Spontaneous mentalizing predicts the fundamental attribution error.

PubMed

Moran, Joseph M; Jolly, Eshin; Mitchell, Jason P

2014-03-01

When explaining the reasons for others' behavior, perceivers often overemphasize underlying dispositions and personality traits over the power of the situation, a tendency known as the fundamental attribution error. One possibility is that this bias results from the spontaneous processing of others' mental states, such as their momentary feelings or more enduring personality characteristics. Here, we use fMRI to test this hypothesis. Participants read a series of stories that described a target's ambiguous behavior in response to a specific social situation and later judged whether that act was attributable to the target's internal dispositions or to external situational factors. Neural regions consistently associated with mental state inference-especially, the medial pFC-strongly predicted whether participants later made dispositional attributions. These results suggest that the spontaneous engagement of mentalizing may underlie the biased tendency to attribute behavior to dispositional over situational forces.

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.

Aptamer-Targeted Gold Nanoparticles As Molecular-Specific Contrast Agents for Reflectance Imaging

PubMed Central

2008-01-01

Targeted metallic nanoparticles have shown potential as a platform for development of molecular-specific contrast agents. Aptamers have recently been demonstrated as ideal candidates for molecular targeting applications. In this study, we investigated the development of aptamer-based gold nanoparticles as contrast agents, using aptamers as targeting agents and gold nanoparticles as imaging agents. We devised a novel conjugation approach using an extended aptamer design where the extension is complementary to an oligonucleotide sequence attached to the surface of the gold nanoparticles. The chemical and optical properties of the aptamer−gold conjugates were characterized using size measurements and oligonucleotide quantitation assays. We demonstrate this conjugation approach to create a contrast agent designed for detection of prostate-specific membrane antigen (PSMA), obtaining reflectance images of PSMA(+) and PSMA(−) cell lines treated with the anti-PSMA aptamer−gold conjugates. This design strategy can easily be modified to incorporate multifunctional agents as part of a multimodal platform for reflectance imaging applications. PMID:18512972

Perceptions of plagiarisers: The influence of target physical attractiveness, transgression severity, and sex on attributions of guilt and punishment.

PubMed

Swami, Viren; Arthey, Elizabeth; Furnham, Adrian

2017-09-01

The attractiveness-leniency effect (ALE) suggests that physically attractive targets are less likely to be perceived as guilty compared to less attractive targets. Here, we tested the ALE in relation to attributions of students who have committed plagiarism. British adults (N=165) were shown one of eight vignette-photograph pairings varying in target sex (female/male), physical attractiveness (high/low), and transgression severity (serious/minor), and provided attributions of guilt and severity of punishment. Analyses of variance revealed significant interactions between attractiveness and transgression severity for both dependent measures. Attractive targets were perceived as guiltier and deserving of more severe punishments in the serious transgression condition, but there was no significant difference between attractive and less attractive targets in the minor transgression condition. These results are discussed in terms of a reverse attribution bias, in which attractive individuals are judged more negatively when they fail to live up to higher standards of conduct. Copyright © 2017 Elsevier Ltd. All rights reserved.

An innovative pre-targeting strategy for tumor cell specific imaging and therapy.

PubMed

Qin, Si-Yong; Peng, Meng-Yun; Rong, Lei; Jia, Hui-Zhen; Chen, Si; Cheng, Si-Xue; Feng, Jun; Zhang, Xian-Zheng

2015-09-21

A programmed pre-targeting system for tumor cell imaging and targeting therapy was established based on the "biotin-avidin" interaction. In this programmed functional system, transferrin-biotin can be actively captured by tumor cells with the overexpression of transferrin receptors, thus achieving the pre-targeting modality. Depending upon avidin-biotin recognition, the attachment of multivalent FITC-avidin to biotinylated tumor cells not only offered the rapid fluorescence labelling, but also endowed the pre-targeted cells with targeting sites for the specifically designed biotinylated peptide nano-drug. Owing to the successful pre-targeting, tumorous HepG2 and HeLa cells were effectively distinguished from the normal 3T3 cells via fluorescence imaging. In addition, the self-assembled peptide nano-drug resulted in enhanced cell apoptosis in the observed HepG2 cells. The tumor cell specific pre-targeting strategy is applicable for a variety of different imaging and therapeutic agents for tumor treatments.

Cell-specific targeting by heterobivalent ligands.

