into consideration not only selective organelle uptake and localization, but also selective targeting of critical macromolecular structures.

Influence of Translation Initiation on Organellar Protein Targeting in Arabidopsis

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

Sally A. Mackenzie

2011-04-18

A primary focus of the Mackenzie laboratory is the elucidation of processes and machinery for mitochondrial genome maintenance and transmission in higher plants. We have found that numerous organellar DNA maintenance components in plants appear to be dual targeted to mitochondria and plastids. Of particular interest was the observation that some twin (tandemly arrayed) dual targeting presequences appeared to utilize non-AUG alternative translation initiation, allowing for multiple translation starts at a single gene. Two aspects of this phenomenon were of particular interest: (1) Alternative translation initiation might provide a mechanism to regulate protein targeting temporally and spatially, a possibility thatmore » had not been demonstrated previously, and (2) alternative translation initiation might occur in genes involved in nuclear-controlled mitochondrial genome recombination, thought to be exclusively mitochondrial in their function. During the course of this research, we pursued three aims, with an emphasis on two specific genes of interest: POLgamma2, an organellar DNA polymerase, and MSH1, a MutS homolog thought to participate in mitochondrial, but not plastid, genome recombination surveillance. Our aims were to (1) Identify additional genes within Arabidopsis and other genomes that employ non-AUG alternative translation initiation, (2) Locate sequences upstream to the annotated AUG that confer alternative non-AUG translation initiation activity, and (3) Identify cis and trans factors that influence start site selection in genes with non-AUG starts. Toward these ends, we have shown that non-AUG initiation occurs in a number of genes, likely influencing targeting behavior of the protein. We have also shown that start site selection is strongly influenced by Kozak consensus sequence environment, indicating that alternative translation initiation in plants occurs by relaxation of ribosome scanning.« less

Effects of Mode of Target Task Selection on Learning about Plants in a Mobile Learning Environment: Effortful Manual Selection versus Effortless QR-Code Selection

ERIC Educational Resources Information Center

Gao, Yuan; Liu, Tzu-Chien; Paas, Fred

2016-01-01

This study compared the effects of effortless selection of target plants using quick respond (QR) code technology to effortful manual search and selection of target plants on learning about plants in a mobile device supported learning environment. In addition, it was investigated whether the effectiveness of the 2 selection methods was…

Low Background Assay Results for LZ

NASA Astrophysics Data System (ADS)

Oliver-Mallory, Kelsey; Thomas, Keenan; Lux-Zeplin Collaboration; Berkeley Low Background Facility Team

2016-03-01

The next generation dark matter experiment LUX-ZEPLIN (LZ) requires careful control of intrinsic radioactivity in all critical detector components in order to reach its unprecedented target sensitivity to Weakly Interacting Massive Particles (WIMPs): 2 ×10-48 cm2 at 50 GeV/c2. Appropriate material selection is essential to meeting this goal, and an extensive campaign of low background screening is currently being carried out using assay devices at the Sanford Underground Research Facility and the Boulby Underground Laboratory. We will present results from this work, including measurements for the Ti cryostat, PMT bases, PMT raw materials, PTFE, and other components. This work was partially supported by the U.S. Department of Energy (DOE) under Award Number DE-AC02-05CH11231, and is based upon work supported by the National Science Foundation Graduate Research Fellowship under Grant No. 1106400.

The role of epigenetics and long noncoding RNA MIAT in neuroendocrine prostate cancer.

PubMed

Crea, Francesco; Venalainen, Erik; Ci, Xinpei; Cheng, Hongwei; Pikor, Larissa; Parolia, Abhijit; Xue, Hui; Nur Saidy, Nur Ridzwan; Lin, Dong; Lam, Wan; Collins, Colin; Wang, Yuzhuo

2016-05-01

Neuroendocrine prostate cancer (NEPC) is the most lethal prostatic neoplasm. NEPC is thought to originate from the transdifferentiation of AR-positive adenocarcinoma cells. We have previously shown that an epigenetic/noncoding interactome (ENI) orchestrates cancer cells' plasticity, thereby allowing the emergence of metastatic, drug-resistant neoplasms. The primary objective of this manuscript is to discuss evidence indicating that some components of the ENI (Polycomb genes, miRNAs) play a key role in NEPC initiation and progression. Long noncoding RNAs represent vast and largely unexplored component of the ENI. Their role in NEPC has not been investigated. We show preliminary evidence indicating that a lncRNA (MIAT) is selectively upregulated in NEPCs and might interact with Polycomb genes. Our results indicate that long noncoding RNAs can be exploited as new biomarkers and therapeutic targets for NEPC.

AtlasCBS: a web server to map and explore chemico-biological space

NASA Astrophysics Data System (ADS)

Cortés-Cabrera, Álvaro; Morreale, Antonio; Gago, Federico; Abad-Zapatero, Celerino

2012-09-01

New approaches are needed that can help decrease the unsustainable failure in small-molecule drug discovery. Ligand Efficiency Indices (LEI) are making a great impact on early-stage compound selection and prioritization. Given a target-ligand database with chemical structures and associated biological affinities/activities for a target, the AtlasCBS server generates two-dimensional, dynamical representations of its contents in terms of LEI. These variables allow an effective decoupling of the chemical (angular) and biological (radial) components. BindingDB, PDBBind and ChEMBL databases are currently implemented. Proprietary datasets can also be uploaded and compared. The utility of this atlas-like representation in the future of drug design is highlighted with some examples. The web server can be accessed at http://ub.cbm.uam.es/atlascbs and https://www.ebi.ac.uk/chembl/atlascbs.

Micro-Doppler Signal Time-Frequency Algorithm Based on STFRFT.

PubMed

Pang, Cunsuo; Han, Yan; Hou, Huiling; Liu, Shengheng; Zhang, Nan

2016-09-24

This paper proposes a time-frequency algorithm based on short-time fractional order Fourier transformation (STFRFT) for identification of a complicated movement targets. This algorithm, consisting of a STFRFT order-changing and quick selection method, is effective in reducing the computation load. A multi-order STFRFT time-frequency algorithm is also developed that makes use of the time-frequency feature of each micro-Doppler component signal. This algorithm improves the estimation accuracy of time-frequency curve fitting through multi-order matching. Finally, experiment data were used to demonstrate STFRFT's performance in micro-Doppler time-frequency analysis. The results validated the higher estimate accuracy of the proposed algorithm. It may be applied to an LFM (Linear frequency modulated) pulse radar, SAR (Synthetic aperture radar), or ISAR (Inverse synthetic aperture radar), for improving the probability of target recognition.

Antidepressant action of ketamine via mTOR is mediated by inhibition of nitrergic Rheb degradation.

PubMed

Harraz, M M; Tyagi, R; Cortés, P; Snyder, S H

2016-03-01

As traditional antidepressants act only after weeks/months, the discovery that ketamine, an antagonist of glutamate/N-methyl-D-aspartate (NMDA) receptors, elicits antidepressant actions in hours has been transformative. Its mechanism of action has been elusive, though enhanced mammalian target of rapamycin (mTOR) signaling is a major feature. We report a novel signaling pathway wherein NMDA receptor activation stimulates generation of nitric oxide (NO), which S-nitrosylates glyceraldehyde-3-phosphate dehydrogenase (GAPDH). Nitrosylated GAPDH complexes with the ubiquitin-E3-ligase Siah1 and Rheb, a small G protein that activates mTOR. Siah1 degrades Rheb leading to reduced mTOR signaling, while ketamine, conversely, stabilizes Rheb that enhances mTOR signaling. Drugs selectively targeting components of this pathway may offer novel approaches to the treatment of depression.

AtlasCBS: a web server to map and explore chemico-biological space.

PubMed

Cortés-Cabrera, Alvaro; Morreale, Antonio; Gago, Federico; Abad-Zapatero, Celerino

2012-09-01

New approaches are needed that can help decrease the unsustainable failure in small-molecule drug discovery. Ligand Efficiency Indices (LEI) are making a great impact on early-stage compound selection and prioritization. Given a target-ligand database with chemical structures and associated biological affinities/activities for a target, the AtlasCBS server generates two-dimensional, dynamical representations of its contents in terms of LEI. These variables allow an effective decoupling of the chemical (angular) and biological (radial) components. BindingDB, PDBBind and ChEMBL databases are currently implemented. Proprietary datasets can also be uploaded and compared. The utility of this atlas-like representation in the future of drug design is highlighted with some examples. The web server can be accessed at http://ub.cbm.uam.es/atlascbs and https://www.ebi.ac.uk/chembl/atlascbs.

Multiple source/multiple target fluid transfer apparatus

DOEpatents

Turner, Terry D.

1997-01-01

A fluid transfer apparatus includes: a) a plurality of orifices for connection with fluid sources; b) a plurality of orifices for connection with fluid targets; c) a set of fluid source conduits and fluid target conduits associated with the orifices; d) a pump fluidically interposed between the source and target conduits to transfer fluid therebetween; e) a purge gas conduit in fluid communication with the fluid source conduits, fluid target conduits and pump to receive and pass a purge gas under pressure; f) a solvent conduit in fluid communication with the fluid source conduits, fluid target conduits and pump to receive and pass solvent, the solvent conduit including a solvent valve; g) pump control means for controlling operation of the pump; h) purge gas valve control means for controlling operation of the purge gas valve to selectively impart flow of purge gas to the fluid source conduits, fluid target conduits and pump; i) solvent valve control means for controlling operation of the solvent valve to selectively impart flow of solvent to the fluid source conduits, fluid target conduits and pump; and j) source and target valve control means for controlling operation of the fluid source conduit valves and the fluid target conduit valves to selectively impart passage of fluid between a selected one of the fluid source conduits and a selected one of the fluid target conduits through the pump and to enable passage of solvent or purge gas through selected fluid source conduits and selected fluid target conduits.

Multiple source/multiple target fluid transfer apparatus

DOEpatents

Turner, T.D.

1997-08-26

A fluid transfer apparatus includes: (a) a plurality of orifices for connection with fluid sources; (b) a plurality of orifices for connection with fluid targets; (c) a set of fluid source conduits and fluid target conduits associated with the orifices; (d) a pump fluidically interposed between the source and target conduits to transfer fluid there between; (e) a purge gas conduit in fluid communication with the fluid source conduits, fluid target conduits and pump to receive and pass a purge gas under pressure; (f) a solvent conduit in fluid communication with the fluid source conduits, fluid target conduits and pump to receive and pass solvent, the solvent conduit including a solvent valve; (g) pump control means for controlling operation of the pump; (h) purge gas valve control means for controlling operation of the purge gas valve to selectively impart flow of purge gas to the fluid source conduits, fluid target conduits and pump; (i) solvent valve control means for controlling operation of the solvent valve to selectively impart flow of solvent to the fluid source conduits, fluid target conduits and pump; and (j) source and target valve control means for controlling operation of the fluid source conduit valves and the fluid target conduit valves to selectively impart passage of fluid between a selected one of the fluid source conduits and a selected one of the fluid target conduits through the pump and to enable passage of solvent or purge gas through selected fluid source conduits and selected fluid target conduits. 6 figs.

How do we select multiple features? Transient costs for selecting two colors rather than one, persistent costs for color-location conjunctions.

PubMed

Lo, Shih-Yu; Holcombe, Alex O

2014-02-01

In a previous study Lo, Howard, & Holcombe (Vision Research 63:20-33, 2012), selecting two colors did not induce a performance cost, relative to selecting one color. For example, requiring possible report of both a green and a red target did not yield a worse performance than when both targets were green. Yet a cost of selecting multiple colors was observed when selection needed be contingent on both color and location. When selecting a red target to the left and a green target to the right, superimposing a green distractor to the left and a red distractor to the right impeded performance. Possibly, participants cannot confine attention to a color at a particular location. As a result, distractors that share the target colors disrupt attentional selection of the targets. The attempt to select the targets must then be repeated, which increases the likelihood that the trial terminates when selection is not effective, even for long trials. Consistent with this, here we find a persistent cost of selecting two colors when the conjunction of color and location is needed, but the cost is confined to short exposure durations when the observer just has to monitor red and green stimuli without the need to use the location information. These results suggest that selecting two colors is time-consuming but effective, whereas selection of simultaneous conjunctions is never entirely successful.

Selective autophagy limits cauliflower mosaic virus infection by NBR1-mediated targeting of viral capsid protein and particles

PubMed Central

Hafrén, Anders; Macia, Jean-Luc; Love, Andrew J.; Milner, Joel J.; Drucker, Martin; Hofius, Daniel

2017-01-01

Autophagy plays a paramount role in mammalian antiviral immunity including direct targeting of viruses and their individual components, and many viruses have evolved measures to antagonize or even exploit autophagy mechanisms for the benefit of infection. In plants, however, the functions of autophagy in host immunity and viral pathogenesis are poorly understood. In this study, we have identified both anti- and proviral roles of autophagy in the compatible interaction of cauliflower mosaic virus (CaMV), a double-stranded DNA pararetrovirus, with the model plant Arabidopsis thaliana. We show that the autophagy cargo receptor NEIGHBOR OF BRCA1 (NBR1) targets nonassembled and virus particle-forming capsid proteins to mediate their autophagy-dependent degradation, thereby restricting the establishment of CaMV infection. Intriguingly, the CaMV-induced virus factory inclusions seem to protect against autophagic destruction by sequestering capsid proteins and coordinating particle assembly and storage. In addition, we found that virus-triggered autophagy prevents extensive senescence and tissue death of infected plants in a largely NBR1-independent manner. This survival function significantly extends the timespan of virus production, thereby increasing the chances for virus particle acquisition by aphid vectors and CaMV transmission. Together, our results provide evidence for the integration of selective autophagy into plant immunity against viruses and reveal potential viral strategies to evade and adapt autophagic processes for successful pathogenesis. PMID:28223514

Highly selective detection of single-nucleotide polymorphisms using a quartz crystal microbalance biosensor based on the toehold-mediated strand displacement reaction.

PubMed

Wang, Dingzhong; Tang, Wei; Wu, Xiaojie; Wang, Xinyi; Chen, Gengjia; Chen, Qiang; Li, Na; Liu, Feng

2012-08-21

Toehold-mediated strand displacement reaction (SDR) is first introduced to develop a simple quartz crystal microbalance (QCM) biosensor without an enzyme or label at normal temperature for highly selective and sensitive detection of single-nucleotide polymorphism (SNP) in the p53 tumor suppressor gene. A hairpin capture probe with an external toehold is designed and immobilized on the gold electrode surface of QCM. A successive SDR is initiated by the target sequence hybridization with the toehold domain and ends with the unfolding of the capture probe. Finally, the open-loop capture probe hybridizes with the streptavidin-coupled reporter probe as an efficient mass amplifier to enhance the QCM signal. The proposed biosensor displays remarkable specificity to target the p53 gene fragment against single-base mutant sequences (e.g., the largest discrimination factor is 63 to C-C mismatch) and high sensitivity with the detection limit of 0.3 nM at 20 °C. As the crucial component of the fabricated biosensor for providing the high discrimination capability, the design rationale of the capture probe is further verified by fluorescence sensing and atomic force microscopy imaging. Additionally, a recovery of 84.1% is obtained when detecting the target sequence in spiked HeLa cells lysate, demonstrating the feasibility of employing this biosensor in detecting SNPs in biological samples.

An adaptive tracker for ShipIR/NTCS

NASA Astrophysics Data System (ADS)

Ramaswamy, Srinivasan; Vaitekunas, David A.

2015-05-01

A key component in any image-based tracking system is the adaptive tracking algorithm used to segment the image into potential targets, rank-and-select the best candidate target, and the gating of the selected target to further improve tracker performance. This paper will describe a new adaptive tracker algorithm added to the naval threat countermeasure simulator (NTCS) of the NATO-standard ship signature model (ShipIR). The new adaptive tracking algorithm is an optional feature used with any of the existing internal NTCS or user-defined seeker algorithms (e.g., binary centroid, intensity centroid, and threshold intensity centroid). The algorithm segments the detected pixels into clusters, and the smallest set of clusters that meet the detection criterion is obtained by using a knapsack algorithm to identify the set of clusters that should not be used. The rectangular area containing the chosen clusters defines an inner boundary, from which a weighted centroid is calculated as the aim-point. A track-gate is then positioned around the clusters, taking into account the rate of change of the bounding area and compensating for any gimbal displacement. A sequence of scenarios is used to test the new tracking algorithm on a generic unclassified DDG ShipIR model, with and without flares, and demonstrate how some of the key seeker signals are impacted by both the ship and flare intrinsic signatures.

Establishment of a universal and rational gene detection strategy through three-way junction-based remote transduction.

PubMed

Tang, Yidan; Lu, Baiyang; Zhu, Zhentong; Li, Bingling

2018-01-21

The polymerase chain reaction and many isothermal amplifications are able to achieve super gene amplification. Unfortunately, most commonly-used transduction methods, such as dye staining and Taqman-like probing, still suffer from shortcomings including false signals or difficult probe design, or are incompatible with multi-analysis. Here a universal and rational gene detection strategy has been established by translating isothermal amplicons to enzyme-free strand displacement circuits via three-way junction-based remote transduction. An assistant transduction probe was imported to form a partial hybrid with the target single-stranded nucleic acid. After systematic optimization the hybrid could serve as an associative trigger to activate a downstream circuit detector via a strand displacement reaction across the three-way junction. By doing so, the detection selectivity can be double-guaranteed through both amplicon-transducer recognition and the amplicon-circuit reaction. A well-optimized circuit can be immediately applied to a new target detection through simply displacing only 10-12 nt on only one component, according to the target. More importantly, this property for the first time enables multi-analysis and logic-analysis in a single reaction, sharing a single fluorescence reporter. In an applicable model, trace amounts of Cronobacter and Enterobacteria genes have been clearly distinguished from samples with no bacteria or one bacterium, with ultra-high sensitivity and selectivity.

Ultrasonic Analysis of Peptide- and Antibody-Targeted Microbubble Contrast Agents for Molecular Imaging of αvβ3-Expressing Cells

PubMed Central

Dayton, Paul A.; Pearson, David; Clark, Jarrod; Simon, Scott; Schumann, Patricia A.; Zutshi, Reena; Matsunaga, Terry O.; Ferrara, Katherine W.

2008-01-01

The goal of targeted ultrasound contrast agents is to significantly and selectively enhance the detection of a targeted vascular site. In this manuscript, three distinct contrast agents targeted to the αvβ3 integrin are examined. The αvβ3 integrin has been shown to be highly expressed on metastatic tumors and endothelial cells during neovascularization, and its expression has been shown to correlate with tumor grade. Specific adhesion of these contrast agents to αvβ3-expressing cell monolayers is demonstrated in vitro, and compared with that of nontargeted agents. Acoustic studies illustrate a backscatter amplitude increase from monolayers exposed to the targeted contrast agents of up to 13-fold (22 dB) relative to enhancement due to control bubbles. A linear dependence between the echo amplitude and bubble concentration was observed for bound agents. The decorrelation of the echo from adherent targeted agents is observed over successive pulses as a function of acoustic pressure and bubble density. Frequency–domain analysis demonstrates that adherent targeted bubbles exhibit high-amplitude narrowband echo components, in contrast to the primarily wideband response from free microbubbles. Results suggest that adherent targeted contrast agents are differentiable from free-floating microbubbles, that targeted contrast agents provide higher sensitivity in the detection of angiogenesis, and that conventional ultrasound imaging techniques such as signal subtraction or decorrelation detection can be used to detect integrin-expressing vasculature with sufficient signal-to-noise. PMID:15296677

Cancer-linked targets modulated by curcumin

PubMed Central

Hasima, Noor; Aggarwal, Bharat B

2012-01-01

In spite of major advances in oncology, the World Health Organization predicts that cancer incidence will double within the next two decades. Although it is well understood that cancer is a hyperproliferative disorder mediated through dysregulation of multiple cell signaling pathways, most cancer drug development remains focused on modulation of specific targets, mostly one at a time, with agents referred to as “targeted therapies,” “smart drugs,” or “magic bullets.” How many cancer targets there are is not known, and how many targets must be attacked to control cancer growth is not well understood. Although more than 90% of cancer-linked deaths are due to metastasis of the tumor to vital organs, most drug targeting is focused on killing the primary tumor. Besides lacking specificity, the targeted drugs induce toxicity and side effects that sometimes are greater problems than the disease itself. Furthermore, the cost of some of these drugs is so high that most people cannot afford them. The present report describes the potential anticancer properties of curcumin, a component of the Indian spice turmeric (Curcuma longa), known for its safety and low cost. Curcumin can selectively modulate multiple cell signaling pathways linked to inflammation and to survival, growth, invasion, angiogenesis, and metastasis of cancer cells. More clinical trials of curcumin are needed to prove its usefulness in the cancer setting. PMID:23301199

Molecularly Imprinted Sol-Gel-Based QCM Sensor Arrays for the Detection and Recognition of Volatile Aldehydes.

PubMed

Liu, Chuanjun; Wyszynski, Bartosz; Yatabe, Rui; Hayashi, Kenshi; Toko, Kiyoshi

2017-02-16

The detection and recognition of metabolically derived aldehydes, which have been identified as important products of oxidative stress and biomarkers of cancers; are considered as an effective approach for early cancer detection as well as health status monitoring. Quartz crystal microbalance (QCM) sensor arrays based on molecularly imprinted sol-gel (MISG) materials were developed in this work for highly sensitive detection and highly selective recognition of typical aldehyde vapors including hexanal (HAL); nonanal (NAL) and bezaldehyde (BAL). The MISGs were prepared by a sol-gel procedure using two matrix precursors: tetraethyl orthosilicate (TEOS) and tetrabutoxytitanium (TBOT). Aminopropyltriethoxysilane (APT); diethylaminopropyltrimethoxysilane (EAP) and trimethoxy-phenylsilane (TMP) were added as functional monomers to adjust the imprinting effect of the matrix. Hexanoic acid (HA); nonanoic acid (NA) and benzoic acid (BA) were used as psuedotemplates in view of their analogous structure to the target molecules as well as the strong hydrogen-bonding interaction with the matrix. Totally 13 types of MISGs with different components were prepared and coated on QCM electrodes by spin coating. Their sensing characters towards the three aldehyde vapors with different concentrations were investigated qualitatively. The results demonstrated that the response of individual sensors to each target strongly depended on the matrix precursors; functional monomers and template molecules. An optimization of the 13 MISG materials was carried out based on statistical analysis such as principle component analysis (PCA); multivariate analysis of covariance (MANCOVA) and hierarchical cluster analysis (HCA). The optimized sensor array consisting of five channels showed a high discrimination ability on the aldehyde vapors; which was confirmed by quantitative comparison with a randomly selected array. It was suggested that both the molecularly imprinting (MIP) effect and the matrix effect contributed to the sensitivity and selectivity of the optimized sensor array. The developed MISGs were expected to be promising materials for the detection and recognition of volatile aldehydes contained in exhaled breath or human body odor.

