A bioinformatics approach for precision medicine off-label drug drug selection among triple negative breast cancer patients.

PubMed

Cheng, Lijun; Schneider, Bryan P; Li, Lang

2016-07-01

Cancer has been extensively characterized on the basis of genomics. The integration of genetic information about cancers with data on how the cancers respond to target based therapy to help to optimum cancer treatment. The increasing usage of sequencing technology in cancer research and clinical practice has enormously advanced our understanding of cancer mechanisms. The cancer precision medicine is becoming a reality. Although off-label drug usage is a common practice in treating cancer, it suffers from the lack of knowledge base for proper cancer drug selections. This eminent need has become even more apparent considering the upcoming genomics data. In this paper, a personalized medicine knowledge base is constructed by integrating various cancer drugs, drug-target database, and knowledge sources for the proper cancer drugs and their target selections. Based on the knowledge base, a bioinformatics approach for cancer drugs selection in precision medicine is developed. It integrates personal molecular profile data, including copy number variation, mutation, and gene expression. By analyzing the 85 triple negative breast cancer (TNBC) patient data in the Cancer Genome Altar, we have shown that 71.7% of the TNBC patients have FDA approved drug targets, and 51.7% of the patients have more than one drug target. Sixty-five drug targets are identified as TNBC treatment targets and 85 candidate drugs are recommended. Many existing TNBC candidate targets, such as Poly (ADP-Ribose) Polymerase 1 (PARP1), Cell division protein kinase 6 (CDK6), epidermal growth factor receptor, etc., were identified. On the other hand, we found some additional targets that are not yet fully investigated in the TNBC, such as Gamma-Glutamyl Hydrolase (GGH), Thymidylate Synthetase (TYMS), Protein Tyrosine Kinase 6 (PTK6), Topoisomerase (DNA) I, Mitochondrial (TOP1MT), Smoothened, Frizzled Class Receptor (SMO), etc. Our additional analysis of target and drug selection strategy is also fully supported by the drug screening data on TNBC cell lines in the Cancer Cell Line Encyclopedia. The proposed bioinformatics approach lays a foundation for cancer precision medicine. It supplies much needed knowledge base for the off-label cancer drug usage in clinics. © The Author 2016. Published by Oxford University Press on behalf of the American Medical Informatics Association. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Anatomical constraints on attention: Hemifield independence is a signature of multifocal spatial selection

PubMed Central

Alvarez, George A; Gill, Jonathan; Cavanagh, Patrick

2012-01-01

Previous studies have shown independent attentional selection of targets in the left and right visual hemifields during attentional tracking (Alvarez & Cavanagh, 2005) but not during a visual search (Luck, Hillyard, Mangun, & Gazzaniga, 1989). Here we tested whether multifocal spatial attention is the critical process that operates independently in the two hemifields. It is explicitly required in tracking (attend to a subset of object locations, suppress the others) but not in the standard visual search task (where all items are potential targets). We used a modified visual search task in which observers searched for a target within a subset of display items, where the subset was selected based on location (Experiments 1 and 3A) or based on a salient feature difference (Experiments 2 and 3B). The results show hemifield independence in this subset visual search task with location-based selection but not with feature-based selection; this effect cannot be explained by general difficulty (Experiment 4). Combined, these findings suggest that hemifield independence is a signature of multifocal spatial attention and highlight the need for cognitive and neural theories of attention to account for anatomical constraints on selection mechanisms. PMID:22637710

Selective Attention and Distraction in Context-Interactive Situations in Children and Adults.

ERIC Educational Resources Information Center

Ackerman, Brian P.

1987-01-01

Results from three experiments suggest that attention to context may benefit target recall in situations in which the context can be meaningfully related to the target. Adults seem to be more able to engage in context-interactive processing of stimulus information than are children, who base target selection on perceptual information. (PCB)

A Novel Sensor Selection and Power Allocation Algorithm for Multiple-Target Tracking in an LPI Radar Network

PubMed Central

She, Ji; Wang, Fei; Zhou, Jianjiang

2016-01-01

Radar networks are proven to have numerous advantages over traditional monostatic and bistatic radar. With recent developments, radar networks have become an attractive platform due to their low probability of intercept (LPI) performance for target tracking. In this paper, a joint sensor selection and power allocation algorithm for multiple-target tracking in a radar network based on LPI is proposed. It is found that this algorithm can minimize the total transmitted power of a radar network on the basis of a predetermined mutual information (MI) threshold between the target impulse response and the reflected signal. The MI is required by the radar network system to estimate target parameters, and it can be calculated predictively with the estimation of target state. The optimization problem of sensor selection and power allocation, which contains two variables, is non-convex and it can be solved by separating power allocation problem from sensor selection problem. To be specific, the optimization problem of power allocation can be solved by using the bisection method for each sensor selection scheme. Also, the optimization problem of sensor selection can be solved by a lower complexity algorithm based on the allocated powers. According to the simulation results, it can be found that the proposed algorithm can effectively reduce the total transmitted power of a radar network, which can be conducive to improving LPI performance. PMID:28009819

Drug Discovery for Neglected Diseases: Molecular Target-Based and Phenotypic Approaches

PubMed Central

2013-01-01

Drug discovery for neglected tropical diseases is carried out using both target-based and phenotypic approaches. In this paper, target-based approaches are discussed, with a particular focus on human African trypanosomiasis. Target-based drug discovery can be successful, but careful selection of targets is required. There are still very few fully validated drug targets in neglected diseases, and there is a high attrition rate in target-based drug discovery for these diseases. Phenotypic screening is a powerful method in both neglected and non-neglected diseases and has been very successfully used. Identification of molecular targets from phenotypic approaches can be a way to identify potential new drug targets. PMID:24015767

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

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.

Selectivity on-target of bromodomain chemical probes by structure-guided medicinal chemistry and chemical biology

PubMed Central

Galdeano, Carles; Ciulli, Alessio

2017-01-01

Targeting epigenetic proteins is a rapidly growing area for medicinal chemistry and drug discovery. Recent years have seen an explosion of interest in developing small molecules binding to bromodomains, the readers of acetyl-lysine modifications. A plethora of co-crystal structures has motivated focused fragment-based design and optimization programs within both industry and academia. These efforts have yielded several compounds entering the clinic, and many more are increasingly being used as chemical probes to interrogate bromodomain biology. High selectivity of chemical probes is necessary to ensure biological activity is due to an on-target effect. Here, we review the state-of-the-art of bromodomain-targeting compounds, focusing on the structural basis for their on-target selectivity or lack thereof. We also highlight chemical biology approaches to enhance on-target selectivity. PMID:27193077

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.

Autonomous Exploration for Gathering Increased Science

NASA Technical Reports Server (NTRS)

Bornstein, Benjamin J.; Castano, Rebecca; Estlin, Tara A.; Gaines, Daniel M.; Anderson, Robert C.; Thompson, David R.; DeGranville, Charles K.; Chien, Steve A.; Tang, Benyang; Burl, Michael C.;

Object-based target templates guide attention during visual search.

PubMed

Berggren, Nick; Eimer, Martin

2018-05-03

During visual search, attention is believed to be controlled in a strictly feature-based fashion, without any guidance by object-based target representations. To challenge this received view, we measured electrophysiological markers of attentional selection (N2pc component) and working memory (sustained posterior contralateral negativity; SPCN) in search tasks where two possible targets were defined by feature conjunctions (e.g., blue circles and green squares). Critically, some search displays also contained nontargets with two target features (incorrect conjunction objects, e.g., blue squares). Because feature-based guidance cannot distinguish these objects from targets, any selective bias for targets will reflect object-based attentional control. In Experiment 1, where search displays always contained only one object with target-matching features, targets and incorrect conjunction objects elicited identical N2pc and SPCN components, demonstrating that attentional guidance was entirely feature-based. In Experiment 2, where targets and incorrect conjunction objects could appear in the same display, clear evidence for object-based attentional control was found. The target N2pc became larger than the N2pc to incorrect conjunction objects from 250 ms poststimulus, and only targets elicited SPCN components. This demonstrates that after an initial feature-based guidance phase, object-based templates are activated when they are required to distinguish target and nontarget objects. These templates modulate visual processing and control access to working memory, and their activation may coincide with the start of feature integration processes. Results also suggest that while multiple feature templates can be activated concurrently, only a single object-based target template can guide attention at any given time. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

Recovery of niobium from irradiated targets

DOEpatents

Phillips, Dennis R.; Jamriska, Sr., David J.; Hamilton, Virginia T.

1994-01-01

A process for selective separation of niobium from proton irradiated molybdenum targets is provided and includes dissolving the molybdenum target in a hydrogen peroxide solution to form a first ion-containing solution, contacting the first ion-containing solution with a cationic resin whereby ions selected form the group consisting of molybdenum, biobium, technetium, selenium, vanadium, arsenic, germanium, zirconium and rubidium remain in a second ion-containing solution while ions selected from the group consisting of rubidium, zinc, beryllium, cobalt, iron, manganese, chromium, strontium, yttrium and zirconium are selectively adsorbed by the cationic resin; adjusting the pH of the second ion-containing solution to within a range of from about 5.0 to about 6.0; contacting the pH adjusting second ion-containing solution with a dextran-based material for a time to selectively separate niobium from the solution and recovering the niobium from the dextran-based material.

The effects of visual search efficiency on object-based attention

PubMed Central

Rosen, Maya; Cutrone, Elizabeth; Behrmann, Marlene

2017-01-01

The attentional prioritization hypothesis of object-based attention (Shomstein & Yantis in Perception & Psychophysics, 64, 41–51, 2002) suggests a two-stage selection process comprising an automatic spatial gradient and flexible strategic (prioritization) selection. The combined attentional priorities of these two stages of object-based selection determine the order in which participants will search the display for the presence of a target. The strategic process has often been likened to a prioritized visual search. By modifying the double-rectangle cueing paradigm (Egly, Driver, & Rafal in Journal of Experimental Psychology: General, 123, 161–177, 1994) and placing it in the context of a larger-scale visual search, we examined how the prioritization search is affected by search efficiency. By probing both targets located on the cued object and targets external to the cued object, we found that the attentional priority surrounding a selected object is strongly modulated by search mode. However, the ordering of the prioritization search is unaffected by search mode. The data also provide evidence that standard spatial visual search and object-based prioritization search may rely on distinct mechanisms. These results provide insight into the interactions between the mode of visual search and object-based selection, and help define the modulatory consequences of search efficiency for object-based attention. PMID:25832192

Salience-Based Selection: Attentional Capture by Distractors Less Salient Than the Target

PubMed Central

Goschy, Harriet; Müller, Hermann Joseph

2013-01-01

Current accounts of attentional capture predict the most salient stimulus to be invariably selected first. However, existing salience and visual search models assume noise in the map computation or selection process. Consequently, they predict the first selection to be stochastically dependent on salience, implying that attention could even be captured first by the second most salient (instead of the most salient) stimulus in the field. Yet, capture by less salient distractors has not been reported and salience-based selection accounts claim that the distractor has to be more salient in order to capture attention. We tested this prediction using an empirical and modeling approach of the visual search distractor paradigm. For the empirical part, we manipulated salience of target and distractor parametrically and measured reaction time interference when a distractor was present compared to absent. Reaction time interference was strongly correlated with distractor salience relative to the target. Moreover, even distractors less salient than the target captured attention, as measured by reaction time interference and oculomotor capture. In the modeling part, we simulated first selection in the distractor paradigm using behavioral measures of salience and considering the time course of selection including noise. We were able to replicate the result pattern we obtained in the empirical part. We conclude that each salience value follows a specific selection time distribution and attentional capture occurs when the selection time distributions of target and distractor overlap. Hence, selection is stochastic in nature and attentional capture occurs with a certain probability depending on relative salience. PMID:23382820

Computational approach for elucidating interactions of cross-species miRNAs and their targets in Flaviviruses.

PubMed

Shinde, Santosh P; Banerjee, Amit Kumar; Arora, Neelima; Murty, U S N; Sripathi, Venkateswara Rao; Pal-Bhadra, Manika; Bhadra, Utpal

2015-03-01

Combating viral diseases has been a challenging task since time immemorial. Available molecular approaches are limited and not much effective for this daunting task. MicroRNA based therapies have shown promise in recent times. MicroRNAs are tiny non-coding RNAs that regulate translational repression of target mRNA in highly specific manner. In this study, we have determined the target regions for human and viral microRNAs in the conserved genomic regions of selected viruses of Flaviviridae family using miRanda and performed a comparative target selectivity analysis among them. Specific target regions were determined and they were compared extensively among themselves by exploring their position to determine the vicinity. Based on the multiplicity and cooperativity analysis, interaction maps were developed manually to represent the interactions between top-ranking miRNAs and genomes of the viruses considered in this study. Self-organizing map (SOM) was used to cluster the best-ranked microRNAs based on the vital physicochemical properties. This study will provide deep insight into the interrelation of the viral and human microRNAs interactions with the selected Flaviviridae genomes and will help to identify cross-species microRNA targets on the viral genome.

Information-based cues at point of choice to change selection and consumption of food, alcohol and tobacco products: a systematic review.

PubMed

Carter, Patrice; Bignardi, Giacomo; Hollands, Gareth J; Marteau, Theresa M

2018-03-27

Reducing harmful consumption of food, alcohol, and tobacco products would prevent many cancers, diabetes and cardiovascular disease. Placing information-based cues in the environments in which we select and consume these products has the potential to contribute to changing these behaviours. In this review, information-based cues are defined as those which comprise any combination of words, symbols, numbers or pictures that convey information about a product or its use. We specifically exclude cues which are located on the products themselves. We conducted a systematic review of randomised, cluster- randomised, and non-randomised controlled trials to assess the impact of such cues on selection and consumption. Thirteen studies met the inclusion criteria, of which 12 targeted food (most commonly fruit and vegetables), one targeted alcohol sales, and none targeted tobacco products. Ten studies reported statistically significant effects on some or all of the targeted products, although studies were insufficiently homogenous to justify meta-analysis. Existing evidence suggests information-based cues can influence selection and consumption of food and alcohol products, although significant uncertainty remains. The current evidence base is limited both in quality and quantity, with relatively few, heterogeneous studies at unclear or high risk of bias. Additional, more rigorously conducted studies are warranted to better estimate the potential for these interventions to change selection and consumption of food, alcohol and tobacco products. PROSPERO. 2016; CRD42016051884 .

Design of a bioactive small molecule that targets r(AUUCU) repeats in spinocerebellar ataxia 10.

PubMed

Yang, Wang-Yong; Gao, Rui; Southern, Mark; Sarkar, Partha S; Disney, Matthew D

2016-06-01

RNA is an important target for chemical probes of function and lead therapeutics; however, it is difficult to target with small molecules. One approach to tackle this problem is to identify compounds that target RNA structures and utilize them to multivalently target RNA. Here we show that small molecules can be identified to selectively bind RNA base pairs by probing a library of RNA-focused small molecules. A small molecule that selectively binds AU base pairs informed design of a dimeric compound (2AU-2) that targets the pathogenic RNA, expanded r(AUUCU) repeats, that causes spinocerebellar ataxia type 10 (SCA10) in patient-derived cells. Indeed, 2AU-2 (50 nM) ameliorates various aspects of SCA10 pathology including improvement of mitochondrial dysfunction, reduced activation of caspase 3, and reduction of nuclear foci. These studies provide a first-in-class chemical probe to study SCA10 RNA toxicity and potentially define broadly applicable compounds targeting RNA AU base pairs in cells.

Oligo-branched peptides for tumor targeting: from magic bullets to magic forks.

PubMed

Falciani, Chiara; Pini, Alessandro; Bracci, Luisa

2009-02-01

Selective targeting of tumor cells is the final goal of research and drug discovery for cancer diagnosis, imaging and therapy. After the invention of hybridoma technology, the concept of magic bullet was introduced into the field of oncology, referring to selective killing of tumor cells, by specific antibodies. More recently, small molecules and peptides have also been proposed as selective targeting agents. We analyze the state of the art of tumor-selective agents that are presently available and tested in clinical settings. A novel approach based on 'armed' oligo-branched peptides as tumor targeting agents, is discussed and compared with existing tumor-selective therapies mediated by antibodies, small molecules or monomeric peptides. Oligo-branched peptides could be novel drugs that combine the advantages of antibodies and small molecules.

Dense and dynamic 3D selection for game-based virtual environments.

PubMed

Cashion, Jeffrey; Wingrave, Chadwick; LaViola, Joseph J

2012-04-01

3D object selection is more demanding when, 1) objects densly surround the target object, 2) the target object is significantly occluded, and 3) when the target object is dynamically changing location. Most 3D selection techniques and guidelines were developed and tested on static or mostly sparse environments. In contrast, games tend to incorporate densly packed and dynamic objects as part of their typical interaction. With the increasing popularity of 3D selection in games using hand gestures or motion controllers, our current understanding of 3D selection needs revision. We present a study that compared four different selection techniques under five different scenarios based on varying object density and motion dynamics. We utilized two existing techniques, Raycasting and SQUAD, and developed two variations of them, Zoom and Expand, using iterative design. Our results indicate that while Raycasting and SQUAD both have weaknesses in terms of speed and accuracy in dense and dynamic environments, by making small modifications to them (i.e., flavoring), we can achieve significant performance increases.

Variable selection for confounder control, flexible modeling and Collaborative Targeted Minimum Loss-based Estimation in causal inference

PubMed Central

Schnitzer, Mireille E.; Lok, Judith J.; Gruber, Susan

2015-01-01

This paper investigates the appropriateness of the integration of flexible propensity score modeling (nonparametric or machine learning approaches) in semiparametric models for the estimation of a causal quantity, such as the mean outcome under treatment. We begin with an overview of some of the issues involved in knowledge-based and statistical variable selection in causal inference and the potential pitfalls of automated selection based on the fit of the propensity score. Using a simple example, we directly show the consequences of adjusting for pure causes of the exposure when using inverse probability of treatment weighting (IPTW). Such variables are likely to be selected when using a naive approach to model selection for the propensity score. We describe how the method of Collaborative Targeted minimum loss-based estimation (C-TMLE; van der Laan and Gruber, 2010) capitalizes on the collaborative double robustness property of semiparametric efficient estimators to select covariates for the propensity score based on the error in the conditional outcome model. Finally, we compare several approaches to automated variable selection in low-and high-dimensional settings through a simulation study. From this simulation study, we conclude that using IPTW with flexible prediction for the propensity score can result in inferior estimation, while Targeted minimum loss-based estimation and C-TMLE may benefit from flexible prediction and remain robust to the presence of variables that are highly correlated with treatment. However, in our study, standard influence function-based methods for the variance underestimated the standard errors, resulting in poor coverage under certain data-generating scenarios. PMID:26226129

Variable Selection for Confounder Control, Flexible Modeling and Collaborative Targeted Minimum Loss-Based Estimation in Causal Inference.

PubMed

Schnitzer, Mireille E; Lok, Judith J; Gruber, Susan

2016-05-01

This paper investigates the appropriateness of the integration of flexible propensity score modeling (nonparametric or machine learning approaches) in semiparametric models for the estimation of a causal quantity, such as the mean outcome under treatment. We begin with an overview of some of the issues involved in knowledge-based and statistical variable selection in causal inference and the potential pitfalls of automated selection based on the fit of the propensity score. Using a simple example, we directly show the consequences of adjusting for pure causes of the exposure when using inverse probability of treatment weighting (IPTW). Such variables are likely to be selected when using a naive approach to model selection for the propensity score. We describe how the method of Collaborative Targeted minimum loss-based estimation (C-TMLE; van der Laan and Gruber, 2010 [27]) capitalizes on the collaborative double robustness property of semiparametric efficient estimators to select covariates for the propensity score based on the error in the conditional outcome model. Finally, we compare several approaches to automated variable selection in low- and high-dimensional settings through a simulation study. From this simulation study, we conclude that using IPTW with flexible prediction for the propensity score can result in inferior estimation, while Targeted minimum loss-based estimation and C-TMLE may benefit from flexible prediction and remain robust to the presence of variables that are highly correlated with treatment. However, in our study, standard influence function-based methods for the variance underestimated the standard errors, resulting in poor coverage under certain data-generating scenarios.

Literature-based discovery of diabetes- and ROS-related targets

PubMed Central

2010-01-01

Background Reactive oxygen species (ROS) are known mediators of cellular damage in multiple diseases including diabetic complications. Despite its importance, no comprehensive database is currently available for the genes associated with ROS. Methods We present ROS- and diabetes-related targets (genes/proteins) collected from the biomedical literature through a text mining technology. A web-based literature mining tool, SciMiner, was applied to 1,154 biomedical papers indexed with diabetes and ROS by PubMed to identify relevant targets. Over-represented targets in the ROS-diabetes literature were obtained through comparisons against randomly selected literature. The expression levels of nine genes, selected from the top ranked ROS-diabetes set, were measured in the dorsal root ganglia (DRG) of diabetic and non-diabetic DBA/2J mice in order to evaluate the biological relevance of literature-derived targets in the pathogenesis of diabetic neuropathy. Results SciMiner identified 1,026 ROS- and diabetes-related targets from the 1,154 biomedical papers (http://jdrf.neurology.med.umich.edu/ROSDiabetes/). Fifty-three targets were significantly over-represented in the ROS-diabetes literature compared to randomly selected literature. These over-represented targets included well-known members of the oxidative stress response including catalase, the NADPH oxidase family, and the superoxide dismutase family of proteins. Eight of the nine selected genes exhibited significant differential expression between diabetic and non-diabetic mice. For six genes, the direction of expression change in diabetes paralleled enhanced oxidative stress in the DRG. Conclusions Literature mining compiled ROS-diabetes related targets from the biomedical literature and led us to evaluate the biological relevance of selected targets in the pathogenesis of diabetic neuropathy. PMID:20979611

A Deterministic Approach to Active Debris Removal Target Selection

NASA Astrophysics Data System (ADS)

Lidtke, A.; Lewis, H.; Armellin, R.

2014-09-01

Many decisions, with widespread economic, political and legal consequences, are being considered based on space debris simulations that show that Active Debris Removal (ADR) may be necessary as the concerns about the sustainability of spaceflight are increasing. The debris environment predictions are based on low-accuracy ephemerides and propagators. This raises doubts about the accuracy of those prognoses themselves but also the potential ADR target-lists that are produced. Target selection is considered highly important as removal of many objects will increase the overall mission cost. Selecting the most-likely candidates as soon as possible would be desirable as it would enable accurate mission design and allow thorough evaluation of in-orbit validations, which are likely to occur in the near-future, before any large investments are made and implementations realized. One of the primary factors that should be used in ADR target selection is the accumulated collision probability of every object. A conjunction detection algorithm, based on the smart sieve method, has been developed. Another algorithm is then applied to the found conjunctions to compute the maximum and true probabilities of collisions taking place. The entire framework has been verified against the Conjunction Analysis Tools in AGIs Systems Toolkit and relative probability error smaller than 1.5% has been achieved in the final maximum collision probability. Two target-lists are produced based on the ranking of the objects according to the probability they will take part in any collision over the simulated time window. These probabilities are computed using the maximum probability approach, that is time-invariant, and estimates of the true collision probability that were computed with covariance information. The top-priority targets are compared, and the impacts of the data accuracy and its decay are highlighted. General conclusions regarding the importance of Space Surveillance and Tracking for the purpose of ADR are also drawn and a deterministic method for ADR target selection, which could reduce the number of ADR missions to be performed, is proposed.

A systematic approach to prioritize drug targets using machine learning, a molecular descriptor-based classification model, and high-throughput screening of plant derived molecules: a case study in oral cancer.

PubMed

Randhawa, Vinay; Kumar Singh, Anil; Acharya, Vishal

2015-12-01

Systems-biology inspired identification of drug targets and machine learning-based screening of small molecules which modulate their activity have the potential to revolutionize modern drug discovery by complementing conventional methods. To utilize the effectiveness of such pipelines, we first analyzed the dysregulated gene pairs between control and tumor samples and then implemented an ensemble-based feature selection approach to prioritize targets in oral squamous cell carcinoma (OSCC) for therapeutic exploration. Based on the structural information of known inhibitors of CXCR4-one of the best targets identified in this study-a feature selection was implemented for the identification of optimal structural features (molecular descriptor) based on which a classification model was generated. Furthermore, the CXCR4-centered descriptor-based classification model was finally utilized to screen a repository of plant derived small-molecules to obtain potential inhibitors. The application of our methodology may assist effective selection of the best targets which may have previously been overlooked, that in turn will lead to the development of new oral cancer medications. The small molecules identified in this study can be ideal candidates for trials as potential novel anti-oral cancer agents. Importantly, distinct steps of this whole study may provide reference for the analysis of other complex human diseases.

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

Micromotor-based lab-on-chip immunoassays

NASA Astrophysics Data System (ADS)

García, Miguel; Orozco, Jahir; Guix, Maria; Gao, Wei; Sattayasamitsathit, Sirilak; Escarpa, Alberto; Merkoçi, Arben; Wang, Joseph

2013-01-01

Here we describe the first example of using self-propelled antibody-functionalized synthetic catalytic microengines for capturing and transporting target proteins between the different reservoirs of a lab-on-a-chip (LOC) device. A new catalytic polymer/Ni/Pt microtube engine, containing carboxy moieties on its mixed poly(3,4-ethylenedioxythiophene) (PEDOT)/COOH-PEDOT polymeric outermost layer, is further functionalized with the antibody receptor to selectively recognize and capture the target protein. The new motor-based microchip immunoassay operations are carried out without any bulk fluid flow, replacing the common washing steps in antibody-based protein bioassays with the active transport of the captured protein throughout the different reservoirs, where each step of the immunoassay takes place. A first microchip format involving an `on-the-fly' double-antibody sandwich assay (DASA) is used for demonstrating the selective capture of the target protein, in the presence of excess of non-target proteins. A secondary antibody tagged with a polymeric-sphere tracer allows the direct visualization of the binding events. In a second approach the immuno-nanomotor captures and transports the microsphere-tagged antigen through a microchannel network. An anti-protein-A modified microengine is finally used to demonstrate the selective capture, transport and convenient label-free optical detection of a Staphylococcus aureus target bacteria (containing proteinA in its cell wall) in the presence of a large excess of non-target (Saccharomyces cerevisiae) cells. The resulting nanomotor-based microchip immunoassay offers considerable potential for diverse applications in clinical diagnostics, environmental and security monitoring fields.Here we describe the first example of using self-propelled antibody-functionalized synthetic catalytic microengines for capturing and transporting target proteins between the different reservoirs of a lab-on-a-chip (LOC) device. A new catalytic polymer/Ni/Pt microtube engine, containing carboxy moieties on its mixed poly(3,4-ethylenedioxythiophene) (PEDOT)/COOH-PEDOT polymeric outermost layer, is further functionalized with the antibody receptor to selectively recognize and capture the target protein. The new motor-based microchip immunoassay operations are carried out without any bulk fluid flow, replacing the common washing steps in antibody-based protein bioassays with the active transport of the captured protein throughout the different reservoirs, where each step of the immunoassay takes place. A first microchip format involving an `on-the-fly' double-antibody sandwich assay (DASA) is used for demonstrating the selective capture of the target protein, in the presence of excess of non-target proteins. A secondary antibody tagged with a polymeric-sphere tracer allows the direct visualization of the binding events. In a second approach the immuno-nanomotor captures and transports the microsphere-tagged antigen through a microchannel network. An anti-protein-A modified microengine is finally used to demonstrate the selective capture, transport and convenient label-free optical detection of a Staphylococcus aureus target bacteria (containing proteinA in its cell wall) in the presence of a large excess of non-target (Saccharomyces cerevisiae) cells. The resulting nanomotor-based microchip immunoassay offers considerable potential for diverse applications in clinical diagnostics, environmental and security monitoring fields. Electronic supplementary information (ESI) available. See DOI: 10.1039/c2nr32400h

Feature-based attention to unconscious shapes and colors.

PubMed

Schmidt, Filipp; Schmidt, Thomas

2010-08-01

Two experiments employed feature-based attention to modulate the impact of completely masked primes on subsequent pointing responses. Participants processed a color cue to select a pair of possible pointing targets out of multiple targets on the basis of their color, and then pointed to the one of those two targets with a prespecified shape. All target pairs were preceded by prime pairs triggering either the correct or the opposite response. The time interval between cue and primes was varied to modulate the time course of feature-based attentional selection. In a second experiment, the roles of color and shape were switched. Pointing trajectories showed large priming effects that were amplified by feature-based attention, indicating that attention modulated the earliest phases of motor output. Priming effects as well as their attentional modulation occurred even though participants remained unable to identify the primes, indicating distinct processes underlying visual awareness, attention, and response control.

MultiMiTar: a novel multi objective optimization based miRNA-target prediction method.

PubMed

Mitra, Ramkrishna; Bandyopadhyay, Sanghamitra

2011-01-01

Machine learning based miRNA-target prediction algorithms often fail to obtain a balanced prediction accuracy in terms of both sensitivity and specificity due to lack of the gold standard of negative examples, miRNA-targeting site context specific relevant features and efficient feature selection process. Moreover, all the sequence, structure and machine learning based algorithms are unable to distribute the true positive predictions preferentially at the top of the ranked list; hence the algorithms become unreliable to the biologists. In addition, these algorithms fail to obtain considerable combination of precision and recall for the target transcripts that are translationally repressed at protein level. In the proposed article, we introduce an efficient miRNA-target prediction system MultiMiTar, a Support Vector Machine (SVM) based classifier integrated with a multiobjective metaheuristic based feature selection technique. The robust performance of the proposed method is mainly the result of using high quality negative examples and selection of biologically relevant miRNA-targeting site context specific features. The features are selected by using a novel feature selection technique AMOSA-SVM, that integrates the multi objective optimization technique Archived Multi-Objective Simulated Annealing (AMOSA) and SVM. MultiMiTar is found to achieve much higher Matthew's correlation coefficient (MCC) of 0.583 and average class-wise accuracy (ACA) of 0.8 compared to the others target prediction methods for a completely independent test data set. The obtained MCC and ACA values of these algorithms range from -0.269 to 0.155 and 0.321 to 0.582, respectively. Moreover, it shows a more balanced result in terms of precision and sensitivity (recall) for the translationally repressed data set as compared to all the other existing methods. An important aspect is that the true positive predictions are distributed preferentially at the top of the ranked list that makes MultiMiTar reliable for the biologists. MultiMiTar is now available as an online tool at www.isical.ac.in/~bioinfo_miu/multimitar.htm. MultiMiTar software can be downloaded from www.isical.ac.in/~bioinfo_miu/multimitar-download.htm.

Early and late selection processes have separable influences on the neural substrates of attention.

PubMed

Drisdelle, Brandi Lee; Jolicoeur, Pierre

2018-05-01

To improve our understanding of the mechanisms of target selection, we examined how the spatial separation of salient items and their similarity to a pre-defined target interact using lateralised electrophysiological correlates of visual spatial attention (N2pc component) and visual short-term memory (VSTM; SPCN component). Using these features of target selection, we sought to expand on previous work proposing a model of early and late selection, where the N2pc is suggested to reflect the selection probability of visual stimuli (Aubin and Jolicoeur, 2016). The authors suggested that early-selection processes could be enhanced when items are adjacent. In the present work, the stimuli were short oriented lines, all of which were grey except for two that were blue and hence salient. A decrease in N2pc amplitude with decreasing spatial separation between salient items was observed. The N2pc increased in amplitude with increasing similarity of salient distractors to the target template, but only in target-absent trials. There was no interaction between these two factors, suggesting that separable attentional mechanisms influenced the N2pc. The findings suggest that selection is initially based on easily-distinguished attributes (i.e., both blue items) followed by a later identification-based process (if necessary), which depends on feature similarity to a target template. For the SPCN component, the results were in line with previous work: for target-present trials, an increase in similarity of salient distractors was associated with an increase in SPCN amplitude, suggesting more information was maintained in VSTM. In sum, results suggest there is a need for further inspection of salient distractors when they are similar to the target, increasing the need for focal attention, demonstrated by an increase in N2pc amplitude, followed by a higher probability of transfer to VSTM, demonstrated by an increase in SPCN amplitude. Copyright © 2018 Elsevier B.V. All rights reserved.

Structure Mapping in Autism Spectrum Disorder: Levels of Information Processing and Relations to Executive Functions.

PubMed

Hetzroni, Orit E; Shalahevich, Kiril

2018-03-01

Analogical reasoning was investigated among children with autism spectrum disorders (ASD) without intellectual disabilities and typical development (TD). Children were asked to select one of two targets in two conditions: (1) with and without spatial structure similarity; (2) with and without a perceptual distractor. Results demonstrate that children with ASD were able to select targets based on structural similarity, but this ability decreased to chance level when presented with a perceptual distractor. Everyday executive functions were positively correlated with structural selections among children with ASD. Results suggest that although children with ASD were able to select based on systematicity principle, perceptual distractor decreased their selection so that their cognitive system produced less structure similarities, that negatively affects spatial analogical reasoning.

Precise Spatially Selective Photothermolysis Using Modulated Femtosecond Lasers and Real-time Multimodal Microscopy Monitoring.

PubMed

Huang, Yimei; Lui, Harvey; Zhao, Jianhua; Wu, Zhenguo; Zeng, Haishan

2017-01-01

The successful application of lasers in the treatment of skin diseases and cosmetic surgery is largely based on the principle of conventional selective photothermolysis which relies strongly on the difference in the absorption between the therapeutic target and its surroundings. However, when the differentiation in absorption is not sufficient, collateral damage would occur due to indiscriminate and nonspecific tissue heating. To deal with such cases, we introduce a novel spatially selective photothermolysis method based on multiphoton absorption in which the radiant energy of a tightly focused near-infrared femtosecond laser beam can be directed spatially by aiming the laser focal point to the target of interest. We construct a multimodal optical microscope to perform and monitor the spatially selective photothermolysis. We demonstrate that precise alteration of the targeted tissue is achieved while leaving surrounding tissue intact by choosing appropriate femtosecond laser exposure with multimodal optical microscopy monitoring in real time.

Precise Spatially Selective Photothermolysis Using Modulated Femtosecond Lasers and Real-time Multimodal Microscopy Monitoring

PubMed Central

Huang, Yimei; Lui, Harvey; Zhao, Jianhua; Wu, Zhenguo; Zeng, Haishan

2017-01-01

The successful application of lasers in the treatment of skin diseases and cosmetic surgery is largely based on the principle of conventional selective photothermolysis which relies strongly on the difference in the absorption between the therapeutic target and its surroundings. However, when the differentiation in absorption is not sufficient, collateral damage would occur due to indiscriminate and nonspecific tissue heating. To deal with such cases, we introduce a novel spatially selective photothermolysis method based on multiphoton absorption in which the radiant energy of a tightly focused near-infrared femtosecond laser beam can be directed spatially by aiming the laser focal point to the target of interest. We construct a multimodal optical microscope to perform and monitor the spatially selective photothermolysis. We demonstrate that precise alteration of the targeted tissue is achieved while leaving surrounding tissue intact by choosing appropriate femtosecond laser exposure with multimodal optical microscopy monitoring in real time. PMID:28255346

Remote sensing image ship target detection method based on visual attention model

NASA Astrophysics Data System (ADS)

Sun, Yuejiao; Lei, Wuhu; Ren, Xiaodong

2017-11-01

The traditional methods of detecting ship targets in remote sensing images mostly use sliding window to search the whole image comprehensively. However, the target usually occupies only a small fraction of the image. This method has high computational complexity for large format visible image data. The bottom-up selective attention mechanism can selectively allocate computing resources according to visual stimuli, thus improving the computational efficiency and reducing the difficulty of analysis. Considering of that, a method of ship target detection in remote sensing images based on visual attention model was proposed in this paper. The experimental results show that the proposed method can reduce the computational complexity while improving the detection accuracy, and improve the detection efficiency of ship targets in remote sensing images.

Data integration to prioritize drugs using genomics and curated data.

PubMed

Louhimo, Riku; Laakso, Marko; Belitskin, Denis; Klefström, Juha; Lehtonen, Rainer; Hautaniemi, Sampsa

2016-01-01

Genomic alterations affecting drug target proteins occur in several tumor types and are prime candidates for patient-specific tailored treatments. Increasingly, patients likely to benefit from targeted cancer therapy are selected based on molecular alterations. The selection of a precision therapy benefiting most patients is challenging but can be enhanced with integration of multiple types of molecular data. Data integration approaches for drug prioritization have successfully integrated diverse molecular data but do not take full advantage of existing data and literature. We have built a knowledge-base which connects data from public databases with molecular results from over 2200 tumors, signaling pathways and drug-target databases. Moreover, we have developed a data mining algorithm to effectively utilize this heterogeneous knowledge-base. Our algorithm is designed to facilitate retargeting of existing drugs by stratifying samples and prioritizing drug targets. We analyzed 797 primary tumors from The Cancer Genome Atlas breast and ovarian cancer cohorts using our framework. FGFR, CDK and HER2 inhibitors were prioritized in breast and ovarian data sets. Estrogen receptor positive breast tumors showed potential sensitivity to targeted inhibitors of FGFR due to activation of FGFR3. Our results suggest that computational sample stratification selects potentially sensitive samples for targeted therapies and can aid in precision medicine drug repositioning. Source code is available from http://csblcanges.fimm.fi/GOPredict/.

The minimal amount of starting DNA for Agilent’s hybrid capture-based targeted massively parallel sequencing

PubMed Central

Chung, Jongsuk; Son, Dae-Soon; Jeon, Hyo-Jeong; Kim, Kyoung-Mee; Park, Gahee; Ryu, Gyu Ha; Park, Woong-Yang; Park, Donghyun

2016-01-01

Targeted capture massively parallel sequencing is increasingly being used in clinical settings, and as costs continue to decline, use of this technology may become routine in health care. However, a limited amount of tissue has often been a challenge in meeting quality requirements. To offer a practical guideline for the minimum amount of input DNA for targeted sequencing, we optimized and evaluated the performance of targeted sequencing depending on the input DNA amount. First, using various amounts of input DNA, we compared commercially available library construction kits and selected Agilent’s SureSelect-XT and KAPA Biosystems’ Hyper Prep kits as the kits most compatible with targeted deep sequencing using Agilent’s SureSelect custom capture. Then, we optimized the adapter ligation conditions of the Hyper Prep kit to improve library construction efficiency and adapted multiplexed hybrid selection to reduce the cost of sequencing. In this study, we systematically evaluated the performance of the optimized protocol depending on the amount of input DNA, ranging from 6.25 to 200 ng, suggesting the minimal input DNA amounts based on coverage depths required for specific applications. PMID:27220682

Discovery: an interactive resource for the rational selection and comparison of putative drug target proteins in malaria

PubMed Central

Joubert, Fourie; Harrison, Claudia M; Koegelenberg, Riaan J; Odendaal, Christiaan J; de Beer, Tjaart AP

2009-01-01

Background Up to half a billion human clinical cases of malaria are reported each year, resulting in about 2.7 million deaths, most of which occur in sub-Saharan Africa. Due to the over-and misuse of anti-malarials, widespread resistance to all the known drugs is increasing at an alarming rate. Rational methods to select new drug target proteins and lead compounds are urgently needed. The Discovery system provides data mining functionality on extensive annotations of five malaria species together with the human and mosquito hosts, enabling the selection of new targets based on multiple protein and ligand properties. Methods A web-based system was developed where researchers are able to mine information on malaria proteins and predicted ligands, as well as perform comparisons to the human and mosquito host characteristics. Protein features used include: domains, motifs, EC numbers, GO terms, orthologs, protein-protein interactions, protein-ligand interactions and host-pathogen interactions among others. Searching by chemical structure is also available. Results An in silico system for the selection of putative drug targets and lead compounds is presented, together with an example study on the bifunctional DHFR-TS from Plasmodium falciparum. Conclusion The Discovery system allows for the identification of putative drug targets and lead compounds in Plasmodium species based on the filtering of protein and chemical properties. PMID:19642978

Drug target identification in protozoan parasites.

PubMed

Müller, Joachim; Hemphill, Andrew

2016-08-01

Despite the fact that diseases caused by protozoan parasites represent serious challenges for public health, animal production and welfare, only a limited panel of drugs has been marketed for clinical applications. Herein, the authors investigate two strategies, namely whole organism screening and target-based drug design. The present pharmacopoeia has resulted from whole organism screening, and the mode of action and targets of selected drugs are discussed. However, the more recent extensive genome sequencing efforts and the development of dry and wet lab genomics and proteomics that allow high-throughput screening of interactions between micromolecules and recombinant proteins has resulted in target-based drug design as the predominant focus in anti-parasitic drug development. Selected examples of target-based drug design studies are presented, and calcium-dependent protein kinases, important drug targets in apicomplexan parasites, are discussed in more detail. Despite the enormous efforts in target-based drug development, this approach has not yet generated market-ready antiprotozoal drugs. However, whole-organism screening approaches, comprising of both in vitro and in vivo investigations, should not be disregarded. The repurposing of already approved and marketed drugs could be a suitable strategy to avoid fastidious approval procedures, especially in the case of neglected or veterinary parasitoses.

Missing texture reconstruction method based on error reduction algorithm using Fourier transform magnitude estimation scheme.

PubMed

Ogawa, Takahiro; Haseyama, Miki

2013-03-01

A missing texture reconstruction method based on an error reduction (ER) algorithm, including a novel estimation scheme of Fourier transform magnitudes is presented in this brief. In our method, Fourier transform magnitude is estimated for a target patch including missing areas, and the missing intensities are estimated by retrieving its phase based on the ER algorithm. Specifically, by monitoring errors converged in the ER algorithm, known patches whose Fourier transform magnitudes are similar to that of the target patch are selected from the target image. In the second approach, the Fourier transform magnitude of the target patch is estimated from those of the selected known patches and their corresponding errors. Consequently, by using the ER algorithm, we can estimate both the Fourier transform magnitudes and phases to reconstruct the missing areas.

Polarization and Color Filtering Applied to Enhance Photogrammetric Measurements of Reflective Surfaces

NASA Technical Reports Server (NTRS)

Wells, Jeffrey M.; Jones, Thomas W.; Danehy, Paul M.

2005-01-01

Techniques for enhancing photogrammetric measurement of reflective surfaces by reducing noise were developed utilizing principles of light polarization. Signal selectivity with polarized light was also compared to signal selectivity using chromatic filters. Combining principles of linear cross polarization and color selectivity enhanced signal-to-noise ratios by as much as 800 fold. More typical improvements with combining polarization and color selectivity were about 100 fold. We review polarization-based techniques and present experimental results comparing the performance of traditional retroreflective targeting materials, cornercube targets returning depolarized light, and color selectivity.

THINK OUTSIDE THE COLOR BOX: PROBABILISTIC TARGET SELECTION AND THE SDSS-XDQSOQUASAR TARGETING CATALOG

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

BOVY, J.; Sheldon, E.; Hennawi, J.F.

2011-03-10

We present the SDSS-XDQSO quasar targeting catalog for efficient flux-based quasar target selection down to the faint limit of the Sloan Digital Sky Survey (SDSS) catalog, even at medium redshifts (2.5 {approx}< z {approx}< 3) where the stellar contamination is significant. We build models of the distributions of stars and quasars in flux space down to the flux limit by applying the extreme-deconvolution method to estimate the underlying density. We convolve this density with the flux uncertainties when evaluating the probability that an object is a quasar. This approach results in a targeting algorithm that is more principled, more efficient,more » and faster than other similar methods. We apply the algorithm to derive low-redshift (z < 2.2), medium-redshift (2.2 {le} z {le} 3.5), and high-redshift (z > 3.5) quasar probabilities for all 160,904,060 point sources with dereddened i-band magnitude between 17.75 and 22.45 mag in the 14,555 deg{sup 2} of imaging from SDSS Data Release 8. The catalog can be used to define a uniformly selected and efficient low- or medium-redshift quasar survey, such as that needed for the SDSS-III's Baryon Oscillation Spectroscopic Survey project. We show that the XDQSO technique performs as well as the current best photometric quasar-selection technique at low redshift, and outperforms all other flux-based methods for selecting the medium-redshift quasars of our primary interest. We make code to reproduce the XDQSO quasar target selection publicly available.« less

Mapping protein-protein interactions with phage-displayed combinatorial peptide libraries.

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

Kay, B. K.; Castagnoli, L.; Biosciences Division

This unit describes the process and analysis of affinity selecting bacteriophage M13 from libraries displaying combinatorial peptides fused to either a minor or major capsid protein. Direct affinity selection uses target protein bound to a microtiter plate followed by purification of selected phage by ELISA. Alternatively, there is a bead-based affinity selection method. These methods allow one to readily isolate peptide ligands that bind to a protein target of interest and use the consensus sequence to search proteomic databases for putative interacting proteins.

Fast cat-eye effect target recognition based on saliency extraction

NASA Astrophysics Data System (ADS)

Li, Li; Ren, Jianlin; Wang, Xingbin

2015-09-01

Background complexity is a main reason that results in false detection in cat-eye target recognition. Human vision has selective attention property which can help search the salient target from complex unknown scenes quickly and precisely. In the paper, we propose a novel cat-eye effect target recognition method named Multi-channel Saliency Processing before Fusion (MSPF). This method combines traditional cat-eye target recognition with the selective characters of visual attention. Furthermore, parallel processing enables it to achieve fast recognition. Experimental results show that the proposed method performs better in accuracy, robustness and speed compared to other methods.

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;…

Oculomotor selection underlies feature retention in visual working memory.

PubMed

Hanning, Nina M; Jonikaitis, Donatas; Deubel, Heiner; Szinte, Martin

2016-02-01

Oculomotor selection, spatial task relevance, and visual working memory (WM) are described as three processes highly intertwined and sustained by similar cortical structures. However, because task-relevant locations always constitute potential saccade targets, no study so far has been able to distinguish between oculomotor selection and spatial task relevance. We designed an experiment that allowed us to dissociate in humans the contribution of task relevance, oculomotor selection, and oculomotor execution to the retention of feature representations in WM. We report that task relevance and oculomotor selection lead to dissociable effects on feature WM maintenance. In a first task, in which an object's location was encoded as a saccade target, its feature representations were successfully maintained in WM, whereas they declined at nonsaccade target locations. Likewise, we observed a similar WM benefit at the target of saccades that were prepared but never executed. In a second task, when an object's location was marked as task relevant but constituted a nonsaccade target (a location to avoid), feature representations maintained at that location did not benefit. Combined, our results demonstrate that oculomotor selection is consistently associated with WM, whereas task relevance is not. This provides evidence for an overlapping circuitry serving saccade target selection and feature-based WM that can be dissociated from processes encoding task-relevant locations. Copyright © 2016 the American Physiological Society.

Phage display selection of peptides that target calcium-binding proteins.

PubMed

Vetter, Stefan W

2013-01-01

Phage display allows to rapidly identify peptide sequences with binding affinity towards target proteins, for example, calcium-binding proteins (CBPs). Phage technology allows screening of 10(9) or more independent peptide sequences and can identify CBP binding peptides within 2 weeks. Adjusting of screening conditions allows selecting CBPs binding peptides that are either calcium-dependent or independent. Obtained peptide sequences can be used to identify CBP target proteins based on sequence homology or to quickly obtain peptide-based CBP inhibitors to modulate CBP-target interactions. The protocol described here uses a commercially available phage display library, in which random 12-mer peptides are displayed on filamentous M13 phages. The library was screened against the calcium-binding protein S100B.

Targeted training of the decision rule benefits rule-guided behavior in Parkinson's disease.

PubMed

Ell, Shawn W

2013-12-01

The impact of Parkinson's disease (PD) on rule-guided behavior has received considerable attention in cognitive neuroscience. The majority of research has used PD as a model of dysfunction in frontostriatal networks, but very few attempts have been made to investigate the possibility of adapting common experimental techniques in an effort to identify the conditions that are most likely to facilitate successful performance. The present study investigated a targeted training paradigm designed to facilitate rule learning and application using rule-based categorization as a model task. Participants received targeted training in which there was no selective-attention demand (i.e., stimuli varied along a single, relevant dimension) or nontargeted training in which there was selective-attention demand (i.e., stimuli varied along a relevant dimension as well as an irrelevant dimension). Following training, all participants were tested on a rule-based task with selective-attention demand. During the test phase, PD patients who received targeted training performed similarly to control participants and outperformed patients who did not receive targeted training. As a preliminary test of the generalizability of the benefit of targeted training, a subset of the PD patients were tested on the Wisconsin card sorting task (WCST). PD patients who received targeted training outperformed PD patients who did not receive targeted training on several WCST performance measures. These data further characterize the contribution of frontostriatal circuitry to rule-guided behavior. Importantly, these data also suggest that PD patient impairment, on selective-attention-demanding tasks of rule-guided behavior, is not inevitable and highlight the potential benefit of targeted training.

Recovery of germanium-68 from irradiated targets

DOEpatents

Phillips, Dennis R.; Jamriska, Sr., David J.; Hamilton, Virginia T.

1993-01-01

A process for selective separation of germanium-68 from proton irradiated molybdenum targets is provided and includes dissolving the molybdenum target in a hydrogen peroxide solution to form a first ion-containing solution, contacting the first ion-containing solution with a cationic resin whereby ions selected from the group consisting of molybdenum, niobium, technetium, selenium, vanadium, arsenic, germanium, zirconium and rubidium remain in a second ion-containing solution while ions selected from the group consisting of rubidium, zinc, beryllium, cobalt, iron, manganese, chromium, strontium, yttrium and zirconium are selectively adsorbed by the first resin, adjusting the pH of the second ion-containing solution to within a range of from about 0.7 to about 3.0, adjusting the soluble metal halide concentration in the second ion-containing solution to a level adapted for subsequent separation of germanium, contacting the pH-adjusted, soluble metal halide-containing second ion-containing solution with a dextran-based material whereby germanium ions are separated by the dextran-based material, and recovering the germanium from the dextran-based material, preferably by distillation.

Selective Mitochondrial Targeting Exerts Anxiolytic Effects In Vivo

PubMed Central

Nussbaumer, Markus; Asara, John M; Teplytska, Larysa; Murphy, Michael P; Logan, Angela; Turck, Christoph W; Filiou, Michaela D

2016-01-01

Current treatment strategies for anxiety disorders are predominantly symptom-based. However, a third of anxiety patients remain unresponsive to anxiolytics highlighting the need for more effective, mechanism-based therapeutic approaches. We have previously compared high vs low anxiety mice and identified changes in mitochondrial pathways, including oxidative phosphorylation and oxidative stress. In this work, we show that selective pharmacological targeting of these mitochondrial pathways exerts anxiolytic effects in vivo. We treated high anxiety-related behavior (HAB) mice with MitoQ, an antioxidant that selectively targets mitochondria. MitoQ administration resulted in decreased anxiety-related behavior in HAB mice. This anxiolytic effect was specific for high anxiety as MitoQ treatment did not affect the anxiety phenotype of C57BL/6N and DBA/2J mouse strains. We furthermore investigated the molecular underpinnings of the MitoQ-driven anxiolytic effect and found that MitoQ treatment alters the brain metabolome and that the response to MitoQ treatment is characterized by distinct molecular signatures. These results indicate that a mechanism-driven approach based on selective mitochondrial targeting has the potential to attenuate the high anxiety phenotype in vivo, thus paving the way for translational implementation as long-term MitoQ administration is well-tolerated with no reported side effects in mice and humans. PMID:26567514

Selective Mitochondrial Targeting Exerts Anxiolytic Effects In Vivo.

PubMed

Nussbaumer, Markus; Asara, John M; Teplytska, Larysa; Murphy, Michael P; Logan, Angela; Turck, Christoph W; Filiou, Michaela D

2016-06-01

Current treatment strategies for anxiety disorders are predominantly symptom-based. However, a third of anxiety patients remain unresponsive to anxiolytics highlighting the need for more effective, mechanism-based therapeutic approaches. We have previously compared high vs low anxiety mice and identified changes in mitochondrial pathways, including oxidative phosphorylation and oxidative stress. In this work, we show that selective pharmacological targeting of these mitochondrial pathways exerts anxiolytic effects in vivo. We treated high anxiety-related behavior (HAB) mice with MitoQ, an antioxidant that selectively targets mitochondria. MitoQ administration resulted in decreased anxiety-related behavior in HAB mice. This anxiolytic effect was specific for high anxiety as MitoQ treatment did not affect the anxiety phenotype of C57BL/6N and DBA/2J mouse strains. We furthermore investigated the molecular underpinnings of the MitoQ-driven anxiolytic effect and found that MitoQ treatment alters the brain metabolome and that the response to MitoQ treatment is characterized by distinct molecular signatures. These results indicate that a mechanism-driven approach based on selective mitochondrial targeting has the potential to attenuate the high anxiety phenotype in vivo, thus paving the way for translational implementation as long-term MitoQ administration is well-tolerated with no reported side effects in mice and humans.

Inside the Black Box of Audit and Feedback: a Laboratory Study to Explore Determinants of Improvement Target Selection by Healthcare Professionals in Cardiac Rehabilitation.

PubMed

Gude, Wouter T; van der Veer, Sabine N; van Engen-Verheul, Mariëtte M; de Keizer, Nicolette F; Peek, Niels

2015-01-01

Audit and feedback (A&F) is widely used to aid healthcare professionals in improving clinical performance, but there is little understanding of the underlying mechanism that determines its effectiveness. The aim of this paper is to investigate the process by which healthcare professionals select indicators as improvement targets based on A&F. We performed a laboratory study among 41 healthcare professionals in the context of a web-based A&F intervention designed to improve the quality of cardiac rehabilitation care in the Netherlands. Feedback was provided on eighteen quality indicators, including a score and a colour (representing a recommendation for selection (red and yellow) or non-selection (green)). Indicators with more room for improvement were more likely to be selected, although this varied substantially between participants. In more than a quarter of the cases, participants did not select indicators with obvious room for improvement (yellow or red colour), or selected indicators without apparent room for improvement (green colour). We conclude that personal preferences and beliefs concerning quality and performance targets may dilute the efficiency of A&F.

Micromotor-based lab-on-chip immunoassays.

PubMed

García, Miguel; Orozco, Jahir; Guix, Maria; Gao, Wei; Sattayasamitsathit, Sirilak; Escarpa, Alberto; Merkoçi, Arben; Wang, Joseph

2013-02-21

Here we describe the first example of using self-propelled antibody-functionalized synthetic catalytic microengines for capturing and transporting target proteins between the different reservoirs of a lab-on-a-chip (LOC) device. A new catalytic polymer/Ni/Pt microtube engine, containing carboxy moieties on its mixed poly(3,4-ethylenedioxythiophene) (PEDOT)/COOH-PEDOT polymeric outermost layer, is further functionalized with the antibody receptor to selectively recognize and capture the target protein. The new motor-based microchip immunoassay operations are carried out without any bulk fluid flow, replacing the common washing steps in antibody-based protein bioassays with the active transport of the captured protein throughout the different reservoirs, where each step of the immunoassay takes place. A first microchip format involving an 'on-the-fly' double-antibody sandwich assay (DASA) is used for demonstrating the selective capture of the target protein, in the presence of excess of non-target proteins. A secondary antibody tagged with a polymeric-sphere tracer allows the direct visualization of the binding events. In a second approach the immuno-nanomotor captures and transports the microsphere-tagged antigen through a microchannel network. An anti-protein-A modified microengine is finally used to demonstrate the selective capture, transport and convenient label-free optical detection of a Staphylococcus aureus target bacteria (containing proteinA in its cell wall) in the presence of a large excess of non-target (Saccharomyces cerevisiae) cells. The resulting nanomotor-based microchip immunoassay offers considerable potential for diverse applications in clinical diagnostics, environmental and security monitoring fields.

Priming and the guidance by visual and categorical templates in visual search.

PubMed

Wilschut, Anna; Theeuwes, Jan; Olivers, Christian N L

2014-01-01

Visual search is thought to be guided by top-down templates that are held in visual working memory. Previous studies have shown that a search-guiding template can be rapidly and strongly implemented from a visual cue, whereas templates are less effective when based on categorical cues. Direct visual priming from cue to target may underlie this difference. In two experiments we first asked observers to remember two possible target colors. A postcue then indicated which of the two would be the relevant color. The task was to locate a briefly presented and masked target of the cued color among irrelevant distractor items. Experiment 1 showed that overall search accuracy improved more rapidly on the basis of a direct visual postcue that carried the target color, compared to a neutral postcue that pointed to the memorized color. However, selectivity toward the target feature, i.e., the extent to which observers searched selectively among items of the cued vs. uncued color, was found to be relatively unaffected by the presence of the visual signal. In Experiment 2 we compared search that was based on either visual or categorical information, but now controlled for direct visual priming. This resulted in no differences in overall performance nor selectivity. Altogether the results suggest that perceptual processing of visual search targets is facilitated by priming from visual cues, whereas attentional selectivity is enhanced by a working memory template that can formed from both visual and categorical input. Furthermore, if the priming is controlled for, categorical- and visual-based templates similarly enhance search guidance.

Fragment-based approaches to the discovery of kinase inhibitors.

PubMed

Mortenson, Paul N; Berdini, Valerio; O'Reilly, Marc

2014-01-01

Protein kinases are one of the most important families of drug targets, and aberrant kinase activity has been linked to a large number of disease areas. Although eminently targetable using small molecules, kinases present a number of challenges as drug targets, not least obtaining selectivity across such a large and relatively closely related target family. Fragment-based drug discovery involves screening simple, low-molecular weight compounds to generate initial hits against a target. These hits are then optimized to more potent compounds via medicinal chemistry, usually facilitated by structural biology. Here, we will present a number of recent examples of fragment-based approaches to the discovery of kinase inhibitors, detailing the construction of fragment-screening libraries, the identification and validation of fragment hits, and their optimization into potent and selective lead compounds. The advantages of fragment-based methodologies will be discussed, along with some of the challenges associated with using this route. Finally, we will present a number of key lessons derived both from our own experience running fragment screens against kinases and from a large number of published studies.

The modulation of inhibition of return by object-internal structure: implications for theories of object-based attentional selection.

PubMed

Reppa, Irene; Leek, E Charles

2003-06-01

Recently, Vecera, Behrmann, and McGoldrick (2000), using a divided-attention task, reported that targets are detected more accurately when they occur on the same structural part of an object, suggesting that attention can be directed toward object-internal features. We present converging evidence using the object-based inhibition of return (IOR) paradigm as an implicit measure of selection. The results show that IOR is attenuated when cues and targets appear on the same part of an object relative to when they are separated by a part boundary. These findings suggest that object-based mechanisms of selection can operate over shape representations that make explicit information about object-internal structure.

Arrayed antibody library technology for therapeutic biologic discovery.

PubMed

Bentley, Cornelia A; Bazirgan, Omar A; Graziano, James J; Holmes, Evan M; Smider, Vaughn V

2013-03-15

Traditional immunization and display antibody discovery methods rely on competitive selection amongst a pool of antibodies to identify a lead. While this approach has led to many successful therapeutic antibodies, targets have been limited to proteins which are easily purified. In addition, selection driven discovery has produced a narrow range of antibody functionalities focused on high affinity antagonism. We review the current progress in developing arrayed protein libraries for screening-based, rather than selection-based, discovery. These single molecule per microtiter well libraries have been screened in multiplex formats against both purified antigens and directly against targets expressed on the cell surface. This facilitates the discovery of antibodies against therapeutically interesting targets (GPCRs, ion channels, and other multispanning membrane proteins) and epitopes that have been considered poorly accessible to conventional discovery methods. Copyright © 2013. Published by Elsevier Inc.

Improved training for target detection using Fukunaga-Koontz transform and distance classifier correlation filter

NASA Astrophysics Data System (ADS)

Elbakary, M. I.; Alam, M. S.; Aslan, M. S.

2008-03-01

In a FLIR image sequence, a target may disappear permanently or may reappear after some frames and crucial information such as direction, position and size related to the target are lost. If the target reappears at a later frame, it may not be tracked again because the 3D orientation, size and location of the target might be changed. To obtain information about the target before disappearing and to detect the target after reappearing, distance classifier correlation filter (DCCF) is trained manualy by selecting a number of chips randomly. This paper introduces a novel idea to eliminates the manual intervention in training phase of DCCF. Instead of selecting the training chips manually and selecting the number of the training chips randomly, we adopted the K-means algorithm to cluster the training frames and based on the number of clusters we select the training chips such that a training chip for each cluster. To detect and track the target after reappearing in the field-ofview ,TBF and DCCF are employed. The contduced experiemnts using real FLIR sequences show results similar to the traditional agorithm but eleminating the manual intervention is the advantage of the proposed algorithm.

Drug target identification in protozoan parasites

PubMed Central

Müller, Joachim; Hemphill, Andrew

2016-01-01

Introduction Despite the fact that diseases caused by protozoan parasites represent serious challenges for public health, animal production and welfare, only a limited panel of drugs has been marketed for clinical applications. Areas covered Herein, the authors investigate two strategies, namely whole organism screening and target-based drug design. The present pharmacopoeia has resulted from whole organism screening, and the mode of action and targets of selected drugs are discussed. However, the more recent extensive genome sequencing efforts and the development of dry and wet lab genomics and proteomics that allow high-throughput screening of interactions between micromolecules and recombinant proteins has resulted in target-based drug design as the predominant focus in anti-parasitic drug development. Selected examples of target-based drug design studies are presented, and calcium-dependent protein kinases, important drug targets in apicomplexan parasites, are discussed in more detail. Expert opinion Despite the enormous efforts in target-based drug development, this approach has not yet generated market-ready antiprotozoal drugs. However, whole-organism screening approaches, comprising of both in vitro and in vivo investigations, should not be disregarded. The repurposing of already approved and marketed drugs could be a suitable strategy to avoid fastidious approval procedures, especially in the case of neglected or veterinary parasitoses. PMID:27238605

Action video games and improved attentional control: Disentangling selection- and response-based processes.

PubMed

Chisholm, Joseph D; Kingstone, Alan

2015-10-01

Research has demonstrated that experience with action video games is associated with improvements in a host of cognitive tasks. Evidence from paradigms that assess aspects of attention has suggested that action video game players (AVGPs) possess greater control over the allocation of attentional resources than do non-video-game players (NVGPs). Using a compound search task that teased apart selection- and response-based processes (Duncan, 1985), we required participants to perform an oculomotor capture task in which they made saccades to a uniquely colored target (selection-based process) and then produced a manual directional response based on information within the target (response-based process). We replicated the finding that AVGPs are less susceptible to attentional distraction and, critically, revealed that AVGPs outperform NVGPs on both selection-based and response-based processes. These results not only are consistent with the improved-attentional-control account of AVGP benefits, but they suggest that the benefit of action video game playing extends across the full breadth of attention-mediated stimulus-response processes that impact human performance.

Optimizing drilling performance using a selected drilling fluid

DOEpatents

Judzis, Arnis [Salt Lake City, UT; Black, Alan D [Coral Springs, FL; Green, Sidney J [Salt Lake City, UT; Robertson, Homer A [West Jordan, UT; Bland, Ronald G [Houston, TX; Curry, David Alexander [The Woodlands, TX; Ledgerwood, III, Leroy W.

2011-04-19

To improve drilling performance, a drilling fluid is selected based on one or more criteria and to have at least one target characteristic. Drilling equipment is used to drill a wellbore, and the selected drilling fluid is provided into the wellbore during drilling with the drilling equipment. The at least one target characteristic of the drilling fluid includes an ability of the drilling fluid to penetrate into formation cuttings during drilling to weaken the formation cuttings.

Colorectal cancer chemoprevention: the potential of a selective approach.

PubMed

Ben-Amotz, Oded; Arber, Nadir; Kraus, Sarah

2010-10-01

Colorectal cancer (CRC) is a leading cause of cancer death, and therefore demands special attention. Novel recent approaches for the chemoprevention of CRC focus on selective targeting of key pathways. We review the study by Zhang and colleagues, evaluating a selective approach targeting APC-deficient premalignant cells using retinoid-based therapy and TNF-related apoptosis-inducing ligand (TRAIL). This study demonstrates that induction of TRAIL-mediated death signaling contributes to the chemopreventive value of all-trans-retinyl acetate (RAc) by sensitizing premalignant adenoma cells for apoptosis without affecting normal cells. We discuss these important findings, raise few points that deserve consideration, and may further contribute to the development of RAc-based combination therapies with improved efficacy. The authors clearly demonstrate a synergistic interaction between TRAIL, RAc and APC, which leads to the specific cell death of premalignant target cells. The study adds to the growing body of literature related to CRC chemoprevention, and provides solid data supporting a potentially selective approach for preventing CRC using RAc and TRAIL.

System-level multi-target drug discovery from natural products with applications to cardiovascular diseases.

PubMed

Zheng, Chunli; Wang, Jinan; Liu, Jianling; Pei, Mengjie; Huang, Chao; Wang, Yonghua

2014-08-01

The term systems pharmacology describes a field of study that uses computational and experimental approaches to broaden the view of drug actions rooted in molecular interactions and advance the process of drug discovery. The aim of this work is to stick out the role that the systems pharmacology plays across the multi-target drug discovery from natural products for cardiovascular diseases (CVDs). Firstly, based on network pharmacology methods, we reconstructed the drug-target and target-target networks to determine the putative protein target set of multi-target drugs for CVDs treatment. Secondly, we reintegrated a compound dataset of natural products and then obtained a multi-target compounds subset by virtual-screening process. Thirdly, a drug-likeness evaluation was applied to find the ADME-favorable compounds in this subset. Finally, we conducted in vitro experiments to evaluate the reliability of the selected chemicals and targets. We found that four of the five randomly selected natural molecules can effectively act on the target set for CVDs, indicating the reasonability of our systems-based method. This strategy may serve as a new model for multi-target drug discovery of complex diseases.

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.

In-silico Leishmania target selectivity of antiparasitic terpenoids.

PubMed

Ogungbe, Ifedayo Victor; Setzer, William N

2013-07-03

Neglected Tropical Diseases (NTDs), like leishmaniasis, are major causes of mortality in resource-limited countries. The mortality associated with these diseases is largely due to fragile healthcare systems, lack of access to medicines, and resistance by the parasites to the few available drugs. Many antiparasitic plant-derived isoprenoids have been reported, and many of them have good in vitro activity against various forms of Leishmania spp. In this work, potential Leishmania biochemical targets of antiparasitic isoprenoids were studied in silico. Antiparasitic monoterpenoids selectively docked to L. infantum nicotinamidase, L. major uridine diphosphate-glucose pyrophosphorylase and methionyl t-RNA synthetase. The two protein targets selectively targeted by germacranolide sesquiterpenoids were L. major methionyl t-RNA synthetase and dihydroorotate dehydrogenase. Diterpenoids generally favored docking to L. mexicana glycerol-3-phosphate dehydrogenase. Limonoids also showed some selectivity for L. mexicana glycerol-3-phosphate dehydrogenase and L. major dihydroorotate dehydrogenase while withanolides docked more selectively with L. major uridine diphosphate-glucose pyrophosphorylase. The selectivity of the different classes of antiparasitic compounds for the protein targets considered in this work can be explored in fragment- and/or structure-based drug design towards the development of leads for new antileishmanial drugs.

Automated Threshold Selection for Template-Based Sonar Target Detection

DTIC Science & Technology

2017-08-01

test based on the distribution of the matched filter correlations. From the matched filter output we evaluate target sized areas and surrounding...synthetic aperture sonar data that were part of the evaluation . Figure 3 shows a nearly uniform seafloor. Figure 4 is more complex, with

Lead selection and characterization of antitubercular compounds using the Nested Chemical Library.

PubMed

Sipos, Anna; Pató, János; Székely, Rita; Hartkoorn, Ruben C; Kékesi, László; Őrfi, László; Szántai-Kis, Csaba; Mikušová, Katarína; Svetlíková, Zuzana; Korduláková, Jana; Nagaraja, Valakunja; Godbole, Adwait Anand; Bush, Natassja; Collin, Frédéric; Maxwell, Anthony; Cole, Stewart T; Kéri, György

2015-06-01

Discovering new drugs to treat tuberculosis more efficiently and to overcome multidrug resistance is a world health priority. To find novel antitubercular agents several approaches have been used in various institutions worldwide, including target-based approaches against several validated mycobacterial enzymes and phenotypic screens. We screened more than 17,000 compounds from Vichem's Nested Chemical Library™ using an integrated strategy involving whole cell-based assays with Corynebacterium glutamicum and Mycobacterium tuberculosis, and target-based assays with protein kinases PknA, PknB and PknG as well as other targets such as PimA and bacterial topoisomerases simultaneously. With the help of the target-based approach we have found very potent hits inhibiting the selected target enzymes, but good minimal inhibitory concentrations (MIC) against M. tuberculosis were not achieved. Focussing on the whole cell-based approach several potent hits were found which displayed minimal inhibitory concentrations (MIC) against M. tuberculosis below 10 μM and were non-mutagenic, non-cytotoxic and the targets of some of the hits were also identified. The most active hits represented various scaffolds. Medicinal chemistry-based lead optimization was performed applying various strategies and, as a consequence, a series of novel potent compounds were synthesized. These efforts resulted in some effective potential antitubercular lead compounds which were confirmed in phenotypic assays. Copyright © 2015 Elsevier Ltd. All rights reserved.

Highly Multiplexed RNA Aptamer Selection using a Microplate-based Microcolumn Device.

PubMed

Reinholt, Sarah J; Ozer, Abdullah; Lis, John T; Craighead, Harold G

2016-07-19

We describe a multiplexed RNA aptamer selection to 19 different targets simultaneously using a microcolumn-based device, MEDUSA (Microplate-based Enrichment Device Used for the Selection of Aptamers), as well as a modified selection process, that significantly reduce the time and reagents needed for selections. We exploited MEDUSA's reconfigurable design between parallel and serially-connected microcolumns to enable the use of just 2 aliquots of starting library, and its 96-well microplate compatibility to enable the continued use of high-throughput techniques in downstream processes. Our modified selection protocol allowed us to perform the equivalent of a 10-cycle selection in the time it takes for 4 traditional selection cycles. Several aptamers were discovered with nanomolar dissociation constants. Furthermore, aptamers were identified that not only bound with high affinity, but also acted as inhibitors to significantly reduce the activity of their target protein, mouse decapping exoribonuclease (DXO). The aptamers resisted DXO's exoribonuclease activity, and in studies monitoring DXO's degradation of a 30-nucleotide substrate, less than 1 μM of aptamer demonstrated significant inhibition of DXO activity. This aptamer selection method using MEDUSA helps to overcome some of the major challenges with traditional aptamer selections, and provides a platform for high-throughput selections that lends itself to process automation.

Multi atlas based segmentation: Should we prefer the best atlas group over the group of best atlases?

PubMed

Zaffino, Paolo; Ciardo, Delia; Raudaschl, Patrik; Fritscher, Karl; Ricotti, Rosalinda; Alterio, Daniela; Marvaso, Giulia; Fodor, Cristiana; Baroni, Guido; Amato, Francesco; Orecchia, Roberto; Jereczek-Fossa, Barbara Alicja; Sharp, Gregory C; Spadea, Maria Francesca

2018-05-22

Multi Atlas Based Segmentation (MABS) uses a database of atlas images, and an atlas selection process is used to choose an atlas subset for registration and voting. In the current state of the art, atlases are chosen according to a similarity criterion between the target subject and each atlas in the database. In this paper, we propose a new concept for atlas selection that relies on selecting the best performing group of atlases rather than the group of highest scoring individual atlases. Experiments were performed using CT images of 50 patients, with contours of brainstem and parotid glands. The dataset was randomly split in 2 groups: 20 volumes were used as an atlas database and 30 served as target subjects for testing. Classic oracle group selection, where atlases are chosen by the highest Dice Similarity Coefficient (DSC) with the target, was performed. This was compared to oracle Group selection, where all the combinations of atlas subgroups were considered and scored by computing DSC with the target subject. Subsequently, Convolutional Neural Networks (CNNs) were designed to predict the best group of atlases. The results were compared also with the selection strategy based on Normalized Mutual Information (NMI). Oracle group was proved to be significantly better that classic oracle selection (p<10-5). Atlas group selection led to a median±interquartile DSC of 0.740±0.084, 0.718±0.086 and 0.670±0.097 for brainstem and left/right parotid glands respectively, outperforming NMI selection 0.676±0.113, 0.632±0.104 and 0.606±0.118 (p<0.001) as well as classic oracle selection. The implemented methodology is a proof of principle that selecting the atlases by considering the performance of the entire group of atlases instead of each single atlas leads to higher segmentation accuracy, being even better then current oracle strategy. This finding opens a new discussion about the most appropriate atlas selection criterion for MABS. © 2018 Institute of Physics and Engineering in Medicine.