PubMed

Josan, Jatinder S; Handl, Heather L; Sankaranarayanan, Rajesh; Xu, Liping; Lynch, Ronald M; Vagner, Josef; Mash, Eugene A; Hruby, Victor J; Gillies, Robert J

2011-07-20

Current cancer therapies exploit either differential metabolism or targeting to specific individual gene products that are overexpressed in aberrant cells. The work described herein proposes an alternative approach--to specifically target combinations of cell-surface receptors using heteromultivalent ligands ("receptor combination approach"). As a proof-of-concept that functionally unrelated receptors can be noncovalently cross-linked with high avidity and specificity, a series of heterobivalent ligands (htBVLs) were constructed from analogues of the melanocortin peptide ligand ([Nle(4), dPhe(7)]-α-MSH) and the cholecystokinin peptide ligand (CCK-8). Binding of these ligands to cells expressing the human Melanocortin-4 receptor and the Cholecystokinin-2 receptor was analyzed. The MSH(7) and CCK(6) were tethered with linkers of varying rigidity and length, constructed from natural and/or synthetic building blocks. Modeling data suggest that a linker length of 20-50 Å is needed to simultaneously bind these two different G-protein coupled receptors (GPCRs). These ligands exhibited up to 24-fold enhancement in binding affinity to cells that expressed both (bivalent binding), compared to cells with only one (monovalent binding) of the cognate receptors. The htBVLs had up to 50-fold higher affinity than that of a monomeric CCK ligand, i.e., Ac-CCK(6)-NH(2). Cell-surface targeting of these two cell types with labeled heteromultivalent ligand demonstrated high avidity and specificity, thereby validating the receptor combination approach. This ability to noncovalently cross-link heterologous receptors and target individual cells using a receptor combination approach opens up new possibilities for specific cell targeting in vivo for therapy or imaging.

Cell-Specific Targeting by Heterobivalent Ligands

PubMed Central

Josan, Jatinder S.; Handl, Heather L.; Sankaranarayanan, Rajesh; Xu, Liping; Lynch, Ronald M.; Vagner, Josef; Mash, Eugene A.; Hruby, Victor J.; Gillies, Robert J.

2012-01-01

Current cancer therapies exploit either differential metabolism or targeting to specific individual gene products that are overexpressed in aberrant cells. The work described herein proposes an alternative approach—to specifically target combinations of cell-surface receptors using heteromultivalent ligands (“receptor combination approach”). As a proof-of-concept that functionally unrelated receptors can be noncovalently cross-linked with high avidity and specificity, a series of heterobivalent ligands (htBVLs) were constructed from analogues of the melanocortin peptide ligand ([Nle4, DPhe7]-α-MSH) and the cholecystokinin peptide ligand (CCK-8). Binding of these ligands to cells expressing the human Melanocortin-4 receptor and the Cholecystokinin-2 receptor was analyzed. The MSH(7) and CCK(6) were tethered with linkers of varying rigidity and length, constructed from natural and/or synthetic building blocks. Modeling data suggest that a linker length of 20–50 Å is needed to simultaneously bind these two different G-protein coupled receptors (GPCRs). These ligands exhibited up to 24-fold enhancement in binding affinity to cells that expressed both (bivalent binding), compared to cells with only one (monovalent binding) of the cognate receptors. The htBVLs had up to 50-fold higher affinity than that of a monomeric CCK ligand, i.e., Ac-CCK(6)-NH2. Cell-surface targeting of these two cell types with labeled heteromultivalent ligand demonstrated high avidity and specificity, thereby validating the receptor combination approach. This ability to noncovalently cross-link heterologous receptors and target individual cells using a receptor combination approach opens up new possibilities for specific cell targeting in vivo for therapy or imaging. PMID:21639139

Advances in targeted proteomics and applications to biomedical research

PubMed Central

Shi, Tujin; Song, Ehwang; Nie, Song; Rodland, Karin D.; Liu, Tao; Qian, Wei-Jun; Smith, Richard D.

2016-01-01

Targeted proteomics technique has emerged as a powerful protein quantification tool in systems biology, biomedical research, and increasing for clinical applications. The most widely used targeted proteomics approach, selected reaction monitoring (SRM), also known as multiple reaction monitoring (MRM), can be used for quantification of cellular signaling networks and preclinical verification of candidate protein biomarkers. As an extension to our previous review on advances in SRM sensitivity herein we review recent advances in the method and technology for further enhancing SRM sensitivity (from 2012 to present), and highlighting its broad biomedical applications in human bodily fluids, tissue and cell lines. Furthermore, we also review two recently introduced targeted proteomics approaches, parallel reaction monitoring (PRM) and data-independent acquisition (DIA) with targeted data extraction on fast scanning high-resolution accurate-mass (HR/AM) instruments. Such HR/AM targeted quantification with monitoring all target product ions addresses SRM limitations effectively in specificity and multiplexing; whereas when compared to SRM, PRM and DIA are still in the infancy with a limited number of applications. Thus, for HR/AM targeted quantification we focus our discussion on method development, data processing and analysis, and its advantages and limitations in targeted proteomics. Finally, general perspectives on the potential of achieving both high sensitivity and high sample throughput for large-scale quantification of hundreds of target proteins are discussed. PMID:27302376