Molecularly Imprinted Sol-Gel-Based QCM Sensor Arrays for the Detection and Recognition of Volatile Aldehydes

PubMed Central

Liu, Chuanjun; Wyszynski, Bartosz; Yatabe, Rui; Hayashi, Kenshi; Toko, Kiyoshi

2017-01-01

The detection and recognition of metabolically derived aldehydes, which have been identified as important products of oxidative stress and biomarkers of cancers; are considered as an effective approach for early cancer detection as well as health status monitoring. Quartz crystal microbalance (QCM) sensor arrays based on molecularly imprinted sol-gel (MISG) materials were developed in this work for highly sensitive detection and highly selective recognition of typical aldehyde vapors including hexanal (HAL); nonanal (NAL) and bezaldehyde (BAL). The MISGs were prepared by a sol-gel procedure using two matrix precursors: tetraethyl orthosilicate (TEOS) and tetrabutoxytitanium (TBOT). Aminopropyltriethoxysilane (APT); diethylaminopropyltrimethoxysilane (EAP) and trimethoxy-phenylsilane (TMP) were added as functional monomers to adjust the imprinting effect of the matrix. Hexanoic acid (HA); nonanoic acid (NA) and benzoic acid (BA) were used as psuedotemplates in view of their analogous structure to the target molecules as well as the strong hydrogen-bonding interaction with the matrix. Totally 13 types of MISGs with different components were prepared and coated on QCM electrodes by spin coating. Their sensing characters towards the three aldehyde vapors with different concentrations were investigated qualitatively. The results demonstrated that the response of individual sensors to each target strongly depended on the matrix precursors; functional monomers and template molecules. An optimization of the 13 MISG materials was carried out based on statistical analysis such as principle component analysis (PCA); multivariate analysis of covariance (MANCOVA) and hierarchical cluster analysis (HCA). The optimized sensor array consisting of five channels showed a high discrimination ability on the aldehyde vapors; which was confirmed by quantitative comparison with a randomly selected array. It was suggested that both the molecularly imprinting (MIP) effect and the matrix effect contributed to the sensitivity and selectivity of the optimized sensor array. The developed MISGs were expected to be promising materials for the detection and recognition of volatile aldehydes contained in exhaled breath or human body odor. PMID:28212347

Temporal dissociation between the focal and orientation components of spatial attention in central and peripheral vision.

PubMed

Albonico, Andrea; Malaspina, Manuela; Bricolo, Emanuela; Martelli, Marialuisa; Daini, Roberta

2016-11-01

Selective attention, i.e. the ability to concentrate one's limited processing resources on one aspect of the environment, is a multifaceted concept that includes different processes like spatial attention and its subcomponents of orienting and focusing. Several studies, indeed, have shown that visual tasks performance is positively influenced not only by attracting attention to the target location (orientation component), but also by the adjustment of the size of the attentional window according to task demands (focal component). Nevertheless, the relative weight of the two components in central and peripheral vision has never been studied. We conducted two experiments to explore whether different components of spatial attention have different effects in central and peripheral vision. In order to do so, participants underwent either a detection (Experiment 1) or a discrimination (Experiment 2) task where different types of cues elicited different components of spatial attention: a red dot, a small square and a big square (an optimal stimulus for the orientation component, an optimal and a sub-optimal stimulus for the focal component respectively). Response times and cue-size effects indicated a stronger effect of the small square or of the dot in different conditions, suggesting the existence of a dissociation in terms of mechanisms between the focal and the orientation components of spatial attention. Specifically, we found that the orientation component was stronger in periphery, while the focal component was noticeable only in central vision and characterized by an exogenous nature. Copyright © 2016 Elsevier B.V. All rights reserved.

VARIABLE SELECTION IN NONPARAMETRIC ADDITIVE MODELS

PubMed Central

Huang, Jian; Horowitz, Joel L.; Wei, Fengrong

2010-01-01

We consider a nonparametric additive model of a conditional mean function in which the number of variables and additive components may be larger than the sample size but the number of nonzero additive components is “small” relative to the sample size. The statistical problem is to determine which additive components are nonzero. The additive components are approximated by truncated series expansions with B-spline bases. With this approximation, the problem of component selection becomes that of selecting the groups of coefficients in the expansion. We apply the adaptive group Lasso to select nonzero components, using the group Lasso to obtain an initial estimator and reduce the dimension of the problem. We give conditions under which the group Lasso selects a model whose number of components is comparable with the underlying model, and the adaptive group Lasso selects the nonzero components correctly with probability approaching one as the sample size increases and achieves the optimal rate of convergence. The results of Monte Carlo experiments show that the adaptive group Lasso procedure works well with samples of moderate size. A data example is used to illustrate the application of the proposed method. PMID:21127739

Selecting a Targeting Method to Identify BPL Households in India

ERIC Educational Resources Information Center

Alkire, Sabina; Seth, Suman

2013-01-01

This paper proposes how to select a methodology to target multidimensionally poor households, and how to update that targeting exercise periodically. We present this methodology in the context of discussions regarding the selection of a targeting methodology in India. In 1992, 1997, and 2002 the Indian government identified households that are…

Role of Oxidative Stress in the Suppression of Immune Responses in Peripheral Blood Mononuclear Cells Exposed to Combustible Tobacco Product Preparation.

PubMed

Arimilli, Subhashini; Schmidt, Eckhardt; Damratoski, Brad E; Prasad, G L

2017-10-01

Cigarette smoking is a major risk factor for several human diseases. Chronic inflammation, resulting from increased oxidative stress, has been suggested as a mechanism that contributes to the increased susceptibility of smokers to cancer and microbial infections. We have previously shown that whole-smoke conditioned medium (WS-CM) and total particulate matter (TPM) prepared from Kentucky 3R4F reference cigarettes [collectively called as combustible tobacco product preparations (TPPs)] potently suppressed agonist-stimulated cytokine secretion and target cell killing in peripheral blood mononuclear cells (PBMCs). Here we have investigated the role of oxidative stress from TPPs, which alters inflammatory responses in vitro. Particularly, we investigated the mechanisms of WS-CM-induced suppression of select cytokine secretions in Toll-like receptor (TLR) agonist-stimulated cells and target cell killing by effector cells in PBMCs. Pretreatment with N-acetyl cysteine (NAC), a precursor of reduced glutathione and an established anti-oxidant, protected against DNA damage and cytotoxicity caused by exposure to WS-CM. Similarly, secretion of tumor necrosis factor (TNF), interleukin (IL)-6, and IL-8 in response to TLR-4 stimulation was restored by pretreatment with NAC. Target cell killing, a functional measure of cytolytic cells in PBMCs, is suppressed by WS-CM. Pretreatment with NAC restored the target cell killing in WS-CM treated PBMCs. This was accompanied by higher perforin levels in the effector cell populations. Collectively, these data suggest that reducing oxidative stress caused by cigarette smoke components restores select immune responses in this ex vivo model.

Spectroscopy of reactive species produced by low-energy atmospheric-pressure plasma on conductive target material surface

NASA Astrophysics Data System (ADS)

Yamada, Hiromasa; Sakakita, Hajime; Kato, Susumu; Kim, Jaeho; Kiyama, Satoru; Fujiwara, Masanori; Itagaki, Hirotomo; Okazaki, Toshiya; Ikehara, Sanae; Nakanishi, Hayao; Shimizu, Nobuyuki; Ikehara, Yuzuru

2016-10-01

A method for blood coagulation using low-energy atmospheric-pressure plasma (LEAPP) is confirmed as an alternative procedure to reduce tissue damage caused by heat. Blood coagulation using LEAPP behaves differently depending on working gas species; helium is more effective than argon in promoting fast coagulation. To analyse the difference in reactive species produced by helium and argon plasma, spectroscopic measurements were conducted without and with a target material. To compare emissions, blood coagulation experiments using LEAPP for both plasmas were performed under almost identical conditions. Although many kinds of reactive species such as hydroxyl radicals and excited nitrogen molecules were observed with similar intensity in both plasmas, intensities of nitrogen ion molecules and nitric oxide molecules were extremely strong in the helium plasma. It is considered that nitrogen ion molecules were mainly produced by penning ionization by helium metastable. Near the target, a significant increase in the emissions of reactive species is observed. There is a possibility that electron acceleration was induced in a local electric field formed on the surface. However, in argon plasma, emissions from nitrogen ion were not measured even near the target surface. These differences between the two plasmas may be producing the difference in blood coagulation behaviour. To control the surrounding gas of the plasma, a gas-component-controllable chamber was assembled. Filling the chamber with O2/He or N2/He gas mixtures selectively produces either reactive oxygen species or reactive nitrogen species. Through selective treatments, this chamber would be useful in studying the effects of specific reactive species on blood coagulation.

Selective endosomal microautophagy is starvation-inducible in Drosophila.

PubMed

Mukherjee, Anindita; Patel, Bindi; Koga, Hiroshi; Cuervo, Ana Maria; Jenny, Andreas

2016-11-01

Autophagy delivers cytosolic components to lysosomes for degradation and is thus essential for cellular homeostasis and to cope with different stressors. As such, autophagy counteracts various human diseases and its reduction leads to aging-like phenotypes. Macroautophagy (MA) can selectively degrade organelles or aggregated proteins, whereas selective degradation of single proteins has only been described for chaperone-mediated autophagy (CMA) and endosomal microautophagy (eMI). These 2 autophagic pathways are specific for proteins containing KFERQ-related targeting motifs. Using a KFERQ-tagged fluorescent biosensor, we have identified an eMI-like pathway in Drosophila melanogaster. We show that this biosensor localizes to late endosomes and lysosomes upon prolonged starvation in a KFERQ- and Hsc70-4- dependent manner. Furthermore, fly eMI requires endosomal multivesicular body formation mediated by ESCRT complex components. Importantly, induction of Drosophila eMI requires longer starvation than the induction of MA and is independent of the critical MA genes atg5, atg7, and atg12. Furthermore, inhibition of Tor signaling induces eMI in flies under nutrient rich conditions, and, as eMI in Drosophila also requires atg1 and atg13, our data suggest that these genes may have a novel, additional role in regulating eMI in flies. Overall, our data provide the first evidence for a novel, starvation-inducible, catabolic process resembling endosomal microautophagy in the Drosophila fat body.

An extensive library of surrogate peptides for all human proteins.

PubMed

Mohammed, Yassene; Borchers, Christoph H

2015-11-03

Selecting the most appropriate surrogate peptides to represent a target protein is a major component of experimental design in Multiple Reaction Monitoring (MRM). Our software PeptidePicker with its v-score remains distinctive in its approach of integrating information about the proteins, their tryptic peptides, and the suitability of these peptides for MRM that is available online in UniProtKB, NCBI's dbSNP, ExPASy, PeptideAtlas, PRIDE, and GPMDB. The scoring algorithm reflects our "best knowledge" for selecting candidate peptides for MRM, based on the uniqueness of the peptide in the targeted proteome, its physiochemical properties, and whether it has previously been observed. Here we present an updated approach where we have already compiled a list of all possible surrogate peptides of the human proteome. Using our stringent selection criteria, the list includes 165k suitable MRM peptides covering 17k proteins of the human reviewed proteins in UniProtKB. Compared to average of 2-4min per protein for retrieving and integrating the information, the precompiled list includes all peptides available instantly. This allows a more cohesive and faster design of a multiplexed MRM experiment and provides insights into evidence for a protein's existence. We will keep this list up-to-date as proteomics data repositories continue to grow. This article is part of a Special Issue entitled: Computational Proteomics. Copyright © 2015 Elsevier B.V. All rights reserved.

Computational design of nanoparticle drug delivery systems for selective targeting

NASA Astrophysics Data System (ADS)

Duncan, Gregg A.; Bevan, Michael A.

2015-09-01

Ligand-functionalized nanoparticles capable of selectively binding to diseased versus healthy cell populations are attractive for improved efficacy of nanoparticle-based drug and gene therapies. However, nanoparticles functionalized with high affinity targeting ligands may lead to undesired off-target binding to healthy cells. In this work, Monte Carlo simulations were used to quantitatively determine net surface interactions, binding valency, and selectivity between targeted nanoparticles and cell surfaces. Dissociation constant, KD, and target membrane protein density, ρR, are explored over a range representative of healthy and cancerous cell surfaces. Our findings show highly selective binding to diseased cell surfaces can be achieved with multiple, weaker affinity targeting ligands that can be further optimized by varying the targeting ligand density, ρL. Using the approach developed in this work, nanomedicines can be optimally designed for exclusively targeting diseased cells and tissues.Ligand-functionalized nanoparticles capable of selectively binding to diseased versus healthy cell populations are attractive for improved efficacy of nanoparticle-based drug and gene therapies. However, nanoparticles functionalized with high affinity targeting ligands may lead to undesired off-target binding to healthy cells. In this work, Monte Carlo simulations were used to quantitatively determine net surface interactions, binding valency, and selectivity between targeted nanoparticles and cell surfaces. Dissociation constant, KD, and target membrane protein density, ρR, are explored over a range representative of healthy and cancerous cell surfaces. Our findings show highly selective binding to diseased cell surfaces can be achieved with multiple, weaker affinity targeting ligands that can be further optimized by varying the targeting ligand density, ρL. Using the approach developed in this work, nanomedicines can be optimally designed for exclusively targeting diseased cells and tissues. Electronic supplementary information (ESI) available: Movie showing simulation renderings of targeted (ρL = 1820/μm2, KD = 120 μM) nanoparticle selective binding to cancer (ρR = 256/μm2) vs. healthy (ρR = 64/μm2) cell surfaces. Target membrane proteins have linear color scale depending on binding energy ranging from white when unbound (URL = 0) to red when tightly bound (URL = UM). See DOI: 10.1039/c5nr03691g

Psychological factors in oral mucosal and orofacial pain conditions.

PubMed

Alrashdan, Mohammad S; Alkhader, Mustafa

2017-01-01

The psychological aspects of chronic pain conditions represent a key component of the pain experience, and orofacial pain conditions are not an exception. In this review, we highlight how psychological factors affect some common oral mucosal and orofacial pain conditions (namely, oral lichen planus, recurrent aphthous stomatitis, burning mouth syndrome, and temporomandibular disorders) with emphasis on the significance of supplementing classical biomedical treatment modalities with appropriate psychological counseling to improve treatment outcomes in targeted patients. A literature search restricted to reports with highest relevance to the selected mucosal and orofacial pain conditions was carried out to retrieve data.

Structures and mechanisms of vesicle coat components and multisubunit tethering complexes

PubMed Central

Jackson, Lauren P; Kümmel, Daniel; Reinisch, Karin M; Owen, David J

2012-01-01

Eukaryotic cells face a logistical challenge in ensuring prompt and precise delivery of vesicular cargo to specific organelles within the cell. Coat protein complexes select cargo and initiate vesicle formation, while multisubunit tethering complexes participate in the delivery of vesicles to target membranes. Understanding these macromolecular assemblies has greatly benefited from their structural characterization. Recent structural data highlight principles in coat recruitment and uncoating in both the endocytic and retrograde pathways, and studies on the architecture of tethering complexes provide a framework for how they might link vesicles to the respective acceptor compartments and the fusion machinery. PMID:22728063

Hand and Wrist Injuries in Boxing and the Martial Arts.

PubMed

Drury, Benjamin Todd; Lehman, Thomas P; Rayan, Ghazi

2017-02-01

Hand and wrist injuries in martial arts are typically a reflection of the combat nature of this discipline. In striking sports, the axial load mechanism of injury is common and causes fractures and dislocations; in grappling sports, sprain injuries and degenerative changes predominate. There is clear evidence to support that hand protection reduces the risk of hand injury. Traditional training in martial arts on proper technique and target selection in striking sports reduces the risk of hand injury, and is an important component of hand and wrist injury prevention. Copyright © 2016 Elsevier Inc. All rights reserved.

Cramer-Rao Lower Bound Evaluation for Linear Frequency Modulation Based Active Radar Networks Operating in a Rice Fading Environment

PubMed Central

Shi, Chenguang; Salous, Sana; Wang, Fei; Zhou, Jianjiang

2016-01-01

This paper investigates the joint target parameter (delay and Doppler) estimation performance of linear frequency modulation (LFM)-based radar networks in a Rice fading environment. The active radar networks are composed of multiple radar transmitters and multichannel receivers placed on moving platforms. First, the log-likelihood function of the received signal for a Rician target is derived, where the received signal scattered off the target comprises of dominant scatterer (DS) component and weak isotropic scatterers (WIS) components. Then, the analytically closed-form expressions of the Cramer-Rao lower bounds (CRLBs) on the Cartesian coordinates of target position and velocity are calculated, which can be adopted as a performance metric to access the target parameter estimation accuracy for LFM-based radar network systems in a Rice fading environment. It is found that the cumulative Fisher information matrix (FIM) is a linear combination of both DS component and WIS components, and it also demonstrates that the joint CRLB is a function of signal-to-noise ratio (SNR), target’s radar cross section (RCS) and transmitted waveform parameters, as well as the relative geometry between the target and the radar network architectures. Finally, numerical results are provided to indicate that the joint target parameter estimation performance of active radar networks can be significantly improved with the exploitation of DS component. PMID:27929433

A principal components analysis of dynamic spatial memory biases.

PubMed

Motes, Michael A; Hubbard, Timothy L; Courtney, Jon R; Rypma, Bart

2008-09-01

Research has shown that spatial memory for moving targets is often biased in the direction of implied momentum and implied gravity, suggesting that representations of the subjective experiences of these physical principles contribute to such biases. The present study examined the association between these spatial memory biases. Observers viewed targets that moved horizontally from left to right before disappearing or viewed briefly shown stationary targets. After a target disappeared, observers indicated the vanishing position of the target. Principal components analysis revealed that biases along the horizontal axis of motion loaded on separate components from biases along the vertical axis orthogonal to motion. The findings support the hypothesis that implied momentum and implied gravity biases have unique influences on spatial memory. (c) 2008 APA, all rights reserved.

Selection and response bias as determinants of priming of pop-out search: Revelations from diffusion modeling.

PubMed

Burnham, Bryan R

2018-05-03

During visual search, both top-down factors and bottom-up properties contribute to the guidance of visual attention, but selection history can influence attention independent of bottom-up and top-down factors. For example, priming of pop-out (PoP) is the finding that search for a singleton target is faster when the target and distractor features repeat than when those features trade roles between trials. Studies have suggested that such priming (selection history) effects on pop-out search manifest either early, by biasing the selection of the preceding target feature, or later in processing, by facilitating response and target retrieval processes. The present study was designed to examine the influence of selection history on pop-out search by introducing a speed-accuracy trade-off manipulation in a pop-out search task. Ratcliff diffusion modeling (RDM) was used to examine how selection history influenced both attentional bias and response execution processes. The results support the hypothesis that selection history biases attention toward the preceding target's features on the current trial and also influences selection of the response to the target.

Selective attention and the auditory vertex potential. I - Effects of stimulus delivery rate. II - Effects of signal intensity and masking noise

NASA Technical Reports Server (NTRS)

Schwent, V. L.; Hillyard, S. A.; Galambos, R.

1976-01-01

The effects of varying the rate of delivery of dichotic tone pip stimuli on selective attention measured by evoked-potential amplitudes and signal detectability scores were studied. The subjects attended to one channel (ear) of tones, ignored the other, and pressed a button whenever occasional targets - tones of a slightly higher pitch were detected in the attended ear. Under separate conditions, randomized interstimulus intervals were short, medium, and long. Another study compared the effects of attention on the N1 component of the auditory evoked potential for tone pips presented alone and when white noise was added to make the tones barely above detectability threshold in a three-channel listening task. Major conclusions are that (1) N1 is enlarged to stimuli in an attended channel only in the short interstimulus interval condition (averaging 350 msec), (2) N1 and P3 are related to different modes of selective attention, and (3) attention selectivity in multichannel listening task is greater when tones are faint and/or difficult to detect.

Selection of phage-displayed accessible recombinant targeted antibodies (SPARTA): methodology and applications.

PubMed

D'Angelo, Sara; Staquicini, Fernanda I; Ferrara, Fortunato; Staquicini, Daniela I; Sharma, Geetanjali; Tarleton, Christy A; Nguyen, Huynh; Naranjo, Leslie A; Sidman, Richard L; Arap, Wadih; Bradbury, Andrew Rm; Pasqualini, Renata

2018-05-03

We developed a potentially novel and robust antibody discovery methodology, termed selection of phage-displayed accessible recombinant targeted antibodies (SPARTA). This combines an in vitro screening step of a naive human antibody library against known tumor targets, with in vivo selections based on tumor-homing capabilities of a preenriched antibody pool. This unique approach overcomes several rate-limiting challenges to generate human antibodies amenable to rapid translation into medical applications. As a proof of concept, we evaluated SPARTA on 2 well-established tumor cell surface targets, EphA5 and GRP78. We evaluated antibodies that showed tumor-targeting selectivity as a representative panel of antibody-drug conjugates (ADCs) and were highly efficacious. Our results validate a discovery platform to identify and validate monoclonal antibodies with favorable tumor-targeting attributes. This approach may also extend to other diseases with known cell surface targets and affected tissues easily isolated for in vivo selection.