Cell-Based Selection Expands the Utility of DNA-Encoded Small-Molecule Library Technology to Cell Surface Drug Targets: Identification of Novel Antagonists of the NK3 Tachykinin Receptor.

PubMed

Wu, Zining; Graybill, Todd L; Zeng, Xin; Platchek, Michael; Zhang, Jean; Bodmer, Vera Q; Wisnoski, David D; Deng, Jianghe; Coppo, Frank T; Yao, Gang; Tamburino, Alex; Scavello, Genaro; Franklin, G Joseph; Mataruse, Sibongile; Bedard, Katie L; Ding, Yun; Chai, Jing; Summerfield, Jennifer; Centrella, Paolo A; Messer, Jeffrey A; Pope, Andrew J; Israel, David I

2015-12-14

DNA-encoded small-molecule library technology has recently emerged as a new paradigm for identifying ligands against drug targets. To date, this technology has been used with soluble protein targets that are produced and used in a purified state. Here, we describe a cell-based method for identifying small-molecule ligands from DNA-encoded libraries against integral membrane protein targets. We use this method to identify novel, potent, and specific inhibitors of NK3, a member of the tachykinin family of G-protein coupled receptors (GPCRs). The method is simple and broadly applicable to other GPCRs and integral membrane proteins. We have extended the application of DNA-encoded library technology to membrane-associated targets and demonstrate the feasibility of selecting DNA-tagged, small-molecule ligands from complex combinatorial libraries against targets in a heterogeneous milieu, such as the surface of a cell.

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.

High-order graph matching based feature selection for Alzheimer's disease identification.

PubMed

Liu, Feng; Suk, Heung-Il; Wee, Chong-Yaw; Chen, Huafu; Shen, Dinggang

2013-01-01

One of the main limitations of l1-norm feature selection is that it focuses on estimating the target vector for each sample individually without considering relations with other samples. However, it's believed that the geometrical relation among target vectors in the training set may provide useful information, and it would be natural to expect that the predicted vectors have similar geometric relations as the target vectors. To overcome these limitations, we formulate this as a graph-matching feature selection problem between a predicted graph and a target graph. In the predicted graph a node is represented by predicted vector that may describe regional gray matter volume or cortical thickness features, and in the target graph a node is represented by target vector that include class label and clinical scores. In particular, we devise new regularization terms in sparse representation to impose high-order graph matching between the target vectors and the predicted ones. Finally, the selected regional gray matter volume and cortical thickness features are fused in kernel space for classification. Using the ADNI dataset, we evaluate the effectiveness of the proposed method and obtain the accuracies of 92.17% and 81.57% in AD and MCI classification, respectively.

Fragment-based design of symmetrical bis-benzimidazoles as selective inhibitors of the trimethoprim-resistant, type II R67 dihydrofolate reductase.

PubMed

Bastien, Dominic; Ebert, Maximilian C C J C; Forge, Delphine; Toulouse, Jacynthe; Kadnikova, Natalia; Perron, Florent; Mayence, Annie; Huang, Tien L; Vanden Eynde, Jean Jacques; Pelletier, Joelle N

2012-04-12

The continuously increasing use of trimethoprim as a common antibiotic for medical use and for prophylactic application in terrestrial and aquatic animal farming has increased its prevalence in the environment. This has been accompanied by increased drug resistance, generally in the form of alterations in the drug target, dihydrofolate reductase (DHFR). The most highly resistant variants of DHFR are known as type II DHFR, among which R67 DHFR is the most broadly studied variant. We report the first attempt at designing specific inhibitors to this emerging drug target by fragment-based design. The detection of inhibition in R67 DHFR was accompanied by parallel monitoring of the human DHFR, as an assessment of compound selectivity. By those means, small aromatic molecules of 150-250 g/mol (fragments) inhibiting R67 DHFR selectively in the low millimolar range were identified. More complex, symmetrical bis-benzimidazoles and a bis-carboxyphenyl were then assayed as fragment-based leads, which procured selective inhibition of the target in the low micromolar range (K(i) = 2-4 μM). The putative mode of inhibition is discussed according to molecular modeling supported by in vitro tests. © 2012 American Chemical Society

An Effective and Robust Decentralized Target Tracking Scheme in Wireless Camera Sensor Networks.

PubMed

Fu, Pengcheng; Cheng, Yongbo; Tang, Hongying; Li, Baoqing; Pei, Jun; Yuan, Xiaobing

2017-03-20

In this paper, we propose an effective and robust decentralized tracking scheme based on the square root cubature information filter (SRCIF) to balance the energy consumption and tracking accuracy in wireless camera sensor networks (WCNs). More specifically, regarding the characteristics and constraints of camera nodes in WCNs, some special mechanisms are put forward and integrated in this tracking scheme. First, a decentralized tracking approach is adopted so that the tracking can be implemented energy-efficiently and steadily. Subsequently, task cluster nodes are dynamically selected by adopting a greedy on-line decision approach based on the defined contribution decision (CD) considering the limited energy of camera nodes. Additionally, we design an efficient cluster head (CH) selection mechanism that casts such selection problem as an optimization problem based on the remaining energy and distance-to-target. Finally, we also perform analysis on the target detection probability when selecting the task cluster nodes and their CH, owing to the directional sensing and observation limitations in field of view (FOV) of camera nodes in WCNs. From simulation results, the proposed tracking scheme shows an obvious improvement in balancing the energy consumption and tracking accuracy over the existing methods.

An Effective and Robust Decentralized Target Tracking Scheme in Wireless Camera Sensor Networks

PubMed Central

Fu, Pengcheng; Cheng, Yongbo; Tang, Hongying; Li, Baoqing; Pei, Jun; Yuan, Xiaobing

2017-01-01

In this paper, we propose an effective and robust decentralized tracking scheme based on the square root cubature information filter (SRCIF) to balance the energy consumption and tracking accuracy in wireless camera sensor networks (WCNs). More specifically, regarding the characteristics and constraints of camera nodes in WCNs, some special mechanisms are put forward and integrated in this tracking scheme. First, a decentralized tracking approach is adopted so that the tracking can be implemented energy-efficiently and steadily. Subsequently, task cluster nodes are dynamically selected by adopting a greedy on-line decision approach based on the defined contribution decision (CD) considering the limited energy of camera nodes. Additionally, we design an efficient cluster head (CH) selection mechanism that casts such selection problem as an optimization problem based on the remaining energy and distance-to-target. Finally, we also perform analysis on the target detection probability when selecting the task cluster nodes and their CH, owing to the directional sensing and observation limitations in field of view (FOV) of camera nodes in WCNs. From simulation results, the proposed tracking scheme shows an obvious improvement in balancing the energy consumption and tracking accuracy over the existing methods. PMID:28335537

Combining Phage and Yeast Cell Surface Antibody Display to Identify Novel Cell Type-Selective Internalizing Human Monoclonal Antibodies.

PubMed

Bidlingmaier, Scott; Su, Yang; Liu, Bin

2015-01-01

Using phage antibody display, large libraries can be generated and screened to identify monoclonal antibodies with affinity for target antigens. However, while library size and diversity is an advantage of the phage display method, there is limited ability to quantitatively enrich for specific binding properties such as affinity. One way of overcoming this limitation is to combine the scale of phage display selections with the flexibility and quantitativeness of FACS-based yeast surface display selections. In this chapter we describe protocols for generating yeast surface antibody display libraries using phage antibody display selection outputs as starting material and FACS-based enrichment of target antigen-binding clones from these libraries. These methods should be widely applicable for the identification of monoclonal antibodies with specific binding properties.

A long-term target detection approach in infrared image sequence

NASA Astrophysics Data System (ADS)

Li, Hang; Zhang, Qi; Wang, Xin; Hu, Chao

2016-10-01

An automatic target detection method used in long term infrared (IR) image sequence from a moving platform is proposed. Firstly, based on POME(the principle of maximum entropy), target candidates are iteratively segmented. Then the real target is captured via two different selection approaches. At the beginning of image sequence, the genuine target with litter texture is discriminated from other candidates by using contrast-based confidence measure. On the other hand, when the target becomes larger, we apply online EM method to estimate and update the distributions of target's size and position based on the prior detection results, and then recognize the genuine one which satisfies both the constraints of size and position. Experimental results demonstrate that the presented method is accurate, robust and efficient.

Performance evaluation of structure based and ligand based virtual screening methods on ten selected anti-cancer targets.

PubMed

Ramasamy, Thilagavathi; Selvam, Chelliah

2015-10-15

Virtual screening has become an important tool in drug discovery process. Structure based and ligand based approaches are generally used in virtual screening process. To date, several benchmark sets for evaluating the performance of the virtual screening tool are available. In this study, our aim is to compare the performance of both structure based and ligand based virtual screening methods. Ten anti-cancer targets and their corresponding benchmark sets from 'Demanding Evaluation Kits for Objective In silico Screening' (DEKOIS) library were selected. X-ray crystal structures of protein-ligand complexes were selected based on their resolution. Openeye tools such as FRED, vROCS were used and the results were carefully analyzed. At EF1%, vROCS produced better results but at EF5% and EF10%, both FRED and ROCS produced almost similar results. It was noticed that the enrichment factor values were decreased while going from EF1% to EF5% and EF10% in many cases. Published by Elsevier Ltd.

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.

A multi-model approach to nucleic acid-based drug development.

PubMed

Gautherot, Isabelle; Sodoyer, Regís

2004-01-01

With the advent of functional genomics and the shift of interest towards sequence-based therapeutics, the past decades have witnessed intense research efforts on nucleic acid-mediated gene regulation technologies. Today, RNA interference is emerging as a groundbreaking discovery, holding promise for development of genetic modulators of unprecedented potency. Twenty-five years after the discovery of antisense RNA and ribozymes, gene control therapeutics are still facing developmental difficulties, with only one US FDA-approved antisense drug currently available in the clinic. Limited predictability of target site selection models is recognized as one major stumbling block that is shared by all of the so-called complementary technologies, slowing the progress towards a commercial product. Currently employed in vitro systems for target site selection include RNAse H-based mapping, antisense oligonucleotide microarrays, and functional screening approaches using libraries of catalysts with randomized target-binding arms to identify optimal ribozyme/DNAzyme cleavage sites. Individually, each strategy has its drawbacks from a drug development perspective. Utilization of message-modulating sequences as therapeutic agents requires that their action on a given target transcript meets criteria of potency and selectivity in the natural physiological environment. In addition to sequence-dependent characteristics, other factors will influence annealing reactions and duplex stability, as well as nucleic acid-mediated catalysis. Parallel consideration of physiological selection systems thus appears essential for screening for nucleic acid compounds proposed for therapeutic applications. Cellular message-targeting studies face issues relating to efficient nucleic acid delivery and appropriate analysis of response. For reliability and simplicity, prokaryotic systems can provide a rapid and cost-effective means of studying message targeting under pseudo-cellular conditions, but such approaches also have limitations. To streamline nucleic acid drug discovery, we propose a multi-model strategy integrating high-throughput-adapted bacterial screening, followed by reporter-based and/or natural cellular models and potentially also in vitro assays for characterization of the most promising candidate sequences, before final in vivo testing.

Molecular image-directed biopsies: improving clinical biopsy selection in patients with multiple tumors

NASA Astrophysics Data System (ADS)

Harmon, Stephanie A.; Tuite, Michael J.; Jeraj, Robert

2016-10-01

Site selection for image-guided biopsies in patients with multiple lesions is typically based on clinical feasibility and physician preference. This study outlines the development of a selection algorithm that, in addition to clinical requirements, incorporates quantitative imaging data for automatic identification of candidate lesions for biopsy. The algorithm is designed to rank potential targets by maximizing a lesion-specific score, incorporating various criteria separated into two categories: (1) physician-feasibility category including physician-preferred lesion location and absolute volume scores, and (2) imaging-based category including various modality and application-specific metrics. This platform was benchmarked in two clinical scenarios, a pre-treatment setting and response-based setting using imaging from metastatic prostate cancer patients with high disease burden (multiple lesions) undergoing conventional treatment and receiving whole-body [18F]NaF PET/CT scans pre- and mid-treatment. Targeting of metastatic lesions was robust to different weighting ratios and candidacy for biopsy was physician confirmed. Lesion ranked as top targets for biopsy remained so for all patients in pre-treatment and post-treatment biopsy selection after sensitivity testing was completed for physician-biased or imaging-biased scenarios. After identifying candidates, biopsy feasibility was evaluated by a physician and confirmed for 90% (32/36) of high-ranking lesions, of which all top choices were confirmed. The remaining cases represented lesions with high anatomical difficulty for targeting, such as proximity to sciatic nerve. This newly developed selection method was successfully used to quantitatively identify candidate lesions for biopsies in patients with multiple lesions. In a prospective study, we were able to successfully plan, develop, and implement this technique for the selection of a pre-treatment biopsy location.

Targeted estrogen delivery reverses the metabolic syndrome

PubMed Central

Finan, Brian; Yang, Bin; Ottaway, Nickki; Stemmer, Kerstin; Müller, Timo D; Yi, Chun-Xia; Habegger, Kirk; Schriever, Sonja C; García-Cáceres, Cristina; Kabra, Dhiraj G; Hembree, Jazzminn; Holland, Jenna; Raver, Christine; Seeley, Randy J; Hans, Wolfgang; Irmler, Martin; Beckers, Johannes; de Angelis, Martin Hrabě; Tiano, Joseph P; Mauvais-Jarvis, Franck; Perez-Tilve, Diego; Pfluger, Paul; Zhang, Lianshan; Gelfanov, Vasily; DiMarchi, Richard D; Tschöp, Matthias H

2013-01-01

We report the development of a new combinatorial approach that allows for peptide-mediated selective tissue targeting of nuclear hormone pharmacology while eliminating adverse effects in other tissues. Specifically, we report the development of a glucagon-like peptide-1 (GLP-1)-estrogen conjugate that has superior sex-independent efficacy over either of the individual hormones alone to correct obesity, hyperglycemia and dyslipidemia in mice. The therapeutic benefits are driven by pleiotropic dual hormone action to improve energy, glucose and lipid metabolism, as shown by loss-of-function models and genetic action profiling. Notably, the peptide-based targeting strategy also prevents hallmark side effects of estrogen in male and female mice, such as reproductive endocrine toxicity and oncogenicity. Collectively, selective activation of estrogen receptors in GLP-1–targeted tissues produces unprecedented efficacy to enhance the metabolic benefits of GLP-1 agonism. This example of targeting the metabolic syndrome represents the discovery of a new class of therapeutics that enables synergistic co-agonism through peptide-based selective delivery of small molecules. Although our observations with the GLP-1–estrogen conjugate justify translational studies for diabetes and obesity, the multitude of other possible combinations of peptides and small molecules may offer equal promise for other diseases. PMID:23142820

An off-on fluorescence probe targeting mitochondria based on oxidation-reduction response for tumor cell and tissue imaging

NASA Astrophysics Data System (ADS)

Yao, Hanchun; Cao, Li; Zhao, Weiwei; Zhang, Suge; Zeng, Man; Du, Bin

2017-10-01

In this study, a tumor-targeting poly( d, l-lactic-co-glycolic acid) (PLGA) loaded "off-on" fluorescent probe nanoparticle (PFN) delivery system was developed to evaluate the region of tumor by off-on fluorescence. The biodegradability of the nanosize PFN delivery system readily released the probe under tumor acidic conditions. The probe with good biocompatibility was used to monitor the intracellular glutathione (GSH) of cancer cells and selectively localize to mitochondria for tumor imaging. The incorporated tumor-targeting probe was based on the molecular photoinduced electron transfer (PET) mechanism preventing fluorescence ("off" state) and could be easily released under tumor acidic conditions. However, the released tumor-targeting fluorescence probe molecule was selective towards GSH with high selectivity and an ultra-sensitivity for the mitochondria of cancer cells and tissues significantly increasing the probe molecule fluorescence signal ("on" state). The tumor-targeting fluorescence probe showed sensitivity to GSH avoiding interference from cysteine and homocysteine. The PFNs could enable fluorescence-guided cancer imaging during cancer therapy. This work may expand the biological applications of PFNs as a diagnostic reagent, which will be beneficial for fundamental research in tumor imaging. [Figure not available: see fulltext.

Occurrence Prospect of HDR and Target Site Selection Study in Southeastern of China

NASA Astrophysics Data System (ADS)

Lin, W.; Gan, H.

2017-12-01

Hot dry rock (HDR) geothermal resource is one of the most important clean energy in future. Site selection a HDR resource is a fundamental work to explore the HDR resources. This paper compiled all the HDR development projects domestic and abroad, and summarized the location of HDR geothermal geological index. After comparing the geological background of HDR in the southeast coastal area of China, Yangjiang Xinzhou in Guangdong province, Leizhou Peninsula area, Lingshui in Hainan province and Huangshadong in Guangzhou were selected from some key potential target area along the southeast coast of China. Deep geothermal field model of the study area is established based on the comprehensive analysis of the target area of deep geothermal geological background and deep thermal anomalies. This paper also compared the hot dry rock resources target locations, and proposed suggestions for the priority exploration target area and exploration scheme.

Construction and applications of exon-trapping gene-targeting vectors with a novel strategy for negative selection.

PubMed

Saito, Shinta; Ura, Kiyoe; Kodama, Miho; Adachi, Noritaka

2015-06-30

Targeted gene modification by homologous recombination provides a powerful tool for studying gene function in cells and animals. In higher eukaryotes, non-homologous integration of targeting vectors occurs several orders of magnitude more frequently than does targeted integration, making the gene-targeting technology highly inefficient. For this reason, negative-selection strategies have been employed to reduce the number of drug-resistant clones associated with non-homologous vector integration, particularly when artificial nucleases to introduce a DNA break at the target site are unavailable or undesirable. As such, an exon-trap strategy using a promoterless drug-resistance marker gene provides an effective way to counterselect non-homologous integrants. However, constructing exon-trapping targeting vectors has been a time-consuming and complicated process. By virtue of highly efficient att-mediated recombination, we successfully developed a simple and rapid method to construct plasmid-based vectors that allow for exon-trapping gene targeting. These exon-trap vectors were useful in obtaining correctly targeted clones in mouse embryonic stem cells and human HT1080 cells. Most importantly, with the use of a conditionally cytotoxic gene, we further developed a novel strategy for negative selection, thereby enhancing the efficiency of counterselection for non-homologous integration of exon-trap vectors. Our methods will greatly facilitate exon-trapping gene-targeting technologies in mammalian cells, particularly when combined with the novel negative selection strategy.

In Vitro Selection for Small-Molecule-Triggered Strand Displacement and Riboswitch Activity.

PubMed

Martini, Laura; Meyer, Adam J; Ellefson, Jared W; Milligan, John N; Forlin, Michele; Ellington, Andrew D; Mansy, Sheref S

2015-10-16

An in vitro selection method for ligand-responsive RNA sensors was developed that exploited strand displacement reactions. The RNA library was based on the thiamine pyrophosphate (TPP) riboswitch, and RNA sequences capable of hybridizing to a target duplex DNA in a TPP regulated manner were identified. After three rounds of selection, RNA molecules that mediated a strand exchange reaction upon TPP binding were enriched. The enriched sequences also showed riboswitch activity. Our results demonstrated that small-molecule-responsive nucleic acid sensors can be selected to control the activity of target nucleic acid circuitry.

Using Negative Reinforcement to Increase Self-Feeding in a Child with Food Selectivity

ERIC Educational Resources Information Center

Vaz, Petula C. M.; Volkert, Valerie M.; Piazza, Cathleen C.

2011-01-01

We examined the effects of a negative reinforcement-based treatment on the self-feeding of 1 child with food selectivity by type and texture. Self-feeding increased when the child could choose to either self-feed 1 bite of a target food or be fed 1 bite of the target food and 5 bites of another food. Possible mechanisms that underlie the…

Selective pressures for accurate altruism targeting: evidence from digital evolution for difficult-to-test aspects of inclusive fitness theory.

PubMed

Clune, Jeff; Goldsby, Heather J; Ofria, Charles; Pennock, Robert T

2011-03-07

Inclusive fitness theory predicts that natural selection will favour altruist genes that are more accurate in targeting altruism only to copies of themselves. In this paper, we provide evidence from digital evolution in support of this prediction by competing multiple altruist-targeting mechanisms that vary in their accuracy in determining whether a potential target for altruism carries a copy of the altruist gene. We compete altruism-targeting mechanisms based on (i) kinship (kin targeting), (ii) genetic similarity at a level greater than that expected of kin (similarity targeting), and (iii) perfect knowledge of the presence of an altruist gene (green beard targeting). Natural selection always favoured the most accurate targeting mechanism available. Our investigations also revealed that evolution did not increase the altruism level when all green beard altruists used the same phenotypic marker. The green beard altruism levels stably increased only when mutations that changed the altruism level also changed the marker (e.g. beard colour), such that beard colour reliably indicated the altruism level. For kin- and similarity-targeting mechanisms, we found that evolution was able to stably adjust altruism levels. Our results confirm that natural selection favours altruist genes that are increasingly accurate in targeting altruism to only their copies. Our work also emphasizes that the concept of targeting accuracy must include both the presence of an altruist gene and the level of altruism it produces.

The Dynamics of Scaling: A Memory-Based Anchor Model of Category Rating and Absolute Identification

ERIC Educational Resources Information Center

Petrov, Alexander A.; Anderson, John R.

2005-01-01

A memory-based scaling model--ANCHOR--is proposed and tested. The perceived magnitude of the target stimulus is compared with a set of anchors in memory. Anchor selection is probabilistic and sensitive to similarity, base-level strength, and recency. The winning anchor provides a reference point near the target and thereby converts the global…

Cell specific aptamer-photosensitizer conjugates as a molecular tool in photodynamic therapy

PubMed Central

Mallikaratchy, Prabodhika; Tang, Zhiwen

2010-01-01

This paper describes the application of a molecular construct of a photosensitizer and an aptamer for photo-therapeutically targeting tumor cells. The key step in increasing selectivity in chemotherapeutic drugs is to create effective molecular platforms that could target cancer cells but not normal cells. Recently, we have developed a strategy via cell-SELEX (Systematic Evolution of Ligands by Exponential Enrichment) to obtain cell specific aptamers using intact viable cells as targets to select aptamers that can recognize cell membrane proteins with high selectivity and excellent affinity. We have identified an aptamer TD05 that only recognizes Ramos cells, a Burkitt’s lymphoma cell line. Here, the high specificity of aptamers in target cell binding and an efficient phototherapy reagent, Ce6, are molecularly engineered to construct a highly selective Aptamer-photosensitizer conjugates (APS) to effectively destroy target cancer cells. Introduction of the APS conjugates followed by irradiation of light selectively destroyed target Ramos cells but not acute lymphoblastic leukemia and myeloid leukemia cell lines. This study demonstrates that the use of cancer specific aptamers conjugated to a photosensitizer will enhance the selectivity of photodynamic therapy. Coupled with the advantages of the cell-SELEX in generating multiple effective aptamers for diseased cell recognition, we will be able to develop highly efficient photosensitizer based therapeutical reagents for clinical applications. PMID:18058891

Learning to rank atlases for multiple-atlas segmentation.

PubMed

Sanroma, Gerard; Wu, Guorong; Gao, Yaozong; Shen, Dinggang

2014-10-01

Recently, multiple-atlas segmentation (MAS) has achieved a great success in the medical imaging area. The key assumption is that multiple atlases have greater chances of correctly labeling a target image than a single atlas. However, the problem of atlas selection still remains unexplored. Traditionally, image similarity is used to select a set of atlases. Unfortunately, this heuristic criterion is not necessarily related to the final segmentation performance. To solve this seemingly simple but critical problem, we propose a learning-based atlas selection method to pick up the best atlases that would lead to a more accurate segmentation. Our main idea is to learn the relationship between the pairwise appearance of observed instances (i.e., a pair of atlas and target images) and their final labeling performance (e.g., using the Dice ratio). In this way, we select the best atlases based on their expected labeling accuracy. Our atlas selection method is general enough to be integrated with any existing MAS method. We show the advantages of our atlas selection method in an extensive experimental evaluation in the ADNI, SATA, IXI, and LONI LPBA40 datasets. As shown in the experiments, our method can boost the performance of three widely used MAS methods, outperforming other learning-based and image-similarity-based atlas selection methods.

Discovery-2: an interactive resource for the rational selection and comparison of putative drug target proteins in malaria

PubMed Central

2013-01-01

Background Drug resistance to anti-malarial compounds remains a serious problem, with resistance to newer pharmaceuticals developing at an alarming rate. The development of new anti-malarials remains a priority, and the rational selection of putative targets is a key element of this process. Discovery-2 is an update of the original Discovery in silico resource for the rational selection of putative drug target proteins, enabling researchers to obtain information for a protein which may be useful for the selection of putative drug targets, and to perform advanced filtering of proteins encoded by the malaria genome based on a series of molecular properties. Methods An updated in silico resource has been developed where researchers are able to mine information on malaria proteins and predicted ligands, as well as perform comparisons to the human and mosquito host characteristics. Protein properties used include: domains, motifs, EC numbers, GO terms, orthologs, protein-protein interactions, protein-ligand interactions. Newly added features include drugability measures from ChEMBL, automated literature relations and links to clinical trial information. Searching by chemical structure is also available. Results The updated functionality of the Discovery-2 resource is presented, together with a detailed case study of the Plasmodium falciparum S-adenosyl-L-homocysteine hydrolase (PfSAHH) protein. A short example of a chemical search with pyrimethamine is also illustrated. Conclusion The updated Discovery-2 resource allows researchers to obtain detailed properties of proteins from the malaria genome, which may be of interest in the target selection process, and to perform advanced filtering and selection of proteins based on a relevant range of molecular characteristics. PMID:23537208

Feature Extraction and Selection Strategies for Automated Target Recognition

NASA Technical Reports Server (NTRS)

Greene, W. Nicholas; Zhang, Yuhan; Lu, Thomas T.; Chao, Tien-Hsin

2010-01-01

Several feature extraction and selection methods for an existing automatic target recognition (ATR) system using JPLs Grayscale Optical Correlator (GOC) and Optimal Trade-Off Maximum Average Correlation Height (OT-MACH) filter were tested using MATLAB. The ATR system is composed of three stages: a cursory region of-interest (ROI) search using the GOC and OT-MACH filter, a feature extraction and selection stage, and a final classification stage. Feature extraction and selection concerns transforming potential target data into more useful forms as well as selecting important subsets of that data which may aide in detection and classification. The strategies tested were built around two popular extraction methods: Principal Component Analysis (PCA) and Independent Component Analysis (ICA). Performance was measured based on the classification accuracy and free-response receiver operating characteristic (FROC) output of a support vector machine(SVM) and a neural net (NN) classifier.

Feature extraction and selection strategies for automated target recognition

NASA Astrophysics Data System (ADS)

Greene, W. Nicholas; Zhang, Yuhan; Lu, Thomas T.; Chao, Tien-Hsin

2010-04-01

Several feature extraction and selection methods for an existing automatic target recognition (ATR) system using JPLs Grayscale Optical Correlator (GOC) and Optimal Trade-Off Maximum Average Correlation Height (OT-MACH) filter were tested using MATLAB. The ATR system is composed of three stages: a cursory regionof- interest (ROI) search using the GOC and OT-MACH filter, a feature extraction and selection stage, and a final classification stage. Feature extraction and selection concerns transforming potential target data into more useful forms as well as selecting important subsets of that data which may aide in detection and classification. The strategies tested were built around two popular extraction methods: Principal Component Analysis (PCA) and Independent Component Analysis (ICA). Performance was measured based on the classification accuracy and free-response receiver operating characteristic (FROC) output of a support vector machine(SVM) and a neural net (NN) classifier.

[Segment analysis of the target market of physiotherapeutic services].

PubMed

Babaskin, D V

2010-01-01

The objective of the present study was to demonstrate the possibilities to analyse selected segments of the target market of physiotherapeutic services provided by medical and preventive-facilities of two major types. The main features of a target segment, such as provision of therapeutic massage, are illustrated in terms of two characteristics, namely attractiveness to the users and the ability of a given medical facility to satisfy their requirements. Based on the analysis of portfolio of the available target segments the most promising ones (winner segments) were selected for further marketing studies. This choice does not exclude the possibility of involvement of other segments of medical services in marketing activities.

Selective targeting of melanoma by PEG-masked protein-based multifunctional nanoparticles

PubMed Central

Vannucci, Luca; Falvo, Elisabetta; Fornara, Manuela; Di Micco, Patrizio; Benada, Oldrich; Krizan, Jiri; Svoboda, Jan; Hulikova-Capkova, Katarina; Morea, Veronica; Boffi, Alberto; Ceci, Pierpaolo

2012-01-01

Background Nanoparticle-based systems are promising for the development of imaging and therapeutic agents. The main advantage of nanoparticles over traditional systems lies in the possibility of loading multiple functionalities onto a single molecule, which are useful for therapeutic and/or diagnostic purposes. These functionalities include targeting moieties which are able to recognize receptors overexpressed by specific cells and tissues. However, targeted delivery of nanoparticles requires an accurate system design. We present here a rationally designed, genetically engineered, and chemically modified protein-based nanoplatform for cell/tissue-specific targeting. Methods Our nanoparticle constructs were based on the heavy chain of the human protein ferritin (HFt), a highly symmetrical assembly of 24 subunits enclosing a hollow cavity. HFt-based nanoparticles were produced using both genetic engineering and chemical functionalization methods to impart several functionalities, ie, the α-melanocyte-stimulating hormone peptide as a melanoma-targeting moiety, stabilizing and HFt-masking polyethylene glycol molecules, rhodamine fluorophores, and magnetic resonance imaging agents. The constructs produced were extensively characterized by a number of physicochemical techniques, and assayed for selective melanoma-targeting in vitro and in vivo. Results Our HFt-based nanoparticle constructs functionalized with the α-melanocyte-stimulating hormone peptide moiety and polyethylene glycol molecules were specifically taken up by melanoma cells but not by other cancer cell types in vitro. Moreover, experiments in melanoma-bearing mice indicate that these constructs have an excellent tumor-targeting profile and a long circulation time in vivo. Conclusion By masking human HFt with polyethylene glycol and targeting it with an α-melanocyte-stimulating hormone peptide, we developed an HFt-based melanoma-targeting nanoplatform for application in melanoma diagnosis and treatment. These results could be of general interest, because the same strategy can be exploited to develop ad hoc nanoplatforms for specific delivery towards any cell/tissue type for which a suitable targeting moiety is available. PMID:22619508

Toehold-mediated strand displacement reaction triggered isothermal DNA amplification for highly sensitive and selective fluorescent detection of single-base mutation.

PubMed

Zhu, Jing; Ding, Yongshun; Liu, Xingti; Wang, Lei; Jiang, Wei

2014-09-15

Highly sensitive and selective detection strategy for single-base mutations is essential for risk assessment of malignancy and disease prognosis. In this work, a fluorescent detection method for single-base mutation was proposed based on high selectivity of toehold-mediated strand displacement reaction (TSDR) and powerful signal amplification capability of isothermal DNA amplification. A discrimination probe was specially designed with a stem-loop structure and an overhanging toehold domain. Hybridization between the toehold domain and the perfect matched target initiated the TSDR along with the unfolding of the discrimination probe. Subsequently, the target sequence acted as a primer to initiate the polymerization and nicking reactions, which released a great abundant of short sequences. Finally, the released strands were annealed with the reporter probe, launching another polymerization and nicking reaction to produce lots of G-quadruplex DNA, which could bind the N-methyl mesoporphyrin IX to yield an enhanced fluorescence response. However, when there was even a single base mismatch in the target DNA, the TSDR was suppressed and so subsequent isothermal DNA amplification and fluorescence response process could not occur. The proposed approach has been successfully implemented for the identification of the single-base mutant sequences in the human KRAS gene with a detection limit of 1.8 pM. Furthermore, a recovery of 90% was obtained when detecting the target sequence in spiked HeLa cells lysate, demonstrating the feasibility of this detection strategy for single-base mutations in biological samples. Copyright © 2014 Elsevier B.V. All rights reserved.

Transport and energy selection of laser generated protons for postacceleration with a compact linac

NASA Astrophysics Data System (ADS)

Sinigardi, Stefano; Turchetti, Giorgio; Londrillo, Pasquale; Rossi, Francesco; Giove, Dario; De Martinis, Carlo; Sumini, Marco

2013-03-01

Laser accelerated proton beams have a considerable potential for various applications including oncological therapy. However, the most consolidated target normal sheath acceleration regime based on irradiation of solid targets provides an exponential energy spectrum with a significant divergence. The low count number at the cutoff energy seriously limits at present its possible use. One realistic scenario for the near future is offered by hybrid schemes. The use of transport lines for collimation and energy selection has been considered. We present here a scheme based on a high field pulsed solenoid and collimators which allows one to select a beam suitable for injection at 30 MeV into a compact linac in order to double its energy while preserving a significant intensity. The results are based on a fully 3D simulation starting from laser acceleration.

TESTING INDICATOR GROUPS FOR RESERVE SELECTION: ARE RARE SPECIES AT RISK OF BEING LEFT OUT?

EPA Science Inventory

Indicators of biodiversity are potential tools for selecting areas for conservation when information about species' distributions is scarce. The concept involves selecting areas based on groups of conservation targets whose distributions represent more broadly defined patterns o...

Design and Evaluation of Fusion Approach for Combining Brain and Gaze Inputs for Target Selection

PubMed Central

Évain, Andéol; Argelaguet, Ferran; Casiez, Géry; Roussel, Nicolas; Lécuyer, Anatole

2016-01-01

Gaze-based interfaces and Brain-Computer Interfaces (BCIs) allow for hands-free human–computer interaction. In this paper, we investigate the combination of gaze and BCIs. We propose a novel selection technique for 2D target acquisition based on input fusion. This new approach combines the probabilistic models for each input, in order to better estimate the intent of the user. We evaluated its performance against the existing gaze and brain–computer interaction techniques. Twelve participants took part in our study, in which they had to search and select 2D targets with each of the evaluated techniques. Our fusion-based hybrid interaction technique was found to be more reliable than the previous gaze and BCI hybrid interaction techniques for 10 participants over 12, while being 29% faster on average. However, similarly to what has been observed in hybrid gaze-and-speech interaction, gaze-only interaction technique still provides the best performance. Our results should encourage the use of input fusion, as opposed to sequential interaction, in order to design better hybrid interfaces. PMID:27774048

π-Clamp-mediated cysteine conjugation

NASA Astrophysics Data System (ADS)

Zhang, Chi; Welborn, Matthew; Zhu, Tianyu; Yang, Nicole J.; Santos, Michael S.; van Voorhis, Troy; Pentelute, Bradley L.

2016-02-01

Site-selective functionalization of complex molecules is one of the most significant challenges in chemistry. Typically, protecting groups or catalysts must be used to enable the selective modification of one site among many that are similarly reactive, and general strategies that selectively tune the local chemical environment around a target site are rare. Here, we show a four-amino-acid sequence (Phe-Cys-Pro-Phe), which we call the ‘π-clamp’, that tunes the reactivity of its cysteine thiol for site-selective conjugation with perfluoroaromatic reagents. We use the π-clamp to selectively modify one cysteine site in proteins containing multiple endogenous cysteine residues. These examples include antibodies and cysteine-based enzymes that would be difficult to modify selectively using standard cysteine-based methods. Antibodies modified using the π-clamp retained binding affinity to their targets, enabling the synthesis of site-specific antibody-drug conjugates for selective killing of HER2-positive breast cancer cells. The π-clamp is an unexpected approach to mediate site-selective chemistry and provides new avenues to modify biomolecules for research and therapeutics.

Motor cortex guides selection of predictable movement targets

PubMed Central

Woodgate, Philip J.W.; Strauss, Soeren; Sami, Saber A.; Heinke, Dietmar

2016-01-01

The present paper asks whether the motor cortex contributes to prediction-based guidance of target selection. This question was inspired by recent evidence that suggests (i) recurrent connections from the motor system into the attentional system may extract movement-relevant perceptual information and (ii) that the motor cortex cannot only generate predictions of the sensory consequences of movements but may also operate as predictor of perceptual events in general. To test this idea we employed a choice reaching task requiring participants to rapidly reach and touch a predictable or unpredictable colour target. Motor cortex activity was modulated via transcranial direct current stimulation (tDCS). In Experiment 1 target colour repetitions were predictable. Under such conditions anodal tDCS facilitated selection versus sham and cathodal tDCS. This improvement was apparent for trajectory curvature but not movement initiation. Conversely, where no predictability of colour was embedded reach performance was unaffected by tDCS. Finally, the results of a key-press experiment suggested that motor cortex involvement is restricted to tasks where the predictable target colour is movement-relevant. The outcomes are interpreted as evidence that the motor system contributes to the top-down guidance of selective attention to movement targets. PMID:25835319

Burglar Target Selection

PubMed Central

Townsley, Michael; Bernasco, Wim; Ruiter, Stijn; Johnson, Shane D.; White, Gentry; Baum, Scott

2015-01-01

Objectives: This study builds on research undertaken by Bernasco and Nieuwbeerta and explores the generalizability of a theoretically derived offender target selection model in three cross-national study regions. Methods: Taking a discrete spatial choice approach, we estimate the impact of both environment- and offender-level factors on residential burglary placement in the Netherlands, the United Kingdom, and Australia. Combining cleared burglary data from all study regions in a single statistical model, we make statistical comparisons between environments. Results: In all three study regions, the likelihood an offender selects an area for burglary is positively influenced by proximity to their home, the proportion of easily accessible targets, and the total number of targets available. Furthermore, in two of the three study regions, juvenile offenders under the legal driving age are significantly more influenced by target proximity than adult offenders. Post hoc tests indicate the magnitudes of these impacts vary significantly between study regions. Conclusions: While burglary target selection strategies are consistent with opportunity-based explanations of offending, the impact of environmental context is significant. As such, the approach undertaken in combining observations from multiple study regions may aid criminology scholars in assessing the generalizability of observed findings across multiple environments. PMID:25866418

ProSelection: A Novel Algorithm to Select Proper Protein Structure Subsets for in Silico Target Identification and Drug Discovery Research.

PubMed

Wang, Nanyi; Wang, Lirong; Xie, Xiang-Qun

2017-11-27

Molecular docking is widely applied to computer-aided drug design and has become relatively mature in the recent decades. Application of docking in modeling varies from single lead compound optimization to large-scale virtual screening. The performance of molecular docking is highly dependent on the protein structures selected. It is especially challenging for large-scale target prediction research when multiple structures are available for a single target. Therefore, we have established ProSelection, a docking preferred-protein selection algorithm, in order to generate the proper structure subset(s). By the ProSelection algorithm, protein structures of "weak selectors" are filtered out whereas structures of "strong selectors" are kept. Specifically, the structure which has a good statistical performance of distinguishing active ligands from inactive ligands is defined as a strong selector. In this study, 249 protein structures of 14 autophagy-related targets are investigated. Surflex-dock was used as the docking engine to distinguish active and inactive compounds against these protein structures. Both t test and Mann-Whitney U test were used to distinguish the strong from the weak selectors based on the normality of the docking score distribution. The suggested docking score threshold for active ligands (SDA) was generated for each strong selector structure according to the receiver operating characteristic (ROC) curve. The performance of ProSelection was further validated by predicting the potential off-targets of 43 U.S. Federal Drug Administration approved small molecule antineoplastic drugs. Overall, ProSelection will accelerate the computational work in protein structure selection and could be a useful tool for molecular docking, target prediction, and protein-chemical database establishment research.

Efficacy Trial of a Selective Prevention Program Targeting Both Eating Disorder Symptoms and Unhealthy Weight Gain among Female College Students

ERIC Educational Resources Information Center

Stice, Eric; Rohde, Paul; Shaw, Heather; Marti, C. Nathan

2012-01-01

Objective: Evaluate a selective prevention program targeting both eating disorder symptoms and unhealthy weight gain in young women. Method: Female college students at high-risk for these outcomes by virtue of body image concerns (N = 398; M age = 18.4 years, SD = 0.6) were randomized to the Healthy Weight group-based 4-hr prevention program,…

The guidance of visual search by shape features and shape configurations.

PubMed

McCants, Cody W; Berggren, Nick; Eimer, Martin

2018-03-01

Representations of target features (attentional templates) guide attentional object selection during visual search. In many search tasks, targets objects are defined not by a single feature but by the spatial configuration of their component shapes. We used electrophysiological markers of attentional selection processes to determine whether the guidance of shape configuration search is entirely part-based or sensitive to the spatial relationship between shape features. Participants searched for targets defined by the spatial arrangement of two shape components (e.g., hourglass above circle). N2pc components were triggered not only by targets but also by partially matching distractors with one target shape (e.g., hourglass above hexagon) and by distractors that contained both target shapes in the reverse arrangement (e.g., circle above hourglass), in line with part-based attentional control. Target N2pc components were delayed when a reverse distractor was present on the opposite side of the same display, suggesting that early shape-specific attentional guidance processes could not distinguish between targets and reverse distractors. The control of attention then became sensitive to spatial configuration, which resulted in a stronger attentional bias for target objects relative to reverse and partially matching distractors. Results demonstrate that search for target objects defined by the spatial arrangement of their component shapes is initially controlled in a feature-based fashion but can later be guided by templates for spatial configurations. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

Advancing cancer drug discovery towards more agile development of targeted combination therapies.

PubMed

Carragher, Neil O; Unciti-Broceta, Asier; Cameron, David A

2012-01-01

Current drug-discovery strategies are typically 'target-centric' and are based upon high-throughput screening of large chemical libraries against nominated targets and a selection of lead compounds with optimized 'on-target' potency and selectivity profiles. However, high attrition of targeted agents in clinical development suggest that combinations of targeted agents will be most effective in treating solid tumors if the biological networks that permit cancer cells to subvert monotherapies are identified and retargeted. Conventional drug-discovery and development strategies are suboptimal for the rational design and development of novel drug combinations. In this article, we highlight a series of emerging technologies supporting a less reductionist, more agile, drug-discovery and development approach for the rational design, validation, prioritization and clinical development of novel drug combinations.

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

Plasma block acceleration based upon the interaction between double targets and an ultra-intense linearly polarized laser pulse

NASA Astrophysics Data System (ADS)

Xu, Yanxia; Wang, Jiaxiang; Hora, Heinrich; Qi, Xin; Xing, Yifan; Yang, Lei; Zhu, Wenjun

2018-04-01

A new scheme of plasma block acceleration based upon the interaction between double targets and an ultra-intense linearly polarized laser pulse with intensity I ˜ 1022 W/cm2 is investigated via two-dimensional particle-in-cell simulations. The targets are composed of a pre-target of low-density aluminium plasma and an overdense main-target of hydrogen plasma. Through intensive parameter optimization, we have observed highly efficient plasma block accelerations with a monochromatic proton beam peaked at GeVs. The underlying mechanism is attributed to the enhancement of the charge separation field due to the properly selected pre-target.

Detection of target-probe oligonucleotide hybridization using synthetic nanopore resistive pulse sensing.

PubMed

Booth, Marsilea Adela; Vogel, Robert; Curran, James M; Harbison, SallyAnn; Travas-Sejdic, Jadranka

2013-07-15

Despite the plethora of DNA sensor platforms available, a portable, sensitive, selective and economic sensor able to rival current fluorescence-based techniques would find use in many applications. In this research, probe oligonucleotide-grafted particles are used to detect target DNA in solution through a resistive pulse nanopore detection technique. Using carbodiimide chemistry, functionalized probe DNA strands are attached to carboxylated dextran-based magnetic particles. Subsequent incubation with complementary target DNA yields a change in surface properties as the two DNA strands hybridize. Particle-by-particle analysis with resistive pulse sensing is performed to detect these changes. A variable pressure method allows identification of changes in the surface charge of particles. As proof-of-principle, we demonstrate that target hybridization is selectively detected at micromolar concentrations (nanomoles of target) using resistive pulse sensing, confirmed by fluorescence and phase analysis light scattering as complementary techniques. The advantages, feasibility and limitations of using resistive pulse sensing for sample analysis are discussed. Copyright © 2013 Elsevier B.V. All rights reserved.

A genomic scan for selection reveals candidates for genes involved in the evolution of cultivated sunflower (Helianthus annuus).

PubMed

Chapman, Mark A; Pashley, Catherine H; Wenzler, Jessica; Hvala, John; Tang, Shunxue; Knapp, Steven J; Burke, John M

2008-11-01

Genomic scans for selection are a useful tool for identifying genes underlying phenotypic transitions. In this article, we describe the results of a genome scan designed to identify candidates for genes targeted by selection during the evolution of cultivated sunflower. This work involved screening 492 loci derived from ESTs on a large panel of wild, primitive (i.e., landrace), and improved sunflower (Helianthus annuus) lines. This sampling strategy allowed us to identify candidates for selectively important genes and investigate the likely timing of selection. Thirty-six genes showed evidence of selection during either domestication or improvement based on multiple criteria, and a sequence-based test of selection on a subset of these loci confirmed this result. In view of what is known about the structure of linkage disequilibrium across the sunflower genome, these genes are themselves likely to have been targeted by selection, rather than being merely linked to the actual targets. While the selection candidates showed a broad range of putative functions, they were enriched for genes involved in amino acid synthesis and protein catabolism. Given that a similar pattern has been detected in maize (Zea mays), this finding suggests that selection on amino acid composition may be a general feature of the evolution of crop plants. In terms of genomic locations, the selection candidates were significantly clustered near quantitative trait loci (QTL) that contribute to phenotypic differences between wild and cultivated sunflower, and specific instances of QTL colocalization provide some clues as to the roles that these genes may have played during sunflower evolution.

Quantitative self-assembly prediction yields targeted nanomedicines

NASA Astrophysics Data System (ADS)

Shamay, Yosi; Shah, Janki; Işık, Mehtap; Mizrachi, Aviram; Leibold, Josef; Tschaharganeh, Darjus F.; Roxbury, Daniel; Budhathoki-Uprety, Januka; Nawaly, Karla; Sugarman, James L.; Baut, Emily; Neiman, Michelle R.; Dacek, Megan; Ganesh, Kripa S.; Johnson, Darren C.; Sridharan, Ramya; Chu, Karen L.; Rajasekhar, Vinagolu K.; Lowe, Scott W.; Chodera, John D.; Heller, Daniel A.

2018-02-01

Development of targeted nanoparticle drug carriers often requires complex synthetic schemes involving both supramolecular self-assembly and chemical modification. These processes are generally difficult to predict, execute, and control. We describe herein a targeted drug delivery system that is accurately and quantitatively predicted to self-assemble into nanoparticles based on the molecular structures of precursor molecules, which are the drugs themselves. The drugs assemble with the aid of sulfated indocyanines into particles with ultrahigh drug loadings of up to 90%. We devised quantitative structure-nanoparticle assembly prediction (QSNAP) models to identify and validate electrotopological molecular descriptors as highly predictive indicators of nano-assembly and nanoparticle size. The resulting nanoparticles selectively targeted kinase inhibitors to caveolin-1-expressing human colon cancer and autochthonous liver cancer models to yield striking therapeutic effects while avoiding pERK inhibition in healthy skin. This finding enables the computational design of nanomedicines based on quantitative models for drug payload selection.

Information-based approach to performance estimation and requirements allocation in multisensor fusion for target recognition

NASA Astrophysics Data System (ADS)

Harney, Robert C.

1997-03-01

A novel methodology offering the potential for resolving two of the significant problems of implementing multisensor target recognition systems, i.e., the rational selection of a specific sensor suite and optimal allocation of requirements among sensors, is presented. Based on a sequence of conjectures (and their supporting arguments) concerning the relationship of extractable information content to recognition performance of a sensor system, a set of heuristics (essentially a reformulation of Johnson's criteria applicable to all sensor and data types) is developed. An approach to quantifying the information content of sensor data is described. Coupling this approach with the widely accepted Johnson's criteria for target recognition capabilities results in a quantitative method for comparing the target recognition ability of diverse sensors (imagers, nonimagers, active, passive, electromagnetic, acoustic, etc.). Extension to describing the performance of multiple sensors is straightforward. The application of the technique to sensor selection and requirements allocation is discussed.

Creation of a Novel Class of Potent and Selective MutT Homologue 1 (MTH1) Inhibitors Using Fragment-Based Screening and Structure-Based Drug Design.

PubMed

Rahm, Fredrik; Viklund, Jenny; Trésaugues, Lionel; Ellermann, Manuel; Giese, Anja; Ericsson, Ulrika; Forsblom, Rickard; Ginman, Tobias; Günther, Judith; Hallberg, Kenth; Lindström, Johan; Persson, Lars Boukharta; Silvander, Camilla; Talagas, Antoine; Díaz-Sáez, Laura; Fedorov, Oleg; Huber, Kilian V M; Panagakou, Ioanna; Siejka, Paulina; Gorjánácz, Mátyás; Bauser, Marcus; Andersson, Martin

2018-03-22

Recent literature has both suggested and questioned MTH1 as a novel cancer target. BAY-707 was just published as a target validation small molecule probe for assessing the effects of pharmacological inhibition of MTH1 on tumor cell survival, both in vitro and in vivo. (1) In this report, we describe the medicinal chemistry program creating BAY-707, where fragment-based methods were used to develop a series of highly potent and selective MTH1 inhibitors. Using structure-based drug design and rational medicinal chemistry approaches, the potency was increased over 10,000 times from the fragment starting point while maintaining high ligand efficiency and drug-like properties.

Label-free optical detection of single-base mismatches by the combination of nuclease and gold nanoparticles.

PubMed

Liu, Meiying; Yuan, Min; Lou, Xinhui; Mao, Hongju; Zheng, Dongmei; Zou, Ruxing; Zou, Nengli; Tang, Xiangrong; Zhao, Jianlong

2011-07-15

We report here an optical approach that enables highly selective and colorimetric single-base mismatch detection without the need of target modification, precise temperature control or stringent washes. The method is based on the finding that nucleoside monophosphates (dNMPs), which are digested elements of DNA, can better stabilize unmodified gold nanoparticles (AuNPs) than single-stranded DNA (ssDNA) and double-stranded DNA (dsDNA) with the same base-composition and concentration. The method combines the exceptional mismatch discrimination capability of the structure-selective nucleases with the attractive optical property of AuNPs. Taking S1 nuclease as one example, the perfectly matched 16-base synthetic DNA target was distinctively differentiated from those with single-base mutation located at any position of the 16-base synthetic target. Single-base mutations present in targets with varied length up to 80-base, located either in the middle or near to the end of the targets, were all effectively detected. In order to prove that the method can be potentially used for real clinic samples, the single-base mismatch detections with two HBV genomic DNA samples were conducted. To further prove the generality of this method and potentially overcome the limitation on the detectable lengths of the targets of the S1 nuclease-based method, we also demonstrated the use of a duplex-specific nuclease (DSN) for color reversed single-base mismatch detection. The main limitation of the demonstrated methods is that it is limited to detect mutations in purified ssDNA targets. However, the method coupled with various convenient ssDNA generation and purification techniques, has the potential to be used for the future development of detector-free testing kits in single nucleotide polymorphism screenings for disease diagnostics and treatments. Copyright © 2011 Elsevier B.V. All rights reserved.

Selective Detection of Target Volatile Organic Compounds in Contaminated Humid Air Using a Sensor Array with Principal Component Analysis

PubMed Central

Itoh, Toshio; Akamatsu, Takafumi; Tsuruta, Akihiro; Shin, Woosuck

2017-01-01

We investigated selective detection of the target volatile organic compounds (VOCs) nonanal, n-decane, and acetoin for lung cancer-related VOCs, and acetone and methyl i-butyl ketone for diabetes-related VOCs, in humid air with simulated VOC contamination (total concentration: 300 μg/m3). We used six “grain boundary-response type” sensors, including four commercially available sensors (TGS 2600, 2610, 2610, and 2620) and two Pt, Pd, and Au-loaded SnO2 sensors (Pt, Pd, Au/SnO2), and two “bulk-response type” sensors, including Zr-doped CeO2 (CeZr10), i.e., eight sensors in total. We then analyzed their sensor signals using principal component analysis (PCA). Although the six “grain boundary-response type” sensors were found to be insufficient for selective detection of the target gases in humid air, the addition of two “bulk-response type” sensors improved the selectivity, even with simulated VOC contamination. To further improve the discrimination, we selected appropriate sensors from the eight sensors based on the PCA results. The selectivity to each target gas was maintained and was not affected by contamination. PMID:28753948

Shape recognition of microbial cells by colloidal cell imprints

NASA Astrophysics Data System (ADS)

Borovička, Josef; Stoyanov, Simeon D.; Paunov, Vesselin N.

2013-08-01

We have engineered a class of colloids which can recognize the shape and size of targeted microbial cells and selectively bind to their surfaces. These imprinted colloid particles, which we called ``colloid antibodies'', were fabricated by partial fragmentation of silica shells obtained by templating the targeted microbial cells. We successfully demonstrated the shape and size recognition between such colloidal imprints and matching microbial cells. High percentage of binding events of colloidal imprints with the size matching target particles was achieved. We demonstrated selective binding of colloidal imprints to target microbial cells in a binary mixture of cells of different shapes and sizes, which also resulted in high binding selectivity. We explored the role of the electrostatic interactions between the target cells and their colloid imprints by pre-coating both of them with polyelectrolytes. Selective binding occurred predominantly in the case of opposite surface charges of the colloid cell imprint and the targeted cells. The mechanism of the recognition is based on the amplification of the surface adhesion in the case of shape and size match due to the increased contact area between the target cell and the colloidal imprint. We also tested the selective binding for colloid imprints of particles of fixed shape and varying sizes. The concept of cell recognition by colloid imprints could be used for development of colloid antibodies for shape-selective binding of microbes. Such colloid antibodies could be additionally functionalized with surface groups to enhance their binding efficiency to cells of specific shape and deliver a drug payload directly to their surface or allow them to be manipulated using external fields. They could benefit the pharmaceutical industry in developing selective antimicrobial therapies and formulations.

FOXP2 Targets Show Evidence of Positive Selection in European Populations

PubMed Central

Ayub, Qasim; Yngvadottir, Bryndis; Chen, Yuan; Xue, Yali; Hu, Min; Vernes, Sonja C.; Fisher, Simon E.; Tyler-Smith, Chris

2013-01-01

Forkhead box P2 (FOXP2) is a highly conserved transcription factor that has been implicated in human speech and language disorders and plays important roles in the plasticity of the developing brain. The pattern of nucleotide polymorphisms in FOXP2 in modern populations suggests that it has been the target of positive (Darwinian) selection during recent human evolution. In our study, we searched for evidence of selection that might have followed FOXP2 adaptations in modern humans. We examined whether or not putative FOXP2 targets identified by chromatin-immunoprecipitation genomic screening show evidence of positive selection. We developed an algorithm that, for any given gene list, systematically generates matched lists of control genes from the Ensembl database, collates summary statistics for three frequency-spectrum-based neutrality tests from the low-coverage resequencing data of the 1000 Genomes Project, and determines whether these statistics are significantly different between the given gene targets and the set of controls. Overall, there was strong evidence of selection of FOXP2 targets in Europeans, but not in the Han Chinese, Japanese, or Yoruba populations. Significant outliers included several genes linked to cellular movement, reproduction, development, and immune cell trafficking, and 13 of these constituted a significant network associated with cardiac arteriopathy. Strong signals of selection were observed for CNTNAP2 and RBFOX1, key neurally expressed genes that have been consistently identified as direct FOXP2 targets in multiple studies and that have themselves been associated with neurodevelopmental disorders involving language dysfunction. PMID:23602712

The effect of friend selection on social influences in obesity.

PubMed

Trogdon, Justin G; Allaire, Benjamin T

2014-12-01

We present an agent-based model of weight choice and peer selection that simulates the effect of peer selection on social multipliers for weight loss interventions. The model generates social clustering around weight through two mechanisms: a causal link from others' weight to an individual's weight and the propensity to select peers based on weight. We simulated weight loss interventions and tried to identify intervention targets that maximized the spillover of weight loss from intervention participants to nonparticipants. Social multipliers increase with the number of intervention participants' friends. For example, when friend selection was based on a variable exogenous to weight, the weight lost among non-participants increased by 23% (14.3lb vs. 11.6lb) when targeting the most popular obese. Holding constant the number of participants' friends, multipliers increase with increased weight clustering due to selection, up to a point. For example, among the most popular obese, social multipliers when matching on a characteristic correlated with weight (1.189) were higher than when matching on the exogenous characteristic (1.168) and when matching on weight (1.180). Increased weight clustering also implies more obese "friends of friends" of participants, who reduce social multipliers. Copyright © 2014 Elsevier B.V. All rights reserved.

Genome-wide comparative diversity uncovers multiple targets of selection for improvement in hexaploid wheat landraces and cultivars.

PubMed

Cavanagh, Colin R; Chao, Shiaoman; Wang, Shichen; Huang, Bevan Emma; Stephen, Stuart; Kiani, Seifollah; Forrest, Kerrie; Saintenac, Cyrille; Brown-Guedira, Gina L; Akhunova, Alina; See, Deven; Bai, Guihua; Pumphrey, Michael; Tomar, Luxmi; Wong, Debbie; Kong, Stephan; Reynolds, Matthew; da Silva, Marta Lopez; Bockelman, Harold; Talbert, Luther; Anderson, James A; Dreisigacker, Susanne; Baenziger, Stephen; Carter, Arron; Korzun, Viktor; Morrell, Peter Laurent; Dubcovsky, Jorge; Morell, Matthew K; Sorrells, Mark E; Hayden, Matthew J; Akhunov, Eduard

2013-05-14

Domesticated crops experience strong human-mediated selection aimed at developing high-yielding varieties adapted to local conditions. To detect regions of the wheat genome subject to selection during improvement, we developed a high-throughput array to interrogate 9,000 gene-associated single-nucleotide polymorphisms (SNP) in a worldwide sample of 2,994 accessions of hexaploid wheat including landraces and modern cultivars. Using a SNP-based diversity map we characterized the impact of crop improvement on genomic and geographic patterns of genetic diversity. We found evidence of a small population bottleneck and extensive use of ancestral variation often traceable to founders of cultivars from diverse geographic regions. Analyzing genetic differentiation among populations and the extent of haplotype sharing, we identified allelic variants subjected to selection during improvement. Selective sweeps were found around genes involved in the regulation of flowering time and phenology. An introgression of a wild relative-derived gene conferring resistance to a fungal pathogen was detected by haplotype-based analysis. Comparing selective sweeps identified in different populations, we show that selection likely acts on distinct targets or multiple functionally equivalent alleles in different portions of the geographic range of wheat. The majority of the selected alleles were present at low frequency in local populations, suggesting either weak selection pressure or temporal variation in the targets of directional selection during breeding probably associated with changing agricultural practices or environmental conditions. The developed SNP chip and map of genetic variation provide a resource for advancing wheat breeding and supporting future population genomic and genome-wide association studies in wheat.

Genome-wide comparative diversity uncovers multiple targets of selection for improvement in hexaploid wheat landraces and cultivars

PubMed Central

Cavanagh, Colin R.; Chao, Shiaoman; Wang, Shichen; Huang, Bevan Emma; Stephen, Stuart; Kiani, Seifollah; Forrest, Kerrie; Saintenac, Cyrille; Brown-Guedira, Gina L.; Akhunova, Alina; See, Deven; Bai, Guihua; Pumphrey, Michael; Tomar, Luxmi; Wong, Debbie; Kong, Stephan; Reynolds, Matthew; da Silva, Marta Lopez; Bockelman, Harold; Talbert, Luther; Anderson, James A.; Dreisigacker, Susanne; Baenziger, Stephen; Carter, Arron; Korzun, Viktor; Morrell, Peter Laurent; Dubcovsky, Jorge; Morell, Matthew K.; Sorrells, Mark E.; Hayden, Matthew J.; Akhunov, Eduard

2013-01-01

Domesticated crops experience strong human-mediated selection aimed at developing high-yielding varieties adapted to local conditions. To detect regions of the wheat genome subject to selection during improvement, we developed a high-throughput array to interrogate 9,000 gene-associated single-nucleotide polymorphisms (SNP) in a worldwide sample of 2,994 accessions of hexaploid wheat including landraces and modern cultivars. Using a SNP-based diversity map we characterized the impact of crop improvement on genomic and geographic patterns of genetic diversity. We found evidence of a small population bottleneck and extensive use of ancestral variation often traceable to founders of cultivars from diverse geographic regions. Analyzing genetic differentiation among populations and the extent of haplotype sharing, we identified allelic variants subjected to selection during improvement. Selective sweeps were found around genes involved in the regulation of flowering time and phenology. An introgression of a wild relative-derived gene conferring resistance to a fungal pathogen was detected by haplotype-based analysis. Comparing selective sweeps identified in different populations, we show that selection likely acts on distinct targets or multiple functionally equivalent alleles in different portions of the geographic range of wheat. The majority of the selected alleles were present at low frequency in local populations, suggesting either weak selection pressure or temporal variation in the targets of directional selection during breeding probably associated with changing agricultural practices or environmental conditions. The developed SNP chip and map of genetic variation provide a resource for advancing wheat breeding and supporting future population genomic and genome-wide association studies in wheat. PMID:23630259

The prospect of gene therapy for prostate cancer: update on theory and status.

PubMed

Koeneman, K S; Hsieh, J T

2001-09-01

Molecularly based novel therapeutic agents are needed to address the problem of locally recurrent, or metastatic, advanced hormone-refractory prostate cancer. Recent basic science advances in mechanisms of gene expression, vector delivery, and targeting have rendered clinically relevant gene therapy to the prostatic fossa and distant sites feasible in the near future. Current research and clinical investigative efforts involving methods for more effective vector delivery and targeting, with enhanced gene expression to selected (specific) sites, are reviewed. These areas of research involve tissue-specific promoters, transgene exploration, vector design and delivery, and selective vector targeting. The 'vectorology' involved mainly addresses selective tissue homing with ligands, mechanisms of innate immune system evasion for durable transgene expression, and the possibility of repeat administration.

A new functional method to choose the target lobe for lung volume reduction in emphysema - comparison with the conventional densitometric method.

PubMed

Hetzel, Juergen; Boeckeler, Michael; Horger, Marius; Ehab, Ahmed; Kloth, Christopher; Wagner, Robert; Freitag, Lutz; Slebos, Dirk-Jan; Lewis, Richard Alexander; Haentschel, Maik

2017-01-01

Lung volume reduction (LVR) improves breathing mechanics by reducing hyperinflation. Lobar selection usually focuses on choosing the most destroyed emphysematous lobes as seen on an inspiratory CT scan. However, it has never been shown to what extent these densitometric CT parameters predict the least deflation of an individual lobe during expiration. The addition of expiratory CT analysis allows measurement of the extent of lobar air trapping and could therefore provide additional functional information for choice of potential treatment targets. To determine lobar vital capacity/lobar total capacity (LVC/LTC) as a functional parameter for lobar air trapping using on an inspiratory and expiratory CT scan. To compare lobar selection by LVC/LTC with the established morphological CT density parameters. 36 patients referred for endoscopic LVR were studied. LVC/LTC, defined as delta volume over maximum volume of a lobe, was calculated using inspiratory and expiratory CT scans. The CT morphological parameters of mean lung density (MLD), low attenuation volume (LAV), and 15th percentile of Hounsfield units (15%P) were determined on an inspiratory CT scan for each lobe. We compared and correlated LVC/LTC with MLD, LAV, and 15%P. There was a weak correlation between the functional parameter LVC/LTC and all inspiratory densitometric parameters. Target lobe selection using lowest lobar deflation (lowest LVC/LTC) correlated with target lobe selection based on lowest MLD in 18 patients (50.0%), with the highest LAV in 13 patients (36.1%), and with the lowest 15%P in 12 patients (33.3%). CT-based measurement of deflation (LVC/LTC) as a functional parameter correlates weakly with all densitometric CT parameters on a lobar level. Therefore, morphological criteria based on inspiratory CT densitometry partially reflect the deflation of particular lung lobes, and may be of limited value as a sole predictor for target lobe selection in LVR.

Band selection method based on spectrum difference in targets of interest in hyperspectral imagery

NASA Astrophysics Data System (ADS)

Zhang, Xiaohan; Yang, Guang; Yang, Yongbo; Huang, Junhua

2016-10-01

While hyperspectral data shares rich spectrum information, it has numbers of bands with high correlation coefficients, causing great data redundancy. A reasonable band selection is important for subsequent processing. Bands with large amount of information and low correlation should be selected. On this basis, according to the needs of target detection applications, the spectral characteristics of the objects of interest are taken into consideration in this paper, and a new method based on spectrum difference is proposed. Firstly, according to the spectrum differences of targets of interest, a difference matrix which represents the different spectral reflectance of different targets in different bands is structured. By setting a threshold, the bands satisfying the conditions would be left, constituting a subset of bands. Then, the correlation coefficients between bands are calculated and correlation matrix is given. According to the size of the correlation coefficient, the bands can be set into several groups. At last, the conception of normalized variance is used on behalf of the information content of each band. The bands are sorted by the value of its normalized variance. Set needing number of bands, and the optimum band combination solution can be get by these three steps. This method retains the greatest degree of difference between the target of interest and is easy to achieve by computer automatically. Besides, false color image synthesis experiment is carried out using the bands selected by this method as well as other 3 methods to show the performance of method in this paper.

Sequence-based design of bioactive small molecules that target precursor microRNAs.

PubMed

Velagapudi, Sai Pradeep; Gallo, Steven M; Disney, Matthew D

2014-04-01

Oligonucleotides are designed to target RNA using base pairing rules, but they can be hampered by poor cellular delivery and nonspecific stimulation of the immune system. Small molecules are preferred as lead drugs or probes but cannot be designed from sequence. Herein, we describe an approach termed Inforna that designs lead small molecules for RNA from solely sequence. Inforna was applied to all human microRNA hairpin precursors, and it identified bioactive small molecules that inhibit biogenesis by binding nuclease-processing sites (44% hit rate). Among 27 lead interactions, the most avid interaction is between a benzimidazole (1) and precursor microRNA-96. Compound 1 selectively inhibits biogenesis of microRNA-96, upregulating a protein target (FOXO1) and inducing apoptosis in cancer cells. Apoptosis is ablated when FOXO1 mRNA expression is knocked down by an siRNA, validating compound selectivity. Markedly, microRNA profiling shows that 1 only affects microRNA-96 biogenesis and is at least as selective as an oligonucleotide.

Sequence-based design of bioactive small molecules that target precursor microRNAs

PubMed Central

Velagapudi, Sai Pradeep; Gallo, Steven M.; Disney, Matthew D.

2014-01-01

Oligonucleotides are designed to target RNA using base pairing rules, however, they are hampered by poor cellular delivery and non-specific stimulation of the immune system. Small molecules are preferred as lead drugs or probes, but cannot be designed from sequence. Herein, we describe an approach termed Inforna that designs lead small molecules for RNA from solely sequence. Inforna was applied to all human microRNA precursors and identified bioactive small molecules that inhibit biogenesis by binding to nuclease processing sites (41% hit rate). Amongst 29 lead interactions, the most avid interaction is between a benzimidazole (1) and precursor microRNA-96. Compound 1 selectively inhibits biogenesis of microRNA-96, upregulating a protein target (FOXO1) and inducing apoptosis in cancer cells. Apoptosis is ablated when FOXO1 mRNA expression is knocked down by an siRNA, validating compound selectivity. Importantly, microRNA profiling shows that 1 only significantly effects microRNA-96 biogenesis and is more selective than an oligonucleotide. PMID:24509821

DNA targeting specificity of RNA-guided Cas9 nucleases.

PubMed

Hsu, Patrick D; Scott, David A; Weinstein, Joshua A; Ran, F Ann; Konermann, Silvana; Agarwala, Vineeta; Li, Yinqing; Fine, Eli J; Wu, Xuebing; Shalem, Ophir; Cradick, Thomas J; Marraffini, Luciano A; Bao, Gang; Zhang, Feng

2013-09-01

The Streptococcus pyogenes Cas9 (SpCas9) nuclease can be efficiently targeted to genomic loci by means of single-guide RNAs (sgRNAs) to enable genome editing. Here, we characterize SpCas9 targeting specificity in human cells to inform the selection of target sites and avoid off-target effects. Our study evaluates >700 guide RNA variants and SpCas9-induced indel mutation levels at >100 predicted genomic off-target loci in 293T and 293FT cells. We find that SpCas9 tolerates mismatches between guide RNA and target DNA at different positions in a sequence-dependent manner, sensitive to the number, position and distribution of mismatches. We also show that SpCas9-mediated cleavage is unaffected by DNA methylation and that the dosage of SpCas9 and sgRNA can be titrated to minimize off-target modification. To facilitate mammalian genome engineering applications, we provide a web-based software tool to guide the selection and validation of target sequences as well as off-target analyses.

Object-based implicit learning in visual search: perceptual segmentation constrains contextual cueing.

PubMed

Conci, Markus; Müller, Hermann J; von Mühlenen, Adrian

2013-07-09

In visual search, detection of a target is faster when it is presented within a spatial layout of repeatedly encountered nontarget items, indicating that contextual invariances can guide selective attention (contextual cueing; Chun & Jiang, 1998). However, perceptual regularities may interfere with contextual learning; for instance, no contextual facilitation occurs when four nontargets form a square-shaped grouping, even though the square location predicts the target location (Conci & von Mühlenen, 2009). Here, we further investigated potential causes for this interference-effect: We show that contextual cueing can reliably occur for targets located within the region of a segmented object, but not for targets presented outside of the object's boundaries. Four experiments demonstrate an object-based facilitation in contextual cueing, with a modulation of context-based learning by relatively subtle grouping cues including closure, symmetry, and spatial regularity. Moreover, the lack of contextual cueing for targets located outside the segmented region was due to an absence of (latent) learning of contextual layouts, rather than due to an attentional bias towards the grouped region. Taken together, these results indicate that perceptual segmentation provides a basic structure within which contextual scene regularities are acquired. This in turn argues that contextual learning is constrained by object-based selection.

A long-term target detection approach in infrared image sequence

NASA Astrophysics Data System (ADS)

Li, Hang; Zhang, Qi; Li, Yuanyuan; Wang, Liqiang

2015-12-01

An automatic target detection method used in long term infrared (IR) image sequence from a moving platform is proposed. Firstly, based on non-linear histogram equalization, target candidates are coarse-to-fine segmented by using two self-adapt thresholds generated in the intensity space. Then the real target is captured via two different selection approaches. At the beginning of image sequence, the genuine target with litter texture is discriminated from other candidates by using contrast-based confidence measure. On the other hand, when the target becomes larger, we apply online EM method to iteratively estimate and update the distributions of target's size and position based on the prior detection results, and then recognize the genuine one which satisfies both the constraints of size and position. Experimental results demonstrate that the presented method is accurate, robust and efficient.

Attention to Color Sharpens Neural Population Tuning via Feedback Processing in the Human Visual Cortex Hierarchy.

PubMed

Bartsch, Mandy V; Loewe, Kristian; Merkel, Christian; Heinze, Hans-Jochen; Schoenfeld, Mircea A; Tsotsos, John K; Hopf, Jens-Max

2017-10-25

Attention can facilitate the selection of elementary object features such as color, orientation, or motion. This is referred to as feature-based attention and it is commonly attributed to a modulation of the gain and tuning of feature-selective units in visual cortex. Although gain mechanisms are well characterized, little is known about the cortical processes underlying the sharpening of feature selectivity. Here, we show with high-resolution magnetoencephalography in human observers (men and women) that sharpened selectivity for a particular color arises from feedback processing in the human visual cortex hierarchy. To assess color selectivity, we analyze the response to a color probe that varies in color distance from an attended color target. We find that attention causes an initial gain enhancement in anterior ventral extrastriate cortex that is coarsely selective for the target color and transitions within ∼100 ms into a sharper tuned profile in more posterior ventral occipital cortex. We conclude that attention sharpens selectivity over time by attenuating the response at lower levels of the cortical hierarchy to color values neighboring the target in color space. These observations support computational models proposing that attention tunes feature selectivity in visual cortex through backward-propagating attenuation of units less tuned to the target. SIGNIFICANCE STATEMENT Whether searching for your car, a particular item of clothing, or just obeying traffic lights, in everyday life, we must select items based on color. But how does attention allow us to select a specific color? Here, we use high spatiotemporal resolution neuromagnetic recordings to examine how color selectivity emerges in the human brain. We find that color selectivity evolves as a coarse to fine process from higher to lower levels within the visual cortex hierarchy. Our observations support computational models proposing that feature selectivity increases over time by attenuating the responses of less-selective cells in lower-level brain areas. These data emphasize that color perception involves multiple areas across a hierarchy of regions, interacting with each other in a complex, recursive manner. Copyright © 2017 the authors 0270-6474/17/3710346-12$15.00/0.