Knowledge-based approach for generating target system specifications from a domain model

NASA Technical Reports Server (NTRS)

Gomaa, Hassan; Kerschberg, Larry; Sugumaran, Vijayan

1992-01-01

Several institutions in industry and academia are pursuing research efforts in domain modeling to address unresolved issues in software reuse. To demonstrate the concepts of domain modeling and software reuse, a prototype software engineering environment is being developed at George Mason University to support the creation of domain models and the generation of target system specifications. This prototype environment, which is application domain independent, consists of an integrated set of commercial off-the-shelf software tools and custom-developed software tools. This paper describes the knowledge-based tool that was developed as part of the environment to generate target system specifications from a domain model.

Neurochemical differences between target-specific populations of rat dorsal raphe projection neurons.

PubMed

Prouty, Eric W; Chandler, Daniel J; Waterhouse, Barry D

2017-11-15

Serotonin (5-HT)-containing neurons in the dorsal raphe (DR) nucleus project throughout the forebrain and are implicated in many physiological processes and neuropsychiatric disorders. Diversity among these neurons has been characterized in terms of their neurochemistry and anatomical organization, but a clear sense of whether these attributes align with specific brain functions or terminal fields is lacking. DR 5-HT neurons can co-express additional neuroactive substances, increasing the potential for individualized regulation of target circuits. The goal of this study was to link DR neurons to a specific functional role by characterizing cells according to both their neurotransmitter expression and efferent connectivity; specifically, cells projecting to the medial prefrontal cortex (mPFC), a region implicated in cognition, emotion, and responses to stress. Following retrograde tracer injection, brainstem sections from Sprague-Dawley rats were immunohistochemically stained for markers of serotonin, glutamate, GABA, and nitric oxide (NO). 98% of the mPFC-projecting serotonergic neurons co-expressed the marker for glutamate, while the markers for NO and GABA were observed in 60% and less than 1% of those neurons, respectively. To identify potential target-specific differences in co-transmitter expression, we also characterized DR neurons projecting to a visual sensory structure, the lateral geniculate nucleus (LGN). The proportion of serotonergic neurons co-expressing NO was greater amongst cells targeting the mPFC vs LGN (60% vs 22%). The established role of 5-HT in affective disorders and the emerging role of NO in stress signaling suggest that the impact of 5-HT/NO co-localization in DR neurons that regulate mPFC circuit function may be clinically relevant. Copyright © 2017 Elsevier B.V. All rights reserved.

Selection of phage-displayed accessible recombinant targeted antibodies (SPARTA): methodology and applications.

PubMed

D'Angelo, Sara; Staquicini, Fernanda I; Ferrara, Fortunato; Staquicini, Daniela I; Sharma, Geetanjali; Tarleton, Christy A; Nguyen, Huynh; Naranjo, Leslie A; Sidman, Richard L; Arap, Wadih; Bradbury, Andrew Rm; Pasqualini, Renata

2018-05-03

We developed a potentially novel and robust antibody discovery methodology, termed selection of phage-displayed accessible recombinant targeted antibodies (SPARTA). This combines an in vitro screening step of a naive human antibody library against known tumor targets, with in vivo selections based on tumor-homing capabilities of a preenriched antibody pool. This unique approach overcomes several rate-limiting challenges to generate human antibodies amenable to rapid translation into medical applications. As a proof of concept, we evaluated SPARTA on 2 well-established tumor cell surface targets, EphA5 and GRP78. We evaluated antibodies that showed tumor-targeting selectivity as a representative panel of antibody-drug conjugates (ADCs) and were highly efficacious. Our results validate a discovery platform to identify and validate monoclonal antibodies with favorable tumor-targeting attributes. This approach may also extend to other diseases with known cell surface targets and affected tissues easily isolated for in vivo selection.

Target-specific contrast agents for magnetic resonance microscopy

PubMed Central

Blackwell, Megan L.; Farrar, Christian T.; Fischl, Bruce; Rosen, Bruce R.