The Mechanism of Room-Temperature Ionic-Liquid-Based Electrochemical CO₂ Reduction: A Review.

PubMed

Lim, Hyung-Kyu; Kim, Hyungjun

2017-03-28

Electrochemical CO₂ conversion technology is becoming indispensable in the development of a sustainable carbon-based economy. While various types of electrocatalytic systems have been designed, those based on room-temperature ionic liquids (RTILs) have attracted considerable attention because of their high efficiencies and selectivities. Furthermore, it should be possible to develop more advanced electrocatalytic systems for commercial use because target-specific characteristics can be fine-tuned using various combinations of RTIL ions. To achieve this goal, we require a systematic understanding of the role of the RTIL components in electrocatalytic systems, however, their role has not yet been clarified by experiment or theory. Thus, the purpose of this short review is to summarize recent experimental and theoretical mechanistic studies to provide insight into and to develop guidelines for the successful development of new CO₂ conversion systems. The results discussed here can be summarized as follows. Complex physical and chemical interactions between the RTIL components and the reaction intermediates, in particular at the electrode surface, are critical for determining the activity and selectivity of the electrocatalytic system, although no single factor dominates. Therefore, more fundamental research is required to understand the physical, chemical, and thermodynamic characteristics of complex RTIL-based electrocatalytic systems.

Affective ERP Processing in a Visual Oddball Task: Arousal, Valence, and Gender

PubMed Central

Rozenkrants, Bella; Polich, John

2008-01-01

Objective To assess affective event-related brain potentials (ERPs) using visual pictures that were highly distinct on arousal level/valence category ratings and a response task. Methods Images from the International Affective Pictures System (IAPS) were selected to obtain distinct affective arousal (low, high) and valence (negative, positive) rating levels. The pictures were used as target stimuli in an oddball paradigm, with a visual pattern as the standard stimulus. Participants were instructed to press a button whenever a picture occurred and to ignore the standard. Task performance and response time did not differ across conditions. Results High-arousal compared to low-arousal stimuli produced larger amplitudes for the N2, P3, early slow wave, and late slow wave components. Valence amplitude effects were weak overall and originated primarily from the later waveform components and interactions with electrode position. Gender differences were negligible. Conclusion The findings suggest that arousal level is the primary determinant of affective oddball processing, and valence minimally influences ERP amplitude. Significance Affective processing engages selective attentional mechanisms that are primarily sensitive to the arousal properties of emotional stimuli. The application and nature of task demands are important considerations for interpreting these effects. PMID:18783987

Passive millimeter-wave imaging polarimeter system

NASA Astrophysics Data System (ADS)

Persons, Christopher M.; Martin, Christopher A.; Jones, Michael W.; Kolinko, Vladimir; Lovberg, John A.

2009-05-01

The Army has identified a need to rapidly identify, map, and classify natural and manmade features to aid situational awareness as well as mission and tactical planning. To address these needs, Digital Fusion and Trex Enterprises have designed a full Stokes, passive MMW imaging polarimeter that is capable of being deployed on an unmanned aerial vehicle. Results of a detailed trade study are presented, where an architecture, waveband and target platform are selected. The selected architecture is a pushbroom phased-array system, which allows the system to collect a wide fieldof- view image with minimal components and weight. W band is chosen as a trade-off between spatial resolution, weather penetration, and component availability. The trade study considers several unmanned aerial system (UAS) platforms that are capable of low-level flight and that can support the MMW antenna. The utility of the passive Stokes imager is demonstrated through W band phenomenology data collections at horizontal and vertical polarization using a variety of natural and manmade materials. The concept design is detailed, along with hardware and procedures for both radiometric and polarimetric calibration. Finally, a scaled version of the concept design is presented, which is being fabricated for an upcoming demonstration on a small, manned aircraft.

Motor pathway convergence predicts syllable repertoire size in oscine birds

PubMed Central

Moore, Jordan M.; Székely, Tamás; Büki, József; DeVoogd, Timothy J.

2011-01-01

Behavioral specializations are frequently associated with expansions of the brain regions controlling them. This principle of proper mass spans sensory, motor, and cognitive abilities and has been observed in a wide variety of vertebrate species. Yet, it is unknown if this concept extrapolates to entire neural pathways or how selection on a behavioral capacity might otherwise shape circuit structure. We investigate these questions by comparing the songs and neuroanatomy of 49 species from 17 families of songbirds, which vary immensely in the number of unique song components they produce and possess a conserved neural network dedicated to this behavior. We find that syllable repertoire size is strongly related to the degree of song motor pathway convergence. Repertoire size is more accurately predicted by the number of neurons in higher motor areas relative to that in their downstream targets than by the overall number of neurons in the song motor pathway. Additionally, the convergence values along serial premotor and primary motor projections account for distinct portions of the behavioral variation. These findings suggest that selection on song has independently shaped different components of this hierarchical pathway, and they elucidate how changes in pathway structure could have underlain elaborations of this learned motor behavior. PMID:21918109

JAK inhibitors suppress t(8;21) fusion protein-induced leukemia

PubMed Central

Lo, Miao-Chia; Peterson, Luke F.; Yan, Ming; Cong, Xiuli; Hickman, Justin H.; DeKelver, Russel C.; Niewerth, Denise; Zhang, Dong-Er

2014-01-01

Oncogenic mutations in components of the JAK/STAT pathway, including those in cytokine receptors and JAKs, lead to increased activity of downstream signaling and are frequently found in leukemia and other hematological disorders. Thus, small-molecule inhibitors of this pathway have been the focus of targeted therapy in these hematological diseases. We previously showed that t(8;21) fusion protein AML1-ETO and its alternatively spliced variant AML1-ETO9a (AE9a) enhance the JAK/STAT pathway via down-regulation of CD45, a negative regulator of this pathway. To investigate the therapeutic potential of targeting JAK/STAT in t(8;21) leukemia, we examined the effects of a JAK2-selective inhibitor TG101209 and a JAK1/2-selective inhibitor INCB18424 on t(8;21) leukemia cells. TG101209 and INCB18424 inhibited proliferation and promoted apoptosis of these cells. Furthermore, TG101209 treatment in AE9a leukemia mice reduced tumor burden and significantly prolonged survival. TG101209 also significantly impaired the leukemia-initiating potential of AE9a leukemia cells in secondary recipient mice. These results demonstrate the potential therapeutic efficacy of JAK inhibitors in treating t(8;21) AML. PMID:23812420

Targeting Activation of Specific NF-κB Subunits Prevents Stress-Dependent Atherothrombotic Gene Expression

PubMed Central

Djuric, Zdenka; Kashif, Muhammed; Fleming, Thomas; Muhammad, Sajjad; Piel, David; von Bauer, Rüdiger; Bea, Florian; Herzig, Stephan; Zeier, Martin; Pizzi, Marina; Isermann, Berend; Hecker, Markus; Schwaninger, Markus; Bierhaus, Angelika; Nawroth, Peter P

2012-01-01

Psychosocial stress has been shown to be a contributing factor in the development of atherosclerosis. Although the underlying mechanisms have not been elucidated entirely, it has been shown previously that the transcription factor nuclear factor-κB (NF-κB) is an important component of stress-activated signaling pathway. In this study, we aimed to decipher the mechanisms of stress-induced NF-κB-mediated gene expression, using an in vitro and in vivo model of psychosocial stress. Induction of stress led to NF-κB-dependent expression of proinflammatory (tissue factor, intracellular adhesive molecule 1 [ICAM-1]) and protective genes (manganese superoxide dismutase [MnSOD]) via p50, p65 or cRel. Selective inhibition of the different subunits and the respective kinases showed that inhibition of cRel leads to the reduction of atherosclerotic lesions in apolipoprotein−/− (ApoE−/−) mice via suppression of proinflammatory gene expression. This observation may therefore provide a possible explanation for ineffectiveness of antioxidant therapies and suggests that selective targeting of cRel activation may provide a novel approach for the treatment of stress-related inflammatory vascular disease. PMID:23114885

Forging a modern generation of polyphenol-based therapeutics.

PubMed

Wright, Bernice

2013-06-01

The long-standing debate that polyphenol secondary metabolites from dietary plants are important nutritional components continues due to compelling evidence for their abilities to ameliorate degenerative conditions including, cancer, neurological disorders and cardiovascular disease. The clinical use of polyphenols is not, however, mainstream as issues regarding poor selectivity, dosage, toxicity and delivery methods are unresolved. The paper by Rieder et al. suggests that the lack of selectivity, at least for the stilbene, resveratrol, may not be a major limiting factor. The present commentary is a critique of this significant finding that is focused on deciding how the use of resveratrol as clinical medicine could be advanced, and how this new information integrates with current knowledge of polyphenol physiological effects. This commentary suggests that the multi-target nature of polyphenols may be translated into reliable therapy using the current systems/network pharmacology approach concerned with developing viable therapeutic agents that achieve specific effects through interactions with a wide array of targets. This article is a commentary on Rieder et al., pp. 1244-1258 of BJP 167:6. To view this paper visit http://dx.doi.org/10.1111/j.1476-5381.2012.02063.x. © 2013 The Author. British Journal of Pharmacology © 2013 The British Pharmacological Society.

A meta-cognitive learning algorithm for a Fully Complex-valued Relaxation Network.

PubMed

Savitha, R; Suresh, S; Sundararajan, N

2012-08-01

This paper presents a meta-cognitive learning algorithm for a single hidden layer complex-valued neural network called "Meta-cognitive Fully Complex-valued Relaxation Network (McFCRN)". McFCRN has two components: a cognitive component and a meta-cognitive component. A Fully Complex-valued Relaxation Network (FCRN) with a fully complex-valued Gaussian like activation function (sech) in the hidden layer and an exponential activation function in the output layer forms the cognitive component. The meta-cognitive component contains a self-regulatory learning mechanism which controls the learning ability of FCRN by deciding what-to-learn, when-to-learn and how-to-learn from a sequence of training data. The input parameters of cognitive components are chosen randomly and the output parameters are estimated by minimizing a logarithmic error function. The problem of explicit minimization of magnitude and phase errors in the logarithmic error function is converted to system of linear equations and output parameters of FCRN are computed analytically. McFCRN starts with zero hidden neuron and builds the number of neurons required to approximate the target function. The meta-cognitive component selects the best learning strategy for FCRN to acquire the knowledge from training data and also adapts the learning strategies to implement best human learning components. Performance studies on a function approximation and real-valued classification problems show that proposed McFCRN performs better than the existing results reported in the literature. Copyright © 2012 Elsevier Ltd. All rights reserved.

Evaluating the efficacy of fully automated approaches for the selection of eye blink ICA components

PubMed Central

Pontifex, Matthew B.; Miskovic, Vladimir; Laszlo, Sarah

2017-01-01

Independent component analysis (ICA) offers a powerful approach for the isolation and removal of eye blink artifacts from EEG signals. Manual identification of the eye blink ICA component by inspection of scalp map projections, however, is prone to error, particularly when non-artifactual components exhibit topographic distributions similar to the blink. The aim of the present investigation was to determine the extent to which automated approaches for selecting eye blink related ICA components could be utilized to replace manual selection. We evaluated popular blink selection methods relying on spatial features [EyeCatch()], combined stereotypical spatial and temporal features [ADJUST()], and a novel method relying on time-series features alone [icablinkmetrics()] using both simulated and real EEG data. The results of this investigation suggest that all three methods of automatic component selection are able to accurately identify eye blink related ICA components at or above the level of trained human observers. However, icablinkmetrics(), in particular, appears to provide an effective means of automating ICA artifact rejection while at the same time eliminating human errors inevitable during manual component selection and false positive component identifications common in other automated approaches. Based upon these findings, best practices for 1) identifying artifactual components via automated means and 2) reducing the accidental removal of signal-related ICA components are discussed. PMID:28191627

Identifying potential selective fluorescent probes for cancer-associated protein carbonic anhydrase IX using a computational approach.

PubMed

Kamstra, Rhiannon L; Floriano, Wely B

2014-11-01

Carbonic anhydrase IX (CAIX) is a biomarker for tumor hypoxia. Fluorescent inhibitors of CAIX have been used to study hypoxic tumor cell lines. However, these inhibitor-based fluorescent probes may have a therapeutic effect that is not appropriate for monitoring treatment efficacy. In the search for novel fluorescent probes that are not based on known inhibitors, a database of 20,860 fluorescent compounds was virtually screened against CAIX using hierarchical virtual ligand screening (HierVLS). The screening database contained 14,862 compounds tagged with the ATTO680 fluorophore plus an additional 5998 intrinsically fluorescent compounds. Overall ranking of compounds to identify hit molecular probe candidates utilized a principal component analysis (PCA) approach. Four potential binding sites, including the catalytic site, were identified within the structure of the protein and targeted for virtual screening. Available sequence information for 23 carbonic anhydrase isoforms was used to prioritize the four sites based on the estimated "uniqueness" of each site in CAIX relative to the other isoforms. A database of 32 known inhibitors and 478 decoy compounds was used to validate the methodology. A receiver-operating characteristic (ROC) analysis using the first principal component (PC1) as predictive score for the validation database yielded an area under the curve (AUC) of 0.92. AUC is interpreted as the probability that a binder will have a better score than a non-binder. The use of first component analysis of binding energies for multiple sites is a novel approach for hit selection. The very high prediction power for this approach increases confidence in the outcome from the fluorescent library screening. Ten of the top scoring candidates for isoform-selective putative binding sites are suggested for future testing as fluorescent molecular probe candidates. Copyright © 2014 Elsevier Inc. All rights reserved.

Input Control Processes in Rapid Serial Visual Presentations: Target Selection and Distractor Inhibition

ERIC Educational Resources Information Center

Olivers, Christian N. L.; Watson, Derrick G.

2006-01-01

The attentional blink refers to the finding that the 2nd of 2 targets embedded in a stream of rapidly presented distractors is often missed. Whereas most theories of the attentional blink focus on limited-capacity processes that occur after target selection, the present work investigates the selection process itself. Identifying a target letter…

Channel formation by the binding component of Clostridium botulinum C2 toxin: glutamate 307 of C2II affects channel properties in vitro and pH-dependent C2I translocation in vivo.

PubMed

Blöcker, Dagmar; Bachmeyer, Christoph; Benz, Roland; Aktories, Klaus; Barth, Holger

2003-05-13

The binding component (C2II) of the binary Clostridium botulinum C2 toxin mediates transport of the actin ADP-ribosylating enzyme component (C2I) into the cytosol of target cells. C2II (80 kDa) is activated by trypsin cleavage, and proteolytically activated C2II (60 kDa) oligomerizes to heptamers in solution. Activated C2II forms channels in lipid bilayer membranes which are highly cation selective and voltage-gated. A role for this channel in C2I translocation across the cell membrane into the cytosol is discussed. Amino acid residues 303-331 of C2II contain a conserved pattern of alternating hydrophobic and hydrophilic residues, which likely facilitates membrane insertion and channel formation by creating two antiparallel beta-strands. Some of the residues are in strategic positions within the putative C2II channel, in particular, glutamate 307 (E307) localized in its center and glycine 316 (G316) localized on the trans side of the membrane. Here, single-lysine substitutions of these amino acids and the double mutant E307K/G316K of C2II were analyzed in vivo and in artificial lipid bilayer experiments. The pH dependence of C2I transport across cellular membranes was altered, and a pH of

HER2 monoclonal antibodies that do not interfere with receptor heterodimerization-mediated signaling induce effective internalization and represent valuable components for rational antibody-drug conjugate design.

PubMed

de Goeij, Bart E C G; Peipp, Matthias; de Haij, Simone; van den Brink, Edward N; Kellner, Christian; Riedl, Thilo; de Jong, Rob; Vink, Tom; Strumane, Kristin; Bleeker, Wim K; Parren, Paul W H I

2014-01-01

The human epidermal growth factor receptor (HER)2 provides an excellent target for selective delivery of cytotoxic drugs to tumor cells by antibody-drug conjugates (ADC) as has been clinically validated by ado-trastuzumab emtansine (Kadcyla(TM)). While selecting a suitable antibody for an ADC approach often takes specificity and efficient antibody-target complex internalization into account, the characteristics of the optimal antibody candidate remain poorly understood. We studied a large panel of human HER2 antibodies to identify the characteristics that make them most suitable for an ADC approach. As a model toxin, amenable to in vitro high-throughput screening, we employed Pseudomonas exotoxin A (ETA') fused to an anti-kappa light chain domain antibody. Cytotoxicity induced by HER2 antibodies, which were thus non-covalently linked to ETA', was assessed for high and low HER2 expressing tumor cell lines and correlated with internalization and downmodulation of HER2 antibody-target complexes. Our results demonstrate that HER2 antibodies that do not inhibit heterodimerization of HER2 with related ErbB receptors internalize more efficiently and show greater ETA'-mediated cytotoxicity than antibodies that do inhibit such heterodimerization. Moreover, stimulation with ErbB ligand significantly enhanced ADC-mediated tumor kill by antibodies that do not inhibit HER2 heterodimerization. This suggests that the formation of HER2/ErbB-heterodimers enhances ADC internalization and subsequent killing of tumor cells. Our study indicates that selecting HER2 ADCs that allow piggybacking of HER2 onto other ErbB receptors provides an attractive strategy for increasing ADC delivery and tumor cell killing capacity to both high and low HER2 expressing tumor cells.

Targeted pancreatic cancer therapy with the small molecule drug conjugate SW IV-134.

PubMed

Hashim, Yassar M; Spitzer, Dirk; Vangveravong, Suwanna; Hornick, Mary C; Garg, Gunjal; Hornick, John R; Goedegebuure, Peter; Mach, Robert H; Hawkins, William G

2014-07-01

Pancreatic adenocarcinoma is highly resistant to conventional therapeutics and has been shown to evade apoptosis by deregulation of the X-linked and cellular inhibitors of apoptosis proteins (XIAP and cIAP). Second mitochondria-derived activator of caspases (Smac) induces and amplifies cell death by reversing the anti-apoptotic activity of IAPs. Thus, Smac-derived peptide analogues (peptidomimetics) have been developed and shown to represent promising cancer therapeutics. Sigma-2 receptors are overexpressed in many proliferating tumor cells including pancreatic cancer. Selected ligands to this receptor are rapidly internalized by cancer cells. These characteristics have made the sigma-2 receptor an attractive target for drug delivery because selective delivery to cancer cells has the potential to increase therapeutic efficacy while minimizing toxicity to normal tissues. Here, we describe the initial characterization of SW IV-134, a chemically linked drug conjugate between the sigma-2 ligand SW43 and the Smac mimetic SW IV-52 as a novel treatment option for pancreatic adenocarcinoma. The tumor killing characteristics of our dual-domain therapeutic SW IV-134 was far greater than either component in isolation or in an equimolar mix and suggests enhanced cellular delivery when chemically linked to the sigma-2 ligand. One of the key findings was that SW IV-134 retained target selectivity of the Smac cargo with the involvement of the NF-κB/TNFα signaling pathway. Importantly, SW IV-134 slowed tumor growth and improved survival in murine models of pancreatic cancer. Our data support further study of this novel therapeutic and this drug delivery strategy because it may eventually benefit patients with pancreatic cancer. Copyright © 2014 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

Visual encoding and fixation target selection in free viewing: presaccadic brain potentials

PubMed Central

Nikolaev, Andrey R.; Jurica, Peter; Nakatani, Chie; Plomp, Gijs; van Leeuwen, Cees

2013-01-01

In scrutinizing a scene, the eyes alternate between fixations and saccades. During a fixation, two component processes can be distinguished: visual encoding and selection of the next fixation target. We aimed to distinguish the neural correlates of these processes in the electrical brain activity prior to a saccade onset. Participants viewed color photographs of natural scenes, in preparation for a change detection task. Then, for each participant and each scene we computed an image heat map, with temperature representing the duration and density of fixations. The temperature difference between the start and end points of saccades was taken as a measure of the expected task-relevance of the information concentrated in specific regions of a scene. Visual encoding was evaluated according to whether subsequent change was correctly detected. Saccades with larger temperature difference were more likely to be followed by correct detection than ones with smaller temperature differences. The amplitude of presaccadic activity over anterior brain areas was larger for correct detection than for detection failure. This difference was observed for short “scrutinizing” but not for long “explorative” saccades, suggesting that presaccadic activity reflects top-down saccade guidance. Thus, successful encoding requires local scanning of scene regions which are expected to be task-relevant. Next, we evaluated fixation target selection. Saccades “moving up” in temperature were preceded by presaccadic activity of higher amplitude than those “moving down”. This finding suggests that presaccadic activity reflects attention deployed to the following fixation location. Our findings illustrate how presaccadic activity can elucidate concurrent brain processes related to the immediate goal of planning the next saccade and the larger-scale goal of constructing a robust representation of the visual scene. PMID:23818877

Attentional Selection and Suppression in Children With Attention-Deficit/Hyperactivity Disorder.