Peptide Beacons: A New Design for Polypeptide-Based Optical Biosensors

PubMed Central

Oh, Kenneth J.; Cash, Kevin J.; Hugenberg, Verena; Plaxco, Kevin W.

2008-01-01

Phage display and other in vitro selection techniques produce short polypeptides that tightly and specifically bind to any of a wide range of macromolecular targets. Here we demonstrate a potentially general means of converting such polypeptides into optical biosensors. The sensing architecture we have developed, termed peptide beacons, is based on the observation that, whereas short peptides are almost invariably unfolded and highly dynamic, they become rigid when complexed to their target. Using this effect to segregate a long-lived fluorophore from an electron transfer-based contact quencher, both covalently attached to the peptide, we have produced a robust optical sensor for anti-HIV antibodies. The binding-induced segregation of the fluorophore-quencher pair produces a six-fold increase in sensor emission, thus allowing us to readily detect as low as ∼250 pM of the target antibody. Because the sensor is based on binding-induced folding and a visible-light fluorophore, it is sufficiently selective to work directly in complex, contaminant-ridden samples such as saliva and blood. PMID:17461545

Chemical biology based on target-selective degradation of proteins and carbohydrates using light-activatable organic molecules.

PubMed

Toshima, Kazunobu

2013-05-01

Proteins and carbohydrates play crucial roles in a wide range of biological processes, including serious diseases. The development of novel and innovative methods for selective control of specific proteins and carbohydrates functions has attracted much attention in the field of chemical biology. In this account article, the development of novel chemical tools, which can degrade target proteins and carbohydrates by irradiation with a specific wavelength of light under mild conditions without any additives, is introduced. This novel class of photochemical agents promise bright prospects for finding not only molecular-targeted bioprobes for understanding of the structure-activity relationships of proteins and carbohydrates but also novel therapeutic drugs targeting proteins and carbohydrates.

Progress and Challenges in Developing Aptamer-Functionalized Targeted Drug Delivery Systems.

PubMed

Jiang, Feng; Liu, Biao; Lu, Jun; Li, Fangfei; Li, Defang; Liang, Chao; Dang, Lei; Liu, Jin; He, Bing; Badshah, Shaikh Atik; Lu, Cheng; He, Xiaojuan; Guo, Baosheng; Zhang, Xiao-Bing; Tan, Weihong; Lu, Aiping; Zhang, Ge

2015-10-09

Aptamers, which can be screened via systematic evolution of ligands by exponential enrichment (SELEX), are superior ligands for molecular recognition due to their high selectivity and affinity. The interest in the use of aptamers as ligands for targeted drug delivery has been increasing due to their unique advantages. Based on their different compositions and preparation methods, aptamer-functionalized targeted drug delivery systems can be divided into two main categories: aptamer-small molecule conjugated systems and aptamer-nanomaterial conjugated systems. In this review, we not only summarize recent progress in aptamer selection and the application of aptamers in these targeted drug delivery systems but also discuss the advantages, challenges and new perspectives associated with these delivery systems.

Peptide-Based Technologies to Alter Adenoviral Vector Tropism: Ways and Means for Systemic Treatment of Cancer

PubMed Central

Reetz, Julia; Herchenröder, Ottmar; Pützer, Brigitte M.

2014-01-01

Due to the fundamental progress in elucidating the molecular mechanisms of human diseases and the arrival of the post-genomic era, increasing numbers of therapeutic genes and cellular targets are available for gene therapy. Meanwhile, the most important challenge is to develop gene delivery vectors with high efficiency through target cell selectivity, in particular under in situ conditions. The most widely used vector system to transduce cells is based on adenovirus (Ad). Recent endeavors in the development of selective Ad vectors that target cells or tissues of interest and spare the alteration of all others have focused on the modification of the virus broad natural tropism. A popular way of Ad targeting is achieved by directing the vector towards distinct cellular receptors. Redirecting can be accomplished by linking custom-made peptides with specific affinity to cellular surface proteins via genetic integration, chemical coupling or bridging with dual-specific adapter molecules. Ideally, targeted vectors are incapable of entering cells via their native receptors. Such altered vectors offer new opportunities to delineate functional genomics in a natural environment and may enable efficient systemic therapeutic approaches. This review provides a summary of current state-of-the-art techniques to specifically target adenovirus-based gene delivery vectors. PMID:24699364

Novel Chemokine-Based Immunotoxins for Potent and Selective Targeting of Cytomegalovirus Infected Cells

PubMed Central

Spiess, Katja; Jeppesen, Mads G.; Malmgaard-Clausen, Mikkel; Krzywkowski, Karen

2017-01-01

Immunotoxins as antiviral therapeutics are largely unexplored but have promising prospective due to their high selectivity potential and their unparalleled efficiency. One recent example targeted the virus-encoded G protein-coupled receptor US28 as a strategy for specific and efficient treatment of human cytomegalovirus (HCMV) infections. US28 is expressed on virus-infected cells and scavenge chemokines by rapid internalization. The chemokine-based fusion-toxin protein (FTP) consisted of a variant (F49A) of CX3CL1 specifically targeting US28 linked to the catalytic domain of Pseudomonas exotoxin A (PE). Here, we systematically seek to improve F49A-FTP by modifications in its three structural domains; we generated variants with (1) altered chemokine sequence (K14A, F49L, and F49E), (2) shortened and elongated linker region, and (3) modified toxin domain. Only F49L-FTP displayed higher selectivity in its binding to US28 versus CX3CR1, the endogenous receptor for CX3CL1, but this was not matched by a more selective killing of US28-expressing cells. A longer linker and different toxin variants decreased US28 affinity and selective killing. Thereby, F49A-FTP represents the best candidate for HCMV treatment. Many viruses encode internalizing receptors suggesting that not only HCMV but also, for instance, Epstein-Barr virus and Kaposi's sarcoma-associated herpesvirus may be targeted by FTPs. PMID:28251165

Novel Chemokine-Based Immunotoxins for Potent and Selective Targeting of Cytomegalovirus Infected Cells.

PubMed

Spiess, Katja; Jeppesen, Mads G; Malmgaard-Clausen, Mikkel; Krzywkowski, Karen; Kledal, Thomas N; Rosenkilde, Mette M

2017-01-01

Immunotoxins as antiviral therapeutics are largely unexplored but have promising prospective due to their high selectivity potential and their unparalleled efficiency. One recent example targeted the virus-encoded G protein-coupled receptor US28 as a strategy for specific and efficient treatment of human cytomegalovirus (HCMV) infections. US28 is expressed on virus-infected cells and scavenge chemokines by rapid internalization. The chemokine-based fusion-toxin protein (FTP) consisted of a variant (F49A) of CX 3 CL1 specifically targeting US28 linked to the catalytic domain of Pseudomonas exotoxin A (PE). Here, we systematically seek to improve F49A-FTP by modifications in its three structural domains; we generated variants with (1) altered chemokine sequence (K14A, F49L, and F49E), (2) shortened and elongated linker region, and (3) modified toxin domain. Only F49L-FTP displayed higher selectivity in its binding to US28 versus CX 3 CR1, the endogenous receptor for CX 3 CL1, but this was not matched by a more selective killing of US28-expressing cells. A longer linker and different toxin variants decreased US28 affinity and selective killing. Thereby, F49A-FTP represents the best candidate for HCMV treatment. Many viruses encode internalizing receptors suggesting that not only HCMV but also, for instance, Epstein-Barr virus and Kaposi's sarcoma-associated herpesvirus may be targeted by FTPs.

A class of selective antibacterials derived from a protein kinase inhibitor pharmacophore

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

Miller, J. Richard; Dunham, Steve; Mochalkin, Igor

2009-06-25

As the need for novel antibiotic classes to combat bacterial drug resistance increases, the paucity of leads resulting from target-based antibacterial screening of pharmaceutical compound libraries is of major concern. One explanation for this lack of success is that antibacterial screening efforts have not leveraged the eukaryotic bias resulting from more extensive chemistry efforts targeting eukaryotic gene families such as G protein-coupled receptors and protein kinases. Consistent with a focus on antibacterial target space resembling these eukaryotic targets, we used whole-cell screening to identify a series of antibacterial pyridopyrimidines derived from a protein kinase inhibitor pharmacophore. In bacteria, the pyridopyrimidinesmore » target the ATP-binding site of biotin carboxylase (BC), which catalyzes the first enzymatic step of fatty acid biosynthesis. These inhibitors are effective in vitro and in vivo against fastidious Gram-negative pathogens including Haemophilus influenzae. Although the BC active site has architectural similarity to those of eukaryotic protein kinases, inhibitor binding to the BC ATP-binding site is distinct from the protein kinase-binding mode, such that the inhibitors are selective for bacterial BC. In summary, we have discovered a promising class of potent antibacterials with a previously undescribed mechanism of action. In consideration of the eukaryotic bias of pharmaceutical libraries, our findings also suggest that pursuit of a novel inhibitor leads for antibacterial targets with active-site structural similarity to known human targets will likely be more fruitful than the traditional focus on unique bacterial target space, particularly when structure-based and computational methodologies are applied to ensure bacterial selectivity.« less

Rationalizing fragment based drug discovery for BACE1: insights from FB-QSAR, FB-QSSR, multi objective (MO-QSPR) and MIF studies

NASA Astrophysics Data System (ADS)

Manoharan, Prabu; Vijayan, R. S. K.; Ghoshal, Nanda

2010-10-01

The ability to identify fragments that interact with a biological target is a key step in FBDD. To date, the concept of fragment based drug design (FBDD) is increasingly driven by bio-physical methods. To expand the boundaries of QSAR paradigm, and to rationalize FBDD using In silico approach, we propose a fragment based QSAR methodology referred here in as FB-QSAR. The FB-QSAR methodology was validated on a dataset consisting of 52 Hydroxy ethylamine (HEA) inhibitors, disclosed by GlaxoSmithKline Pharmaceuticals as potential anti-Alzheimer agents. To address the issue of target selectivity, a major confounding factor in the development of selective BACE1 inhibitors, FB-QSSR models were developed using the reported off target activity values. A heat map constructed, based on the activity and selectivity profile of the individual R-group fragments, and was in turn used to identify superior R-group fragments. Further, simultaneous optimization of multiple properties, an issue encountered in real-world drug discovery scenario, and often overlooked in QSAR approaches, was addressed using a Multi Objective (MO-QSPR) method that balances properties, based on the defined objectives. MO-QSPR was implemented using Derringer and Suich desirability algorithm to identify the optimal level of independent variables ( X) that could confer a trade-off between selectivity and activity. The results obtained from FB-QSAR were further substantiated using MIF (Molecular Interaction Fields) studies. To exemplify the potentials of FB-QSAR and MO-QSPR in a pragmatic fashion, the insights gleaned from the MO-QSPR study was reverse engineered using Inverse-QSAR in a combinatorial fashion to enumerate some prospective novel, potent and selective BACE1 inhibitors.

Rationalizing fragment based drug discovery for BACE1: insights from FB-QSAR, FB-QSSR, multi objective (MO-QSPR) and MIF studies.

PubMed

Manoharan, Prabu; Vijayan, R S K; Ghoshal, Nanda

2010-10-01

The ability to identify fragments that interact with a biological target is a key step in FBDD. To date, the concept of fragment based drug design (FBDD) is increasingly driven by bio-physical methods. To expand the boundaries of QSAR paradigm, and to rationalize FBDD using In silico approach, we propose a fragment based QSAR methodology referred here in as FB-QSAR. The FB-QSAR methodology was validated on a dataset consisting of 52 Hydroxy ethylamine (HEA) inhibitors, disclosed by GlaxoSmithKline Pharmaceuticals as potential anti-Alzheimer agents. To address the issue of target selectivity, a major confounding factor in the development of selective BACE1 inhibitors, FB-QSSR models were developed using the reported off target activity values. A heat map constructed, based on the activity and selectivity profile of the individual R-group fragments, and was in turn used to identify superior R-group fragments. Further, simultaneous optimization of multiple properties, an issue encountered in real-world drug discovery scenario, and often overlooked in QSAR approaches, was addressed using a Multi Objective (MO-QSPR) method that balances properties, based on the defined objectives. MO-QSPR was implemented using Derringer and Suich desirability algorithm to identify the optimal level of independent variables (X) that could confer a trade-off between selectivity and activity. The results obtained from FB-QSAR were further substantiated using MIF (Molecular Interaction Fields) studies. To exemplify the potentials of FB-QSAR and MO-QSPR in a pragmatic fashion, the insights gleaned from the MO-QSPR study was reverse engineered using Inverse-QSAR in a combinatorial fashion to enumerate some prospective novel, potent and selective BACE1 inhibitors.

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.

Multiple products monitoring as a robust approach for peptide quantification.

PubMed

Baek, Je-Hyun; Kim, Hokeun; Shin, Byunghee; Yu, Myeong-Hee

2009-07-01

Quantification of target peptides and proteins is crucial for biomarker discovery. Approaches such as selected reaction monitoring (SRM) and multiple reaction monitoring (MRM) rely on liquid chromatography and mass spectrometric analysis of defined peptide product ions. These methods are not very widespread because the determination of quantifiable product ion using either SRM or MRM is a very time-consuming process. We developed a novel approach for quantifying target peptides without such an arduous process of ion selection. This method is based on monitoring multiple product ions (multiple products monitoring: MpM) from full-range MS2 spectra of a target precursor. The MpM method uses a scoring system that considers both the absolute intensities of product ions and the similarities between the query MS2 spectrum and the reference MS2 spectrum of the target peptide. Compared with conventional approaches, MpM greatly improves sensitivity and selectivity of peptide quantification using an ion-trap mass spectrometer.

Precise small molecule recognition of a toxic CUG RNA repeat expansion

PubMed Central

Rzuczek, Suzanne G; Colgan, Lesley A; Nakai, Yoshio; Cameron, Michael D; Furling, Denis; Yasuda, Ryohei; Disney, Matthew D

2017-01-01

Excluding the ribosome and riboswitches, developing small molecules that selectively target RNA is a longstanding problem in chemical biology. A typical cellular RNA is difficult to target because it has little tertiary, but abundant secondary structure. We designed allele-selective compounds that target such an RNA, the toxic noncoding repeat expansion (r(CUG)exp) that causes myotonic dystrophy type 1 (DM1). We developed several strategies to generate allele-selective small molecules, including non-covalent binding, covalent binding, cleavage and on-site probe synthesis. Covalent binding and cleavage enabled target profiling in cells derived from individuals with DM1, showing precise recognition of r(CUG)exp. In the on-site probe synthesis approach, small molecules bound adjacent sites in r(CUG)exp and reacted to afford picomolar inhibitors via a proximity-based click reaction only in DM1-affected cells. We expanded this approach to image r(CUG)exp in its natural context. PMID:27941760

Precise small-molecule recognition of a toxic CUG RNA repeat expansion.

PubMed

Rzuczek, Suzanne G; Colgan, Lesley A; Nakai, Yoshio; Cameron, Michael D; Furling, Denis; Yasuda, Ryohei; Disney, Matthew D

2017-02-01

Excluding the ribosome and riboswitches, developing small molecules that selectively target RNA is a longstanding problem in chemical biology. A typical cellular RNA is difficult to target because it has little tertiary, but abundant secondary structure. We designed allele-selective compounds that target such an RNA, the toxic noncoding repeat expansion (r(CUG) exp ) that causes myotonic dystrophy type 1 (DM1). We developed several strategies to generate allele-selective small molecules, including non-covalent binding, covalent binding, cleavage and on-site probe synthesis. Covalent binding and cleavage enabled target profiling in cells derived from individuals with DM1, showing precise recognition of r(CUG) exp . In the on-site probe synthesis approach, small molecules bound adjacent sites in r(CUG) exp and reacted to afford picomolar inhibitors via a proximity-based click reaction only in DM1-affected cells. We expanded this approach to image r(CUG) exp in its natural context.

Data-driven confounder selection via Markov and Bayesian networks.

PubMed

Häggström, Jenny

2018-06-01

To unbiasedly estimate a causal effect on an outcome unconfoundedness is often assumed. If there is sufficient knowledge on the underlying causal structure then existing confounder selection criteria can be used to select subsets of the observed pretreatment covariates, X, sufficient for unconfoundedness, if such subsets exist. Here, estimation of these target subsets is considered when the underlying causal structure is unknown. The proposed method is to model the causal structure by a probabilistic graphical model, for example, a Markov or Bayesian network, estimate this graph from observed data and select the target subsets given the estimated graph. The approach is evaluated by simulation both in a high-dimensional setting where unconfoundedness holds given X and in a setting where unconfoundedness only holds given subsets of X. Several common target subsets are investigated and the selected subsets are compared with respect to accuracy in estimating the average causal effect. The proposed method is implemented with existing software that can easily handle high-dimensional data, in terms of large samples and large number of covariates. The results from the simulation study show that, if unconfoundedness holds given X, this approach is very successful in selecting the target subsets, outperforming alternative approaches based on random forests and LASSO, and that the subset estimating the target subset containing all causes of outcome yields smallest MSE in the average causal effect estimation. © 2017, The International Biometric Society.

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.

Emerging principles in protease-based drug discovery

PubMed Central

Drag, Marcin; Salvesen, Guy S.

2010-01-01

Proteases have an important role in many signalling pathways, and represent potential drug targets for diseases ranging from cardiovascular disorders to cancer, as well as for combating many parasites and viruses. Although inhibitors of well-established protease targets such as angiotensin-converting enzyme and HIV protease have shown substantial therapeutic success, developing drugs for new protease targets has proved challenging in recent years. This in part could be due to issues such as the difficulty of achieving selectivity when targeting protease active sites. This Perspective discusses the general principles in protease-based drug discovery, highlighting the lessons learned and the emerging strategies, such as targeting allosteric sites, which could help harness the therapeutic potential of new protease targets. PMID:20811381

Can we use genetic and genomic approaches to identify candidate animals for targeted selective treatment.

PubMed

Laurenson, Yan C S M; Kyriazakis, Ilias; Bishop, Stephen C

2013-10-18

Estimated breeding values (EBV) for faecal egg count (FEC) and genetic markers for host resistance to nematodes may be used to identify resistant animals for selective breeding programmes. Similarly, targeted selective treatment (TST) requires the ability to identify the animals that will benefit most from anthelmintic treatment. A mathematical model was used to combine the concepts and evaluate the potential of using genetic-based methods to identify animals for a TST regime. EBVs obtained by genomic prediction were predicted to be the best determinant criterion for TST in terms of the impact on average empty body weight and average FEC, whereas pedigree-based EBVs for FEC were predicted to be marginally worse than using phenotypic FEC as a determinant criterion. Whilst each method has financial implications, if the identification of host resistance is incorporated into a wider genomic selection indices or selective breeding programmes, then genetic or genomic information may be plausibly included in TST regimes. Copyright © 2013 Elsevier B.V. All rights reserved.

Nanoparticle-based targeted therapeutics in head-and-neck cancer.

PubMed

Wu, Ting-Ting; Zhou, Shui-Hong

2015-01-01

Head-and-neck cancer is a major form of the disease worldwide. Treatment consists of surgery, radiation therapy and chemotherapy, but these have not resulted in improved survival rates over the past few decades. Versatile nanoparticles, with selective tumor targeting, are considered to have the potential to improve these poor outcomes. Application of nanoparticle-based targeted therapeutics has extended into many areas, including gene silencing, chemotherapeutic drug delivery, radiosensitization, photothermal therapy, and has shown much promise. In this review, we discuss recent advances in the field of nanoparticle-mediated targeted therapeutics for head-and-neck cancer, with an emphasis on the description of targeting points, including future perspectives.

Tandem application of ligand-based virtual screening and G4-OAS assay to identify novel G-quadruplex-targeting chemotypes.

PubMed

Musumeci, Domenica; Amato, Jussara; Zizza, Pasquale; Platella, Chiara; Cosconati, Sandro; Cingolani, Chiara; Biroccio, Annamaria; Novellino, Ettore; Randazzo, Antonio; Giancola, Concetta; Pagano, Bruno; Montesarchio, Daniela

2017-05-01

G-quadruplex (G4) structures are key elements in the regulation of cancer cell proliferation and their targeting is deemed to be a promising strategy in anticancer therapy. A tandem application of ligand-based virtual screening (VS) calculations together with the experimental G-quadruplex on Oligo Affinity Support (G4-OAS) assay was employed to discover novel G4-targeting compounds. The interaction of the selected compounds with the investigated G4 in solution was analysed through a series of biophysical techniques and their biological activity investigated by immunofluorescence and MTT assays. A focused library of 60 small molecules, designed as putative G4 groove binders, was identified through the VS. The G4-OAS experimental screening led to the selection of 7 ligands effectively interacting with the G4-forming human telomeric DNA. Evaluation of the biological activity of the selected compounds showed that 3 ligands of this sub-library induced a marked telomere-localized DNA damage response in human tumour cells. The combined application of virtual and experimental screening tools proved to be a successful strategy to identify new bioactive chemotypes able to target the telomeric G4 DNA. These compounds may represent useful leads for the development of more potent and selective G4 ligands. Expanding the repertoire of the available G4-targeting chemotypes with improved physico-chemical features, in particular aiming at the discovery of novel, selective G4 telomeric ligands, can help in developing effective anti-cancer drugs with fewer side effects. This article is part of a Special Issue entitled "G-quadruplex" Guest Editor: Dr. Concetta Giancola and Dr. Daniela Montesarchio. Copyright © 2017 Elsevier B.V. All rights reserved.

The Role of Color in Search Templates for Real-world Target Objects.

PubMed

Nako, Rebecca; Smith, Tim J; Eimer, Martin

2016-11-01

During visual search, target representations (attentional templates) control the allocation of attention to template-matching objects. The activation of new attentional templates can be prompted by verbal or pictorial target specifications. We measured the N2pc component of the ERP as a temporal marker of attentional target selection to determine the role of color signals in search templates for real-world search target objects that are set up in response to word or picture cues. On each trial run, a word cue (e.g., "apple") was followed by three search displays that contained the cued target object among three distractors. The selection of the first target was based on the word cue only, whereas selection of the two subsequent targets could be controlled by templates set up after the first visual presentation of the target (picture cue). In different trial runs, search displays either contained objects in their natural colors or monochromatic objects. These two display types were presented in different blocks (Experiment 1) or in random order within each block (Experiment 2). RTs were faster, and target N2pc components emerged earlier for the second and third display of each trial run relative to the first display, demonstrating that pictures are more effective than word cues in guiding search. N2pc components were triggered more rapidly for targets in the second and third display in trial runs with colored displays. This demonstrates that when visual target attributes are fully specified by picture cues, the additional presence of color signals in target templates facilitates the speed with which attention is allocated to template-matching objects. No such selection benefits for colored targets were found when search templates were set up in response to word cues. Experiment 2 showed that color templates activated by word cues can even impair the attentional selection of noncolored targets. Results provide new insights into the status of color during the guidance of visual search for real-world target objects. Color is a powerful guiding feature when the precise visual properties of these objects are known but seems to be less important when search targets are specified by word cues.

Poster — Thur Eve — 59: Atlas Selection for Automated Segmentation of Pelvic CT for Prostate Radiotherapy

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

Mallawi, A; Farrell, T; Diamond, K

2014-08-15

Automated atlas-based segmentation has recently been evaluated for use in planning prostate cancer radiotherapy. In the typical approach, the essential step is the selection of an atlas from a database that best matches the target image. This work proposes an atlas selection strategy and evaluates its impact on the final segmentation accuracy. Prostate length (PL), right femoral head diameter (RFHD), and left femoral head diameter (LFHD) were measured in CT images of 20 patients. Each subject was then taken as the target image to which all remaining 19 images were affinely registered. For each pair of registered images, the overlapmore » between prostate and femoral head contours was quantified using the Dice Similarity Coefficient (DSC). Finally, we designed an atlas selection strategy that computed the ratio of PL (prostate segmentation), RFHD (right femur segmentation), and LFHD (left femur segmentation) between the target subject and each subject in the atlas database. Five atlas subjects yielding ratios nearest to one were then selected for further analysis. RFHD and LFHD were excellent parameters for atlas selection, achieving a mean femoral head DSC of 0.82 ± 0.06. PL had a moderate ability to select the most similar prostate, with a mean DSC of 0.63 ± 0.18. The DSC obtained with the proposed selection method were slightly lower than the maximums established using brute force, but this does not include potential improvements expected with deformable registration. Atlas selection based on PL for prostate and femoral diameter for femoral heads provides reasonable segmentation accuracy.« less

Multi-Conformer Ensemble Docking to Difficult Protein Targets

DOE PAGES

Ellingson, Sally R.; Miao, Yinglong; Baudry, Jerome; ...

2014-09-08

We investigate large-scale ensemble docking using five proteins from the Directory of Useful Decoys (DUD, dud.docking.org) for which docking to crystal structures has proven difficult. Molecular dynamics trajectories are produced for each protein and an ensemble of representative conformational structures extracted from the trajectories. Docking calculations are performed on these selected simulation structures and ensemble-based enrichment factors compared with those obtained using docking in crystal structures of the same protein targets or random selection of compounds. We also found simulation-derived snapshots with improved enrichment factors that increased the chemical diversity of docking hits for four of the five selected proteins.more » A combination of all the docking results obtained from molecular dynamics simulation followed by selection of top-ranking compounds appears to be an effective strategy for increasing the number and diversity of hits when using docking to screen large libraries of chemicals against difficult protein targets.« less

Multicolor fluorescence "click"-chemistry as a means to select membrane targets for pre-targeting approaches by function of their receptor kinetics.

PubMed

van der Wal, Steffen; de Korne, Clarize M; Sand, Laurens L G; van Willigen, Danny M; Hogendoorn, Pancras C W; Szuhai, Karoly; van Leeuwen, Fijs W B; Buckle, Tessa

2018-06-04

Availability of a receptor for theranostic pre-targeting approaches was assessed using a novel "click" chemistry-based de-activatable fluorescence-quenching concept. Efficacy was evaluated in a cell-based model system that exhibits both membranous (available) and internalized (unavailable) receptor-fractions of the clinically relevant receptor chemokine receptor 4 (CXCR4). Proof of concept was based on a de-activatable tracer consisting out of a CXCR4 specific peptide functionalized with a Cy5 dye comprising a chemo-selective azide handle (N3-Cy5-AcTZ14011). Reaction with a Cy7 quencher dye (Cy7-DBCO) resulted in optically silent Cy7-["click"]-Cy5-AcTZ14011. In situ a >90% FRET-based reduction of signal intensity of N3-Cy5-AcTZ14011 (KD 222.4 ± 25.2 nM) was seen within minutes after quencher addition. In cells, discrimination between the membranous and internalized receptor-fraction could be made through quantitative assessment of quenching/internalization kinetics. As such, using this approach screening of membrane receptors and their applicability in receptor-(pre-)targeted theranostics can become straightforward. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Using a community-based definition of poverty for targeting poor households for premium subsidies in the context of a community health insurance in Burkina Faso.

PubMed

Savadogo, Germain; Souarès, Aurelia; Sié, Ali; Parmar, Divya; Bibeau, Gilles; Sauerborn, Rainer

2015-02-06

One of the biggest challenges in subsidizing premiums of poor households for community health insurance is the identification and selection of these households. Generally, poverty assessments in developing countries are based on monetary terms. The household is regarded as poor if its income or consumption is lower than a predefined poverty cut-off. These measures fail to recognize the multi-dimensional character of poverty, ignoring community members' perception and understanding of poverty, leaving them voiceless and powerless in the identification process. Realizing this, the steering committee of Nouna's health insurance devised a method to involve community members to better define 'perceived' poverty, using this as a key element for the poor selection. The community-identified poor were then used to effectively target premium subsidies for the insurance scheme. The study was conducted in the Nouna's Health District located in northwest Burkina Faso. Participants in each village were selected to take part in focus-group discussions (FGD) organized in 41 villages and 7 sectors of Nouna's town to discuss criteria and perceptions of poverty. The discussions were audio recorded, transcribed and analyzed in French using the software NVivo 9. From the FGD on poverty and the subjective definitions and perceptions of the community members, we found that poverty was mainly seen as scarcity of basic needs, vulnerability, deprivation of capacities, powerlessness, voicelessness, indecent living conditions, and absence of social capital and community networks for support in times of need. Criteria and poverty groups as described by community members can be used to identify poor who can then be targeted for subsidies. Policies targeting the poorest require the establishment of effective selection strategies. These policies are well-conditioned by proper identification of the poor people. Community perceptions and criteria of poverty are grounded in reality, to better appreciate the issue. It is crucial to take these perceptions into account in undertaking community development actions which target the poor. For most community-based health insurance schemes with limited financial resources, using a community-based definition of poverty in the targeting of the poorest might be a less costly alternative.

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.

Benchmark data sets for structure-based computational target prediction.

PubMed

Schomburg, Karen T; Rarey, Matthias

2014-08-25

Structure-based computational target prediction methods identify potential targets for a bioactive compound. Methods based on protein-ligand docking so far face many challenges, where the greatest probably is the ranking of true targets in a large data set of protein structures. Currently, no standard data sets for evaluation exist, rendering comparison and demonstration of improvements of methods cumbersome. Therefore, we propose two data sets and evaluation strategies for a meaningful evaluation of new target prediction methods, i.e., a small data set consisting of three target classes for detailed proof-of-concept and selectivity studies and a large data set consisting of 7992 protein structures and 72 drug-like ligands allowing statistical evaluation with performance metrics on a drug-like chemical space. Both data sets are built from openly available resources, and any information needed to perform the described experiments is reported. We describe the composition of the data sets, the setup of screening experiments, and the evaluation strategy. Performance metrics capable to measure the early recognition of enrichments like AUC, BEDROC, and NSLR are proposed. We apply a sequence-based target prediction method to the large data set to analyze its content of nontrivial evaluation cases. The proposed data sets are used for method evaluation of our new inverse screening method iRAISE. The small data set reveals the method's capability and limitations to selectively distinguish between rather similar protein structures. The large data set simulates real target identification scenarios. iRAISE achieves in 55% excellent or good enrichment a median AUC of 0.67 and RMSDs below 2.0 Å for 74% and was able to predict the first true target in 59 out of 72 cases in the top 2% of the protein data set of about 8000 structures.

Near Surface Swimming of Salmonella Typhimurium Explains Target-Site Selection and Cooperative Invasion

PubMed Central

Kreibich, Saskia; Vonaesch, Pascale; Andritschke, Daniel; Rout, Samuel; Weidner, Kerstin; Sormaz, Milos; Songhet, Pascal; Horvath, Peter; Chabria, Mamta; Vogel, Viola; Spori, Doris M.; Jenny, Patrick; Hardt, Wolf-Dietrich

2012-01-01

Targeting of permissive entry sites is crucial for bacterial infection. The targeting mechanisms are incompletely understood. We have analyzed target-site selection by S. Typhimurium. This enteropathogenic bacterium employs adhesins (e.g. fim) and the type III secretion system 1 (TTSS-1) for host cell binding, the triggering of ruffles and invasion. Typically, S. Typhimurium invasion is focused on a subset of cells and multiple bacteria invade via the same ruffle. It has remained unclear how this is achieved. We have studied target-site selection in tissue culture by time lapse microscopy, movement pattern analysis and modeling. Flagellar motility (but not chemotaxis) was required for reaching the host cell surface in vitro. Subsequently, physical forces trapped the pathogen for ∼1.5–3 s in “near surface swimming”. This increased the local pathogen density and facilitated “scanning” of the host surface topology. We observed transient TTSS-1 and fim-independent “stopping” and irreversible TTSS-1-mediated docking, in particular at sites of prominent topology, i.e. the base of rounded-up cells and membrane ruffles. Our data indicate that target site selection and the cooperative infection of membrane ruffles are attributable to near surface swimming. This mechanism might be of general importance for understanding infection by flagellated bacteria. PMID:22911370

A Method for Selecting Structure-switching Aptamers Applied to a Colorimetric Gold Nanoparticle Assay

PubMed Central

Martin, Jennifer A.; Smith, Joshua E.; Warren, Mercedes; Chávez, Jorge L.; Hagen, Joshua A.; Kelley-Loughnane, Nancy

2015-01-01

Small molecules provide rich targets for biosensing applications due to their physiological implications as biomarkers of various aspects of human health and performance. Nucleic acid aptamers have been increasingly applied as recognition elements on biosensor platforms, but selecting aptamers toward small molecule targets requires special design considerations. This work describes modification and critical steps of a method designed to select structure-switching aptamers to small molecule targets. Binding sequences from a DNA library hybridized to complementary DNA capture probes on magnetic beads are separated from nonbinders via a target-induced change in conformation. This method is advantageous because sequences binding the support matrix (beads) will not be further amplified, and it does not require immobilization of the target molecule. However, the melting temperature of the capture probe and library is kept at or slightly above RT, such that sequences that dehybridize based on thermodynamics will also be present in the supernatant solution. This effectively limits the partitioning efficiency (ability to separate target binding sequences from nonbinders), and therefore many selection rounds will be required to remove background sequences. The reported method differs from previous structure-switching aptamer selections due to implementation of negative selection steps, simplified enrichment monitoring, and extension of the length of the capture probe following selection enrichment to provide enhanced stringency. The selected structure-switching aptamers are advantageous in a gold nanoparticle assay platform that reports the presence of a target molecule by the conformational change of the aptamer. The gold nanoparticle assay was applied because it provides a simple, rapid colorimetric readout that is beneficial in a clinical or deployed environment. Design and optimization considerations are presented for the assay as proof-of-principle work in buffer to provide a foundation for further extension of the work toward small molecule biosensing in physiological fluids. PMID:25870978

Photostick: a method for selective isolation of target cells from culture† †Electronic supplementary information (ESI) available. See DOI: 10.1039/c4sc03676j Click here for additional data file.

PubMed Central

Chien, Miao-Ping; Werley, Christopher A.; Farhi, Samouil L.

2015-01-01

Sorting of target cells from a heterogeneous pool is technically difficult when the selection criterion is complex, e.g. a dynamic response, a morphological feature, or a combination of multiple parameters. At present, mammalian cell selections are typically performed either via static fluorescence (e.g. fluorescence activated cell sorter), via survival (e.g. antibiotic resistance), or via serial operations (flow cytometry, laser capture microdissection). Here we present a simple protocol for selecting cells based on any static or dynamic property that can be identified by video microscopy and image processing. The “photostick” technique uses a cell-impermeant photochemical crosslinker and digital micromirror array-based patterned illumination to immobilize selected cells on the culture dish. Other cells are washed away with mild protease treatment. The crosslinker also labels the selected cells with a fluorescent dye and a biotin for later identification. The photostick protocol preserves cell viability, permits genetic profiling of selected cells, and can be performed with complex functional selection criteria such as neuronal firing patterns. PMID:25705368

The significance of transferrin receptors in oncology: the development of functional nano-based drug delivery systems.

PubMed

Tortorella, Stephanie; Karagiannis, Tom C

2014-01-01

Anticancer therapeutic research aims to improve clinical management of the disease through the development of strategies that involve currently-relevant treatment options and targeted delivery. Tumour-specific and -targeted delivery of compounds to the site of malignancy allows for enhanced cellular uptake, increased therapeutic benefit with high intratumoural drug concentrations, and decreased systemic exposure. Due to the upregulation of transferrin receptor expression in a wide variety of cancers, its function and its highly efficient recycling pathway, strategies involving the selective targeting of the receptor are well documented. Direct conjugation and immunotoxin studies using the transferrin peptide or anti-transferrin receptor antibodies as the targeting moiety have established the capacity to enhance cellular uptake, cross the blood brain barrier, limit systemic toxicity and reverse multi-drug resistance. Limitations in direct conjugation, including the difficulty in linking an adequate amount of therapeutic compound to the ligand or antibody have identified the requirement to develop novel delivery methods. The application of nanoparticulate theory in the development of functional drug delivery systems has proven to be most promising, with the ability to selectively modify size-dependent properties and surface chemistry. The transferrin modification on a range of nanoparticle formulations enhances selective cellular uptake through transferrin-mediated processes, and increases therapeutic benefit through the ability to encapsulate high concentrations of relevant drug to the tumour site. Although ineffective in crossing the blood brain barrier in its free form, chemotherapeutic compounds including doxorubicin, may be loaded into transferrin-conjugated nanocarriers and impart cytotoxic effects in glioma cells in vitro and in vivo. Additionally, transferrin-targeted nanoparticles may be used in selective diagnostic applications with enhanced selectivity and sensitivity. Four transferrin-modified nano-based drug delivery systems are currently in early phases of human clinical trials. Despite the collective promise, inconsistencies in some studies have exposed some limitations in current formulations and the difficulty in translating preliminary studies into clinically-relevant therapeutic options. The main objective of this review is to investigate the development of transferrin targeted nano-based drug delivery systems in order to establish the use of transferrin as a cancer-targeted moiety, and to ultimately evaluate the progression of cancer therapeutic strategies for future research.

Visual Foraging With Fingers and Eye Gaze

PubMed Central

Thornton, Ian M.; Smith, Irene J.; Chetverikov, Andrey; Kristjánsson, Árni

2016-01-01

A popular model of the function of selective visual attention involves search where a single target is to be found among distractors. For many scenarios, a more realistic model involves search for multiple targets of various types, since natural tasks typically do not involve a single target. Here we present results from a novel multiple-target foraging paradigm. We compare finger foraging where observers cancel a set of predesignated targets by tapping them, to gaze foraging where observers cancel items by fixating them for 100 ms. During finger foraging, for most observers, there was a large difference between foraging based on a single feature, where observers switch easily between target types, and foraging based on a conjunction of features where observers tended to stick to one target type. The pattern was notably different during gaze foraging where these condition differences were smaller. Two conclusions follow: (a) The fact that a sizeable number of observers (in particular during gaze foraging) had little trouble switching between different target types raises challenges for many prominent theoretical accounts of visual attention and working memory. (b) While caveats must be noted for the comparison of gaze and finger foraging, the results suggest that selection mechanisms for gaze and pointing have different operational constraints. PMID:27433323

Gene silencing in Tribolium castaneum as a tool for the targeted identification of candidate RNAi targets in crop pests.

PubMed

Knorr, Eileen; Fishilevich, Elane; Tenbusch, Linda; Frey, Meghan L F; Rangasamy, Murugesan; Billion, Andre; Worden, Sarah E; Gandra, Premchand; Arora, Kanika; Lo, Wendy; Schulenberg, Greg; Valverde-Garcia, Pablo; Vilcinskas, Andreas; Narva, Kenneth E

2018-02-01

RNAi shows potential as an agricultural technology for insect control, yet, a relatively low number of robust lethal RNAi targets have been demonstrated to control insects of agricultural interest. In the current study, a selection of lethal RNAi target genes from the iBeetle (Tribolium castaneum) screen were used to demonstrate efficacy of orthologous targets in the economically important coleopteran pests Diabrotica virgifera virgifera and Meligethes aeneus. Transcript orthologs of 50 selected genes were analyzed in D. v. virgifera diet-based RNAi bioassays; 21 of these RNAi targets showed mortality and 36 showed growth inhibition. Low dose injection- and diet-based dsRNA assays in T. castaneum and D. v. virgifera, respectively, enabled the identification of the four highly potent RNAi target genes: Rop, dre4, ncm, and RpII140. Maize was genetically engineered to express dsRNA directed against these prioritized candidate target genes. T 0 plants expressing Rop, dre4, or RpII140 RNA hairpins showed protection from D. v. virgifera larval feeding damage. dsRNA targeting Rop, dre4, ncm, and RpII140 in M. aeneus also caused high levels of mortality both by injection and feeding. In summary, high throughput systems for model organisms can be successfully used to identify potent RNA targets for difficult-to-work with agricultural insect pests.

Use of Targeted Therapeutics in Epithelial Ovarian Cancer: A Review of Current Literature and Future Directions.

PubMed

Vetter, Monica Hagan; Hays, John L

2018-03-01

Epithelial ovarian cancer (EOC) is the leading cause of gynecologic cancer death in the United States. Most patients will ultimately fail platinum-based chemotherapy and have the disease recur. Interest is increasing in the use of targeted therapies in the treatment of EOC. This review focuses on the current use of targeted therapeutics in EOC as well as future directions. A literature search of Medline and PubMed was conducted (January 2000-October 2017) to identify recent reports of targeted drugs in EOC. A wide range of targeted therapeutics is currently being used as both monotherapy and in combination in the treatment of EOC. Clinically, the most commonly used classes of drugs currently are antiangiogenics and poly (ADP-ribose) polymerase inhibitors. However, a number of drugs in varying stages in development target a wide range of biochemical pathways. Activity and response rates of these drugs vary greatly. Questions continue about combination drug therapy and appropriate patient selection. The use of targeted therapeutics in the treatment of EOC, both as monotherapy and in combination, will continue to expand as more mechanisms of tumorigenesis are identified. Multiple clinical trials of a wide range of targeted therapeutics are currently ongoing. Evidence-based selection of drug targets and appropriate patient populations will allow strategic application of targeted therapeutics. Copyright © 2018 Elsevier HS Journals, Inc. All rights reserved.

Targeted quantitative analysis of Streptococcus pyogenes virulence factors by multiple reaction monitoring.

PubMed

Lange, Vinzenz; Malmström, Johan A; Didion, John; King, Nichole L; Johansson, Björn P; Schäfer, Juliane; Rameseder, Jonathan; Wong, Chee-Hong; Deutsch, Eric W; Brusniak, Mi-Youn; Bühlmann, Peter; Björck, Lars; Domon, Bruno; Aebersold, Ruedi

2008-08-01

In many studies, particularly in the field of systems biology, it is essential that identical protein sets are precisely quantified in multiple samples such as those representing differentially perturbed cell states. The high degree of reproducibility required for such experiments has not been achieved by classical mass spectrometry-based proteomics methods. In this study we describe the implementation of a targeted quantitative approach by which predetermined protein sets are first identified and subsequently quantified at high sensitivity reliably in multiple samples. This approach consists of three steps. First, the proteome is extensively mapped out by multidimensional fractionation and tandem mass spectrometry, and the data generated are assembled in the PeptideAtlas database. Second, based on this proteome map, peptides uniquely identifying the proteins of interest, proteotypic peptides, are selected, and multiple reaction monitoring (MRM) transitions are established and validated by MS2 spectrum acquisition. This process of peptide selection, transition selection, and validation is supported by a suite of software tools, TIQAM (Targeted Identification for Quantitative Analysis by MRM), described in this study. Third, the selected target protein set is quantified in multiple samples by MRM. Applying this approach we were able to reliably quantify low abundance virulence factors from cultures of the human pathogen Streptococcus pyogenes exposed to increasing amounts of plasma. The resulting quantitative protein patterns enabled us to clearly define the subset of virulence proteins that is regulated upon plasma exposure.

The SDSS-XDQSO quasar targeting catalog

NASA Astrophysics Data System (ADS)

Bovy, Jo; Hennawi, J. F.; Hogg, D. W.; Myers, A. D.; Ross, N. P.

2011-01-01

We present the SDSS-XDQSO quasar targeting catalog for efficient flux-based quasar target selection down to the faint limit of the SDSS catalog, even at medium redshifts (2.5 < z < 3). We build models of the distributions of stars and quasars in flux space down to the flux limit by applying the extreme-deconvolution method (XD) to estimate the underlying density. We properly convolve this density with the flux uncertainties when evaluating the probability that an object is a quasar. This results in a targeting algorithm that is more principled, more efficient, and faster than other similar methods. We apply the algorithm to derive low- (z < 2.2), medium- (2.2 <= z 3.5) quasar probabilities for all 160,904,060 point-sources with dereddened i-and magnitude between 17.75 and 22.45 mag in SDSS Data Release 8. The catalog can be used to define a uniformly selected and efficient low- or medium-redshift quasar survey, such as that needed for the SDSS-III Baryon Oscillation Spectroscopic Survey project. We show that the XDQSO technique performs as well as the current best photometric quasar selection technique at low redshift, and out-performs all other flux-based methods for selecting the medium-redshift quasars of our primary interest. Research supported by NASA (grant NNX08AJ48G) and the NSF (grant AST-0908357).

Dual-threshold segmentation using Arimoto entropy based on chaotic bee colony optimization

NASA Astrophysics Data System (ADS)

Li, Li

2018-03-01

In order to extract target from complex background more quickly and accurately, and to further improve the detection effect of defects, a method of dual-threshold segmentation using Arimoto entropy based on chaotic bee colony optimization was proposed. Firstly, the method of single-threshold selection based on Arimoto entropy was extended to dual-threshold selection in order to separate the target from the background more accurately. Then intermediate variables in formulae of Arimoto entropy dual-threshold selection was calculated by recursion to eliminate redundant computation effectively and to reduce the amount of calculation. Finally, the local search phase of artificial bee colony algorithm was improved by chaotic sequence based on tent mapping. The fast search for two optimal thresholds was achieved using the improved bee colony optimization algorithm, thus the search could be accelerated obviously. A large number of experimental results show that, compared with the existing segmentation methods such as multi-threshold segmentation method using maximum Shannon entropy, two-dimensional Shannon entropy segmentation method, two-dimensional Tsallis gray entropy segmentation method and multi-threshold segmentation method using reciprocal gray entropy, the proposed method can segment target more quickly and accurately with superior segmentation effect. It proves to be an instant and effective method for image segmentation.

Multifunctional gold nanorods for selective plasmonic photothermal therapy in pancreatic cancer cells using ultra-short pulse near-infrared laser irradiation.

PubMed

Patino, Tania; Mahajan, Ujjwal; Palankar, Raghavendra; Medvedev, Nikolay; Walowski, Jakob; Münzenberg, Markus; Mayerle, Julia; Delcea, Mihaela

2015-03-12

Gold nanorods (AuNRs) have attracted considerable attention in plasmonic photothermal therapy for cancer treatment by exploiting their selective and localized heating effect due to their unique photophysical properties. Here we describe a strategy to design a novel multifunctional platform based on AuNRs to: (i) specifically target the adenocarcinoma MUC-1 marker through the use of the EPPT-1 peptide, (ii) enhance cellular uptake through a myristoylated polyarginine peptide (MPAP) and (iii) selectively induce cell death by ultra-short near infrared laser pulses. We used a biotin-avidin based approach to conjugate EPPT-1 and MPAP to AuNRs. Dual-peptide (EPPT-1+MPAP) labelled AuNRs showed a significantly higher uptake by pancreatic ductal adenocarcinoma cells when compared to their single peptide or avidin conjugated counterparts. In addition, we selectively induced cell death by ultra-short near infrared laser pulses in small target volumes (∼1 μm3), through the creation of plasmonic nanobubbles that lead to the destruction of a local cell environment. Our approach opens new avenues for conjugation of multiple ligands on AuNRs targeting cancer cells and tumors and it is relevant for plasmonic photothermal therapy.

Addressing the selective role of distinct prefrontal areas in response suppression: A study with brain tumor patients.

PubMed

Arbula, Sandra; Pacella, Valentina; De Pellegrin, Serena; Rossetto, Marta; Denaro, Luca; D'Avella, Domenico; Della Puppa, Alessandro; Vallesi, Antonino

2017-06-01

The diverging evidence for functional localization of response inhibition within the prefrontal cortex might be justified by the still unclear involvement of other intrinsically related cognitive processes like response selection and sustained attention. In this study, the main aim was to understand whether inhibitory impairments, previously found in patients with both left and right frontal lesions, could be better accounted for by assessing these potentially related cognitive processes. We tested 37 brain tumor patients with left prefrontal, right prefrontal and non-prefrontal lesions and a healthy control group on Go/No-Go and Foreperiod tasks. In both types of tasks inhibitory impairments are likely to cause false alarms, although additionally the former task requires response selection and the latter target detection abilities. Irrespective of the task context, patients with right prefrontal damage showed frequent Go and target omissions, probably due to sustained attention lapses. Left prefrontal patients, on the other hand, showed both Go and target omissions and high false alarm rates to No-Go and warning stimuli, suggesting a decisional rather than an inhibitory impairment. An exploratory whole-brain voxel-based lesion-symptom mapping analysis confirmed the association of left ventrolateral and dorsolateral prefrontal lesions with target discrimination failure, and right ventrolateral and medial prefrontal lesions with target detection failure. Results from this study show how left and right prefrontal areas, which previous research has linked to response inhibition, underlie broader cognitive control processes, particularly involved in response selection and target detection. Based on these findings, we suggest that successful inhibitory control relies on more than one functionally distinct process which, if assessed appropriately, might help us to better understand inhibitory impairments across different pathologies. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

More complete gene silencing by fewer siRNAs: transparent optimized design and biophysical signature

PubMed Central

Ladunga, Istvan

2007-01-01

Highly accurate knockdown functional analyses based on RNA interference (RNAi) require the possible most complete hydrolysis of the targeted mRNA while avoiding the degradation of untargeted genes (off-target effects). This in turn requires significant improvements to target selection for two reasons. First, the average silencing activity of randomly selected siRNAs is as low as 62%. Second, applying more than five different siRNAs may lead to saturation of the RNA-induced silencing complex (RISC) and to the degradation of untargeted genes. Therefore, selecting a small number of highly active siRNAs is critical for maximizing knockdown and minimizing off-target effects. To satisfy these needs, a publicly available and transparent machine learning tool is presented that ranks all possible siRNAs for each targeted gene. Support vector machines (SVMs) with polynomial kernels and constrained optimization models select and utilize the most predictive effective combinations from 572 sequence, thermodynamic, accessibility and self-hairpin features over 2200 published siRNAs. This tool reaches an accuracy of 92.3% in cross-validation experiments. We fully present the underlying biophysical signature that involves free energy, accessibility and dinucleotide characteristics. We show that while complete silencing is possible at certain structured target sites, accessibility information improves the prediction of the 90% active siRNA target sites. Fast siRNA activity predictions can be performed on our web server at . PMID:17169992

Immobilized magnetic beads-based multi-target affinity selection coupled with HPLC-MS for screening active compounds from traditional Chinese medicine and natural products.

PubMed

Chen, Yaqi; Chen, Zhui; Wang, Yi

2015-01-01

Screening and identifying active compounds from traditional Chinese medicine (TCM) and other natural products plays an important role in drug discovery. Here, we describe a magnetic beads-based multi-target affinity selection-mass spectrometry approach for screening bioactive compounds from natural products. Key steps and parameters including activation of magnetic beads, enzyme/protein immobilization, characterization of functional magnetic beads, screening and identifying active compounds from a complex mixture by LC/MS, are illustrated. The proposed approach is rapid and efficient in screening and identification of bioactive compounds from complex natural products.

Artificial selection reveals sex differences in the genetic basis of sexual attractiveness.

PubMed

Gosden, Thomas P; Reddiex, Adam J; Chenoweth, Stephen F

2018-05-07

Mutual mate choice occurs when males and females base mating decisions on shared traits. Despite increased awareness, the extent to which mutual choice drives phenotypic change remains poorly understood. When preferences in both sexes target the same traits, it is unclear how evolution will proceed and whether responses to sexual selection from male choice will match or oppose responses to female choice. Answering this question is challenging, as it requires understanding, genetic relationships between the traits targeted by choice, mating success, and, ultimately, fitness for both sexes. Addressing this, we applied artificial selection to the cuticular hydrocarbons of the fly Drosophila serrata that are targeted by mutual choice and tracked evolutionary changes in males and females alongside changes in mating success. After 10 generations, significant trait evolution occurred in both sexes, but intriguingly there were major sex differences in the associated fitness consequences. Sexually selected trait evolution in males led to a genetically based increase in male mating success. By contrast, although trait evolution also occurred in females, there was no change in mating success. Our results suggest that phenotypic sexual selection on females from male choice is environmentally, rather than genetically, generated. Thus, compared with female choice, male choice is at best a weak driver of signal trait evolution in this species. Instead, the evolution of apparent female ornamentation seems more likely due to a correlated response to sexual selection on males and possibly other forms of natural selection.

Mapping the timecourse of goal-directed attention to location and colour in human vision.

PubMed

Adams, Rachel C; Chambers, Christopher D

2012-03-01

Goal-directed attention prioritises perception of task-relevant stimuli according to location, features, or onset time. In this study we compared the behavioural timecourse of goal-directed selection to locations and colours by varying the stimulus-onset asynchrony (SOA) between cue and target in a strategic cueing paradigm. Participants reported the presence or absence of a target following prior information regarding its location or colour. Results revealed that preparatory selection by colour is more effective at enhancing perceptual sensitivity than selection by location, even though both types of cue provided equivalent overall information. More detailed analysis revealed that this advantage arose due a limitation of spatial attention in maintaining a sufficiently broad focus (>2°) for target detection across multiple stimuli. In contrast, when target stimuli fell within 2° of the spatial attention spotlight, the strategic advantages and speed of spatial and colour attention were equated. Our findings are consistent with the conclusion that, under spatially optimal conditions, prior spatial and colour information are equally proficient at guiding top-down selection. When spatial locations are ambiguous, however, colour-based selection is the more efficient mechanism. Copyright © 2012 Elsevier B.V. All rights reserved.

FOXP2 targets show evidence of positive selection in European populations.

PubMed

Ayub, Qasim; Yngvadottir, Bryndis; Chen, Yuan; Xue, Yali; Hu, Min; Vernes, Sonja C; Fisher, Simon E; Tyler-Smith, Chris

2013-05-02

Forkhead box P2 (FOXP2) is a highly conserved transcription factor that has been implicated in human speech and language disorders and plays important roles in the plasticity of the developing brain. The pattern of nucleotide polymorphisms in FOXP2 in modern populations suggests that it has been the target of positive (Darwinian) selection during recent human evolution. In our study, we searched for evidence of selection that might have followed FOXP2 adaptations in modern humans. We examined whether or not putative FOXP2 targets identified by chromatin-immunoprecipitation genomic screening show evidence of positive selection. We developed an algorithm that, for any given gene list, systematically generates matched lists of control genes from the Ensembl database, collates summary statistics for three frequency-spectrum-based neutrality tests from the low-coverage resequencing data of the 1000 Genomes Project, and determines whether these statistics are significantly different between the given gene targets and the set of controls. Overall, there was strong evidence of selection of FOXP2 targets in Europeans, but not in the Han Chinese, Japanese, or Yoruba populations. Significant outliers included several genes linked to cellular movement, reproduction, development, and immune cell trafficking, and 13 of these constituted a significant network associated with cardiac arteriopathy. Strong signals of selection were observed for CNTNAP2 and RBFOX1, key neurally expressed genes that have been consistently identified as direct FOXP2 targets in multiple studies and that have themselves been associated with neurodevelopmental disorders involving language dysfunction. Copyright © 2013 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

Identification of quinazoline based inhibitors of IRAK4 for the treatment of inflammation

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

Smith, Graham F.; Altman, Michael D.; Andresen, Brian

Interleukin-1 receptor associated kinase 4 (IRAK4) has been implicated in IL-1R and TLR based signaling. Therefore selective inhibition of the kinase activity of this protein represents an attractive target for the treatment of inflammatory diseases. Medicinal chemistry optimization of high throughput screening (HTS) hits with the help of structure based drug design led to the identification of orally-bioavailable quinazoline based IRAK4 inhibitors with excellent pharmacokinetic profile and kinase selectivity. These highly selective IRAK4 compounds show activity in vivo via oral dosing in a TLR7 driven model of inflammation.

Shaping Attention with Reward: Effects of Reward on Space- and Object-Based Selection

PubMed Central

Shomstein, Sarah; Johnson, Jacoba

2014-01-01

The contribution of rewarded actions to automatic attentional selection remains obscure. We hypothesized that some forms of automatic orienting, such as object-based selection, can be completely abandoned in lieu of reward maximizing strategy. While presenting identical visual stimuli to the observer, in a set of two experiments, we manipulate what is being rewarded (different object targets or random object locations) and the type of reward received (money or points). It was observed that reward alone guides attentional selection, entirely predicting behavior. These results suggest that guidance of selective attention, while automatic, is flexible and can be adjusted in accordance with external non-sensory reward-based factors. PMID:24121412

Do selective immunisation against tuberculosis and hepatitis B reach the targeted populations? A nationwide register-based study evaluating the recommendations in the Norwegian Childhood Immunisation Programme.

PubMed

Feiring, Berit; Laake, Ida; Molden, Tor; Håberg, Siri E; Nøkleby, Hanne; Seterelv, Siri Schøyen; Magnus, Per; Trogstad, Lill

2016-04-12

Selective immunisation is an alternative to universal vaccination if children at increased risk of disease can be identified. Within the Norwegian Childhood Immunisation Programme, BCG vaccine against tuberculosis and vaccine against hepatitis B virus (HBV) are offered only to children with parents from countries with high burden of the respective disease. We wanted to study whether this selective immunisation policy reaches the targeted groups. The study population was identified through the Norwegian Central Population Registry and consisted of all children born in Norway 2007-2010 and residing in Norway until their second birthday, in total 240,484 children. Information on vaccinations from the Norwegian Immunisation Registry, and on parental country of birth from Statistics Norway, was linked to the population registry by personal identifiers. The coverage of BCG and HBV vaccine was compared with the coverage of vaccines in the universal programme. Among the study population, 16.1% and 15.9% belonged to the target groups for BCG and HBV vaccine, respectively. Among children in the BCG target group the BCG vaccine coverage was lower than the coverage of pertussis and measles vaccine (83.6% vs. 98.6% and 92.3%, respectively). Likewise, the HBV vaccine coverage was lower than the coverage of pertussis and measles vaccine in the HBV target group (90.0% vs. 98.6% and 92.3%, respectively). The coverage of the targeted vaccines was highest among children with parents from South Asia and Sub-Saharan Africa. The coverage of vaccines in the universal programme was similar in targeted and non-targeted groups. Children targeted by selective vaccination had lower coverage of the target vaccines than of vaccines in the universal programme, indicating that selective vaccination is challenging. Improved routines for identifying eligible children and delivering the target vaccines are needed. Universal vaccination of all children with these vaccines could be considered. Copyright © 2016 Elsevier Ltd. All rights reserved.

WFIRST: Exoplanet Target Selection and Scheduling with Greedy Optimization

NASA Astrophysics Data System (ADS)

Keithly, Dean; Garrett, Daniel; Delacroix, Christian; Savransky, Dmitry

2018-01-01

We present target selection and scheduling algorithms for missions with direct imaging of exoplanets, and the Wide Field Infrared Survey Telescope (WFIRST) in particular, which will be equipped with a coronagraphic instrument (CGI). Optimal scheduling of CGI targets can maximize the expected value of directly imaged exoplanets (completeness). Using target completeness as a reward metric and integration time plus overhead time as a cost metric, we can maximize the sum completeness for a mission with a fixed duration. We optimize over these metrics to create a list of target stars using a greedy optimization algorithm based off altruistic yield optimization (AYO) under ideal conditions. We simulate full missions using EXOSIMS by observing targets in this list for their predetermined integration times. In this poster, we report the theoretical maximum sum completeness, mean number of detected exoplanets from Monte Carlo simulations, and the ideal expected value of the simulated missions.

Self Organizing Map-Based Classification of Cathepsin k and S Inhibitors with Different Selectivity Profiles Using Different Structural Molecular Fingerprints: Design and Application for Discovery of Novel Hits.

PubMed

Ihmaid, Saleh K; Ahmed, Hany E A; Zayed, Mohamed F; Abadleh, Mohammed M

2016-01-30

The main step in a successful drug discovery pipeline is the identification of small potent compounds that selectively bind to the target of interest with high affinity. However, there is still a shortage of efficient and accurate computational methods with powerful capability to study and hence predict compound selectivity properties. In this work, we propose an affordable machine learning method to perform compound selectivity classification and prediction. For this purpose, we have collected compounds with reported activity and built a selectivity database formed of 153 cathepsin K and S inhibitors that are considered of medicinal interest. This database has three compound sets, two K/S and S/K selective ones and one non-selective KS one. We have subjected this database to the selectivity classification tool 'Emergent Self-Organizing Maps' for exploring its capability to differentiate selective cathepsin inhibitors for one target over the other. The method exhibited good clustering performance for selective ligands with high accuracy (up to 100 %). Among the possibilites, BAPs and MACCS molecular structural fingerprints were used for such a classification. The results exhibited the ability of the method for structure-selectivity relationship interpretation and selectivity markers were identified for the design of further novel inhibitors with high activity and target selectivity.

Progress and Challenges in Developing Aptamer-Functionalized Targeted Drug Delivery Systems

PubMed Central

Jiang, Feng; Liu, Biao; Lu, Jun; Li, Fangfei; Li, Defang; Liang, Chao; Dang, Lei; Liu, Jin; He, Bing; Atik Badshah, Shaikh; Lu, Cheng; He, Xiaojuan; Guo, Baosheng; Zhang, Xiao-Bing; Tan, Weihong; Lu, Aiping; Zhang, Ge

2015-01-01

Aptamers, which can be screened via systematic evolution of ligands by exponential enrichment (SELEX), are superior ligands for molecular recognition due to their high selectivity and affinity. The interest in the use of aptamers as ligands for targeted drug delivery has been increasing due to their unique advantages. Based on their different compositions and preparation methods, aptamer-functionalized targeted drug delivery systems can be divided into two main categories: aptamer-small molecule conjugated systems and aptamer-nanomaterial conjugated systems. In this review, we not only summarize recent progress in aptamer selection and the application of aptamers in these targeted drug delivery systems but also discuss the advantages, challenges and new perspectives associated with these delivery systems. PMID:26473828

Development of a fraction collection approach in capillary electrophoresis SELEX for aptamer selection.

PubMed

Luo, Zhaofeng; Zhou, Hongmin; Jiang, Hao; Ou, Huichao; Li, Xin; Zhang, Liyun

2015-04-21

Aptamers have attracted much attention due to their ability to bind to target molecules with high affinity and specificity. The development of an approach capable of efficiently generating aptamers through systematic evolution of ligands by exponential enrichment (SELEX) is particularly challenging. Herein, a fraction collection approach in capillary electrophoresis SELEX (FCE-SELEX) for the partition of a bound DNA-target complex is developed. By integrating fraction collection with a facile oil seal method for avoiding contamination while amplifying the bound DNA-target complex, in a single round of selection, a streptavidin-binding aptamer (SBA) has been generated. The affinity of aptamer SBA-36 for streptavidin (SA) is determined as 30.8 nM by surface plasmon resonance (SPR). Selectivity and biotin competition experiments demonstrate that the SBA-36 aptamer selected by FCE-SELEX is as efficient as those from other methods. Based on the ability of fraction collection in partition and collection of the aptamer-target complex from the original DNA library, FCE-SELEX can be a universal tool for the development of aptamers.

Activation loop targeting strategy for design of receptor-interacting protein kinase 2 (RIPK2) inhibitors.

PubMed

Suebsuwong, Chalada; Pinkas, Daniel M; Ray, Soumya S; Bufton, Joshua C; Dai, Bing; Bullock, Alex N; Degterev, Alexei; Cuny, Gregory D

2018-02-15

Development of selective kinase inhibitors remains a challenge due to considerable amino acid sequence similarity among family members particularly in the ATP binding site. Targeting the activation loop might offer improved inhibitor selectivity since this region of kinases is less conserved. However, the strategy presents difficulties due to activation loop flexibility. Herein, we report the design of receptor-interacting protein kinase 2 (RIPK2) inhibitors based on pan-kinase inhibitor regorafenib that aim to engage basic activation loop residues Lys169 or Arg171. We report development of CSR35 that displayed >10-fold selective inhibition of RIPK2 versus VEGFR2, the target of regorafenib. A co-crystal structure of CSR35 with RIPK2 revealed a resolved activation loop with an ionic interaction between the carboxylic acid installed in the inhibitor and the side-chain of Lys169. Our data provides principle feasibility of developing activation loop targeting type II inhibitors as a complementary strategy for achieving improved selectivity. Copyright © 2018 The Author(s). Published by Elsevier Ltd.. All rights reserved.

Feature-based attention is functionally distinct from relation-based attention: The double dissociation between color-based capture and color-relation-based capture of attention.

PubMed

Du, Feng; Jiao, Jun

2016-04-01

The present study used a spatial blink task and a cuing task to examine the boundary between feature-based capture and relation-based capture. Feature-based capture occurs when distractors match the target feature such as target color. The occurrence of relation-based capture is contingent upon the feature relation between target and distractor (e.g., color relation). The results show that color distractors that match the target-nontarget color relation do not consistently capture attention when they appear outside of the attentional window, but distractors appearing outside the attentional window that match the target color consistently capture attention. In contrast, color distractors that best match the target-nontarget color relation but not the target color, are more likely to capture attention when they appear within the attentional window. Consistently, color cues that match the target-nontarget color relation produce a cuing effect when they appear within the attentional window, while target-color matched cues do not. Such a double dissociation between color-based capture and color-relation-based capture indicates functionally distinct mechanisms for these 2 types of attentional selection. This also indicates that the spatial blink task and the uninformative cuing task are measuring distinctive aspects of involuntary attention. (PsycINFO Database Record (c) 2016 APA, all rights reserved).

Adapting an Evidence-Based Intervention Targeting HIV-Infected Prisoners in Malaysia

PubMed Central

Copenhaver, Michael M.; Tunku, Noor; Ezeabogu, Ifeoma; Potrepka, Jessica; Zahari, Muhammad Muhsin A.; Kamarulzaman, Adeeba; Altice, Frederick L.

2011-01-01

HIV-infected prisoners in Malaysia represent a critical target population for secondary HIV risk reduction interventions and care. We report on the process and outcome of our formative research aimed at systematically selecting and adapting an EBI designed to reduce secondary HIV risk and improve adherence to antiretroviral therapy among soon-to-be-released HIV-infected prisoners. Our formative work involved a critical examination of established EBIs and associated published reports complemented by data elicited through structured interviews and focus groups with key stakeholders, members of the target population, and their family members. Based on all information, we adapted the Holistic Health Recovery Program targeting people living with HIV (HHRP+), an EBI, to consist of eight 2-hour sessions that cover a range of specified topics so that participants may individually apply intervention content as needed to accommodate their particular substance abuse, HIV risk, and antiretroviral adherence issues. This study provides a complete example of the process of selecting and adapting an EBI—taking into account both empirical evidence and input from target organization stakeholders and target population members and their families—for use in real world prison settings where high-risk populations are concentrated. PMID:21860786

A molecularly imprinted polymer (MIP)-coated microbeam MEMS sensor for chemical detection

NASA Astrophysics Data System (ADS)

Holthoff, Ellen L.; Li, Lily; Hiller, Tobias; Turner, Kimberly L.

2015-05-01

Recently, microcantilever-based technology has emerged as a viable sensing platform due to its many advantages such as small size, high sensitivity, and low cost. However, microcantilevers lack the inherent ability to selectively identify hazardous chemicals (e.g., explosives, chemical warfare agents). The key to overcoming this challenge is to functionalize the top surface of the microcantilever with a receptor material (e.g., a polymer coating) so that selective binding between the cantilever and analyte of interest takes place. Molecularly imprinted polymers (MIPs) can be utilized as artificial recognition elements for target chemical analytes of interest. Molecular imprinting involves arranging polymerizable functional monomers around a template molecule followed by polymerization and template removal. The selectivity for the target analyte is based on the spatial orientation of the binding site and covalent or noncovalent interactions between the functional monomer and the analyte. In this work, thin films of sol-gel-derived xerogels molecularly imprinted for TNT and dimethyl methylphosphonate (DMMP), a chemical warfare agent stimulant, have demonstrated selectivity and stability in combination with a fixed-fixed beam microelectromechanical systems (MEMS)-based gas sensor. The sensor was characterized by parametric bifurcation noise-based tracking.

Neuropeptide Y Y1 receptors meditate targeted delivery of anticancer drug with encapsulated nanoparticles to breast cancer cells with high selectivity and its potential for breast cancer therapy.

PubMed

Li, Juan; Shen, Zheyu; Ma, Xuehua; Ren, Wenzhi; Xiang, Lingchao; Gong, An; Xia, Tian; Guo, Junming; Wu, Aiguo

2015-03-11

By enabling nanoparticle-based drug delivery system to actively target cancer cells with high selectivity, active targeted molecules have attracted great attention in the application of nanoparticles for anticancer drug delivery. However, the clinical application of most active targeted molecules in breast cancer therapy is limited, due to the low expression of their receptors in breast tumors or coexpression in the normal and tumor breast tissues. Here, a neuropeptide Y Y1 receptors ligand PNBL-NPY, as a novel targeted molecule, is conjugated with anticancer drug doxorubicin encapsulating albumin nanoparticles to investigate the effect of Y1 receptors on the delivery of drug-loaded nanoparticles to breast cancer cells and its potential for breast cancer therapy. The PNBL-NPY can actively recognize and bind to the Y1 receptors that are significantly overexpressed on the surface of the breast cancer cells, and the drug-loaded nanoparticles are delivered directly into the cancer cells through internalization. This system is highly selective and able to distinguish the breast cancer cells from the normal cells, due to normal breast cells that express Y2 receptors only. It is anticipated that this study may provide a guidance in the development of Y1 receptor-based nanoparticulate drug delivery system for a safer and more efficient breast cancer therapy.

Targeted Screening With Combined Age- and Morphology-Based Criteria Enriches Detection of Lynch Syndrome in Endometrial Cancer.

PubMed

Lin, Douglas I; Hecht, Jonathan L

2016-06-01

Endometrial cancer is associated with Lynch syndrome in 2% to 6% of cases. Adequate screening may prevent of a second cancer and incident cancers in family members via risk-reducing strategies. The goal of the study was to evaluate the detection rate of Lynch syndrome via a targeted screening approach. In 2009, we incorporated targeted Lynch syndrome screening via immunohistochemistry for MLH1, PMS2, MSH2, and MSH6, followed by MLH1 promoter hypermethylation, in select cases of endometrial carcinoma. Criteria for patient selection included (1) all patients <50 years; (2) patients of any age with tumors showing features of microsatellite instability (lower uterine segment-centered tumors, hard to classify carcinomas, increased peritumoral or tumor infiltrating lymphocytes and cases with synchronous ovarian carcinomas); (3) clinician's request based on family or personal history; and (4) ad hoc retrospective testing based on the established criteria on patients discovered on follow-up visits. By using a targeted screening approach in a 4.5-year period, approximately 2.1% of endometrial cancers (7 of 328) were potentially associated with Lynch syndrome. Therefore, targeted screening with combined age and morphology based criteria enriches detection of Lynch syndrome in endometrial cancer. However, the detection rate is lower than the rates from published series that offer universal screening. © The Author(s) 2016.

A Targeted Multifunctional Platform for Imaging and Treatment of Breast Cancer and Its Metastases Based on Adenoviral Vectors and Magnetic Nanoparticles

DTIC Science & Technology

2007-08-01

selective or are genetically modified to be selective for replication competence in tu- mor cells. In this regard, herpesvirus samiri (HVS) was de...logy 76, 4559-4566 Ring CJ (2002) Cytolytic viruses as potential anti -cancer agents . The Journal of General Virology 83, 491-502 Riviere C, Danos O...precursors for tumor stroma and targeted-delivery vehicles for anti - cancer agents . Journal of the National Cancer Institute 96, 1593-1603 Takanami

Target-specific NMR detection of protein-ligand interactions with antibody-relayed 15N-group selective STD.

PubMed

Hetényi, Anasztázia; Hegedűs, Zsófia; Fajka-Boja, Roberta; Monostori, Éva; Kövér, Katalin E; Martinek, Tamás A

2016-12-01

Fragment-based drug design has been successfully applied to challenging targets where the detection of the weak protein-ligand interactions is a key element. 1 H saturation transfer difference (STD) NMR spectroscopy is a powerful technique for this work but it requires pure homogeneous proteins as targets. Monoclonal antibody (mAb)-relayed 15 N-GS STD spectroscopy has been developed to resolve the problem of protein mixtures and impure proteins. A 15 N-labelled target-specific mAb is selectively irradiated and the saturation is relayed through the target to the ligand. Tests on the anti-Gal-1 mAb/Gal-1/lactose system showed that the approach is experimentally feasible in a reasonable time frame. This method allows detection and identification of binding molecules directly from a protein mixture in a multicomponent system.