2009-01-01

High-resolution ex vivo magnetic resonance (MR) imaging can be used to delineate prominent architectonic features in the human brain, but increased contrast is required to visualize more subtle distinctions. To aid MR sensitivity to cell density and myelination, we have begun the development of target-specific paramagnetic contrast agents. This work details the first application of luxol fast blue (LFB), an optical stain for myelin, as a white matter-selective MR contrast agent for human ex vivo brain tissue. Formalin-fixed human visual cortex was imaged with an isotropic resolution between 80 and 150 μm at 4.7 and 14 T before and after en bloc staining with LFB. Longitudinal (R1) and transverse (R2) relaxation rates in LFB-stained tissue increased proportionally with myelination at both field strengths. Changes in R1 resulted in larger contrast-to-noise ratios (CNR), per unit time, on T1-weighted images between more myelinated cortical layers (IV–VI) and adjacent, superficial layers (I–III) at both field strengths. Specifically, CNR for LFB-treated samples increased by 229±13% at 4.7 T and 269±25% at 14 T when compared to controls. Also, additional cortical layers (IVca, IVd, and Va) were resolvable in 14T-MR images of LFB-treated samples but not in control samples. After imaging, samples were sliced in 40-micron sections, mounted, and photographed. Both the macroscopic and microscopic distributions of LFB were found to mimic those of traditional histological preparations. Our results suggest target-specific contrast agents will enable more detailed MR images with applications in imaging pathological ex vivo samples and constructing better MR atlases from ex vivo brains. PMID:19385012

A Dual-Specific Targeting Approach Based on the Simultaneous Recognition of Duplex and Quadruplex Motifs.

PubMed

Nguyen, Thi Quynh Ngoc; Lim, Kah Wai; Phan, Anh Tuân

2017-09-20

Small-molecule ligands targeting nucleic acids have been explored as potential therapeutic agents. Duplex groove-binding ligands have been shown to recognize DNA in a sequence-specific manner. On the other hand, quadruplex-binding ligands exhibit high selectivity between quadruplex and duplex, but show limited discrimination between different quadruplex structures. Here we propose a dual-specific approach through the simultaneous application of duplex- and quadruplex-binders. We demonstrated that a quadruplex-specific ligand and a duplex-specific ligand can simultaneously interact at two separate binding sites of a quadruplex-duplex hybrid harbouring both quadruplex and duplex structural elements. Such a dual-specific targeting strategy would combine the sequence specificity of duplex-binders and the strong binding affinity of quadruplex-binders, potentially allowing the specific targeting of unique quadruplex structures. Future research can be directed towards the development of conjugated compounds targeting specific genomic quadruplex-duplex sites, for which the linker would be highly context-dependent in terms of length and flexibility, as well as the attachment points onto both ligands.

Single-Cell Droplet Microfluidic Screening for Antibodies Specifically Binding to Target Cells.

PubMed

Shembekar, Nachiket; Hu, Hongxing; Eustace, David; Merten, Christoph A

2018-02-20

Monoclonal antibodies are a main player in modern drug discovery. Many antibody screening formats exist, each with specific advantages and limitations. Nonetheless, it remains challenging to screen antibodies for the binding of cell-surface receptors (the most important class of all drug targets) or for the binding to target cells rather than purified proteins. Here, we present a high-throughput droplet microfluidics approach employing dual-color normalized fluorescence readout to detect antibody binding. This enables us to obtain quantitative data on target cell recognition, using as little as 33 fg of IgG per assay. Starting with an excess of hybridoma cells releasing unspecific antibodies, individual clones secreting specific binders (of target cells co-encapsulated into droplets) could be enriched 220-fold after sorting 80,000 clones in a single experiment. This opens the way for therapeutic antibody discovery, especially since the single-cell approach is in principle also applicable to primary human plasma cells. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

Application-specific coarse-grained reconfigurable array: architecture and design methodology

NASA Astrophysics Data System (ADS)

Zhou, Li; Liu, Dongpei; Zhang, Jianfeng; Liu, Hengzhu

2015-06-01

Coarse-grained reconfigurable arrays (CGRAs) have shown potential for application in embedded systems in recent years. Numerous reconfigurable processing elements (PEs) in CGRAs provide flexibility while maintaining high performance by exploring different levels of parallelism. However, a difference remains between the CGRA and the application-specific integrated circuit (ASIC). Some application domains, such as software-defined radios (SDRs), require flexibility with performance demand increases. More effective CGRA architectures are expected to be developed. Customisation of a CGRA according to its application can improve performance and efficiency. This study proposes an application-specific CGRA architecture template composed of generic PEs (GPEs) and special PEs (SPEs). The hardware of the SPE can be customised to accelerate specific computational patterns. An automatic design methodology that includes pattern identification and application-specific function unit generation is also presented. A mapping algorithm based on ant colony optimisation is provided. Experimental results on the SDR target domain show that compared with other ordinary and application-specific reconfigurable architectures, the CGRA generated by the proposed method performs more efficiently for given applications.