PubMed

Wang, Encong; Sun, Li; Sun, Meirong; Huang, Jing; Tao, Ye; Zhao, Xixi; Wu, Zhanliang; Ding, Yulong; Newman, Daniel P; Bellgrove, Mark A; Wang, Yufeng; Song, Yan

2016-07-01

Attention-deficit/hyperactivity disorder (ADHD) is a prevalent neurodevelopmental disorder with prominent impairments in directing and sustaining attention. The aim of this study was to identify the neurophysiologic bases of attention deficits in ADHD, focusing on electroencephalography markers of attentional selection (posterior contralateral N2 [N2pc]) and suppression (distractor positivity [P D ]). The electroencephalography data were collected from 135 children 9-15 years old with and without ADHD while they searched for a shape target in either the absence (experiment 1) or the presence (experiment 2) of a salient but irrelevant color distractor. In experiment 1, the shape target elicited a smaller N2pc in children with ADHD (n = 38) compared with typically developing children (n = 36). The smaller N2pc amplitude predicted higher levels of inattentive symptoms in children with ADHD. Moreover, the target-elicited N2pc was followed by a positivity in typically developing children but not in children with ADHD. In experiment 2, the salient but irrelevant color distractor elicited a smaller P D component in children with ADHD (n = 32) compared with typically developing children (n = 29). The smaller P D predicted higher inattentive symptom severity as well as lower behavioral accuracy in children with ADHD. The correlation between N2pc/P D amplitudes and ADHD symptom severity suggests that these signals of attentional selection and suppression may serve as potential candidates for neurophysiologic markers of ADHD. Our findings provide a neurophysiologic basis for the subjective reports of attention deficits in children with ADHD and highlight the importance of spatial attention impairments in ADHD. Copyright © 2016 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

The Use of Matrix Training to Promote Generative Language with Children with Autism

ERIC Educational Resources Information Center

Frampton, Sarah E.; Wymer, Sarah C.; Hansen, Bethany; Shillingsburg, M. Alice

2016-01-01

Matrix training consists of planning instruction by arranging components of desired skills across 2 axes. After training with diagonal targets that each combine 2 unique skill components, responses to nondiagonal targets, consisting of novel combinations of the components, may emerge. A multiple-probe design across participants was used to…

77 FR 48570 - Self-Regulatory Organizations; The NASDAQ Stock Market LLC; Order Approving a Proposed Rule...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-08-14

... Underlying Securities) of the NASDAQ Options Market rules.\\11\\ Additionally, the Target Component's and the...\\ Additionally, the Target Component's and the Benchmark Component's trading volume (in all markets in which the...-Regulatory Organizations; The NASDAQ Stock Market LLC; Order Approving a Proposed Rule Change Relating to the...

The coming of age of chaperone-mediated autophagy.

PubMed

Kaushik, Susmita; Cuervo, Ana Maria

2018-06-01

Chaperone-mediated autophagy (CMA) was the first studied process that indicated that degradation of intracellular components by the lysosome can be selective - a concept that is now well accepted for other forms of autophagy. Lysosomes can degrade cellular cytosol in a nonspecific manner but can also discriminate what to target for degradation with the involvement of a degradation tag, a chaperone and a sophisticated mechanism to make the selected proteins cross the lysosomal membrane through a dedicated translocation complex. Recent studies modulating CMA activity in vivo using transgenic mouse models have demonstrated that selectivity confers on CMA the ability to participate in the regulation of multiple cellular functions. Timely degradation of specific cellular proteins by CMA modulates, for example, glucose and lipid metabolism, DNA repair, cellular reprograming and the cellular response to stress. These findings expand the physiological relevance of CMA beyond its originally identified role in protein quality control and reveal that CMA failure with age may aggravate diseases, such as ageing-associated neurodegeneration and cancer.

Lubricant Selection Manual, Phase 3

NASA Technical Reports Server (NTRS)

Kannel, J. W.; Lowry, J. A.; Dufrane, K. F.

1991-01-01

Future spacecraft must be designated to operate for very long time periods in space. For example, a target goal for the Space Station is 30 years of operation. Although the actual life may be significantly less than this optimistic goal, the life will certainly be a critical issue in design. The bearings on primary components such as the alpha and beta joints must obviously be designed and lubricated with the objective of optimum performance life. In addition to these joints, there will be numerous other tribological (rubbing or rolling) interfaced that will be required to function for the life of the spacecraft. A major key to adequate performance of tribological interface is proper lubrication. Lubricants can be divided into two basic classes: solid films and liquids. Both types have been used extensively in space applications. Both have advantages and disadvantages that must be carefully considered in their selection. The purpose here is to summarize selection criteria for liquid and solid lubricants applied to long-life spacecraft.

Selection and Implementation of Skill Acquisition Programs by Special Education Teachers and Staff for Students With Autism Spectrum Disorder.

PubMed

Kodak, Tiffany; Cariveau, Tom; LeBlanc, Brittany A; Mahon, Jacob J; Carroll, Regina A

2018-01-01

The present investigation examined special education teachers' selection and use of teaching strategies for receptive identification training with children with autism spectrum disorder (ASD) in their classrooms. Teachers first responded to a survey in which they provided examples of receptive identification tasks taught in their classrooms, rated the efficacy of teaching strategies, described how they determined whether skills were mastered, listed any assessments they conducted to identify relevant prerequisite skills prior to receptive identification training, described how they selected teaching strategies for use in their classrooms, and listed their years of experience as a teacher and working with children with ASD. Subsequent observations of implementation of teaching strategies during trial-based instruction occurred in a proportion of teachers' classrooms. The results of the observations showed that participants did not consistently implement components of trial-based instruction as described in the literature, and there were differences in implementation depending on the types of skills targeted during instruction.

Evolution of egg target size: an analysis of selection on correlated characters.

PubMed

Podolsky, R D

2001-12-01

In broadcast-spawning marine organisms, chronic sperm limitation should select for traits that improve chances of sperm-egg contact. One mechanism may involve increasing the size of the physical or chemical target for sperm. However, models of fertilization kinetics predict that increasing egg size can reduce net zygote production due to an associated decline in fecundity. An alternate method for increasing physical target size is through addition of energetically inexpensive external structures, such as the jelly coats typical of eggs in species from several phyla. In selection experiments on eggs of the echinoid Dendraster excentricus, in which sperm was used as the agent of selection, eggs with larger overall targets were favored in fertilization. Actual shifts in target size following selection matched quantitative predictions of a model that assumed fertilization was proportional to target size. Jelly volume and ovum volume, two characters that contribute to target size, were correlated both within and among females. A cross-sectional analysis of selection partitioned the independent effects of these characters on fertilization success and showed that they experience similar direct selection pressures. Coupled with data on relative organic costs of the two materials, these results suggest that, under conditions where fertilization is limited by egg target size, selection should favor investment in low-cost accessory structures and may have a relatively weak effect on the evolution of ovum size.

Target-object integration, attention distribution, and object orientation interactively modulate object-based selection.

PubMed

Al-Janabi, Shahd; Greenberg, Adam S

2016-10-01

The representational basis of attentional selection can be object-based. Various studies have suggested, however, that object-based selection is less robust than spatial selection across experimental paradigms. We sought to examine the manner by which the following factors might explain this variation: Target-Object Integration (targets 'on' vs. part 'of' an object), Attention Distribution (narrow vs. wide), and Object Orientation (horizontal vs. vertical). In Experiment 1, participants discriminated between two targets presented 'on' an object in one session, or presented as a change 'of' an object in another session. There was no spatial cue-thus, attention was initially focused widely-and the objects were horizontal or vertical. We found evidence of object-based selection only when targets constituted a change 'of' an object. Additionally, object orientation modulated the sign of object-based selection: We observed a same-object advantage for horizontal objects, but a same-object cost for vertical objects. In Experiment 2, an informative cue preceded a single target presented 'on' an object or as a change 'of' an object (thus, attention was initially focused narrowly). Unlike in Experiment 1, we found evidence of object-based selection independent of target-object integration. We again found that the sign of selection was modulated by the objects' orientation. This result may reflect a meridian effect, which emerged due to anisotropies in the cortical representations when attention is oriented endogenously. Experiment 3 revealed that object orientation did not modulate object-based selection when attention was oriented exogenously. Our findings suggest that target-object integration, attention distribution, and object orientation modulate object-based selection, but only in combination.

Dispersive liquid-liquid microextraction and gas chromatography accurate mass spectrometry for extraction and non-targeted profiling of volatile and semi-volatile compounds in grape marc distillates.

PubMed

Fontana, Ariel; Rodríguez, Isaac; Cela, Rafael

2018-04-20

The suitability of dispersive liquid-liquid microextraction (DLLME) and gas chromatography accurate mass spectrometry (GC-MS), based on a time-of-flight (TOF) MS analyzer and using electron ionization (EI), for the characterization of volatile and semi-volatile profiles of grape marc distillates (grappa) are evaluated. DLLME conditions are optimized with a selection of compounds, from different chemical families, present in the distillate spirit. Under final working conditions, 2.5 mL of sample and 0.5 mL of organic solvents are consumed in the sample preparation process. The absolute extraction efficiencies ranged from 30 to 100%, depending on the compound. For the same sample volume, DLLME provided higher responses than solid-phase microextraction (SPME) for most of the model compounds. The GC-EI-TOF-MS records of grappa samples were processed using a data mining non-targeted search algorithm. In this way, chromatographic peaks and accurate EI-MS spectra of sample components were linked. The identities of more than 140 of these components are proposed from comparison of their accurate spectra with those in a low resolution EI-MS database, accurate masses of most intense fragment ions of known structure, and available chromatographic retention index. The use of chromatographic and spectral data, associated to the set of components mined from different grappa samples, for multivariate analysis purposes is also illustrated in the study. Copyright © 2018 Elsevier B.V. All rights reserved.

Object selection costs in visual working memory: A diffusion model analysis of the focus of attention.

PubMed

Sewell, David K; Lilburn, Simon D; Smith, Philip L

2016-11-01

A central question in working memory research concerns the degree to which information in working memory is accessible to other cognitive processes (e.g., decision-making). Theories assuming that the focus of attention can only store a single object at a time require the focus to orient to a target representation before further processing can occur. The need to orient the focus of attention implies that single-object accounts typically predict response time costs associated with object selection even when working memory is not full (i.e., memory load is less than 4 items). For other theories that assume storage of multiple items in the focus of attention, predictions depend on specific assumptions about the way resources are allocated among items held in the focus, and how this affects the time course of retrieval of items from the focus. These broad theoretical accounts have been difficult to distinguish because conventional analyses fail to separate components of empirical response times related to decision-making from components related to selection and retrieval processes associated with accessing information in working memory. To better distinguish these response time components from one another, we analyze data from a probed visual working memory task using extensions of the diffusion decision model. Analysis of model parameters revealed that increases in memory load resulted in (a) reductions in the quality of the underlying stimulus representations in a manner consistent with a sample size model of visual working memory capacity and (b) systematic increases in the time needed to selectively access a probed representation in memory. The results are consistent with single-object theories of the focus of attention. The results are also consistent with a subset of theories that assume a multiobject focus of attention in which resource allocation diminishes both the quality and accessibility of the underlying representations. (PsycINFO Database Record (c) 2016 APA, all rights reserved).

Mechanisms underlying intensity-dependent changes in cortical selectivity for frequency-modulated sweeps.

PubMed

Razak, K A

2012-04-01

Frequency-modulated (FM) sweeps are common components of species-specific vocalizations. The intensity of FM sweeps can cover a wide range in the natural environment, but whether intensity affects neural selectivity for FM sweeps is unclear. Bats, such as the pallid bat, which use FM sweeps for echolocation, are suited to address this issue, because the intensity of echoes will vary with target distance. In this study, FM sweep rate selectivity of pallid bat auditory cortex neurons was measured using downward sweeps at different intensities. Neurons became more selective for FM sweep rates present in the bat's echolocation calls as intensity increased. Increased selectivity resulted from stronger inhibition of responses to slower sweep rates. The timing and bandwidth of inhibition generated by frequencies on the high side of the excitatory tuning curve [sideband high-frequency inhibition (HFI)] shape rate selectivity in cortical neurons in the pallid bat. To determine whether intensity-dependent changes in FM rate selectivity were due to altered inhibition, the timing and bandwidth of HFI were quantified at multiple intensities using the two-tone inhibition paradigm. HFI arrived faster relative to excitation as sound intensity increased. The bandwidth of HFI also increased with intensity. The changes in HFI predicted intensity-dependent changes in FM rate selectivity. These data suggest that neural selectivity for a sweep parameter is not static but shifts with intensity due to changes in properties of sideband inhibition.

Ahead of the game protocol: a multi-component, community sport-based program targeting prevention, promotion and early intervention for mental health among adolescent males.

PubMed

Vella, Stewart A; Swann, Christian; Batterham, Marijka; Boydell, Katherine M; Eckermann, Simon; Fogarty, Andrea; Hurley, Diarmuid; Liddle, Sarah K; Lonsdale, Chris; Miller, Andrew; Noetel, Michael; Okely, Anthony D; Sanders, Taren; Telenta, Joanne; Deane, Frank P

2018-03-21

There is a recognised need for targeted community-wide mental health strategies and interventions aimed specifically at prevention and early intervention in promoting mental health. Young males are a high need group who hold particularly negative attitudes towards mental health services, and these views are detrimental for early intervention and help-seeking. Organised sports provide a promising context to deliver community-wide mental health strategies and interventions to adolescent males. The aim of the Ahead of the Game program is to test the effectiveness of a multi-component, community-sport based program targeting prevention, promotion and early intervention for mental health among adolescent males. The Ahead of the Game program will be implemented within a sample drawn from community sporting clubs and evaluated using a sample drawn from a matched control community. Four programs are proposed, including two targeting adolescents, one for parents, and one for sports coaches. One adolescent program aims to increase mental health literacy, intentions to seek and/or provide help for mental health, and to decrease stigmatising attitudes. The second adolescent program aims to increase resilience. The goal of the parent program is to increase parental mental health literacy and confidence to provide help. The coach program is intended to increase coaches' supportive behaviours (e.g., autonomy supportive behaviours), and in turn facilitate high-quality motivation and wellbeing among adolescents. Programs will be complemented by a messaging campaign aimed at adolescents to enhance mental health literacy. The effects of the program on adolescent males' psychological distress and wellbeing will also be explored. Organised sports represent a potentially engaging avenue to promote mental health and prevent the onset of mental health problems among adolescent males. The community-based design, with samples drawn from an intervention and a matched control community, enables evaluation of adolescent males' incremental mental health literacy, help-seeking intentions, stigmatising attitudes, motivation, and resilience impacts from the multi-level, multi-component Ahead of the Game program. Notable risks to the study include self-selection bias, the non-randomised design, and the translational nature of the program. However, strengths include extensive community input, as well as the multi-level and multi-component design. Australian New Zealand Clinical Trials Registry ACTRN12617000709347 . Date registered 17 May 2017. Retrospectively registered.

Selective Attention Enhances Beta-Band Cortical Oscillation to Speech under “Cocktail-Party” Listening Conditions

PubMed Central

Gao, Yayue; Wang, Qian; Ding, Yu; Wang, Changming; Li, Haifeng; Wu, Xihong; Qu, Tianshu; Li, Liang

2017-01-01

Human listeners are able to selectively attend to target speech in a noisy environment with multiple-people talking. Using recordings of scalp electroencephalogram (EEG), this study investigated how selective attention facilitates the cortical representation of target speech under a simulated “cocktail-party” listening condition with speech-on-speech masking. The result shows that the cortical representation of target-speech signals under the multiple-people talking condition was specifically improved by selective attention relative to the non-selective-attention listening condition, and the beta-band activity was most strongly modulated by selective attention. Moreover, measured with the Granger Causality value, selective attention to the single target speech in the mixed-speech complex enhanced the following four causal connectivities for the beta-band oscillation: the ones (1) from site FT7 to the right motor area, (2) from the left frontal area to the right motor area, (3) from the central frontal area to the right motor area, and (4) from the central frontal area to the right frontal area. However, the selective-attention-induced change in beta-band causal connectivity from the central frontal area to the right motor area, but not other beta-band causal connectivities, was significantly correlated with the selective-attention-induced change in the cortical beta-band representation of target speech. These findings suggest that under the “cocktail-party” listening condition, the beta-band oscillation in EEGs to target speech is specifically facilitated by selective attention to the target speech that is embedded in the mixed-speech complex. The selective attention-induced unmasking of target speech may be associated with the improved beta-band functional connectivity from the central frontal area to the right motor area, suggesting a top-down attentional modulation of the speech-motor process. PMID:28239344

Selective Attention Enhances Beta-Band Cortical Oscillation to Speech under "Cocktail-Party" Listening Conditions.

PubMed

Gao, Yayue; Wang, Qian; Ding, Yu; Wang, Changming; Li, Haifeng; Wu, Xihong; Qu, Tianshu; Li, Liang

2017-01-01

Human listeners are able to selectively attend to target speech in a noisy environment with multiple-people talking. Using recordings of scalp electroencephalogram (EEG), this study investigated how selective attention facilitates the cortical representation of target speech under a simulated "cocktail-party" listening condition with speech-on-speech masking. The result shows that the cortical representation of target-speech signals under the multiple-people talking condition was specifically improved by selective attention relative to the non-selective-attention listening condition, and the beta-band activity was most strongly modulated by selective attention. Moreover, measured with the Granger Causality value, selective attention to the single target speech in the mixed-speech complex enhanced the following four causal connectivities for the beta-band oscillation: the ones (1) from site FT7 to the right motor area, (2) from the left frontal area to the right motor area, (3) from the central frontal area to the right motor area, and (4) from the central frontal area to the right frontal area. However, the selective-attention-induced change in beta-band causal connectivity from the central frontal area to the right motor area, but not other beta-band causal connectivities, was significantly correlated with the selective-attention-induced change in the cortical beta-band representation of target speech. These findings suggest that under the "cocktail-party" listening condition, the beta-band oscillation in EEGs to target speech is specifically facilitated by selective attention to the target speech that is embedded in the mixed-speech complex. The selective attention-induced unmasking of target speech may be associated with the improved beta-band functional connectivity from the central frontal area to the right motor area, suggesting a top-down attentional modulation of the speech-motor process.

Investigation of magnetic flux transport and shock formation in a staged Z-pinch

NASA Astrophysics Data System (ADS)

Narkis, J.; Rahman, H. U.; Wessel, F. J.; Beg, F. N.

2017-10-01

Target preheating is an integral component of magnetized inertial fusion in reducing convergence ratio. In the staged Z-pinch concept, it is achieved via one or more shocks. Previous work [Narkis et al., Phys. Plasmas 23, 122706 (2016)] found that shock formation in the target occurred earlier in higher-Z liners due to faster flux transport to the target/liner interface. However, a corresponding increase in magnitude of magnetic pressure was not observed, and target implosion velocity (and therefore shock strength) remained unchanged. To investigate other means of increasing the magnitude of transported flux, a Korteweg-de Vries-Burgers equation from the 1-D single-fluid, resistive magnetohydrodynamic equations is obtained. Solutions to the nondispersive (i.e., Burgers) equation depend on nondimensional coefficients, whose dependence on liner density, temperature, etc., suggests an increase in target implosion velocity, and therefore shock strength, can be obtained by tailoring the mass of a single-liner gas puff to a double-liner configuration. In the selected test cases of 1-D simulated implosions of krypton on deuterium, the peak Mach number increased from ˜ 5 to ˜ 8 . While a notable increase was seen, Mach numbers exceeding 10 (implosion velocities exceeding ˜25 cm/μs) are necessary for adequate shock preheating.

Targeted Cancer Therapy Systems: An In Silico Study of Radiohalogenated Ligands in the Estrogen Receptor and the Synthesis of a Molecular Toolkit for the Fabrication of Customizable Nanoparticles

NASA Astrophysics Data System (ADS)

Barnsley, Kelton K.

Chemotherapy is often limited by off-target toxicity and the development of multi-drug resistance in response to treatment. Strategies which reduce off-target toxicity by passively or actively targeting cancer cells may improve the efficacy of chemotherapy. Herein, two projects relating to targeted therapy are described. In the first project, the binding modes of 1,1-bis(4-hydroxyphenyl)-2-phenylethylenes (THPEs), a class of synthetic estrogens previously developed by our group, in the human estrogen receptor alpha-ligand binding domain were studied using molecular modeling programs YASARA AutoDock and Schrodinger Glide. The results were internally consistent and supported the observation that a bromine or iodine atom at the 2-position of the THPEs contributes positively to their binding in the estrogen receptor. In the second project, a "molecular toolkit" approach to the synthesis of multifunctional nanoparticles was envisioned. Our hypothesis was that the physical and chemical properties of the final product could be defined by controlling the types and relative amounts of prefunctionalized polymer units (PPUs) as well as the emulsification conditions. The design and syntheses of heterobifunctional linkers and other components for a preliminary molecular toolkit are reported, and the literature on select heterobifunctional aliphatic linkers is examined.

Artificial neural networks for acoustic target recognition

NASA Astrophysics Data System (ADS)

Robertson, James A.; Mossing, John C.; Weber, Bruce A.

1995-04-01

Acoustic sensors can be used to detect, track and identify non-line-of-sight targets passively. Attempts to alter acoustic emissions often result in an undesirable performance degradation. This research project investigates the use of neural networks for differentiating between features extracted from the acoustic signatures of sources. Acoustic data were filtered and digitized using a commercially available analog-digital convertor. The digital data was transformed to the frequency domain for additional processing using the FFT. Narrowband peak detection algorithms were incorporated to select peaks above a user defined SNR. These peaks were then used to generate a set of robust features which relate specifically to target components in varying background conditions. The features were then used as input into a backpropagation neural network. A K-means unsupervised clustering algorithm was used to determine the natural clustering of the observations. Comparisons between a feature set consisting of the normalized amplitudes of the first 250 frequency bins of the power spectrum and a set of 11 harmonically related features were made. Initial results indicate that even though some different target types had a tendency to group in the same clusters, the neural network was able to differentiate the targets. Successful identification of acoustic sources under varying operational conditions with high confidence levels was achieved.

Selecting Pixels for Kepler Downlink

NASA Technical Reports Server (NTRS)

Bryson, Stephen T.; Jenkins, Jon M.; Klaus, Todd C.; Cote, Miles T.; Quintana, Elisa V.; Hall, Jennifer R.; Ibrahim, Khadeejah; Chandrasekaran, Hema; Caldwell, Douglas A.; Van Cleve, Jeffrey E.;

Implicit and explicit categorization of natural scenes.