A procedure to select ground-motion time histories for deterministic seismic hazard analysis from the Next Generation Attenuation (NGA) database

NASA Astrophysics Data System (ADS)

Huang, Duruo; Du, Wenqi; Zhu, Hong

2017-10-01

In performance-based seismic design, ground-motion time histories are needed for analyzing dynamic responses of nonlinear structural systems. However, the number of ground-motion data at design level is often limited. In order to analyze seismic performance of structures, ground-motion time histories need to be either selected from recorded strong-motion database or numerically simulated using stochastic approaches. In this paper, a detailed procedure to select proper acceleration time histories from the Next Generation Attenuation (NGA) database for several cities in Taiwan is presented. Target response spectra are initially determined based on a local ground-motion prediction equation under representative deterministic seismic hazard analyses. Then several suites of ground motions are selected for these cities using the Design Ground Motion Library (DGML), a recently proposed interactive ground-motion selection tool. The selected time histories are representatives of the regional seismic hazard and should be beneficial to earthquake studies when comprehensive seismic hazard assessments and site investigations are unavailable. Note that this method is also applicable to site-specific motion selections with the target spectra near the ground surface considering the site effect.

Applications of chemogenomic library screening in drug discovery.

PubMed

Jones, Lyn H; Bunnage, Mark E

2017-04-01

The allure of phenotypic screening, combined with the industry preference for target-based approaches, has prompted the development of innovative chemical biology technologies that facilitate the identification of new therapeutic targets for accelerated drug discovery. A chemogenomic library is a collection of selective small-molecule pharmacological agents, and a hit from such a set in a phenotypic screen suggests that the annotated target or targets of that pharmacological agent may be involved in perturbing the observable phenotype. In this Review, we describe opportunities for chemogenomic screening to considerably expedite the conversion of phenotypic screening projects into target-based drug discovery approaches. Other applications are explored, including drug repositioning, predictive toxicology and the discovery of novel pharmacological modalities.

Targeted nanomedicine for cancer therapeutics: Towards precision medicine overcoming drug resistance.

PubMed

Bar-Zeev, Maya; Livney, Yoav D; Assaraf, Yehuda G

2017-03-01

Intrinsic anticancer drug resistance appearing prior to chemotherapy as well as acquired resistance due to drug treatment, remain the dominant impediments towards curative cancer therapy. Hence, novel targeted strategies to overcome cancer drug resistance constitute a key aim of cancer research. In this respect, targeted nanomedicine offers innovative therapeutic strategies to overcome the various limitations of conventional chemotherapy, enabling enhanced selectivity, early and more precise cancer diagnosis, individualized treatment as well as overcoming of drug resistance, including multidrug resistance (MDR). Delivery systems based on nanoparticles (NPs) include diverse platforms enabling a plethora of rationally designed therapeutic nanomedicines. Here we review NPs designed to enhance antitumor drug uptake and selective intracellular accumulation using strategies including passive and active targeting, stimuli-responsive drug activation or target-activated release, triggered solely in the cancer cell or in specific organelles, cutting edge theranostic multifunctional NPs delivering drug combinations for synergistic therapy, while facilitating diagnostics, and personalization of therapeutic regimens. In the current paper we review the recent findings of the past four years and discuss the advantages and limitations of the various novel NPs-based drug delivery systems. Special emphasis is put on in vivo study-based evidences supporting significant therapeutic impact in chemoresistant cancers. A future perspective is proposed for further research and development of complex targeted, multi-stage responsive nanomedical drug delivery systems for personalized cancer diagnosis and efficacious therapy. Copyright © 2017 Elsevier Ltd. All rights reserved.

Selective Attention and Sensory Modality in Aging: Curses and Blessings.

PubMed

Van Gerven, Pascal W M; Guerreiro, Maria J S

2016-01-01

The notion that selective attention is compromised in older adults as a result of impaired inhibitory control is well established. Yet it is primarily based on empirical findings covering the visual modality. Auditory and especially, cross-modal selective attention are remarkably underexposed in the literature on aging. In the past 5 years, we have attempted to fill these voids by investigating performance of younger and older adults on equivalent tasks covering all four combinations of visual or auditory target, and visual or auditory distractor information. In doing so, we have demonstrated that older adults are especially impaired in auditory selective attention with visual distraction. This pattern of results was not mirrored by the results from our psychophysiological studies, however, in which both enhancement of target processing and suppression of distractor processing appeared to be age equivalent. We currently conclude that: (1) age-related differences of selective attention are modality dependent; (2) age-related differences of selective attention are limited; and (3) it remains an open question whether modality-specific age differences in selective attention are due to impaired distractor inhibition, impaired target enhancement, or both. These conclusions put the longstanding inhibitory deficit hypothesis of aging in a new perspective.

Antibiotic Combinations That Enable One-Step, Targeted Mutagenesis of Chromosomal Genes.

PubMed

Lee, Wonsik; Do, Truc; Zhang, Ge; Kahne, Daniel; Meredith, Timothy C; Walker, Suzanne

2018-06-08

Targeted modification of bacterial chromosomes is necessary to understand new drug targets, investigate virulence factors, elucidate cell physiology, and validate results of -omics-based approaches. For some bacteria, reverse genetics remains a major bottleneck to progress in research. Here, we describe a compound-centric strategy that combines new negative selection markers with known positive selection markers to achieve simple, efficient one-step genome engineering of bacterial chromosomes. The method was inspired by the observation that certain nonessential metabolic pathways contain essential late steps, suggesting that antibiotics targeting a late step can be used to select for the absence of genes that control flux into the pathway. Guided by this hypothesis, we have identified antibiotic/counterselectable markers to accelerate reverse engineering of two increasingly antibiotic-resistant pathogens, Staphylococcus aureus and Acinetobacter baumannii. For S. aureus, we used wall teichoic acid biosynthesis inhibitors to select for the absence of tarO and for A. baumannii, we used colistin to select for the absence of lpxC. We have obtained desired gene deletions, gene fusions, and promoter swaps in a single plating step with perfect efficiency. Our method can also be adapted to generate markerless deletions of genes using FLP recombinase. The tools described here will accelerate research on two important pathogens, and the concept we outline can be readily adapted to any organism for which a suitable target pathway can be identified.

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.

Detection of Sub-fM DNA with Target Recycling and Self-Assembly Amplification on Graphene Field-Effect Biosensors

PubMed Central

2018-01-01

All-electronic DNA biosensors based on graphene field-effect transistors (GFETs) offer the prospect of simple and cost-effective diagnostics. For GFET sensors based on complementary probe DNA, the sensitivity is limited by the binding affinity of the target oligonucleotide, in the nM range for 20 mer targets. We report a ∼20 000× improvement in sensitivity through the use of engineered hairpin probe DNA that allows for target recycling and hybridization chain reaction. This enables detection of 21 mer target DNA at sub-fM concentration and provides superior specificity against single-base mismatched oligomers. The work is based on a scalable fabrication process for biosensor arrays that is suitable for multiplexed detection. This approach overcomes the binding-affinity-dependent sensitivity of nucleic acid biosensors and offers a pathway toward multiplexed and label-free nucleic acid testing with high accuracy and selectivity. PMID:29768011

Detection of Sub-fM DNA with Target Recycling and Self-Assembly Amplification on Graphene Field-Effect Biosensors.

PubMed

Gao, Zhaoli; Xia, Han; Zauberman, Jonathan; Tomaiuolo, Maurizio; Ping, Jinglei; Zhang, Qicheng; Ducos, Pedro; Ye, Huacheng; Wang, Sheng; Yang, Xinping; Lubna, Fahmida; Luo, Zhengtang; Ren, Li; Johnson, Alan T Charlie

2018-06-13

All-electronic DNA biosensors based on graphene field-effect transistors (GFETs) offer the prospect of simple and cost-effective diagnostics. For GFET sensors based on complementary probe DNA, the sensitivity is limited by the binding affinity of the target oligonucleotide, in the nM range for 20 mer targets. We report a ∼20 000× improvement in sensitivity through the use of engineered hairpin probe DNA that allows for target recycling and hybridization chain reaction. This enables detection of 21 mer target DNA at sub-fM concentration and provides superior specificity against single-base mismatched oligomers. The work is based on a scalable fabrication process for biosensor arrays that is suitable for multiplexed detection. This approach overcomes the binding-affinity-dependent sensitivity of nucleic acid biosensors and offers a pathway toward multiplexed and label-free nucleic acid testing with high accuracy and selectivity.

Comparison and evaluation of two exome capture kits and sequencing platforms for variant calling.

PubMed

Zhang, Guoqiang; Wang, Jianfeng; Yang, Jin; Li, Wenjie; Deng, Yutian; Li, Jing; Huang, Jun; Hu, Songnian; Zhang, Bing

2015-08-05

To promote the clinical application of next-generation sequencing, it is important to obtain accurate and consistent variants of target genomic regions at low cost. Ion Proton, the latest updated semiconductor-based sequencing instrument from Life Technologies, is designed to provide investigators with an inexpensive platform for human whole exome sequencing that achieves a rapid turnaround time. However, few studies have comprehensively compared and evaluated the accuracy of variant calling between Ion Proton and Illumina sequencing platforms such as HiSeq 2000, which is the most popular sequencing platform for the human genome. The Ion Proton sequencer combined with the Ion TargetSeq Exome Enrichment Kit together make up TargetSeq-Proton, whereas SureSelect-Hiseq is based on the Agilent SureSelect Human All Exon v4 Kit and the HiSeq 2000 sequencer. Here, we sequenced exonic DNA from four human blood samples using both TargetSeq-Proton and SureSelect-HiSeq. We then called variants in the exonic regions that overlapped between the two exome capture kits (33.6 Mb). The rates of shared variant loci called by two sequencing platforms were from 68.0 to 75.3% in four samples, whereas the concordance of co-detected variant loci reached 99%. Sanger sequencing validation revealed that the validated rate of concordant single nucleotide polymorphisms (SNPs) (91.5%) was higher than the SNPs specific to TargetSeq-Proton (60.0%) or specific to SureSelect-HiSeq (88.3%). With regard to 1-bp small insertions and deletions (InDels), the Sanger sequencing validated rates of concordant variants (100.0%) and SureSelect-HiSeq-specific (89.6%) were higher than those of TargetSeq-Proton-specific (15.8%). In the sequencing of exonic regions, a combination of using of two sequencing strategies (SureSelect-HiSeq and TargetSeq-Proton) increased the variant calling specificity for concordant variant loci and the sensitivity for variant loci called by any one platform. However, for the sequencing of platform-specific variants, the accuracy of variant calling by HiSeq 2000 was higher than that of Ion Proton, specifically for the InDel detection. Moreover, the variant calling software also influences the detection of SNPs and, specifically, InDels in Ion Proton exome sequencing.

Rethinking volitional control over task choice in multitask environments: use of a stimulus set selection strategy in voluntary task switching.

PubMed

Arrington, Catherine M; Weaver, Starla M

2015-01-01

Under conditions of volitional control in multitask environments, subjects may engage in a variety of strategies to guide task selection. The current research examines whether subjects may sometimes use a top-down control strategy of selecting a task-irrelevant stimulus dimension, such as location, to guide task selection. We term this approach a stimulus set selection strategy. Using a voluntary task switching procedure, subjects voluntarily switched between categorizing letter and number stimuli that appeared in two, four, or eight possible target locations. Effects of stimulus availability, manipulated by varying the stimulus onset asynchrony between the two target stimuli, and location repetition were analysed to assess the use of a stimulus set selection strategy. Considered across position condition, Experiment 1 showed effects of both stimulus availability and location repetition on task choice suggesting that only in the 2-position condition, where selection based on location always results in a target at the selected location, subjects may have been using a stimulus set selection strategy on some trials. Experiment 2 replicated and extended these findings in a visually more cluttered environment. These results indicate that, contrary to current models of task selection in voluntary task switching, the top-down control of task selection may occur in the absence of the formation of an intention to perform a particular task.

Highly selective luminescent nanostructures for mitochondrial imaging and targeting

NASA Astrophysics Data System (ADS)

Fanizza, E.; Iacobazzi, R. M.; Laquintana, V.; Valente, G.; Caliandro, G.; Striccoli, M.; Agostiano, A.; Cutrignelli, A.; Lopedota, A.; Curri, M. L.; Franco, M.; Depalo, N.; Denora, N.

2016-02-01

Here a luminescent hybrid nanostructure based on functionalized quantum dots (QDs) is used as a fluorescent imaging agent able to target selectively mitochondria thanks to the molecular recognition of the translocator protein (TSPO). The selective targeting of such an 18 kDa protein mainly located in the outer mitochondrial membrane and overexpressed in several pathological states including neurodegenerative diseases and cancers may provide valuable information for the early diagnosis and therapy of human disorders. In particular, the rational design of amino functionalized luminescent silica coated QD nanoparticles (QD@SiO2 NPs) provides a versatile nanoplatform to anchor a potent and selective TSPO ligand, characterized by a 2-phenyl-imidazo[1,2-a]pyridine acetamide structure along with a derivatizable carboxylic end group, useful to conjugate the TSPO ligand and achieve TSPO-QD@SiO2 NPs by means of a covalent amide bond. The colloidal stability and optical properties of the proposed nanomaterials are comprehensively investigated and their potential as mitochondrial imaging agents is fully assessed. Sub-cellular fractionation, together with confocal laser scanning fluorescence microscopy and co-localization analysis of targeted TSPO-QD@SiO2 NPs in C6 glioma cells overexpressing the TSPO, proves the great potential of these multifunctional nanosystems as in vitro selective mitochondrial imaging agents.Here a luminescent hybrid nanostructure based on functionalized quantum dots (QDs) is used as a fluorescent imaging agent able to target selectively mitochondria thanks to the molecular recognition of the translocator protein (TSPO). The selective targeting of such an 18 kDa protein mainly located in the outer mitochondrial membrane and overexpressed in several pathological states including neurodegenerative diseases and cancers may provide valuable information for the early diagnosis and therapy of human disorders. In particular, the rational design of amino functionalized luminescent silica coated QD nanoparticles (QD@SiO2 NPs) provides a versatile nanoplatform to anchor a potent and selective TSPO ligand, characterized by a 2-phenyl-imidazo[1,2-a]pyridine acetamide structure along with a derivatizable carboxylic end group, useful to conjugate the TSPO ligand and achieve TSPO-QD@SiO2 NPs by means of a covalent amide bond. The colloidal stability and optical properties of the proposed nanomaterials are comprehensively investigated and their potential as mitochondrial imaging agents is fully assessed. Sub-cellular fractionation, together with confocal laser scanning fluorescence microscopy and co-localization analysis of targeted TSPO-QD@SiO2 NPs in C6 glioma cells overexpressing the TSPO, proves the great potential of these multifunctional nanosystems as in vitro selective mitochondrial imaging agents. Electronic supplementary information (ESI) available: Additional TEM micrographs, fluorescence and UV-Vis absorbance spectra of silica coated QD nanoparticles and TSPO ligand. See DOI: 10.1039/c5nr08139d

Selective inhibitors of zinc-dependent histone deacetylases. Therapeutic targets relevant to cancer.

PubMed

Kollar, Jakub; Frecer, Vladimir

2015-01-01

Histone deacetylases (HDACs), which act on acetylated histones and/or other non-histone protein substrates, represent validated epigenetic targets for the treatment of cancer and other human diseases. The inhibition of HDAC activity was shown to induce cell cycle arrest, differentiation, apoptosis as well as a decrease in proliferation, angiogenesis, migration, and cell resistance to chemotherapy. Targeting single HDAC isoforms with selective inhibitors will help to reveal the role of individual HDACs in cancer development or uncover further biological consequences of protein acetylation. This review focuses on conventional zinc-containing HDACs. In its first part, the biological role of individual HDACs in various types of cancer is summarized. In the second part, promising HDAC inhibitors showing activity both in enzymatic and cell-based assays are surveyed with an emphasis on the inhibitors selective to the individual HDACs.

Selection of specific protein binders for pre-defined targets from an optimized library of artificial helicoidal repeat proteins (alphaRep).

PubMed

Guellouz, Asma; Valerio-Lepiniec, Marie; Urvoas, Agathe; Chevrel, Anne; Graille, Marc; Fourati-Kammoun, Zaineb; Desmadril, Michel; van Tilbeurgh, Herman; Minard, Philippe

2013-01-01

We previously designed a new family of artificial proteins named αRep based on a subgroup of thermostable helicoidal HEAT-like repeats. We have now assembled a large optimized αRep library. In this library, the side chains at each variable position are not fully randomized but instead encoded by a distribution of codons based on the natural frequency of side chains of the natural repeats family. The library construction is based on a polymerization of micro-genes and therefore results in a distribution of proteins with a variable number of repeats. We improved the library construction process using a "filtration" procedure to retain only fully coding modules that were recombined to recreate sequence diversity. The final library named Lib2.1 contains 1.7×10(9) independent clones. Here, we used phage display to select, from the previously described library or from the new library, new specific αRep proteins binding to four different non-related predefined protein targets. Specific binders were selected in each case. The results show that binders with various sizes are selected including relatively long sequences, with up to 7 repeats. ITC-measured affinities vary with Kd values ranging from micromolar to nanomolar ranges. The formation of complexes is associated with a significant thermal stabilization of the bound target protein. The crystal structures of two complexes between αRep and their cognate targets were solved and show that the new interfaces are established by the variable surfaces of the repeated modules, as well by the variable N-cap residues. These results suggest that αRep library is a new and versatile source of tight and specific binding proteins with favorable biophysical properties.

Selection of Specific Protein Binders for Pre-Defined Targets from an Optimized Library of Artificial Helicoidal Repeat Proteins (alphaRep)

PubMed Central

Chevrel, Anne; Graille, Marc; Fourati-Kammoun, Zaineb; Desmadril, Michel; van Tilbeurgh, Herman; Minard, Philippe

2013-01-01

We previously designed a new family of artificial proteins named αRep based on a subgroup of thermostable helicoidal HEAT-like repeats. We have now assembled a large optimized αRep library. In this library, the side chains at each variable position are not fully randomized but instead encoded by a distribution of codons based on the natural frequency of side chains of the natural repeats family. The library construction is based on a polymerization of micro-genes and therefore results in a distribution of proteins with a variable number of repeats. We improved the library construction process using a “filtration” procedure to retain only fully coding modules that were recombined to recreate sequence diversity. The final library named Lib2.1 contains 1.7×109 independent clones. Here, we used phage display to select, from the previously described library or from the new library, new specific αRep proteins binding to four different non-related predefined protein targets. Specific binders were selected in each case. The results show that binders with various sizes are selected including relatively long sequences, with up to 7 repeats. ITC-measured affinities vary with Kd values ranging from micromolar to nanomolar ranges. The formation of complexes is associated with a significant thermal stabilization of the bound target protein. The crystal structures of two complexes between αRep and their cognate targets were solved and show that the new interfaces are established by the variable surfaces of the repeated modules, as well by the variable N-cap residues. These results suggest that αRep library is a new and versatile source of tight and specific binding proteins with favorable biophysical properties. PMID:24014183

Autonomous Selection of a Rover Laser Target on Mars

NASA Image and Video Library

2016-07-21

NASA's Curiosity Mars rover autonomously selects some of the targets for the laser and telescopic camera of the rover's Chemistry and Camera (ChemCam) instrument. For example, on-board software analyzed the image on the left, chose the target highlighted with the yellow dot, and pointed ChemCam to acquire laser analysis and the image on the right. Most ChemCam targets are still selected by scientists discussing rocks or soil seen in images the rover has sent to Earth, but the autonomous targeting provides an added capability. It can offer a head start on acquiring composition information at a location just reached by a drive. The software for target selection and instrument pointing is called AEGIS, for Autonomous Exploration for Gathering Increased Science. The image on the left was taken by the left eye of Curiosity's stereo Navigation Camera (Navcam) a few minutes after the rover completed a drive of about 43 feet (13 meters) on July 14, 2016, during the 1,400th Martian day, or sol, of the rover's work on Mars. Using AEGIS for target selection and pointing based on the Navcam imagery, Curiosity's ChemCam zapped a grid of nine points on a rock chosen for meeting criteria set by the science team. In this run, parameters were set to find bright-toned outcrop rock rather than darker rocks, which in this area tend to be loose on the surface. Within less than 30 minutes after the Navcam image was taken, ChemCam had used its laser on all nine points and had taken before-and-after images of the target area with its remote micro-imager (RMI) camera. The image at right combines those two RMI exposures. The nine laser targets are marked in red at the center. On the Navcam image at left, the yellow dot identifies the selected target area, which is about 2.2 inches (5.6 centimeters) in diameter. An unannotated version of this Sol 1400 Navcam image is available. ChemCam records spectra of glowing plasma generated when the laser hits a target point. These spectra provide information about the chemical elements present in the target. The light-toned patch of bedrock identified by AEGIS on Sol 1400 appears, geochemically, to belong to the "Stimson" sandstone unit of lower Mount Sharp. In mid-2016, Curiosity typically uses AEGIS for selecting a ChemCam target more than once per week. http://photojournal.jpl.nasa.gov/catalog/PIA20762

Discovery and Characterization of a Highly Potent and Selective Aminopyrazoline-Based in Vivo Probe (BAY-598) for the Protein Lysine Methyltransferase SMYD2.

PubMed

Eggert, Erik; Hillig, Roman C; Koehr, Silke; Stöckigt, Detlef; Weiske, Jörg; Barak, Naomi; Mowat, Jeffrey; Brumby, Thomas; Christ, Clara D; Ter Laak, Antonius; Lang, Tina; Fernandez-Montalvan, Amaury E; Badock, Volker; Weinmann, Hilmar; Hartung, Ingo V; Barsyte-Lovejoy, Dalia; Szewczyk, Magdalena; Kennedy, Steven; Li, Fengling; Vedadi, Masoud; Brown, Peter J; Santhakumar, Vijayaratnam; Arrowsmith, Cheryl H; Stellfeld, Timo; Stresemann, Carlo

2016-05-26

Protein lysine methyltransferases have recently emerged as a new target class for the development of inhibitors that modulate gene transcription or signaling pathways. SET and MYND domain containing protein 2 (SMYD2) is a catalytic SET domain containing methyltransferase reported to monomethylate lysine residues on histone and nonhistone proteins. Although several studies have uncovered an important role of SMYD2 in promoting cancer by protein methylation, the biology of SMYD2 is far from being fully understood. Utilization of highly potent and selective chemical probes for target validation has emerged as a concept which circumvents possible limitations of knockdown experiments and, in particular, could result in an improved exploration of drug targets with a complex underlying biology. Here, we report the development of a potent, selective, and cell-active, substrate-competitive inhibitor of SMYD2, which is the first reported inhibitor suitable for in vivo target validation studies in rodents.

VizieR Online Data Catalog: Deconvolved Spitzer images of 89 protostars (Velusamy+, 2014)

NASA Astrophysics Data System (ADS)

Velusamy, T.; Langer, W. D.; Thompson, T.

2016-03-01

The sample of Class 0 protostars, H2 jets, and outflow sour selected for HiRes deconvolution of Spitzer images are listed in Table1. The majority of our target protostellar objects were selected from "The Youngest Protostars" webpage hosted by the University of Kent (http://astro.kent.ac.uk/protostars/old/), which are based on the young Class 0 objects compiled by Froebrich 2005 (cat. J/ApJS/156/169). In addition to these objects, our sample includes some Herbig-Haro (HH) sources and a few well known jet outflow sources. Our sample also includes one high-mass protostar (IRAS20126+4104; cf. Caratti o Garatti et al., 2008A&A...485..137C) to demonstrate the use of HiRes for such sources. Our choice for target selection was primarily based on the availability of Spitzer images in IRAC and MIPS bands in the archives and the feasibility for reprocessing based on the published Spitzer images wherever available. (1 data file).

Protozoacidal Trojan-Horse: use of a ligand-lytic peptide for selective destruction of symbiotic protozoa within termite guts.

PubMed

Sethi, Amit; Delatte, Jennifer; Foil, Lane; Husseneder, Claudia

2014-01-01

For novel biotechnology-based termite control, we developed a cellulose bait containing freeze-dried genetically engineered yeast which expresses a protozoacidal lytic peptide attached to a protozoa-recognizing ligand. The yeast acts as a 'Trojan-Horse' that kills the cellulose-digesting protozoa in the termite gut, which leads to the death of termites, presumably due to inefficient cellulose digestion. The ligand targets the lytic peptide specifically to protozoa, thereby increasing its protozoacidal efficiency while protecting non-target organisms. After ingestion of the bait, the yeast propagates in the termite's gut and is spread throughout the termite colony via social interactions. This novel paratransgenesis-based strategy could be a good supplement for current termite control using fortified biological control agents in addition to chemical insecticides. Moreover, this ligand-lytic peptide system could be used for drug development to selectively target disease-causing protozoa in humans or other vertebrates.

Discovery of thienoquinolone derivatives as selective and ATP non-competitive CDK5/p25 inhibitors by structure-based virtual screening

PubMed Central

Chatterjee, Arindam; Doerksen, Robert J.; Khan, Ikhlas A.

2014-01-01

Calpain mediated cleavage of CDK5 natural precursor p35 causes a stable complex formation of CDK5/p25, which leads to hyperphosphorylation of tau. Thus inhibition of this complex is a viable target for numerous acute and chronic neurodegenerative diseases involving tau protein, including Alzheimer’s disease. Since CDK5 has the highest sequence homology with its mitotic counterpart CDK2, our primary goal was to design selective CDK5/p25 inhibitors targeting neurodegeneration. A novel structure-based virtual screening protocol comprised of e-pharmacophore models and virtual screening work-flow was used to identify nine compounds from a commercial database containing 2.84 million compounds. An ATP non-competitive and selective thieno[3,2-c]quinolin-4(5H)-one inhibitor (10) with ligand efficiency (LE) of 0.3 was identified as the lead molecule. Further SAR optimization led to the discovery of several low micromolar inhibitors with good selectivity. The research represents a new class of potent ATP non-competitive CDK5/p25 inhibitors with good CDK2/E selectivity. PMID:25438765

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.

Protecting My Interests: HRM and Targets' Coping with Workplace Bullying

ERIC Educational Resources Information Center

D'Cruz, Premilla; Noronha, Ernesto

2010-01-01

Based on a study rooted in van Manen's hermeneutic phenomenology, conducted with agents working in international facing call centers in Mumbai and Bangalore, India, this paper describes targets' coping with workplace bullying. Data were gathered through conversational interviews and were subject to sententious and selective thematic analyses. The…

Cancer cell-selective, clathrin-mediated endocytosis of aptamer decorated nanoparticles

PubMed Central

Engelberg, Shira; Modrejewski, Julia; Walter, Johanna G.; Livney, Yoav D.; Assaraf, Yehuda G.

2018-01-01

Lung cancer is the leading cause of cancer mortality worldwide, resulting in 88% deaths of all diagnosed patients. Hence, novel therapeutic modalities are urgently needed. Single-stranded oligonucleotide-based aptamers (APTs) are excellent ligands for tumor cell targeting. However, the molecular mechanisms underlying their internalization into living cells have been poorly studied. Towards the application of APTs for active drug targeting to cancer cells, we herein studied the mechanism underlying S15-APT internalization into human non-small cell lung cancer A549 cells. We thus delineated the mode of entry of a model nanomedical system based on quantum dots (QDs) decorated with S15-APTs as a selective targeting moiety for uptake by A549 cells. These APT-decorated QDs displayed selective binding to, and internalization by target A549 cells, but not by normal human bronchial epithelial BEAS2B, cervical carcinoma (HeLa) and colon adenocarcinoma CaCo-2 cells, hence demonstrating high specificity. Flow cytometric analysis revealed a remarkably low dissociation constant of S15-APTs-decorated QDs to A549 cells (Kd = 13.1 ± 1.6 nM). Through the systematic application of a series of established inhibitors of known mechanisms of endocytosis, we show that the uptake of S15-APTs proceeds via a classical clathrin-dependent receptor-mediated endocytosis. This cancer cell-selective mode of entry could possibly be used in the future to evade plasma membrane-localized multidrug resistance efflux pumps, thereby overcoming an important mechanism of cancer multidrug resistance. PMID:29765515

Cancer cell-selective, clathrin-mediated endocytosis of aptamer decorated nanoparticles.

PubMed

Engelberg, Shira; Modrejewski, Julia; Walter, Johanna G; Livney, Yoav D; Assaraf, Yehuda G

2018-04-20

Lung cancer is the leading cause of cancer mortality worldwide, resulting in 88% deaths of all diagnosed patients. Hence, novel therapeutic modalities are urgently needed. Single-stranded oligonucleotide-based aptamers (APTs) are excellent ligands for tumor cell targeting. However, the molecular mechanisms underlying their internalization into living cells have been poorly studied. Towards the application of APTs for active drug targeting to cancer cells, we herein studied the mechanism underlying S15-APT internalization into human non-small cell lung cancer A549 cells. We thus delineated the mode of entry of a model nanomedical system based on quantum dots (QDs) decorated with S15-APTs as a selective targeting moiety for uptake by A549 cells. These APT-decorated QDs displayed selective binding to, and internalization by target A549 cells, but not by normal human bronchial epithelial BEAS2B, cervical carcinoma (HeLa) and colon adenocarcinoma CaCo-2 cells, hence demonstrating high specificity. Flow cytometric analysis revealed a remarkably low dissociation constant of S15-APTs-decorated QDs to A549 cells (K d = 13.1 ± 1.6 nM). Through the systematic application of a series of established inhibitors of known mechanisms of endocytosis, we show that the uptake of S15-APTs proceeds via a classical clathrin-dependent receptor-mediated endocytosis. This cancer cell-selective mode of entry could possibly be used in the future to evade plasma membrane-localized multidrug resistance efflux pumps, thereby overcoming an important mechanism of cancer multidrug resistance.

Glioma Selectivity of Magnetically Targeted Nanoparticles: A Role of Abnormal Tumor Hydrodynamics

PubMed Central

Chertok, Beata; David, Allan E.; Huang, Yongzhuo; Yang, Victor C.

2007-01-01

Magnetic targeting is a promising strategy for achieving localized drug delivery. Application of this strategy to treat brain tumors, however, is complicated by their deep intracranial location, since magnetic field density cannot be focused at a distance from an externally applied magnet. This study intended to examine whether, with magnetic targeting, pathological alteration in brain tumor flow dynamics could be of value in discriminating the diseased site from healthy brain. To address this question, the capture of magnetic nanoparticles was first assessed in vitro using a simple flow system under theoretically estimated glioma and normal brain flow conditions. Secondly, accumulation of nanoparticles via magnetic targeting was evaluated in vivo using 9L-glioma bearing rats. In vitro results that predicted a 7.6-fold increase in nanoparticle capture at glioma-versus contralateral brain-relevant flow rates were relatively consistent with the 9.6-fold glioma selectivity of nanoparticle accumulation over the contralateral brain observed in vivo. Based on these finding, the in vitro ratio of nanoparticle capture can be viewed as a plausible indicator of in vivo glioma selectivity. Overall, it can be concluded that the decreased blood flow rate in glioma, reflecting tumor vascular abnormalities, is an important contributor to glioma-selective nanoparticle accumulation with magnetic targeting. PMID:17628157

Glioma selectivity of magnetically targeted nanoparticles: a role of abnormal tumor hydrodynamics.

PubMed

Chertok, Beata; David, Allan E; Huang, Yongzhuo; Yang, Victor C

2007-10-08

Magnetic targeting is a promising strategy for achieving localized drug delivery. Application of this strategy to treat brain tumors, however, is complicated by their deep intracranial location, since magnetic field density cannot be focused at a distance from an externally applied magnet. This study intended to examine whether, with magnetic targeting, pathological alteration in brain tumor flow dynamics could be of value in discriminating the diseased site from healthy brain. To address this question, the capture of magnetic nanoparticles was first assessed in vitro using a simple flow system under theoretically estimated glioma and normal brain flow conditions. Secondly, accumulation of nanoparticles via magnetic targeting was evaluated in vivo using 9L-glioma bearing rats. In vitro results that predicted a 7.6-fold increase in nanoparticle capture at glioma- versus contralateral brain-relevant flow rates were relatively consistent with the 9.6-fold glioma selectivity of nanoparticle accumulation over the contralateral brain observed in vivo. Based on these finding, the in vitro ratio of nanoparticle capture can be viewed as a plausible indicator of in vivo glioma selectivity. Overall, it can be concluded that the decreased blood flow rate in glioma, reflecting tumor vascular abnormalities, is an important contributor to glioma-selective nanoparticle accumulation with magnetic targeting.

Neuroplasticity of selective attention: Research foundations and preliminary evidence for a gene by intervention interaction

PubMed Central

Stevens, Courtney; Pakulak, Eric; Hampton Wray, Amanda; Bell, Theodore A.; Neville, Helen J.

2017-01-01

This article reviews the trajectory of our research program on selective attention, which has moved from basic research on the neural processes underlying selective attention to translational studies using selective attention as a neurobiological target for evidence-based interventions. We use this background to present a promising preliminary investigation of how genetic and experiential factors interact during development (i.e., gene × intervention interactions). Our findings provide evidence on how exposure to a family-based training can modify the associations between genotype (5-HTTLPR) and the neural mechanisms of selective attention in preschool children from lower socioeconomic status backgrounds. PMID:28819066

Neuroplasticity of selective attention: Research foundations and preliminary evidence for a gene by intervention interaction.

PubMed

Isbell, Elif; Stevens, Courtney; Pakulak, Eric; Hampton Wray, Amanda; Bell, Theodore A; Neville, Helen J

2017-08-29

This article reviews the trajectory of our research program on selective attention, which has moved from basic research on the neural processes underlying selective attention to translational studies using selective attention as a neurobiological target for evidence-based interventions. We use this background to present a promising preliminary investigation of how genetic and experiential factors interact during development (i.e., gene × intervention interactions). Our findings provide evidence on how exposure to a family-based training can modify the associations between genotype (5-HTTLPR) and the neural mechanisms of selective attention in preschool children from lower socioeconomic status backgrounds.

Improved Frame Mode Selection for AMR-WB+ Based on Decision Tree

NASA Astrophysics Data System (ADS)

Kim, Jong Kyu; Kim, Nam Soo

In this letter, we propose a coding mode selection method for the AMR-WB+ audio coder based on a decision tree. In order to reduce computation while maintaining good performance, decision tree classifier is adopted with the closed loop mode selection results as the target classification labels. The size of the decision tree is controlled by pruning, so the proposed method does not increase the memory requirement significantly. Through an evaluation test on a database covering both speech and music materials, the proposed method is found to achieve a much better mode selection accuracy compared with the open loop mode selection module in the AMR-WB+.

Adaptive block online learning target tracking based on super pixel segmentation

NASA Astrophysics Data System (ADS)

Cheng, Yue; Li, Jianzeng

2018-04-01

Video target tracking technology under the unremitting exploration of predecessors has made big progress, but there are still lots of problems not solved. This paper proposed a new algorithm of target tracking based on image segmentation technology. Firstly we divide the selected region using simple linear iterative clustering (SLIC) algorithm, after that, we block the area with the improved density-based spatial clustering of applications with noise (DBSCAN) clustering algorithm. Each sub-block independently trained classifier and tracked, then the algorithm ignore the failed tracking sub-block while reintegrate the rest of the sub-blocks into tracking box to complete the target tracking. The experimental results show that our algorithm can work effectively under occlusion interference, rotation change, scale change and many other problems in target tracking compared with the current mainstream algorithms.

Domain Adaptation for Pedestrian Detection Based on Prediction Consistency

PubMed Central

Huan-ling, Tang; Zhi-yong, An

2014-01-01

Pedestrian detection is an active area of research in computer vision. It remains a quite challenging problem in many applications where many factors cause a mismatch between source dataset used to train the pedestrian detector and samples in the target scene. In this paper, we propose a novel domain adaptation model for merging plentiful source domain samples with scared target domain samples to create a scene-specific pedestrian detector that performs as well as rich target domain simples are present. Our approach combines the boosting-based learning algorithm with an entropy-based transferability, which is derived from the prediction consistency with the source classifications, to selectively choose the samples showing positive transferability in source domains to the target domain. Experimental results show that our approach can improve the detection rate, especially with the insufficient labeled data in target scene. PMID:25013850

Marine natural products for multi-targeted cancer treatment: A future insight.

PubMed

Kumar, Maushmi S; Adki, Kaveri M

2018-05-30

Cancer is world's second largest alarming disease, which involves abnormal cell growth and have potential to spread to other parts of the body. Most of the available anticancer drugs are designed to act on specific targets by altering the activity of involved transporters and genes. As cancer cells exhibit complex cellular machinery, the regeneration of cancer tissues and chemo resistance towards the therapy has been the main obstacle in cancer treatment. This fact encourages the researchers to explore the multitargeted use of existing medicines to overcome the shortcomings of chemotherapy for alternative and safer treatment strategies. Recent developments in genomics-proteomics and an understanding of the molecular pharmacology of cancer have also challenged researchers to come up with target-based drugs. The literature supports the evidence of natural compounds exhibiting antioxidant, antimitotic, anti-inflammatory, antibiotic as well as anticancer activity. In this review, we have selected marine sponges as a prolific source of bioactive compounds which can be explored for their possible use in cancer and have tried to link their role in cancer pathway. To prove this, we revisited the literature for the selection of cancer genes for the multitargeted use of existing drugs and natural products. We used Cytoscape network analysis and Search tool for retrieval of interacting genes/ proteins (STRING) to study the possible interactions to show the links between the antioxidants, antibiotics, anti-inflammatory and antimitotic agents and their targets for their possible use in cancer. We included total 78 pathways, their genes and natural compounds from the above four pharmacological classes used in cancer treatment for multitargeted approach. Based on the Cytoscape network analysis results, we shortlist 22 genes based on their average shortest path length connecting one node to all other nodes in a network. These selected genes are CDKN2A, FH, VHL, STK11, SUFU, RB1, MEN1, HRPT2, EXT1, 2, CDK4, p14, p16, TSC1, 2, AXIN2, SDBH C, D, NF1, 2, BHD, PTCH, GPC3, CYLD and WT1. The selected genes were analysed using STRING for their protein-protein interactions. Based on the above findings, we propose the selected genes to be considered as major targets and are suggested to be studied for discovering marine natural products as drug lead in cancer treatment. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

A Support Vector Learning-Based Particle Filter Scheme for Target Localization in Communication-Constrained Underwater Acoustic Sensor Networks

PubMed Central

Zhang, Chenglin; Yan, Lei; Han, Song; Guan, Xinping

2017-01-01

Target localization, which aims to estimate the location of an unknown target, is one of the key issues in applications of underwater acoustic sensor networks (UASNs). However, the constrained property of an underwater environment, such as restricted communication capacity of sensor nodes and sensing noises, makes target localization a challenging problem. This paper relies on fractional sensor nodes to formulate a support vector learning-based particle filter algorithm for the localization problem in communication-constrained underwater acoustic sensor networks. A node-selection strategy is exploited to pick fractional sensor nodes with short-distance pattern to participate in the sensing process at each time frame. Subsequently, we propose a least-square support vector regression (LSSVR)-based observation function, through which an iterative regression strategy is used to deal with the distorted data caused by sensing noises, to improve the observation accuracy. At the same time, we integrate the observation to formulate the likelihood function, which effectively update the weights of particles. Thus, the particle effectiveness is enhanced to avoid “particle degeneracy” problem and improve localization accuracy. In order to validate the performance of the proposed localization algorithm, two different noise scenarios are investigated. The simulation results show that the proposed localization algorithm can efficiently improve the localization accuracy. In addition, the node-selection strategy can effectively select the subset of sensor nodes to improve the communication efficiency of the sensor network. PMID:29267252

A Support Vector Learning-Based Particle Filter Scheme for Target Localization in Communication-Constrained Underwater Acoustic Sensor Networks.

PubMed

Li, Xinbin; Zhang, Chenglin; Yan, Lei; Han, Song; Guan, Xinping

2017-12-21

Target localization, which aims to estimate the location of an unknown target, is one of the key issues in applications of underwater acoustic sensor networks (UASNs). However, the constrained property of an underwater environment, such as restricted communication capacity of sensor nodes and sensing noises, makes target localization a challenging problem. This paper relies on fractional sensor nodes to formulate a support vector learning-based particle filter algorithm for the localization problem in communication-constrained underwater acoustic sensor networks. A node-selection strategy is exploited to pick fractional sensor nodes with short-distance pattern to participate in the sensing process at each time frame. Subsequently, we propose a least-square support vector regression (LSSVR)-based observation function, through which an iterative regression strategy is used to deal with the distorted data caused by sensing noises, to improve the observation accuracy. At the same time, we integrate the observation to formulate the likelihood function, which effectively update the weights of particles. Thus, the particle effectiveness is enhanced to avoid "particle degeneracy" problem and improve localization accuracy. In order to validate the performance of the proposed localization algorithm, two different noise scenarios are investigated. The simulation results show that the proposed localization algorithm can efficiently improve the localization accuracy. In addition, the node-selection strategy can effectively select the subset of sensor nodes to improve the communication efficiency of the sensor network.

A novel heterogeneous training sample selection method on space-time adaptive processing

NASA Astrophysics Data System (ADS)

Wang, Qiang; Zhang, Yongshun; Guo, Yiduo

2018-04-01

The performance of ground target detection about space-time adaptive processing (STAP) decreases when non-homogeneity of clutter power is caused because of training samples contaminated by target-like signals. In order to solve this problem, a novel nonhomogeneous training sample selection method based on sample similarity is proposed, which converts the training sample selection into a convex optimization problem. Firstly, the existing deficiencies on the sample selection using generalized inner product (GIP) are analyzed. Secondly, the similarities of different training samples are obtained by calculating mean-hausdorff distance so as to reject the contaminated training samples. Thirdly, cell under test (CUT) and the residual training samples are projected into the orthogonal subspace of the target in the CUT, and mean-hausdorff distances between the projected CUT and training samples are calculated. Fourthly, the distances are sorted in order of value and the training samples which have the bigger value are selective preference to realize the reduced-dimension. Finally, simulation results with Mountain-Top data verify the effectiveness of the proposed method.

Filopodia Conduct Target Selection in Cortical Neurons Using Differences in Signal Kinetics of a Single Kinase.

PubMed

Mao, Yu-Ting; Zhu, Julia X; Hanamura, Kenji; Iurilli, Giuliano; Datta, Sandeep Robert; Dalva, Matthew B

2018-05-16

Dendritic filopodia select synaptic partner axons by interviewing the cell surface of potential targets, but how filopodia decipher the complex pattern of adhesive and repulsive molecular cues to find appropriate contacts is unknown. Here, we demonstrate in cortical neurons that a single cue is sufficient for dendritic filopodia to reject or select specific axonal contacts for elaboration as synaptic sites. Super-resolution and live-cell imaging reveals that EphB2 is located in the tips of filopodia and at nascent synaptic sites. Surprisingly, a genetically encoded indicator of EphB kinase activity, unbiased classification, and a photoactivatable EphB2 reveal that simple differences in the kinetics of EphB kinase signaling at the tips of filopodia mediate the choice between retraction and synaptogenesis. This may enable individual filopodia to choose targets based on differences in the activation rate of a single tyrosine kinase, greatly simplifying the process of partner selection and suggesting a general principle. Copyright © 2018 Elsevier Inc. All rights reserved.

What Can Crystal Structures of Aminergic Receptors Tell Us about Designing Subtype-Selective Ligands?

PubMed Central

Michino, Mayako; Beuming, Thijs; Donthamsetti, Prashant; Newman, Amy Hauck; Javitch, Jonathan A.

2015-01-01

G protein–coupled receptors (GPCRs) are integral membrane proteins that represent an important class of drug targets. In particular, aminergic GPCRs interact with a significant portion of drugs currently on the market. However, most drugs that target these receptors are associated with undesirable side effects, which are due in part to promiscuous interactions with close homologs of the intended target receptors. Here, based on a systematic analysis of all 37 of the currently available high-resolution crystal structures of aminergic GPCRs, we review structural elements that contribute to and can be exploited for designing subtype-selective compounds. We describe the roles of secondary binding pockets (SBPs), as well as differences in ligand entry pathways to the orthosteric binding site, in determining selectivity. In addition, using the available crystal structures, we have identified conformational changes in the SBPs that are associated with receptor activation and explore the implications of these changes for the rational development of selective ligands with tailored efficacy. PMID:25527701

Choice-Based Segmentation as an Enrollment Management Tool

ERIC Educational Resources Information Center

Young, Mark R.

2002-01-01

This article presents an approach to enrollment management based on target marketing strategies developed from a choice-based segmentation methodology. Students are classified into "switchable" or "non-switchable" segments based on their probability of selecting specific majors. A modified multinomial logit choice model is used to identify…

PeptidePicker: a scientific workflow with web interface for selecting appropriate peptides for targeted proteomics experiments.

PubMed

Mohammed, Yassene; Domański, Dominik; Jackson, Angela M; Smith, Derek S; Deelder, André M; Palmblad, Magnus; Borchers, Christoph H

2014-06-25

One challenge in Multiple Reaction Monitoring (MRM)-based proteomics is to select the most appropriate surrogate peptides to represent a target protein. We present here a software package to automatically generate these most appropriate surrogate peptides for an LC/MRM-MS analysis. Our method integrates information about the proteins, their tryptic peptides, and the suitability of these peptides for MRM which is available online in UniProtKB, NCBI's dbSNP, ExPASy, PeptideAtlas, PRIDE, and GPMDB. The scoring algorithm reflects our knowledge in choosing the best candidate peptides for MRM, based on the uniqueness of the peptide in the targeted proteome, its physiochemical properties, and whether it previously has been observed. The modularity of the workflow allows further extension and additional selection criteria to be incorporated. We have developed a simple Web interface where the researcher provides the protein accession number, the subject organism, and peptide-specific options. Currently, the software is designed for human and mouse proteomes, but additional species can be easily be added. Our software improved the peptide selection by eliminating human error, considering multiple data sources and all of the isoforms of the protein, and resulted in faster peptide selection - approximately 50 proteins per hour compared to 8 per day. Compiling a list of optimal surrogate peptides for target proteins to be analyzed by LC/MRM-MS has been a cumbersome process, in which expert researchers retrieved information from different online repositories and used their own reasoning to find the most appropriate peptides. Our scientific workflow automates this process by integrating information from different data sources including UniProt, Global Proteome Machine, NCBI's dbSNP, and PeptideAtlas, simulating the researchers' reasoning, and incorporating their knowledge of how to select the best proteotypic peptides for an MRM analysis. The developed software can help to standardize the selection of peptides, eliminate human error, and increase productivity. Copyright © 2014 Elsevier B.V. All rights reserved.

Attentional selection and suppression in children and adults.

PubMed

Sun, Meirong; Wang, Encong; Huang, Jing; Zhao, Chenguang; Guo, Jialiang; Li, Dongwei; Sun, Li; Du, Boqi; Ding, Yulong; Song, Yan

2018-05-15

The fundamental role of covert spatial attention is to enhance the processing of attended items while simultaneously ignoring irrelevant items. However, relatively little is known about how brain electrophysiological activities associated with target selection and distractor suppression are involved as they develop and become fully functional. The current study aimed to identify the neurophysiological bases of the development of covert spatial attention, focusing on electroencephalographic (EEG) markers of attentional selection (N2pc) and suppression (P D ). EEG data were collected from healthy young adults and typically developing children (9-15 years old) as they searched for a shape singleton target in either the absence or the presence of a salient-but-irrelevant color singleton distractor. The ERP results showed that a lateral shape target elicited a smaller N2pc in children compared with adults regardless of whether a distractor was present or not. Moreover, the target-elicited N2pc was always followed by a similar positivity in both age groups. Counterintuitively, a lateral salient-but-irrelevant distractor elicited a large P D in children with low behavioral accuracy, whereas high-accuracy children exhibited a small and "adult-like" P D . More importantly, we found no evidence for a correlation between the target-elicited N2pc and the distractor-elicited P D in either age group. Our results provide neurophysiological evidence for the developmental differences between target selection and distractor suppression. Compared with adults, 9-15-year-old children deploy insufficient attentional selection resources to targets but use "adult-like" or even more attentional suppression resources to resist irrelevant distractors. A video abstract of this article can be viewed at: https://www.youtube.com/watch?v=NhWapx0d75I. © 2018 John Wiley & Sons Ltd.

Multifunctional gold nanorods for selective plasmonic photothermal therapy in pancreatic cancer cells using ultra-short pulse near-infrared laser irradiation

NASA Astrophysics Data System (ADS)

Patino, Tania; Mahajan, Ujjwal; Palankar, Raghavendra; Medvedev, Nikolay; Walowski, Jakob; Münzenberg, Markus; Mayerle, Julia; Delcea, Mihaela

2015-03-01

Gold nanorods (AuNRs) have attracted considerable attention in plasmonic photothermal therapy for cancer treatment by exploiting their selective and localized heating effect due to their unique photophysical properties. Here we describe a strategy to design a novel multifunctional platform based on AuNRs to: (i) specifically target the adenocarcinoma MUC-1 marker through the use of the EPPT-1 peptide, (ii) enhance cellular uptake through a myristoylated polyarginine peptide (MPAP) and (iii) selectively induce cell death by ultra-short near infrared laser pulses. We used a biotin-avidin based approach to conjugate EPPT-1 and MPAP to AuNRs. Dual-peptide (EPPT-1 + MPAP) labelled AuNRs showed a significantly higher uptake by pancreatic ductal adenocarcinoma cells when compared to their single peptide or avidin conjugated counterparts. In addition, we selectively induced cell death by ultra-short near infrared laser pulses in small target volumes (~1 μm3), through the creation of plasmonic nanobubbles that lead to the destruction of a local cell environment. Our approach opens new avenues for conjugation of multiple ligands on AuNRs targeting cancer cells and tumors and it is relevant for plasmonic photothermal therapy.Gold nanorods (AuNRs) have attracted considerable attention in plasmonic photothermal therapy for cancer treatment by exploiting their selective and localized heating effect due to their unique photophysical properties. Here we describe a strategy to design a novel multifunctional platform based on AuNRs to: (i) specifically target the adenocarcinoma MUC-1 marker through the use of the EPPT-1 peptide, (ii) enhance cellular uptake through a myristoylated polyarginine peptide (MPAP) and (iii) selectively induce cell death by ultra-short near infrared laser pulses. We used a biotin-avidin based approach to conjugate EPPT-1 and MPAP to AuNRs. Dual-peptide (EPPT-1 + MPAP) labelled AuNRs showed a significantly higher uptake by pancreatic ductal adenocarcinoma cells when compared to their single peptide or avidin conjugated counterparts. In addition, we selectively induced cell death by ultra-short near infrared laser pulses in small target volumes (~1 μm3), through the creation of plasmonic nanobubbles that lead to the destruction of a local cell environment. Our approach opens new avenues for conjugation of multiple ligands on AuNRs targeting cancer cells and tumors and it is relevant for plasmonic photothermal therapy. Electronic supplementary information (ESI) available: Size distribution histograms of the hydrodynamic diameter and ζ-potential of functionalized and CTAB stabilized AuNRs. Characterization of TR-AV functionalized AuNRs after 48 h at 4 °C. The ζ-potential of TR-AV functionalized AuNRs and CTAB stabilized AuNRs. The ζ-potential of peptide-conjugated AuNRs in water. See DOI: 10.1039/c5nr00114e

Synthesis and triplex forming properties of pyrimidine derivative containing extended functionality.

PubMed

Gianolio, D A; McLaughlin, L W

1999-08-01

Two pyrimidine nucleosides have been synthesized containing extended hydrogen bonding functionality. In one case the side chain is based upon semicarbazide and in the second monoacetylated carbohydrazide was employed. DNA sequences could be prepared using both analogue nucleosides in a reverse coupling protocol, and provided that the normal capping step was eliminated and that the iodine-based oxidizing solution was replaced with one based upon 10-camphorsulfonyl oxaziridine. Both derivatives exhibited moderate effects in targeting selectively C-G base pairs embedded within a polypurine target sequence.

Adaptive Spatial Filter Based on Similarity Indices to Preserve the Neural Information on EEG Signals during On-Line Processing

PubMed Central

Villa-Parra, Ana Cecilia; Bastos-Filho, Teodiano; López-Delis, Alberto; Frizera-Neto, Anselmo; Krishnan, Sridhar

2017-01-01

This work presents a new on-line adaptive filter, which is based on a similarity analysis between standard electrode locations, in order to reduce artifacts and common interferences throughout electroencephalography (EEG) signals, but preserving the useful information. Standard deviation and Concordance Correlation Coefficient (CCC) between target electrodes and its correspondent neighbor electrodes are analyzed on sliding windows to select those neighbors that are highly correlated. Afterwards, a model based on CCC is applied to provide higher values of weight to those correlated electrodes with lower similarity to the target electrode. The approach was applied to brain computer-interfaces (BCIs) based on Canonical Correlation Analysis (CCA) to recognize 40 targets of steady-state visual evoked potential (SSVEP), providing an accuracy (ACC) of 86.44 ± 2.81%. In addition, also using this approach, features of low frequency were selected in the pre-processing stage of another BCI to recognize gait planning. In this case, the recognition was significantly (p<0.01) improved for most of the subjects (ACC≥74.79%), when compared with other BCIs based on Common Spatial Pattern, Filter Bank-Common Spatial Pattern, and Riemannian Geometry. PMID:29186848

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

Heijkoop, Sabrina T., E-mail: s.heijkoop@erasmusmc.nl; Langerak, Thomas R.; Quint, Sandra

Purpose: To evaluate the clinical implementation of an online adaptive plan-of-the-day protocol for nonrigid target motion management in locally advanced cervical cancer intensity modulated radiation therapy (IMRT). Methods and Materials: Each of the 64 patients had four markers implanted in the vaginal fornix to verify the position of the cervix during treatment. Full and empty bladder computed tomography (CT) scans were acquired prior to treatment to build a bladder volume-dependent cervix-uterus motion model for establishment of the plan library. In the first phase of clinical implementation, the library consisted of one IMRT plan based on a single model-predicted internal targetmore » volume (mpITV), covering the target for the whole pretreatment observed bladder volume range, and a 3D conformal radiation therapy (3DCRT) motion-robust backup plan based on the same mpITV. The planning target volume (PTV) combined the ITV and nodal clinical target volume (CTV), expanded with a 1-cm margin. In the second phase, for patients showing >2.5-cm bladder-induced cervix-uterus motion during planning, two IMRT plans were constructed, based on mpITVs for empty-to-half-full and half-full-to-full bladder. In both phases, a daily cone beam CT (CBCT) scan was acquired to first position the patient based on bony anatomy and nodal targets and then select the appropriate plan. Daily post-treatment CBCT was used to verify plan selection. Results: Twenty-four and 40 patients were included in the first and second phase, respectively. In the second phase, 11 patients had two IMRT plans. Overall, an IMRT plan was used in 82.4% of fractions. The main reasons for selecting the motion-robust backup plan were uterus outside the PTV (27.5%) and markers outside their margin (21.3%). In patients with two IMRT plans, the half-full-to-full bladder plan was selected on average in 45% of the first 12 fractions, which was reduced to 35% in the last treatment fractions. Conclusions: The implemented online adaptive plan-of-the-day protocol for locally advanced cervical cancer enables (almost) daily tissue-sparing IMRT.« less

Does Angling Technique Selectively Target Fishes Based on Their Behavioural Type?

PubMed Central

Wilson, Alexander D. M.; Brownscombe, Jacob W.; Sullivan, Brittany; Jain-Schlaepfer, Sofia; Cooke, Steven J.

2015-01-01

Recently, there has been growing recognition that fish harvesting practices can have important impacts on the phenotypic distributions and diversity of natural populations through a phenomenon known as fisheries-induced evolution. Here we experimentally show that two common recreational angling techniques (active crank baits versus passive soft plastics) differentially target wild largemouth bass (Micropterus salmoides) and rock bass (Ambloplites rupestris) based on variation in their behavioural tendencies. Fish were first angled in the wild using both techniques and then brought back to the laboratory and tested for individual-level differences in common estimates of personality (refuge emergence, flight-initiation-distance, latency-to-recapture and with a net, and general activity) in an in-lake experimental arena. We found that different angling techniques appear to selectively target these species based on their boldness (as characterized by refuge emergence, a standard measure of boldness in fishes) but not other assays of personality. We also observed that body size was independently a significant predictor of personality in both species, though this varied between traits and species. Our results suggest a context-dependency for vulnerability to capture relative to behaviour in these fish species. Ascertaining the selective pressures angling practices exert on natural populations is an important area of fisheries research with significant implications for ecology, evolution, and resource management. PMID:26284779

Identification of potential isoform-selective histone deacetylase inhibitors for cancer therapy: a combined approach of structure-based virtual screening, ADMET prediction and molecular dynamics simulation assay.

PubMed

Uba, Abdullahi Ibrahim; Yelekçi, Kemal

2017-10-23

Histone deacetylases (HDACs) have gained increased attention as targets for anticancer drug design and development. HDAC inhibitors have proven to be effective for reversing the malignant phenotype in HDAC-dependent cancer cases. However, lack of selectivity of the many HDAC inhibitors in clinical use and trials contributes to toxicities to healthy cells. It is believed that, the continued identification of isoform-selective inhibitors will eliminate these undesirable adverse effects - a task that remains a major challenge to HDAC inhibitor designs. Here, in an attempt to identify isoform-selective inhibitors, a large compound library containing 2,703,000 compounds retrieved from Otava database was screened against class I HDACs by exhaustive approach of structure-based virtual screening using rDOCK and Autodock Vina. A total of 41 compounds were found to show high-isoform selectivity and were further redocked into their respective targets using Autodock4. Thirty-six compounds showed remarkable isoform selectivity and passed drug-likeness and absorption, distribution, metabolism, elimination and toxicity prediction tests using ADMET Predictor™ and admetSAR. Furthermore, to study the stability of ligand binding modes, 10 ns-molecular dynamics (MD) simulations of the free HDAC isoforms and their complexes with respective best-ranked ligands were performed using nanoscale MD software. The inhibitors remained bound to their respective targets over time of the simulation and the overall potential energy, root-mean-square deviation, root-mean-square fluctuation profiles suggested that the detected compounds may be potential isoform-selective HDAC inhibitors or serve as promising scaffolds for further optimization towards the design of selective inhibitors for cancer therapy.

Bacterial fatty acid metabolism in modern antibiotic discovery.

PubMed

Yao, Jiangwei; Rock, Charles O

2017-11-01

Bacterial fatty acid synthesis is essential for many pathogens and different from the mammalian counterpart. These features make bacterial fatty acid synthesis a desirable target for antibiotic discovery. The structural divergence of the conserved enzymes and the presence of different isozymes catalyzing the same reactions in the pathway make bacterial fatty acid synthesis a narrow spectrum target rather than the traditional broad spectrum target. Furthermore, bacterial fatty acid synthesis inhibitors are single-targeting, rather than multi-targeting like traditional monotherapeutic, broad-spectrum antibiotics. The single-targeting nature of bacterial fatty acid synthesis inhibitors makes overcoming fast-developing, target-based resistance a necessary consideration for antibiotic development. Target-based resistance can be overcome through multi-targeting inhibitors, a cocktail of single-targeting inhibitors, or by making the single targeting inhibitor sufficiently high affinity through a pathogen selective approach such that target-based mutants are still susceptible to therapeutic concentrations of drug. Many of the pathogens requiring new antibiotic treatment options encode for essential bacterial fatty acid synthesis enzymes. This review will evaluate the most promising targets in bacterial fatty acid metabolism for antibiotic therapeutics development and review the potential and challenges in advancing each of these targets to the clinic and circumventing target-based resistance. This article is part of a Special Issue entitled: Bacterial Lipids edited by Russell E. Bishop. Copyright © 2016 Elsevier B.V. All rights reserved.

Centroid tracker and aimpoint selection

NASA Astrophysics Data System (ADS)

Venkateswarlu, Ronda; Sujata, K. V.; Venkateswara Rao, B.

1992-11-01

Autonomous fire and forget weapons have gained importance to achieve accurate first pass kill by hitting the target at an appropriate aim point. Centroid of the image presented by a target in the field of view (FOV) of a sensor is generally accepted as the aimpoint for these weapons. Centroid trackers are applicable only when the target image is of significant size in the FOV of the sensor but does not overflow the FOV. But as the range between the sensor and the target decreases the image of the target will grow and finally overflow the FOV at close ranges and the centroid point on the target will keep on changing which is not desirable. And also centroid need not be the most desired/vulnerable point on the target. For hardened targets like tanks, proper aimpoint selection and guidance up to almost zero range is essential to achieve maximum kill probability. This paper presents a centroid tracker realization. As centroid offers a stable tracking point, it can be used as a reference to select the proper aimpoint. The centroid and the desired aimpoint are simultaneously tracked to avoid jamming by flares and also to take care of the problems arising due to image overflow. Thresholding of gray level image to binary image is a crucial step in centroid tracker. Different thresholding algorithms are discussed and a suitable algorithm is chosen. The real-time hardware implementation of centroid tracker with a suitable thresholding technique is presented including the interfacing to a multimode tracker for autonomous target tracking and aimpoint selection. The hardware uses very high speed arithmetic and programmable logic devices to meet the speed requirement and a microprocessor based subsystem for the system control. The tracker has been evaluated in a field environment.

Lateral position detection and control for friction stir systems

DOEpatents

Fleming, Paul; Lammlein, David H.; Cook, George E.; Wilkes, Don Mitchell; Strauss, Alvin M.; Delapp, David R.; Hartman, Daniel A.

2012-06-05

An apparatus and computer program are disclosed for processing at least one workpiece using a rotary tool with rotating member for contacting and processing the workpiece. The methods include oscillating the rotary tool laterally with respect to a selected propagation path for the rotating member with respect to the workpiece to define an oscillation path for the rotating member. The methods further include obtaining force signals or parameters related to the force experienced by the rotary tool at least while the rotating member is disposed at the extremes of the oscillation. The force signals or parameters associated with the extremes can then be analyzed to determine a lateral position of the selected path with respect to a target path and a lateral offset value can be determined based on the lateral position. The lateral distance between the selected path and the target path can be decreased based on the lateral offset value.

Lateral position detection and control for friction stir systems

DOEpatents

Fleming, Paul [Boulder, CO; Lammlein, David H [Houston, TX; Cook, George E [Brentwood, TN; Wilkes, Don Mitchell [Nashville, TN; Strauss, Alvin M [Nashville, TN; Delapp, David R [Ashland City, TN; Hartman, Daniel A [Fairhope, AL

2011-11-08

Friction stir methods are disclosed for processing at least one workpiece using a rotary tool with rotating member for contacting and processing the workpiece. The methods include oscillating the rotary tool laterally with respect to a selected propagation path for the rotating member with respect to the workpiece to define an oscillation path for the rotating member. The methods further include obtaining force signals or parameters related to the force experienced by the rotary tool at least while the rotating member is disposed at the extremes of the oscillation. The force signals or parameters associated with the extremes can then be analyzed to determine a lateral position of the selected path with respect to a target path and a lateral offset value can be determined based on the lateral position. The lateral distance between the selected path and the target path can be decreased based on the lateral offset value.

Target-matched insertion gain derived from three different hearing aid selection procedures.

PubMed

Punch, J L; Shovels, A H; Dickinson, W W; Calder, J H; Snead, C

1995-11-01

Three hearing aid selection procedures were compared to determine if any one was superior in producing prescribed real-ear insertion gain. For each of three subject groups, 12 in-the-ear style hearing aids with Class D circuitry and similar dispenser controls were ordered from one of three manufacturers. Subject groups were classified based on the type of information included on the hearing aid order form: (1) the subject's audiogram, (2) a three-part matrix specifying the desired maximum output, full-on gain, and frequency response slope of the hearing aid, or (3) the desired 2-cc coupler full-in grain of the hearing aid, based on real-ear coupler difference (RECD) measurements. Following electroacoustic adjustments aimed at approximating a commonly used target insertion gain formula, results revealed no significant differences among any of the three selection procedures with respect to obtaining acceptable insertion gain values.

Evaluating complementary networks of restoration plantings for landscape-scale occurrence of temporally dynamic species.

PubMed

Ikin, Karen; Tulloch, Ayesha; Gibbons, Philip; Ansell, Dean; Seddon, Julian; Lindenmayer, David

2016-10-01

Multibillion dollar investments in land restoration make it critical that conservation goals are achieved cost-effectively. Approaches developed for systematic conservation planning offer opportunities to evaluate landscape-scale, temporally dynamic biodiversity outcomes from restoration and improve on traditional approaches that focus on the most species-rich plantings. We investigated whether it is possible to apply a complementarity-based approach to evaluate the extent to which an existing network of restoration plantings meets representation targets. Using a case study of woodland birds of conservation concern in southeastern Australia, we compared complementarity-based selections of plantings based on temporally dynamic species occurrences with selections based on static species occurrences and selections based on ranking plantings by species richness. The dynamic complementarity approach, which incorporated species occurrences over 5 years, resulted in higher species occurrences and proportion of targets met compared with the static complementarity approach, in which species occurrences were taken at a single point in time. For equivalent cost, the dynamic complementarity approach also always resulted in higher average minimum percent occurrence of species maintained through time and a higher proportion of the bird community meeting representation targets compared with the species-richness approach. Plantings selected under the complementarity approaches represented the full range of planting attributes, whereas those selected under the species-richness approach were larger in size. Our results suggest that future restoration policy should not attempt to achieve all conservation goals within individual plantings, but should instead capitalize on restoration opportunities as they arise to achieve collective value of multiple plantings across the landscape. Networks of restoration plantings with complementary attributes of age, size, vegetation structure, and landscape context lead to considerably better outcomes than conventional restoration objectives of site-scale species richness and are crucial for allocating restoration investment wisely to reach desired conservation goals. © 2016 Society for Conservation Biology.

Controlling the Growth of Future LEO Debris Populations with Active Debris Removal

NASA Technical Reports Server (NTRS)

Liou, J.-C.; Johnson, N. L.; Hill, N. M.

2008-01-01

Active debris removal (ADR) was suggested as a potential means to remediate the low Earth orbit (LEO) debris environment as early as the 1980s. The reasons ADR has not become practical are due to its technical difficulties and the high cost associated with the approach. However, as the LEO debris populations continue to increase, ADR may be the only option to preserve the near-Earth environment for future generations. An initial study was completed in 2007 to demonstrate that a simple ADR target selection criterion could be developed to reduce the future debris population growth. The present paper summarizes a comprehensive study based on more realistic simulation scenarios, including fragments generated from the 2007 Fengyun-1C event, mitigation measures, and other target selection options. The simulations were based on the NASA long-term orbital debris projection model, LEGEND. A scenario, where at the end of mission lifetimes, spacecraft and upper stages were moved to 25-year decay orbits, was adopted as the baseline environment for comparison. Different annual removal rates and different ADR target selection criteria were tested, and the resulting 200-year future environment projections were compared with the baseline scenario. Results of this parametric study indicate that (1) an effective removal strategy can be developed based on the mass and collision probability of each object as the selection criterion, and (2) the LEO environment can be stabilized in the next 200 years with an ADR removal rate of five objects per year.

Category-based guidance of spatial attention during visual search for feature conjunctions.

PubMed

Nako, Rebecca; Grubert, Anna; Eimer, Martin

2016-10-01

The question whether alphanumerical category is involved in the control of attentional target selection during visual search remains a contentious issue. We tested whether category-based attentional mechanisms would guide the allocation of attention under conditions where targets were defined by a combination of alphanumerical category and a basic visual feature, and search displays could contain both targets and partially matching distractor objects. The N2pc component was used as an electrophysiological marker of attentional object selection in tasks where target objects were defined by a conjunction of color and category (Experiment 1) or shape and category (Experiment 2). Some search displays contained the target or a nontarget object that matched either the target color/shape or its category among 3 nonmatching distractors. In other displays, the target and a partially matching nontarget object appeared together. N2pc components were elicited not only by targets and by color- or shape-matching nontargets, but also by category-matching nontarget objects, even on trials where a target was present in the same display. On these trials, the summed N2pc components to the 2 types of partially matching nontargets were initially equal in size to the target N2pc, suggesting that attention was allocated simultaneously and independently to all objects with target-matching features during the early phase of attentional processing. Results demonstrate that alphanumerical category is a genuine guiding feature that can operate in parallel with color or shape information to control the deployment of attention during visual search. (PsycINFO Database Record (c) 2016 APA, all rights reserved).

Miklós Bodanszky Award Lecture: Advances in the selective targeting of protein phosphatase‐1 and phosphatase‐2A with peptides

PubMed Central

2017-01-01

Protein phosphatase‐1 and phosphatase‐2A are two ubiquitously expressed enzymes known to catalyze the majority of dephosphorylation reactions on serine and threonine inside cells. They play roles in most cellular processes and are tightly regulated by regulatory subunits in holoenzymes. Their misregulation and malfunction contribute to disease development and progression, such as in cancer, diabetes, viral infections, and neurological as well as heart diseases. Therefore, targeting these phosphatases for therapeutic use would be highly desirable; however, their complex regulation and high conservation of the active site have been major hurdles for selectively targeting them in the past. In the last decade, new approaches have been developed to overcome these hurdles and have strongly revived the field. I will focus here on peptide‐based approaches, which contributed to showing that these phosphatases can be targeted selectively and aided in rethinking the design of selective phosphatase modulators. Finally, I will give a perspective on www.depod.org, the human dephosphorylation database, and how it can aid phosphatase modulator design. © 2017 The Authors. Journal of Peptide Science published by European Peptide Society and John Wiley & Sons Ltd. PMID:28876538

Reversibly Switchable, pH-Dependent Peptide Ligand Binding via 3,5-Diiodotyrosine Substitutions.

PubMed

Ngambenjawong, Chayanon; Sylvestre, Meilyn; Gustafson, Heather H; Pineda, Julio Marco B; Pun, Suzie H

2018-04-20

Cell type-specific targeting ligands utilized in drug delivery applications typically recognize receptors that are overexpressed on the cells of interest. Nonetheless, these receptors may also be expressed, to varying extents, on off-target cells, contributing to unintended side effects. For the selectivity profile of targeting ligands in cancer therapy to be improved, stimuli-responsive masking of these ligands with acid-, redox-, or enzyme-cleavable molecules has been reported, whereby the targeting ligands are exposed in specific environments, e.g., acidic tumor hypoxia. One possible drawback of these systems lies in their one-time, permanent trigger, which enables the "demasked" ligands to bind off-target cells if released back into the systemic circulation. A promising strategy to address the aforementioned problem is to design ligands that show selective binding based on ionization state, which may be microenvironment-dependent. In this study, we report a systematic strategy to engineer low pH-selective targeting peptides using an M2 macrophage-targeting peptide (M2pep) as an example. 3,5-Diiodotyrosine mutagenesis into native tyrosine residues of M2pep confers pH-dependent binding behavior specific to acidic environment (pH 6) when the amino acid is protonated into the native tyrosine-like state. At physiological pH of 7.4, the hydroxyl group of 3,5-diiodotyrosine on the peptide is deprotonated leading to interruption of the peptide native binding property. Our engineered pH-responsive M2pep (Ac-Y-Î-Î) binds target M2 macrophages more selectively at pH 6 than at pH 7.4. In addition, 3,5-diiodotyrosine substitutions also improve serum stability of the peptide. Finally, we demonstrate pH-dependent reversibility in target binding via a postbinding peptide elution study. The strategy presented here should be applicable for engineering pH-dependent functionality of other targeting peptides with potential applications in physiology-dependent in vivo targeting applications (e.g., targeting hypoxic tumor/inflammation) or in in vitro receptor identification.

Measured Visual Motion Sensitivity at Fixed Contrast in the Periphery and Far Periphery

DTIC Science & Technology

2017-08-01

group Soldier performance. Soldier performance depends on visual detection of enemy personnel and materiel. Vision modeling in IWARS is neither...a highly time-critical and order- dependent activity, these unrealistic characterizations of target detection time and order severely limit the...recognize that MVTs should depend on target contrast, so we selected a target design different from that used in the Monaco et al. (2007) study. Based

Development of MRM-based assays for the absolute quantitation of plasma proteins.