Advances in targeted proteomics and applications to biomedical research

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

Shi, Tujin; Song, Ehwang; Nie, Song

Targeted proteomics technique has emerged as a powerful protein quantification tool in systems biology, biomedical research, and increasing for clinical applications. The most widely used targeted proteomics approach, selected reaction monitoring (SRM), also known as multiple reaction monitoring (MRM), can be used for quantification of cellular signaling networks and preclinical verification of candidate protein biomarkers. As an extension to our previous review on advances in SRM sensitivity (Shi et al., Proteomics, 12, 1074–1092, 2012) herein we review recent advances in the method and technology for further enhancing SRM sensitivity (from 2012 to present), and highlighting its broad biomedical applications inmore » human bodily fluids, tissue and cell lines. Furthermore, we also review two recently introduced targeted proteomics approaches, parallel reaction monitoring (PRM) and data-independent acquisition (DIA) with targeted data extraction on fast scanning high-resolution accurate-mass (HR/AM) instruments. Such HR/AM targeted quantification with monitoring all target product ions addresses SRM limitations effectively in specificity and multiplexing; whereas when compared to SRM, PRM and DIA are still in the infancy with a limited number of applications. Thus, for HR/AM targeted quantification we focus our discussion on method development, data processing and analysis, and its advantages and limitations in targeted proteomics. Finally, general perspectives on the potential of achieving both high sensitivity and high sample throughput for large-scale quantification of hundreds of target proteins are discussed.« less

Bypassing Protein Corona Issue on Active Targeting: Zwitterionic Coatings Dictate Specific Interactions of Targeting Moieties and Cell Receptors.

PubMed

Safavi-Sohi, Reihaneh; Maghari, Shokoofeh; Raoufi, Mohammad; Jalali, Seyed Amir; Hajipour, Mohammad J; Ghassempour, Alireza; Mahmoudi, Morteza

2016-09-07

Surface functionalization strategies for targeting nanoparticles (NP) to specific organs, cells, or organelles, is the foundation for new applications of nanomedicine to drug delivery and biomedical imaging. Interaction of NPs with biological media leads to the formation of a biomolecular layer at the surface of NPs so-called as "protein corona". This corona layer can shield active molecules at the surface of NPs and cause mistargeting or unintended scavenging by the liver, kidney, or spleen. To overcome this corona issue, we have designed biotin-cysteine conjugated silica NPs (biotin was employed as a targeting molecule and cysteine was used as a zwitterionic ligand) to inhibit corona-induced mistargeting and thus significantly enhance the active targeting capability of NPs in complex biological media. To probe the targeting yield of our engineered NPs, we employed both modified silicon wafer substrates with streptavidin (i.e., biotin receptor) to simulate a target and a cell-based model platform using tumor cell lines that overexpress biotin receptors. In both cases, after incubation with human plasma (thus forming a protein corona), cellular uptake/substrate attachment of the targeted NPs with zwitterionic coatings were significantly higher than the same NPs without zwitterionic coating. Our results demonstrated that NPs with a zwitterionic surface can considerably facilitate targeting yield of NPs and provide a promising new type of nanocarriers in biological applications.

Kicking the (barking) dog effect: the moderating role of target attributes on triggered displaced aggression.

PubMed

Pedersen, William C; Bushman, Brad J; Vasquez, Eduardo A; Miller, Norman

2008-10-01

Sometimes aggression is displaced onto a target who is not totally innocent but emits a mildly irritating behavior called a triggering event. In three experiments, the authors examine stable personal attributes of targets that can impact such triggered displaced aggression (TDA). Lower levels of TDA were directed to targets whose attitudes were similar as compared to dissimilar to those of the actor (Experiment 1) and to targets who were ingroup as compared to out-group members (Experiment 2). Conceptually replicating the findings of Experiments 1 and 2, the manipulated valence of the target (viz., liked, neutral, and disliked) functioned in a similar manner, with positive valence serving a buffering function against a triggering action that followed an initial provocation (Experiment 3). The results from all three experiments are consistent with cognitive neoassociationist theory.

Quality Attribute Techniques Framework

NASA Astrophysics Data System (ADS)

Chiam, Yin Kia; Zhu, Liming; Staples, Mark

The quality of software is achieved during its development. Development teams use various techniques to investigate, evaluate and control potential quality problems in their systems. These “Quality Attribute Techniques” target specific product qualities such as safety or security. This paper proposes a framework to capture important characteristics of these techniques. The framework is intended to support process tailoring, by facilitating the selection of techniques for inclusion into process models that target specific product qualities. We use risk management as a theory to accommodate techniques for many product qualities and lifecycle phases. Safety techniques have motivated the framework, and safety and performance techniques have been used to evaluate the framework. The evaluation demonstrates the ability of quality risk management to cover the development lifecycle and to accommodate two different product qualities. We identify advantages and limitations of the framework, and discuss future research on the framework.