PubMed

Codispoti, Maurizio; Ferrari, Vera; De Cesarei, Andrea; Cardinale, Rossella

2006-01-01

Event-related potential (ERP) studies have consistently found that emotionally arousing (pleasant and unpleasant) pictures elicit a larger late positive potential (LPP) than neutral pictures in a window from 400 to 800 ms after picture onset. In addition, an early ERP component has been reported to vary with emotional arousal in a window from about 150 to 300 ms with affective, compared to neutral stimuli, prompting significantly less positivity over occipito-temporal sites. Similar early and late ERP components have been found in explicit categorization tasks, suggesting that selective attention to target features results in similar cortical changes. Several studies have shown that the affective modulation of the LPP persisted even when the same pictures are repeated several times, when they are presented as distractors, or when participants are engaged in a competing task. These results indicate that categorization of affective stimuli is an obligatory process. On the other hand, perceptual factors (e.g., stimulus size) seem to affect the early ERP component but not the affective modulation of the LPP. Although early and late ERP components vary with stimulus relevance, given that they are differentially affected by stimulus and task manipulations, they appear to index different facets of picture processing.

Sexual selection and population divergence II. Divergence in different sexual traits and signal modalities in field crickets (Teleogryllus oceanicus).

PubMed

Pascoal, Sonia; Mendrok, Magdalena; Wilson, Alastair J; Hunt, John; Bailey, Nathan W

2017-06-01

Sexual selection can target many different types of traits. However, the relative influence of different sexually selected traits during evolutionary divergence is poorly understood. We used the field cricket Teleogryllus oceanicus to quantify and compare how five traits from each of three sexual signal modalities and components diverge among allopatric populations: male advertisement song, cuticular hydrocarbon (CHC) profiles and forewing morphology. Population divergence was unexpectedly consistent: we estimated the among-population (genetic) variance-covariance matrix, D, for all 15 traits, and D max explained nearly two-thirds of its variation. CHC and wing traits were most tightly integrated, whereas song varied more independently. We modeled the dependence of among-population trait divergence on genetic distance estimated from neutral markers to test for signatures of selection versus neutral divergence. For all three sexual trait types, phenotypic variation among populations was largely explained by a neutral model of divergence. Our findings illustrate how phenotypic integration across different types of sexual traits might impose constraints on the evolution of mating isolation and divergence via sexual selection. © 2017 The Author(s). Evolution © 2017 The Society for the Study of Evolution.

WE-AB-209-05: Development of an Ultra-Fast High Quality Whole Breast Radiotherapy Treatment Planning System

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

Sheng, Y; Li, T; Yoo, S

2016-06-15

Purpose: To enable near-real-time (<20sec) and interactive planning without compromising quality for whole breast RT treatment planning using tangential fields. Methods: Whole breast RT plans from 20 patients treated with single energy (SE, 6MV, 10 patients) or mixed energy (ME, 6/15MV, 10 patients) were randomly selected for model training. Additional 20 cases were used as validation cohort. The planning process for a new case consists of three fully automated steps:1. Energy Selection. A classification model automatically selects energy level. To build the energy selection model, principle component analysis (PCA) was applied to the digital reconstructed radiographs (DRRs) of training casesmore » to extract anatomy-energy relationship.2. Fluence Estimation. Once energy is selected, a random forest (RF) model generates the initial fluence. This model summarizes the relationship between patient anatomy’s shape based features and the output fluence. 3. Fluence Fine-tuning. This step balances the overall dose contribution throughout the whole breast tissue by automatically selecting reference points and applying centrality correction. Fine-tuning works at beamlet-level until the dose distribution meets clinical objectives. Prior to finalization, physicians can also make patient-specific trade-offs between target coverage and high-dose volumes.The proposed method was validated by comparing auto-plans with manually generated clinical-plans using Wilcoxon Signed-Rank test. Results: In 19/20 cases the model suggested the same energy combination as clinical-plans. The target volume coverage V100% was 78.1±4.7% for auto-plans, and 79.3±4.8% for clinical-plans (p=0.12). Volumes receiving 105% Rx were 69.2±78.0cc for auto-plans compared to 83.9±87.2cc for clinical-plans (p=0.13). The mean V10Gy, V20Gy of the ipsilateral lung was 24.4±6.7%, 18.6±6.0% for auto plans and 24.6±6.7%, 18.9±6.1% for clinical-plans (p=0.04, <0.001). Total computational time for auto-plans was < 20s. Conclusion: We developed an automated method that generates breast radiotherapy plans with accurate energy selection, similar target volume coverage, reduced hotspot volumes, and significant reduction in planning time, allowing for near-real-time planning.« less

An integrated strategy using UPLC-QTOF-MSE and UPLC-QTOF-MRM (enhanced target) for pharmacokinetics study of wine processed Schisandra Chinensis fructus in rats.

PubMed

Liu, Kuangyi; Song, Yonggui; Liu, Yali; Peng, Mi; Li, Hanyun; Li, Xueliang; Feng, Bingwei; Xu, Pengfei; Su, Dan

2017-05-30

Currently the pharmacokinetic (PK) research of herbal medicines is still limited and facing critical technical challenges on quantitative analysis of multi-components from biological matrices which often accompanied by lacking of authentic standards and low concentration. This present work contributes to the development of an integrated strategy for extensive pharmacokinetics assessments, and a selective and sensitive method independent of authentic standards for multi-components analysis based on the use of ultra-performance liquid chromatography/quadrupole-time-of-flight/MS E (UPLC-TOF-MS E ) and UPLC-TOF-MRM (rnhanced target). Initially, phytochemicals were identified by UPLC-TOF-MS E analysis, subsequently the identified components were matched with authentic standards and pre-classified, and UPLC-QTOF-MRM method optimized and developed. To guarantee reliable results, three rules are necessary: (1) detection with a mass error of less than 5ppm; (2) same class chemical compositions with structural high similarity between analytes with and without authentic reference substance; (3) a matching retention time between TOF-MRM mode and TOF-MS E within 0.2min. The developed and validated method was applied for the simultaneous determination of 12 lignans in rat plasma after administered with wine processed Schisandra Chinensis fructus (WPSCF) extract. Such an approach was found capable of providing extensive pharmacokinetic profiles of multi-components absorbed into blood after oral administrated with WPSCF extract. The results also indicated that significant difference in pharmacokinetics parameters of dibenzocyclooctadiene lignans was observed between schizandrin and gomisin compounds. For lignans, the absorption via gastrointestinal tract were all rapid and maintained relatively long retention time, especially for schisantherin A and schisantherin B with higher plasma exposure. Copyright © 2017 Elsevier B.V. All rights reserved.

Characteristics of the personal and environmental components of person-environment fit in very old age: a comparison between people with self-reported Parkinson's disease and matched controls.

PubMed

Slaug, Björn; Nilsson, Maria H; Iwarsson, Susanne

2013-12-01

To investigate differences and similarities in person-environment (P-E) fit problems between very old people with self-reported Parkinson's disease (PD) and matched controls. Data collected for the cross-national ENABLE-AGE Survey Study were used to identify people with self-reported PD (n = 20), and to select three matched controls per individual (n = 60). The matching criteria were age (mean = 82 years), sex, country, and type of housing. The data analysis targeted P-E fit (i.e. accessibility) problems, including studying the personal and environmental components separately. The personal component was analyzed in terms of functional limitations, and the environmental component in terms of physical environmental barriers. In comparison to the matched controls, the participants with PD had more functional limitations, used more mobility devices and were subjected to more P-E fit problems, though the number of environmental barriers did not differ from the controls. In the PD sample, P-E fit problems were significantly stronger associated with poor balance and incoordination, and the environmental barriers that generated the most severe P-E fit problems were more often located to the exterior surroundings of the housing compared to the controls. The novel contribution of this explorative study is the demonstration of the type of knowledge that can be generated by unfolding and comparing the composition of P-E fit (accessibility) problems among people with self-reported PD as compared with matched controls. The knowledge thereby generated can be used to develop more targeted rehabilitation approaches, efficient housing adaptation services and societal planning for people with neurodegenerative disorders.

Key steps in type III secretion system (T3SS) towards translocon assembly with potential sensor at plant plasma membrane.

PubMed

Ji, Hongtao; Dong, Hansong

2015-09-01

Many plant- and animal-pathogenic Gram-negative bacteria employ the type III secretion system (T3SS) to translocate effector proteins from bacterial cells into the cytosol of eukaryotic host cells. The effector translocation occurs through an integral component of T3SS, the channel-like translocon, assembled by hydrophilic and hydrophobic proteinaceous translocators in a two-step process. In the first, hydrophilic translocators localize to the tip of a proteinaceous needle in animal pathogens, or a proteinaceous pilus in plant pathogens, and associate with hydrophobic translocators, which insert into host plasma membranes in the second step. However, the pilus needs to penetrate plant cell walls in advance. All hydrophilic translocators so far identified in plant pathogens are characteristic of harpins: T3SS accessory proteins containing a unitary hydrophilic domain or an additional enzymatic domain. Two-domain harpins carrying a pectate lyase domain potentially target plant cell walls and facilitate the penetration of the pectin-rich middle lamella by the bacterial pilus. One-domain harpins target plant plasma membranes and may play a crucial role in translocon assembly, which may also involve contrapuntal associations of hydrophobic translocators. In all cases, sensory components in the target plasma membrane are indispensable for the membrane recognition of translocators and the functionality of the translocon. The conjectural sensors point to membrane lipids and proteins, and a phosphatidic acid and an aquaporin are able to interact with selected harpin-type translocators. Interactions between translocators and their sensors at the target plasma membrane are assumed to be critical for translocon assembly. © 2014 BSPP AND JOHN WILEY & SONS LTD.

Exploring the switching of the focus of attention within working memory: A combined event-related potential and behavioral study.

PubMed

Frenken, Marius; Berti, Stefan

2018-04-01

Working memory enables humans to maintain selected information for cognitive processes and ensures instant access to the memorized contents. Theories suggest that switching the focus of attention between items within working memory realizes the access. This is reflected in object-switching costs in response times when the item for the task processing is to be changed. Another correlate of attentional allocation in working memory is the P3a-component of the human event-related potential. The aim of this study was to demonstrate that switching of attention within working memory is a separable processing step. Participants completed a cued memory-updating task in which they were instructed to update one memory item at a time out of a memory list of four digits by applying a mathematical operation indicated by a target sign. The hypotheses predicted (1) prolonged updating times in switch (different item compared to previous trial) versus repetition trials (same item), (2) an influence of cues (valid/neutral) presented before the mathematical target on switching costs, and (3) that the P3a-component is more pronounced in the cue-target interval in the valid cue condition and more pronounced in the post-target interval in the neutral cue condition. A student's t-test verified the first hypothesis, repeated-measurement analyses of variance demonstrated that hypotheses 2 and 3 should be rejected. Results suggest that switching of attention within working memory could not be separated from further processing steps and retro-cue benefits are not due to a head start of retrieval as well as that switch costs represent internal processes. Copyright © 2018 Elsevier B.V. All rights reserved.

Effects of eribulin, vincristine, paclitaxel and ixabepilone on fast axonal transport and kinesin-1 driven microtubule gliding: implications for chemotherapy-induced peripheral neuropathy.

PubMed

LaPointe, Nichole E; Morfini, Gerardo; Brady, Scott T; Feinstein, Stuart C; Wilson, Leslie; Jordan, Mary Ann

2013-07-01

Chemotherapy-induced peripheral neuropathy (CIPN) is a serious, painful and dose-limiting side effect of cancer drugs that target microtubules. The mechanisms underlying the neuronal damage are unknown, but may include disruption of fast axonal transport, an essential microtubule-based process that moves cellular components over long distances between neuronal cell bodies and nerve terminals. This idea is supported by the "dying back" pattern of degeneration observed in CIPN, and by the selective vulnerability of sensory neurons bearing the longest axonal projections. In this study, we test the hypothesis that microtubule-targeting drugs disrupt fast axonal transport using vesicle motility assays in isolated squid axoplasm and a cell-free microtubule gliding assay with defined components. We compare four clinically-used drugs, eribulin, vincristine, paclitaxel and ixabepilone. Of these, eribulin is associated with a relatively low incidence of severe neuropathy, while vincristine has a relatively high incidence. In vesicle motility assays, we found that all four drugs inhibited anterograde (conventional kinesin-dependent) fast axonal transport, with the potency being vincristine=ixabepilone>paclitaxel=eribulin. Interestingly, eribulin and paclitaxel did not inhibit retrograde (cytoplasmic dynein-dependent) fast axonal transport, in contrast to vincristine and ixabepilone. Similarly, vincristine and ixabepilone both exerted significant inhibitory effects in an in vitro microtubule gliding assay consisting of recombinant kinesin (kinesin-1) and microtubules composed of purified bovine brain tubulin, whereas paclitaxel and eribulin had negligible effects. Our results suggest that (i) inhibition of microtubule-based fast axonal transport may be a significant contributor to neurotoxicity induced by microtubule-targeting drugs, and (ii) that individual microtubule-targeting drugs affect fast axonal transport through different mechanisms. Copyright © 2013 Elsevier Inc. All rights reserved.

Evolution in fluctuating environments: decomposing selection into additive components of the Robertson-Price equation.

PubMed

Engen, Steinar; Saether, Bernt-Erik

2014-03-01

We analyze the stochastic components of the Robertson-Price equation for the evolution of quantitative characters that enables decomposition of the selection differential into components due to demographic and environmental stochasticity. We show how these two types of stochasticity affect the evolution of multivariate quantitative characters by defining demographic and environmental variances as components of individual fitness. The exact covariance formula for selection is decomposed into three components, the deterministic mean value, as well as stochastic demographic and environmental components. We show that demographic and environmental stochasticity generate random genetic drift and fluctuating selection, respectively. This provides a common theoretical framework for linking ecological and evolutionary processes. Demographic stochasticity can cause random variation in selection differentials independent of fluctuating selection caused by environmental variation. We use this model of selection to illustrate that the effect on the expected selection differential of random variation in individual fitness is dependent on population size, and that the strength of fluctuating selection is affected by how environmental variation affects the covariance in Malthusian fitness between individuals with different phenotypes. Thus, our approach enables us to partition out the effects of fluctuating selection from the effects of selection due to random variation in individual fitness caused by demographic stochasticity. © 2013 The Author(s). Evolution © 2013 The Society for the Study of Evolution.

Protein-RNA specificity by high-throughput principal component analysis of NMR spectra.

PubMed

Collins, Katherine M; Oregioni, Alain; Robertson, Laura E; Kelly, Geoff; Ramos, Andres

2015-03-31

Defining the RNA target selectivity of the proteins regulating mRNA metabolism is a key issue in RNA biology. Here we present a novel use of principal component analysis (PCA) to extract the RNA sequence preference of RNA binding proteins. We show that PCA can be used to compare the changes in the nuclear magnetic resonance (NMR) spectrum of a protein upon binding a set of quasi-degenerate RNAs and define the nucleobase specificity. We couple this application of PCA to an automated NMR spectra recording and processing protocol and obtain an unbiased and high-throughput NMR method for the analysis of nucleobase preference in protein-RNA interactions. We test the method on the RNA binding domains of three important regulators of RNA metabolism. © The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research.

Carbon fiber composites application in ITER plasma facing components

NASA Astrophysics Data System (ADS)

Barabash, V.; Akiba, M.; Bonal, J. P.; Federici, G.; Matera, R.; Nakamura, K.; Pacher, H. D.; Rödig, M.; Vieider, G.; Wu, C. H.

1998-10-01

Carbon Fiber Composites (CFCs) are one of the candidate armour materials for the plasma facing components of the International Thermonuclear Experimental Reactor (ITER). For the present reference design, CFC has been selected as armour for the divertor target near the plasma strike point mainly because of unique resistance to high normal and off-normal heat loads. It does not melt under disruptions and might have higher erosion lifetime in comparison with other possible armour materials. Issues related to CFC application in ITER are described in this paper. They include erosion lifetime, tritium codeposition with eroded material and possible methods for the removal of the codeposited layers, neutron irradiation effect, development of joining technologies with heat sink materials, and thermomechanical performance. The status of the development of new advanced CFCs for ITER application is also described. Finally, the remaining R&D needs are critically discussed.

Using suggestion to model different types of automatic writing.

PubMed

Walsh, E; Mehta, M A; Oakley, D A; Guilmette, D N; Gabay, A; Halligan, P W; Deeley, Q

2014-05-01

Our sense of self includes awareness of our thoughts and movements, and our control over them. This feeling can be altered or lost in neuropsychiatric disorders as well as in phenomena such as "automatic writing" whereby writing is attributed to an external source. Here, we employed suggestion in highly hypnotically suggestible participants to model various experiences of automatic writing during a sentence completion task. Results showed that the induction of hypnosis, without additional suggestion, was associated with a small but significant reduction of control, ownership, and awareness for writing. Targeted suggestions produced a double dissociation between thought and movement components of writing, for both feelings of control and ownership, and additionally, reduced awareness of writing. Overall, suggestion produced selective alterations in the control, ownership, and awareness of thought and motor components of writing, thus enabling key aspects of automatic writing, observed across different clinical and cultural settings, to be modelled. Copyright © 2014. Published by Elsevier Inc.

Marine snail venoms: use and trends in receptor and channel neuropharmacology.

PubMed

Favreau, Philippe; Stöcklin, Reto

2009-10-01

Venoms are rich mixtures of mainly peptides and proteins evolved by nature to catch and digest preys or for protection against predators. They represent extensive sources of potent and selective bioactive compounds that can lead to original active ingredients, for use as drugs, as pharmacological tools in research and for the biotechnology industry. Among the most fascinating venomous animals, marine snails offer a unique set of pharmacologically active components, targeting a wide diversity of receptors and ion channels. Recent advances still continue to demonstrate their huge neuropharmacological potential. In the quest for interesting pharmacological profiles, researchers face a vast number of venom components to investigate within time and technological constraints. A brief perspective on marine snail venom's complexity and features is given followed by the different discovery strategies and pharmacological approaches, exemplified with some recent developments. These advances will hopefully help further uncovering new pharmacologically important venom molecules.

Start-Stop Moment Optimization of Range Extender and Control Strategy Design for Extended -Range Electric Vehicle

NASA Astrophysics Data System (ADS)

Zhao, Jing-bo; Han, Bing-yuan; Bei, Shao-yi

2017-10-01

Range extender is the core component of E-REV, its start-stop control determines the operation modes of vehicle. This paper based on a certain type of E-REV, researched constant power control strategy of range extender in extended-range model, to target range as constraint condition, combined with different driving cycle conditions, by correcting battery SOC for range extender start-stop moment, optimized the control strategy of range extender, and established the vehicle and range extender start-stop control simulation model. Selected NEDC and UDDS conditions simulation results show that: under certain target mileage, the range extender running time reduced by 37.2% and 28.2% in the NEDC condition, and running time UDDS conditions were reduced by 40.6% and 33.5% in the UDDS condition, reached the purpose of meeting the vehicle mileage and reducing consumption and emission.

Analyte-Triggered DNA-Probe Release from a Triplex Molecular Beacon for Nanopore Sensing.

PubMed

Guo, Bingyuan; Sheng, Yingying; Zhou, Ke; Liu, Quansheng; Liu, Lei; Wu, Hai-Chen

2018-03-26

A new nanopore sensing strategy based on triplex molecular beacon was developed for the detection of specific DNA or multivalent proteins. The sensor is composed of a triplex-forming molecular beacon and a stem-forming DNA component that is modified with a host-guest complex. Upon target DNA hybridizing with the molecular beacon loop or multivalent proteins binding to the recognition elements on the stem, the DNA probe is released and produces highly characteristic current signals when translocated through α-hemolysin. The frequency of current signatures can be used to quantify the concentrations of the target molecules. This sensing approach provides a simple, quick, and modular tool for the detection of specific macromolecules with high sensitivity and excellent selectivity. It may find useful applications in point-of-care diagnostics with a portable nanopore kit in the future. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Plasticity of preferred body temperatures as means of coping with climate change?

PubMed Central

Gvoždík, Lumír

2012-01-01

Thermoregulatory behaviour represents an important component of ectotherm non-genetic adaptive capacity that mitigates the impact of ongoing climate change. The buffering role of behavioural thermoregulation has been attributed solely to the ability to maintain near optimal body temperature for sufficiently extended periods under altered thermal conditions. The widespread occurrence of plastic modification of target temperatures that an ectotherm aims to achieve (preferred body temperatures) has been largely overlooked. I argue that plasticity of target temperatures may significantly contribute to an ectotherm's adaptive capacity. Its contribution to population persistence depends on both the effectiveness of acute thermoregulatory adjustments (reactivity) in buffering selection pressures in a changing thermal environment, and the total costs of thermoregulation (i.e. reactivity and plasticity) in a given environment. The direction and magnitude of plastic shifts in preferred body temperatures can be incorporated into mechanistic models, to improve predictions of the impact of global climate change on ectotherm populations. PMID:22072284

Plasticity of preferred body temperatures as means of coping with climate change?

PubMed

Gvozdík, Lumír

2012-04-23

Thermoregulatory behaviour represents an important component of ectotherm non-genetic adaptive capacity that mitigates the impact of ongoing climate change. The buffering role of behavioural thermoregulation has been attributed solely to the ability to maintain near optimal body temperature for sufficiently extended periods under altered thermal conditions. The widespread occurrence of plastic modification of target temperatures that an ectotherm aims to achieve (preferred body temperatures) has been largely overlooked. I argue that plasticity of target temperatures may significantly contribute to an ectotherm's adaptive capacity. Its contribution to population persistence depends on both the effectiveness of acute thermoregulatory adjustments (reactivity) in buffering selection pressures in a changing thermal environment, and the total costs of thermoregulation (i.e. reactivity and plasticity) in a given environment. The direction and magnitude of plastic shifts in preferred body temperatures can be incorporated into mechanistic models, to improve predictions of the impact of global climate change on ectotherm populations.