PubMed

Kuzyk, Michael A; Parker, Carol E; Domanski, Dominik; Borchers, Christoph H

2013-01-01

Multiple reaction monitoring (MRM), sometimes called selected reaction monitoring (SRM), is a directed tandem mass spectrometric technique performed on to triple quadrupole mass spectrometers. MRM assays can be used to sensitively and specifically quantify proteins based on peptides that are specific to the target protein. Stable-isotope-labeled standard peptide analogues (SIS peptides) of target peptides are added to enzymatic digests of samples, and quantified along with the native peptides during MRM analysis. Monitoring of the intact peptide and a collision-induced fragment of this peptide (an ion pair) can be used to provide information on the absolute peptide concentration of the peptide in the sample and, by inference, the concentration of the intact protein. This technique provides high specificity by selecting for biophysical parameters that are unique to the target peptides: (1) the molecular weight of the peptide, (2) the generation of a specific fragment from the peptide, and (3) the HPLC retention time during LC/MRM-MS analysis. MRM is a highly sensitive technique that has been shown to be capable of detecting attomole levels of target peptides in complex samples such as tryptic digests of human plasma. This chapter provides a detailed description of how to develop and use an MRM protein assay. It includes sections on the critical "first step" of selecting the target peptides, as well as optimization of MRM acquisition parameters for maximum sensitivity of the ion pairs that will be used in the final method, and characterization of the final MRM assay.

Parallel Reaction Monitoring: A Targeted Experiment Performed Using High Resolution and High Mass Accuracy Mass Spectrometry

PubMed Central

Rauniyar, Navin

2015-01-01

The parallel reaction monitoring (PRM) assay has emerged as an alternative method of targeted quantification. The PRM assay is performed in a high resolution and high mass accuracy mode on a mass spectrometer. This review presents the features that make PRM a highly specific and selective method for targeted quantification using quadrupole-Orbitrap hybrid instruments. In addition, this review discusses the label-based and label-free methods of quantification that can be performed with the targeted approach. PMID:26633379

Development of a microcapillary column for detecting targeted messenger RNA molecules.

PubMed

Ohnishi, Michihiro

2006-03-24

A capillary column in a rapid-flow system has been developed for detecting targeted messenger RNA (mRNA) molecules. The column has a structure made of two beds-one bed of porous microbeads and one bed of microbeads with a polythymidine base sequence. The targeted eukaryotic mRNA molecules are detected by two-step hybridization (sandwich hybridization) composed of polyadenosine selection of mRNA molecules and formation of a probe-target (targeted mRNA) hybrid. The sandwich hybridization, which is accomplished within 1 h, was tested using synthetic polydeoxynucleotides. Ten picomoles of the targeted polydeoxynucleotide were detected.

Assay Development Process | Office of Cancer Clinical Proteomics Research

Cancer.gov

Typical steps involved in the development of a  mass spectrometry-based targeted assay include: (1) selection of surrogate or signature peptides corresponding to the targeted protein or modification of interest; (2) iterative optimization of instrument and method parameters for optimal detection of the selected peptide; (3) method development for protein extraction from biological matrices such as tissue, whole cell lysates, or blood plasma/serum and proteolytic digestion of proteins (usually with trypsin); (4) evaluation of the assay in the intended biological matrix to determine if e

Structure-Based Identification of Inhibitory Fragments Targeting the p300/CBP-Associated Factor Bromodomain

PubMed Central

2016-01-01

The P300/CBP-associated factor plays a central role in retroviral infection and cancer development, and the C-terminal bromodomain provides an opportunity for selective targeting. Here, we report several new classes of acetyl-lysine mimetic ligands ranging from mM to low micromolar affinity that were identified using fragment screening approaches. The binding modes of the most attractive fragments were determined using high resolution crystal structures providing chemical starting points and structural models for the development of potent and selective PCAF inhibitors. PMID:26731131

Indolyl Azaspiroketal Mannich Bases Are Potent Antimycobacterial Agents with Selective Membrane Permeabilizing Effects and in Vivo Activity.

PubMed

Nyantakyi, Samuel Agyei; Li, Ming; Gopal, Pooja; Zimmerman, Matthew; Dartois, Véronique; Gengenbacher, Martin; Dick, Thomas; Go, Mei-Lin

2018-06-25

The inclusion of an azaspiroketal Mannich base in the membrane targeting antitubercular 6-methoxy-1- n-octyl-1 H-indole scaffold resulted in analogs with improved selectivity and submicromolar activity against Mycobacterium tuberculosis H37Rv. The potency enhancing properties of the spiro-fused ring motif was affirmed by SAR and validated in a mouse model of tuberculosis. As expected for membrane inserting agents, the indolyl azaspiroketal Mannich bases perturbed phospholipid vesicles, permeabilized bacterial cells, and induced the mycobacterial cell envelope stress reporter promoter p iniBAC. Surprisingly, their membrane disruptive effects did not appear to be associated with bacterial membrane depolarization. This profile was not uniquely associated with azaspiroketal Mannich bases but was characteristic of indolyl Mannich bases as a class. Whereas resistant mycobacteria could not be isolated for a less potent indolyl Mannich base, the more potent azaspiroketal analog displayed low spontaneous resistance mutation frequency of 10 -8 /CFU. This may indicate involvement of an additional envelope-related target in its mechanism of action.

Specific and selective target detection of supra-genome 21 Mers Salmonella via silicon nanowires biosensor

NASA Astrophysics Data System (ADS)

Mustafa, Mohammad Razif Bin; Dhahi, Th S.; Ehfaed, Nuri. A. K. H.; Adam, Tijjani; Hashim, U.; Azizah, N.; Mohammed, Mohammed; Noriman, N. Z.

2017-09-01

The nano structure based on silicon can be surface modified to be used as label-free biosensors that allow real-time measurements. The silicon nanowire surface was functionalized using 3-aminopropyltrimethoxysilane (APTES), which functions as a facilitator to immobilize biomolecules on the silicon nanowire surface. The process is simple, economical; this will pave the way for point-of-care applications. However, the surface modification and subsequent detection mechanism still not clear. Thus, study proposed step by step process of silicon nano surface modification and its possible in specific and selective target detection of Supra-genome 21 Mers Salmonella. The device captured the molecule with precisely; the approach took the advantages of strong binding chemistry created between APTES and biomolecule. The results indicated how modifications of the nanowires provide sensing capability with strong surface chemistries that can lead to specific and selective target detection.

A community-engaged approach to select geographic areas for interventions to reduce health disparities.

PubMed

Cromley, Ellen; Kleinman, Lawrence C; Ramos, Michelle A; Arniella, Guedy; Viswanathan, Nalini; Garel, Mischka; Horowitz, Carol R

2011-01-01

While neighborhood-based approaches to eliminate health disparities are on the rise, there is little guidance on how researchers may engage with community partners to select geographic areas for interventions to reduce health disparities. We aimed to identify a small geographic area to target interventions to improve diabetes-related outcomes. We describe lessons learned from a community-engaged approach to specify the geographic area of focus. A community-academic partnership of more than 20 organizations collaborated to develop and employ a 5-stage process to specify a target area for diabetes preventions and control activities. A coalition with local knowledge and ties to the community can develop criteria and direct a process leading to selection of a geographic area, increased research capacity, and strengthened relationships among partners. A participatory approach can be effective in defining a geographic area for targeting interventions to reduce health disparities.

Selection of DNA aptamers against Human Cardiac Troponin I for colorimetric sensor based dot blot application.

PubMed

Dorraj, Ghamar Soltan; Rassaee, Mohammad Javad; Latifi, Ali Mohammad; Pishgoo, Bahram; Tavallaei, Mahmood

2015-08-20

Troponin T and I are ideal markers which are highly sensitive and specific for myocardial injury and have shown better efficacy than earlier markers. Since aptamers are ssDNA or RNA that bind to a wide variety of target molecules, the purpose of this research was to select an aptamer from a 79bp single-stranded DNA (ssDNA) random library that was used to bind the Human Cardiac Troponin I from a synthetic nucleic acids library by systematic evolution of ligands exponential enrichment (Selex) based on several selection and amplification steps. Human Cardiac Troponin I protein was coated onto the surface of streptavidin magnetic beads to extract specific aptamer from a large and diverse random ssDNA initial oligonucleotide library. As a result, several aptamers were selected and further examined for binding affinity and specificity. Finally TnIApt 23 showed beast affinity in nanomolar range (2.69nM) toward the target protein. A simple and rapid colorimetric detection assay for Human Cardiac Troponin I using the novel and specific aptamer-AuNPs conjugates based on dot blot assay was developed. The detection limit for this protein using aptamer-AuNPs-based assay was found to be 5ng/ml. Copyright © 2015 Elsevier B.V. All rights reserved.

Prediction-based Dynamic Energy Management in Wireless Sensor Networks

PubMed Central

Wang, Xue; Ma, Jun-Jie; Wang, Sheng; Bi, Dao-Wei

2007-01-01

Energy consumption is a critical constraint in wireless sensor networks. Focusing on the energy efficiency problem of wireless sensor networks, this paper proposes a method of prediction-based dynamic energy management. A particle filter was introduced to predict a target state, which was adopted to awaken wireless sensor nodes so that their sleep time was prolonged. With the distributed computing capability of nodes, an optimization approach of distributed genetic algorithm and simulated annealing was proposed to minimize the energy consumption of measurement. Considering the application of target tracking, we implemented target position prediction, node sleep scheduling and optimal sensing node selection. Moreover, a routing scheme of forwarding nodes was presented to achieve extra energy conservation. Experimental results of target tracking verified that energy-efficiency is enhanced by prediction-based dynamic energy management.

Research on filter’s parameter selection based on PROMETHEE method

NASA Astrophysics Data System (ADS)

Zhu, Hui-min; Wang, Hang-yu; Sun, Shi-yan

2018-03-01

The selection of filter’s parameters in target recognition was studied in this paper. The PROMETHEE method was applied to the optimization problem of Gabor filter parameters decision, the correspondence model of the elemental relation between two methods was established. The author took the identification of military target as an example, problem about the filter’s parameter decision was simulated and calculated by PROMETHEE. The result showed that using PROMETHEE method for the selection of filter’s parameters was more scientific. The human disturbance caused by the experts method and empirical method could be avoided by this way. The method can provide reference for the parameter configuration scheme decision of the filter.

Targeting the undruggable: Advances and obstacles in current RNAi therapy

PubMed Central

Wu, Sherry Y.; Lopez-Berestein, Gabriel; Calin, George A.; Sood, Anil K.

2014-01-01

RNA interference (RNAi) therapeutics represents a rapidly emerging platform for personalized cancer treatment. Recent advances in delivery, target selection, and safety of RNAi cancer therapy provide unprecedented opportunities for clinical translation. Here, we discuss these advances and present strategies for making RNAi-based therapy a viable part of cancer management. PMID:24920658

Rule of five in 2015 and beyond: Target and ligand structural limitations, ligand chemistry structure and drug discovery project decisions.

PubMed

Lipinski, Christopher A

2016-06-01

The rule of five (Ro5), based on physicochemical profiles of phase II drugs, is consistent with structural limitations in protein targets and the drug target ligands. Three of four parameters in Ro5 are fundamental to the structure of both target and drug binding sites. The chemical structure of the drug ligand depends on the ligand chemistry and design philosophy. Two extremes of chemical structure and design philosophy exist; ligands constructed in the medicinal chemistry synthesis laboratory without input from natural selection and natural product (NP) metabolites biosynthesized based on evolutionary selection. Exceptions to Ro5 are found mostly among NPs. Chemistry chameleon-like behavior of some NPs due to intra-molecular hydrogen bonding as exemplified by cyclosporine A is a strong contributor to NP Ro5 outliers. The fragment derived, drug Navitoclax is an example of the extensive expertise, resources, time and key decisions required for the rare discovery of a non-NP Ro5 outlier. Copyright © 2016 Elsevier B.V. All rights reserved.

Application of target costing in machining

NASA Astrophysics Data System (ADS)

Gopalakrishnan, Bhaskaran; Kokatnur, Ameet; Gupta, Deepak P.

2004-11-01

In today's intensely competitive and highly volatile business environment, consistent development of low cost and high quality products meeting the functionality requirements is a key to a company's survival. Companies continuously strive to reduce the costs while still producing quality products to stay ahead in the competition. Many companies have turned to target costing to achieve this objective. Target costing is a structured approach to determine the cost at which a proposed product, meeting the quality and functionality requirements, must be produced in order to generate the desired profits. It subtracts the desired profit margin from the company's selling price to establish the manufacturing cost of the product. Extensive literature review revealed that companies in automotive, electronic and process industries have reaped the benefits of target costing. However target costing approach has not been applied in the machining industry, but other techniques based on Geometric Programming, Goal Programming, and Lagrange Multiplier have been proposed for application in this industry. These models follow a forward approach, by first selecting a set of machining parameters, and then determining the machining cost. Hence in this study we have developed an algorithm to apply the concepts of target costing, which is a backward approach that selects the machining parameters based on the required machining costs, and is therefore more suitable for practical applications in process improvement and cost reduction. A target costing model was developed for turning operation and was successfully validated using practical data.

Directed evolution of the TALE N-terminal domain for recognition of all 5' bases.

PubMed

Lamb, Brian M; Mercer, Andrew C; Barbas, Carlos F

2013-11-01

Transcription activator-like effector (TALE) proteins can be designed to bind virtually any DNA sequence. General guidelines for design of TALE DNA-binding domains suggest that the 5'-most base of the DNA sequence bound by the TALE (the N0 base) should be a thymine. We quantified the N0 requirement by analysis of the activities of TALE transcription factors (TALE-TF), TALE recombinases (TALE-R) and TALE nucleases (TALENs) with each DNA base at this position. In the absence of a 5' T, we observed decreases in TALE activity up to >1000-fold in TALE-TF activity, up to 100-fold in TALE-R activity and up to 10-fold reduction in TALEN activity compared with target sequences containing a 5' T. To develop TALE architectures that recognize all possible N0 bases, we used structure-guided library design coupled with TALE-R activity selections to evolve novel TALE N-terminal domains to accommodate any N0 base. A G-selective domain and broadly reactive domains were isolated and characterized. The engineered TALE domains selected in the TALE-R format demonstrated modularity and were active in TALE-TF and TALEN architectures. Evolved N-terminal domains provide effective and unconstrained TALE-based targeting of any DNA sequence as TALE binding proteins and designer enzymes.

Simple Monitoring of Gene Targeting Efficiency in Human Somatic Cell Lines Using the PIGA Gene

PubMed Central

Karnan, Sivasundaram; Konishi, Yuko; Ota, Akinobu; Takahashi, Miyuki; Damdindorj, Lkhagvasuren; Hosokawa, Yoshitaka; Konishi, Hiroyuki

2012-01-01

Gene targeting in most of human somatic cell lines has been labor-intensive because of low homologous recombination efficiency. The development of an experimental system that permits a facile evaluation of gene targeting efficiency in human somatic cell lines is the first step towards the improvement of this technology and its application to a broad range of cell lines. In this study, we utilized phosphatidylinositol glycan anchor biosynthesis class A (PIGA), a gene essential for the synthesis of glycosylphosphatidyl inositol (GPI) anchors, as a reporter of gene targeting events in human somatic cell lines. Targeted disruption of PIGA was quantitatively detected with FLAER, a reagent that specifically binds to GPI anchors. Using this PIGA-based reporter system, we successfully detected adeno-associated virus (AAV)-mediated gene targeting events both with and without promoter-trap enrichment of gene-targeted cell population. The PIGA-based reporter system was also capable of reproducing previous findings that an AAV-mediated gene targeting achieves a remarkably higher ratio of homologous versus random integration (H/R ratio) of targeting vectors than a plasmid-mediated gene targeting. The PIGA-based system also detected an approximately 2-fold increase in the H/R ratio achieved by a small negative selection cassette introduced at the end of the AAV-based targeting vector with a promoter-trap system. Thus, our PIGA-based system is useful for monitoring AAV-mediated gene targeting and will assist in improving gene targeting technology in human somatic cell lines. PMID:23056640

A novel 9 × 9 map-based solvent selection strategy for targeted counter-current chromatography isolation of natural products.

PubMed

Liang, Junling; Meng, Jie; Wu, Dingfang; Guo, Mengzhe; Wu, Shihua

2015-06-26

Counter-current chromatography (CCC) is an efficient liquid-liquid chromatography technique for separation and purification of complex mixtures like natural products extracts and synthetic chemicals. However, CCC is still a challenging process requiring some special technical knowledge especially in the selection of appropriated solvent systems. In this work, we introduced a new 9 × 9 map-based solvent selection strategy for CCC isolation of targets, which permit more than 60 hexane-ethyl acetate-methanol-water (HEMWat) solvent systems as the start candidates for the selection of solvent systems. Among these solvent systems, there are clear linear correlations between partition coefficient (K) and the system numbers. Thus, an appropriate CCC solvent system (i.e., sweet spot for K = 1) may be hit by measurement of k values of the target only in two random solvent systems. Besides this, surprisingly, we found that through two sweet spots, we could get a line ("Sweet line") where there are infinite sweet solvent systems being suitable for CCC separation. In these sweet solvent systems, the target has the same partition coefficient (K) but different solubilities. Thus, the better sweet solvent system with higher sample solubility can be obtained for high capacity CCC preparation. Furthermore, we found that there is a zone ("Sweet zone") where all solvent systems have their own sweet partition coefficients values for the target in range of 0.4 < K< 2.5 or extended range of 0.25 < K < 16. All results were validated by using 14 pure GUESSmix mimic natural products as standards and further confirmed by isolation of several targets including honokiol and magnolol from the extracts of Magnolia officinalis Rehd. Et Wils and tanshinone IIA from Salvia miltiorrhiza Bunge. In practice, it is much easier to get a suitable solvent system only by making a simple screening two to four HEMWat two-phase solvent systems to obtain the sweet line or sweet zone without special knowledge or comprehensive standards as references. This is an important advancement for solvent system selection and also will be very useful for isolation of current natural products including Traditional Chinese Medicines. Copyright © 2015 Elsevier B.V. All rights reserved.

Selective robust optimization: A new intensity-modulated proton therapy optimization strategy

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

Li, Yupeng; Niemela, Perttu; Siljamaki, Sami

2015-08-15

Purpose: To develop a new robust optimization strategy for intensity-modulated proton therapy as an important step in translating robust proton treatment planning from research to clinical applications. Methods: In selective robust optimization, a worst-case-based robust optimization algorithm is extended, and terms of the objective function are selectively computed from either the worst-case dose or the nominal dose. Two lung cancer cases and one head and neck cancer case were used to demonstrate the practical significance of the proposed robust planning strategy. The lung cancer cases had minimal tumor motion less than 5 mm, and, for the demonstration of the methodology,more » are assumed to be static. Results: Selective robust optimization achieved robust clinical target volume (CTV) coverage and at the same time increased nominal planning target volume coverage to 95.8%, compared to the 84.6% coverage achieved with CTV-based robust optimization in one of the lung cases. In the other lung case, the maximum dose in selective robust optimization was lowered from a dose of 131.3% in the CTV-based robust optimization to 113.6%. Selective robust optimization provided robust CTV coverage in the head and neck case, and at the same time improved controls over isodose distribution so that clinical requirements may be readily met. Conclusions: Selective robust optimization may provide the flexibility and capability necessary for meeting various clinical requirements in addition to achieving the required plan robustness in practical proton treatment planning settings.« less

A study of swing-curve physics in diffraction-based overlay

NASA Astrophysics Data System (ADS)

Bhattacharyya, Kaustuve; den Boef, Arie; Storms, Greet; van Heijst, Joost; Noot, Marc; An, Kevin; Park, Noh-Kyoung; Jeon, Se-Ra; Oh, Nang-Lyeom; McNamara, Elliott; van de Mast, Frank; Oh, SeungHwa; Lee, Seung Yoon; Hwang, Chan; Lee, Kuntack

2016-03-01

With the increase of process complexity in advanced nodes, the requirements of process robustness in overlay metrology continues to tighten. Especially with the introduction of newer materials in the film-stack along with typical stack variations (thickness, optical properties, profile asymmetry etc.), the signal formation physics in diffraction-based overlay (DBO) becomes an important aspect to apply in overlay metrology target and recipe selection. In order to address the signal formation physics, an effort is made towards studying the swing-curve phenomena through wavelength and polarizations on production stacks using simulations as well as experimental technique using DBO. The results provide a wealth of information on target and recipe selection for robustness. Details from simulation and measurements will be reported in this technical publication.

In vitro selection of electrochemical peptide probes using bioorthogonal tRNA for influenza virus detection.

PubMed

K C, Tara Bahadur; Tada, Seiichi; Zhu, Liping; Uzawa, Takanori; Minagawa, Noriko; Luo, Shyh-Chyang; Zhao, Haichao; Yu, Hsiao-Hua; Aigaki, Toshiro; Ito, Yoshihiro

2018-05-17

An electrosensitive peptide probe has been developed from an in vitro selection technique using biorthogonal tRNA prepared with an electroreactive non-natural amino acid, 3,4-ethylenedioxythiophene-conjugated aminophenylalanine. The selected probe quantitatively detected the influenza virus based on a signal "turn-on" mechanism. The developed strategy could be used to develop electrochemical biosensors toward a variety of targets.

Dosimetric advantages of a clinical daily adaptive plan selection strategy compared with a non-adaptive strategy in cervical cancer radiation therapy.

PubMed

van de Schoot, Agustinus J A J; de Boer, Peter; Visser, Jorrit; Stalpers, Lukas J A; Rasch, Coen R N; Bel, Arjan

2017-05-01

Radiation therapy (RT) using a daily plan selection adaptive strategy can be applied to account for interfraction organ motion while limiting organ at risk dose. The aim of this study was to quantify the dosimetric consequences of daily plan selection compared with non-adaptive RT in cervical cancer. Ten consecutive patients who received pelvic irradiation, planning CTs (full and empty bladder), weekly post-fraction CTs and pre-fraction CBCTs were included. Non-adaptive plans were generated based on the PTV defined using the full bladder planning CT. For the adaptive strategy, multiple PTVs were created based on both planning CTs by ITVs of the primary CTVs (i.e., GTV, cervix, corpus-uterus and upper part of the vagina) and corresponding library plans were generated. Daily CBCTs were rigidly aligned to the full bladder planning CT for plan selection. For daily plan recalculation, selected CTs based on initial similarity were deformably registered to CBCTs. Differences in daily target coverage (D 98%  > 95%) and in V 0.5Gy , V 1.5Gy , V 2Gy , D 50% and D 2% for rectum, bladder and bowel were assessed. Non-adaptive RT showed inadequate primary CTV coverage in 17% of the daily fractions. Plan selection compensated for anatomical changes and improved primary CTV coverage significantly (p < 0.01) to 98%. Compared with non-adaptive RT, plan selection decreased the fraction dose to rectum and bowel indicated by significant (p < 0.01) improvements for daily V 0.5Gy , V 1.5Gy , V 2Gy , D 50% and D 2% . However, daily plan selection significantly increased the bladder V 1.5Gy , V 2Gy , D 50% and D 2% . In cervical cancer RT, a non-adaptive strategy led to inadequate target coverage for individual patients. Daily plan selection corrected for day-to-day anatomical variations and resulted in adequate target coverage in all fractions. The dose to bowel and rectum was decreased significantly when applying adaptive RT.

Feature-based attentional modulation increases with stimulus separation in divided-attention tasks.

PubMed

Sally, Sharon L; Vidnyánsky, Zoltán; Papathomas, Thomas V

2009-01-01

Attention modifies our visual experience by selecting certain aspects of a scene for further processing. It is therefore important to understand factors that govern the deployment of selective attention over the visual field. Both location and feature-specific mechanisms of attention have been identified and their modulatory effects can interact at a neural level (Treue and Martinez-Trujillo, 1999). The effects of spatial parameters on feature-based attentional modulation were examined for the feature dimensions of orientation, motion and color using three divided-attention tasks. Subjects performed concurrent discriminations of two briefly presented targets (Gabor patches) to the left and right of a central fixation point at eccentricities of +/-2.5 degrees , 5 degrees , 10 degrees and 15 degrees in the horizontal plane. Gabors were size-scaled to maintain consistent single-task performance across eccentricities. For all feature dimensions, the data show a linear increase in the attentional effects with target separation. In a control experiment, Gabors were presented on an isoeccentric viewing arc at 10 degrees and 15 degrees at the closest spatial separation (+/-2.5 degrees ) of the main experiment. Under these conditions, the effects of feature-based attentional effects were largely eliminated. Our results are consistent with the hypothesis that feature-based attention prioritizes the processing of attended features. Feature-based attentional mechanisms may have helped direct the attentional focus to the appropriate target locations at greater separations, whereas similar assistance may not have been necessary at closer target spacings. The results of the present study specify conditions under which dual-task performance benefits from sharing similar target features and may therefore help elucidate the processes by which feature-based attention operates.

Spatially selective depleting tumor-associated negative regulatory T-(Treg) cells with near infrared photoimmunotherapy (NIR-PIT): A new cancer immunotherapy (Conference Presentation)

NASA Astrophysics Data System (ADS)

Kobayashi, Hisataka

2017-02-01

Near infrared photoimmunotherapy (NIR-PIT) is a new type of molecularly-targeted photo-therapy based on conjugating a near infrared silica-phthalocyanine dye, IR700, to a monoclonal antibody (MAb) targeting target-specific cell-surface molecules. When exposed to NIR light, the conjugate rapidly induces a highly-selective cell death only in receptor-positive, MAb-IR700-bound cells. Current immunotherapies for cancer seek to modulate the balance among different immune cell populations, thereby promoting anti-tumor immune responses. However, because these are systemic therapies, they often cause treatment-limiting autoimmune adverse effects. It would be ideal to manipulate the balance between suppressor and effector cells within the tumor without disturbing homeostasis elsewhere in the body. CD4+CD25+Foxp3+ regulatory T cells (Tregs) are well-known immune-suppressor cells that play a key role in tumor immuno-evasion and have been the target of systemic immunotherapies. We used CD25-targeted NIR-PIT to selectively deplete Tregs, thus activating CD8+ T and NK cells and restoring local anti-tumor immunity. This not only resulted in regression of the treated tumor but also induced responses in separate untreated tumors of the same cell-line derivation. We conclude that CD25-targeted NIR-PIT causes spatially selective depletion of Tregs, thereby providing an alternative approach to cancer immunotherapy that can treat not only local tumors but also distant metastatic tumors.

Evaluation of a novel ultra small target technology supporting on-product overlay measurements

NASA Astrophysics Data System (ADS)

Smilde, Henk-Jan H.; den Boef, Arie; Kubis, Michael; Jak, Martin; van Schijndel, Mark; Fuchs, Andreas; van der Schaar, Maurits; Meyer, Steffen; Morgan, Stephen; Wu, Jon; Tsai, Vincent; Wang, Cathy; Bhattacharyya, Kaustuve; Chen, Kai-Hsiung; Huang, Guo-Tsai; Ke, Chih-Ming; Huang, Jacky

2012-03-01

Reducing the size of metrology targets is essential for in-die overlay metrology in advanced semiconductor manufacturing. In this paper, μ-diffraction-based overlay (μDBO) measurements with a YieldStar metrology tool are presented for target-sizes down to 10 × 10 μm2. The μDBO technology enables selection of only the diffraction efficiency information from the grating by efficiently separating it from product structure reflections. Therefore, μDBO targets -even when located adjacent to product environment- give excellent correlation with 40 × 160 μm2 reference targets. Although significantly smaller than standard scribe-line targets, they can achieve total-measurement-uncertainty values of below 0.5 nm on a wide range of product layers. This shows that the new μDBO technique allows for accurate metrology on ultra small in-die targets, while retaining the excellent TMU performance of diffraction-based overlay metrology.

Feature-based RNN target recognition

NASA Astrophysics Data System (ADS)

Bakircioglu, Hakan; Gelenbe, Erol

1998-09-01

Detection and recognition of target signatures in sensory data obtained by synthetic aperture radar (SAR), forward- looking infrared, or laser radar, have received considerable attention in the literature. In this paper, we propose a feature based target classification methodology to detect and classify targets in cluttered SAR images, that makes use of selective signature data from sensory data, together with a neural network technique which uses a set of trained networks based on the Random Neural Network (RNN) model (Gelenbe 89, 90, 91, 93) which is trained to act as a matched filter. We propose and investigate radial features of target shapes that are invariant to rotation, translation, and scale, to characterize target and clutter signatures. These features are then used to train a set of learning RNNs which can be used to detect targets within clutter with high accuracy, and to classify the targets or man-made objects from natural clutter. Experimental data from SAR imagery is used to illustrate and validate the proposed method, and to calculate Receiver Operating Characteristics which illustrate the performance of the proposed algorithm.

The development of Army relevant peptide-based surface enhanced Raman scattering (SERS) sensors for biological threat detection

NASA Astrophysics Data System (ADS)

Farrell, Mikella E.; Strobbia, Pietro; Sarkes, Deborah A.; Stratis-Cullum, Dimitra N.; Cullum, Brian M.; Pellegrino, Paul M.

2016-05-01

The utility of peptide-based molecular sensing for the development of novel biosensors has resulted in a significant increase in their development and usage for sensing targets like chemical, biological, energetic and toxic materials. Using peptides as a molecular recognition element is particularly advantageous because there are several mature peptide synthesis protocols that already exist, peptide structures can be tailored, selected and manipulated to be highly discerning towards desired targets, peptides can be modified to be very stable in a host of environments and stable under many different conditions, and through the development of bifunctionalized peptides can be synthesized to also bind onto desired sensing platforms (various metal materials, glass, etc.). Two examples of the several Army relevant biological targets for peptide-based sensing platforms include Ricin and Abrin. Ricin and Abrin are alarming threats because both can be weaponized and there is no antidote for exposure. Combining the sensitivity of SERS with the selectivity of a bifunctional peptide allows for the emergence of dynamic hazard sensor for Army application.

Corruption of phage display libraries by target-unrelated clones: diagnosis and countermeasures.

PubMed

Thomas, William D; Golomb, Miriam; Smith, George P

2010-12-15

Phage display is used to discover peptides or proteins with a desired target property-most often, affinity for a target selector molecule. Libraries of phage clones displaying diverse surface peptides are subject to a selection process designed to enrich for the target behavior and subsequently propagated to restore phage numbers. A recurrent problem is enrichment of clones, called target-unrelated phages or peptides (TUPs), that lack the target behavior. Many TUPs are propagation related; they have mutations conferring a growth advantage and are enriched during the propagations accompanying selection. Unlike other filamentous phage libraries, fd-tet-based libraries are relatively resistant to propagation-related TUP corruption. Their minus-strand origin is disrupted by a large cassette that simultaneously confers resistance to tetracycline and imposes a rate-limiting growth defect that cannot be bypassed with simple mutations. Nonetheless, a new type of propagation-related TUP emerged in the output of in vivo selections from an fd-tet library. The founding clone had a complex rearrangement that restored the minus-strand origin while retaining tetracycline resistance. The rearrangement involved two recombination events, one with a contaminant having a wild-type minus-strand origin. The founder's infectivity advantage spread by simple recombination to clones displaying different peptides. We propose measures for minimizing TUP corruption. Copyright © 2010 Elsevier Inc. All rights reserved.

Corruption of phage-display libraries by target-unrelated clones: Diagnosis and countermeasures

PubMed Central

Thomas, William D.; Golomb, Miriam; Smith, George P.

2010-01-01

Phage display is used to discover peptides or proteins with a desired target property—most often, affinity for a target selector molecule. Libraries of phage clones displaying diverse surface peptides are subject to a selection process designed to enrich for the target behavior, and subsequently propagated to restore phage numbers. A recurrent problem is enrichment of clones, called target-unrelated phage (TUPs), that lack the target behavior. Many TUPs are propagation-related; they have mutations conferring a growth advantage, and are enriched during the propagations accompanying selection. Unlike other filamentous phage libraries, fd-tet-based libraries are relatively resistant to propagation-related TUP corruption. Their minus strand origin is disrupted by a large cassette that simultaneously confers resistance to tetracycline and imposes a rate-limiting growth defect that cannot be bypassed with simple mutations. Nonetheless, a new type of propagation-related TUP emerged in the output of in vivo selections from an fd-tet library. The founding clone had a complex rearrangement that restored the minus strand origin while retaining tetracycline resistance. The rearrangement involved two recombination events, one with a contaminant having a wild-type minus strand origin. The founder’s infectivity advantage spread by simple recombination to clones displaying different peptides. We propose measures for minimizing TUP corruption. PMID:20692225

Early Probe and Drug Discovery in Academia: A Minireview.

PubMed

Roy, Anuradha

2018-02-09

Drug discovery encompasses processes ranging from target selection and validation to the selection of a development candidate. While comprehensive drug discovery work flows are implemented predominantly in the big pharma domain, early discovery focus in academia serves to identify probe molecules that can serve as tools to study targets or pathways. Despite differences in the ultimate goals of the private and academic sectors, the same basic principles define the best practices in early discovery research. A successful early discovery program is built on strong target definition and validation using a diverse set of biochemical and cell-based assays with functional relevance to the biological system being studied. The chemicals identified as hits undergo extensive scaffold optimization and are characterized for their target specificity and off-target effects in in vitro and in animal models. While the active compounds from screening campaigns pass through highly stringent chemical and Absorption, Distribution, Metabolism, and Excretion (ADME) filters for lead identification, the probe discovery involves limited medicinal chemistry optimization. The goal of probe discovery is identification of a compound with sub-µM activity and reasonable selectivity in the context of the target being studied. The compounds identified from probe discovery can also serve as starting scaffolds for lead optimization studies.

VizieR Online Data Catalog: Detection of 715 Kepler planet candidates host stars (Law+, 2014)

NASA Astrophysics Data System (ADS)

Law, N. M.; Morton, T.; Baranec, C.; Riddle, R.; Ravichandran, G.; Ziegler, C.; Johnson, J. A.; Tendulkar, S. P.; Bui, K.; Burse, M. P.; Das, H. K.; Dekany, R. G.; Kulkarni, S.; Punnadi, S.; Ramaprakash, A. N.

2017-03-01

We selected targets from the KOIs catalog based on a Q1-Q6 Kepler data search (Batalha et al. 2013, J/ApJS/204/24). Our initial targets were selected randomly from the Q1-Q6 KOIs, requiring only that the targets are brighter than mi = 16.0, a restriction which removed only 2% of the KOIs. While it is our intent to observe every KOI with Robo-AO, this initial target selection provides a wide coverage of the range of KOI properties. Given Robo-AO's low time overheads, we took the time to re-observe KOIs which already had detected companions, to produce a complete and homogenous survey. We obtained high-angular-resolution images of the 715 Kepler targeted planet candidate host stars in summer 2012. We performed all the observations in a queue-scheduled mode with the Robo-AO laser adaptive optics system (Baranec et al. 2012SPIE.8447E..04B; 2013, J. Visualized Exp., 72, e50021; Riddle et al. 2012SPIE.8447E..2OR) mounted on the robotic Palomar 60 inch telescope (Cenko et al. 2006PASP..118.1396C). (4 data files).

Targeting tumor glycolysis by a mitotropic agent.

PubMed

Ganapathy-Kanniappan, Shanmugasundaram

2016-01-01

Metabolic reprogramming is one of the hallmarks of cancer. Altered metabolism in cancer cells is exemplified by enhanced glucose utilization, a biochemical signature that is clinically exploited for cancer diagnosis using positron-emission tomography and computed tomography imaging. Accordingly, disrupting the glucose metabolism of cancer cells has been contemplated as a potential therapeutic strategy against cancer. Experimental evidences indicate that targeting glucose metabolism by inhibition of glycolysis or oxidative phosphorylation promotes anticancer effects. Yet, successful clinical translation of antimetabolites or energy blockers to treat cancer remains a challenge, primarily due to lack of efficacy and/or systemic toxicity. Recently, using nanotechnology, Marrache and Dhar have documented the feasibility of delivering a glycolytic inhibitor through triphenylphosphonium (TPP), a mitotropic agent that selectively targets mitochondria based on membrane potential. Furthermore, by utilizing gold nanoparticles the investigators also demonstrated the potential for simultaneous induction of photothermal therapy, thus facilitating an additional line of attack on cancer cells. The report establishes that specific inhibition of tumor glycolysis is achievable through TPP-dependent selective targeting of cancer cells. This nanotechnological approach involving TPP-guided selective delivery of an antiglycolytic agent complemented with photothermal therapy provides a new window of opportunity for effective and specific targeting of tumor glycolysis.

A synthetic intrabody-based selective and generic inhibitor of GPCR endocytosis

NASA Astrophysics Data System (ADS)

Ghosh, Eshan; Srivastava, Ashish; Baidya, Mithu; Kumari, Punita; Dwivedi, Hemlata; Nidhi, Kumari; Ranjan, Ravi; Dogra, Shalini; Koide, Akiko; Yadav, Prem N.; Sidhu, Sachdev S.; Koide, Shohei; Shukla, Arun K.

2017-12-01

Beta-arrestins (βarrs) critically mediate desensitization, endocytosis and signalling of G protein-coupled receptors (GPCRs), and they scaffold a large number of interaction partners. However, allosteric modulation of their scaffolding abilities and direct targeting of their interaction interfaces to modulate GPCR functions selectively have not been fully explored yet. Here we identified a series of synthetic antibody fragments (Fabs) against different conformations of βarrs from phage display libraries. Several of these Fabs allosterically and selectively modulated the interaction of βarrs with clathrin and ERK MAP kinase. Interestingly, one of these Fabs selectively disrupted βarr-clathrin interaction, and when expressed as an intrabody, it robustly inhibited agonist-induced endocytosis of a broad set of GPCRs without affecting ERK MAP kinase activation. Our data therefore demonstrate the feasibility of selectively targeting βarr interactions using intrabodies and provide a novel framework for fine-tuning GPCR functions with potential therapeutic implications.

An evolution based biosensor receptor DNA sequence generation algorithm.

PubMed

Kim, Eungyeong; Lee, Malrey; Gatton, Thomas M; Lee, Jaewan; Zang, Yupeng

2010-01-01

A biosensor is composed of a bioreceptor, an associated recognition molecule, and a signal transducer that can selectively detect target substances for analysis. DNA based biosensors utilize receptor molecules that allow hybridization with the target analyte. However, most DNA biosensor research uses oligonucleotides as the target analytes and does not address the potential problems of real samples. The identification of recognition molecules suitable for real target analyte samples is an important step towards further development of DNA biosensors. This study examines the characteristics of DNA used as bioreceptors and proposes a hybrid evolution-based DNA sequence generating algorithm, based on DNA computing, to identify suitable DNA bioreceptor recognition molecules for stable hybridization with real target substances. The Traveling Salesman Problem (TSP) approach is applied in the proposed algorithm to evaluate the safety and fitness of the generated DNA sequences. This approach improves efficiency and stability for enhanced and variable-length DNA sequence generation and allows extension to generation of variable-length DNA sequences with diverse receptor recognition requirements.

Robotic Spectroscopy at the Dark Sky Observatory

NASA Astrophysics Data System (ADS)

Rosenberg, Daniel E.; Gray, Richard O.; Mashburn, Jonathan; Swenson, Aaron W.; McGahee, Courtney E.; Briley, Michael M.

2018-06-01

Spectroscopic observations using the classification-resolution Gray-Miller spectrograph attached to the Dark Sky Observatory 32 inch telescope (Appalachian State University, North Carolina) have been automated with a robotic script called the “Robotic Spectroscopist” (RS). RS runs autonomously during the night and controls all operations related to spectroscopic observing. At the heart of RS are a number of algorithms that first select and center the target star in the field of an imaging camera and then on the spectrograph slit. RS monitors the observatory weather station, and suspends operations and closes the dome when weather conditions warrant, and can reopen and resume observations when the weather improves. RS selects targets from a list using a queue-observing protocol based on observer-assigned priorities, but also uses target-selection criteria based on weather conditions, especially seeing. At the end of the night RS transfers the data files to the main campus, where they are reduced with an automatic pipeline. Our experience has shown that RS is more efficient and consistent than a human observer, and produces data sets that are ideal for automatic reduction. RS should be adaptable for use at other similar observatories, and so we are making the code freely available to the astronomical community.

Seat Capacity Selection for an Advanced Short-Haul Aircraft Design

NASA Technical Reports Server (NTRS)

Marien, Ty V.

2016-01-01

A study was performed to determine the target seat capacity for a proposed advanced short-haul aircraft concept projected to enter the fleet by 2030. This analysis projected the potential demand in the U.S. for a short-haul aircraft using a transportation theory approach, rather than selecting a target seat capacity based on recent industry trends or current market demand. A transportation systems model was used to create a point-to-point network of short-haul trips and then predict the number of annual origin-destination trips on this network. Aircraft of varying seat capacities were used to meet the demand on this network, assuming a single aircraft type for the entire short-haul fleet. For each aircraft size, the ticket revenue and operational costs were used to calculate a total market profitability metric for all feasible flights. The different aircraft sizes were compared, based on this market profitability metric and also the total number of annual round trips and markets served. Sensitivity studies were also performed to determine the effect of changing the aircraft cruise speed and maximum trip length. Using this analysis, the advanced short-haul aircraft design team was able to select a target seat capacity for their design.

Discovering Cepheid and RR Lyrae Stars: Pan-STARRS Science Archive @ STScI and Robotically Controlled Telescopes

NASA Astrophysics Data System (ADS)

Johnson, Elizabeth; Strolger, Louis-Gregory; Engle, Scott G.; Anderson, Richard I.; Rest, Armin; Calamida, Annalisa; Dosovitz Fox, Ori; Laney, David

2017-01-01

Cepheid and RR Lyrae stars are an integral part of the cosmic distance ladder and are also useful for studying galactic structure and stellar ages. This project aims to greatly expand the number of known periodic variables in our galaxy by identifying candidates in the PanSTARRS-1 3pi catalog, and carrying out systematically targeted characterization with robotically controlled telescopes. Candidate targets are selected from available detection tables based on color and variability indices and are then fully vetted using robotic telescopes: the RCT 1.3 meter (Kitt Peak National Observatory) and RATIR 1.5 meter (Mexico). Here we present work to develop a full, semi-automated prescription for candidate selection, targeted follow-up photometry, cataloging, and classification, which allows the review of approximately 25 variable candidates every two weeks. We make comparisons of our sample selection and purity from a similar study based on Pan-STARRS data (Hernitschek et al. 2016), as well as candidates identified in Gaia DR1. The goal, through continued observation and analysis, is to identify at least 10,000 new variables, hundreds of which will be new Cepheid and RR Lyrae stars.

The Effects of Practice-Based Training on Graduate Teaching Assistants’ Classroom Practices

PubMed Central

Becker, Erin A.; Easlon, Erin J.; Potter, Sarah C.; Guzman-Alvarez, Alberto; Spear, Jensen M.; Facciotti, Marc T.; Igo, Michele M.; Singer, Mitchell; Pagliarulo, Christopher

2017-01-01

Evidence-based teaching is a highly complex skill, requiring repeated cycles of deliberate practice and feedback to master. Despite existing well-characterized frameworks for practice-based training in K–12 teacher education, the major principles of these frameworks have not yet been transferred to instructor development in higher educational contexts, including training of graduate teaching assistants (GTAs). We sought to determine whether a practice-based training program could help GTAs learn and use evidence-based teaching methods in their classrooms. We implemented a weekly training program for introductory biology GTAs that included structured drills of techniques selected to enhance student practice, logic development, and accountability and reduce apprehension. These elements were selected based on their previous characterization as dimensions of active learning. GTAs received regular performance feedback based on classroom observations. To quantify use of target techniques and levels of student participation, we collected and coded 160 h of video footage. We investigated the relationship between frequency of GTA implementation of target techniques and student exam scores; however, we observed no significant relationship. Although GTAs adopted and used many of the target techniques with high frequency, techniques that enforced student participation were not stably adopted, and their use was unresponsive to formal feedback. We also found that techniques discussed in training, but not practiced, were not used at quantifiable frequencies, further supporting the importance of practice-based training for influencing instructional practices. PMID:29146664

A dual selection based, targeted gene replacement tool for Magnaporthe grisea and Fusarium oxysporum.

PubMed

Khang, Chang Hyun; Park, Sook-Young; Lee, Yong-Hwan; Kang, Seogchan

2005-06-01

Rapid progress in fungal genome sequencing presents many new opportunities for functional genomic analysis of fungal biology through the systematic mutagenesis of the genes identified through sequencing. However, the lack of efficient tools for targeted gene replacement is a limiting factor for fungal functional genomics, as it often necessitates the screening of a large number of transformants to identify the desired mutant. We developed an efficient method of gene replacement and evaluated factors affecting the efficiency of this method using two plant pathogenic fungi, Magnaporthe grisea and Fusarium oxysporum. This method is based on Agrobacterium tumefaciens-mediated transformation with a mutant allele of the target gene flanked by the herpes simplex virus thymidine kinase (HSVtk) gene as a conditional negative selection marker against ectopic transformants. The HSVtk gene product converts 5-fluoro-2'-deoxyuridine to a compound toxic to diverse fungi. Because ectopic transformants express HSVtk, while gene replacement mutants lack HSVtk, growing transformants on a medium amended with 5-fluoro-2'-deoxyuridine facilitates the identification of targeted mutants by counter-selecting against ectopic transformants. In addition to M. grisea and F. oxysporum, the method and associated vectors are likely to be applicable to manipulating genes in a broad spectrum of fungi, thus potentially serving as an efficient, universal functional genomic tool for harnessing the growing body of fungal genome sequence data to study fungal biology.

A high content, high throughput cellular thermal stability assay for measuring drug-target engagement in living cells.

PubMed

Massey, Andrew J

2018-01-01

Determining and understanding drug target engagement is critical for drug discovery. This can be challenging within living cells as selective readouts are often unavailable. Here we describe a novel method for measuring target engagement in living cells based on the principle of altered protein thermal stabilization / destabilization in response to ligand binding. This assay (HCIF-CETSA) utilizes high content, high throughput single cell immunofluorescent detection to determine target protein levels following heating of adherent cells in a 96 well plate format. We have used target engagement of Chk1 by potent small molecule inhibitors to validate the assay. Target engagement measured by this method was subsequently compared to target engagement measured by two alternative methods (autophosphorylation and CETSA). The HCIF-CETSA method appeared robust and a good correlation in target engagement measured by this method and CETSA for the selective Chk1 inhibitor V158411 was observed. However, these EC50 values were 23- and 12-fold greater than the autophosphorylation IC50. The described method is therefore a valuable advance in the CETSA method allowing the high throughput determination of target engagement in adherent cells.

Distinctive Behaviors of Druggable Proteins in Cellular Networks

PubMed Central

Workman, Paul; Al-Lazikani, Bissan

2015-01-01

The interaction environment of a protein in a cellular network is important in defining the role that the protein plays in the system as a whole, and thus its potential suitability as a drug target. Despite the importance of the network environment, it is neglected during target selection for drug discovery. Here, we present the first systematic, comprehensive computational analysis of topological, community and graphical network parameters of the human interactome and identify discriminatory network patterns that strongly distinguish drug targets from the interactome as a whole. Importantly, we identify striking differences in the network behavior of targets of cancer drugs versus targets from other therapeutic areas and explore how they may relate to successful drug combinations to overcome acquired resistance to cancer drugs. We develop, computationally validate and provide the first public domain predictive algorithm for identifying druggable neighborhoods based on network parameters. We also make available full predictions for 13,345 proteins to aid target selection for drug discovery. All target predictions are available through canSAR.icr.ac.uk. Underlying data and tools are available at https://cansar.icr.ac.uk/cansar/publications/druggable_network_neighbourhoods/. PMID:26699810

Targeting kinase signaling pathways with constrained peptide scaffolds

PubMed Central

Hanold, Laura E.; Fulton, Melody D.; Kennedy, Eileen J.

2017-01-01

Kinases are amongst the largest families in the human proteome and serve as critical mediators of a myriad of cell signaling pathways. Since altered kinase activity is implicated in a variety of pathological diseases, kinases have become a prominent class of proteins for targeted inhibition. Although numerous small molecule and antibody-based inhibitors have already received clinical approval, several challenges may still exist with these strategies including resistance, target selection, inhibitor potency and in vivo activity profiles. Constrained peptide inhibitors have emerged as an alternative strategy for kinase inhibition. Distinct from small molecule inhibitors, peptides can provide a large binding surface area that allows them to bind shallow protein surfaces rather than defined pockets within the target protein structure. By including chemical constraints within the peptide sequence, additional benefits can be bestowed onto the peptide scaffold such as improved target affinity and target selectivity, cell permeability and proteolytic resistance. In this review, we highlight examples of diverse chemistries that are being employed to constrain kinase-targeting peptide scaffolds and highlight their application to modulate kinase signaling as well as their potential clinical implications. PMID:28185915

A ratiometric electrochemical biosensor for the exosomal microRNAs detection based on bipedal DNA walkers propelled by locked nucleic acid modified toehold mediate strand displacement reaction.

PubMed

Zhang, Jing; Wang, Liang-Liang; Hou, Mei-Feng; Xia, Yao-Kun; He, Wen-Hui; Yan, An; Weng, Yun-Ping; Zeng, Lu-Peng; Chen, Jing-Hua

2018-04-15

Sensitive and selective detection of microRNAs (miRNAs) in cancer cells derived exosomes have attracted rapidly growing interest owing to their potential in diagnostic and prognostic applications. Here, we design a ratiometric electrochemical biosensor based on bipedal DNA walkers for the attomolar detection of exosomal miR-21. In the presence of miR-21, DNA walkers are activated to walk continuously along DNA tracks, resulting in conformational changes as well as considerable increases of the signal ratio produced by target-respond and target-independent reporters. With the signal cascade amplification of DNA walkers, the biosensor exhibits ultrahigh sensitivity with the limit of detection (LOD) down to 67 aM. Furthermore, owing to the background-correcting function of target-independent reporters termed as reference reporters, the biosensor is robust and stable enough to be applied in the detection of exosomal miR-21 extracted from breast cancer cell lines and serums. In addition, because locked nucleic acid (LNA) modified toehold mediate strand displacement reaction (TMSDR) has extraordinary discriminative ability, the biosensor displays excellent selectivity even against the single-base-mismatched target. It is worth mentioning that our sensor is regenerative and stable for at least 5 cycles without diminution in sensitivity. In brief, the high sensitivity, selectivity and reproducibility, together with cheap, make the proposed biosensor a promising approach for exosomal miRNAs detection, in conjunction with early point-of-care testing (POCT) of cancer. Copyright © 2017 Elsevier B.V. All rights reserved.

[Missile-Type Tumor-Targeting Polymer Drug, P-THP, Seeks Tumors via Three Different Steps Based on the EPR Effect].

PubMed

Maeda, Hiroshi; Fang, Jun; Ulbrich, Karel; Etrych, Tomáš; Nakamura, Hideaki

2016-05-01

The enhanced permeability and retention (EPR) effect, a tumor-targeting principle of nanomedicine, serves as a standard for tumor-targeted anticancer drug design. There are 3 key issues in ideal EPR-based antitumor drug design: i) stability in blood circulation; ii) tumor-selective accumulation (EPR effect) and efficient release of the active anticancer moiety in tumor tissues; and iii) the active uptake of the active drug into tumor cells. Using these principles, we developed N-(2- hydroxypropyl)methacrylamide (HPMA) copolymer-conjugated pirarubicin (P-THP), which uses hydrazone bond linkage; it was shown to exhibit prolonged circulation time, thereby resulting in good tumor-selective accumulation. More importantly, the hydrazone bond ensured selective and rapid release of the active drug, pirarubicin (THP), in acidic tumor environments. Further, compared to other anthracycline anticancer drugs (eg, doxorubicin), THP demonstrated more rapid intracellular uptake. Consequently, P-THP showed remarkable antitumor effect with minimal side effects. In a clinical pilot study of a stage IV prostate cancer patient with multiple metastases in the lung and bone, P-THP (50-75 mg administered once every 2-3 weeks) was shown to clear the metastatic nodules in the lung almost completely after 3 treatments where 50-70 mg THP equivalent each was administerd per 70 kg body wt, and bone metastasis disappeared after 6 months. There was no recurrence after 2 years. The patient also retained an excellent quality of life during the treatment without any apparent side effects. Thus, we propose the clinical development of P-THP as an EPR-based tumor-targeted anticancer drug.

Repetition priming in selective attention: A TVA analysis.

PubMed

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

2015-09-01

Current behavior is influenced by events in the recent past. In visual attention, this is expressed in many variations of priming effects. Here, we investigate color priming in a brief exposure digit-recognition task. Observers performed a masked odd-one-out singleton recognition task where the target-color either repeated or changed between subsequent trials. Performance was measured by recognition accuracy over exposure durations. The purpose of the study was to replicate earlier findings of perceptual priming in brief displays and to model those results based on a Theory of Visual Attention (TVA; Bundesen, 1990). We tested 4 different definitions of a generic TVA-model and assessed their explanatory power. Our hypothesis was that priming effects could be explained by selective mechanisms, and that target-color repetitions would only affect the selectivity parameter (α) of our models. Repeating target colors enhanced performance for all 12 observers. As predicted, this was only true under conditions that required selection of a target among distractors, but not when a target was presented alone. Model fits by TVA were obtained with a trial-by-trial maximum likelihood estimation procedure that estimated 4-15 free parameters, depending on the particular model. We draw two main conclusions. Color priming can be modeled simply as a change in selectivity between conditions of repetition or swap of target color. Depending on the desired resolution of analysis; priming can accurately be modeled by a simple four parameter model, where VSTM capacity and spatial biases of attention are ignored, or more fine-grained by a 10 parameter model that takes these aspects into account. Copyright © 2015 Elsevier B.V. All rights reserved.

In vitro Selection and Interaction Studies of a DNA Aptamer Targeting Protein A

PubMed Central

Stoltenburg, Regina; Schubert, Thomas; Strehlitz, Beate

2015-01-01

A new DNA aptamer targeting Protein A is presented. The aptamer was selected by use of the FluMag-SELEX procedure. The SELEX technology (Systematic Evolution of Ligands by EXponential enrichment) is widely applied as an in vitro selection and amplification method to generate target-specific aptamers and exists in various modified variants. FluMag-SELEX is one of them and is characterized by the use of magnetic beads for target immobilization and fluorescently labeled oligonucleotides for monitoring the aptamer selection progress. Structural investigations and sequence truncation experiments of the selected aptamer for Protein A led to the conclusion, that a stem-loop structure at its 5’-end including the 5’-primer binding site is essential for aptamer-target binding. Extensive interaction analyses between aptamer and Protein A were performed by methods like surface plasmon resonance, MicroScale Thermophoresis and bead-based binding assays using fluorescence measurements. The binding of the aptamer to its target was thus investigated in assays with immobilization of one of the binding partners each, and with both binding partners in solution. Affinity constants were determined in the low micromolar to submicromolar range, increasing to the nanomolar range under the assumption of avidity. Protein A provides more than one binding site for the aptamer, which may overlap with the known binding sites for immunoglobulins. The aptamer binds specifically to both native and recombinant Protein A, but not to other immunoglobulin-binding proteins like Protein G and L. Cross specificity to other proteins was not found. The application of the aptamer is directed to Protein A detection or affinity purification. Moreover, whole cells of Staphylococcus aureus, presenting Protein A on the cell surface, could also be bound by the aptamer. PMID:26221730

In vitro Selection and Interaction Studies of a DNA Aptamer Targeting Protein A.

PubMed

Stoltenburg, Regina; Schubert, Thomas; Strehlitz, Beate

2015-01-01

A new DNA aptamer targeting Protein A is presented. The aptamer was selected by use of the FluMag-SELEX procedure. The SELEX technology (Systematic Evolution of Ligands by EXponential enrichment) is widely applied as an in vitro selection and amplification method to generate target-specific aptamers and exists in various modified variants. FluMag-SELEX is one of them and is characterized by the use of magnetic beads for target immobilization and fluorescently labeled oligonucleotides for monitoring the aptamer selection progress. Structural investigations and sequence truncation experiments of the selected aptamer for Protein A led to the conclusion, that a stem-loop structure at its 5'-end including the 5'-primer binding site is essential for aptamer-target binding. Extensive interaction analyses between aptamer and Protein A were performed by methods like surface plasmon resonance, MicroScale Thermophoresis and bead-based binding assays using fluorescence measurements. The binding of the aptamer to its target was thus investigated in assays with immobilization of one of the binding partners each, and with both binding partners in solution. Affinity constants were determined in the low micromolar to submicromolar range, increasing to the nanomolar range under the assumption of avidity. Protein A provides more than one binding site for the aptamer, which may overlap with the known binding sites for immunoglobulins. The aptamer binds specifically to both native and recombinant Protein A, but not to other immunoglobulin-binding proteins like Protein G and L. Cross specificity to other proteins was not found. The application of the aptamer is directed to Protein A detection or affinity purification. Moreover, whole cells of Staphylococcus aureus, presenting Protein A on the cell surface, could also be bound by the aptamer.

Small Molecule Inhibition of microRNA-210 Reprograms an Oncogenic Hypoxic Circuit.

PubMed

Costales, Matthew G; Haga, Christopher L; Velagapudi, Sai Pradeep; Childs-Disney, Jessica L; Phinney, Donald G; Disney, Matthew D

2017-03-08

A hypoxic state is critical to the metastatic and invasive characteristics of cancer. Numerous pathways play critical roles in cancer maintenance, many of which include noncoding RNAs such as microRNA (miR)-210 that regulates hypoxia inducible factors (HIFs). Herein, we describe the identification of a small molecule named Targapremir-210 that binds to the Dicer site of the miR-210 hairpin precursor. This interaction inhibits production of the mature miRNA, derepresses glycerol-3-phosphate dehydrogenase 1-like enzyme (GPD1L), a hypoxia-associated protein negatively regulated by miR-210, decreases HIF-1α, and triggers apoptosis of triple negative breast cancer cells only under hypoxic conditions. Further, Targapremir-210 inhibits tumorigenesis in a mouse xenograft model of hypoxic triple negative breast cancer. Many factors govern molecular recognition of biological targets by small molecules. For protein, chemoproteomics and activity-based protein profiling are invaluable tools to study small molecule target engagement and selectivity in cells. Such approaches are lacking for RNA, leaving a void in the understanding of its druggability. We applied Chemical Cross-Linking and Isolation by Pull Down (Chem-CLIP) to study the cellular selectivity and the on- and off-targets of Targapremir-210. Targapremir-210 selectively recognizes the miR-210 precursor and can differentially recognize RNAs in cells that have the same target motif but have different expression levels, revealing this important feature for selectively drugging RNAs for the first time. These studies show that small molecules can be rapidly designed to selectively target RNAs and affect cellular responses to environmental conditions, resulting in favorable benefits against cancer. Further, they help define rules for identifying druggable targets in the transcriptome.

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.

Agonistic TAM-163 antibody targeting tyrosine kinase receptor-B: applying mechanistic modeling to enable preclinical to clinical translation and guide clinical trial design.

PubMed

Vugmeyster, Yulia; Rohde, Cynthia; Perreault, Mylene; Gimeno, Ruth E; Singh, Pratap

2013-01-01

TAM-163, an agonist monoclonal antibody targeting tyrosine receptor kinase-B (TrkB), is currently being investigated as a potential body weight modulatory agent in humans. To support the selection of the dose range for the first-in-human (FIH) trial of TAM-163, we conducted a mechanistic analysis of the pharmacokinetic (PK) and pharmacodynamic (PD) data (e.g., body weight gain) obtained in lean cynomolgus and obese rhesus monkeys following single doses ranging from 0.3 to 60 mg/kg. A target-mediated drug disposition (TMDD) model was used to describe the observed nonlinear PK and Emax approach was used to describe the observed dose-dependent PD effect. The TMDD model development was supported by the experimental determination of the binding affinity constant (9.4 nM) and internalization rate of the drug-target complex (2.08 h(-1)). These mechanistic analyses enabled linking of exposure, target (TrkB) coverage, and pharmacological activity (e.g., PD) in monkeys, and indicated that ≥ 38% target coverage (time-average) was required to achieve significant body weight gain in monkeys. Based on the scaling of the TMDD model from monkeys to humans and assuming similar relationship between the target coverage and pharmacological activity between monkey and humans, subcutaneous (SC) doses of 1 and 15 mg/kg in humans were projected to be the minimally and the fully pharmacologically active doses, respectively. Based on the minimal anticipated biological effect level (MABEL) approach for starting dose selection, the dose of 0.05 mg/kg (3 mg for a 60 kg human) SC was recommended as the starting dose for FIH trials, because at this dose level<10% target coverage was projected at Cmax (and all other time points). This study illustrates a rational mechanistic approach for the selection of FIH dose range for a therapeutic protein with a complex model of action.

A SPR strategy for high-throughput ligand screenings based on synthetic peptides mimicking a selected subdomain of the target protein: a proof of concept on HER2 receptor.

PubMed

Monfregola, Luca; Vitale, Rosa Maria; Amodeo, Pietro; De Luca, Stefania

2009-10-01

The discovery of pharmaceutical agents is a complex, lengthy and costly process, critically depending on the availability of rapid and efficient screening methods. In particular, when targets are large, multidomain proteins, their complexity may affect unfavorably technical feasibility, costs and unambiguity of binding test interpretation. A possible strategy to overcome these problems relies on molecular design of receptor fragments that are: sensible targets for ligand screenings, conformationally stable also as standalone domains, easily synthesized and immobilized on chip for Biacore experiments. An additional desirable feature for new ligands is the ability of selectively targeting alternative conformational states typical of many proteins. To test the feasibility of such approach on a case with potential applicative interest, we developed a surface plasmon resonance (SPR)-based screening method for drug candidates toward HER2, a Tyr-kinase receptor targeted in anticancer therapies. HER2 was mimicked by HER2-DIVMP, a modified fragment of it immobilized onto the sensor surface specifically modeling HER2 domain IV in its bounded form, designed by structural comparison of HER2 alone and in complex with Herceptin, a monoclonal therapeutic anti-HER2 antibody. This design and its implementation in SPR devices was validated by investigating Herceptin- HER2-DIVMP affinity, measuring its dissociation constant (K(D)=19.2 nM). An efficient synthetic procedure to prepare the HER2-DIVMP peptide was also developed. The HER2-DIVMP conformational stability suggested by experimental and computational results, makes it also a valuable candidate as a mold to design new molecules selectively targeting domain IV of HER2.

Engineering a Cell-surface Aptamer Circuit for Targeted and Amplified Photodynamic Cancer Therapy

PubMed Central

Han, Da; Zhu, Guizhi; Wu, Cuichen; Zhu, Zhi; Chen, Tao; Zhang, Xiaobing

2013-01-01

Photodynamic therapy (PDT) is one of the most promising and noninvasive methods for clinical treatment of different malignant diseases. Here, we present a novel strategy of designing an aptamer-based DNA nanocircuit capable of the selective recognition of cancer cells, controllable activation of photosensitizer and amplification of photodynamic therapeutic effect. The aptamers can selectively recognize target cancer cells and bind to the specific proteins on cell membranes. Then the overhanging catalyst sequence on aptamer can trigger a toehold-mediated catalytic strand displacement to activate photosensitizer and achieve amplified therapeutic effect. The specific binding-induced activation allows the DNA circuit to distinguish diseased cells from healthy cells, reducing damage to nearby healthy cells. Moreover, the catalytic amplification reaction will only take place close to the target cancer cells, resulting in a high local concentration of singlet oxygen to selectively kill the target cells. The principle employed in this study demonstrated the feasibility of assembling a DNA circuit on cell membranes and could further broaden the utility of DNA circuits for applications in biology, biotechnology, and biomedicine. PMID:23397942

Selecting Great Lakes streams for lampricide treatment based on larval sea lamprey surveys

USGS Publications Warehouse

Christie, Gavin C.; Adams, Jean V.; Steeves, Todd B.; Slade, Jeffrey W.; Cuddy, Douglas W.; Fodale, Michael F.; Young, Robert J.; Kuc, Miroslaw; Jones, Michael L.

2003-01-01

The Empiric Stream Treatment Ranking (ESTR) system is a data-driven, model-based, decision tool for selecting Great Lakes streams for treatment with lampricide, based on estimates from larval sea lamprey (Petromyzon marinus) surveys conducted throughout the basin. The 2000 ESTR system was described and applied to larval assessment surveys conducted from 1996 to 1999. A comparative analysis of stream survey and selection data was conducted and improvements to the stream selection process were recommended. Streams were selected for treatment based on treatment cost, predicted treatment effectiveness, and the projected number of juvenile sea lampreys produced. On average, lampricide treatments were applied annually to 49 streams with 1,075 ha of larval habitat, killing 15 million larval and 514,000 juvenile sea lampreys at a total cost of $5.3 million, and marginal and mean costs of $85 and $10 per juvenile killed. The numbers of juvenile sea lampreys killed for given treatment costs showed a pattern of diminishing returns with increasing investment. Of the streams selected for treatment, those with > 14 ha of larval habitat targeted 73% of the juvenile sea lampreys for 60% of the treatment cost. Suggested improvements to the ESTR system were to improve accuracy and precision of model estimates, account for uncertainty in estimates, include all potentially productive streams in the process (not just those surveyed in the current year), consider the value of all larvae killed during treatment (not just those predicted to metamorphose the following year), use lake-specific estimates of damage, and establish formal suppression targets.

Magnetic Resonance Imaging Targeted Biopsy Improves Selection of Patients Considered for Active Surveillance for Clinically Low Risk Prostate Cancer Based on Systematic Biopsies.

PubMed

Ouzzane, Adil; Renard-Penna, Raphaele; Marliere, François; Mozer, Pierre; Olivier, Jonathan; Barkatz, Johann; Puech, Philippe; Villers, Arnauld

2015-08-01

Current selection criteria for active surveillance based on systematic biopsy underestimate prostate cancer volume and grade. We investigated the role of additional magnetic resonance imaging targeted biopsy in reclassifying patients eligible for active surveillance based on systematic biopsy. We performed a study at 2 institutions in a total of 281 men with increased prostate specific antigen. All men met certain criteria, including 1) prebiopsy magnetic resonance imaging, 12-core transrectal systematic biopsy and 2 additional magnetic resonance imaging targeted biopsies of lesions suspicious for cancer during the same sequence as systematic biopsy, and 2) eligibility for active surveillance based on systematic biopsy results. Criteria for active surveillance were prostate specific antigen less than 10 ng/ml, no Gleason grade 4/5, 5 mm or less involvement of any biopsy core and 2 or fewer positive systematic biopsy cores. Patient characteristics were compared between reclassified and nonreclassified groups based on magnetic resonance imaging targeted biopsy results. On magnetic resonance imaging 58% of the 281 patients had suspicious lesions. Magnetic resonance imaging targeted biopsy was positive for cancer in 81 of 163 patients (50%). Of 281 patients 28 (10%) were reclassified by magnetic resonance imaging targeted biopsy as ineligible for active surveillance based on Gleason score in 8, cancer length in 20 and Gleason score plus cancer length in 9. Suspicious areas on magnetic resonance imaging were in the anterior part of the prostate in 15 of the 28 men (54%). Reclassified patients had a smaller prostate volume (37 vs 52 cc) and were older (66.5 vs 63 years) than those who were not reclassified (p < 0.05). Magnetic resonance imaging targeted biopsy reclassified 10% of patients who were eligible for active surveillance based on systematic biopsy. Its incorporation into the active surveillance eligibility criteria may decrease the risk of reclassification to higher stages during followup. Copyright © 2015 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

Bioassisted Phytomining of Gold

NASA Astrophysics Data System (ADS)

Maluckov, Biljana S.

2015-05-01

Bioassisted phytomining implies targeted use of microorganisms and plants for the selective recovery of the metal. Metals from undissolved compounds are dissolved by applying specially chosen microorganisms and therefore become available to the hyperaccumulating plants. In the article, the selective extraction method of base metals and the precious metal gold by using microorganisms and plants is discussed.

Pharmacologic Treatment of Hypertension in Adults Aged 60 Years or Older to Higher Versus Lower Blood Pressure Targets: A Clinical Practice Guideline From the American College of Physicians and the American Academy of Family Physicians.

PubMed

Qaseem, Amir; Wilt, Timothy J; Rich, Robert; Humphrey, Linda L; Frost, Jennifer; Forciea, Mary Ann

2017-03-21

The American College of Physicians (ACP) and the American Academy of Family Physicians (AAFP) jointly developed this guideline to present the evidence and provide clinical recommendations based on the benefits and harms of higher versus lower blood pressure targets for the treatment of hypertension in adults aged 60 years or older. This guideline is based on a systematic review of published randomized, controlled trials for primary outcomes and observational studies for harms only (identified through EMBASE, the Cochrane Database of Systematic Reviews, MEDLINE, and ClinicalTrials.gov), from database inception through January 2015. The MEDLINE search was updated through September 2016. Evaluated outcomes included all-cause mortality, morbidity and mortality related to stroke, major cardiac events (fatal and nonfatal myocardial infarction and sudden cardiac death), and harms. This guideline grades the evidence and recommendations using the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) method. The target audience for this guideline includes all clinicians, and the target patient population includes all adults aged 60 years or older with hypertension. ACP and AAFP recommend that clinicians initiate treatment in adults aged 60 years or older with systolic blood pressure persistently at or above 150 mm Hg to achieve a target systolic blood pressure of less than 150 mm Hg to reduce the risk for mortality, stroke, and cardiac events. (Grade: strong recommendation, high-quality evidence). ACP and AAFP recommend that clinicians select the treatment goals for adults aged 60 years or older based on a periodic discussion of the benefits and harms of specific blood pressure targets with the patient. ACP and AAFP recommend that clinicians consider initiating or intensifying pharmacologic treatment in adults aged 60 years or older with a history of stroke or transient ischemic attack to achieve a target systolic blood pressure of less than 140 mm Hg to reduce the risk for recurrent stroke. (Grade: weak recommendation, moderate-quality evidence). ACP and AAFP recommend that clinicians select the treatment goals for adults aged 60 years or older based on a periodic discussion of the benefits and harms of specific blood pressure targets with the patient. ACP and AAFP recommend that clinicians consider initiating or intensifying pharmacologic treatment in some adults aged 60 years or older at high cardiovascular risk, based on individualized assessment, to achieve a target systolic blood pressure of less than 140 mm Hg to reduce the risk for stroke or cardiac events. (Grade: weak recommendation, low-quality evidence). ACP and AAFP recommend that clinicians select the treatment goals for adults aged 60 years or older based on a periodic discussion of the benefits and harms of specific blood pressure targets with the patient.

The selectivity of protein-imprinted gels and its relation to protein properties: A computer simulation study.

PubMed

Yankelov, Rami; Yungerman, Irena; Srebnik, Simcha

2017-07-01

Polymer-based protein recognition systems have enormous potential within clinical and diagnostic fields due to their reusability, biocompatibility, ease of manufacturing, and potential specificity. Imprinted polymer matrices have been extensively studied and applied as a simple technique for creating artificial polymer-based recognition gels for a target molecule. Although this technique has been proven effective when targeting small molecules (such as drugs), imprinting of proteins have so far resulted in materials with limited selectivity due to the large molecular size of the protein and aqueous environment. Using coarse-grained molecular simulation, we investigate the relation between protein makeup, polymer properties, and the selectivity of imprinted gels. Nonspecific binding that results in poor selectivity is shown to be strongly dependent on surface chemistry of the template and competitor proteins as well as on polymer chemistry. Residence time distributions of proteins diffusing within the gels provide a transparent picture of the relation between polymer constitution, protein properties, and the nonspecific interactions with the imprinted gel. The pronounced effect of protein surface chemistry on imprinted gel specificity is demonstrated. Copyright © 2017 John Wiley & Sons, Ltd.

Virus-Based Cancer Therapeutics for Targeted Photodynamic Therapy.

PubMed

Cao, Binrui; Xu, Hong; Yang, Mingying; Mao, Chuanbin

2018-01-01

Cancer photodynamic therapy (PDT) involves the absorption of light by photosensitizers (PSs) to generate cytotoxic singlet oxygen for killing cancer cells. The success of this method is usually limited by the lack of selective accumulation of the PS at cancer cells. Bioengineered viruses with cancer cell-targeting peptides fused on their surfaces are great drug carriers that can guide the PS to cancer cells for targeted cancer treatment. Here, we use cell-targeting fd bacteriophages (phages) as an example to describe how to chemically conjugate PSs (e.g., pyropheophorbide-a (PPa)) onto a phage particle to achieve targeted PDT.