Intracellular Protein Delivery System Using a Target-Specific Repebody and Translocation Domain of Bacterial Exotoxin.

PubMed

Kim, Hee-Yeon; Kang, Jung Ae; Ryou, Jeong-Hyun; Lee, Gyeong Hee; Choi, Dae Seong; Lee, Dong Eun; Kim, Hak-Sung

2017-11-17

With the high efficacy of protein-based therapeutics and plenty of intracellular drug targets, cytosolic protein delivery in a cell-specific manner has attracted considerable attention in the field of precision medicine. Herein, we present an intracellular protein delivery system based on a target-specific repebody and the translocation domain of Pseudomonas aeruginosa exotoxin A. The delivery platform was constructed by genetically fusing an EGFR-specific repebody as a targeting moiety to the translocation domain, while a protein cargo was fused to the C-terminal end of the delivery platform. The delivery platform was revealed to efficiently translocate a protein cargo to the cytosol in a target-specific manner. We demonstrate the utility and potential of the delivery platform by showing a remarkable tumor regression with negligible toxicity in a xenograft mice model when gelonin was used as the cytotoxic protein cargo. The present platform can find wide applications to the cell-selective cytosolic delivery of diverse proteins in many areas.

Specifically targeted delivery of protein to phagocytic macrophages

PubMed Central

Yu, Min; Chen, Zeming; Guo, Wenjun; Wang, Jin; Feng, Yupeng; Kong, Xiuqi; Hong, Zhangyong

2015-01-01

Macrophages play important roles in the pathogenesis of various diseases, and are important potential therapeutic targets. Furthermore, macrophages are key antigen-presenting cells and important in vaccine design. In this study, we report on the novel formulation (bovine serum albumin [BSA]-loaded glucan particles [GMP-BSA]) based on β-glucan particles from cell walls of baker’s yeast for the targeted delivery of protein to macrophages. Using this formulation, chitosan, tripolyphosphate, and alginate were used to fabricate colloidal particles with the model protein BSA via electrostatic interactions, which were caged and incorporated BSA very tightly within the β-glucan particle shells. The prepared GMP-BSA exhibited good protein-release behavior and avoided protein leakage. The particles were also highly specific to phagocytic macrophages, such as Raw 264.7 cells, primary bone marrow-derived macrophages, and peritoneal exudate macrophages, whereas the particles were not taken up by nonphagocytic cells, including NIH3T3, AD293, HeLa, and Caco-2. We hypothesize that these tightly encapsulated protein-loaded glucan particles deliver various types of proteins to macrophages with notably high selectivity, and may have broad applications in targeted drug delivery or vaccine design against macrophages. PMID:25784802

Identifying attributes of food literacy: a scoping review.

PubMed

Azevedo Perry, Elsie; Thomas, Heather; Samra, H Ruby; Edmonstone, Shannon; Davidson, Lyndsay; Faulkner, Amy; Petermann, Lisa; Manafò, Elizabeth; Kirkpatrick, Sharon I

2017-09-01

An absence of food literacy measurement tools makes it challenging for nutrition practitioners to assess the impact of food literacy on healthy diets and to evaluate the outcomes of food literacy interventions. The objective of the present scoping review was to identify the attributes of food literacy. A scoping review of peer-reviewed and grey literature was conducted and attributes of food literacy identified. Subjects included in the search were high-risk groups. Eligible articles were limited to research from Canada, USA, the UK, Australia and New Zealand. The search identified nineteen peer-reviewed and thirty grey literature sources. Fifteen identified food literacy attributes were organized into five categories. Food and Nutrition Knowledge informs decisions about intake and distinguishing between 'healthy' and 'unhealthy' foods. Food Skills focuses on techniques of food purchasing, preparation, handling and storage. Self-Efficacy and Confidence represent one's capacity to perform successfully in specific situations. Ecologic refers to beyond self and the interaction of macro- and microsystems with food decisions and behaviours. Food Decisions reflects the application of knowledge, information and skills to make food choices. These interdependent attributes are depicted in a proposed conceptual model. The lack of evaluated tools inhibits the ability to assess and monitor food literacy; tailor, target and evaluate programmes; identify gaps in programming; engage in advocacy; and allocate resources. The present scoping review provides the foundation for the development of a food literacy measurement tool to address these gaps.

Targeted sequencing of clade-specific markers from skin microbiomes for forensic human identification.