Determining the multi-scale hedge ratios of stock index futures using the lower partial moments method

NASA Astrophysics Data System (ADS)

Dai, Jun; Zhou, Haigang; Zhao, Shaoquan

2017-01-01

This paper considers a multi-scale future hedge strategy that minimizes lower partial moments (LPM). To do this, wavelet analysis is adopted to decompose time series data into different components. Next, different parametric estimation methods with known distributions are applied to calculate the LPM of hedged portfolios, which is the key to determining multi-scale hedge ratios over different time scales. Then these parametric methods are compared with the prevailing nonparametric kernel metric method. Empirical results indicate that in the China Securities Index 300 (CSI 300) index futures and spot markets, hedge ratios and hedge efficiency estimated by the nonparametric kernel metric method are inferior to those estimated by parametric hedging model based on the features of sequence distributions. In addition, if minimum-LPM is selected as a hedge target, the hedging periods, degree of risk aversion, and target returns can affect the multi-scale hedge ratios and hedge efficiency, respectively.

Thermal-electric coupled-field finite element modeling and experimental testing of high-temperature ion sources for the production of radioactive ion beams

NASA Astrophysics Data System (ADS)

Manzolaro, M.; Meneghetti, G.; Andrighetto, A.; Vivian, G.; D'Agostini, F.

2016-02-01

In isotope separation on line facilities the target system and the related ion source are two of the most critical components. In the context of the selective production of exotic species (SPES) project, a 40 MeV 200 μA proton beam directly impinges a uranium carbide target, generating approximately 1013 fissions per second. The radioactive isotopes produced in this way are then directed to the ion source, where they can be ionized and finally accelerated to the subsequent areas of the facility. In this work both the surface ion source and the plasma ion source adopted for the SPES facility are presented and studied by means of numerical thermal-electric models. Then, numerical results are compared with temperature and electric potential difference measurements, and finally the main advantages of the proposed simulation approach are discussed.

Ibrutinib (PCI-32765) in Chronic Lymphocytic Leukemia

PubMed Central

Jain, Nitin; O’Brien, Susan

2015-01-01

SYNOPSIS B-cell receptor (BCR) signaling is essential for chronic lymphocytic leukemia (CLL) cell survival. Many kinases in the BCR signaling pathway are currently being studied as potential therapeutic targets. These include Lyn, Syk, PI3 and Bruton tyrosine (BTK). Ibrutinib (PCI-32765) is a novel first-in-class selective inhibitor of BTK. Preclinical evidence suggests that ibrutinib inhibits CLL cell survival and proliferation. In addition, it also affects CLL cell migration and homing. Early clinical data in CLL and non-Hodgkin’s lymphoma patients is very encouraging. In relapsed-refractory patients with CLL, a 67% response rate was observed (420mg dose cohort) with single-agent ibrutinib. Long-term follow-up of these studies and other ongoing/planned studies of ibrutinib either as single-agent or in combination with monoclonal antibodies and chemoimmunotherapy is eagerly awaited. It is likely that ibrutinib and other drugs targeting the BCR pathway will become an integral component of CLL therapy. PMID:23915749

A Novel Bifunctional Alkylphenol Anesthetic Allows Characterization of γ-Aminobutyric Acid, Type A (GABAA), Receptor Subunit Binding Selectivity in Synaptosomes.

PubMed

Woll, Kellie A; Murlidaran, Sruthi; Pinch, Benika J; Hénin, Jérôme; Wang, Xiaoshi; Salari, Reza; Covarrubias, Manuel; Dailey, William P; Brannigan, Grace; Garcia, Benjamin A; Eckenhoff, Roderic G

2016-09-23

Propofol, an intravenous anesthetic, is a positive modulator of the GABAA receptor, but the mechanistic details, including the relevant binding sites and alternative targets, remain disputed. Here we undertook an in-depth study of alkylphenol-based anesthetic binding to synaptic membranes. We designed, synthesized, and characterized a chemically active alkylphenol anesthetic (2-((prop-2-yn-1-yloxy)methyl)-5-(3-(trifluoromethyl)-3H-diazirin-3-yl)phenol, AziPm-click (1)), for affinity-based protein profiling (ABPP) of propofol-binding proteins in their native state within mouse synaptosomes. The ABPP strategy captured ∼4% of the synaptosomal proteome, including the unbiased capture of five α or β GABAA receptor subunits. Lack of γ2 subunit capture was not due to low abundance. Consistent with this, independent molecular dynamics simulations with alchemical free energy perturbation calculations predicted selective propofol binding to interfacial sites, with higher affinities for α/β than γ-containing interfaces. The simulations indicated hydrogen bonding is a key component leading to propofol-selective binding within GABAA receptor subunit interfaces, with stable hydrogen bonds observed between propofol and α/β cavity residues but not γ cavity residues. We confirmed this by introducing a hydrogen bond-null propofol analogue as a protecting ligand for targeted-ABPP and observed a lack of GABAA receptor subunit protection. This investigation demonstrates striking interfacial GABAA receptor subunit selectivity in the native milieu, suggesting that asymmetric occupancy of heteropentameric ion channels by alkylphenol-based anesthetics is sufficient to induce modulation of activity. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

A Novel Bifunctional Alkylphenol Anesthetic Allows Characterization of γ-Aminobutyric Acid, Type A (GABAA), Receptor Subunit Binding Selectivity in Synaptosomes*

PubMed Central

Woll, Kellie A.; Murlidaran, Sruthi; Pinch, Benika J.; Hénin, Jérôme; Wang, Xiaoshi; Salari, Reza; Covarrubias, Manuel; Dailey, William P.; Brannigan, Grace; Garcia, Benjamin A.; Eckenhoff, Roderic G.

2016-01-01

Propofol, an intravenous anesthetic, is a positive modulator of the GABAA receptor, but the mechanistic details, including the relevant binding sites and alternative targets, remain disputed. Here we undertook an in-depth study of alkylphenol-based anesthetic binding to synaptic membranes. We designed, synthesized, and characterized a chemically active alkylphenol anesthetic (2-((prop-2-yn-1-yloxy)methyl)-5-(3-(trifluoromethyl)-3H-diazirin-3-yl)phenol, AziPm-click (1)), for affinity-based protein profiling (ABPP) of propofol-binding proteins in their native state within mouse synaptosomes. The ABPP strategy captured ∼4% of the synaptosomal proteome, including the unbiased capture of five α or β GABAA receptor subunits. Lack of γ2 subunit capture was not due to low abundance. Consistent with this, independent molecular dynamics simulations with alchemical free energy perturbation calculations predicted selective propofol binding to interfacial sites, with higher affinities for α/β than γ-containing interfaces. The simulations indicated hydrogen bonding is a key component leading to propofol-selective binding within GABAA receptor subunit interfaces, with stable hydrogen bonds observed between propofol and α/β cavity residues but not γ cavity residues. We confirmed this by introducing a hydrogen bond-null propofol analogue as a protecting ligand for targeted-ABPP and observed a lack of GABAA receptor subunit protection. This investigation demonstrates striking interfacial GABAA receptor subunit selectivity in the native milieu, suggesting that asymmetric occupancy of heteropentameric ion channels by alkylphenol-based anesthetics is sufficient to induce modulation of activity. PMID:27462076

77 FR 38347 - Self-Regulatory Organizations; The NASDAQ Stock Market LLC; Notice of Filing of Proposed Rule...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-06-27

... Component of the Alpha Pair. To calculate the daily total return today of a Target Component or a Benchmark... Benchmark Component, respectively, would be subtracted from today's closing market price for the Target...''). The Price Difference would be added to any declared dividend, if today were an ``ex-dividend'' date...

Capture-SELEX: Selection of DNA Aptamers for Aminoglycoside Antibiotics

PubMed Central

2012-01-01

Small organic molecules are challenging targets for an aptamer selection using the SELEX technology (SELEX—Systematic Evolution of Ligans by EXponential enrichment). Often they are not suitable for immobilization on solid surfaces, which is a common procedure in known aptamer selection methods. The Capture-SELEX procedure allows the selection of DNA aptamers for solute targets. A special SELEX library was constructed with the aim to immobilize this library on magnetic beads or other surfaces. For this purpose a docking sequence was incorporated into the random region of the library enabling hybridization to a complementary oligo fixed on magnetic beads. Oligonucleotides of the library which exhibit high affinity to the target and a secondary structure fitting to the target are released from the beads for binding to the target during the aptamer selection process. The oligonucleotides of these binding complexes were amplified, purified, and immobilized via the docking sequence to the magnetic beads as the starting point of the following selection round. Based on this Capture-SELEX procedure, the successful DNA aptamer selection for the aminoglycoside antibiotic kanamycin A as a small molecule target is described. PMID:23326761

Computational selection of antibody-drug conjugate targets for breast cancer

PubMed Central

Fauteux, François; Hill, Jennifer J.; Jaramillo, Maria L.; Pan, Youlian; Phan, Sieu; Famili, Fazel; O'Connor-McCourt, Maureen

2016-01-01

The selection of therapeutic targets is a critical aspect of antibody-drug conjugate research and development. In this study, we applied computational methods to select candidate targets overexpressed in three major breast cancer subtypes as compared with a range of vital organs and tissues. Microarray data corresponding to over 8,000 tissue samples were collected from the public domain. Breast cancer samples were classified into molecular subtypes using an iterative ensemble approach combining six classification algorithms and three feature selection techniques, including a novel kernel density-based method. This feature selection method was used in conjunction with differential expression and subcellular localization information to assemble a primary list of targets. A total of 50 cell membrane targets were identified, including one target for which an antibody-drug conjugate is in clinical use, and six targets for which antibody-drug conjugates are in clinical trials for the treatment of breast cancer and other solid tumors. In addition, 50 extracellular proteins were identified as potential targets for non-internalizing strategies and alternative modalities. Candidate targets linked with the epithelial-to-mesenchymal transition were identified by analyzing differential gene expression in epithelial and mesenchymal tumor-derived cell lines. Overall, these results show that mining human gene expression data has the power to select and prioritize breast cancer antibody-drug conjugate targets, and the potential to lead to new and more effective cancer therapeutics. PMID:26700623

The role of the P3 and CNV components in voluntary and automatic temporal orienting: A high spatial-resolution ERP study.

PubMed

Mento, Giovanni

2017-12-01

A main distinction has been proposed between voluntary and automatic mechanisms underlying temporal orienting (TO) of selective attention. Voluntary TO implies the endogenous directing of attention induced by symbolic cues. Conversely, automatic TO is exogenously instantiated by the physical properties of stimuli. A well-known example of automatic TO is sequential effects (SEs), which refer to the adjustments in participants' behavioral performance as a function of the trial-by-trial sequential distribution of the foreperiod between two stimuli. In this study a group of healthy adults underwent a cued reaction time task purposely designed to assess both voluntary and automatic TO. During the task, both post-cue and post-target event-related potentials (ERPs) were recorded by means of a high spatial resolution EEG system. In the results of the post-cue analysis, the P3a and P3b were identified as two distinct ERP markers showing distinguishable spatiotemporal features and reflecting automatic and voluntary a priori expectancy generation, respectively. The brain source reconstruction further revealed that distinct cortical circuits supported these two temporally dissociable components. Namely, the voluntary P3b was supported by a left sensorimotor network, while the automatic P3a was generated by a more distributed frontoparietal circuit. Additionally, post-cue contingent negative variation (CNV) and post-target P3 modulations were observed as common markers of voluntary and automatic expectancy implementation and response selection, although partially dissociable neural networks subserved these two mechanisms. Overall, these results provide new electrophysiological evidence suggesting that distinct neural substrates can be recruited depending on the voluntary or automatic cognitive nature of the cognitive mechanisms subserving TO. Copyright © 2017 Elsevier Ltd. All rights reserved.

Enhanced Flight Termination System (EFTS): Flight Demonstration and Results

NASA Technical Reports Server (NTRS)

Tow, David; Arce, Dennis

2008-01-01

The Enhanced Flight Termination System (EFTS) program was initiated and propelled due to the inadvertent terminations of Global Hawk and the Strategic Target System and the NASA Inspector General's assessment letter and recommendations regarding the exploration of low-cost, lightweight space COMSEC for FTS. Additionally, the standard analog and high alphabet systems most commonly used in FTS are secure, but not encrypted. A study group was initiated to select and document a robust, affordable, reliable technology that provides encrypted FTS capability. A flight demonstration was conducted to gain experience using EFTS in an operational environment, provide confidence in the use of the EFTS components, integrate EFTS into an existing range infrastructure to demonstrate the scalability of system components, to provide a command controller that generated the EFTS waveform using an existing range infrastructure, and to provide a report documenting the results of the demonstration. The primary goal of the demonstration was to obtain operational experience with EFTS. Areas of operational experience include: mission planning, pre-flight configuration and testing, mission monitoring and recording, vehicle termination, developing mission procedures. and post mission data reduction and other post mission activities. An Advanced Medium-Range Air-to-Air Missile (AMRAAM) was selected to support the EFTS demonstration due to interest in future use of EFTS by the AMRAAM program, familiarity of EFTS by range personnel, and the availability of existing operational environment to support EFTS testing with available program funding. For demonstration purposes, the AMRAAM was successfully terminated using an EFTS receiver and successfully demonstrating EFTS. The EFTS monitoring software with spectrum analyzer and digital graphical display of aircraft, missile, and target were also demonstrated.

Gas chromatography/mass spectrometry based component profiling and quality prediction for Japanese sake.

PubMed

Mimura, Natsuki; Isogai, Atsuko; Iwashita, Kazuhiro; Bamba, Takeshi; Fukusaki, Eiichiro

2014-10-01

Sake is a Japanese traditional alcoholic beverage, which is produced by simultaneous saccharification and alcohol fermentation of polished and steamed rice by Aspergillus oryzae and Saccharomyces cerevisiae. About 300 compounds have been identified in sake, and the contribution of individual components to the sake flavor has been examined at the same time. However, only a few compounds could explain the characteristics alone and most of the attributes still remain unclear. The purpose of this study was to examine the relationship between the component profile and the attributes of sake. Gas chromatography coupled with mass spectrometry (GC/MS)-based non-targeted analysis was employed to obtain the low molecular weight component profile of Japanese sake including both nonvolatile and volatile compounds. Sake attributes and overall quality were assessed by analytical descriptive sensory test and the prediction model of the sensory score from the component profile was constructed by means of orthogonal projections to latent structures (OPLS) regression analysis. Our results showed that 12 sake attributes [ginjo-ka (aroma of premium ginjo sake), grassy/aldehydic odor, sweet aroma/caramel/burnt odor, sulfury odor, sour taste, umami, bitter taste, body, amakara (dryness), aftertaste, pungent/smoothness and appearance] and overall quality were accurately explained by component profiles. In addition, we were able to select statistically significant components according to variable importance on projection (VIP). Our methodology clarified the correlation between sake attribute and 200 low molecular components and presented the importance of each component thus, providing new insights to the flavor study of sake. Copyright © 2014 The Society for Biotechnology, Japan. Published by Elsevier B.V. All rights reserved.

Small molecules targeting viral RNA.

PubMed

Hermann, Thomas

2016-11-01

Highly conserved noncoding RNA (ncRNA) elements in viral genomes and transcripts offer new opportunities to expand the repertoire of drug targets for the development of antiinfective therapy. Ligands binding to ncRNA architectures are able to affect interactions, structural stability or conformational changes and thereby block processes essential for viral replication. Proof of concept for targeting functional RNA by small molecule inhibitors has been demonstrated for multiple viruses with RNA genomes. Strategies to identify antiviral compounds as inhibitors of ncRNA are increasingly emphasizing consideration of drug-like properties of candidate molecules emerging from screening and ligand design. Recent efforts of antiviral lead discovery for RNA targets have provided drug-like small molecules that inhibit viral replication and include inhibitors of human immunodeficiency virus (HIV), hepatitis C virus (HCV), severe respiratory syndrome coronavirus (SARS CoV), and influenza A virus. While target selectivity remains a challenge for the discovery of useful RNA-binding compounds, a better understanding is emerging of properties that define RNA targets amenable for inhibition by small molecule ligands. Insight from successful approaches of targeting viral ncRNA in HIV, HCV, SARS CoV, and influenza A will provide a basis for the future exploration of RNA targets for therapeutic intervention in other viral pathogens which create urgent, unmet medical needs. Viruses for which targeting ncRNA components in the genome or transcripts may be promising include insect-borne flaviviruses (Dengue, Zika, and West Nile) and filoviruses (Ebola and Marburg). WIREs RNA 2016, 7:726-743. doi: 10.1002/wrna.1373 For further resources related to this article, please visit the WIREs website. © 2016 Wiley Periodicals, Inc.

Correlation study between vibrational environmental and failure rates of civil helicopter components

NASA Technical Reports Server (NTRS)

Alaniz, O.

1979-01-01

An investigation of two selected helicopter types, namely, the Models 206A/B and 212, is reported. An analysis of the available vibration and reliability data for these two helicopter types resulted in the selection of ten components located in five different areas of the helicopter and consisting primarily of instruments, electrical components, and other noncritical flight hardware. The potential for advanced technology in suppressing vibration in helicopters was assessed. The are still several unknowns concerning both the vibration environment and the reliability of helicopter noncritical flight components. Vibration data for the selected components were either insufficient or inappropriate. The maintenance data examined for the selected components were inappropriate due to variations in failure mode identification, inconsistent reporting, or inaccurate informaton.

Neurons with object-centered spatial selectivity in macaque SEF: do they represent locations or rules?

PubMed

Tremblay, Léon; Gettner, Sonya N; Olson, Carl R

2002-01-01

In macaque monkeys performing a task that requires eye movements to the leftmost or rightmost of two dots in a horizontal array, some neurons in the supplementary eye field (SEF) fire differentially according to which side of the array is the target regardless of the array's location on the screen. We refer to these neurons as exhibiting selectivity for object-centered location. This form of selectivity might arise from involvement of the neurons in either of two processes: representing the locations of targets or representing the rules by which targets are selected. To distinguish between these possibilities, we monitored neuronal activity in the SEF of two monkeys performing a task that required the selection of targets by either an object-centered spatial rule or a color rule. On each trial, a sample array consisting of two side-by-side dots appeared; then a cue flashed on one dot; then the display vanished and a delay ensued. Next a target array consisting of two side-by-side dots appeared at an unpredictable location and another delay ensued; finally the monkey had to make an eye movement to one of the target dots. On some trials, the monkey had to select the dot on the same side as the cue (right or left). On other trials, he had to select the target of the same color as the cue (red or green). Neuronal activity robustly encoded the object-centered locations first of the cue and then of the target regardless of the whether the monkey was following a rule based on object-centered location or color. Neuronal activity was at most weakly affected by the type of rule the monkey was following (object-centered-location or color) or by the color of the cue and target (red or green). On trials involving a color rule, neuronal activity was moderately enhanced when the cue and target appeared on opposite sides of their respective arrays. We conclude that the general function of SEF neurons selective for object-centered location is to represent where the cue and target are in their respective arrays rather than to represent the rule for target selection.

Automatic parameter selection for feature-based multi-sensor image registration

NASA Astrophysics Data System (ADS)

DelMarco, Stephen; Tom, Victor; Webb, Helen; Chao, Alan

2006-05-01

Accurate image registration is critical for applications such as precision targeting, geo-location, change-detection, surveillance, and remote sensing. However, the increasing volume of image data is exceeding the current capacity of human analysts to perform manual registration. This image data glut necessitates the development of automated approaches to image registration, including algorithm parameter value selection. Proper parameter value selection is crucial to the success of registration techniques. The appropriate algorithm parameters can be highly scene and sensor dependent. Therefore, robust algorithm parameter value selection approaches are a critical component of an end-to-end image registration algorithm. In previous work, we developed a general framework for multisensor image registration which includes feature-based registration approaches. In this work we examine the problem of automated parameter selection. We apply the automated parameter selection approach of Yitzhaky and Peli to select parameters for feature-based registration of multisensor image data. The approach consists of generating multiple feature-detected images by sweeping over parameter combinations and using these images to generate estimated ground truth. The feature-detected images are compared to the estimated ground truth images to generate ROC points associated with each parameter combination. We develop a strategy for selecting the optimal parameter set by choosing the parameter combination corresponding to the optimal ROC point. We present numerical results showing the effectiveness of the approach using registration of collected SAR data to reference EO data.

Systems Perturbation Analysis of a Large-Scale Signal Transduction Model Reveals Potentially Influential Candidates for Cancer Therapeutics

PubMed Central

Puniya, Bhanwar Lal; Allen, Laura; Hochfelder, Colleen; Majumder, Mahbubul; Helikar, Tomáš

2016-01-01

Dysregulation in signal transduction pathways can lead to a variety of complex disorders, including cancer. Computational approaches such as network analysis are important tools to understand system dynamics as well as to identify critical components that could be further explored as therapeutic targets. Here, we performed perturbation analysis of a large-scale signal transduction model in extracellular environments that stimulate cell death, growth, motility, and quiescence. Each of the model’s components was perturbed under both loss-of-function and gain-of-function mutations. Using 1,300 simulations under both types of perturbations across various extracellular conditions, we identified the most and least influential components based on the magnitude of their influence on the rest of the system. Based on the premise that the most influential components might serve as better drug targets, we characterized them for biological functions, housekeeping genes, essential genes, and druggable proteins. The most influential components under all environmental conditions were enriched with several biological processes. The inositol pathway was found as most influential under inactivating perturbations, whereas the kinase and small lung cancer pathways were identified as the most influential under activating perturbations. The most influential components were enriched with essential genes and druggable proteins. Moreover, known cancer drug targets were also classified in influential components based on the affected components in the network. Additionally, the systemic perturbation analysis of the model revealed a network motif of most influential components which affect each other. Furthermore, our analysis predicted novel combinations of cancer drug targets with various effects on other most influential components. We found that the combinatorial perturbation consisting of PI3K inactivation and overactivation of IP3R1 can lead to increased activity levels of apoptosis-related components and tumor-suppressor genes, suggesting that this combinatorial perturbation may lead to a better target for decreasing cell proliferation and inducing apoptosis. Finally, our approach shows a potential to identify and prioritize therapeutic targets through systemic perturbation analysis of large-scale computational models of signal transduction. Although some components of the presented computational results have been validated against independent gene expression data sets, more laboratory experiments are warranted to more comprehensively validate the presented results. PMID:26904540

Method and apparatus for aligning a solar concentrator using two lasers

DOEpatents

Diver Jr., Richard Boyer

2003-07-22

A method and apparatus are provided for aligning the facets of a solar concentrator. A first laser directs a first laser beam onto a selected facet of the concentrator such that a target board positioned adjacent to the first laser at approximately one focal length behind the focal point of the concentrator is illuminated by the beam after reflection thereof off of the selected facet. A second laser, located adjacent to the vertex of the optical axis of the concentrator, is used to direct a second laser beam onto the target board at a target point thereon. By adjusting the selected facet to cause the first beam to illuminate the target point on the target board produced by the second beam, the selected facet can be brought into alignment with the target point. These steps are repeated for other selected facets of the concentrator, as necessary, to provide overall alignment of the concentrator.