Nanoengineered capsules for selective SERS analysis of biological samples

NASA Astrophysics Data System (ADS)

You, Yil-Hwan; Schechinger, Monika; Locke, Andrea; Coté, Gerard; McShane, Mike

2018-02-01

Metal nanoparticles conjugated with DNA oligomers have been intensively studied for a variety of applications, including optical diagnostics. Assays based on aggregation of DNA-coated particles in proportion to the concentration of target analyte have not been widely adopted for clinical analysis, however, largely due to the nonspecific responses observed in complex biofluids. While sample pre-preparation such as dialysis is helpful to enable selective sensing, here we sought to prove that assay encapsulation in hollow microcapsules could remove this requirement and thereby facilitate more rapid analysis on complex samples. Gold nanoparticle-based assays were incorporated into capsules comprising polyelectrolyte multilayer (PEMs), and the response to small molecule targets and larger proteins were compared. Gold nanoparticles were able to selectively sense small Raman dyes (Rhodamine 6G) in the presence of large protein molecules (BSA) when encapsulated. A ratiometric based microRNA-17 sensing assay exhibited drastic reduction in response after encapsulation, with statistically-significant relative Raman intensity changes only at a microRNA-17 concentration of 10 nM compared to a range of 0-500 nM for the corresponding solution-phase response.

Determinants of Global Color-Based Selection in Human Visual Cortex.

PubMed

Bartsch, Mandy V; Boehler, Carsten N; Stoppel, Christian M; Merkel, Christian; Heinze, Hans-Jochen; Schoenfeld, Mircea A; Hopf, Jens-Max

2015-09-01

Feature attention operates in a spatially global way, with attended feature values being prioritized for selection outside the focus of attention. Accounts of global feature attention have emphasized feature competition as a determining factor. Here, we use magnetoencephalographic recordings in humans to test whether competition is critical for global feature selection to arise. Subjects performed a color/shape discrimination task in one visual field (VF), while irrelevant color probes were presented in the other unattended VF. Global effects of color attention were assessed by analyzing the response to the probe as a function of whether or not the probe's color was a target-defining color. We find that global color selection involves a sequence of modulations in extrastriate cortex, with an initial phase in higher tier areas (lateral occipital complex) followed by a later phase in lower tier retinotopic areas (V3/V4). Importantly, these modulations appeared with and without color competition in the focus of attention. Moreover, early parts of the modulation emerged for a task-relevant color not even present in the focus of attention. All modulations, however, were eliminated during simple onset-detection of the colored target. These results indicate that global color-based attention depends on target discrimination independent of feature competition in the focus of attention. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

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…

Identification of cancer-cytotoxic modulators of PDE3A by predictive chemogenomics | Office of Cancer Genomics

Cancer.gov

High cancer death rates indicate the need for new anticancer therapeutic agents. Approaches to discovering new cancer drugs include target-based drug discovery and phenotypic screening. Here, we identified phosphodiesterase 3A modulators as cell-selective cancer cytotoxic compounds through phenotypic compound library screening and target deconvolution by predictive chemogenomics.

Label fusion based brain MR image segmentation via a latent selective model

NASA Astrophysics Data System (ADS)

Liu, Gang; Guo, Xiantang; Zhu, Kai; Liao, Hengxu

2018-04-01

Multi-atlas segmentation is an effective approach and increasingly popular for automatically labeling objects of interest in medical images. Recently, segmentation methods based on generative models and patch-based techniques have become the two principal branches of label fusion. However, these generative models and patch-based techniques are only loosely related, and the requirement for higher accuracy, faster segmentation, and robustness is always a great challenge. In this paper, we propose novel algorithm that combines the two branches using global weighted fusion strategy based on a patch latent selective model to perform segmentation of specific anatomical structures for human brain magnetic resonance (MR) images. In establishing this probabilistic model of label fusion between the target patch and patch dictionary, we explored the Kronecker delta function in the label prior, which is more suitable than other models, and designed a latent selective model as a membership prior to determine from which training patch the intensity and label of the target patch are generated at each spatial location. Because the image background is an equally important factor for segmentation, it is analyzed in label fusion procedure and we regard it as an isolated label to keep the same privilege between the background and the regions of interest. During label fusion with the global weighted fusion scheme, we use Bayesian inference and expectation maximization algorithm to estimate the labels of the target scan to produce the segmentation map. Experimental results indicate that the proposed algorithm is more accurate and robust than the other segmentation methods.

Selective Fenton-like oxidation of methylene blue on modified Fe-zeolites prepared via molecular imprinting technique.

PubMed

Zhang, Yuanyuan; Shang, Jiaobo; Song, Yanqun; Rong, Chuan; Wang, Yinghui; Huang, Wenyu; Yu, Kefu

2017-02-01

A facile strategy to increase the selectivity of heterogeneous Fenton oxidation is investigated. The increase was reached by increasing selective adsorption of heterogeneous Fenton catalyst to a target pollutant. The heterogeneous Fenton catalyst was prepared by a two-step process. First, zeolite particles were imprinted by the target pollutant, methylene blue (MB), in their aggregations, and second, iron ions were loaded on the zeolite aggregations to form the molecule imprinted Fe-zeolites (MI-FZ) Fenton catalyst. Its adsorption amount for MB reached as high as 44.6 mg g -1 while the adsorption amount of un-imprinted Fe-zeolites (FZ) is only 15.6 mg g -1 . Fenton removal efficiency of MI-FZ for MB was 87.7%, being 33.9% higher than that of FZ. The selective Fenton oxidation of MI-FZ for MB was further confirmed by its removal performance for the mixed MB and bisphenol A (BPA) in solution. The removal efficiency of MB was 44.7% while that of BPA was only 14.9%. This fact shows that molecular imprinting is suitable to prepare the Fe-zeolites (FZ)-based Fenton catalyst with high selectivity for removal of target pollutants, at least MB.

Generation of an arrayed CRISPR-Cas9 library targeting epigenetic regulators: from high-content screens to in vivo assays

PubMed Central

2017-01-01

ABSTRACT The CRISPR-Cas9 system has revolutionized genome engineering, allowing precise modification of DNA in various organisms. The most popular method for conducting CRISPR-based functional screens involves the use of pooled lentiviral libraries in selection screens coupled with next-generation sequencing. Screens employing genome-scale pooled small guide RNA (sgRNA) libraries are demanding, particularly when complex assays are used. Furthermore, pooled libraries are not suitable for microscopy-based high-content screens or for systematic interrogation of protein function. To overcome these limitations and exploit CRISPR-based technologies to comprehensively investigate epigenetic mechanisms, we have generated a focused sgRNA library targeting 450 epigenetic regulators with multiple sgRNAs in human cells. The lentiviral library is available both in an arrayed and pooled format and allows temporally-controlled induction of gene knock-out. Characterization of the library showed high editing activity of most sgRNAs and efficient knock-out at the protein level in polyclonal populations. The sgRNA library can be used for both selection and high-content screens, as well as for targeted investigation of selected proteins without requiring isolation of knock-out clones. Using a variety of functional assays we show that the library is suitable for both in vitro and in vivo applications, representing a unique resource to study epigenetic mechanisms in physiological and pathological conditions. PMID:29327641

Targeting the interleukin-11 receptor α in metastatic prostate cancer: A first-in-man study

PubMed Central

Pasqualini, Renata; Millikan, Randall E; Christianson, Dawn R; Cardó-Vila, Marina; Driessen, Wouter H P; Giordano, Ricardo J; Hajitou, Amin; Hoang, Anh G; Wen, Sijin; Barnhart, Kirstin F; Baze, Wallace B; Marcott, Valerie D; Hawke, David H; Do, Kim-Anh; Navone, Nora M; Efstathiou, Eleni; Troncoso, Patricia; Lobb, Roy R; Logothetis, Christopher J; Arap, Wadih

2015-01-01

BACKGROUND Receptors in tumor blood vessels are attractive targets for ligand-directed drug discovery and development. The authors have worked systematically to map human endothelial receptors (“vascular zip codes”) within tumors through direct peptide library selection in cancer patients. Previously, they selected a ligand-binding motif to the interleukin-11 receptor alpha (IL-11Rα) in the human vasculature. METHODS The authors generated a ligand-directed, peptidomimetic drug (bone metastasis-targeting peptidomimetic-11 [BMTP-11]) for IL-11Rα–based human tumor vascular targeting. Preclinical studies (efficacy/toxicity) included evaluating BMTP-11 in prostate cancer xenograft models, drug localization, targeted apoptotic effects, pharmacokinetic/pharmacodynamic analyses, and dose-range determination, including formal (good laboratory practice) toxicity across rodent and nonhuman primate species. The initial BMTP-11 clinical development also is reported based on a single-institution, open-label, first-in-class, first-in-man trial (National Clinical Trials number NCT00872157) in patients with metastatic, castrate-resistant prostate cancer. RESULTS BMTP-11 was preclinically promising and, thus, was chosen for clinical development in patients. Limited numbers of patients who had castrate-resistant prostate cancer with osteoblastic bone metastases were enrolled into a phase 0 trial with biology-driven endpoints. The authors demonstrated biopsy-verified localization of BMTP-11 to tumors in the bone marrow and drug-induced apoptosis in all patients. Moreover, the maximum tolerated dose was identified on a weekly schedule (20-30 mg/m2). Finally, a renal dose-limiting toxicity was determined, namely, dose-dependent, reversible nephrotoxicity with proteinuria and casts involving increased serum creatinine. CONCLUSIONS These biologic endpoints establish BMTP-11 as a targeted drug candidate in metastatic, castrate-resistant prostate cancer. Within a larger discovery context, the current findings indicate that functional tumor vascular ligand-receptor targeting systems may be identified through direct combinatorial selection of peptide libraries in cancer patients. Cancer 2015;121:2411–2421. © 2015 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society. The authors report on the development of a new ligand-directed peptidomimetic (termed bone metastasis-targeting peptidomimetic-11) for interleukin-11 receptor-based human vascular targeting, including the translation from preclinical studies to a first-in-class, first-in-man clinical trial in patients with metastatic, castrate-resistant prostate cancer. PMID:25832466

Targeted proteomic assays for quantitation of proteins identified by proteogenomic analysis of ovarian cancer

DOE PAGES

Song, Ehwang; Gao, Yuqian; Wu, Chaochao; ...

2017-07-19

Here, mass spectrometry (MS) based targeted proteomic methods such as selected reaction monitoring (SRM) are becoming the method of choice for preclinical verification of candidate protein biomarkers. The Clinical Proteomic Tumor Analysis Consortium (CPTAC) of the National Cancer Institute has investigated the standardization and analytical validation of the SRM assays and demonstrated robust analytical performance on different instruments across different laboratories. An Assay Portal has also been established by CPTAC to provide the research community a resource consisting of large set of targeted MS-based assays, and a depository to share assays publicly, providing that assays meet the guidelines proposed bymore » CPTAC. Herein, we report 98 SRM assays covering 70 candidate protein biomarkers previously reported as associated with ovarian cancer that have been thoroughly characterized according to the CPTAC Assay Characterization Guidance Document. The experiments, methods and results for characterizing these SRM assays for their MS response, repeatability, selectivity, stability, and reproducible detection of endogenous analytes are described in detail.« less

Anti-tubulin drugs conjugated to anti-ErbB antibodies selectively radiosensitize.

PubMed

Adams, Stephen R; Yang, Howard C; Savariar, Elamprakash N; Aguilera, Joe; Crisp, Jessica L; Jones, Karra A; Whitney, Michael A; Lippman, Scott M; Cohen, Ezra E W; Tsien, Roger Y; Advani, Sunil J

2016-10-04

Tumour resistance to radiotherapy remains a barrier to improving cancer patient outcomes. To overcome radioresistance, certain drugs have been found to sensitize cells to ionizing radiation (IR). In theory, more potent radiosensitizing drugs should increase tumour kill and improve patient outcomes. In practice, clinical utility of potent radiosensitizing drugs is curtailed by off-target side effects. Here we report potent anti-tubulin drugs conjugated to anti-ErbB antibodies selectively radiosensitize to tumours based on surface receptor expression. While two classes of potent anti-tubulins, auristatins and maytansinoids, indiscriminately radiosensitize tumour cells, conjugating these potent anti-tubulins to anti-ErbB antibodies restrict their radiosensitizing capacity. Of translational significance, we report that a clinically used maytansinoid ADC, ado-trastuzumab emtansine (T-DM1), with IR prolongs tumour control in target expressing HER2+ tumours but not target negative tumours. In contrast to ErbB signal inhibition, our findings establish an alternative therapeutic paradigm for ErbB-based radiosensitization using antibodies to restrict radiosensitizer delivery.

Anti-tubulin drugs conjugated to anti-ErbB antibodies selectively radiosensitize

PubMed Central

Adams, Stephen R.; Yang, Howard C.; Savariar, Elamprakash N.; Aguilera, Joe; Crisp, Jessica L.; Jones, Karra A.; Whitney, Michael A.; Lippman, Scott M.; Cohen, Ezra E. W.; Tsien, Roger Y.; Advani, Sunil J.

2016-01-01

Tumour resistance to radiotherapy remains a barrier to improving cancer patient outcomes. To overcome radioresistance, certain drugs have been found to sensitize cells to ionizing radiation (IR). In theory, more potent radiosensitizing drugs should increase tumour kill and improve patient outcomes. In practice, clinical utility of potent radiosensitizing drugs is curtailed by off-target side effects. Here we report potent anti-tubulin drugs conjugated to anti-ErbB antibodies selectively radiosensitize to tumours based on surface receptor expression. While two classes of potent anti-tubulins, auristatins and maytansinoids, indiscriminately radiosensitize tumour cells, conjugating these potent anti-tubulins to anti-ErbB antibodies restrict their radiosensitizing capacity. Of translational significance, we report that a clinically used maytansinoid ADC, ado-trastuzumab emtansine (T-DM1), with IR prolongs tumour control in target expressing HER2+ tumours but not target negative tumours. In contrast to ErbB signal inhibition, our findings establish an alternative therapeutic paradigm for ErbB-based radiosensitization using antibodies to restrict radiosensitizer delivery. PMID:27698471

Protozoacidal Trojan-Horse: Use of a Ligand-Lytic Peptide for Selective Destruction of Symbiotic Protozoa within Termite Guts

PubMed Central

Sethi, Amit; Delatte, Jennifer; Foil, Lane; Husseneder, Claudia

2014-01-01

For novel biotechnology-based termite control, we developed a cellulose bait containing freeze-dried genetically engineered yeast which expresses a protozoacidal lytic peptide attached to a protozoa-recognizing ligand. The yeast acts as a ‘Trojan-Horse’ that kills the cellulose-digesting protozoa in the termite gut, which leads to the death of termites, presumably due to inefficient cellulose digestion. The ligand targets the lytic peptide specifically to protozoa, thereby increasing its protozoacidal efficiency while protecting non-target organisms. After ingestion of the bait, the yeast propagates in the termite's gut and is spread throughout the termite colony via social interactions. This novel paratransgenesis-based strategy could be a good supplement for current termite control using fortified biological control agents in addition to chemical insecticides. Moreover, this ligand-lytic peptide system could be used for drug development to selectively target disease-causing protozoa in humans or other vertebrates. PMID:25198727

SDSS-IV eBOSS emission-line galaxy pilot survey

DOE PAGES

Comparat, J.; Delubac, T.; Jouvel, S.; ...

2016-08-09

The Sloan Digital Sky Survey IV extended Baryonic Oscillation Spectroscopic Survey (SDSS-IV/eBOSS) will observe 195,000 emission-line galaxies (ELGs) to measure the Baryonic Acoustic Oscillation standard ruler (BAO) at redshift 0.9. To test different ELG selection algorithms, 9,000 spectra were observed with the SDSS spectrograph as a pilot survey based on data from several imaging surveys. First, using visual inspection and redshift quality flags, we show that the automated spectroscopic redshifts assigned by the pipeline meet the quality requirements for a reliable BAO measurement. We also show the correlations between sky emission, signal-to-noise ratio in the emission lines, and redshift error.more » Then we provide a detailed description of each target selection algorithm we tested and compare them with the requirements of the eBOSS experiment. As a result, we provide reliable redshift distributions for the different target selection schemes we tested. Lastly, we determine an target selection algorithms that is best suited to be applied on DECam photometry because they fulfill the eBOSS survey efficiency requirements.« less

Identification of chondrocyte-binding peptides by phage display.

PubMed

Cheung, Crystal S F; Lui, Julian C; Baron, Jeffrey

2013-07-01

As an initial step toward targeting cartilage tissue for potential therapeutic applications, we sought cartilage-binding peptides using phage display, a powerful technology for selection of peptides that bind to molecules of interest. A library of phage displaying random 12-amino acid peptides was iteratively incubated with cultured chondrocytes to select phage that bind cartilage. The resulting phage clones demonstrated increased affinity to chondrocytes by ELISA, when compared to a wild-type, insertless phage. Furthermore, the selected phage showed little preferential binding to other cell types, including primary skin fibroblast, myocyte and hepatocyte cultures, suggesting a tissue-specific interaction. Immunohistochemical staining revealed that the selected phage bound chondrocytes themselves and the surrounding extracellular matrix. FITC-tagged peptides were synthesized based on the sequence of cartilage-binding phage clones. These peptides, but not a random peptide, bound cultured chondrocytes, and extracelluar matrix. In conclusion, using phage display, we identified peptide sequences that specifically target chondrocytes. We anticipate that such peptides may be coupled to therapeutic molecules to provide targeted treatment for cartilage disorders. Copyright © 2013 Orthopaedic Research Society.

A bilateral advantage in controlling access to visual short-term memory.

PubMed

Holt, Jessica L; Delvenne, Jean-François

2014-01-01

Recent research on visual short-term memory (VSTM) has revealed the existence of a bilateral field advantage (BFA--i.e., better memory when the items are distributed in the two visual fields than if they are presented in the same hemifield) for spatial location and bar orientation, but not for color (Delvenne, 2005; Umemoto, Drew, Ester, & Awh, 2010). Here, we investigated whether a BFA in VSTM is constrained by attentional selective processes. It has indeed been previously suggested that the BFA may be a general feature of selective attention (Alvarez & Cavanagh, 2005; Delvenne, 2005). Therefore, the present study examined whether VSTM for color benefits from bilateral presentation if attentional selective processes are particularly engaged. Participants completed a color change detection task whereby target stimuli were presented either across both hemifields or within one single hemifield. In order to engage attentional selective processes, some trials contained irrelevant stimuli that needed to be ignored. Targets were selected based on spatial locations (Experiment 1) or on a salient feature (Experiment 2). In both cases, the results revealed a BFA only when irrelevant stimuli were presented among the targets. Overall, the findings strongly suggest that attentional selective processes at encoding can constrain whether a BFA is observed in VSTM.

Identification of DNA primase inhibitors via a combined fragment-based and virtual screening

NASA Astrophysics Data System (ADS)

Ilic, Stefan; Akabayov, Sabine R.; Arthanari, Haribabu; Wagner, Gerhard; Richardson, Charles C.; Akabayov, Barak

2016-11-01

The structural differences between bacterial and human primases render the former an excellent target for drug design. Here we describe a technique for selecting small molecule inhibitors of the activity of T7 DNA primase, an ideal model for bacterial primases due to their common structural and functional features. Using NMR screening, fragment molecules that bind T7 primase were identified and then exploited in virtual filtration to select larger molecules from the ZINC database. The molecules were docked to the primase active site using the available primase crystal structure and ranked based on their predicted binding energies to identify the best candidates for functional and structural investigations. Biochemical assays revealed that some of the molecules inhibit T7 primase-dependent DNA replication. The binding mechanism was delineated via NMR spectroscopy. Our approach, which combines fragment based and virtual screening, is rapid and cost effective and can be applied to other targets.

Selective Inhibition of Plant Serine Hydrolases by Agrochemicals Revealed by Competitive ABPP

PubMed Central

Kaschani, Farnusch; Nickel, Sabrina; Pandey, Bikram; Cravatt, Benjamin F.; Kaiser, Markus; van der Hoorn, Renier A. L.

2013-01-01

Organophosphate and –phosphonates and their thiol derivatives are often used in agroindustry as herbicides and insecticides, but their potential off-targets in the plant and their consumers are poorly investigated. Here, we use competitive Activity-based Protein Profiling (ABPP) of serine hydrolases (SHs) to detect targets of these agrochemicals and other compounds in Arabidopsis thaliana. Using broad-range and specific probes, and by overexpression of various SHs in planta, we are able to confirm eight SH-compound interactions, including selective inhibition of carboxylesterase CXE12, prolyloligopeptidase, methylesterase MES2 and tripeptidyl peptidase TPP2. These observations can be used for the design of novel probes and selective inhibitors and may help to assess physiological effects of agrochemicals on crop plants. PMID:21764588

Oligonucleotide Sensor Based on Selective Capture of Upconversion Nanoparticles Triggered by Target-Induced DNA Interstrand Ligand Reaction

PubMed Central

2017-01-01

We present a sensor that exploits the phenomenon of upconversion luminescence to detect the presence of specific sequences of small oligonucleotides such as miRNAs among others. The sensor is based on NaYF4:Yb,Er@SiO2 nanoparticles functionalized with ssDNA that contain azide groups on the 3′ ends. In the presence of a target sequence, interstrand ligation is possible via the click-reaction between one azide of the upconversion probe and a DBCO-ssDNA-biotin probe present in the solution. As a result of this specific and selective process, biotin is covalently attached to the surface of the upconversion nanoparticles. The presence of biotin on the surface of the nanoparticles allows their selective capture on a streptavidin-coated support, giving a luminescent signal proportional to the amount of target strands present in the test samples. With the aim of studying the analytical properties of the sensor, total RNA samples were extracted from healthy mosquitoes and were spiked-in with a specific target sequence at different concentrations. The result of these experiments revealed that the sensor was able to detect 10–17 moles per well (100 fM) of the target sequence in mixtures containing 100 ng of total RNA per well. A similar limit of detection was found for spiked human serum samples, demonstrating the suitability of the sensor for detecting specific sequences of small oligonucleotides under real conditions. In contrast, in the presence of noncomplementary sequences or sequences having mismatches, the luminescent signal was negligible or conspicuously reduced. PMID:28332400

Optical filter selection for high confidence discrimination of strongly overlapping infrared chemical spectra.

PubMed

Major, Kevin J; Poutous, Menelaos K; Ewing, Kenneth J; Dunnill, Kevin F; Sanghera, Jasbinder S; Aggarwal, Ishwar D

2015-09-01

Optical filter-based chemical sensing techniques provide a new avenue to develop low-cost infrared sensors. These methods utilize multiple infrared optical filters to selectively measure different response functions for various chemicals, dependent on each chemical's infrared absorption. Rather than identifying distinct spectral features, which can then be used to determine the identity of a target chemical, optical filter-based approaches rely on measuring differences in the ensemble response between a given filter set and specific chemicals of interest. Therefore, the results of such methods are highly dependent on the original optical filter choice, which will dictate the selectivity, sensitivity, and stability of any filter-based sensing method. Recently, a method has been developed that utilizes unique detection vector operations defined by optical multifilter responses, to discriminate between volatile chemical vapors. This method, comparative-discrimination spectral detection (CDSD), is a technique which employs broadband optical filters to selectively discriminate between chemicals with highly overlapping infrared absorption spectra. CDSD has been shown to correctly distinguish between similar chemicals in the carbon-hydrogen stretch region of the infrared absorption spectra from 2800-3100 cm(-1). A key challenge to this approach is how to determine which optical filter sets should be utilized to achieve the greatest discrimination between target chemicals. Previous studies used empirical approaches to select the optical filter set; however this is insufficient to determine the optimum selectivity between strongly overlapping chemical spectra. Here we present a numerical approach to systematically study the effects of filter positioning and bandwidth on a number of three-chemical systems. We describe how both the filter properties, as well as the chemicals in each set, affect the CDSD results and subsequent discrimination. These results demonstrate the importance of choosing the proper filter set and chemicals for comparative discrimination, in order to identify the target chemical of interest in the presence of closely matched chemical interferents. These findings are an integral step in the development of experimental prototype sensors, which will utilize CDSD.

Selection and characterization, application of a DNA aptamer targeted to Streptococcus pyogenes in cooked chicken.

PubMed

Huang, Yukun; Wang, Xin; Duan, Nuo; Xia, Yu; Wang, Zhouping; Che, Zhenming; Wang, Lijun; Yang, Xiao; Chen, Xianggui

2018-06-15

An aptamer against Streptococcus pyogenes was selected and identified, and a fluorescent method based on the reported aptamer was established to detect S. pyogenes in the cooked chicken. Through a twelve rounds of whole-bacterium SELEX (systematic evolution of ligands by exponential enrichment) selection in vitro, a set of aptamers binding to the whole cell of S. pyogenes were generated, harvesting a low-level dissociation constant (K d ) value of 44 ± 5 nmol L -1 of aptamer S-12. Aptamer-based quantification of S. pyogenes in the cooked chicken sample was implemented in a fluorescence resonance energy transfer-based assay by using graphene oxide, resulting in a limit of detection of 70 cfu mL -1 . The selected aptamer showed affinity and selectivity recognizing S. pyogenes; besides, more biosensors based on the selected aptamer as a molecular recognition element could be developed in the innovative determinations of S. pyogenes. Copyright © 2018 Elsevier Inc. All rights reserved.

A label-free DNA hairpin biosensor for colorimetric detection of target with suitable functional DNA partners.

PubMed

Nie, Ji; Zhang, De-Wen; Tie, Cai; Zhou, Ying-Lin; Zhang, Xin-Xiang

2013-11-15

The combination of aptamer and peroxidase-mimicking DNAzyme within a hairpin structure can form a functional DNA probe. The activities of both aptamer (as biorecognition element) and DNAzyme (as signal amplification element) are blocked via base pairing in the hairpin structure. The presence of target triggers the opening of the hairpin to form target/aptamer complex and releases G-quadruplex sequence which can generate amplified colorimetric signals. In this work, we elaborated a universal and simple procedure to design an efficient and sensitive hairpin probe with suitable functional DNA partners. A fill-in-the-blank process was developed for sequence design, and two key points including the pretreatment of the hairpin probe and the selection of suitable signal transducer sequence were proved to enhance the detection sensitivity. Cocaine was chosen as a model target for a proof of concept. A series of hairpins with different numbers of base pairs in the stem region were prepared. Hairpin-C10 with ten base pairs was screened out and a lowest detectable cocaine concentration of 5 μM by colorimetry was obtained. The proposed functional DNA hairpin showed good selectivity and satisfactory analysis in spiked biologic fluid. The whole "mix-and-measure" detection based on DNA hairpin without the need of immobilization and labeling was indicated to be time and labor saving. The strategy has potential to be transplanted into more smart hairpins toward other targets for general application in bioanalytical chemistry. Copyright © 2013 Elsevier B.V. All rights reserved.

Optimization of Self-Directed Target Coverage in Wireless Multimedia Sensor Network

PubMed Central

Yang, Yang; Wang, Yufei; Pi, Dechang; Wang, Ruchuan

2014-01-01

Video and image sensors in wireless multimedia sensor networks (WMSNs) have directed view and limited sensing angle. So the methods to solve target coverage problem for traditional sensor networks, which use circle sensing model, are not suitable for WMSNs. Based on the FoV (field of view) sensing model and FoV disk model proposed, how expected multimedia sensor covers the target is defined by the deflection angle between target and the sensor's current orientation and the distance between target and the sensor. Then target coverage optimization algorithms based on expected coverage value are presented for single-sensor single-target, multisensor single-target, and single-sensor multitargets problems distinguishingly. Selecting the orientation that sensor rotated to cover every target falling in the FoV disk of that sensor for candidate orientations and using genetic algorithm to multisensor multitargets problem, which has NP-complete complexity, then result in the approximated minimum subset of sensors which covers all the targets in networks. Simulation results show the algorithm's performance and the effect of number of targets on the resulting subset. PMID:25136667

Dorsal premotor cortex: neural correlates of reach target decisions based on a color-location matching rule and conflicting sensory evidence

PubMed Central

Coallier, Émilie; Michelet, Thomas

2015-01-01

We recorded single-neuron activity in dorsal premotor (PMd) and primary motor cortex (M1) of two monkeys in a reach-target selection task. The monkeys chose between two color-coded potential targets by determining which target's color matched the predominant color of a multicolored checkerboard-like Decision Cue (DC). Different DCs contained differing numbers of colored squares matching each target. The DCs provided evidence about the correct target ranging from unambiguous (one color only) to very ambiguous and conflicting (nearly equal number of squares of each color). Differences in choice behavior (reach response times and success rates as a function of DC ambiguity) of the monkeys suggested that each applied a different strategy for using the target-choice evidence in the DCs. Nevertheless, the appearance of the DCs evoked a transient coactivation of PMd neurons preferring both potential targets in both monkeys. Reach response time depended both on how long it took activity to increase in neurons that preferred the chosen target and on how long it took to suppress the activity of neurons that preferred the rejected target, in both correct-choice and error-choice trials. These results indicate that PMd neurons in this task are not activated exclusively by a signal proportional to the net color bias of the DCs. They are instead initially modulated by the conflicting evidence supporting both response choices; final target selection may result from a competition between representations of the alternative choices. The results also indicate a temporal overlap between action selection and action initiation processes in PMd and M1. PMID:25787952

Targeted drug delivery using genetically engineered diatom biosilica.

PubMed

Delalat, Bahman; Sheppard, Vonda C; Rasi Ghaemi, Soraya; Rao, Shasha; Prestidge, Clive A; McPhee, Gordon; Rogers, Mary-Louise; Donoghue, Jacqueline F; Pillay, Vinochani; Johns, Terrance G; Kröger, Nils; Voelcker, Nicolas H

2015-11-10

The ability to selectively kill cancerous cell populations while leaving healthy cells unaffected is a key goal in anticancer therapeutics. The use of nanoporous silica-based materials as drug-delivery vehicles has recently proven successful, yet production of these materials requires costly and toxic chemicals. Here we use diatom microalgae-derived nanoporous biosilica to deliver chemotherapeutic drugs to cancer cells. The diatom Thalassiosira pseudonana is genetically engineered to display an IgG-binding domain of protein G on the biosilica surface, enabling attachment of cell-targeting antibodies. Neuroblastoma and B-lymphoma cells are selectively targeted and killed by biosilica displaying specific antibodies sorbed with drug-loaded nanoparticles. Treatment with the same biosilica leads to tumour growth regression in a subcutaneous mouse xenograft model of neuroblastoma. These data indicate that genetically engineered biosilica frustules may be used as versatile 'backpacks' for the targeted delivery of poorly water-soluble anticancer drugs to tumour sites.

Sequence-specific antimicrobials using efficiently delivered RNA-guided nucleases.

PubMed

Citorik, Robert J; Mimee, Mark; Lu, Timothy K

2014-11-01

Current antibiotics tend to be broad spectrum, leading to indiscriminate killing of commensal bacteria and accelerated evolution of drug resistance. Here, we use CRISPR-Cas technology to create antimicrobials whose spectrum of activity is chosen by design. RNA-guided nucleases (RGNs) targeting specific DNA sequences are delivered efficiently to microbial populations using bacteriophage or bacteria carrying plasmids transmissible by conjugation. The DNA targets of RGNs can be undesirable genes or polymorphisms, including antibiotic resistance and virulence determinants in carbapenem-resistant Enterobacteriaceae and enterohemorrhagic Escherichia coli. Delivery of RGNs significantly improves survival in a Galleria mellonella infection model. We also show that RGNs enable modulation of complex bacterial populations by selective knockdown of targeted strains based on genetic signatures. RGNs constitute a class of highly discriminatory, customizable antimicrobials that enact selective pressure at the DNA level to reduce the prevalence of undesired genes, minimize off-target effects and enable programmable remodeling of microbiota.

Promysalin Elicits Species-Selective Inhibition of Pseudomonas aeruginosa by Targeting Succinate Dehydrogenase.

PubMed

Keohane, Colleen E; Steele, Andrew D; Fetzer, Christian; Khowsathit, Jittasak; Van Tyne, Daria; Moynié, Lucile; Gilmore, Michael S; Karanicolas, John; Sieber, Stephan A; Wuest, William M

2018-02-07

Natural products have served as an inspiration to scientists both for their complex three-dimensional architecture and exquisite biological activity. Promysalin is one such Pseudomonad secondary metabolite that exhibits narrow-spectrum antibacterial activity, originally isolated from the rhizosphere. We herein utilize affinity-based protein profiling (AfBPP) to identify succinate dehydrogenase (Sdh) as the biological target of the natural product. The target was further validated in silico, in vitro, in vivo, and through the selection, and sequencing, of a resistant mutant. Succinate dehydrogenase plays an essential role in primary metabolism of Pseudomonas aeruginosa as the only enzyme that is involved both in the tricarboxylic acid cycle (TCA) and in respiration via the electron transport chain. These findings add credence to other studies that suggest that the TCA cycle is an understudied target in the development of novel therapeutics to combat P. aeruginosa, a significant pathogen in clinical settings.

Development of molecularly imprinted polymer-based field effect transistor for sugar chain sensing

NASA Astrophysics Data System (ADS)

Nishitani, Shoichi; Kajisa, Taira; Sakata, Toshiya

2017-04-01

In this study, we developed a molecularly imprinted polymer-based field-effect transistor (MIP-gate FET) for selectively detecting sugar chains in aqueous media, focusing on 3‧-sialyllactose (3SLac) and 6‧-sialyllactose (6SLac). The FET biosensor enables the detection of small molecules as long as they have intrinsic charges. Additionally, the MIP gels include the template for the target molecule, which is selectively trapped without requiring enzyme-target molecule reaction. The MIP gels were synthesized on the gate surface of the FET device, including phenylboronic acid (PBA), which enables binding to sugar chains. Firstly, the 3SLac-MIP-gate FET quantitatively detected 3SLac at µM levels. This is because the FET device recognized the change in molecular charges on the basis of PBA-3SLac binding in the MIP gel. Moreover, 3SLac was selectively detected using the 3SLac- and 6SLac-MIP-gate FETs to some extent, where the detecting signal from the competent was suppressed by 40% at maximum. Therefore, a platform based on the MIP-coupled FET biosensor is suitable for a selective biosensing system in an enzyme-free manner, which can be applied widely in medical fields. However, we need to further improve the selectivity of MIP-gate FETs to discriminate more clearly between similar structures of sugar chains such as 3SLac and 6SLac.

Identification of novel malarial cysteine protease inhibitors using structure-based virtual screening of a focused cysteine protease inhibitor library.

PubMed

Shah, Falgun; Mukherjee, Prasenjit; Gut, Jiri; Legac, Jennifer; Rosenthal, Philip J; Tekwani, Babu L; Avery, Mitchell A

2011-04-25

Malaria, in particular that caused by Plasmodium falciparum , is prevalent across the tropics, and its medicinal control is limited by widespread drug resistance. Cysteine proteases of P. falciparum , falcipain-2 (FP-2) and falcipain-3 (FP-3), are major hemoglobinases, validated as potential antimalarial drug targets. Structure-based virtual screening of a focused cysteine protease inhibitor library built with soft rather than hard electrophiles was performed against an X-ray crystal structure of FP-2 using the Glide docking program. An enrichment study was performed to select a suitable scoring function and to retrieve potential candidates against FP-2 from a large chemical database. Biological evaluation of 50 selected compounds identified 21 diverse nonpeptidic inhibitors of FP-2 with a hit rate of 42%. Atomic Fukui indices were used to predict the most electrophilic center and its electrophilicity in the identified hits. Comparison of predicted electrophilicity of electrophiles in identified hits with those in known irreversible inhibitors suggested the soft-nature of electrophiles in the selected target compounds. The present study highlights the importance of focused libraries and enrichment studies in structure-based virtual screening. In addition, few compounds were screened against homologous human cysteine proteases for selectivity analysis. Further evaluation of structure-activity relationships around these nonpeptidic scaffolds could help in the development of selective leads for antimalarial chemotherapy.

Targeted Molecular Imaging of Cancer Cells Using MS2-Based 129 Xe NMR

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

Jeong, Keunhong; Netirojjanakul, Chawita; Munch, Henrik K.

Targeted, selective, and highly sensitive 129Xe NMR nanoscale biosensors have been synthesized using a spherical MS2 viral capsid, Cryptophane A molecules, and DNA aptamers. The biosensors showed strong binding specificity toward targeted lymphoma cells (Ramos line). Hyperpolarized 129Xe NMR signal contrast and hyper-CEST 129Xe MRI image contrast indicated its promise as highly sensitive hyperpolarized 129Xe NMR nanoscale biosensor for future applications in cancer detection in vivo.

Aptamer entrapment in microfluidic channel using one-step sol-gel process, in view of the integration of a new selective extraction phase for lab-on-a-chip.

PubMed

Perréard, Camille; d'Orlyé, Fanny; Griveau, Sophie; Liu, Baohong; Bedioui, Fethi; Varenne, Anne

2017-10-01

There is a great demand for integrating sample treatment into μTASs. In this context, we developed a new sol-gel phase for extraction of trace compounds in complex matrices. For this purpose, the incorporation of aptamers in silica-based gel within PDMS/glass microfluidic channels was performed for the first time by a one-step sol-gel process. The effective gel attachment onto microchannel walls and aptamer incorporation in the polymerized gel were evaluated using fluorescence microscopy. A good gel stability and aptamer incorporation inside the microchannel was demonstrated upon rinsing and over storage time. The ability of gel-encapsulated aptamers to interact with its specific target (either sulforhodamine B as model fluorescent target, or diclofenac, a pain killer drug) was assessed too. The binding capacity of entrapped aptamers was quantified (in the micromolar range) and the selectivity of the interaction was evidenced. Preservation of aptamers binding affinity to target molecules was therefore demonstrated. Dissociation constant of the aptamer-target complex and interaction selectivity were evaluated similar to those in bulk solution. This opens the way to new selective on-chip SPE techniques for sample pretreatment. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Highly stable aptamers selected from a 2'-fully modified fGmH RNA library for targeting biomaterials.

PubMed

Friedman, Adam D; Kim, Dongwook; Liu, Rihe

2015-01-01

When developed as targeting ligands for the in vivo delivery of biomaterials to biological systems, RNA aptamers immediately face numerous obstacles, in particular nuclease degradation and post-selection 2' modification. This study aims to develop a novel class of highly stable, 2'-fully modified RNA aptamers that are ideal for the targeted delivery of biomaterials. We demonstrated the facile transcription of a fGmH (2'-F-dG, 2'-OMe-dA/dC/dU) RNA library with unexpected hydrophobicity, the direct selection of aptamers from a fGmH RNA library that bind Staphylococcus aureus Protein A (SpA) as a model target, and the superior nuclease and serum stability of these aptamers compared to 2'-partially modified RNA variants. Characterizations of fGmH RNA aptamers binding to purified SpA and to endogenous SpA present on the surface of S. aureus cells demonstrate fGmH RNA aptamer selectivity and stability. Significantly, fGmH RNA aptamers were able to functionalize, stabilize, and specifically deliver aggregation-prone silver nanoparticles (AgNPs) to S. aureus with SpA-dependent antimicrobial effects. This study describes a novel aptamer class with considerable potential to improve the in vivo applicability of nucleic acid-based affinity molecules to biomaterials.

Miklós Bodanszky Award Lecture: Advances in the selective targeting of protein phosphatase-1 and phosphatase-2A with peptides.

PubMed

Köhn, Maja

2017-10-01

Protein phosphatase-1 and phosphatase-2A are two ubiquitously expressed enzymes known to catalyze the majority of dephosphorylation reactions on serine and threonine inside cells. They play roles in most cellular processes and are tightly regulated by regulatory subunits in holoenzymes. Their misregulation and malfunction contribute to disease development and progression, such as in cancer, diabetes, viral infections, and neurological as well as heart diseases. Therefore, targeting these phosphatases for therapeutic use would be highly desirable; however, their complex regulation and high conservation of the active site have been major hurdles for selectively targeting them in the past. In the last decade, new approaches have been developed to overcome these hurdles and have strongly revived the field. I will focus here on peptide-based approaches, which contributed to showing that these phosphatases can be targeted selectively and aided in rethinking the design of selective phosphatase modulators. Finally, I will give a perspective on www.depod.org, the human dephosphorylation database, and how it can aid phosphatase modulator design. © 2017 The Authors. Journal of Peptide Science published by European Peptide Society and John Wiley & Sons Ltd. © 2017 The Authors. Journal of Peptide Science published by European Peptide Society and John Wiley & Sons Ltd.

Biomarker-Based Metabolic Labeling for Redirected and Enhanced Immune Response.

PubMed

Li, Shanshan; Yu, Bingchen; Wang, Jiajia; Zheng, Yueqin; Zhang, Huajie; Walker, Margaret J; Yuan, Zhengnan; Zhu, He; Zhang, Jun; Wang, Peng George; Wang, Binghe

2018-06-01

Installation of an antibody-recruiting moiety on the surface of disease-relevant cells can lead to the selective destruction of targets by the immune system. Such an approach can be an alternative strategy to traditional chemotherapeutics in cancer therapy and possibly other diseases. Herein we describe the development of a new strategy to selectively label targets with an antibody-recruiting moiety through its covalent and stable installation, complementing existing methods of employing reversible binding. This is achieved through selective delivery of 1,3,4- O-acetyl- N-azidoacetylmannosamine (Ac 3 ManNAz) to folate receptor-overexpressing cells using an Ac 3 ManNAz-folate conjugate via a cleavable linker. As such, Ac 3 ManNAz is converted to cell surface glycan bearing an azido group, which serves as an anchor to introduce l-rhamnose (Rha), a hapten, via a click reaction with aza-dibenzocyclooctyne (DBCO)-Rha. We tested this method in several cell lines including KB, HEK-293, and MCF7 and were able to demonstrate the following: 1) Rha can be selectively installed to the folate receptor overexpressing cell surface and 2) the Rha installed on the target surface can recruit anti-rhamnose (anti-Rha) antibodies, leading to the destruction of target cells via complement-dependent cytotoxicity (CDC) and antibody-dependent cellular phagocytosis (ADCP).

Cell selection and characterization of a novel human endothelial cell specific nanobody.

PubMed

Ahmadvand, Davoud; Rasaee, Mohammad J; Rahbarizadeh, Fatemeh; Kontermann, Roland E; Sheikholislami, Farzaneh

2009-05-01

Antibody-based targeting of angiogenesis and vascular targeting therapy of cancer are extremely attractive conceptually and open new important diagnostic and therapeutic opportunities. Compelling evidence suggests that CD105 represents an ideal target for anti-angiogenic therapy and its presence in solid tumor vasculature has prognostic value. Camelids produce functional antibodies devoid of light chains and constant heavy chain domain (CH1). Nanobodies, the antigen-binding fragments of such heavy chain antibodies, are therefore comprised in one single domain. The aim of this study was to explore the possibilities of using anti-endoglin nanobody as an angiogenesis inhibitor. The anti-CD105 nanobody (AR-86a) was isolated from immune library by selections on purified antigens and target cells. Immunocytochemistry and FACS analysis showed that the purified nanobody reacted specifically with human umbilical vein endothelial cells (HUVECs) but not with other cell lines such as MDA-MB-453, Mel III, T-47D, MCF-7, AGO and HT 29. Further, selected nanobody potently inhibited proliferation of human endothelial cells and formation of capillary-like structures. This selected high affinity anti-endoglin nanobody may offer high specificity towards tumors with reduced side effects, and may be less likely to elicit drug resistance compared to conventional therapy.

A bend, flip and trap mechanism for transposon integration

PubMed Central

Morris, Elizabeth R; Grey, Heather; McKenzie, Grant; Jones, Anita C; Richardson, Julia M

2016-01-01

Cut-and-paste DNA transposons of the mariner/Tc1 family are useful tools for genome engineering and are inserted specifically at TA target sites. A crystal structure of the mariner transposase Mos1 (derived from Drosophila mauritiana), in complex with transposon ends covalently joined to target DNA, portrays the transposition machinery after DNA integration. It reveals severe distortion of target DNA and flipping of the target adenines into extra-helical positions. Fluorescence experiments confirm dynamic base flipping in solution. Transposase residues W159, R186, F187 and K190 stabilise the target DNA distortions and are required for efficient transposon integration and transposition in vitro. Transposase recognises the flipped target adenines via base-specific interactions with backbone atoms, offering a molecular basis for TA target sequence selection. Our results will provide a template for re-designing mariner/Tc1 transposases with modified target specificities. DOI: http://dx.doi.org/10.7554/eLife.15537.001 PMID:27223327

An efficient procedure for marker-free mutagenesis of S. coelicolor by site-specific recombination for secondary metabolite overproduction.

PubMed

Zhang, Bo; Zhang, Lin; Dai, Ruixue; Yu, Meiying; Zhao, Guoping; Ding, Xiaoming

2013-01-01

Streptomyces bacteria are known for producing important natural compounds by secondary metabolism, especially antibiotics with novel biological activities. Functional studies of antibiotic-biosynthesizing gene clusters are generally through homologous genomic recombination by gene-targeting vectors. Here, we present a rapid and efficient method for construction of gene-targeting vectors. This approach is based on Streptomyces phage φBT1 integrase-mediated multisite in vitro site-specific recombination. Four 'entry clones' were assembled into a circular plasmid to generate the destination gene-targeting vector by a one-step reaction. The four 'entry clones' contained two clones of the upstream and downstream flanks of the target gene, a selectable marker and an E. coli-Streptomyces shuttle vector. After targeted modification of the genome, the selectable markers were removed by φC31 integrase-mediated in vivo site-specific recombination between pre-placed attB and attP sites. Using this method, part of the calcium-dependent antibiotic (CDA) and actinorhodin (Act) biosynthetic gene clusters were deleted, and the rrdA encoding RrdA, a negative regulator of Red production, was also deleted. The final prodiginine production of the engineered strain was over five times that of the wild-type strain. This straightforward φBT1 and φC31 integrase-based strategy provides an alternative approach for rapid gene-targeting vector construction and marker removal in streptomycetes.

A pretargeted nanoparticle system for tumor cell labeling

PubMed Central

Gunn, Jonathan; Park, Steven I.; Veiseh, Omid; Press, Oliver W.; Zhang, Miqin

2011-01-01

Nanoparticle-based cancer diagnostics and therapeutics can be significantly enhanced by selective tissue localization, but the strategy can be complicated by the requirement of a targeting ligand conjugated on nanoparticles, that is specific to only one or a limited few types of neoplastic cells, necessitating the development of multiple nanoparticle systems for different diseases. Here, we present a new nanoparticle system that capitalizes on a targeting pretreatment strategy, where a circulating fusion protein (FP) selectively prelabels the targeted cellular epitope, and a biotinylated iron oxide nanoparticle serves as a secondary label that binds to the FP on the target cell. This approach enables a single nanoparticle formulation to be used with any one of existing fusion proteins to bind a variety of target cells. We demonstrated this approach with two fusion proteins against two model cancer cell lines: lymphoma (Ramos) and leukemia (Jurkat), which showed 72.2% and 91.1% positive labeling, respectively. Notably, TEM analysis showed that a large nanoparticle population was endocytosed via attachment to the non-internalizing CD20 epitope. PMID:21107453

A pretargeted nanoparticle system for tumor cell labeling.

PubMed

Gunn, Jonathan; Park, Steven I; Veiseh, Omid; Press, Oliver W; Zhang, Miqin

2011-03-01

Nanoparticle-based cancer diagnostics and therapeutics can be significantly enhanced by selective tissue localization, but the strategy can be complicated by the requirement of a targeting ligand conjugated on nanoparticles, that is specific to only one or a limited few types of neoplastic cells, necessitating the development of multiple nanoparticle systems for different diseases. Here, we present a new nanoparticle system that capitalizes on a targeting pretreatment strategy, where a circulating fusion protein (FP) selectively prelabels the targeted cellular epitope, and a biotinylated iron oxide nanoparticle serves as a secondary label that binds to the FP on the target cell. This approach enables a single nanoparticle formulation to be used with any one of existing fusion proteins to bind a variety of target cells. We demonstrated this approach with two fusion proteins against two model cancer cell lines: lymphoma (Ramos) and leukemia (Jurkat), which showed 72.2% and 91.1% positive labeling, respectively. Notably, TEM analysis showed that a large nanoparticle population was endocytosed via attachment to the non-internalizing CD20 epitope.

Studies for aluminum photoionization in hot cavity for the selective production of exotic species projecta)

NASA Astrophysics Data System (ADS)

Scarpa, D.; Vasquez, J.; Tomaselli, A.; Grassi, D.; Biasetto, L.; Cavazza, A.; Corradetti, S.; Manzolaro, M.; Montano, J.; Andrighetto, A.; Prete, G.

2012-02-01

Selective production of exotic species (SPES) is an ISOL-based accelerator facility that will be built in the Legnaro INFN Laboratory (Italy), intended to provide an intense neutron-rich radioactive ion beams obtained by proton induced fission of an uranium carbide target. Beside this main target, a silicon carbide (SiC) target will the first to be used to deliver some p-rich beams. This target will validate also the functionality of the SPES facility with aluminum beam as result of hitting SiC target with protons. In the past off-line studies on laser photoionization of aluminum have performed in Pavia Spectroscopy Laboratory and in Laboratori Nazionali di Legnaro where, recently, a XeCl excimer laser was installed in order to test the laser ionization in the SPES hot cavity. Results are promising to justify further studies with this technique, aiming a better characterization of the SPES ion extraction capability under laser photoionization.

Integration of systems biology with bioprocess engineering: L: -threonine production by systems metabolic engineering of Escherichia coli.

PubMed

Lee, Sang Yup; Park, Jin Hwan

2010-01-01

Random mutation and selection or targeted metabolic engineering without consideration of its impact on the entire metabolic and regulatory networks can unintentionally cause genetic alterations in the region, which is not directly related to the target metabolite. This is one of the reasons why strategies for developing industrial strains are now shifted towards targeted metabolic engineering based on systems biology, which is termed systems metabolic engineering. Using systems metabolic engineering strategies, all the metabolic engineering works are conducted in systems biology framework, whereby entire metabolic and regulatory networks are thoroughly considered in an integrated manner. The targets for purposeful engineering are selected after all possible effects on the entire metabolic and regulatory networks are thoroughly considered. Finally, the strain, which is capable of producing the target metabolite to a high level close to the theoretical maximum value, can be constructed. Here we review strategies and applications of systems biology successfully implemented on bioprocess engineering, with particular focus on developing L: -threonine production strains of Escherichia coli.

CETSA screening identifies known and novel thymidylate synthase inhibitors and slow intracellular activation of 5-fluorouracil

PubMed Central

Almqvist, Helena; Axelsson, Hanna; Jafari, Rozbeh; Dan, Chen; Mateus, André; Haraldsson, Martin; Larsson, Andreas; Molina, Daniel Martinez; Artursson, Per; Lundbäck, Thomas; Nordlund, Pär

2016-01-01

Target engagement is a critical factor for therapeutic efficacy. Assessment of compound binding to native target proteins in live cells is therefore highly desirable in all stages of drug discovery. We report here the first compound library screen based on biophysical measurements of intracellular target binding, exemplified by human thymidylate synthase (TS). The screen selected accurately for all the tested known drugs acting on TS. We also identified TS inhibitors with novel chemistry and marketed drugs that were not previously known to target TS, including the DNA methyltransferase inhibitor decitabine. By following the cellular uptake and enzymatic conversion of known drugs we correlated the appearance of active metabolites over time with intracellular target engagement. These data distinguished a much slower activation of 5-fluorouracil when compared with nucleoside-based drugs. The approach establishes efficient means to associate drug uptake and activation with target binding during drug discovery. PMID:27010513

Visual working memory simultaneously guides facilitation and inhibition during visual search.

PubMed

Dube, Blaire; Basciano, April; Emrich, Stephen M; Al-Aidroos, Naseem

2016-07-01

During visual search, visual working memory (VWM) supports the guidance of attention in two ways: It stores the identity of the search target, facilitating the selection of matching stimuli in the search array, and it maintains a record of the distractors processed during search so that they can be inhibited. In two experiments, we investigated whether the full contents of VWM can be used to support both of these abilities simultaneously. In Experiment 1, participants completed a preview search task in which (a) a subset of search distractors appeared before the remainder of the search items, affording participants the opportunity to inhibit them, and (b) the search target varied from trial to trial, requiring the search target template to be maintained in VWM. We observed the established signature of VWM-based inhibition-reduced ability to ignore previewed distractors when the number of distractors exceeds VWM's capacity-suggesting that VWM can serve this role while also representing the target template. In Experiment 2, we replicated Experiment 1, but added to the search displays a singleton distractor that sometimes matched the color (a task-irrelevant feature) of the search target, to evaluate capture. We again observed the signature of VWM-based preview inhibition along with attentional capture by (and, thus, facilitation of) singletons matching the target template. These findings indicate that more than one VWM representation can bias attention at a time, and that these representations can separately affect selection through either facilitation or inhibition, placing constraints on existing models of the VWM-based guidance of attention.

Beyond Helper Phage: Using "Helper Cells" to Select Peptide Affinity Ligands.

PubMed

Phipps, M Lisa; Lillo, Antoinetta M; Shou, Yulin; Schmidt, Emily N; Paavola, Chad D; Naranjo, Leslie; Bemdich, Sara; Swanson, Basil I; Bradbury, Andrew R M; Martinez, Jennifer S

2016-01-01

Peptides are important affinity ligands for microscopy, biosensing, and targeted delivery. However, because they can have low affinity for their targets, their selection from large naïve libraries can be challenging. When selecting peptidic ligands from display libraries, it is important to: 1) ensure efficient display; 2) maximize the ability to select high affinity ligands; and 3) minimize the effect of the display context on binding. The "helper cell" packaging system has been described as a tool to produce filamentous phage particles based on phagemid constructs with varying display levels, while remaining free of helper phage contamination. Here we report on the first use of this system for peptide display, including the systematic characterization and optimization of helper cells, their inefficient use in antibody display and their use in creating and selecting from a set of phage display peptide libraries. Our libraries were analyzed with unprecedented precision by standard or deep sequencing, and shown to be superior in quality than commercial gold standards. Using our helper cell libraries, we have obtained ligands recognizing Yersinia pestis surface antigen F1V and L-glutamine-binding periplasmic protein QBP. In the latter case, unlike any of the peptide library selections described so far, we used a combination of phage and yeast display to select intriguing peptide ligands. Based on the success of our selections we believe that peptide libraries obtained with helper cells are not only suitable, but preferable to traditional phage display libraries for selection of peptidic ligands.

Rafts, Nanoparticles and Neural Disease

PubMed Central

Gulati, Vishal; Wallace, Ron

2012-01-01

This review examines the role of membrane rafts in neural disease as a rationale for drug targeting utilizing lipid-based nanoparticles. The article begins with an overview of methodological issues involving the existence, sizes, and lifetimes of rafts, and then examines raft function in the etiologies of three major neural diseases—epilepsy, Parkinson’s disease, and Alzheimer’s disease—selected as promising candidates for raft-based therapeutics. Raft-targeting drug delivery systems involving liposomes and solid lipid nanoparticles are then examined in detail. PMID:28348305

Screening Mammalian Cells on a Hydrogel: Functionalized Small Molecule Microarray.

PubMed

Zhu, Biwei; Jiang, Bo; Na, Zhenkun; Yao, Shao Q

2017-01-01

Mammalian cell-based microarray technology has gained wide attention, for its plethora of promising applications. The platform is able to provide simultaneous information on multiple parameters for a given target, or even multiple target proteins, in a complex biological system. Here we describe the preparation of mammalian cell-based microarrays using selectively captured of human prostate cancer cells (PC-3). This platform was then used in controlled drug release and measuring the associated drug effects on these cancer cells.

Prediction of Protein Structure by Template-Based Modeling Combined with the UNRES Force Field.

PubMed

Krupa, Paweł; Mozolewska, Magdalena A; Joo, Keehyoung; Lee, Jooyoung; Czaplewski, Cezary; Liwo, Adam

2015-06-22

A new approach to the prediction of protein structures that uses distance and backbone virtual-bond dihedral angle restraints derived from template-based models and simulations with the united residue (UNRES) force field is proposed. The approach combines the accuracy and reliability of template-based methods for the segments of the target sequence with high similarity to those having known structures with the ability of UNRES to pack the domains correctly. Multiplexed replica-exchange molecular dynamics with restraints derived from template-based models of a given target, in which each restraint is weighted according to the accuracy of the prediction of the corresponding section of the molecule, is used to search the conformational space, and the weighted histogram analysis method and cluster analysis are applied to determine the families of the most probable conformations, from which candidate predictions are selected. To test the capability of the method to recover template-based models from restraints, five single-domain proteins with structures that have been well-predicted by template-based methods were used; it was found that the resulting structures were of the same quality as the best of the original models. To assess whether the new approach can improve template-based predictions with incorrectly predicted domain packing, four such targets were selected from the CASP10 targets; for three of them the new approach resulted in significantly better predictions compared with the original template-based models. The new approach can be used to predict the structures of proteins for which good templates can be found for sections of the sequence or an overall good template can be found for the entire sequence but the prediction quality is remarkably weaker in putative domain-linker regions.

Sensitive and Specific Target Sequences Selected from Retrotransposons of Schistosoma japonicum for the Diagnosis of Schistosomiasis

PubMed Central

Xu, Jing; Zhu, Xing-Quan; Wang, Sheng-Yue; Xia, Chao-Ming

2012-01-01

Background Schistosomiasis japonica is a serious debilitating and sometimes fatal disease. Accurate diagnostic tests play a key role in patient management and control of the disease. However, currently available diagnostic methods are not ideal, and the detection of the parasite DNA in blood samples has turned out to be one of the most promising tools for the diagnosis of schistosomiasis. In our previous investigations, a 230-bp sequence from the highly repetitive retrotransposon SjR2 was identified and it showed high sensitivity and specificity for detecting Schistosoma japonicum DNA in the sera of rabbit model and patients. Recently, 29 retrotransposons were found in S. japonicum genome by our group. The present study highlighted the key factors for selecting a new perspective sensitive target DNA sequence for the diagnosis of schistosomiasis, which can serve as example for other parasitic pathogens. Methodology/Principal Findings In this study, we demonstrated that the key factors based on the bioinformatic analysis for selecting target sequence are the higher genome proportion, repetitive complete copies and partial copies, and active ESTs than the others in the chromosome genome. New primers based on 25 novel retrotransposons and SjR2 were designed and their sensitivity and specificity for detecting S. japonicum DNA were compared. The results showed that a new 303-bp sequence from non-long terminal repeat (LTR) retrotransposon (SjCHGCS19) had high sensitivity and specificity. The 303-bp target sequence was amplified from the sera of rabbit model at 3 d post-infection by nested-PCR and it became negative at 17 weeks post-treatment. Furthermore, the percentage sensitivity of the nested-PCR was 97.67% in 43 serum samples of S. japonicum-infected patients. Conclusions/Significance Our findings highlighted the key factors based on the bioinformatic analysis for selecting target sequence from S. japonicum genome, which provide basis for establishing powerful molecular diagnostic techniques that can be used for monitoring early infection and therapy efficacy to support schistosomiasis control programs. PMID:22479661

High-resolution monochromatic x-ray imaging system based on spherically bent crystals.

PubMed

Aglitskiy, Y; Lehecka, T; Obenschain, S; Bodner, S; Pawley, C; Gerber, K; Sethian, J; Brown, C M; Seely, J; Feldman, U; Holland, G

1998-08-01

We have developed an improved x-ray imaging system based on spherically curved crystals. It is designed and used for diagnostics of targets ablatively accelerated by the Nike KrF laser. A spherically curved quartz crystal (d = .?, R = mm) has been used to produce monochromatic backlit images with the He-like Si resonance line (1865 eV) as the source of radiation. The spatial resolution of the x-ray optical system is 1.7 mum in selected places and 2-3 mum over a larger area. Time-resolved backlit monochromatic images of polystyrene planar targets driven by the Nike facility have been obtained with a spatial resolution of 2.5 mum in selected places and 5 mum over the focal spot of the Nike laser.

The Speed of Serial Attention Shifts in Visual Search: Evidence from the N2pc Component.

PubMed

Grubert, Anna; Eimer, Martin

2016-02-01

Finding target objects among distractors in visual search display is often assumed to be based on sequential movements of attention between different objects. However, the speed of such serial attention shifts is still under dispute. We employed a search task that encouraged the successive allocation of attention to two target objects in the same search display and measured N2pc components to determine how fast attention moved between these objects. Each display contained one digit in a known color (fixed-color target) and another digit whose color changed unpredictably across trials (variable-color target) together with two gray distractor digits. Participants' task was to find the fixed-color digit and compare its numerical value with that of the variable-color digit. N2pc components to fixed-color targets preceded N2pc components to variable-color digits, demonstrating that these two targets were indeed selected in a fixed serial order. The N2pc to variable-color digits emerged approximately 60 msec after the N2pc to fixed-color digits, which shows that attention can be reallocated very rapidly between different target objects in the visual field. When search display durations were increased, thereby relaxing the temporal demands on serial selection, the two N2pc components to fixed-color and variable-color targets were elicited within 90 msec of each other. Results demonstrate that sequential shifts of attention between different target locations can operate very rapidly at speeds that are in line with the assumptions of serial selection models of visual search.

Trispecific antibodies for CD16A-directed NK cell engagement and dual-targeting of tumor cells.

PubMed

Gantke, Thorsten; Weichel, Michael; Herbrecht, Carmen; Reusch, Uwe; Ellwanger, Kristina; Fucek, Ivica; Eser, Markus; Müller, Thomas; Griep, Remko; Molkenthin, Vera; Zhukovsky, Eugene A; Treder, Martin

2017-09-01

Bispecific antibodies that redirect the lytic activity of cytotoxic immune effector cells, such as T- and NK cells, onto tumor cells have emerged as a highly attractive and clinically validated treatment modality for hematological malignancies. Advancement of this therapeutic concept into solid tumor indications, however, is hampered by the scarcity of targetable antigens that are surface-expressed on tumor cells but demonstrate only limited expression on healthy tissues. To overcome this limitation, the concept of dual-targeting, i.e. the simultaneous targeting of two tumor-expressed surface antigens with limited co-expression on non-malignant cells, with multispecific antibodies has been proposed to increase tumor selectivity of antibody-induced effector cell cytotoxicity. Here, a novel CD16A (FcγRIIIa)-directed trispecific, tetravalent antibody format, termed aTriFlex, is described, that is capable of redirecting NK cell cytotoxicity to two surface-expressed antigens. Using a BCMA/CD200-based in vitro model system, the potential use of aTriFlex antibodies for dual-targeting and selective induction of NK cell-mediated target cell lysis was investigated. Bivalent bispecific target cell binding was found to result in significant avidity gains and up to 17-fold increased in vitro potency. These data suggest trispecific aTriFlex antibodies may support dual-targeting strategies to redirect NK cell cytotoxicity with increased selectivity to enable targeting of solid tumor antigens. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Single Nanochannel-Aptamer-Based Biosensor for Ultrasensitive and Selective Cocaine Detection.

PubMed

Wang, Jian; Hou, Jue; Zhang, Huacheng; Tian, Ye; Jiang, Lei

2018-01-17

Ultrasensitive and selective detection of molecules at nano or sub-nanomolar level is very important for many areas such as early diagnosis and drug testing. Herein, we report a high-sensitive cocaine sensor based on a single nanochannel coupled with DNA aptamers. The single nanochannel-aptamer-based biosensor can recognize cocaine molecules with an excellent sensitivity and good selectivity. A linear relationship between target cocaine concentration and output ionic current is obtained in a wide concentration range of cocaine from 1 nM to 10 μM. The cocaine sensor also shows a detection limit down to 1 nM. This study provides a new avenue to develop new nanochannel-aptamer-based biosensors for rapid and ultratrace detection of a variety of illicit drugs.

Molybdenum target specifications for cyclotron production of 99mTc based on patient dose estimates.

PubMed

Hou, X; Tanguay, J; Buckley, K; Schaffer, P; Bénard, F; Ruth, T J; Celler, A

2016-01-21

In response to the recognized fragility of reactor-produced (99)Mo supply, direct production of (99m)Tc via (100)Mo(p,2n)(99m)Tc reaction using medical cyclotrons has been investigated. However, due to the existence of other Molybdenum (Mo) isotopes in the target, in parallel with (99m)Tc, other technetium (Tc) radioactive isotopes (impurities) will be produced. They will be incorporated into the labeled radiopharmaceuticals and result in increased patient dose. The isotopic composition of the target and beam energy are main factors that determine production of impurities, thus also dose increases. Therefore, they both must be considered when selecting targets for clinical (99m)Tc production. Although for any given Mo target, the patient dose can be predicted based on complicated calculations of production yields for each Tc radioisotope, it would be very difficult to reverse these calculations to specify target composition based on dosimetry considerations. In this article, a relationship between patient dosimetry and Mo target composition is studied. A simple and easy algorithm for dose estimation, based solely on the knowledge of target composition and beam energy, is described. Using this algorithm, the patient dose increase due to every Mo isotope that could be present in the target is estimated. Most importantly, a technique to determine Mo target composition thresholds that would meet any given dosimetry requirement is proposed.

Molybdenum target specifications for cyclotron production of 99mTc based on patient dose estimates

NASA Astrophysics Data System (ADS)

Hou, X.; Tanguay, J.; Buckley, K.; Schaffer, P.; Bénard, F.; Ruth, T. J.; Celler, A.

2016-01-01

In response to the recognized fragility of reactor-produced 99Mo supply, direct production of 99mTc via 100Mo(p,2n)99mTc reaction using medical cyclotrons has been investigated. However, due to the existence of other Molybdenum (Mo) isotopes in the target, in parallel with 99mTc, other technetium (Tc) radioactive isotopes (impurities) will be produced. They will be incorporated into the labeled radiopharmaceuticals and result in increased patient dose. The isotopic composition of the target and beam energy are main factors that determine production of impurities, thus also dose increases. Therefore, they both must be considered when selecting targets for clinical 99mTc production. Although for any given Mo target, the patient dose can be predicted based on complicated calculations of production yields for each Tc radioisotope, it would be very difficult to reverse these calculations to specify target composition based on dosimetry considerations. In this article, a relationship between patient dosimetry and Mo target composition is studied. A simple and easy algorithm for dose estimation, based solely on the knowledge of target composition and beam energy, is described. Using this algorithm, the patient dose increase due to every Mo isotope that could be present in the target is estimated. Most importantly, a technique to determine Mo target composition thresholds that would meet any given dosimetry requirement is proposed.

Ranking targets in structure-based virtual screening of three-dimensional protein libraries: methods and problems.

PubMed

Kellenberger, Esther; Foata, Nicolas; Rognan, Didier

2008-05-01

Structure-based virtual screening is a promising tool to identify putative targets for a specific ligand. Instead of docking multiple ligands into a single protein cavity, a single ligand is docked in a collection of binding sites. In inverse screening, hits are in fact targets which have been prioritized within the pool of best ranked proteins. The target rate depends on specificity and promiscuity in protein-ligand interactions and, to a considerable extent, on the effectiveness of the scoring function, which still is the Achilles' heel of molecular docking. In the present retrospective study, virtual screening of the sc-PDB target library by GOLD docking was carried out for four compounds (biotin, 4-hydroxy-tamoxifen, 6-hydroxy-1,6-dihydropurine ribonucleoside, and methotrexate) of known sc-PDB targets and, several ranking protocols based on GOLD fitness score and topological molecular interaction fingerprint (IFP) comparison were evaluated. For the four investigated ligands, the fusion of GOLD fitness and two IFP scores allowed the recovery of most targets, including the rare proteins which are not readily suitable for statistical analysis, while significantly filtering out most false positive entries. The current survey suggests that selecting a small number of targets (<20) for experimental evaluation is achievable with a pure structure-based approach.

Directed evolution of the TALE N-terminal domain for recognition of all 5′ bases

PubMed Central

Lamb, Brian M.; Mercer, Andrew C.; Barbas, Carlos F.

2013-01-01

Transcription activator-like effector (TALE) proteins can be designed to bind virtually any DNA sequence. General guidelines for design of TALE DNA-binding domains suggest that the 5′-most base of the DNA sequence bound by the TALE (the N0 base) should be a thymine. We quantified the N0 requirement by analysis of the activities of TALE transcription factors (TALE-TF), TALE recombinases (TALE-R) and TALE nucleases (TALENs) with each DNA base at this position. In the absence of a 5′ T, we observed decreases in TALE activity up to >1000-fold in TALE-TF activity, up to 100-fold in TALE-R activity and up to 10-fold reduction in TALEN activity compared with target sequences containing a 5′ T. To develop TALE architectures that recognize all possible N0 bases, we used structure-guided library design coupled with TALE-R activity selections to evolve novel TALE N-terminal domains to accommodate any N0 base. A G-selective domain and broadly reactive domains were isolated and characterized. The engineered TALE domains selected in the TALE-R format demonstrated modularity and were active in TALE-TF and TALEN architectures. Evolved N-terminal domains provide effective and unconstrained TALE-based targeting of any DNA sequence as TALE binding proteins and designer enzymes. PMID:23980031

Margin selection to compensate for loss of target dose coverage due to target motion during external‐beam radiation therapy of the lung

PubMed Central

Osei, Ernest; Barnett, Rob

2015-01-01

The aim of this study is to provide guidelines for the selection of external‐beam radiation therapy target margins to compensate for target motion in the lung during treatment planning. A convolution model was employed to predict the effect of target motion on the delivered dose distribution. The accuracy of the model was confirmed with radiochromic film measurements in both static and dynamic phantom modes. 502 unique patient breathing traces were recorded and used to simulate the effect of target motion on a dose distribution. A 1D probability density function (PDF) representing the position of the target throughout the breathing cycle was generated from each breathing trace obtained during 4D CT. Changes in the target D95 (the minimum dose received by 95% of the treatment target) due to target motion were analyzed and shown to correlate with the standard deviation of the PDF. Furthermore, the amount of target D95 recovered per millimeter of increased field width was also shown to correlate with the standard deviation of the PDF. The sensitivity of changes in dose coverage with respect to target size was also determined. Margin selection recommendations that can be used to compensate for loss of target D95 were generated based on the simulation results. These results are discussed in the context of clinical plans. We conclude that, for PDF standard deviations less than 0.4 cm with target sizes greater than 5 cm, little or no additional margins are required. Targets which are smaller than 5 cm with PDF standard deviations larger than 0.4 cm are most susceptible to loss of coverage. The largest additional required margin in this study was determined to be 8 mm. PACS numbers: 87.53.Bn, 87.53.Kn, 87.55.D‐, 87.55.Gh

Differential evolution algorithm-based kernel parameter selection for Fukunaga-Koontz Transform subspaces construction

NASA Astrophysics Data System (ADS)

Binol, Hamidullah; Bal, Abdullah; Cukur, Huseyin

2015-10-01

The performance of the kernel based techniques depends on the selection of kernel parameters. That's why; suitable parameter selection is an important problem for many kernel based techniques. This article presents a novel technique to learn the kernel parameters in kernel Fukunaga-Koontz Transform based (KFKT) classifier. The proposed approach determines the appropriate values of kernel parameters through optimizing an objective function constructed based on discrimination ability of KFKT. For this purpose we have utilized differential evolution algorithm (DEA). The new technique overcomes some disadvantages such as high time consumption existing in the traditional cross-validation method, and it can be utilized in any type of data. The experiments for target detection applications on the hyperspectral images verify the effectiveness of the proposed method.

Determinants for DNA target structure selectivity of the human LINE-1 retrotransposon endonuclease.

PubMed

Repanas, Kostas; Zingler, Nora; Layer, Liliana E; Schumann, Gerald G; Perrakis, Anastassis; Weichenrieder, Oliver

2007-01-01

The human LINE-1 endonuclease (L1-EN) is the targeting endonuclease encoded by the human LINE-1 (L1) retrotransposon. L1-EN guides the genomic integration of new L1 and Alu elements that presently account for approximately 28% of the human genome. L1-EN bears considerable technological interest, because its target selectivity may ultimately be engineered to allow the site-specific integration of DNA into defined genomic locations. Based on the crystal structure, we generated L1-EN mutants to analyze and manipulate DNA target site recognition. Crystal structures and their dynamic and functional analysis show entire loop grafts to be feasible, resulting in altered specificity, while individual point mutations do not change the nicking pattern of L1-EN. Structural parameters of the DNA target seem more important for recognition than the nucleotide sequence, and nicking profiles on DNA oligonucleotides in vitro are less well defined than the respective integration site consensus in vivo. This suggests that additional factors other than the DNA nicking specificity of L1-EN contribute to the targeted integration of non-LTR retrotransposons.