PubMed

Schmedes, Sarah E; Woerner, August E; Novroski, Nicole M M; Wendt, Frank R; King, Jonathan L; Stephens, Kathryn M; Budowle, Bruce

2018-01-01

The human skin microbiome is comprised of diverse communities of bacterial, eukaryotic, and viral taxa and contributes millions of additional genes to the repertoire of human genes, affecting human metabolism and immune response. Numerous genetic and environmental factors influence the microbiome composition and as such contribute to individual-specific microbial signatures which may be exploited for forensic applications. Previous studies have demonstrated the potential to associate skin microbial profiles collected from touched items to their individual owner, mainly using unsupervised methods from samples collected over short time intervals. Those studies utilize either targeted 16S rRNA or shotgun metagenomic sequencing to characterize skin microbiomes; however, these approaches have limited species and strain resolution and susceptibility to stochastic effects, respectively. Clade-specific markers from the skin microbiome, using supervised learning, can predict individual identity using skin microbiomes from their respective donors with high accuracy. In this study the hidSkinPlex is presented, a novel targeted sequencing method using skin microbiome markers developed for human identification. The hidSkinPlex (comprised of 286 bacterial (and phage) family-, genus-, species-, and subspecies-level markers), initially was evaluated on three bacterial control samples represented in the panel (i.e., Propionibacterium acnes, Propionibacterium granulosum, and Rothia dentocariosa) to assess the performance of the multiplex. The hidSkinPlex was further evaluated for prediction purposes. The hidSkinPlex markers were used to attribute skin microbiomes collected from eight individuals from three body sites (i.e., foot (Fb), hand (Hp) and manubrium (Mb)) to their host donor. Supervised learning, specifically regularized multinomial logistic regression and 1-nearest-neighbor classification were used to classify skin microbiomes to their hosts with up to 92% (Fb), 96% (Mb

Cognitive regulation alters social and dietary choice by changing attribute representations in domain-general and domain-specific brain circuits

PubMed Central

Hutcherson, Cendri A

2018-01-01

Are some people generally more successful using cognitive regulation or does it depend on the choice domain? Why? We combined behavioral computational modeling and multivariate decoding of fMRI responses to identify neural loci of regulation-related shifts in value representations across goals and domains (dietary or altruistic choice). Surprisingly, regulatory goals did not alter integrative value representations in the ventromedial prefrontal cortex, which represented all choice-relevant attributes across goals and domains. Instead, the dorsolateral prefrontal cortex (DLPFC) flexibly encoded goal-consistent values and predicted regulatory success for the majority of choice-relevant attributes, using attribute-specific neural codes. We also identified domain-specific exceptions: goal-dependent encoding of prosocial attributes localized to precuneus and temporo-parietal junction (not DLPFC). Our results suggest that cognitive regulation operated by changing specific attribute representations (not integrated values). Evidence of domain-general and domain-specific neural loci reveals important divisions of labor, explaining when and why regulatory success generalizes (or doesn’t) across contexts and domains. PMID:29813018

Access control based on attribute certificates for medical intranet applications.

PubMed

Mavridis, I; Georgiadis, C; Pangalos, G; Khair, M

2001-01-01

Clinical information systems frequently use intranet and Internet technologies. However these technologies have emphasized sharing and not security, despite the sensitive and private nature of much health information. Digital certificates (electronic documents which recognize an entity or its attributes) can be used to control access in clinical intranet applications. To outline the need for access control in distributed clinical database systems, to describe the use of digital certificates and security policies, and to propose the architecture for a system using digital certificates, cryptography and security policy to control access to clinical intranet applications. We have previously developed a security policy, DIMEDAC (Distributed Medical Database Access Control), which is compatible with emerging public key and privilege management infrastructure. In our implementation approach we propose the use of digital certificates, to be used in conjunction with DIMEDAC. Our proposed access control system consists of two phases: the ways users gain their security credentials; and how these credentials are used to access medical data. Three types of digital certificates are used: identity certificates for authentication; attribute certificates for authorization; and access-rule certificates for propagation of access control policy. Once a user is identified and authenticated, subsequent access decisions are based on a combination of identity and attribute certificates, with access-rule certificates providing the policy framework. Access control in clinical intranet applications can be successfully and securely managed through the use of digital certificates and the DIMEDAC security policy.