Exploring the Therapeutic Mechanism of Desmodium styracifolium on Oxalate Crystal-Induced Kidney Injuries Using Comprehensive Approaches Based on Proteomics and Network Pharmacology.

PubMed

Hou, Jiebin; Chen, Wei; Lu, Hongtao; Zhao, Hongxia; Gao, Songyan; Liu, Wenrui; Dong, Xin; Guo, Zhiyong

2018-01-01

Purpose: As a Chinese medicinal herb, Desmodium styracifolium (Osb.) Merr (DS) has been applied clinically to alleviate crystal-induced kidney injuries, but its effective components and their specific mechanisms still need further exploration. This research first combined the methods of network pharmacology and proteomics to explore the therapeutic protein targets of DS on oxalate crystal-induced kidney injuries to provide a reference for relevant clinical use. Methods: Oxalate-induced kidney injury mouse, rat, and HK-2 cell models were established. Proteins differentially expressed between the oxalate and control groups were respectively screened using iTRAQ combined with MALDI-TOF-MS. The common differential proteins of the three models were further analyzed by molecular docking with DS compounds to acquire differential targets. The inverse docking targets of DS were predicted through the platform of PharmMapper. The protein-protein interaction (PPI) relationship between the inverse docking targets and the differential proteins was established by STRING. Potential targets were further validated by western blot based on a mouse model with DS treatment. The effects of constituent compounds, including luteolin, apigenin, and genistein, were investigated based on an oxalate-stimulated HK-2 cell model. Results: Thirty-six common differentially expressed proteins were identified by proteomic analysis. According to previous research, the 3D structures of 15 major constituents of DS were acquired. Nineteen differential targets, including cathepsin D (CTSD), were found using molecular docking, and the component-differential target network was established. Inverse-docking targets including p38 MAPK and CDK-2 were found, and the network of component-reverse docking target was established. Through PPI analysis, 17 inverse-docking targets were linked to differential proteins. The combined network of component-inverse docking target-differential proteins was then constructed. The expressions of CTSD, p-p38 MAPK, and p-CDK-2 were shown to be increased in the oxalate group and decreased in kidney tissue by the DS treatment. Luteolin, apigenin, and genistein could protect oxalate-stimulated tubular cells as active components of DS. Conclusion: The potential targets including the CTSD, p38 MAPK, and CDK2 of DS in oxalate-induced kidney injuries and the active components (luteolin, apigenin, and genistein) of DS were successfully identified in this study by combining proteomics analysis, network pharmacology prediction, and experimental validation.

Inheritance of evolved resistance to a novel herbicide (pyroxasulfone).

PubMed

Busi, Roberto; Gaines, Todd A; Vila-Aiub, Martin M; Powles, Stephen B

2014-03-01

Agricultural weeds have rapidly adapted to intensive herbicide selection and resistance to herbicides has evolved within ecological timescales. Yet, the genetic basis of broad-spectrum generalist herbicide resistance is largely unknown. This study aims to determine the genetic control of non-target-site herbicide resistance trait(s) that rapidly evolved under recurrent selection of the novel lipid biosynthesis inhibitor pyroxasulfone in Lolium rigidum. The phenotypic segregation of pyroxasulfone resistance in parental, F1 and back-cross (BC) families was assessed in plants exposed to a gradient of pyroxasulfone doses. The inheritance of resistance to chemically dissimilar herbicides (cross-resistance) was also evaluated. Evolved resistance to the novel selective agent (pyroxasulfone) is explained by Mendelian segregation of one semi-dominant allele incrementally herbicide-selected at higher frequency in the progeny. In BC families, cross-resistance is conferred by an incompletely dominant single major locus. This study confirms that herbicide resistance can rapidly evolve to any novel selective herbicide agents by continuous and repeated herbicide use. The results imply that the combination of herbicide options (rotation, mixtures or combinations) to exploit incomplete dominance can provide acceptable control of broad-spectrum generalist resistance-endowing monogenic traits. Herbicide diversity within a set of integrated management tactics can be one important component to reduce the herbicide selection intensity. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Getting the beat: entrainment of brain activity by musical rhythm and pleasantness.

PubMed

Trost, Wiebke; Frühholz, Sascha; Schön, Daniele; Labbé, Carolina; Pichon, Swann; Grandjean, Didier; Vuilleumier, Patrik

2014-12-01

Rhythmic entrainment is an important component of emotion induction by music, but brain circuits recruited during spontaneous entrainment of attention by music and the influence of the subjective emotional feelings evoked by music remain still largely unresolved. In this study we used fMRI to test whether the metric structure of music entrains brain activity and how music pleasantness influences such entrainment. Participants listened to piano music while performing a speeded visuomotor detection task in which targets appeared time-locked to either strong or weak beats. Each musical piece was presented in both a consonant/pleasant and dissonant/unpleasant version. Consonant music facilitated target detection and targets presented synchronously with strong beats were detected faster. FMRI showed increased activation of bilateral caudate nucleus when responding on strong beats, whereas consonance enhanced activity in attentional networks. Meter and consonance selectively interacted in the caudate nucleus, with greater meter effects during dissonant than consonant music. These results reveal that the basal ganglia, involved both in emotion and rhythm processing, critically contribute to rhythmic entrainment of subcortical brain circuits by music. Copyright © 2014 Elsevier Inc. All rights reserved.

Dynamic control of laser driven proton beams by exploiting self-generated, ultrashort electromagnetic pulses

NASA Astrophysics Data System (ADS)

Kar, S.; Ahmed, H.; Nersisyan, G.; Brauckmann, S.; Hanton, F.; Giesecke, A. L.; Naughton, K.; Willi, O.; Lewis, C. L. S.; Borghesi, M.

2016-05-01

As part of the ultrafast charge dynamics initiated by high intensity laser irradiations of solid targets, high amplitude EM pulses propagate away from the interaction point and are transported along any stalks and wires attached to the target. The propagation of these high amplitude pulses along a thin wire connected to a laser irradiated target was diagnosed via the proton radiography technique, measuring a pulse duration of ˜20 ps and a pulse velocity close to the speed of light. The strong electric field associated with the EM pulse can be exploited for controlling dynamically the proton beams produced from a laser-driven source. Chromatic divergence control of broadband laser driven protons (upto 75% reduction in divergence of >5 MeV protons) was obtained by winding the supporting wire around the proton beam axis to create a helical coil structure. In addition to providing focussing and energy selection, the technique has the potential to post-accelerate the transiting protons by the longitudinal component of the curved electric field lines produced by the helical coil lens.

Dynamic control of laser driven proton beams by exploiting self-generated, ultrashort electromagnetic pulses

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

Kar, S., E-mail: s.kar@qub.ac.uk; Ahmed, H.; Nersisyan, G.

As part of the ultrafast charge dynamics initiated by high intensity laser irradiations of solid targets, high amplitude EM pulses propagate away from the interaction point and are transported along any stalks and wires attached to the target. The propagation of these high amplitude pulses along a thin wire connected to a laser irradiated target was diagnosed via the proton radiography technique, measuring a pulse duration of ∼20 ps and a pulse velocity close to the speed of light. The strong electric field associated with the EM pulse can be exploited for controlling dynamically the proton beams produced from amore » laser-driven source. Chromatic divergence control of broadband laser driven protons (upto 75% reduction in divergence of >5 MeV protons) was obtained by winding the supporting wire around the proton beam axis to create a helical coil structure. In addition to providing focussing and energy selection, the technique has the potential to post-accelerate the transiting protons by the longitudinal component of the curved electric field lines produced by the helical coil lens.« less

Interaction Studies of Withania Somnifera's Key Metabolite Withaferin A with Different Receptors Assoociated with Cardiovascular Disease.

PubMed

Ravindran, Rekha; Sharma, Nitika; Roy, Sujata; Thakur, Ashoke R; Ganesh, Subhadra; Kumar, Sriram; Devi, Jamuna; Rajkumar, Johanna

2015-01-01

Withania somnifera commonly known as Ashwagandha in India is used in many herbal formulations to treat various cardiovascular diseases. The key metabolite of this plant, Withaferin A was analyzed for its molecular mechanism through docking studies on different targets of cardiovascular disease. Six receptor proteins associated with cardiovascular disease were selected and interaction studies were performed with Withaferin A using AutoDock Vina. CORINA was used to model the small molecules and HBAT to compute the hydrogen bonding. Among the six targets, β1- adrenergic receptors, HMG-CoA and Angiotensinogen-converting enzyme showed significant interaction with Withaferin A. Pharmacophore modeling was done using PharmaGist to understand the pharmacophoric potential of Withaferin A. Clustering of Withaferin A with different existing drug molecules for cardiovascular disease was performed with ChemMine based on structural similarity and physicochemical properties. The ability of natural active component, Withaferin A to interact with different receptors associated with cardiovascular disease was elucidated with various modeling techniques. These studies conclusively revealed Withaferin A as a potent lead compound against multiple targets associated with cardiovascular disease.

An overview of applied visibility fundamentals: Survey and synthesis of a visibility literature

NASA Astrophysics Data System (ADS)

1982-06-01

The concept of visibility has been defined in numerous ways. One source that is widely used in the United States describes visibility as the greatest distance at which it is just possible to see and identify selected objects or light sources with the unaided eye, or, it may be considered the distance an observer would have to back away from a target before it disappears. The process by which we see distant objects is based on the characteristics of the target, its immediate surroundings, air quality, illumination of the sight path, and the eyes and brain of the observer. Thus, four components of visibility have been noted: (1) target, (2) background, (3) atmosphere, and (4) observer. Most definitions of visibility include the observer as a key element, but it is also possible to measure visibility without the immediate presence of humans by means of instruments such as telephotometers, transmissometers, or nephelometers. Such measurements can be kept in non-dimensional terms and can be compared without human intervention. When used in the field, however, visibility sensors must be calibrated in human terms of visibility measurement.

Peptide-based antibody alternatives for biological sensing in austere environments

NASA Astrophysics Data System (ADS)

Coppock, Matthew B.; Sarkes, Deborah A.; Hurley, Margaret M.; Stratis-Cullum, Dimitra N.

2017-02-01

The most critical component of a biosensor, the biorecognition element, must exhibit high selectivity and strong affinity for a target of interest in operational sensing. Monoclonal antibodies are the current standard reagents for such devices, but their adaptability, manufacturability, and stability greatly limit their effectiveness in fieldable sensors. Peptides have emerged as potential antibody replacements in such applications due to their similar binding performance, extreme chemical and thermal stabilities, and on-demand scalability. In conjunction with modeling capabilities, work at the Army Research Lab focuses on protein catalyzed capture (PCC) agent technology and bacterial display for the discovery of these novel peptide binding reagents. The synthetic, bottom-up PCC agent technology uses an iterative, in situ "click chemistry" approach to produce high performing peptides against specific epitopes translatable to the protein target. Bacterial display allows rapid reagent discovery due to the combination of fast bacterial growth and effective peptide sequence enrichment through multiple rounds of biopanning. Recent advances in both methods are highlighted in regards to the discovery of reagents against Army high priority protein targets for soldier safety, performance, and diagnostics.

Mathematical modeling for novel cancer drug discovery and development.

PubMed

Zhang, Ping; Brusic, Vladimir

2014-10-01

Mathematical modeling enables: the in silico classification of cancers, the prediction of disease outcomes, optimization of therapy, identification of promising drug targets and prediction of resistance to anticancer drugs. In silico pre-screened drug targets can be validated by a small number of carefully selected experiments. This review discusses the basics of mathematical modeling in cancer drug discovery and development. The topics include in silico discovery of novel molecular drug targets, optimization of immunotherapies, personalized medicine and guiding preclinical and clinical trials. Breast cancer has been used to demonstrate the applications of mathematical modeling in cancer diagnostics, the identification of high-risk population, cancer screening strategies, prediction of tumor growth and guiding cancer treatment. Mathematical models are the key components of the toolkit used in the fight against cancer. The combinatorial complexity of new drugs discovery is enormous, making systematic drug discovery, by experimentation, alone difficult if not impossible. The biggest challenges include seamless integration of growing data, information and knowledge, and making them available for a multiplicity of analyses. Mathematical models are essential for bringing cancer drug discovery into the era of Omics, Big Data and personalized medicine.

Characterization of nucleosides and nucleobases in natural Cordyceps by HILIC-ESI/TOF/MS and HILIC-ESI/MS.

PubMed

Zhao, Heng-Qiang; Wang, Xiao; Li, Hong-Mei; Yang, Bin; Yang, Hong-Jun; Huang, Luqi

2013-08-15

A method combining hydrophilic interaction chromatography (HILIC) and electrospray ionization mass spectrometry (ESI-MS) was developed for the characterization and determination of natural Cordyceps. Separation was achieved on a Waters Xbridge Amide column with gradient elution. Identification of 15 target nucleosides and nucleobases was based on retention time, UV spectra and mass measurements of the protonated molecules ([M+H]⁺) and main fragment ions (ESI-TOF/MS). Eight non-target compounds were tentatively identified by ESI-TOF/MS. The 15 target compounds were quantified by HILIC-ESI-MS/MS using time-programmed selective ion monitoring or multiple reaction monitoring in positive-ion mode under optimized mass conditions. This technique showed good linearity, repeatability and recovery. This approach was also successfully implemented in the analysis of nucleosides and nucleobases in 12 batches of natural Cordyceps samples that were collected from different regions in China. The developed HILIC-ESI-MS method exhibited clear advantages in identifying and determining highly polar bioactive components in Cordyceps, as well as their quality control.

Extracting binaural information from simultaneous targets and distractors: Effects of amplitude modulation and asynchronous envelopes

PubMed Central

Stellmack, Mark A.; Byrne, Andrew J.; Viemeister, Neal F.

2010-01-01

When different components of a stimulus carry different binaural information, processing of binaural information in a target component is often affected. The present experiments examine whether such interference is affected by amplitude modulation and the relative phase of modulation of the target and distractors. In all experiments, listeners attempted to discriminate interaural time differences of a target stimulus in the presence of distractor stimuli with ITD=0. In Experiment 1, modulation of the distractors but not the target reduced interference between components. In Experiment 2, synthesized musical notes exhibited little binaural interference when there were slight asynchronies between different streams of notes (31 or 62 ms). The remaining experiments suggested that the reduction in binaural interference in the previous experiments was due neither to the complex spectra of the synthesized notes nor to greater detectability of the target in the presence of modulated distractors. These data suggest that this interference is reduced when components are modulated in ways that result in the target appearing briefly in isolation, not because of segregation cues. These data also suggest that modulation and asynchronies between modulators that might be encountered in real-world listening situations are adequate to reduce binaural interference to inconsequential levels. PMID:20815459

Selective principal component regression analysis of fluorescence hyperspectral image to assess aflatoxin contamination in corn

USDA-ARS?s Scientific Manuscript database

Selective principal component regression analysis (SPCR) uses a subset of the original image bands for principal component transformation and regression. For optimal band selection before the transformation, this paper used genetic algorithms (GA). In this case, the GA process used the regression co...

Purification-Free, Target-Selective Immobilization of a Protein from Cell Lysates.

PubMed

Cha, Jaehyun; Kwon, Inchan

2018-02-27

Protein immobilization has been widely used for laboratory experiments and industrial processes. Preparation of a recombinant protein for immobilization usually requires laborious and expensive purification steps. Here, a novel purification-free, target-selective immobilization technique of a protein from cell lysates is reported. Purification steps are skipped by immobilizing a target protein containing a clickable non-natural amino acid (p-azidophenylalanine) in cell lysates onto alkyne-functionalized solid supports via bioorthogonal azide-alkyne cycloaddition. In order to achieve a target protein-selective immobilization, p-azidophenylalanine was introduced into an exogenous target protein, but not into endogenous non-target proteins using host cells with amber codon-free genomic DNAs. Immobilization of superfolder fluorescent protein (sfGFP) from cell lysates is as efficient as that of the purified sfGFP. Using two fluorescent proteins (sfGFP and mCherry), the authors also demonstrated that the target proteins are immobilized with a minimal immobilization of non-target proteins (target-selective immobilization). © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Chaperone-mediated autophagy components are upregulated in sporadic inclusion-body myositis muscle fibres.

PubMed

Cacciottolo, M; Nogalska, A; D'Agostino, C; Engel, W K; Askanas, V

2013-12-01

Sporadic inclusion-body myositis (s-IBM) is an age-associated degenerative muscle disease. Characteristic features are muscle-fibre vacuolization and intramuscle-fibre accumulations of multiprotein aggregates, which may result from the demonstrated impairments of the 26S proteasome and autophagy. Chaperone-mediated autophagy (CMA) is a selective form of lysosomal degradation targeting proteins carrying the KFERQ motif. Lysosome-associated membrane protein type 2A (LAMP2A) and the heat-shock cognate protein 70 (Hsc70) constitute specific CMA components. Neither CMA components nor CMA activity has been studied in normal or disease human muscle, to our knowledge. We studied CMA components by immunocytochemistry, immunoblots, real-time PCR and immunoprecipitation in: (a) 16 s-IBM, nine aged-matched normal and nine disease control muscle biopsies; and (b) cultured human muscle fibres (CHMFs) with experimentally inhibited activities of either the 26S proteasome or autophagy. Compared with age-matched controls, in s-IBM muscle, LAMP2A and Hsc70 were on a given transverse section accumulated as aggregates in approximately 5% of muscle fibres, where they (a) colocalized with each other and α-synuclein (α-syn), a CMA-targeted protein; and (b) were bound to each other and to α-syn by immunoprecipitation. By immunoblots, LAMP2A was increased sevenfold P < 0.001 and Hsc70 2.6-fold P < 0.05. LAMP2A mRNA was increased 4.4-fold P < 0.001 and Hsc70 mRNA 1.9-fold P < 0.05. In CHMFs inhibition of either the 26S proteasome or autophagy induced CMA, evidenced by a significant increase of both LAMP2A and Hsc70. Our study demonstrates, for the first time, up-regulation of CMA components in s-IBM muscle, and it provides further evidence that altered protein degradation is likely an important pathogenic aspect in s-IBM. © 2013 British Neuropathological Society.

Optimization of multifocal transcranial current stimulation for weighted cortical pattern targeting from realistic modeling of electric fields

PubMed Central

Ruffini, Giulio; Fox, Michael D.; Ripolles, Oscar; Miranda, Pedro Cavaleiro; Pascual-Leone, Alvaro

2014-01-01

Recently, multifocal transcranial current stimulation (tCS) devices using several relatively small electrodes have been used to achieve more focal stimulation of specific cortical targets. However, it is becoming increasingly recognized that many behavioral manifestations of neurological and psychiatric disease are not solely the result of abnormality in one isolated brain region but represent alterations in brain networks. In this paper we describe a method for optimizing the configuration of multifocal tCS for stimulation of brain networks, represented by spatially extended cortical targets. We show how, based on fMRI, PET, EEG or other data specifying a target map on the cortical surface for excitatory, inhibitory or neutral stimulation and a constraint of the maximal number of electrodes, a solution can be produced with the optimal currents and locations of the electrodes. The method described here relies on a fast calculation of multifocal tCS electric fields (including components normal and tangential to the cortical boundaries) using a five layer finite element model of a realistic head. Based on the hypothesis that the effects of current stimulation are to first order due to the interaction of electric fields with populations of elongated cortical neurons, it is argued that the optimization problem for tCS stimulation can be defined in terms of the component of the electric field normal to the cortical surface. Solutions are found using constrained least squares to optimize current intensities, while electrode number and their locations are selected using a genetic algorithm. For direct current tCS (tDCS) applications, we provide some examples of this technique using an available tCS system providing 8 small Ag/AgCl stimulation electrodes. We demonstrate the approach both for localized and spatially extended targets defined using rs-fcMRI and PET data, with clinical applications in stroke and depression. Finally, we extend these ideas to more general stimulation protocols, such as alternating current tCS (tACS). PMID:24345389

A multichannel and wide suitablity digital control device for liquid-crystal microlens controlled electrically

NASA Astrophysics Data System (ADS)

Zhang, Bo; Xin, Zhaowei; Wei, Dong; Zhang, Xinyu; Wang, Haiwei; Xie, Changsheng

2017-11-01

In order to overcome the difficulty in imaging detection of high-speed moving targets under complex environments, and to get more comprehensive image information of the target, there is a urgent need to develop new high-performance optical imaging components. Compared to traditional lenses which have fixed shapes and immutable focal length, liquid-crystal microlens (LCMs) can not only adjust the focal length without changing the external shape, but also realize many practical functions such as swinging focus, spectral selection, depth of field adjustment, etc. The physical properties of spatial electric fields constructed between electrode plates of the LCMs are directly related to the light-field adjusting performances of LCMs, such as the polarity of electric field, the frequency and amplitude of applied voltage signal. In other words, the optical behaviors of LCMs will be affected remarkably by the parameters of driving voltage signal mentioned above. To implement these important functions flexibly and effectively, the driving voltage signal must be powerful and flexible. It had better to have multiple channels to control the direction of swinging focus, with relatively wide variance range to spread spectrum selection range, and with high precision to ensure accurately controlling LCMs. In addition, special waveforms may be required to support special functions of LCMs. Therefore a digital control device, which meet the requirements mentioned above, is designed, and then LCMs with it can realize imaging detection of targets in complex environment.