Intergenerational Projects: Idea Book.

ERIC Educational Resources Information Center

Clay, Rebecca; Ventura-Merkel, Cathy; Eades-Goudy, Dianne; Dubich, Teresa

This book profiles 74 intergenerational programs in the United States. The programs range from basic tutoring projects to a sophisticated corporate-based day care center. Project selection was based on replicatable programs involving mutually beneficial exchanges. Grouped by subjects, profiles include programs targeting both young and old. Most…

Distributed estimation for adaptive sensor selection in wireless sensor networks

NASA Astrophysics Data System (ADS)

Mahmoud, Magdi S.; Hassan Hamid, Matasm M.

2014-05-01

Wireless sensor networks (WSNs) are usually deployed for monitoring systems with the distributed detection and estimation of sensors. Sensor selection in WSNs is considered for target tracking. A distributed estimation scenario is considered based on the extended information filter. A cost function using the geometrical dilution of precision measure is derived for active sensor selection. A consensus-based estimation method is proposed in this paper for heterogeneous WSNs with two types of sensors. The convergence properties of the proposed estimators are analyzed under time-varying inputs. Accordingly, a new adaptive sensor selection (ASS) algorithm is presented in which the number of active sensors is adaptively determined based on the absolute local innovations vector. Simulation results show that the tracking accuracy of the ASS is comparable to that of the other algorithms.

Toward Optimal Target Placement for Neural Prosthetic Devices

PubMed Central

Cunningham, John P.; Yu, Byron M.; Gilja, Vikash; Ryu, Stephen I.; Shenoy, Krishna V.

2008-01-01

Neural prosthetic systems have been designed to estimate continuous reach trajectories (motor prostheses) and to predict discrete reach targets (communication prostheses). In the latter case, reach targets are typically decoded from neural spiking activity during an instructed delay period before the reach begins. Such systems use targets placed in radially symmetric geometries independent of the tuning properties of the neurons available. Here we seek to automate the target placement process and increase decode accuracy in communication prostheses by selecting target locations based on the neural population at hand. Motor prostheses that incorporate intended target information could also benefit from this consideration. We present an optimal target placement algorithm that approximately maximizes decode accuracy with respect to target locations. In simulated neural spiking data fit from two monkeys, the optimal target placement algorithm yielded statistically significant improvements up to 8 and 9% for two and sixteen targets, respectively. For four and eight targets, gains were more modest, as the target layouts found by the algorithm closely resembled the canonical layouts. We trained a monkey in this paradigm and tested the algorithm with experimental neural data to confirm some of the results found in simulation. In all, the algorithm can serve not only to create new target layouts that outperform canonical layouts, but it can also confirm or help select among multiple canonical layouts. The optimal target placement algorithm developed here is the first algorithm of its kind, and it should both improve decode accuracy and help automate target placement for neural prostheses. PMID:18829845

The timecourse of space- and object-based attentional prioritization with varying degrees of certainty

PubMed Central

Drummond, Leslie; Shomstein, Sarah

2013-01-01

The relative contributions of objects (i.e., object-based) and underlying spatial (i.e., space-based representations) to attentional prioritization and selection remain unclear. In most experimental circumstances, the two representations overlap thus their respective contributions cannot be evaluated. Here, a dynamic version of the two-rectangle paradigm allowed for a successful de-coupling of spatial and object representations. Space-based (cued spatial location), cued end of the object, and object-based (locations within the cued object) effects were sampled at several timepoints following the cue with high or low certainty as to target location. In the high uncertainty condition spatial benefits prevailed throughout most of the timecourse, as evidenced by facilitatory and inhibitory effects. Additionally, the cued end of the object, rather than a whole object, received the attentional benefit. When target location was predictable (low uncertainty manipulation), only probabilities guided selection (i.e., evidence by a benefit for the statistically biased location). These results suggest that with high spatial uncertainty, all available information present within the stimulus display is used for the purposes of attentional selection (e.g., spatial locations, cued end of the object) albeit to varying degrees and at different time points. However, as certainty increases, only spatial certainty guides selection (i.e., object ends and whole objects are filtered out). Taken together, these results further elucidate the contributing role of space- and object-representations to attentional guidance. PMID:24367302

Synthesis of fisetin and 2',4',6'-trihydroxydihyrochalcone 4'-O-β-neohesperidoside based on site-selective deacetylation and deoxygenation.

PubMed

Tsunekawa, Ryuji; Hanaya, Kengo; Higashibayashi, Shuhei; Sugai, Takeshi

2018-04-26

Fisetin and 2',4',6'-trihydroxydihyrochalcone 4'-O-β-neohesperidoside were synthesized from commercially available quercetin and naringin in five steps. The key steps are site-selective deacetylation and subsequent deoxygenation. The target molecules were obtained in 37% and 23% yields from the starting materials, respectively.

In silico selection of expression reference genes with demonstrated stability in barley among a diverse set of tissues and cultivars

USDA-ARS?s Scientific Manuscript database

Premise of the study: Reference genes are selected based on the assumption of temporal and spatial expression stability and on their widespread use in model species. They are often used in new target species without validation, presumed as stable. For barley, reference gene validation is lacking, bu...

Induced nanoparticle aggregation for short nucleic acid quantification by depletion isotachophoresis.

PubMed

Marczak, Steven; Senapati, Satyajyoti; Slouka, Zdenek; Chang, Hsueh-Chia

2016-12-15

A rapid (<20min) gel-membrane biochip platform for the detection and quantification of short nucleic acids is presented based on a sandwich assay with probe-functionalized gold nanoparticles and their separation into concentrated bands by depletion-generated gel isotachophoresis. The platform sequentially exploits the enrichment and depletion phenomena of an ion-selective cation-exchange membrane created under an applied electric field. Enrichment is used to concentrate the nanoparticles and targets at a localized position at the gel-membrane interface for rapid hybridization. The depletion generates an isotachophoretic zone without the need for different conductivity buffers, and is used to separate linked nanoparticles from isolated ones in the gel medium and then by field-enhanced aggregation of only the linked particles at the depletion front. The selective field-induced aggregation of the linked nanoparticles during the subsequent depletion step produces two lateral-flow like bands within 1cm for easy visualization and quantification as the aggregates have negligible electrophoretic mobility in the gel and the isolated nanoparticles are isotachophoretically packed against the migrating depletion front. The detection limit for 69-base single-stranded DNA targets is 10 pM (about 10 million copies for our sample volume) with high selectivity against nontargets and a three decade linear range for quantification. The selectivity and signal intensity are maintained in heterogeneous mixtures where the nontargets outnumber the targets 10,000 to 1. The selective field-induced aggregation of DNA-linked nanoparticles at the ion depletion front is attributed to their trailing position at the isotachophoretic front with a large field gradient. Copyright © 2016 Elsevier B.V. All rights reserved.

STK Integrated Message Production List Editor (SIMPLE) for CEO Operations

NASA Technical Reports Server (NTRS)

Trenchard, Mike; Heydorn, James

2014-01-01

Late in fiscal year 2011, the Crew Earth Observations (CEO) team was tasked to upgrade and replace its mission planning and mission operations software systems, which were developed in the Space Shuttle era of the 1980s and 1990s. The impetuses for this change were the planned transition of all workstations to the Windows 7 64-bit operating system and the desire for more efficient and effective use of Satellite Tool Kit (STK) software required for reliable International Space Station (ISS) Earth location tracking. An additional requirement of this new system was the use of the same SQL database of CEO science sites from the SMMS, which was also being developed. STK Integrated Message Production List Editor (SIMPLE) is the essential, all-in-one tool now used by CEO staff to perform daily ISS mission planning to meet its requirement to acquire astronaut photography of specific sites on Earth. The sites are part of a managed, long-term database that has been defined and developed for scientific, educational, and public interest. SIMPLE's end product is a set of basic time and location data computed for an operator-selected set of targets that the ISS crew will be asked to photograph (photography is typically planned 12 to 36 hours out). The CEO operator uses SIMPLE to (a) specify a payload operations planning period; (b) acquire and validate the best available ephemeris data (vectors) for the ISS during the planning period; (c) ingest and display mission-specific site information from the CEO database; (d) identify and display potential current dynamic event targets as map features; (e) compute and display time and location information for each target; (f) screen and select targets based on known crew availability constraints, obliquity constraints, and real-time evaluated constraints to target visibility due to illumination (sun elevation) and atmospheric conditions (weather); and finally (g) incorporate basic, computed time and location information for each selected target into the daily CEO Target List product (message) for submission to ISS payload planning and integration teams for their review and approval prior to uplink. SIMPLE requires and uses the following resources: an ISS mission planning period Greenwich Mean Time start date/time and end date/time), the best available ISS mission ephemeris data (vectors) for that planning period, the STK software package configured for the ISS, and an ISS mission-specific subset of the CEO sites database. The primary advantages realized by the development and implementation of SIMPLE into the CEO payload operations support activity are a smooth transition to the Windows 7 operating system upon scheduled workstation refresh; streamlining of the input and verification of the current ISS ephemeris (vector data); seamless incorporation of selected contents of the SQL database of science sites; the ability to tag and display potential dynamic event opportunities on orbit track maps; simplification of the display and selection of encountered sites based on crew availability, illumination, obliquity, and weather constraints; the incorporation of high-quality mapping of the Earth with various satellite-based datasets for use in describing targets; and the ability to encapsulate and export the essential selected target elements in XML format for use by onboard Earth-location systems, such as Worldmap. SIMPLE is a carefully designed and crafted in-house software package that includes detailed help files for the user and meticulous internal documentation for future modifications. It was delivered in February 2012 for test and evaluation. Following acceptance, it was implemented for CEO mission operations support in May 2012.

Targeting the interleukin-11 receptor α in metastatic prostate cancer: A first-in-man study.

PubMed

Pasqualini, Renata; Millikan, Randall E; Christianson, Dawn R; Cardó-Vila, Marina; Driessen, Wouter H P; Giordano, Ricardo J; Hajitou, Amin; Hoang, Anh G; Wen, Sijin; Barnhart, Kirstin F; Baze, Wallace B; Marcott, Valerie D; Hawke, David H; Do, Kim-Anh; Navone, Nora M; Efstathiou, Eleni; Troncoso, Patricia; Lobb, Roy R; Logothetis, Christopher J; Arap, Wadih

2015-07-15

Receptors in tumor blood vessels are attractive targets for ligand-directed drug discovery and development. The authors have worked systematically to map human endothelial receptors ("vascular zip codes") within tumors through direct peptide library selection in cancer patients. Previously, they selected a ligand-binding motif to the interleukin-11 receptor alpha (IL-11Rα) in the human vasculature. The authors generated a ligand-directed, peptidomimetic drug (bone metastasis-targeting peptidomimetic-11 [BMTP-11]) for IL-11Rα-based human tumor vascular targeting. Preclinical studies (efficacy/toxicity) included evaluating BMTP-11 in prostate cancer xenograft models, drug localization, targeted apoptotic effects, pharmacokinetic/pharmacodynamic analyses, and dose-range determination, including formal (good laboratory practice) toxicity across rodent and nonhuman primate species. The initial BMTP-11 clinical development also is reported based on a single-institution, open-label, first-in-class, first-in-man trial (National Clinical Trials number NCT00872157) in patients with metastatic, castrate-resistant prostate cancer. BMTP-11 was preclinically promising and, thus, was chosen for clinical development in patients. Limited numbers of patients who had castrate-resistant prostate cancer with osteoblastic bone metastases were enrolled into a phase 0 trial with biology-driven endpoints. The authors demonstrated biopsy-verified localization of BMTP-11 to tumors in the bone marrow and drug-induced apoptosis in all patients. Moreover, the maximum tolerated dose was identified on a weekly schedule (20-30 mg/m(2) ). Finally, a renal dose-limiting toxicity was determined, namely, dose-dependent, reversible nephrotoxicity with proteinuria and casts involving increased serum creatinine. These biologic endpoints establish BMTP-11 as a targeted drug candidate in metastatic, castrate-resistant prostate cancer. Within a larger discovery context, the current findings indicate that functional tumor vascular ligand-receptor targeting systems may be identified through direct combinatorial selection of peptide libraries in cancer patients. © 2015 American Cancer Society.

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.

Advancing the sensitivity of selected reaction monitoring-based targeted quantitative proteomics

PubMed Central

Shi, Tujin; Su, Dian; Liu, Tao; Tang, Keqi; Camp, David G.; Qian, Wei-Jun; Smith, Richard D.

2012-01-01

Selected reaction monitoring (SRM)—also known as multiple reaction monitoring (MRM)—has emerged as a promising high-throughput targeted protein quantification technology for candidate biomarker verification and systems biology applications. A major bottleneck for current SRM technology, however, is insufficient sensitivity for e.g., detecting low-abundance biomarkers likely present at the low ng/mL to pg/mL range in human blood plasma or serum, or extremely low-abundance signaling proteins in cells or tissues. Herein we review recent advances in methods and technologies, including front-end immunoaffinity depletion, fractionation, selective enrichment of target proteins/peptides including posttranslational modifications (PTMs), as well as advances in MS instrumentation which have significantly enhanced the overall sensitivity of SRM assays and enabled the detection of low-abundance proteins at low to sub- ng/mL level in human blood plasma or serum. General perspectives on the potential of achieving sufficient sensitivity for detection of pg/mL level proteins in plasma are also discussed. PMID:22577010

Advancing the sensitivity of selected reaction monitoring-based targeted quantitative proteomics

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

Shi, Tujin; Su, Dian; Liu, Tao

2012-04-01

Selected reaction monitoring (SRM)—also known as multiple reaction monitoring (MRM)—has emerged as a promising high-throughput targeted protein quantification technology for candidate biomarker verification and systems biology applications. A major bottleneck for current SRM technology, however, is insufficient sensitivity for e.g., detecting low-abundance biomarkers likely present at the pg/mL to low ng/mL range in human blood plasma or serum, or extremely low-abundance signaling proteins in the cells or tissues. Herein we review recent advances in methods and technologies, including front-end immunoaffinity depletion, fractionation, selective enrichment of target proteins/peptides or their posttranslational modifications (PTMs), as well as advances in MS instrumentation, whichmore » have significantly enhanced the overall sensitivity of SRM assays and enabled the detection of low-abundance proteins at low to sub- ng/mL level in human blood plasma or serum. General perspectives on the potential of achieving sufficient sensitivity for detection of pg/mL level proteins in plasma are also discussed.« less

Selective Sensitization of Zinc Finger Protein Oxidation by Reactive Oxygen Species through Arsenic Binding*

PubMed Central

Zhou, Xixi; Cooper, Karen L.; Sun, Xi; Liu, Ke J.; Hudson, Laurie G.

2015-01-01

Cysteine oxidation induced by reactive oxygen species (ROS) on redox-sensitive targets such as zinc finger proteins plays a critical role in redox signaling and subsequent biological outcomes. We found that arsenic exposure led to oxidation of certain zinc finger proteins based on arsenic interaction with zinc finger motifs. Analysis of zinc finger proteins isolated from arsenic-exposed cells and zinc finger peptides by mass spectrometry demonstrated preferential oxidation of C3H1 and C4 zinc finger configurations. C2H2 zinc finger proteins that do not bind arsenic were not oxidized by arsenic-generated ROS in the cellular environment. The findings suggest that selectivity in arsenic binding to zinc fingers with three or more cysteines defines the target proteins for oxidation by ROS. This represents a novel mechanism of selective protein oxidation and demonstrates how an environmental factor may sensitize certain target proteins for oxidation, thus altering the oxidation profile and redox regulation. PMID:26063799

Visual Search for Motion-Form Conjunctions: Selective Attention to Movement Direction.

PubMed

Von Mühlenen, Adrian; Müller, Hermann J

1999-07-01

In 2 experiments requiring visual search for conjunctions of motion and form, the authors reinvestigated whether motion-based filtering (e.g., P. McLeod, J. Driver, Z. Dienes, & J. Crisp, 1991) is direction selective and whether cuing of the target direction promotes efficient search performance. In both experiments, the authors varied the number of movement directions in the display and the predictability of the target direction. Search was less efficient when items moved in multiple (2, 3, and 4) directions as compared with just 1 direction. Furthermore, precuing of the target direction facilitated the search, even with "wrap-around" displays, relatively more when items moved in multiple directions. The authors proposed 2 principles to explain that pattern of effects: (a) interference on direction computation between items moving in different directions (e.g., N. Qian & R. A. Andersen, 1994) and (b) selective direction tuning of motion detectors involving a receptive-field contraction (cf. J. Moran & R. Desimone, 1985; S. Treue & J. H. R. Maunsell, 1996).

Trajectory Optimization for Missions to Small Bodies with a Focus on Scientific Merit.

PubMed

Englander, Jacob A; Vavrina, Matthew A; Lim, Lucy F; McFadden, Lucy A; Rhoden, Alyssa R; Noll, Keith S

2017-01-01

Trajectory design for missions to small bodies is tightly coupled both with the selection of targets for a mission and with the choice of spacecraft power, propulsion, and other hardware. Traditional methods of trajectory optimization have focused on finding the optimal trajectory for an a priori selection of destinations and spacecraft parameters. Recent research has expanded the field of trajectory optimization to multidisciplinary systems optimization that includes spacecraft parameters. The logical next step is to extend the optimization process to include target selection based not only on engineering figures of merit but also scientific value. This paper presents a new technique to solve the multidisciplinary mission optimization problem for small-bodies missions, including classical trajectory design, the choice of spacecraft power and propulsion systems, and also the scientific value of the targets. This technique, when combined with modern parallel computers, enables a holistic view of the small body mission design process that previously required iteration among several different design processes.

Exploiting an Asp-Glu "switch" in glycogen synthase kinase 3 to design paralog-selective inhibitors for use in acute myeloid leukemia.

PubMed

Wagner, Florence F; Benajiba, Lina; Campbell, Arthur J; Weïwer, Michel; Sacher, Joshua R; Gale, Jennifer P; Ross, Linda; Puissant, Alexandre; Alexe, Gabriela; Conway, Amy; Back, Morgan; Pikman, Yana; Galinsky, Ilene; DeAngelo, Daniel J; Stone, Richard M; Kaya, Taner; Shi, Xi; Robers, Matthew B; Machleidt, Thomas; Wilkinson, Jennifer; Hermine, Olivier; Kung, Andrew; Stein, Adam J; Lakshminarasimhan, Damodharan; Hemann, Michael T; Scolnick, Edward; Zhang, Yan-Ling; Pan, Jen Q; Stegmaier, Kimberly; Holson, Edward B

2018-03-07

Glycogen synthase kinase 3 (GSK3), a key regulatory kinase in the wingless-type MMTV integration site family (WNT) pathway, is a therapeutic target of interest in many diseases. Although dual GSK3α/β inhibitors have entered clinical trials, none has successfully translated to clinical application. Mechanism-based toxicities, driven in part by the inhibition of both GSK3 paralogs and subsequent β-catenin stabilization, are a concern in the translation of this target class because mutations and overexpression of β-catenin are associated with many cancers. Knockdown of GSK3α or GSK3β individually does not increase β-catenin and offers a conceptual resolution to targeting GSK3: paralog-selective inhibition. However, inadequate chemical tools exist. The design of selective adenosine triphosphate (ATP)-competitive inhibitors poses a drug discovery challenge due to the high homology (95% identity and 100% similarity) in this binding domain. Taking advantage of an Asp 133 →Glu 196 "switch" in their kinase hinge, we present a rational design strategy toward the discovery of paralog-selective GSK3 inhibitors. These GSK3α- and GSK3β-selective inhibitors provide insights into GSK3 targeting in acute myeloid leukemia (AML), where GSK3α was identified as a therapeutic target using genetic approaches. The GSK3α-selective compound BRD0705 inhibits kinase function and does not stabilize β-catenin, mitigating potential neoplastic concerns. BRD0705 induces myeloid differentiation and impairs colony formation in AML cells, with no apparent effect on normal hematopoietic cells. Moreover, BRD0705 impairs leukemia initiation and prolongs survival in AML mouse models. These studies demonstrate feasibility of paralog-selective GSK3α inhibition, offering a promising therapeutic approach in AML. Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

Synthetic lipoprotein as nano-material vehicle in the targeted drug delivery.

PubMed

Zhang, Xueqin; Huang, Gangliang

2017-12-01

High-density lipoprotein (HDL) and low-density lipoprotein (LDL), as human endogenous lipoprotein particles, have low toxicity, high selectivity, and good safety. They can avoid the recognition and clearance of human reticuloendothelial system. These synthetic lipoproteins (sLPs) have been attracted extensive attention as the nanovectors for tumor-targeted drug and gene delivery. Herein, recent advances in the field of anticancer based on these two lipid proteins and recombinant lipoproteins (rLPs) as target delivery vectors were analyzed and discussed.

Current trends in nanomaterial embedded field effect transistor-based biosensor.

PubMed

Nehra, Anuj; Pal Singh, Krishna

2015-12-15

Recently, as metal-, polymer-, and carbon-based biocompatible nanomaterials have been increasingly incorporated into biosensing applications, with various nanostructures having been used to increase the efficacy and sensitivity of most of the detecting devices, including field effect transistor (FET)-based devices. These nanomaterial-based methods also became the ideal for the amalgamation of biomolecules, especially for the fabrication of ultrasensitive, low-cost, and robust FET-based biosensors; these are categorically very successful at binding the target specified entities in the confined gated micro-region for high functionality. Furthermore, the contemplation of nanomaterial-based FET biosensors to various applications encompasses the desire for detection of many targets with high selectivity, and specificity. We assess how such devices have empowered the achievement of elevated biosensor performance in terms of high sensitivity, selectivity and low detection limits. We review the recent literature here to illustrate the diversity of FET-based biosensors, based on various kinds of nanomaterials in different applications and sum up that graphene or its assisted composite based FET devices are comparatively more efficient and sensitive with highest signal to noise ratio. Lastly, the future prospects and limitations of the field are also discussed. Copyright © 2015 Elsevier B.V. All rights reserved.

tLyP-1-conjugated mesoporous silica nanoparticles for tumor targeting and penetrating hydrophobic drug delivery

NASA Astrophysics Data System (ADS)

Xu, Baiyao; Ju, Yang; Song, Guanbin; Cui, Yanbin

2013-12-01

Mesoporous silica nanoparticles (MSNs) are among the most appealing candidates for targeted drug delivery, a process for which it is essential that nanoparticles be internalized into targeted cells with high speed and efficiency. Therefore, it is necessary to conjugate a targeting ligand to the surface of a nanocarrier in order to trigger rapid receptor-mediated endocytosis and effective cellular uptake, which occurs following recognition and selective binding to a target cell's membrane receptor. Here, a tumor targeting and penetrating drug delivery system (DDS) based on MSNs ( 100 nm in size) is described. The MSNs were functionalized by engrafting with the tumor-homing and penetrating peptide tLyP-1. The fabricated MSN-tLyP-1 loaded with camptothecin (CPT) showed a robust targeting and penetrating efficiency to HeLa cells and MCF-7 cells and induced the death of these cells. Moreover, the adverse side effect of CPT on human mesenchymal stem cells (hMSCs) was minimized, because the nanoparticles were selectively targeted to the tumor cells, and little hydrophobic CPT was released into the culture medium or blood. The results indicate that the MSN-tLyP-1 DDS has great potential for the delivery of hydrophobic anticancer drugs to target tumors.

Artificial Intelligence Support for Landing Site Selection on Mars

NASA Astrophysics Data System (ADS)

Rongier, G.; Pankratius, V.

2017-12-01

Mars is a key target for planetary exploration; a better understanding of its evolution and habitability requires roving in situ. Landing site selection is becoming more challenging for scientists as new instruments generate higher data volumes. The involved engineering and scientific constraints make site selection and the anticipation of possible onsite actions into a complex optimization problem: there may be multiple acceptable solutions depending on various goals and assumptions. Solutions must also account for missing data, errors, and potential biases. To address these problems, we propose an AI-informed decision support system that allows scientists, mission designers, engineers, and committees to explore alternative site selection choices based on data. In particular, we demonstrate first results of an exploratory case study using fuzzy logic and a simulation of a rover's mobility map based on the fast marching algorithm. Our system computes favorability maps of the entire planet to facilitate landing site selection and allows a definition of different configurations for rovers, science target priorities, landing ellipses, and other constraints. For a rover similar to NASA's Mars 2020 rover, we present results in form of a site favorability map as well as four derived exploration scenarios that depend on different prioritized scientific targets, all visualizing inherent tradeoffs. Our method uses the NASA PDS Geosciences Node and the NASA/ICA Integrated Database of Planetary Features. Under common assumptions, the data products reveal Eastern Margaritifer Terra and Meridiani Planum to be the most favorable sites due to a high concentration of scientific targets and a flat, easily navigable surface. Our method also allows mission designers to investigate which constraints have the highest impact on the mission exploration potential and to change parameter ranges. Increasing the elevation limit for landing, for example, provides access to many additional, more interesting sites on the southern terrains of Mars. The speed of current rovers is another limit to exploration capabilities: our system helps quantify how speed increases can improve the number of reachable targets in the search space. We acknowledge support from NASA AISTNNX15AG84G (PI Pankratius) and NSF ACI1442997 (PI Pankratius).

Molecular docking, molecular modeling, and molecular dynamics studies of azaisoflavone as dual COX-2 inhibitors and TP receptor antagonists.

PubMed

Hadianawala, Murtuza; Mahapatra, Amarjyoti Das; Yadav, Jitender K; Datta, Bhaskar

2018-02-26

Designed multi-target ligand (DML) is an emerging strategy for the development of new drugs and involves the engagement of multiple targets with the same moiety. In the context of NSAIDs it has been suggested that targeting the thromboxane prostanoid (TP) receptor along with cyclooxygenase-2 (COX-2) may help to overcome cardiovascular (CVS) complications associated with COXIBs. In the present work, azaisoflavones were studied for their COX-2 and TP receptor binding activities using structure based drug design (SBDD) techniques. Flavonoids were selected as a starting point based on their known COX-2 inhibitory and TP receptor antagonist activity. Iterative design and docking studies resulted in the evolution of a new class scaffold replacing the benzopyran-4-one ring of flavonoids with quinolin-4-one. The docking and binding parameters of these new compounds are found to be promising in comparison to those of selective COX-2 inhibitors, such as SC-558 and celecoxib. Owing to the lack of structural information, a model for the TP receptor was generated using a threading base alignment method with loop optimization performed using an ab initio method. The model generated was validated against known antagonists for TP receptor using docking/MMGBSA. Finally, the molecules that were designed for selective COX-2 inhibition were docked into the active site of the TP receptor. Iterative structural modifications and docking on these molecules generated a series which displays optimum docking scores and binding interaction for both targets. Molecular dynamics studies on a known TP receptor antagonist and a designed molecule show that both molecules remain in contact with protein throughout the simulation and interact in similar binding modes. Graphical abstract ᅟ.

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.

The future of EPAC-targeted therapies: agonism versus antagonism.

PubMed

Parnell, Euan; Palmer, Timothy M; Yarwood, Stephen J

2015-04-01

Pharmaceutical manipulation of cAMP levels exerts beneficial effects through the regulation of the exchange protein activated by cAMP (EPAC) and protein kinase A (PKA) signalling routes. Recent attention has turned to the specific regulation of EPAC isoforms (EPAC1 and EPAC2) as a more targeted approach to cAMP-based therapies. For example, EPAC2-selective agonists could promote insulin secretion from pancreatic β cells, whereas EPAC1-selective agonists may be useful in the treatment of vascular inflammation. By contrast, EPAC1 and EPAC2 antagonists could both be useful in the treatment of heart failure. Here we discuss whether the best way forward is to design EPAC-selective agonists or antagonists and the current strategies being used to develop isoform-selective, small-molecule regulators of EPAC1 and EPAC2 activity. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

PRISE2: software for designing sequence-selective PCR primers and probes.

PubMed

Huang, Yu-Ting; Yang, Jiue-in; Chrobak, Marek; Borneman, James

2014-09-25

PRISE2 is a new software tool for designing sequence-selective PCR primers and probes. To achieve high level of selectivity, PRISE2 allows the user to specify a collection of target sequences that the primers are supposed to amplify, as well as non-target sequences that should not be amplified. The program emphasizes primer selectivity on the 3' end, which is crucial for selective amplification of conserved sequences such as rRNA genes. In PRISE2, users can specify desired properties of primers, including length, GC content, and others. They can interactively manipulate the list of candidate primers, to choose primer pairs that are best suited for their needs. A similar process is used to add probes to selected primer pairs. More advanced features include, for example, the capability to define a custom mismatch penalty function. PRISE2 is equipped with a graphical, user-friendly interface, and it runs on Windows, Macintosh or Linux machines. PRISE2 has been tested on two very similar strains of the fungus Dactylella oviparasitica, and it was able to create highly selective primers and probes for each of them, demonstrating the ability to create useful sequence-selective assays. PRISE2 is a user-friendly, interactive software package that can be used to design high-quality selective primers for PCR experiments. In addition to choosing primers, users have an option to add a probe to any selected primer pair, enabling design of Taqman and other primer-probe based assays. PRISE2 can also be used to design probes for FISH and other hybridization-based assays.

Programmable spectral engine design of hyperspectral image projectors based on digital micro-mirror device (DMD)

NASA Astrophysics Data System (ADS)

Wang, Xicheng; Gao, Jiaobo; Wu, Jianghui; Li, Jianjun; Cheng, Hongliang

2017-02-01

Recently, hyperspectral image projectors (HIP) have been developed in the field of remote sensing. For the advanced performance of system-level validation, target detection and hyperspectral image calibration, HIP has great possibility of development in military, medicine, commercial and so on. HIP is based on the digital micro-mirror device (DMD) and projection technology, which is capable to project arbitrary programmable spectra (controlled by PC) into the each pixel of the IUT1 (instrument under test), such that the projected image could simulate realistic scenes that hyperspectral image could be measured during its use and enable system-level performance testing and validation. In this paper, we built a visible hyperspectral image projector also called the visible target simulator with double DMDs, which the first DMD is used to product the selected monochromatic light from the wavelength of 410 to 720 um, and the light come to the other one. Then we use computer to load image of realistic scenes to the second DMD, so that the target condition and background could be project by the second DMD with the selected monochromatic light. The target condition can be simulated and the experiment could be controlled and repeated in the lab, making the detector instrument could be tested in the lab. For the moment, we make the focus on the spectral engine design include the optical system, research of DMD programmable spectrum and the spectral resolution of the selected spectrum. The detail is shown.

System and method for progressive band selection for hyperspectral images

NASA Technical Reports Server (NTRS)

Fisher, Kevin (Inventor)

2013-01-01

Disclosed herein are systems, methods, and non-transitory computer-readable storage media for progressive band selection for hyperspectral images. A system having module configured to control a processor to practice the method calculates a virtual dimensionality of a hyperspectral image having multiple bands to determine a quantity Q of how many bands are needed for a threshold level of information, ranks each band based on a statistical measure, selects Q bands from the multiple bands to generate a subset of bands based on the virtual dimensionality, and generates a reduced image based on the subset of bands. This approach can create reduced datasets of full hyperspectral images tailored for individual applications. The system uses a metric specific to a target application to rank the image bands, and then selects the most useful bands. The number of bands selected can be specified manually or calculated from the hyperspectral image's virtual dimensionality.

[Orienting reflex: "targeting reaction" and "searchlight of attention"].

PubMed

Sokolov, E N; Nezlina, N I; Polianskiĭ, V B; Evtikhin, D V

2001-01-01

The concept of orienting reflex based on the principle of vector coding of cognitive and executive processes is proposed. The orienting reflex to non-signal and signal stimuli is a set of orienting reactions: motor, autonomic, neuronal, and subjective emphasizing new and significant stimuli. Two basic mechanisms can be identified within the orienting reflex: a "targeting reaction" and a "searchlight of attention". In the visual system the first one consists in a foveation of a target stimulus. The foveation is performed with participation of premotor neurons excited by saccadic command neurons of the superior colliculi. The "searchlight of attention" is based on the resonance of gamma-oscillations in the reticular thalamus selectively enhancing responses of cortical neurons (involuntary attention). The novelty signal is generated in novelty neurons of the hippocampus, which are selectively tuned to a repeatedly presented standard stimulus. The selective tuning is caused by the depression of plastic synapses representing a "neuronal model" of the standard stimulus. A mismatch of the novel stimulus with the established neuronal model gives rise to a "novelty signal" enhancing the novel input. The novelty signal inhibits current conditioned reflexes (external inhibition) contributing to redirecting the behavior. By triggering the expression of early genes the novelty signal initiates the formation of the long-term memory connected with neoneurogenesis.

Using vertebrate prey capture locations to identify cover type selection patterns of nocturnally foraging Burrowing Owls.

PubMed

Marsh, Alan; Bayne, Erin M; Wellicome, Troy I

2014-07-01

Studies of habitat selection often measure an animal's use of space via radiotelemetry or GPS-based technologies. Such data tend to be analyzed using a resource selection function, despite the fact that the actual resources acquired are typically not recorded. Without explicit proof of resource use, conclusions from RSF models are based on assumptions regarding an animal's behavior and the resources gained. Conservation initiatives are often based on space-use models, and could be detrimental to the target species if these assumptions are incorrect. We used GPS dataloggers and digital video recorders to determine precise locations where nocturnally foraging Burrowing Owls acquired food resources (vertebrate prey). We compared land cover type selection patterns using a presence-only resource selection function (RSF) to a model that incorporated prey capture locations (CRSF). We also compared net prey returns in each cover type to better measure reward relative to foraging effort. The RSF method did not reflect prey capture patterns and cover-type rankings from this model were quite different from models that used only locations where prey was known to have been obtained. Burrowing Owls successfully foraged across all cover types; however, return vs. effort models indicate that different cover types were of higher quality than those identified using resource selection functions. Conclusions about the type of resources acquired should not be made from RSF-style models without evidence that the actual resource of interest was acquired. Conservation efforts based on RSF models alone may be ineffective or detrimental to the target species if the limiting resource and where it is acquired are not properly identified.

Oligonucleotide-based strategies to combat polyglutamine diseases

PubMed Central

Fiszer, Agnieszka; Krzyzosiak, Wlodzimierz J.

2014-01-01

Considerable advances have been recently made in understanding the molecular aspects of pathogenesis and in developing therapeutic approaches for polyglutamine (polyQ) diseases. Studies on pathogenic mechanisms have extended our knowledge of mutant protein toxicity, confirmed the toxicity of mutant transcript and identified other toxic RNA and protein entities. One very promising therapeutic strategy is targeting the causative gene expression with oligonucleotide (ON) based tools. This straightforward approach aimed at halting the early steps in the cascade of pathogenic events has been widely tested for Huntington's disease and spinocerebellar ataxia type 3. In this review, we gather information on the use of antisense oligonucleotides and RNA interference triggers for the experimental treatment of polyQ diseases in cellular and animal models. We present studies testing non-allele-selective and allele-selective gene silencing strategies. The latter include targeting SNP variants associated with mutations or targeting the pathologically expanded CAG repeat directly. We compare gene silencing effectors of various types in a number of aspects, including their design, efficiency in cell culture experiments and pre-clinical testing. We discuss advantages, current limitations and perspectives of various ON-based strategies used to treat polyQ diseases. PMID:24848018

Insights into next developments in advanced gastric cancer.

PubMed

Obermannová, Radka; Lordick, Florian

2016-07-01

The purpose of the review is to delineate novel approaches for biology-based treatment in advanced gastric cancer. We reviewed the latest translational and clinical research articles and congress presentations. A new molecular classification of gastric cancer based on histology, genetic and proteomic alterations has evolved. It provides a roadmap for development of new drugs and combinations and for patient stratification. Anti-HER2 treatment, which is an effective strategy in metastatic gastric cancer, is now also being studied in the perioperative setting. However, resistance mechanisms in advanced disease are poorly understood and optimal patient selection remains challenging. Targeting angiogenesis is an emerging concept in the management of advanced gastric cancer, and ramucirumab has prolonged survival in the second line either as a monotherapy or in combination with paclitaxel. Biomarkers for selecting patients who benefit from ramucirumab are still lacking. Immune checkpoint blockade and inhibition of cancer stemness targets are other emerging directions for the medical treatment of gastric cancer. Large-scale international studies are ongoing. Promising biology-based treatment strategies are evolving. But tumor heterogeneity which is an inherent feature of gastric cancer challenges the development of molecularly targeted and personalized treatment strategies.

Two novel motion-based algorithms for surveillance video analysis on embedded platforms

NASA Astrophysics Data System (ADS)

Vijverberg, Julien A.; Loomans, Marijn J. H.; Koeleman, Cornelis J.; de With, Peter H. N.

2010-05-01

This paper proposes two novel motion-vector based techniques for target detection and target tracking in surveillance videos. The algorithms are designed to operate on a resource-constrained device, such as a surveillance camera, and to reuse the motion vectors generated by the video encoder. The first novel algorithm for target detection uses motion vectors to construct a consistent motion mask, which is combined with a simple background segmentation technique to obtain a segmentation mask. The second proposed algorithm aims at multi-target tracking and uses motion vectors to assign blocks to targets employing five features. The weights of these features are adapted based on the interaction between targets. These algorithms are combined in one complete analysis application. The performance of this application for target detection has been evaluated for the i-LIDS sterile zone dataset and achieves an F1-score of 0.40-0.69. The performance of the analysis algorithm for multi-target tracking has been evaluated using the CAVIAR dataset and achieves an MOTP of around 9.7 and MOTA of 0.17-0.25. On a selection of targets in videos from other datasets, the achieved MOTP and MOTA are 8.8-10.5 and 0.32-0.49 respectively. The execution time on a PC-based platform is 36 ms. This includes the 20 ms for generating motion vectors, which are also required by the video encoder.

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.

Assessment of SRM, MRM(3) , and DIA for the targeted analysis of phosphorylation dynamics in non-small cell lung cancer.

PubMed

Schmidlin, Thierry; Garrigues, Luc; Lane, Catherine S; Mulder, T Celine; van Doorn, Sander; Post, Harm; de Graaf, Erik L; Lemeer, Simone; Heck, Albert J R; Altelaar, A F Maarten

2016-08-01

Hypothesis-driven MS-based targeted proteomics has gained great popularity in a relatively short timespan. Next to the widely established selected reaction monitoring (SRM) workflow, data-independent acquisition (DIA), also referred to as sequential window acquisition of all theoretical spectra (SWATH) was introduced as a high-throughput targeted proteomics method. DIA facilitates increased proteome coverage, however, does not yet reach the sensitivity obtained with SRM. Therefore, a well-informed method selection is crucial for designing a successful targeted proteomics experiment. This is especially the case when targeting less conventional peptides such as those that contain PTMs, as these peptides do not always adhere to the optimal fragmentation considerations for targeted assays. Here, we provide insight into the performance of DIA, SRM, and MRM cubed (MRM(3) ) in the analysis of phosphorylation dynamics throughout the phosphoinositide 3-kinase mechanistic target of rapamycin (PI3K-mTOR) and mitogen-activated protein kinase (MAPK) signaling network. We observe indeed that DIA is less sensitive when compared to SRM, however demonstrates increased flexibility, by postanalysis selection of alternative phosphopeptide precursors. Additionally, we demonstrate the added benefit of MRM(3) , allowing the quantification of two poorly accessible phosphosites. In total, targeted proteomics enabled the quantification of 42 PI3K-mTOR and MAPK phosphosites, gaining a so far unachieved in-depth view mTOR signaling events linked to tyrosine kinase inhibitor resistance in non-small cell lung cancer. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Comparison of different target material options for the European Spallation Source based on certain aspects related to the final disposal

NASA Astrophysics Data System (ADS)

Kókai, Zsófia; Török, Szabina; Zagyvai, Péter; Kiselev, Daniela; Moormann, Rainer; Börcsök, Endre; Zanini, Luca; Takibayev, Alan; Muhrer, Günter; Bevilacqua, Riccardo; Janik, József

2018-02-01

Different target options have been examined for the European Spallation Source, which is under construction in Lund, Sweden. During the design update phase, parameters and characteristics for the target design have been optimized not only for neutronics but also with respect to the waste characteristics related to the final disposal of the target. A rotating, solid tungsten target was eventually selected as baseline concept; the other options considered included mercury and lead-bismuth (LBE) targets suitable for a pulsed source. Since the licensee is obliged to present a decommissioning plan even before the construction phase starts, the radioactive waste category of the target after full operation time is of crucial importance. The results obtained from a small survey among project partners of 7th Framework Program granted by EU 202247 contract have been used. Waste characteristics of different potential spallation target materials were compared. Based on waste index, the tungsten target is the best alternative and the second one is the mercury target. However, all alternatives have HLW category after a 10 year cooling. Based on heat generation alone all of the options would be below the HLW limit after this cooling period. The LBE is the least advantageous alternative based on waste index and heat generation comparison. These results can be useful in compiling the licensing documents of the ESS facility as the target alternatives can be compared from various aspects related to their disposal.

THE SDSS-III BARYON OSCILLATION SPECTROSCOPIC SURVEY: QUASAR TARGET SELECTION FOR DATA RELEASE NINE

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

Ross, Nicholas P.; Kirkpatrick, Jessica A.; Carithers, William C.

2012-03-01

The SDSS-III Baryon Oscillation Spectroscopic Survey (BOSS), a five-year spectroscopic survey of 10,000 deg{sup 2}, achieved first light in late 2009. One of the key goals of BOSS is to measure the signature of baryon acoustic oscillations (BAOs) in the distribution of Ly{alpha} absorption from the spectra of a sample of {approx}150,000 z > 2.2 quasars. Along with measuring the angular diameter distance at z Almost-Equal-To 2.5, BOSS will provide the first direct measurement of the expansion rate of the universe at z > 2. One of the biggest challenges in achieving this goal is an efficient target selection algorithmmore » for quasars in the redshift range 2.2 < z < 3.5, where their colors tend to overlap those of the far more numerous stars. During the first year of the BOSS survey, quasar target selection (QTS) methods were developed and tested to meet the requirement of delivering at least 15 quasars deg{sup -2} in this redshift range, with a goal of 20 out of 40 targets deg{sup -2} allocated to the quasar survey. To achieve these surface densities, the magnitude limit of the quasar targets was set at g {<=} 22.0 or r {<=} 21.85. While detection of the BAO signature in the distribution of Ly{alpha} absorption in quasar spectra does not require a uniform target selection algorithm, many other astrophysical studies do. We have therefore defined a uniformly selected subsample of 20 targets deg{sup -2}, for which the selection efficiency is just over 50% ({approx}10 z > 2.20 quasars deg{sup -2}). This 'CORE' subsample will be fixed for Years Two through Five of the survey. For the remaining 20 targets deg{sup -2}, we will continue to develop improved selection techniques, including the use of additional data sets beyond the Sloan Digital Sky Survey (SDSS) imaging data. In this paper, we describe the evolution and implementation of the BOSS QTS algorithms during the first two years of BOSS operations (through 2011 July), in support of the science investigations based on these data, and we analyze the spectra obtained during the first year. During this year, 11,263 new z > 2.20 quasars were spectroscopically confirmed by BOSS, roughly double the number of previously known quasars with z > 2.20. Our current algorithms select an average of 15 z > 2.20 quasars deg{sup -2} from 40 targets deg{sup -2} using single-epoch SDSS imaging. Multi-epoch optical data and data at other wavelengths can further improve the efficiency and completeness of BOSS QTS.« less

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.

Synergistic target combination prediction from curated signaling networks: Machine learning meets systems biology and pharmacology.

PubMed

Chua, Huey Eng; Bhowmick, Sourav S; Tucker-Kellogg, Lisa

2017-10-01

Given a signaling network, the target combination prediction problem aims to predict efficacious and safe target combinations for combination therapy. State-of-the-art in silico methods use Monte Carlo simulated annealing (mcsa) to modify a candidate solution stochastically, and use the Metropolis criterion to accept or reject the proposed modifications. However, such stochastic modifications ignore the impact of the choice of targets and their activities on the combination's therapeutic effect and off-target effects, which directly affect the solution quality. In this paper, we present mascot, a method that addresses this limitation by leveraging two additional heuristic criteria to minimize off-target effects and achieve synergy for candidate modification. Specifically, off-target effects measure the unintended response of a signaling network to the target combination and is often associated with toxicity. Synergy occurs when a pair of targets exerts effects that are greater than the sum of their individual effects, and is generally a beneficial strategy for maximizing effect while minimizing toxicity. mascot leverages on a machine learning-based target prioritization method which prioritizes potential targets in a given disease-associated network to select more effective targets (better therapeutic effect and/or lower off-target effects); and on Loewe additivity theory from pharmacology which assesses the non-additive effects in a combination drug treatment to select synergistic target activities. Our experimental study on two disease-related signaling networks demonstrates the superiority of mascot in comparison to existing approaches. Copyright © 2017 Elsevier Inc. All rights reserved.

Selective inhibition of plant serine hydrolases by agrochemicals revealed by competitive ABPP.

PubMed

Kaschani, Farnusch; Nickel, Sabrina; Pandey, Bikram; Cravatt, Benjamin F; Kaiser, Markus; van der Hoorn, Renier A L

2012-01-15

Organophosphate and -phosphonates and their thio derivatives are often used in agroindustry as herbicides and insecticides, but their potential off-targets in the plant are poorly investigated. Here, we use competitive activity-based protein profiling (ABPP) of serine hydrolases (SHs) to detect targets of these agrochemicals and other compounds in Arabidopsis thaliana. Using broad-range and specific probes, and by overexpression of various SHs in planta, we are able to confirm eight SH-compound interactions, including selective inhibition of carboxylesterase CXE12, prolyloligopeptidase, methylesterase MES2 and tripeptidyl peptidase TPP2. These observations can be used for the design of novel probes and selective inhibitors and may help to assess physiological effects of agrochemicals on crop plants. Copyright © 2011 Elsevier Ltd. All rights reserved.

Application of Adjoint Methodology in Various Aspects of Sonic Boom Design

NASA Technical Reports Server (NTRS)

Rallabhandi, Sriram K.

2014-01-01

One of the advances in computational design has been the development of adjoint methods allowing efficient calculation of sensitivities in gradient-based shape optimization. This paper discusses two new applications of adjoint methodology that have been developed to aid in sonic boom mitigation exercises. In the first, equivalent area targets are generated using adjoint sensitivities of selected boom metrics. These targets may then be used to drive the vehicle shape during optimization. The second application is the computation of adjoint sensitivities of boom metrics on the ground with respect to parameters such as flight conditions, propagation sampling rate, and selected inputs to the propagation algorithms. These sensitivities enable the designer to make more informed selections of flight conditions at which the chosen cost functionals are less sensitive.

Supramolecular Chemistry of Selective Anion Recognition for Anions of Environmental Relevance

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

Bowman-James, Kristen

2004-12-01

This project have focuses on the basic chemical aspects of anion receptor design of functional pH independent systems, with the ultimate goal of targeting the selective binding of sulfate, as well as design of separations strategies for selective and efficient removal of targeted anions. Key findings include: (1) the first synthetic sulfate-selective anion-binding agents; (2) simple, structure-based methods for modifying the intrinsic anion selectivity of a given class of anion receptors; and (3) the first system capable of extracting sulfate anion from acidic, nitrate-containing aqueous media. Areas probed during the last funding period include: the design, synthesis, and physical andmore » structural characterization of receptors and investigation of anion and dual ion pair extraction using lipophilic amide receptors for anion binding. A new collaboration has been added to the project in addition to the one with Dr. Bruce Moyer at Oak Ridge National Laboratory, with Professor Jonathan Sessler at the University of Texas at Austin.« less

The study of infrared target recognition at sea background based on visual attention computational model

NASA Astrophysics Data System (ADS)

Wang, Deng-wei; Zhang, Tian-xu; Shi, Wen-jun; Wei, Long-sheng; Wang, Xiao-ping; Ao, Guo-qing

2009-07-01

Infrared images at sea background are notorious for the low signal-to-noise ratio, therefore, the target recognition of infrared image through traditional methods is very difficult. In this paper, we present a novel target recognition method based on the integration of visual attention computational model and conventional approach (selective filtering and segmentation). The two distinct techniques for image processing are combined in a manner to utilize the strengths of both. The visual attention algorithm searches the salient regions automatically, and represented them by a set of winner points, at the same time, demonstrated the salient regions in terms of circles centered at these winner points. This provides a priori knowledge for the filtering and segmentation process. Based on the winner point, we construct a rectangular region to facilitate the filtering and segmentation, then the labeling operation will be added selectively by requirement. Making use of the labeled information, from the final segmentation result we obtain the positional information of the interested region, label the centroid on the corresponding original image, and finish the localization for the target. The cost time does not depend on the size of the image but the salient regions, therefore the consumed time is greatly reduced. The method is used in the recognition of several kinds of real infrared images, and the experimental results reveal the effectiveness of the algorithm presented in this paper.

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.

Computational Optimization and Characterization of Molecularly Imprinted Polymers

NASA Astrophysics Data System (ADS)

Terracina, Jacob J.

Molecularly imprinted polymers (MIPs) are a class of materials containing sites capable of selectively binding to the imprinted target molecule. Computational chemistry techniques were used to study the effect of different fabrication parameters (the monomer-to-target ratios, pre-polymerization solvent, temperature, and pH) on the formation of the MIP binding sites. Imprinted binding sites were built in silico for the purposes of better characterizing the receptor - ligand interactions. Chiefly, the sites were characterized with respect to their selectivities and the heterogeneity between sites. First, a series of two-step molecular mechanics (MM) and quantum mechanics (QM) computational optimizations of monomer -- target systems was used to determine optimal monomer-to-target ratios for the MIPs. Imidazole- and xanthine-derived target molecules were studied. The investigation included both small-scale models (one-target) and larger scale models (five-targets). The optimal ratios differed between the small and larger scales. For the larger models containing multiple targets, binding-site surface area analysis was used to evaluate the heterogeneity of the sites. The more fully surrounded sites had greater binding energies. Molecular docking was then used to measure the selectivities of the QM-optimized binding sites by comparing the binding energies of the imprinted target to that of a structural analogue. Selectivity was also shown to improve as binding sites become more fully encased by the monomers. For internal sites, docking consistently showed selectivity favoring the molecules that had been imprinted via QM geometry optimizations. The computationally imprinted sites were shown to exhibit size-, shape-, and polarity-based selectivity. This represented a novel approach to investigate the selectivity and heterogeneity of imprinted polymer binding sites, by applying the rapid orientation screening of MM docking to the highly accurate QM-optimized geometries. Next, we sought to computationally construct and investigate binding sites for their enantioselectivity. Again, a two-step MM [special characters removed] QM optimization scheme was used to "computationally imprint" chiral molecules. Using docking techniques, the imprinted binding sites were shown to exhibit an enantioselective preference for the imprinted molecule over its enantiomer. Docking of structurally similar chiral molecules showed that the sites computationally imprinted with R- or S-tBOC-tyrosine were able to differentiate between R- and S-forms of other tyrosine derivatives. The cross-enantioselectivity did not hold for chiral molecules that did not share the tyrosine H-bonding functional group orientations. Further analysis of the individual monomer - target interactions within the binding site led us to conclude that H-bonding functional groups that are located immediately next to the target's chiral center, and therefore spatially fixed relative to the chiral center, will have a stronger contribution to the enantioselectivity of the site than those groups separated from the chiral center by two or more rotatable bonds. These models were the first computationally imprinted binding sites to exhibit this enantioselective preference for the imprinted target molecules. Finally, molecular dynamics (MD) was used to quantify H-bonding interactions between target molecules, monomers, and solvents representative of the pre-polymerization matrix. It was found that both target dimerization and solvent interference decrease the number of monomer - target H-bonds present. Systems were optimized via simulated annealing to create binding sites that were then subjected to molecular docking analysis. Docking showed that the presence of solvent had a detrimental effect on the sensitivity and selectivity of the sites, and that solvents with more H-bonding capabilities were more disruptive to the binding properties of the site. Dynamic simulations also showed that increasing the temperature of the solution can significantly decrease the number of H-bonds formed between the targets and monomers. It is believed that the monomer - target complexes formed within the pre-polymerization matrix are translated into the selective binding cavities formed during polymerization. Elucidating the nature of these interactions in silico improves our understanding of MIPs, ultimately allowing for more optimized sensing materials.

Trihydroxamate siderophore-fluoroquinolone conjugates are selective sideromycin antibiotics that target Staphylococcus aureus.

PubMed

Wencewicz, Timothy A; Long, Timothy E; Möllmann, Ute; Miller, Marvin J

2013-03-20

Siderophores are multidentate iron(III) chelators used by bacteria for iron assimilation. Sideromycins, also called siderophore-antibiotic conjugates, are a unique subset of siderophores that enter bacterial cells via siderophore uptake pathways and deliver the toxic antibiotic in a "Trojan horse" fashion. Sideromycins represent a novel antibiotic delivery technology with untapped potential for developing sophisticated microbe-selective antibacterial agents that limit the emergence of bacterial resistance. The chemical synthesis of a series of mono-, bis-, and trihydroxamate sideromycins are described here along with their biological evaluation in antibacterial susceptibility assays. The linear hydroxamate siderophores used for the sideromycins in this study were derived from the ferrioxamine family and inspired by the naturally occurring salmycin sideromycins. The antibacterial agents used were a β-lactam carbacepholosporin, Lorabid, and a fluoroquinolone, ciprofloxacin, chosen for the different locations of their biological targets, the periplasm (extracellular) and the cytoplasm (intracellular). The linear hydroxamate-based sideromycins were selectively toxic toward Gram-positive bacteria, especially Staphylococcus aureus SG511 (MIC = 1.0 μM for the trihydroxamate-fluoroquinolone sideromycin). Siderophore-sideromycin competition assays demonstrated that only the fluoroquinolone sideromycins required membrane transport to reach their cytoplasmic biological target and that a trihydroxamate siderophore backbone was required for protein-mediated active transport of the sideromycins into S. aureus cells via siderophore uptake pathways. This work represents a comprehensive study of linear hydroxamate sideromycins and teaches how to build effective hydroxamate-based sideromycins as Gram-positive selective antibiotic agents.

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

Articles including thin film monolayers and multilayers

DOEpatents

Li, DeQuan; Swanson, Basil I.

1995-01-01

Articles of manufacture including: (a) a base substrate having an oxide surface layer, and a multidentate ligand, capable of binding a metal ion, attached to the oxide surface layer of the base substrate, (b) a base substrate having an oxide surface layer, a multidentate ligand, capable of binding a metal ion, attached to the oxide surface layer of the base substrate, and a metal species attached to the multidentate ligand, (c) a base substrate having an oxide surface layer, a multidentate ligand, capable of binding a metal ion, attached to the oxide surface layer of the base substrate, a metal species attached to the multidentate ligand, and a multifunctional organic ligand attached to the metal species, and (d) a base substrate having an oxide surface layer, a multidentate ligand, capable of binding a metal ion, attached to the oxide surface layer of the base substrate, a metal species attached to the multidentate ligand, a multifunctional organic ligand attached to the metal species, and a second metal species attached to the multifunctional organic ligand, are provided, such articles useful in detecting the presence of a selected target species, as nonliear optical materials, or as scavengers for selected target species.

TARGET Research Goals

Cancer.gov

TARGET researchers use various sequencing and array-based methods to examine the genomes, transcriptomes, and for some diseases epigenomes of select childhood cancers. This “multi-omic” approach generates a comprehensive profile of molecular alterations for each cancer type. Alterations are changes in DNA or RNA, such as rearrangements in chromosome structure or variations in gene expression, respectively. Through computational analyses and assays to validate biological function, TARGET researchers predict which alterations disrupt the function of a gene or pathway and promote cancer growth, progression, and/or survival. Researchers identify candidate therapeutic targets and/or prognostic markers from the cancer-associated alterations.

Slippage theory and the flanker paradigm: an early-selection account of selective attention failures.

PubMed

Gaspelin, Nicholas; Ruthruff, Eric; Jung, Kyunghun

2014-06-01

In the flanker paradigm, participants identify a target letter while attempting to ignore an irrelevant flanker. When the identity of this flanker mismatches the target, target identification is slowed (called the flanker compatibility effect). Interestingly, reducing the array set size greatly increases flanker compatibility effects. This finding inspired 2 prominent explanations: perceptual load (mandatory capacity spillover) and dilution (visual interference). However, an alternative explanation, based on early selection theory and attention capture research, can also explain the data pattern. According to this "slippage" account, observers sometimes accidentally allocate spatial attention to the flanker (see Lachter, Forster, & Ruthruff, 2004), especially when the flanker has the property used to find the target (cf. contingent capture). In Experiments 1 through 4, deterring slippage to the flanker nearly eliminated flanker compatibility effects, even at the low set size. In Experiment 5, promoting slippage to the flanker dramatically enhanced compatibility effects, even at the high set size. Thus, slippage strongly modulates flanker effects and can, by itself, readily explain the impact of set size. The perceptual load and dilution accounts are, at best, incomplete, and, at worst, not needed. PsycINFO Database Record (c) 2014 APA, all rights reserved.

Learning a Nonmediated Route for Response Selection in Task Switching

PubMed Central

Schneider, Darryl W.; Logan, Gordon D.

2015-01-01

Two modes of response selection—a mediated route involving categorization and a nonmediated route involving instance-based memory retrieval—have been proposed to explain response congruency effects in task-switching situations. In the present study, we sought a better understanding of the development and characteristics of the nonmediated route. In two experiments involving training and transfer phases, we investigated practice effects at the level of individual target presentations, transfer effects associated with changing category–response mappings, target-specific effects from comparisons of old and new targets during transfer, and the percentage of early responses associated with task-nonspecific response selection (the target preceded the task cue on every trial). The training results suggested that the nonmediated route is quickly learned in the context of target–cue order and becomes increasingly involved in response selection with practice. The transfer results suggested that the target–response instances underlying the nonmediated route involve abstract response labels coding response congruency that can be rapidly remapped to alternative responses but not rewritten when category–response mappings change after practice. Implications for understanding the nonmediated route and its relationship with the mediated route are discussed. PMID:25663003

Production of an 15O beam using a stable oxygen ion beam for in-beam PET imaging

NASA Astrophysics Data System (ADS)

Mohammadi, Akram; Yoshida, Eiji; Tashima, Hideaki; Nishikido, Fumihiko; Inaniwa, Taku; Kitagawa, Atsushi; Yamaya, Taiga

2017-03-01

In advanced ion therapy, the 15O ion beam is a promising candidate to treat hypoxic tumors and simultaneously monitor the delivered dose to a patient using PET imaging. This study aimed at production of an 15O beam by projectile fragmentation of a stable 16O beam in an optimal material, followed by in-beam PET imaging using a prototype OpenPET system, which was developed in the authors' group. The study was carried out in three steps: selection of the optimal target based on the highest production rate of 15O fragments; experimental production of the beam using the optimal target in the Heavy Ion Medical Accelerator Chiba (HIMAC) secondary beam course; and realization of in-beam PET imaging for the produced beam. The optimal target evaluations were done using the Monte Carlo simulation code PHITS. The fluence and mean energy of the secondary particles were simulated and the optimal target was selected based on the production rate of 15O fragments. The highest production rate of 15O was observed for a liquid hydrogen target, 3.27% for a 53 cm thick target from the 16O beam of 430 MeV/u. Since liquid hydrogen is not practically applicable in the HIMAC secondary beam course a hydrogen-rich polyethylene material, which was the second optimal target from the simulation results, was selected as the experimental target. Three polyethylene targets with thicknesses of 5, 11 or 14 cm were used to produce the 15O beam without any degrader in the beam course. The highest production rate was measured as around 0.87% for the 11 cm thick polyethylene target from the 16O beam of 430 MeV/u when the angular acceptance and momentum acceptance were set at ±13 mrad and ±2.5%, respectively. The purity of the produced beam for the three targets were around 75%, insufficient for clinical application, but it was increased to 97% by inserting a wedge shape aluminum degrader with a thickness of 1.76 cm into the beam course and that is sufficiently high. In-beam PET imaging was also performed for all produced beams using the OpenPET system. The purity improvement of the produced 15O beams was confirmed from the PET images.

Sexual selection on morphological and physiological traits and fluctuating asymmetry in the black scavenger fly Sepsis cynipsea.

PubMed

Blanckenhorn, W U; Kraushaar, U R S; Teuschl, Y; Reim, C

2004-05-01

Previous univariate studies of the fly Sepsis cynipsea (Diptera: Sepsidae) have demonstrated spatiotemporally variable and consequently overall weak sexual selection favouring large male size, which is nevertheless stronger on average than fecundity selection favouring larger females. To identify specific target(s) of selection on body size and additional traits possibly affecting mating success, two multivariate field studies of sexual selection were conducted. In one study using seasonal replicates from three populations, we assessed 15 morphological traits. No clear targets of sexual selection on male size could be detected, perhaps because spatiotemporal variation in selection was again strong. In particular, there was no (current) selection on male abdomen length or fore coxa length, the only traits for which S. cynipsea males are not smaller than females. Interestingly, copulating males had a consistently shorter fore femur base, a secondary sexual trait, and a wider clasper (hypopygium) gap, an external genital trait. In a second study using daily and seasonal replicates from one population, we included physiological measures of energy reserves (lipids, glucose, glycogen), in addition to hind tibia length and fluctuating asymmetry (FA) of all pairs of legs. This study again confirmed the mating advantage of large males, and additionally suggests independent positive influences of lipids (the long-term energy stores), with effects of glucose and glycogen (the short-term energy stores) tending to be negative. FA of paired traits was not associated with male mating success. Our study suggests that inclusion of physiological measures and genital traits in phenomenological studies of selection, which is rare, would be fruitful in other species.

Global vision of druggability issues: applications and perspectives.

PubMed

Abi Hussein, Hiba; Geneix, Colette; Petitjean, Michel; Borrel, Alexandre; Flatters, Delphine; Camproux, Anne-Claude

2017-02-01

During the preliminary stage of a drug discovery project, the lack of druggability information and poor target selection are the main causes of frequent failures. Elaborating on accurate computational druggability prediction methods is a requirement for prioritizing target selection, designing new drugs and avoiding side effects. In this review, we describe a survey of recently reported druggability prediction methods mainly based on networks, statistical pocket druggability predictions and virtual screening. An application for a frequent mutation of p53 tumor suppressor is presented, illustrating the complementarity of druggability prediction approaches, the remaining challenges and potential new drug development perspectives. Copyright © 2016 Elsevier Ltd. All rights reserved.

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.

An infrastructure to mine molecular descriptors for ligand selection on virtual screening.

PubMed

Seus, Vinicius Rosa; Perazzo, Giovanni Xavier; Winck, Ana T; Werhli, Adriano V; Machado, Karina S

2014-01-01

The receptor-ligand interaction evaluation is one important step in rational drug design. The databases that provide the structures of the ligands are growing on a daily basis. This makes it impossible to test all the ligands for a target receptor. Hence, a ligand selection before testing the ligands is needed. One possible approach is to evaluate a set of molecular descriptors. With the aim of describing the characteristics of promising compounds for a specific receptor we introduce a data warehouse-based infrastructure to mine molecular descriptors for virtual screening (VS). We performed experiments that consider as target the receptor HIV-1 protease and different compounds for this protein. A set of 9 molecular descriptors are taken as the predictive attributes and the free energy of binding is taken as a target attribute. By applying the J48 algorithm over the data we obtain decision tree models that achieved up to 84% of accuracy. The models indicate which molecular descriptors and their respective values are relevant to influence good FEB results. Using their rules we performed ligand selection on ZINC database. Our results show important reduction in ligands selection to be applied in VS experiments; for instance, the best selection model picked only 0.21% of the total amount of drug-like ligands.

Detection and quantification of proteins and cells by use of elemental mass spectrometry: progress and challenges.

PubMed

Yan, Xiaowen; Yang, Limin; Wang, Qiuquan

2013-07-01

Much progress has been made in identification of the proteins in proteomes, and quantification of these proteins has attracted much interest. In addition to popular tandem mass spectrometric methods based on soft ionization, inductively coupled plasma mass spectrometry (ICPMS), a typical example of mass spectrometry based on hard ionization, usually used for analysis of elements, has unique advantages in absolute quantification of proteins by determination of an element with a definite stoichiometry in a protein or attached to the protein. In this Trends article, we briefly describe state-of-the-art ICPMS-based methods for quantification of proteins, emphasizing protein-labeling and element-tagging strategies developed on the basis of chemically selective reactions and/or biospecific interactions. Recent progress from protein to cell quantification by use of ICPMS is also discussed, and the possibilities and challenges of ICPMS-based protein quantification for universal, selective, or targeted quantification of proteins and cells in a biological sample are also discussed critically. We believe ICPMS-based protein quantification will become ever more important in targeted quantitative proteomics and bioanalysis in the near future.

Selecting among competing models of electro-optic, infrared camera system range performance

USGS Publications Warehouse

Nichols, Jonathan M.; Hines, James E.; Nichols, James D.

2013-01-01

Range performance is often the key requirement around which electro-optical and infrared camera systems are designed. This work presents an objective framework for evaluating competing range performance models. Model selection based on the Akaike’s Information Criterion (AIC) is presented for the type of data collected during a typical human observer and target identification experiment. These methods are then demonstrated on observer responses to both visible and infrared imagery in which one of three maritime targets was placed at various ranges. We compare the performance of a number of different models, including those appearing previously in the literature. We conclude that our model-based approach offers substantial improvements over the traditional approach to inference, including increased precision and the ability to make predictions for some distances other than the specific set for which experimental trials were conducted.

Prediction of intracellular exposure bridges the gap between target- and cell-based drug discovery

PubMed Central

Gordon, Laurie J.; Wayne, Gareth J.; Almqvist, Helena; Axelsson, Hanna; Seashore-Ludlow, Brinton; Treyer, Andrea; Lundbäck, Thomas; West, Andy; Hann, Michael M.; Artursson, Per

2017-01-01

Inadequate target exposure is a major cause of high attrition in drug discovery. Here, we show that a label-free method for quantifying the intracellular bioavailability (Fic) of drug molecules predicts drug access to intracellular targets and hence, pharmacological effect. We determined Fic in multiple cellular assays and cell types representing different targets from a number of therapeutic areas, including cancer, inflammation, and dementia. Both cytosolic targets and targets localized in subcellular compartments were investigated. Fic gives insights on membrane-permeable compounds in terms of cellular potency and intracellular target engagement, compared with biochemical potency measurements alone. Knowledge of the amount of drug that is locally available to bind intracellular targets provides a powerful tool for compound selection in early drug discovery. PMID:28701380

Infrared small target detection based on multiscale center-surround contrast measure

NASA Astrophysics Data System (ADS)

Fu, Hao; Long, Yunli; Zhu, Ran; An, Wei

2018-04-01

Infrared(IR) small target detection plays a critical role in the Infrared Search And Track (IRST) system. Although it has been studied for years, there are some difficulties remained to the clutter environment. According to the principle of human discrimination of small targets from a natural scene that there is a signature of discontinuity between the object and its neighboring regions, we develop an efficient method for infrared small target detection called multiscale centersurround contrast measure (MCSCM). First, to determine the maximum neighboring window size, an entropy-based window selection technique is used. Then, we construct a novel multiscale center-surround contrast measure to calculate the saliency map. Compared with the original image, the MCSCM map has less background clutters and noise residual. Subsequently, a simple threshold is used to segment the target. Experimental results show our method achieves better performance.

Targeted Quantification of Phosphorylation Dynamics in the Context of EGFR-MAPK Pathway.

PubMed

Yi, Lian; Shi, Tujin; Gritsenko, Marina A; X'avia Chan, Chi-Yuet; Fillmore, Thomas L; Hess, Becky M; Swensen, Adam C; Liu, Tao; Smith, Richard D; Wiley, H Steven; Qian, Wei-Jun

2018-04-17

Large-scale phosphoproteomics with coverage of over 10,000 sites of phosphorylation have now been routinely achieved with advanced mass spectrometry (MS)-based workflows. However, accurate targeted MS-based quantification of phosphorylation dynamics, an important direction for gaining quantitative understanding of signaling pathways or networks, has been much less investigated. Herein, we report an assessment of the targeted workflow in the context of signal transduction pathways, using the epidermal growth factor receptor (EGFR)-mitogen-activated protein kinase (MAPK) pathway as our model. A total of 43 phosphopeptides from the EGFR-MAPK pathway were selected for the study. The recovery and sensitivity of two commonly used enrichment methods, immobilized metal affinity chromatography (IMAC) and titanium oxide (TiO 2 ), combined with selected reaction monitoring (SRM)-MS were evaluated. The recovery of phosphopeptides by IMAC and TiO 2 enrichment was quantified to be 38 ± 5% and 58 ± 20%, respectively, based on internal standards. Moreover, both enrichment methods provided comparable sensitivity from 1 to 100 μg starting peptides. Robust quantification was consistently achieved for most targeted phosphopeptides when starting with 25-100 μg peptides. However, the numbers of quantified targets significantly dropped when peptide samples were in the 1-25 μg range. Finally, IMAC-SRM was applied to quantify signaling dynamics of EGFR-MAPK pathway in Hs578T cells following 10 ng/mL EGF treatment. The kinetics of phosphorylation clearly revealed early and late phases of phosphorylation, even for very low abundance proteins. These results demonstrate the feasibility of robust targeted quantification of phosphorylation dynamics for specific pathways, even starting with relatively small amounts of protein.

Targeted Quantification of Phosphorylation Dynamics in the Context of EGFR-MAPK Pathway

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

Yi, Lian; Shi, Tujin; Gritsenko, Marina A.

2018-03-27

Large-scale phosphoproteomics with coverage of over 10,000 sites of phosphorylation have now been routinely achieved with advanced mass spectrometry (MS)-based workflows. However, accurate targeted MS-based quantification of phosphorylation dynamics, an important direction for gaining quantitative understanding of signaling pathways or networks, has been much less investigated. Herein, we report an assessment of the targeted workflow in the context of signal transduction pathways, using the epidermal growth factor receptor (EGFR)–mitogen-activated protein kinase (MAPK) pathway as our model. 43 phosphopeptides from the EGFR–MAPK pathway were selected for the study. The recovery and sensitivity of a workflow consisted of two commonly used enrichmentmore » methods, immobilized metal affinity chromatography (IMAC) and titanium oxide (TiO2), combined with selected reaction monitoring (SRM)-MS, were evaluated. The recovery of phosphopeptides by IMAC and TiO2 enrichment was quantified to be 38 ± 5% and 58 ± 20%, respectively, based on internal standards. Moreover, both enrichment methods provided comparable sensitivity from 1-100 g starting peptides. Robust quantification was consistently achieved for most targeted phosphopeptides when starting with 25-100 g peptides. However, the numbers of quantified targets significantly dropped when peptide samples were in the 1-25g range. Finally, IMAC-SRM was applied to quantify signaling dynamics of EGFR-MAPK pathway in Hs578T cells following 3 ng/mL EGF treatment. The kinetics of phosphorylation clearly revealed early and late phases of phosphorylation, even for very low abundance proteins. These results demonstrate the feasibility of robust targeted quantification of phosphorylation dynamics for specific pathways, even starting with relatively small amounts of protein.« less

Decentralized cooperative TOA/AOA target tracking for hierarchical wireless sensor networks.

PubMed

Chen, Ying-Chih; Wen, Chih-Yu

2012-11-08

This paper proposes a distributed method for cooperative target tracking in hierarchical wireless sensor networks. The concept of leader-based information processing is conducted to achieve object positioning, considering a cluster-based network topology. Random timers and local information are applied to adaptively select a sub-cluster for the localization task. The proposed energy-efficient tracking algorithm allows each sub-cluster member to locally estimate the target position with a Bayesian filtering framework and a neural networking model, and further performs estimation fusion in the leader node with the covariance intersection algorithm. This paper evaluates the merits and trade-offs of the protocol design towards developing more efficient and practical algorithms for object position estimation.