Evaluation of the effect of extraction solvent and organ selection on the chemical profile of Astragalus spinosus using HPTLC- multivariate image analysis.

PubMed

Shawky, Eman; Selim, Dina A

2017-09-01

The evaluation of extraction protocols for untargeted and targeted metabolomics was implemented for root and aerial organs of Astragalus spinosus in this work. The efficiency and complementarity of commonly used extraction solvents, namely petroleum ether, methylene chloride, ethyl acetate and n-butanol were considered for method evaluation using chemometric techniques in conjunction with new, simple, and fast high performance thin layer chromatography (HPTLC) method for fingerprint analysis by extracting information from a digitalized HPTLC plate using ImageJ software. A targeted approach was furtherly implemented by developing and validating an HPTLC method allowing the quantification of three saponin glycosides. The results of untargeted and targeted principle component analysis (PCA) and hierarchical cluster analysis (HCA) revealed that the apparent saponins profile seems to depend on a combined effect of matrix composition and the properties of the selected solvent for extraction, where both the biological matrix of the investigated plant organs, as well as the extraction solvent can influence the precision of metabolite abundances. Although, the aerial part is frequently discarded as waste, it is shown hereby that it has similar chemical profile compared to the medicinal part, roots, yet a different extraction solvents pattern is recognized between the two organs which can be attributed to the differences in the composition, permeability or accessibility of the sample matrix/organ tissues, rather than the chemical structures of the detected metabolites. Copyright © 2017 Elsevier B.V. All rights reserved.

The long term trend of carbon dioxide and solar-induced chlorophyll fluorescence over selected sites using GOSAT target observation data

NASA Astrophysics Data System (ADS)

Kataoka, F.; Higuchi, R.; Kuze, A.; Shiomi, K.

2017-12-01

The Greenhouse gases Observing SATellite (GOSAT) is designed to measure the concentration of major greenhouse gases from space. GOSAT carry the Fourier-Transform Spectrometer, which have three shortwave infrared (SWIR) bands and one thermal infrared (TIR) band. The SWIR bands correspond to the O2A band (0.76 mm), weak-CO2 (1.6 mm) and strong-CO2 (2.0 mm). The SWIR bands observe the backscattered sunlight from surface and retrieve the column-averaged dry air mole fraction of carbon dioxide and methane. The 0.76 mm band can also detect the solar-induced chlorophyll fluorescence (SIF) using high spectral-resolution spectra in O2A band and solar absorption feature (Fraunhofer lines). GOSAT have operated more than 8 years and targeted various kinds of land-cover area (forest, grass, desert, etc.). The long term CO2 and SIF data set potential to address the rate of CO2 uptake through plant photosynthesis. In this work, we evaluated a trend and seasonal fluctuation components of CO2 and SIF using the liner and trigonometric functions fitting. We analyzed the amplitude and phase of the CO2 and SIF seasonal variation and anomalies over selected sites. Spatial distribution from target observation dataset which consist of 16 point per site using an agile pointing system over megacity is presented together with wind data. The data is available from the GOSAT trend viewer at http://www.eorc.jaxa.jp/GOSAT/CO2_monitor/.

Application of Satellite-Derived Atmospheric Motion Vectors for Estimating Mesoscale Flows.

NASA Astrophysics Data System (ADS)

Bedka, Kristopher M.; Mecikalski, John R.

2005-11-01

This study demonstrates methods to obtain high-density, satellite-derived atmospheric motion vectors (AMV) that contain both synoptic-scale and mesoscale flow components associated with and induced by cumuliform clouds through adjustments made to the University of Wisconsin—Madison Cooperative Institute for Meteorological Satellite Studies (UW-CIMSS) AMV processing algorithm. Operational AMV processing is geared toward the identification of synoptic-scale motions in geostrophic balance, which are useful in data assimilation applications. AMVs identified in the vicinity of deep convection are often rejected by quality-control checks used in the production of operational AMV datasets. Few users of these data have considered the use of AMVs with ageostrophic flow components, which often fail checks that assure both spatial coherence between neighboring AMVs and a strong correlation to an NWP-model first-guess wind field. The UW-CIMSS algorithm identifies coherent cloud and water vapor features (i.e., targets) that can be tracked within a sequence of geostationary visible (VIS) and infrared (IR) imagery. AMVs are derived through the combined use of satellite feature tracking and an NWP-model first guess. Reducing the impact of the NWP-model first guess on the final AMV field, in addition to adjusting the target selection and vector-editing schemes, is found to result in greater than a 20-fold increase in the number of AMVs obtained from the UW-CIMSS algorithm for one convective storm case examined here. Over a three-image sequence of Geostationary Operational Environmental Satellite (GOES)-12 VIS and IR data, 3516 AMVs are obtained, most of which contain flow components that deviate considerably from geostrophy. In comparison, 152 AMVs are derived when a tighter NWP-model constraint and no targeting adjustments were imposed, similar to settings used with operational AMV production algorithms. A detailed analysis reveals that many of these 3516 vectors contain low-level (100 70 kPa) convergent and midlevel (70 40 kPa) to upper-level (40 10 kPa) divergent motion components consistent with localized mesoscale flow patterns. The applicability of AMVs for estimating cloud-top cooling rates at the 1-km pixel scale is demonstrated with excellent correspondence to rates identified by a human expert.

Design of in-flight fragment separator using high-power primary beams in the energy of a few hundred MeV/u

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

Kim, J. Y.; Kim, J. W.; Wan, W.

2015-07-15

An in-flight fragment separator usually requires large acceptance and high momentum resolution to minimize the loss of a rare isotope beam of interest produced at a thin target, which is especially important when {sup 238}U fission reactions in the energy of 200 MeV/u are used. The production target and beam dump are located in the pre-separator, where a beam power of up to 400 kW is dissipated. The area is surrounded by thick radiation shielding walls, which result in long drift spaces between adjacent magnetic components at various locations and an asymmetrical layout. Efforts have been made to minimize non-linearmore » effects in the pre-separator beam optics with trials of different separator configurations and correction schemes using COSY Infinity and GICOSY. The main separator is configured to be mirror symmetric such that correction with hexapole and octupole coils can be more readily applied. The separator configuration was finalized to allow the facility design to proceed and the key components including superconducting magnets have been designed and prototyped. In addition, the separator design has been evaluated using LISE++ including a set of wedge degraders at dispersive focal planes to improve the yield and purity of selected isotope beam.« less

Influence of Surface Modifications on the Spatiotemporal Microdistribution of Quantum Dots In Vivo.

PubMed

Nekolla, Katharina; Kick, Kerstin; Sellner, Sabine; Mildner, Karina; Zahler, Stefan; Zeuschner, Dagmar; Krombach, Fritz; Rehberg, Markus

2016-05-01

For biomedical applications of nanoconstructs, it is a general prerequisite to efficiently reach the desired target site. In this regard, it is crucial to determine the spatiotemporal distribution of nanomaterials at the microscopic tissue level. Therefore, the effect of different surface modifications on the distribution of microinjected quantum dots (QDs) in mouse skeletal muscle tissue has been investigated. In vivo real-time fluorescence microscopy and particle tracking reveal that carboxyl QDs preferentially attach to components of the extracellular matrix (ECM), whereas QDs coated with polyethylene glycol (PEG) show little interaction with tissue constituents. Transmission electron microscopy elucidates that carboxyl QDs adhere to collagen fibers as well as basement membranes, a type of ECM located on the basolateral side of blood vessel walls. Moreover, carboxyl QDs have been found in endothelial junctions as well as in caveolae of endothelial cells, enabling them to translocate into the vessel lumen. The in vivo QD distribution is confirmed by in vitro experiments. The data suggest that ECM components act as a selective barrier depending on QD surface modification. For future biomedical applications, such as targeting of blood vessel walls, the findings of this study offer design criteria for nanoconstructs that meet the requirements of the respective application. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

A preliminary study for the development and optimization by experimental design of an in vitro method for prediction of drug buccal absorption.

PubMed

Mura, Paola; Orlandini, Serena; Cirri, Marzia; Maestrelli, Francesca; Mennini, Natascia; Casella, Giada; Furlanetto, Sandra

2018-06-15

The work was aimed at developing an in vitro method able to provide rapid and reliable evaluation of drug absorption through buccal mucosa. Absorption simulator apparatus endowed with an artificial membrane was purposely developed by experimental design. The apparent permeation coefficient (P app ) through excised porcine buccal mucosa of naproxen, selected as model drug, was the target value to obtain with the artificial membrane. The multivariate approach enabled systematic evaluation of the effect on the response (P app ) of simultaneous variations of the variables (kind of lipid components for support impregnation and relative amounts). A screening phase followed by a response-surface study allowed optimization of the lipid-mixture composition to obtain the desired P app value, and definition of a design space where all mixture components combinations fulfilled the desired target at a fixed probability level. The method offers a useful tool for a quick screening in the early stages of drug discovery and/or in preformulation studies, improving efficiency and chance of success in the development of buccal delivery systems. Further studies with other model drugs are planned to confirm the buccal absorption predictive capacity of the developed membrane. Copyright © 2018 Elsevier B.V. All rights reserved.

CRM1 Inhibitors for Antiviral Therapy

PubMed Central

Mathew, Cynthia; Ghildyal, Reena

2017-01-01

Infectious diseases are a major global concern and despite major advancements in medical research, still cause significant morbidity and mortality. Progress in antiviral therapy is particularly hindered by appearance of mutants capable of overcoming the effects of drugs targeting viral components. Alternatively, development of drugs targeting host proteins essential for completion of viral lifecycle holds potential as a viable strategy for antiviral therapy. Nucleocytoplasmic trafficking pathways in particular are involved in several pathological conditions including cancer and viral infections, where hijacking or alteration of function of key transporter proteins, such as Chromosome Region Maintenance1 (CRM1) is observed. Overexpression of CRM1-mediated nuclear export is evident in several solid and hematological malignancies. Interestingly, CRM1-mediated nuclear export of viral components is crucial in various stages of the viral lifecycle and assembly. This review summarizes the role of CRM1 in cancer and selected viruses. Leptomycin B (LMB) is the prototypical inhibitor of CRM1 potent against various cancer cell lines overexpressing CRM1 and in limiting viral infections at nanomolar concentrations in vitro. However, the irreversible shutdown of nuclear export results in high cytotoxicity and limited efficacy in vivo. This has prompted search for synthetic and natural CRM1 inhibitors that can potentially be developed as broadly active antivirals, some of which are summarized in this review. PMID:28702009

Formative research to develop a lifestyle application (app) for African American breast cancer survivors

PubMed Central

Smith, Selina A.; Whitehead, Mary S.; Sheats, Joyce Q.; Fontenot, Brittney; Alema-Mensah, Ernest; Ansa, Benjamin

2016-01-01

Background There is a proliferation of lifestyle-oriented mobile technologies; however, few have targeted users. Through intervention mapping, investigators and community partners completed Steps 1–3 (needs assessment, formulation of change objectives, and selection of theory-based methods) of a process to develop a mobile cancer prevention application (app) for cancer prevention. The aim of this qualitative study was to complete Step 4 (intervention development) by eliciting input from African American (AA) breast cancer survivors (BCSs) to guide app development. Methods Four focus group discussions (n=60) and three individual semi-structured interviews (n=36) were conducted with AA BCSs (40–72 years of age) to assess barriers and strategies for lifestyle change. All focus groups and interviews were recorded and transcribed verbatim. Data were analyzed with NVivo qualitative data analysis software version 10, allowing categories, themes, and patterns to emerge. Results Three categories and related themes emerged from the analysis: 1) perceptions about modifiable risk factors; 2) strategies related to adherence to cancer prevention guidelines; and 3) app components to address barriers to adherence. Participant perceptions, strategies, and recommended components guided development of the app. Conclusions For development of a mobile cancer prevention app, these findings will assist investigators in targeting features that are usable, acceptable, and accessible for AA BCSs. PMID:27583307

What Top-Down Task Sets Do for Us: An ERP Study on the Benefits of Advance Preparation in Visual Search

ERIC Educational Resources Information Center

Eimer, Martin; Kiss, Monika; Nicholas, Susan

2011-01-01

When target-defining features are specified in advance, attentional target selection in visual search is controlled by preparatory top-down task sets. We used ERP measures to study voluntary target selection in the absence of such feature-specific task sets, and to compare it to selection that is guided by advance knowledge about target features.…

Developing a targeted, theory-informed implementation intervention using two theoretical frameworks to address health professional and organisational factors: a case study to improve the management of mild traumatic brain injury in the emergency department.

PubMed

Tavender, Emma J; Bosch, Marije; Gruen, Russell L; Green, Sally E; Michie, Susan; Brennan, Sue E; Francis, Jill J; Ponsford, Jennie L; Knott, Jonathan C; Meares, Sue; Smyth, Tracy; O'Connor, Denise A

2015-05-25

Despite the availability of evidence-based guidelines for the management of mild traumatic brain injury in the emergency department (ED), variations in practice exist. Interventions designed to implement recommended behaviours can reduce this variation. Using theory to inform intervention development is advocated; however, there is no consensus on how to select or apply theory. Integrative theoretical frameworks, based on syntheses of theories and theoretical constructs relevant to implementation, have the potential to assist in the intervention development process. This paper describes the process of applying two theoretical frameworks to investigate the factors influencing recommended behaviours and the choice of behaviour change techniques and modes of delivery for an implementation intervention. A stepped approach was followed: (i) identification of locally applicable and actionable evidence-based recommendations as targets for change, (ii) selection and use of two theoretical frameworks for identifying barriers to and enablers of change (Theoretical Domains Framework and Model of Diffusion of Innovations in Service Organisations) and (iii) identification and operationalisation of intervention components (behaviour change techniques and modes of delivery) to address the barriers and enhance the enablers, informed by theory, evidence and feasibility/acceptability considerations. We illustrate this process in relation to one recommendation, prospective assessment of post-traumatic amnesia (PTA) by ED staff using a validated tool. Four recommendations for managing mild traumatic brain injury were targeted with the intervention. The intervention targeting the PTA recommendation consisted of 14 behaviour change techniques and addressed 6 theoretical domains and 5 organisational domains. The mode of delivery was informed by six Cochrane reviews. It was delivered via five intervention components : (i) local stakeholder meetings, (ii) identification of local opinion leader teams, (iii) a train-the-trainer workshop for appointed local opinion leaders, (iv) local training workshops for delivery by trained local opinion leaders and (v) provision of tools and materials to prompt recommended behaviours. Two theoretical frameworks were used in a complementary manner to inform intervention development in managing mild traumatic brain injury in the ED. The effectiveness and cost-effectiveness of the developed intervention is being evaluated in a cluster randomised trial, part of the Neurotrauma Evidence Translation (NET) program.

Complex patterns of multivariate selection on the ejaculate of a broadcast spawning marine invertebrate.

PubMed

Fitzpatrick, John L; Simmons, Leigh W; Evans, Jonathan P

2012-08-01

Assessing how selection operates on several, potentially interacting, components of the ejaculate is a challenging endeavor. Ejaculates can be subject to natural and/or sexual selection, which can impose both linear (directional) and nonlinear (stabilizing, disruptive, and correlational) selection on different ejaculate components. Most previous studies have examined linear selection of ejaculate components and, consequently, we know very little about patterns of nonlinear selection on the ejaculate. Even less is known about how selection acts on the ejaculate as a functionally integrated unit, despite evidence of covariance among ejaculate components. Here, we assess how selection acts on multiple ejaculate components simultaneously in the broadcast spawning sessile invertebrate Mytilus galloprovincialis using the statistical tools of multivariate selection analyses. Our analyses of relative fertilization rates revealed complex patterns of selection on sperm velocity, motility, and morphology. Interestingly, the most successful ejaculates were made up of slower swimming sperm with relatively low percentages of motile cells, and sperm with smaller head volumes that swam in highly pronounced curved swimming trajectories. These results are consistent with an emerging body of literature on fertilization kinetics in broadcast spawners, and shed light on the fundamental nature of selection acting on the ejaculate as a functionally integrated unit. © 2012 The Author(s). Evolution© 2012 The Society for the Study of Evolution.

The effects of predictor method factors on selection outcomes: A modular approach to personnel selection procedures.

PubMed

Lievens, Filip; Sackett, Paul R

2017-01-01

Past reviews and meta-analyses typically conceptualized and examined selection procedures as holistic entities. We draw on the product design literature to propose a modular approach as a complementary perspective to conceptualizing selection procedures. A modular approach means that a product is broken down into its key underlying components. Therefore, we start by presenting a modular framework that identifies the important measurement components of selection procedures. Next, we adopt this modular lens for reviewing the available evidence regarding each of these components in terms of affecting validity, subgroup differences, and applicant perceptions, as well as for identifying new research directions. As a complement to the historical focus on holistic selection procedures, we posit that the theoretical contributions of a modular approach include improved insight into the isolated workings of the different components underlying selection procedures and greater theoretical connectivity among different selection procedures and their literatures. We also outline how organizations can put a modular approach into operation to increase the variety in selection procedures and to enhance the flexibility in designing them. Overall, we believe that a modular perspective on selection procedures will provide the impetus for programmatic and theory-driven research on the different measurement components of selection procedures. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

Targeting of phage particles towards endothelial cells by antibodies selected through a multi-parameter selection strategy.

PubMed

Mandrup, Ole A; Lykkemark, Simon; Kristensen, Peter

2017-02-10

One of the hallmarks of cancer is sustained angiogenesis. Here, normal endothelial cells are activated, and their formation of new blood vessels leads to continued tumour growth. An improved patient condition is often observed when angiogenesis is prevented or normalized through targeting of these genomically stable endothelial cells. However, intracellular targets constitute a challenge in therapy, as the agents modulating these targets have to be delivered and internalized specifically to the endothelial cells. Selection of antibodies binding specifically to certain cell types is well established. It is nonetheless a challenge to ensure that the binding of antibodies to the target cell will mediate internalization. Previously selection of such antibodies has been performed targeting cancer cell lines; most often using either monovalent display or polyvalent display. In this article, we describe selections that isolate internalizing antibodies by sequential combining monovalent and polyvalent display using two types of helper phages, one which increases display valence and one which reduces background. One of the selected antibodies was found to mediate internalization into human endothelial cells, although our results confirms that the single stranded nature of the DNA packaged into phage particles may limit applications aimed at targeting nucleic acids in mammalian cells.

Selective attention in an insect visual neuron.

PubMed

Wiederman, Steven D; O'Carroll, David C

2013-01-21

Animals need attention to focus on one target amid alternative distracters. Dragonflies, for example, capture flies in swarms comprising prey and conspecifics, a feat that requires neurons to select one moving target from competing alternatives. Diverse evidence, from functional imaging and physiology to psychophysics, highlights the importance of such "competitive selection" in attention for vertebrates. Analogous mechanisms have been proposed in artificial intelligence and even in invertebrates, yet direct neural correlates of attention are scarce from all animal groups. Here, we demonstrate responses from an identified dragonfly visual neuron that perfectly match a model for competitive selection within limits of neuronal variability (r(2) = 0.83). Responses to individual targets moving at different locations within the receptive field differ in both magnitude and time course. However, responses to two simultaneous targets exclusively track those for one target alone rather than any combination of the pair. Irrespective of target size, contrast, or separation, this neuron selects one target from the pair and perfectly preserves the response, regardless of whether the "winner" is the stronger stimulus if presented alone. This neuron is amenable to electrophysiological recordings, providing neuroscientists with a new model system for studying selective attention. Copyright © 2013 Elsevier Ltd. All rights reserved.

Geometric shapes inversion method of space targets by ISAR image segmentation

NASA Astrophysics Data System (ADS)

Huo, Chao-ying; Xing, Xiao-yu; Yin, Hong-cheng; Li, Chen-guang; Zeng, Xiang-yun; Xu, Gao-gui

2017-11-01

The geometric shape of target is an effective characteristic in the process of space targets recognition. This paper proposed a method of shape inversion of space target based on components segmentation from ISAR image. The Radon transformation, Hough transformation, K-means clustering, triangulation will be introduced into ISAR image processing. Firstly, we use Radon transformation and edge detection to extract space target's main body spindle and solar panel spindle from ISAR image. Then the targets' main body, solar panel, rectangular and circular antenna are segmented from ISAR image based on image detection theory. Finally, the sizes of every structural component are computed. The effectiveness of this method is verified using typical targets' simulation data.

Design and Evaluation of Perceptual-based Object Group Selection Techniques

NASA Astrophysics Data System (ADS)

Dehmeshki, Hoda

Selecting groups of objects is a frequent task in graphical user interfaces. It is required prior to many standard operations such as deletion, movement, or modification. Conventional selection techniques are lasso, rectangle selection, and the selection and de-selection of items through the use of modifier keys. These techniques may become time-consuming and error-prone when target objects are densely distributed or when the distances between target objects are large. Perceptual-based selection techniques can considerably improve selection tasks when targets have a perceptual structure, for example when arranged along a line. Current methods to detect such groups use ad hoc grouping algorithms that are not based on results from perception science. Moreover, these techniques do not allow selecting groups with arbitrary arrangements or permit modifying a selection. This dissertation presents two domain-independent perceptual-based systems that address these issues. Based on established group detection models from perception research, the proposed systems detect perceptual groups formed by the Gestalt principles of good continuation and proximity. The new systems provide gesture-based or click-based interaction techniques for selecting groups with curvilinear or arbitrary structures as well as clusters. Moreover, the gesture-based system is adapted for the graph domain to facilitate path selection. This dissertation includes several user studies that show the proposed systems outperform conventional selection techniques when targets form salient perceptual groups and are still competitive when targets are semi-structured.