The Maine Sealant Manual for School-Based and School-Linked Dental Sealant Programs.

ERIC Educational Resources Information Center

Hayward, Kneka, Ed.

This manual is designed for use by school personnel and dental personnel to aid in the development and maintenance of school-based or school-linked dental sealant programs. The sections include (1) "Introduction"; (2) "Guidelines" (school selection, school contacts, dental providers, target grades, and tooth selection…

Targeted cell adhesion on selectively micropatterned polymer arrays on a poly(dimethylsiloxane) surface.

PubMed

Tang, Linzhi; Min, Junhong; Lee, Eun-Cheol; Kim, Jong Sung; Lee, Nae Yoon

2010-02-01

Herein, we introduce the fabrication of polymer micropattern arrays on a chemically inert poly(dimethylsiloxane) (PDMS) surface and employ them for the selective adhesion of cells. To fabricate the micropattern arrays, a mercapto-ester-based photocurable adhesive was coated onto a mercaptosilane-coated PDMS surface and photopolymerized using a photomask to obtain patterned arrays at the microscale level. Robust polymer patterns, 380 microm in diameter, were successfully fabricated onto a PDMS surface, and cells were selectively targeted toward the patterned regions. Next, the performance of the cell adhesion was observed by anchoring cell adhesive linker, an RGD oligopeptide, on the surface of the mercapto-ester-based adhesive-cured layer. The successful anchoring of the RGD linker was confirmed through various surface characterizations such as water contact angle measurement, XPS analysis, FT-IR analysis, and AFM measurement. The micropatterning of a photocurable adhesive onto a PDMS surface can provide high structural rigidity, a highly-adhesive surface, and a physical pathway for selective cell adhesion, while the incorporated polymer micropattern arrays inside a PDMS microfluidic device can serve as a microfluidic platform for disease diagnoses and high-throughput drug screening.

Evolution of I-SceI Homing Endonucleases with Increased DNA Recognition Site Specificity

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

Joshi, Rakesh; Ho, Kwok Ki; Tenney, Kristen

2013-09-18

Elucidating how homing endonucleases undergo changes in recognition site specificity will facilitate efforts to engineer proteins for gene therapy applications. I-SceI is a monomeric homing endonuclease that recognizes and cleaves within an 18-bp target. It tolerates limited degeneracy in its target sequence, including substitution of a C:G{sub +4} base pair for the wild-type A:T{sub +4} base pair. Libraries encoding randomized amino acids at I-SceI residue positions that contact or are proximal to A:T{sub +4} were used in conjunction with a bacterial one-hybrid system to select I-SceI derivatives that bind to recognition sites containing either the A:T{sub +4} or the C:G{submore » +4} base pairs. As expected, isolates encoding wild-type residues at the randomized positions were selected using either target sequence. All I-SceI proteins isolated using the C:G{sub +4} recognition site included small side-chain substitutions at G100 and either contained (K86R/G100T, K86R/G100S and K86R/G100C) or lacked (G100A, G100T) a K86R substitution. Interestingly, the binding affinities of the selected variants for the wild-type A:T{sub +4} target are 4- to 11-fold lower than that of wild-type I-SceI, whereas those for the C:G{sub +4} target are similar. The increased specificity of the mutant proteins is also evident in binding experiments in vivo. These differences in binding affinities account for the observed -36-fold difference in target preference between the K86R/G100T and wild-type proteins in DNA cleavage assays. An X-ray crystal structure of the K86R/G100T mutant protein bound to a DNA duplex containing the C:G{sub +4} substitution suggests how sequence specificity of a homing enzyme can increase. This biochemical and structural analysis defines one pathway by which site specificity is augmented for a homing endonuclease.« less

Beyond helper phage: Using "helper cells" to select peptide affinity ligands

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

Phipps, Mary Lisa; Lillo, Antoinetta M.; Shou, Yulin

Peptides are important affinity ligands for microscopy, biosensing, and targeted delivery. However, because they can have low affinity for their targets, their selection from large naïve libraries can be challenging. When selecting peptidic ligands from display libraries, it is important to: 1) ensure efficient display; 2) maximize the ability to select high affinity ligands; and 3) minimize the effect of the display context on binding. The “helper cell” packaging system has been described as a tool to produce filamentous phage particles based on phagemid constructs with varying display levels, while remaining free of helper phage contamination. Here we report onmore » the first use of this system for peptide display, including the systematic characterization and optimization of helper cells, their inefficient use in antibody display and their use in creating and selecting from a set of phage display peptide libraries. Our libraries were analyzed with unprecedented precision by standard or deep sequencing, and shown to be superior in quality than commercial gold standards. Using our helper cell libraries, we have obtained ligands recognizing Yersinia pestis surface antigen F1V and L-glutamine-binding periplasmic protein QBP. In the latter case, unlike any of the peptide library selections described so far, we used a combination of phage and yeast display to select intriguing peptide ligands. Here, based on the success of our selections we believe that peptide libraries obtained with helper cells are not only suitable, but preferable to traditional phage display libraries for selection of peptidic ligands.« less

Beyond helper phage: Using "helper cells" to select peptide affinity ligands

DOE PAGES

Phipps, Mary Lisa; Lillo, Antoinetta M.; Shou, Yulin; ...

2016-09-14

Peptides are important affinity ligands for microscopy, biosensing, and targeted delivery. However, because they can have low affinity for their targets, their selection from large naïve libraries can be challenging. When selecting peptidic ligands from display libraries, it is important to: 1) ensure efficient display; 2) maximize the ability to select high affinity ligands; and 3) minimize the effect of the display context on binding. The “helper cell” packaging system has been described as a tool to produce filamentous phage particles based on phagemid constructs with varying display levels, while remaining free of helper phage contamination. Here we report onmore » the first use of this system for peptide display, including the systematic characterization and optimization of helper cells, their inefficient use in antibody display and their use in creating and selecting from a set of phage display peptide libraries. Our libraries were analyzed with unprecedented precision by standard or deep sequencing, and shown to be superior in quality than commercial gold standards. Using our helper cell libraries, we have obtained ligands recognizing Yersinia pestis surface antigen F1V and L-glutamine-binding periplasmic protein QBP. In the latter case, unlike any of the peptide library selections described so far, we used a combination of phage and yeast display to select intriguing peptide ligands. Here, based on the success of our selections we believe that peptide libraries obtained with helper cells are not only suitable, but preferable to traditional phage display libraries for selection of peptidic ligands.« less

Selecting Single Model in Combination Forecasting Based on Cointegration Test and Encompassing Test

PubMed Central

Jiang, Chuanjin; Zhang, Jing; Song, Fugen

2014-01-01

Combination forecasting takes all characters of each single forecasting method into consideration, and combines them to form a composite, which increases forecasting accuracy. The existing researches on combination forecasting select single model randomly, neglecting the internal characters of the forecasting object. After discussing the function of cointegration test and encompassing test in the selection of single model, supplemented by empirical analysis, the paper gives the single model selection guidance: no more than five suitable single models can be selected from many alternative single models for a certain forecasting target, which increases accuracy and stability. PMID:24892061

Selecting single model in combination forecasting based on cointegration test and encompassing test.

PubMed

Jiang, Chuanjin; Zhang, Jing; Song, Fugen

2014-01-01

Combination forecasting takes all characters of each single forecasting method into consideration, and combines them to form a composite, which increases forecasting accuracy. The existing researches on combination forecasting select single model randomly, neglecting the internal characters of the forecasting object. After discussing the function of cointegration test and encompassing test in the selection of single model, supplemented by empirical analysis, the paper gives the single model selection guidance: no more than five suitable single models can be selected from many alternative single models for a certain forecasting target, which increases accuracy and stability.

Not looking yourself: The cost of self-selecting photographs for identity verification.

PubMed

White, David; Burton, Amy L; Kemp, Richard I

2016-05-01

Photo-identification is based on the premise that photographs are representative of facial appearance. However, previous studies show that ratings of likeness vary across different photographs of the same face, suggesting that some images capture identity better than others. Two experiments were designed to examine the relationship between likeness judgments and face matching accuracy. In Experiment 1, we compared unfamiliar face matching accuracy for self-selected and other-selected high-likeness images. Surprisingly, images selected by previously unfamiliar viewers - after very limited exposure to a target face - were more accurately matched than self-selected images chosen by the target identity themselves. Results also revealed extremely low inter-rater agreement in ratings of likeness across participants, suggesting that perceptions of image resemblance are inherently unstable. In Experiment 2, we test whether the cost of self-selection can be explained by this general disagreement in likeness judgments between individual raters. We find that averaging across rankings by multiple raters produces image selections that provide superior identification accuracy. However, benefit of other-selection persisted for single raters, suggesting that inaccurate representations of self interfere with our ability to judge which images faithfully represent our current appearance. © 2015 The British Psychological Society.

Laser based in-situ and standoff detection of chemical warfare agents and explosives

NASA Astrophysics Data System (ADS)

Patel, C. Kumar N.

2009-09-01

Laser based detection of gaseous, liquid and solid residues and trace amounts has been developed ever since lasers were invented. However, the lack of availability of reasonably high power tunable lasers in the spectral regions where the relevant targets can be interrogated as well as appropriate techniques for high sensitivity, high selectivity detection has hampered the practical exploitation of techniques for the detection of targets important for homeland security and defense applications. Furthermore, emphasis has been on selectivity without particular attention being paid to the impact of interfering species on the quality of detection. Having high sensitivity is necessary but not a sufficient condition. High sensitivity assures a high probability of detection of the target species. However, it is only recently that the sensor community has come to recognize that any measure of probability of detection must be associated with a probability of false alarm, if it is to have any value as a measure of performance. This is especially true when one attempts to compare performance characteristics of different sensors based on different physical principles. In this paper, I will provide a methodology for characterizing the performance of sensors utilizing optical absorption measurement techniques. However, the underlying principles are equally application to all other sensors. While most of the current progress in high sensitivity, high selectivity detection of CWAs, TICs and explosives involve identifying and quantifying the target species in-situ, there is an urgent need for standoff detection of explosives from safe distances. I will describe our results on CO2 and quantum cascade laser (QCL) based photoacoustic sensors for the detection of CWAs, TICs and explosives as well the very new results on stand-off detection of explosives at distances up to 150 meters. The latter results are critically important for assuring safety of military personnel in battlefield environment, especially from improvised explosive devices (IEDs), and of civilian personnel from terrorist attacks in metropolitan areas.

Cerenkov Luminescence Imaging as a Modality to Evaluate Antibody-Based PET Radiotracers

PubMed Central

D’Souza, Jimson W.; Hensley, Harvey; Doss, Mohan; Beigarten, Charles; Torgov, Michael; Olafsen, Tove; Yu, Jian Q.

2017-01-01

Antibodies, and engineered antibody fragments, labeled with radioisotopes are being developed as radiotracers for the detection and phenotyping of diseases such as cancer. The development of antibody-based radiotracers requires extensive characterization of their in vitro and in vivo properties, including their ability to target tumors in an antigen-selective manner. In this study, we investigated the use of Cerenkov luminescence imaging (CLI) as compared with PET as a modality for evaluating the in vivo behavior of antibody-based radiotracers. Methods: The anti–prostate-specific membrane antigen (PSMA) huJ591 antibody (IgG; 150 kDa) and its minibody (Mb; 80 kDa) format were functionalized with the chelator 1,4,7-triazacyclononane-1-glutaric acid-4,7-diacetic acid (NODAGA) and radiolabeled with the positron-emitting radionuclide 64Cu (half-life, 12.7 h). Immunoreactive preparations of the radiolabeled antibodies were injected into NCr nu/nu mice harboring PSMA-positive CWR22Rv1 and PSMA-negative PC-3 tumor xenografts. Tumor targeting was evaluated by both PET and CLI. Results: 64Cu-NODAGA-PSMA-IgG and 64Cu-NODAGA-PSMA-Mb retained the ability to bind cell surface PSMA, and both radiotracers exhibited selective uptake into PSMA-positive tumors. Under the experimental conditions used, PSMA-selective uptake of 64Cu-NODAGA-PSMA-IgG and 64Cu-NODAGA-PSMA-Mb was observed by CLI as early as 3 h after injection, with tumor-to-background ratios peaking at 24 (IgG) and 16 (Mb) h after injection. Targeting data generated by CLI correlated with that generated by PET and necropsy. Conclusion: CLI provided a rapid and simple assessment of the targeting specificity and pharmacokinetics of the antibody-based PET radiotracers that correlated well with the behavior observed by standard PET imaging. Moreover, CLI provided clear discrimination between uptake kinetics of an intact IgG and its small-molecular-weight derivative Mb. These data support the use of CLI for the evaluation of radiotracer performance. PMID:27539844

Highly Stable Aptamers Selected from a 2′-Fully Modified fGmH RNA Library for Targeting Biomaterials

PubMed Central

Friedman, Adam D.; Kim, Dongwook; Liu, Rihe

2014-01-01

When developed as targeting ligands for the in vivo delivery of biomaterials to biological systems, RNA aptamers immediately face numerous obstacles, in particular nuclease degradation and post-selection 2′ modification. This study aims to develop a novel class of highly stable, 2′-fully modified RNA aptamers that are ideal for the targeted delivery of biomaterials. We demonstrated the facile transcription of a fGmH (2′-F-dG, 2′-OMe-dA/dC/dU) RNA library with unexpected hydrophobicity, the direct selection of aptamers from a fGmH RNA library that bind Staphylococcus aureus Protein A (SpA) as a model target, and the superior nuclease and serum stability of these aptamers compared to 2′-partially modified RNA variants. Characterizations of fGmH RNA aptamers binding to purified SpA and to endogenous SpA present on the surface of S. aureus cells demonstrate fGmH RNA aptamer selectivity and stability. Significantly, fGmH RNA aptamers were able to functionalize, stabilize, and further deliver aggregation-prone silver nanoparticles (AgNPs) to S. aureus with SpA-dependent antimicrobial effects. This study describes a novel aptamer class with considerable potential to improve the in vivo applicability of nucleic acid-based affinity molecules to biomaterials. PMID:25443790

PNA-encoded chemical libraries.

PubMed

Zambaldo, Claudio; Barluenga, Sofia; Winssinger, Nicolas

2015-06-01

Peptide nucleic acid (PNA)-encoded chemical libraries along with DNA-encoded libraries have provided a powerful new paradigm for library synthesis and ligand discovery. PNA-encoding stands out for its compatibility with standard solid phase synthesis and the technology has been used to prepare libraries of peptides, heterocycles and glycoconjugates. Different screening formats have now been reported including selection-based and microarray-based methods that have yielded specific ligands against diverse target classes including membrane receptors, lectins and challenging targets such as Hsp70. Copyright © 2015 Elsevier Ltd. All rights reserved.

A BRDF-BPDF database for the analysis of Earth target reflectances

NASA Astrophysics Data System (ADS)

Breon, Francois-Marie; Maignan, Fabienne

2017-01-01

Land surface reflectance is not isotropic. It varies with the observation geometry that is defined by the sun, view zenith angles, and the relative azimuth. In addition, the reflectance is linearly polarized. The reflectance anisotropy is quantified by the bidirectional reflectance distribution function (BRDF), while its polarization properties are defined by the bidirectional polarization distribution function (BPDF). The POLDER radiometer that flew onboard the PARASOL microsatellite remains the only space instrument that measured numerous samples of the BRDF and BPDF of Earth targets. Here, we describe a database of representative BRDFs and BPDFs derived from the POLDER measurements. From the huge number of data acquired by the spaceborne instrument over a period of 7 years, we selected a set of targets with high-quality observations. The selection aimed for a large number of observations, free of significant cloud or aerosol contamination, acquired in diverse observation geometries with a focus on the backscatter direction that shows the specific hot spot signature. The targets are sorted according to the 16-class International Geosphere-Biosphere Programme (IGBP) land cover classification system, and the target selection aims at a spatial representativeness within the class. The database thus provides a set of high-quality BRDF and BPDF samples that can be used to assess the typical variability of natural surface reflectances or to evaluate models. It is available freely from the PANGAEA website (doi:10.1594/PANGAEA.864090). In addition to the database, we provide a visualization and analysis tool based on the Interactive Data Language (IDL). It allows an interactive analysis of the measurements and a comparison against various BRDF and BPDF analytical models. The present paper describes the input data, the selection principles, the database format, and the analysis tool

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…

Development of a rapid SNP-typing assay to differentiate Bifidobacterium animalis ssp. lactis strains used in probiotic-supplemented dairy products.

PubMed

Lomonaco, Sara; Furumoto, Emily J; Loquasto, Joseph R; Morra, Patrizia; Grassi, Ausilia; Roberts, Robert F

2015-02-01

Identification at the genus, species, and strain levels is desirable when a probiotic microorganism is added to foods. Strains of Bifidobacterium animalis ssp. lactis (BAL) are commonly used worldwide in dairy products supplemented with probiotic strains. However, strain discrimination is difficult because of the high degree of genome identity (99.975%) between different genomes of this subspecies. Typing of monomorphic species can be carried out efficiently by targeting informative single nucleotide polymorphisms (SNP). Findings from a previous study analyzing both reference and commercial strains of BAL identified SNP that could be used to discriminate common strains into 8 groups. This paper describes development of a minisequencing assay based on the primer extension reaction (PER) targeting multiple SNP that can allow strain differentiation of BAL. Based on previous data, 6 informative SNP were selected for further testing, and a multiplex preliminary PCR was optimized to amplify the DNA regions containing the selected SNP. Extension primers (EP) annealing immediately adjacent to the selected SNP were developed and tested in simplex and multiplex PER to evaluate their performance. Twenty-five strains belonging to 9 distinct genomic clusters of B. animalis ssp. lactis were selected and analyzed using the developed minisequencing assay, simultaneously targeting the 6 selected SNP. Fragment analysis was subsequently carried out in duplicate and demonstrated that the assay yielded 8 specific profiles separating the most commonly used commercial strains. This novel multiplex PER approach provides a simple, rapid, flexible SNP-based subtyping method for proper characterization and identification of commercial probiotic strains of BAL from fermented dairy products. To assess the usefulness of this method, DNA was extracted from yogurt manufactured with and without the addition of B. animalis ssp. lactis BB-12. Extracted DNA was then subjected to the minisequencing protocol, resulting in a SNP profile matching the profile for the strain BB-12. Copyright © 2015 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.

Selective elimination of long INterspersed element-1 expressing tumour cells by targeted expression of the HSV-TK suicide gene

PubMed Central

Chendeb, Mariam; Schneider, Robert; Davidson, Irwin; Fadloun, Anas

2017-01-01

In gene therapy, effective and selective suicide gene expression is crucial. We exploited the endogenous Long INterspersed Element-1 (L1) machinery often reactivated in human cancers to integrate the Herpes Simplex Virus Thymidine Kinase (HSV-TK) suicide gene selectively into the genome of cancer cells. We developed a plasmid-based system directing HSV-TK expression only when reverse transcribed and integrated in the host genome via the endogenous L1 ORF1/2 proteins and an Alu element. Delivery of these new constructs into cells followed by Ganciclovir (GCV) treatment selectively induced mortality of L1 ORF1/2 protein expressing cancer cells, but had no effect on primary cells that do not express L1 ORF1/2. This novel strategy for selective targeting of tumour cells provides high tolerability as the HSV-TK gene cannot be expressed without reverse transcription and integration, and high selectivity as these processes take place only in cancer cells expressing high levels of functional L1 ORF1/2. PMID:28415677

Counter Selection Substrate Library Strategy for Developing Specific Protease Substrates and Probes

PubMed Central

Poreba, Marcin; Solberg, Rigmor; Rut, Wioletta; Lunde, Ngoc Nguyen; Kasperkiewicz, Paulina; Snipas, Scott J.; Mihelic, Marko; Turk, Dusan; Turk, Boris; Salvesen, Guy S.; Drag, Marcin

2018-01-01

SUMMARY Legumain (AEP) is a lysosomal cysteine protease that is a lysosomal cysteine protease that was first characterized in leguminous seeds and later discovered in higher eukaryotes. AEP up-regulation is linked to a number of diseases including inflammation, arteriosclerosis and tumorigenesis. Thus legumain is an excellent molecular target for the development of new chemical markers. We deployed a hybrid combinatorial substrate library (HyCoSuL) approach to obtain P1-Asp fluorogenic substrates and biotin-labeled inhibitors that targeted legumain. Since this approach led to probes that were also recognized by caspases, we introduced a Counter Selection Substrate Library (CoSeSuL) approach that biases the peptidic scaffold against caspases, thus delivering highly selective legumain probes. The selectivity of these tools was validated using M38L and HEK293 cells. We also propose that the CoSeSuL methodology can be considered as a general principle in the design of selective probes for other protease families where selectivity is difficult to achieve by conventional sequence-based profiling. PMID:27478158

An online hybrid BCI system based on SSVEP and EMG

NASA Astrophysics Data System (ADS)

Lin, Ke; Cinetto, Andrea; Wang, Yijun; Chen, Xiaogang; Gao, Shangkai; Gao, Xiaorong

2016-04-01

Objective. A hybrid brain-computer interface (BCI) is a device combined with at least one other communication system that takes advantage of both parts to build a link between humans and machines. To increase the number of targets and the information transfer rate (ITR), electromyogram (EMG) and steady-state visual evoked potential (SSVEP) were combined to implement a hybrid BCI. A multi-choice selection method based on EMG was developed to enhance the system performance. Approach. A 60-target hybrid BCI speller was built in this study. A single trial was divided into two stages: a stimulation stage and an output selection stage. In the stimulation stage, SSVEP and EMG were used together. Every stimulus flickered at its given frequency to elicit SSVEP. All of the stimuli were divided equally into four sections with the same frequency set. The frequency of each stimulus in a section was different. SSVEPs were used to discriminate targets in the same section. Different sections were classified using EMG signals from the forearm. Subjects were asked to make different number of fists according to the target section. Canonical Correlation Analysis (CCA) and mean filtering was used to classify SSVEP and EMG separately. In the output selection stage, the top two optimal choices were given. The first choice with the highest probability of an accurate classification was the default output of the system. Subjects were required to make a fist to select the second choice only if the second choice was correct. Main results. The online results obtained from ten subjects showed that the mean accurate classification rate and ITR were 81.0% and 83.6 bits min-1 respectively only using the first choice selection. The ITR of the hybrid system was significantly higher than the ITR of any of the two single modalities (EMG: 30.7 bits min-1, SSVEP: 60.2 bits min-1). After the addition of the second choice selection and the correction task, the accurate classification rate and ITR was enhanced to 85.8% and 90.9 bit min-1. Significance. These results suggest that the hybrid system proposed here is suitable for practical use.

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.

Investigations into Alternative Desorption Agents for Amidoxime-Based Polymeric Uranium Adsorbents

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

Gill, Gary A.; Kuo, Li-Jung; Strivens, Jonathan E.

2015-06-01

Amidoxime-based polymeric braid adsorbents that can extract uranium (U) from seawater are being developed to provide a sustainable supply of fuel for nuclear reactors. A critical step in the development of the technology is to develop elution procedures to selectively remove U from the adsorbents and to do so in a manner that allows the adsorbent material to be reused. This study investigates use of high concentrations of bicarbonate along with targeted chelating agents as an alternative means to the mild acid elution procedures currently in use for selectively eluting uranium from amidoxime-based polymeric adsorbents.

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.

Designing Isoform-selective Inhibitors Against Classical HDACs for Effective Anticancer Therapy: Insight and Perspectives from In Silico.

PubMed

Ganai, Shabir Ahmad

2018-01-01

Histone deacetylase inhibitors, the small molecules modulating the biological activity of histone deacetylases are emerging as potent chemotherapeutic agents. Despite their considerable therapeutic benefits in disease models, the lack of isoform specificity culminates in debilitating off target effects, raising serious concerns regarding their applicability. This emphasizes the pressing and unmet medical need of designing isoform selective inhibitors for safe and effective anticancer therapy. Keeping these grim facts in view, the current article sheds light on structural basis of off-targeting. Furthermore, the article discusses extensively the role of in silico strategies such as Molecular Docking, Molecular Dynamics Simulation and Energetically-optimized structure based pharmacophore approach in designing on-target inhibitors against classical HDACs. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

MSN anti-cancer nanomedicines: chemotherapy enhancement, overcoming of drug resistance, and metastasis inhibition.

PubMed

He, Qianjun; Shi, Jianlin

2014-01-22

In the anti-cancer war, there are three main obstacles resulting in high mortality and recurrence rate of cancers: the severe toxic side effect of anti-cancer drugs to normal tissues due to the lack of tumor-selectivity, the multi-drug resistance (MDR) to free chemotherapeutic drugs and the deadly metastases of cancer cells. The development of state-of-art nanomedicines based on mesoporous silica nanoparticles (MSNs) is expected to overcome the above three main obstacles. In the view of the fast development of anti-cancer strategy, this review highlights the most recent advances of MSN anti-cancer nanomedicines in enhancing chemotherapeutic efficacy, overcoming the MDR and inhibiting metastasis. Furthermore, we give an outlook of the future development of MSNs-based anti-cancer nanomedicines, and propose several innovative and forward-looking anti-cancer strategies, including tumor tissue-cell-nuclear successionally targeted drug delivery strategy, tumor cell-selective nuclear-targeted drug delivery strategy, multi-targeting and multi-drug strategy, chemo-/radio-/photodynamic-/ultrasound-/thermo-combined multi-modal therapy by virtue of functionalized hollow/rattle-structured MSNs. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

S-layer fusion protein as a tool functionalizing emulsomes and CurcuEmulsomes for antibody binding and targeting

PubMed Central

Ucisik, Mehmet H.; Küpcü, Seta; Breitwieser, Andreas; Gelbmann, Nicola; Schuster, Bernhard; Sleytr, Uwe B.

2015-01-01

Selective targeting of tumor cells by nanoparticle-based drug delivery systems is highly desirable because it maximizes the drug concentration at the desired target while simultaneously protecting the surrounding healthy tissues. Here, we show a design for smart nanocarriers based on a biomimetic approach that utilizes the building principle of virus envelope structures. Emulsomes and CurcuEmulsomes comprising a tripalmitin solid core surrounded by phospholipid layers are modified by S-layer proteins that self-assemble into a two-dimensional array to form a surface layer. One significant advantage of this nanoformulation is that it increases the solubility of the lipophilic anti-cancer agent curcumin in the CurcuEmulsomes by a factor of 2700. In order to make the emulsomes specific for IgG, the S-layer protein is fused with two protein G domains. This S-layer fusion protein preserves its recrystallization characteristics, forming an ordered surface layer (square lattice with 13 nm unit-by-unit distance). The GG domains are presented in a predicted orientation and exhibit a selective binding affinity for IgG. PMID:25734967

ELEGANT ENVIRONMENTAL IMMUNOASSAYS

EPA Science Inventory

Immunochemical methods are based on selective antibodies directed to a particular target analyte. The specific binding between antibody and analyte can be used for detection and quantitation. Methods such as the enzyme-linked immunosorbent assay (ELISA) can provide a sensitiv...

Clustering analysis of moving target signatures

NASA Astrophysics Data System (ADS)

Martone, Anthony; Ranney, Kenneth; Innocenti, Roberto

2010-04-01

Previously, we developed a moving target indication (MTI) processing approach to detect and track slow-moving targets inside buildings, which successfully detected moving targets (MTs) from data collected by a low-frequency, ultra-wideband radar. Our MTI algorithms include change detection, automatic target detection (ATD), clustering, and tracking. The MTI algorithms can be implemented in a real-time or near-real-time system; however, a person-in-the-loop is needed to select input parameters for the clustering algorithm. Specifically, the number of clusters to input into the cluster algorithm is unknown and requires manual selection. A critical need exists to automate all aspects of the MTI processing formulation. In this paper, we investigate two techniques that automatically determine the number of clusters: the adaptive knee-point (KP) algorithm and the recursive pixel finding (RPF) algorithm. The KP algorithm is based on a well-known heuristic approach for determining the number of clusters. The RPF algorithm is analogous to the image processing, pixel labeling procedure. Both algorithms are used to analyze the false alarm and detection rates of three operational scenarios of personnel walking inside wood and cinderblock buildings.

Registry-based analysis of participator representativeness: a source of concern for sickness absence research?

PubMed

Knapstad, Marit; Löve, Jesper; Holmgren, Kristina; Hensing, Gunnel; Øverland, Simon

2016-10-21

Selective participation can bias results in epidemiological surveys. The importance of health status is often suggested as a possible explanation for non-participation but few empirical studies exist. In a population-based study, explicitly focused on sickness absence, health and work, we examined whether a history of high levels of sickness absence was associated with non-participation. The study is based on data from official sickness absence registers from participants, non-participants and the total target population of the baseline survey of the Health Assets Project (HAP). HAP is a population-based cohort study in the Västra Götaland region in South Western Sweden. HAP included a random population cohort (n=7984) and 2 cohorts with recent sickness absence (employees (n=6140) and non-employees (n=990)), extracted from the same overall general working-age population. We examined differences in participation rates between cohorts (2008), and differences in previous sickness absence (2001-2008) between participants (individual-level data) and non-participants or the target population (group-level data) within cohorts. Participants had statistically significant less registered sickness absence in the past than non-participants and the target population for some, but not all, of the years analysed. Yet these differences were not of substantial size. Other factors than sickness absence were more important in explaining differences in participation, whereby participants were more likely to be women, older, born in Nordic countries, married and have higher incomes than non-participants. Although specifically addressing sickness absence, having such experience did not add any substantial layer to selective participation in the present survey. Detailed measures are needed to gain a better understanding for health selection in health-related surveys such as those addressing sickness absence, for instance in order to discriminate between selection due to ability or motivation for participation. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

Morpholine Derivative-Functionalized Carbon Dots-Based Fluorescent Probe for Highly Selective Lysosomal Imaging in Living Cells.

PubMed

Wu, Luling; Li, Xiaolin; Ling, Yifei; Huang, Chusen; Jia, Nengqin

2017-08-30

The development of a suitable fluorescent probe for the specific labeling and imaging of lysosomes through the direct visual fluorescent signal is extremely important for understanding the dysfunction of lysosomes, which might induce various pathologies, including neurodegenerative diseases, cancer, and Alzheimer's disease. Herein, a new carbon dot-based fluorescent probe (CDs-PEI-ML) was designed and synthesized for highly selective imaging of lysosomes in live cells. In this probe, PEI (polyethylenimine) is introduced to improve water solubility and provide abundant amine groups for the as-prepared CDs-PEI, and the morpholine group (ML) serves as a targeting unit for lysosomes. More importantly, passivation with PEI could dramatically increase the fluorescence quantum yield of CDs-PEI-ML as well as their stability in fluorescence emission under different excitation wavelength. Consequently, experimental data demonstrated that the target probe CDs-PEI-ML has low cytotoxicity and excellent photostability. Additionally, further live cell imaging experiment indicated that CDs-PEI-ML is a highly selective fluorescent probe for lysosomes. We speculate the mechanism for selective staining of lysosomes that CDs-PEI-ML was initially taken up by lysosomes through the endocytic pathway and then accumulated in acidic lysosomes. It is notable that there was less diffusion of CDs-PEI-ML into cytoplasm, which could be ascribed to the presence of lysosome target group morpholine on surface of CDs-PEI-ML. The blue emission wavelength combined with the high photo stability and ability of long-lasting cell imaging makes CDs-PEI-ML become an alternative fluorescent probe for multicolor labeling and long-term tracking of lysosomes in live cells and the potential application in super-resolution imaging. To best of our knowledge, there are still limited carbon dots-based fluorescent probes that have been studied for specific lysosomal imaging in live cells. The concept of surface functionality of carbon dots will also pave a new avenue for developing carbon dots-based fluorescent probes for subcellular labeling.

Autonomous proximity operations using machine vision for trajectory control and pose estimation

NASA Technical Reports Server (NTRS)

Cleghorn, Timothy F.; Sternberg, Stanley R.

1991-01-01

A machine vision algorithm was developed which permits guidance control to be maintained during autonomous proximity operations. At present this algorithm exists as a simulation, running upon an 80386 based personal computer, using a ModelMATE CAD package to render the target vehicle. However, the algorithm is sufficiently simple, so that following off-line training on a known target vehicle, it should run in real time with existing vision hardware. The basis of the algorithm is a sequence of single camera images of the target vehicle, upon which radial transforms were performed. Selected points of the resulting radial signatures are fed through a decision tree, to determine whether the signature matches that of the known reference signatures for a particular view of the target. Based upon recognized scenes, the position of the maneuvering vehicle with respect to the target vehicles can be calculated, and adjustments made in the former's trajectory. In addition, the pose and spin rates of the target satellite can be estimated using this method.

THE SDSS-IV EXTENDED BARYON OSCILLATION SPECTROSCOPIC SURVEY: QUASAR TARGET SELECTION

DOE PAGES

Myers, Adam D.; Palanque-Delabrouille, Nathalie; Prakash, Abhishek; ...

2015-12-01

As part of the Sloan Digital Sky Survey (SDSS) IV the extended Baryon Oscillation Spectroscopic Survey (eBOSS) will improve measurements of the cosmological distance scale by applying the Baryon Acoustic Oscillation (BAO) method to quasar samples. eBOSS will adopt two approaches to target quasars over 7500 deg 2 . First, a "CORE" quasar sample will combine the optical selection in ugriz using a likelihood-based routine called XDQSOz, with a mid-IR-optical color cut. eBOSS CORE selection (to g < 22 or r < 22) should return ~70 deg -2 quasars at redshifts 0.9 < z < 2.2 and ~7 deg -2more » z > 2.1 quasars. Second, a selection based on variability in multi-epoch imaging from the Palomar Transient Factory should recover an additional ~3-4 deg -2 z > 2.1 quasars to g < 22.5. A linear model of how imaging systematics affect target density recovers the angular distribution of eBOSS CORE quasars over 96.7% (76.7%) of the SDSS north (south) Galactic Cap area. The eBOSS CORE quasar sample should thus be sufficiently dense and homogeneous over 0.9 < z < 2.2 to yield the first few-percent-level BAO constraint near eBOSS quasars at z > 2.1 will be used to improve BAO measurements in the Lyα Forest. Beyond its key cosmological goals, eBOSS should be the next-generation quasar survey, comprising > 500,000 new quasars and > 500,000 uniformly selected spectroscopically confirmed 0.9 < z < 2.2 quasars. At the conclusion of eBOSS, the SDSS will have provided unique spectra for more than 800,000 quasars.« less

Non-homologous end joining-mediated functional marker selection for DNA cloning in the yeast Kluyveromyces marxianus.

PubMed

Hoshida, Hisashi; Murakami, Nobutada; Suzuki, Ayako; Tamura, Ryoko; Asakawa, Jun; Abdel-Banat, Babiker M A; Nonklang, Sanom; Nakamura, Mikiko; Akada, Rinji

2014-01-01

The cloning of DNA fragments into vectors or host genomes has traditionally been performed using Escherichia coli with restriction enzymes and DNA ligase or homologous recombination-based reactions. We report here a novel DNA cloning method that does not require DNA end processing or homologous recombination, but that ensures highly accurate cloning. The method exploits the efficient non-homologous end-joining (NHEJ) activity of the yeast Kluyveromyces marxianus and consists of a novel functional marker selection system. First, to demonstrate the applicability of NHEJ to DNA cloning, a C-terminal-truncated non-functional ura3 selection marker and the truncated region were PCR-amplified separately, mixed and directly used for the transformation. URA3(+) transformants appeared on the selection plates, indicating that the two DNA fragments were correctly joined by NHEJ to generate a functional URA3 gene that had inserted into the yeast chromosome. To develop the cloning system, the shortest URA3 C-terminal encoding sequence that could restore the function of a truncated non-functional ura3 was determined by deletion analysis, and was included in the primers to amplify target DNAs for cloning. Transformation with PCR-amplified target DNAs and C-terminal truncated ura3 produced numerous transformant colonies, in which a functional URA3 gene was generated and was integrated into the chromosome with the target DNAs. Several K. marxianus circular plasmids with different selection markers were also developed for NHEJ-based cloning and recombinant DNA construction. The one-step DNA cloning method developed here is a relatively simple and reliable procedure among the DNA cloning systems developed to date. Copyright © 2013 John Wiley & Sons, Ltd.

Targeted Proteomic Quantification on Quadrupole-Orbitrap Mass Spectrometer*

PubMed Central

Gallien, Sebastien; Duriez, Elodie; Crone, Catharina; Kellmann, Markus; Moehring, Thomas; Domon, Bruno

2012-01-01

There is an immediate need for improved methods to systematically and precisely quantify large sets of peptides in complex biological samples. To date protein quantification in biological samples has been routinely performed on triple quadrupole instruments operated in selected reaction monitoring mode (SRM), and two major challenges remain. Firstly, the number of peptides to be included in one survey experiment needs to be increased to routinely reach several hundreds, and secondly, the degree of selectivity should be improved so as to reliably discriminate the targeted analytes from background interferences. High resolution and accurate mass (HR/AM) analysis on the recently developed Q-Exactive mass spectrometer can potentially address these issues. This instrument presents a unique configuration: it is constituted of an orbitrap mass analyzer equipped with a quadrupole mass filter as the front-end for precursor ion mass selection. This configuration enables new quantitative methods based on HR/AM measurements, including targeted analysis in MS mode (single ion monitoring) and in MS/MS mode (parallel reaction monitoring). The ability of the quadrupole to select a restricted m/z range allows one to overcome the dynamic range limitations associated with trapping devices, and the MS/MS mode provides an additional stage of selectivity. When applied to targeted protein quantification in urine samples and benchmarked with the reference SRM technique, the quadrupole-orbitrap instrument exhibits similar or better performance in terms of selectivity, dynamic range, and sensitivity. This high performance is further enhanced by leveraging the multiplexing capability of the instrument to design novel acquisition methods and apply them to large targeted proteomic studies for the first time, as demonstrated on 770 tryptic yeast peptides analyzed in one 60-min experiment. The increased quality of quadrupole-orbitrap data has the potential to improve existing protein quantification methods in complex samples and address the pressing demand of systems biology or biomarker evaluation studies. PMID:22962056

Prodrug strategy for cancer cell-specific targeting: A recent overview.

PubMed

Zhang, Xian; Li, Xiang; You, Qidong; Zhang, Xiaojin

2017-10-20

The increasing development of targeted cancer therapy provides extensive possibilities in clinical trials, and numerous strategies have been explored. The prodrug is one of the most promising strategies in targeted cancer therapy to improve the selectivity and efficacy of cytotoxic compounds. Compared with normal tissues, cancer cells are characterized by unique aberrant markers, thus inactive prodrugs targeting these markers are excellent therapeutics to release active drugs, killing cancer cells without damaging normal tissues. In this review, we explore an integrated view of potential prodrugs applied in targeted cancer therapy based on aberrant cancer specific markers and some examples are provided for inspiring new ideas of prodrug strategy for cancer cell-specific targeting. Copyright © 2017. Published by Elsevier Masson SAS.

Fitts's law in a selective reaching task: the proximity-to-hand effect of action-centered attention revisited.

PubMed

Welsh, Timothy N; Zbinden, Michele

2009-01-01

The "proximity-to-hand" effect refers to the finding that distractors between the home position and the target cause more interference in a selective reaching movement than distractors farther from the home position. Based largely on the proximity-to-hand effect, Tipper, Lortie, and Baylis (1992) proposed that attention is distributed in an action-centered framework such that the interference caused by a specific stimulus depends on the action. The current experiments sought to determine if there is an attentional preference for stimuli closer to home or for stimuli that activate more efficiently executed actions regardless of the location. Results supported the latter hypothesis in that the greatest interference was observed when the distractor activated an action with a lower index of difficulty than the target, even though that distractor was farther from home than the target. These findings indicate that the action context mediates the influence that nontarget stimuli have on the processing of target responses.

Selective uptake of single-walled carbon nanotubes by circulating monocytes for enhanced tumour delivery

NASA Astrophysics Data System (ADS)

Smith, Bryan Ronain; Ghosn, Eliver Eid Bou; Rallapalli, Harikrishna; Prescher, Jennifer A.; Larson, Timothy; Herzenberg, Leonore A.; Gambhir, Sanjiv Sam

2014-06-01

In cancer imaging, nanoparticle biodistribution is typically visualized in living subjects using `bulk' imaging modalities such as magnetic resonance imaging, computerized tomography and whole-body fluorescence. Accordingly, nanoparticle influx is observed only macroscopically, and the mechanisms by which they target cancer remain elusive. Nanoparticles are assumed to accumulate via several targeting mechanisms, particularly extravasation (leakage into tumour). Here, we show that, in addition to conventional nanoparticle-uptake mechanisms, single-walled carbon nanotubes are almost exclusively taken up by a single immune cell subset, Ly-6Chi monocytes (almost 100% uptake in Ly-6Chi monocytes, below 3% in all other circulating cells), and delivered to the tumour in mice. We also demonstrate that a targeting ligand (RGD) conjugated to nanotubes significantly enhances the number of single-walled carbon nanotube-loaded monocytes reaching the tumour (P < 0.001, day 7 post-injection). The remarkable selectivity of this tumour-targeting mechanism demonstrates an advanced immune-based delivery strategy for enhancing specific tumour delivery with substantial penetration.

Identification of a Drug Targeting an Intrinsically Disordered Protein Involved in Pancreatic Adenocarcinoma

NASA Astrophysics Data System (ADS)

Neira, José L.; Bintz, Jennifer; Arruebo, María; Rizzuti, Bruno; Bonacci, Thomas; Vega, Sonia; Lanas, Angel; Velázquez-Campoy, Adrián; Iovanna, Juan L.; Abián, Olga

2017-01-01

Intrinsically disordered proteins (IDPs) are prevalent in eukaryotes, performing signaling and regulatory functions. Often associated with human diseases, they constitute drug-development targets. NUPR1 is a multifunctional IDP, over-expressed and involved in pancreatic ductal adenocarcinoma (PDAC) development. By screening 1120 FDA-approved compounds, fifteen candidates were selected, and their interactions with NUPR1 were characterized by experimental and simulation techniques. The protein remained disordered upon binding to all fifteen candidates. These compounds were tested in PDAC-derived cell-based assays, and all induced cell-growth arrest and senescence, reduced cell migration, and decreased chemoresistance, mimicking NUPR1-deficiency. The most effective compound completely arrested tumor development in vivo on xenografted PDAC-derived cells in mice. Besides reporting the discovery of a compound targeting an intact IDP and specifically active against PDAC, our study proves the possibility to target the ‘fuzzy’ interface of a protein that remains disordered upon binding to its natural biological partners or to selected drugs.

Targeted Killing of Streptococcus mutans by a Pheromone-Guided “Smart” Antimicrobial Peptide

PubMed Central

Eckert, Randal ; He, Jian; Yarbrough, Daniel K.; Qi, Fengxia; Anderson, Maxwell H.; Shi, Wenyuan

2006-01-01

Within the repertoire of antibiotics available to a prescribing clinician, the majority affect a broad range of microorganisms, including the normal flora. The ecological disruption resulting from antibiotic treatment frequently results in secondary infections or other negative clinical consequences. To address this problem, our laboratory has recently developed a new class of pathogen-selective molecules, called specifically (or selectively) targeted antimicrobial peptides (STAMPs), based on the fusion of a species-specific targeting peptide domain with a wide-spectrum antimicrobial peptide domain. In the current study, we focused on achieving targeted killing of Streptococcus mutans, a cavity-causing bacterium that resides in a multispecies microbial community (dental plaque). In particular, we explored the possibility of utilizing a pheromone produced by S. mutans, namely, the competence stimulating peptide (CSP), as a STAMP targeting domain to mediate S. mutans-specific delivery of an antimicrobial peptide domain. We discovered that STAMPs constructed with peptides derived from CSP were potent against S. mutans grown in liquid or biofilm states but did not affect other oral streptococci tested. Further studies showed that an 8-amino-acid region within the CSP sequence is sufficient for targeted delivery of the antimicrobial peptide domain to S. mutans. The STAMPs presented here are capable of eliminating S. mutans from multispecies biofilms without affecting closely related noncariogenic oral streptococci, indicating the potential of these molecules to be developed into “probiotic” antibiotics which could selectively eliminate pathogens while preserving the protective benefits of a healthy normal flora. PMID:17060534

Mechanism of foreign DNA selection in a bacterial adaptive immune system

PubMed Central

Sashital, Dipali G.; Wiedenheft, Blake; Doudna, Jennifer A.

2012-01-01

Summary In bacterial and archaeal CRISPR immune pathways, DNA sequences from invading bacteriophage or plasmids are integrated into CRISPR loci within the host genome, conferring immunity against subsequent infections. The ribonucleoprotein complex Cascade utilizes RNAs generated from these loci to target complementary “non-self” DNA sequences for destruction, while avoiding binding to “self” sequences within the CRISPR locus. Here we show that CasA, the largest protein subunit of Cascade, is required for non-self target recognition and binding. Combining a 2.3 Å crystal structure of CasA with cryo-EM structures of Cascade, we have identified a loop that is required for viral defense. This loop contacts a conserved 3-base pair motif that is required for non-self target selection. Our data suggest a model in which the CasA loop scans DNA for this short motif prior to target destabilization and binding, maximizing the efficiency of DNA surveillance by Cascade. PMID:22521690

Identification of a Drug Targeting an Intrinsically Disordered Protein Involved in Pancreatic Adenocarcinoma

PubMed Central

Neira, José L.; Bintz, Jennifer; Arruebo, María; Rizzuti, Bruno; Bonacci, Thomas; Vega, Sonia; Lanas, Angel; Velázquez-Campoy, Adrián; Iovanna, Juan L.; Abián, Olga

2017-01-01

Intrinsically disordered proteins (IDPs) are prevalent in eukaryotes, performing signaling and regulatory functions. Often associated with human diseases, they constitute drug-development targets. NUPR1 is a multifunctional IDP, over-expressed and involved in pancreatic ductal adenocarcinoma (PDAC) development. By screening 1120 FDA-approved compounds, fifteen candidates were selected, and their interactions with NUPR1 were characterized by experimental and simulation techniques. The protein remained disordered upon binding to all fifteen candidates. These compounds were tested in PDAC-derived cell-based assays, and all induced cell-growth arrest and senescence, reduced cell migration, and decreased chemoresistance, mimicking NUPR1-deficiency. The most effective compound completely arrested tumor development in vivo on xenografted PDAC-derived cells in mice. Besides reporting the discovery of a compound targeting an intact IDP and specifically active against PDAC, our study proves the possibility to target the ‘fuzzy’ interface of a protein that remains disordered upon binding to its natural biological partners or to selected drugs. PMID:28054562

Photo-ionization of aluminum in a hot cavity for the selective production of exotic species project

NASA Astrophysics Data System (ADS)

Scarpa, D.; Makhathini, L.; Tomaselli, A.; Grassi, D.; Corradetti, S.; Manzolaro, M.; Vasquez, J.; Calderolla, M.; Rossignoli, M.; Monetti, A.; Andrighetto, A.; Prete, G.

2014-02-01

SPES (Selective Production of Exotic Species) is an Isotope Separation On-Line (ISOL) based accelerator facility that will be built in the Legnaro-Istituto Nazionale di Fisica Nucleare (INFN) Laboratory (Italy), intended to provide intense neutron-rich radioactive ion beams obtained by proton-induced fission of a uranium carbide (UCx) target. Besides this main target material, silicon carbide (SiC) will be the first to be used to deliver p-rich beams. This target will also validate the functionality of the SPES facility with aluminum beam as result of impinging SiC target with proton beam. In the past, off line studies on laser photoionization of aluminum have been performed in Pavia Spectroscopy Laboratory and in Laboratori Nazionali di Legnaro; a XeCl excimer laser was installed in order to test the laser ionization in the SPES hot cavity. With the new Wien filter installed a better characterization of the ionization process in terms of efficiency was performed and results are discussed.

Application and comparison of large-scale solution-based DNA capture-enrichment methods on ancient DNA

PubMed Central

Ávila-Arcos, María C.; Cappellini, Enrico; Romero-Navarro, J. Alberto; Wales, Nathan; Moreno-Mayar, J. Víctor; Rasmussen, Morten; Fordyce, Sarah L.; Montiel, Rafael; Vielle-Calzada, Jean-Philippe; Willerslev, Eske; Gilbert, M. Thomas P.

2011-01-01

The development of second-generation sequencing technologies has greatly benefitted the field of ancient DNA (aDNA). Its application can be further exploited by the use of targeted capture-enrichment methods to overcome restrictions posed by low endogenous and contaminating DNA in ancient samples. We tested the performance of Agilent's SureSelect and Mycroarray's MySelect in-solution capture systems on Illumina sequencing libraries built from ancient maize to identify key factors influencing aDNA capture experiments. High levels of clonality as well as the presence of multiple-copy sequences in the capture targets led to biases in the data regardless of the capture method. Neither method consistently outperformed the other in terms of average target enrichment, and no obvious difference was observed either when two tiling designs were compared. In addition to demonstrating the plausibility of capturing aDNA from ancient plant material, our results also enable us to provide useful recommendations for those planning targeted-sequencing on aDNA. PMID:22355593

GREAT: a gradient-based color-sampling scheme for Retinex.

PubMed

Lecca, Michela; Rizzi, Alessandro; Serapioni, Raul Paolo

2017-04-01

Modeling the local color spatial distribution is a crucial step for the algorithms of the Milano Retinex family. Here we present GREAT, a novel, noise-free Milano Retinex implementation based on an image-aware spatial color sampling. For each channel of a color input image, GREAT computes a 2D set of edges whose magnitude exceeds a pre-defined threshold. Then GREAT re-scales the channel intensity of each image pixel, called target, by the average of the intensities of the selected edges weighted by a function of their positions, gradient magnitudes, and intensities relative to the target. In this way, GREAT enhances the input image, adjusting its brightness, contrast and dynamic range. The use of the edges as pixels relevant to color filtering is justified by the importance that edges play in human color sensation. The name GREAT comes from the expression "Gradient RElevAnce for ReTinex," which refers to the threshold-based definition of a gradient relevance map for edge selection and thus for image color filtering.

Frequency-agile dual-frequency lidar for integrated coherent radar-lidar architectures.

PubMed

Vercesi, Valeria; Onori, Daniel; Laghezza, Francesco; Scotti, Filippo; Bogoni, Antonella; Scaffardi, Mirco

2015-04-01

We propose a novel architecture for implementing a dual-frequency lidar (DFL) exploiting differential Doppler shift measurement. The two frequency tones, needed for target velocity measurements, are selected from the spectrum of a mode-locked laser operating in the C-band. The tones' separation is easily controlled by using a programmable wavelength selective switch, thus allowing for a dynamic trade-off among robustness to atmospheric turbulence and sensitivity. Speed measurements for different tone separations equal to 10, 40, 80, and 160 GHz are demonstrated, proving the system's capability of working in different configurations. Thanks to the acquisition system based on an analog-to-digital converter and digital-signal processing, real-time velocity measurements are demonstrated. The MLL-based proposed architecture enables the integration of the DFL with a photonic-based radar that exploits the same laser for generating and receiving radio-frequency signal with high performance, thus allowing for simultaneous or complementary target observations by exploiting the advantages of both radar and lidar.

Improved prediction of peptide detectability for targeted proteomics using a rank-based algorithm and organism-specific data.

PubMed

Qeli, Ermir; Omasits, Ulrich; Goetze, Sandra; Stekhoven, Daniel J; Frey, Juerg E; Basler, Konrad; Wollscheid, Bernd; Brunner, Erich; Ahrens, Christian H

2014-08-28

The in silico prediction of the best-observable "proteotypic" peptides in mass spectrometry-based workflows is a challenging problem. Being able to accurately predict such peptides would enable the informed selection of proteotypic peptides for targeted quantification of previously observed and non-observed proteins for any organism, with a significant impact for clinical proteomics and systems biology studies. Current prediction algorithms rely on physicochemical parameters in combination with positive and negative training sets to identify those peptide properties that most profoundly affect their general detectability. Here we present PeptideRank, an approach that uses learning to rank algorithm for peptide detectability prediction from shotgun proteomics data, and that eliminates the need to select a negative dataset for the training step. A large number of different peptide properties are used to train ranking models in order to predict a ranking of the best-observable peptides within a protein. Empirical evaluation with rank accuracy metrics showed that PeptideRank complements existing prediction algorithms. Our results indicate that the best performance is achieved when it is trained on organism-specific shotgun proteomics data, and that PeptideRank is most accurate for short to medium-sized and abundant proteins, without any loss in prediction accuracy for the important class of membrane proteins. Targeted proteomics approaches have been gaining a lot of momentum and hold immense potential for systems biology studies and clinical proteomics. However, since only very few complete proteomes have been reported to date, for a considerable fraction of a proteome there is no experimental proteomics evidence that would allow to guide the selection of the best-suited proteotypic peptides (PTPs), i.e. peptides that are specific to a given proteoform and that are repeatedly observed in a mass spectrometer. We describe a novel, rank-based approach for the prediction of the best-suited PTPs for targeted proteomics applications. By building on methods developed in the field of information retrieval (e.g. web search engines like Google's PageRank), we circumvent the delicate step of selecting positive and negative training sets and at the same time also more closely reflect the experimentalist´s need for selecting e.g. the 5 most promising peptides for targeting a protein of interest. This approach allows to predict PTPs for not yet observed proteins or for organisms without prior experimental proteomics data such as many non-model organisms. Copyright © 2014 Elsevier B.V. All rights reserved.

Simultaneous fluorescence light-up and selective multicolor nucleobase recognition based on sequence-dependent strong binding of berberine to DNA abasic site.

PubMed

Wu, Fei; Shao, Yong; Ma, Kun; Cui, Qinghua; Liu, Guiying; Xu, Shujuan

2012-04-28

Label-free DNA nucleobase recognition by fluorescent small molecules has received much attention due to its simplicity in mutation identification and drug screening. However, sequence-dependent fluorescence light-up nucleobase recognition and multicolor emission with individual emission energy for individual nucleobases have been seldom realized. Herein, an abasic site (AP site) in a DNA duplex was employed as a binding field for berberine, one of isoquinoline alkaloids. Unlike weak binding of berberine to the fully matched DNAs without the AP site, strong binding of berberine to the AP site occurs and the berberine's fluorescence light-up behaviors are highly dependent on the target nucleobases opposite the AP site in which the targets thymine and cytosine produce dual emission bands, while the targets guanine and adenine only give a single emission band. Furthermore, more intense emissions are observed for the target pyrimidines than purines. The flanking bases of the AP site also produce some modifications of the berberine's emission behavior. The binding selectivity of berberine at the AP site is also confirmed by measurements of fluorescence resonance energy transfer, excited-state lifetime, DNA melting and fluorescence quenching by ferrocyanide and sodium chloride. It is expected that the target pyrimidines cause berberine to be stacked well within DNA base pairs near the AP site, which results in a strong resonance coupling of the electronic transitions to the particular vibration mode to produce the dual emissions. The fluorescent signal-on and emission energy-modulated sensing for nucleobases based on this fluorophore is substantially advantageous over the previously used fluorophores. We expect that this approach will be developed as a practical device for differentiating pyrimidines from purines by positioning an AP site toward a target that is available for readout by this alkaloid probe. This journal is © The Royal Society of Chemistry 2012

RoboTAP: Target priorities for robotic microlensing observations

NASA Astrophysics Data System (ADS)

Hundertmark, M.; Street, R. A.; Tsapras, Y.; Bachelet, E.; Dominik, M.; Horne, K.; Bozza, V.; Bramich, D. M.; Cassan, A.; D'Ago, G.; Figuera Jaimes, R.; Kains, N.; Ranc, C.; Schmidt, R. W.; Snodgrass, C.; Wambsganss, J.; Steele, I. A.; Mao, S.; Ment, K.; Menzies, J.; Li, Z.; Cross, S.; Maoz, D.; Shvartzvald, Y.

2018-01-01

Context. The ability to automatically select scientifically-important transient events from an alert stream of many such events, and to conduct follow-up observations in response, will become increasingly important in astronomy. With wide-angle time domain surveys pushing to fainter limiting magnitudes, the capability to follow-up on transient alerts far exceeds our follow-up telescope resources, and effective target prioritization becomes essential. The RoboNet-II microlensing program is a pathfinder project, which has developed an automated target selection process (RoboTAP) for gravitational microlensing events, which are observed in real time using the Las Cumbres Observatory telescope network. Aims: Follow-up telescopes typically have a much smaller field of view compared to surveys, therefore the most promising microlensing events must be automatically selected at any given time from an annual sample exceeding 2000 events. The main challenge is to select between events with a high planet detection sensitivity, with the aim of detecting many planets and characterizing planetary anomalies. Methods: Our target selection algorithm is a hybrid system based on estimates of the planet detection zones around a microlens. It follows automatic anomaly alerts and respects the expected survey coverage of specific events. Results: We introduce the RoboTAP algorithm, whose purpose is to select and prioritize microlensing events with high sensitivity to planetary companions. In this work, we determine the planet sensitivity of the RoboNet follow-up program and provide a working example of how a broker can be designed for a real-life transient science program conducting follow-up observations in response to alerts; we explore the issues that will confront similar programs being developed for the Large Synoptic Survey Telescope (LSST) and other time domain surveys.

Factor Analysis of Therapist-Identified Treatment Targets in Community-Based Children's Mental Health.

PubMed

Love, Allison R; Okado, Izumi; Orimoto, Trina E; Mueller, Charles W

2018-01-01

The present study used exploratory and confirmatory factor analyses to identify underlying latent factors affecting variation in community therapists' endorsement of treatment targets. As part of a statewide practice management program, therapist completed monthly reports of treatment targets (up to 10 per month) for a sample of youth (n = 790) receiving intensive in-home therapy. Nearly 75 % of youth were diagnosed with multiple co-occurring disorders. Five factors emerged: Disinhibition, Societal Rules Evasion, Social Engagement Deficits, Emotional Distress, and Management of Biodevelopmental Outcomes. Using logistic regression, primary diagnosis predicted therapist selection of Disinhibition and Emotional Distress targets. Client age predicted endorsement of Societal Rules Evasion targets. Practice-to-research implications are discussed.

Context-dependent sequential effects of target selection for action.

PubMed

Moher, Jeff; Song, Joo-Hyun

2013-07-11

Humans exhibit variation in behavior from moment to moment even when performing a simple, repetitive task. Errors are typically followed by cautious responses, minimizing subsequent distractor interference. However, less is known about how variation in the execution of an ultimately correct response affects subsequent behavior. We asked participants to reach toward a uniquely colored target presented among distractors and created two categories to describe participants' responses in correct trials based on analyses of movement trajectories; partial errors referred to trials in which observers initially selected a nontarget for action before redirecting the movement and accurately pointing to the target, and direct movements referred to trials in which the target was directly selected for action. We found that latency to initiate a hand movement was shorter in trials following partial errors compared to trials following direct movements. Furthermore, when the target and distractor colors were repeated, movement time and reach movement curvature toward distractors were greater following partial errors compared to direct movements. Finally, when the colors were repeated, partial errors were more frequent than direct movements following partial-error trials, and direct movements were more frequent following direct-movement trials. The dependence of these latter effects on repeated-task context indicates the involvement of higher-level cognitive mechanisms in an integrated attention-action system in which execution of a partial-error or direct-movement response affects memory representations that bias performance in subsequent trials. Altogether, these results demonstrate that whether a nontarget is selected for action or not has a measurable impact on subsequent behavior.

Infrared moving small target detection based on saliency extraction and image sparse representation

NASA Astrophysics Data System (ADS)

Zhang, Xiaomin; Ren, Kan; Gao, Jin; Li, Chaowei; Gu, Guohua; Wan, Minjie

2016-10-01

Moving small target detection in infrared image is a crucial technique of infrared search and tracking system. This paper present a novel small target detection technique based on frequency-domain saliency extraction and image sparse representation. First, we exploit the features of Fourier spectrum image and magnitude spectrum of Fourier transform to make a rough extract of saliency regions and use a threshold segmentation system to classify the regions which look salient from the background, which gives us a binary image as result. Second, a new patch-image model and over-complete dictionary were introduced to the detection system, then the infrared small target detection was converted into a problem solving and optimization process of patch-image information reconstruction based on sparse representation. More specifically, the test image and binary image can be decomposed into some image patches follow certain rules. We select the target potential area according to the binary patch-image which contains salient region information, then exploit the over-complete infrared small target dictionary to reconstruct the test image blocks which may contain targets. The coefficients of target image patch satisfy sparse features. Finally, for image sequence, Euclidean distance was used to reduce false alarm ratio and increase the detection accuracy of moving small targets in infrared images due to the target position correlation between frames.

Planar optical waveguide based sandwich assay sensors and processes for the detection of biological targets including protein markers, pathogens and cellular debris

DOEpatents

Martinez, Jennifer S [Santa Fe, NM; Swanson, Basil I [Los Alamos, NM; Grace, Karen M [Los Alamos, NM; Grace, Wynne K [Los Alamos, NM; Shreve, Andrew P [Santa Fe, NM

2009-06-02

An assay element is described including recognition ligands bound to a film on a single mode planar optical waveguide, the film from the group of a membrane, a polymerized bilayer membrane, and a self-assembled monolayer containing polyethylene glycol or polypropylene glycol groups therein and an assay process for detecting the presence of a biological target is described including injecting a biological target-containing sample into a sensor cell including the assay element, with the recognition ligands adapted for binding to selected biological targets, maintaining the sample within the sensor cell for time sufficient for binding to occur between selected biological targets within the sample and the recognition ligands, injecting a solution including a reporter ligand into the sensor cell; and, interrogating the sample within the sensor cell with excitation light from the waveguide, the excitation light provided by an evanescent field of the single mode penetrating into the biological target-containing sample to a distance of less than about 200 nanometers from the waveguide thereby exciting the fluorescent-label in any bound reporter ligand within a distance of less than about 200 nanometers from the waveguide and resulting in a detectable signal.

Display technologies: application for the discovery of drug and gene delivery agents

PubMed Central

Sergeeva, Anna; Kolonin, Mikhail G.; Molldrem, Jeffrey J.; Pasqualini, Renata; Arap, Wadih

2007-01-01

Recognition of molecular diversity of cell surface proteomes in disease is essential for the development of targeted therapies. Progress in targeted therapeutics requires establishing effective approaches for high-throughput identification of agents specific for clinically relevant cell surface markers. Over the past decade, a number of platform strategies have been developed to screen polypeptide libraries for ligands targeting receptors selectively expressed in the context of various cell surface proteomes. Streamlined procedures for identification of ligand-receptor pairs that could serve as targets in disease diagnosis, profiling, imaging and therapy have relied on the display technologies, in which polypeptides with desired binding profiles can be serially selected, in a process called biopanning, based on their physical linkage with the encoding nucleic acid. These technologies include virus/phage display, cell display, ribosomal display, mRNA display and covalent DNA display (CDT), with phage display being by far the most utilized. The scope of this review is the recent advancements in the display technologies with a particular emphasis on molecular mapping of cell surface proteomes with peptide phage display. Prospective applications of targeted compounds derived from display libraries in the discovery of targeted drugs and gene therapy vectors are discussed. PMID:17123658

Natural material-decorated mesoporous silica nanoparticle container for multifunctional membrane-controlled targeted drug delivery

PubMed Central

Hu, Yan; Ke, Lei; Chen, Hao; Zhuo, Ma; Yang, Xinzhou; Zhao, Dan; Zeng, Suying; Xiao, Xincai

2017-01-01

To avoid the side effects caused by nonspecific targeting, premature release, weak selectivity, and poor therapeutic efficacy of current nanoparticle-based systems used for drug delivery, we fabricated natural material-decorated nanoparticles as a multifunctional, membrane-controlled targeted drug delivery system. The nanocomposite material coated with a membrane was biocompatible and integrated both specific tumor targeting and responsiveness to stimulation, which improved transmission efficacy and controlled drug release. Mesoporous silica nanoparticles (MSNs), which are known for their biocompatibility and high drug-loading capacity, were selected as a model drug container and carrier. The membrane was established by the polyelectrolyte composite method from chitosan (CS) which was sensitive to the acidic tumor microenvironment, folic acid-modified CS which recognizes the folate receptor expressed on the tumor cell surface, and a CD44 receptor-targeted polysaccharide hyaluronic acid. We characterized the structure of the nanocomposite as well as the drug release behavior under the control of the pH-sensitive membrane switch and evaluated the antitumor efficacy of the system in vitro. Our results provide a basis for the design and fabrication of novel membrane-controlled nanoparticles with improved tumor-targeting therapy. PMID:29200852

Use of Naturally Available Reference Targets to Calibrate Airborne Laser Scanning Intensity Data

PubMed Central

Vain, Ants; Kaasalainen, Sanna; Pyysalo, Ulla; Krooks, Anssi; Litkey, Paula

2009-01-01

We have studied the possibility of calibrating airborne laser scanning (ALS) intensity data, using land targets typically available in urban areas. For this purpose, a test area around Espoonlahti Harbor, Espoo, Finland, for which a long time series of ALS campaigns is available, was selected. Different target samples (beach sand, concrete, asphalt, different types of gravel) were collected and measured in the laboratory. Using tarps, which have certain backscattering properties, the natural samples were calibrated and studied, taking into account the atmospheric effect, incidence angle and flying height. Using data from different flights and altitudes, a time series for the natural samples was generated. Studying the stability of the samples, we could obtain information on the most ideal types of natural targets for ALS radiometric calibration. Using the selected natural samples as reference, the ALS points of typical land targets were calibrated again and examined. Results showed the need for more accurate ground reference data, before using natural samples in ALS intensity data calibration. Also, the NIR camera-based field system was used for collecting ground reference data. This system proved to be a good means for collecting in situ reference data, especially for targets with inhomogeneous surface reflection properties. PMID:22574045

The Assessment of Selectivity in Different Quadrupole-Orbitrap Mass Spectrometry Acquisition Modes

NASA Astrophysics Data System (ADS)

Berendsen, Bjorn J. A.; Wegh, Robin S.; Meijer, Thijs; Nielen, Michel W. F.

2015-02-01

Selectivity of the confirmation of identity in liquid chromatography (tandem) mass spectrometry using Q-Orbitrap instrumentation was assessed using different acquisition modes based on a representative experimental data set constructed from 108 samples, including six different matrix extracts and containing over 100 analytes each. Single stage full scan, all ion fragmentation, and product ion scanning were applied. By generating reconstructed ion chromatograms using unit mass window in targeted MS2, selected reaction monitoring (SRM), regularly applied using triple-quadrupole instruments, was mimicked. This facilitated the comparison of single stage full scan, all ion fragmentation, (mimicked) SRM, and product ion scanning applying a mass window down to 1 ppm. Single factor Analysis of Variance was carried out on the variance (s2) of the mass error to determine which factors and interactions are significant parameters with respect to selectivity. We conclude that selectivity is related to the target compound (mainly the mass defect), the matrix, sample clean-up, concentration, and mass resolution. Selectivity of the different instrumental configurations was quantified by counting the number of interfering peaks observed in the chromatograms. We conclude that precursor ion selection significantly contributes to selectivity: monitoring of a single product ion at high mass accuracy with a 1 Da precursor ion window proved to be equally selective or better to monitoring two transition products in mimicked SRM. In contrast, monitoring a single fragment in all ion fragmentation mode results in significantly lower selectivity versus mimicked SRM. After a thorough inter-laboratory evaluation study, the results of this study can be used for a critical reassessment of the current identification points system and contribute to the next generation of evidence-based and robust performance criteria in residue analysis and sports doping.

New support vector machine-based method for microRNA target prediction.

PubMed

Li, L; Gao, Q; Mao, X; Cao, Y

2014-06-09

MicroRNA (miRNA) plays important roles in cell differentiation, proliferation, growth, mobility, and apoptosis. An accurate list of precise target genes is necessary in order to fully understand the importance of miRNAs in animal development and disease. Several computational methods have been proposed for miRNA target-gene identification. However, these methods still have limitations with respect to their sensitivity and accuracy. Thus, we developed a new miRNA target-prediction method based on the support vector machine (SVM) model. The model supplies information of two binding sites (primary and secondary) for a radial basis function kernel as a similarity measure for SVM features. The information is categorized based on structural, thermodynamic, and sequence conservation. Using high-confidence datasets selected from public miRNA target databases, we obtained a human miRNA target SVM classifier model with high performance and provided an efficient tool for human miRNA target gene identification. Experiments have shown that our method is a reliable tool for miRNA target-gene prediction, and a successful application of an SVM classifier. Compared with other methods, the method proposed here improves the sensitivity and accuracy of miRNA prediction. Its performance can be further improved by providing more training examples.

A Targeted Mulifunctional Platform for Imaging and Treatment of Breast Cancer and Its Metastases Based on Adenoviral Vectors and Magnetic Nanoparticles

DTIC Science & Technology

2008-02-01

tu- mor cells. In this regard, herpesvirus samiri (HVS) was de- monstrated to be naturally selectively oncolytic for the pancreatic cancer line PANC-1...the hexon virus. Therefore, Ad can provide a versatile platform for selective binding of AuNPs, resulting in a multifunctional agent capable of...utility remained unaffected. Therefore, Ad can provide a versatile platform for selective binding of nanoparticles, resulting in a multifunctional agent

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…

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.

Rescue of Targeted Regions of Mammalian Chromosomes by in Vivo Recombination in Yeast

PubMed Central

Kouprina, Natalya; Kawamoto, Kensaku; Barrett, J. Carl; Larionov, Vladimir; Koi, Minoru

1998-01-01

In contrast to other animal cell lines, the chicken pre-B cell lymphoma line, DT40, exhibits a high level of homologous recombination, which can be exploited to generate site-specific alterations in defined target genes or regions. In addition, the ability to generate human/chicken monochromosomal hybrids in the DT40 cell line opens a way for specific targeting of human genes. Here we describe a new strategy for direct isolation of a human chromosomal region that is based on targeting of the chromosome with a vector containing a yeast selectable marker, centromere, and an ARS element. This procedure allows rescue of the targeted region by transfection of total genomic DNA into yeast spheroplasts. Selection for the yeast marker results in isolation of chromosome sequences in the form of large circular yeast artificial chromosomes (YACs) up to 170 kb in size containing the targeted region. These YACs are generated by homologous recombination in yeast between common repeated sequences in the targeted chromosomal fragment. Alternatively, the targeted region can be rescued as a linear YACs when a YAC fragmentation vector is included in the yeast transformation mixture. Because the entire isolation procedure of the chromosomal region, once a target insertion is obtained, can be accomplished in ∼1 week, the new method greatly expands the utility of the homologous recombinationproficient DT40 chicken cell system. PMID:9647640

TargetSpy: a supervised machine learning approach for microRNA target prediction.

PubMed

Sturm, Martin; Hackenberg, Michael; Langenberger, David; Frishman, Dmitrij

2010-05-28

Virtually all currently available microRNA target site prediction algorithms require the presence of a (conserved) seed match to the 5' end of the microRNA. Recently however, it has been shown that this requirement might be too stringent, leading to a substantial number of missed target sites. We developed TargetSpy, a novel computational approach for predicting target sites regardless of the presence of a seed match. It is based on machine learning and automatic feature selection using a wide spectrum of compositional, structural, and base pairing features covering current biological knowledge. Our model does not rely on evolutionary conservation, which allows the detection of species-specific interactions and makes TargetSpy suitable for analyzing unconserved genomic sequences.In order to allow for an unbiased comparison of TargetSpy to other methods, we classified all algorithms into three groups: I) no seed match requirement, II) seed match requirement, and III) conserved seed match requirement. TargetSpy predictions for classes II and III are generated by appropriate postfiltering. On a human dataset revealing fold-change in protein production for five selected microRNAs our method shows superior performance in all classes. In Drosophila melanogaster not only our class II and III predictions are on par with other algorithms, but notably the class I (no-seed) predictions are just marginally less accurate. We estimate that TargetSpy predicts between 26 and 112 functional target sites without a seed match per microRNA that are missed by all other currently available algorithms. Only a few algorithms can predict target sites without demanding a seed match and TargetSpy demonstrates a substantial improvement in prediction accuracy in that class. Furthermore, when conservation and the presence of a seed match are required, the performance is comparable with state-of-the-art algorithms. TargetSpy was trained on mouse and performs well in human and drosophila, suggesting that it may be applicable to a broad range of species. Moreover, we have demonstrated that the application of machine learning techniques in combination with upcoming deep sequencing data results in a powerful microRNA target site prediction tool http://www.targetspy.org.