Access Control based on Attribute Certificates for Medical Intranet Applications

PubMed Central

Georgiadis, Christos; Pangalos, George; Khair, Marie

2001-01-01

Background Clinical information systems frequently use intranet and Internet technologies. However these technologies have emphasized sharing and not security, despite the sensitive and private nature of much health information. Digital certificates (electronic documents which recognize an entity or its attributes) can be used to control access in clinical intranet applications. Objectives To outline the need for access control in distributed clinical database systems, to describe the use of digital certificates and security policies, and to propose the architecture for a system using digital certificates, cryptography and security policy to control access to clinical intranet applications. Methods We have previously developed a security policy, DIMEDAC (Distributed Medical Database Access Control), which is compatible with emerging public key and privilege management infrastructure. In our implementation approach we propose the use of digital certificates, to be used in conjunction with DIMEDAC. Results Our proposed access control system consists of two phases: the ways users gain their security credentials; and how these credentials are used to access medical data. Three types of digital certificates are used: identity certificates for authentication; attribute certificates for authorization; and access-rule certificates for propagation of access control policy. Once a user is identified and authenticated, subsequent access decisions are based on a combination of identity and attribute certificates, with access-rule certificates providing the policy framework. Conclusions Access control in clinical intranet applications can be successfully and securely managed through the use of digital certificates and the DIMEDAC security policy. PMID:11720951

Timescale Halo: Average-Speed Targets Elicit More Positive and Less Negative Attributions than Slow or Fast Targets

PubMed Central

Hernandez, Ivan; Preston, Jesse Lee; Hepler, Justin

2014-01-01

Research on the timescale bias has found that observers perceive more capacity for mind in targets moving at an average speed, relative to slow or fast moving targets. The present research revisited the timescale bias as a type of halo effect, where normal-speed people elicit positive evaluations and abnormal-speed (slow and fast) people elicit negative evaluations. In two studies, participants viewed videos of people walking at a slow, average, or fast speed. We find evidence for a timescale halo effect: people walking at an average-speed were attributed more positive mental traits, but fewer negative mental traits, relative to slow or fast moving people. These effects held across both cognitive and emotional dimensions of mind and were mediated by overall positive/negative ratings of the person. These results suggest that, rather than eliciting greater perceptions of general mind, the timescale bias may reflect a generalized positivity toward average speed people relative to slow or fast moving people. PMID:24421882

Limited Efficiency of Drug Delivery to Specific Intracellular Organelles Using Subcellularly "Targeted" Drug Delivery Systems.

PubMed

Maity, Amit Ranjan; Stepensky, David

2016-01-04

Many drugs have been designed to act on intracellular targets and to affect intracellular processes inside target cells. For the desired effects to be exerted, these drugs should permeate target cells and reach specific intracellular organelles. This subcellular drug targeting approach has been proposed for enhancement of accumulation of these drugs in target organelles and improved efficiency. This approach is based on drug encapsulation in drug delivery systems (DDSs) and/or their decoration with specific targeting moieties that are intended to enhance the drug/DDS accumulation in the intracellular organelle of interest. During recent years, there has been a constant increase in interest in DDSs targeted to specific intracellular organelles, and many different approaches have been proposed for attaining efficient drug delivery to specific organelles of interest. However, it appears that in many studies insufficient efforts have been devoted to quantitative analysis of the major formulation parameters of the DDSs disposition (efficiency of DDS endocytosis and endosomal escape, intracellular trafficking, and efficiency of DDS delivery to the target organelle) and of the resulting pharmacological effects. Thus, in many cases, claims regarding efficient delivery of drug/DDS to a specific organelle and efficient subcellular targeting appear to be exaggerated. On the basis of the available experimental data, it appears that drugs/DDS decoration with specific targeting residues can affect their intracellular fate and result in preferential drug accumulation within an organelle of interest. However, it is not clear whether these approaches will be efficient in in vivo settings and be translated into preclinical and clinical applications. Studies that quantitatively assess the mechanisms, barriers, and efficiencies of subcellular drug delivery and of the associated toxic effects are required to determine the therapeutic potential of subcellular DDS targeting.

Attribute amnesia reflects a lack of memory consolidation for attended information.

PubMed

Chen, Hui; Wyble, Brad

2016-02-01

A recently reported phenomenon, termed attribute amnesia, challenged the commonly held belief that attention plays the determining role in controlling how information is remembered, by showing that participants fail to remember a specific attended attribute (e.g., the target-defining color), even when they had just used that attribute to perform a task (Chen & Wyble, 2015a). The main purpose of the present study sought to better understand the mechanism underlying this phenomenon. The results revealed that attribute amnesia was nearly eliminated once participants were forced to store and hold attended information for a brief time, suggesting that this amnesia effect most likely reflects a lack of memory consolidation for an attended attribute that had been processed to some certain level. In addition, we demonstrated that the effect is not particular to the use of location report or the repetition of targets. One additional finding is that amnesia was markedly absent for location memory, indicating an important difference between memories for locations and attributes such as color or identity. (PsycINFO Database Record (c) 2016 APA, all rights reserved).

Modeling Patient-Specific Magnetic Drug Targeting Within the Intracranial Vasculature

PubMed Central

Patronis, Alexander; Richardson, Robin A.; Schmieschek, Sebastian; Wylie, Brian J. N.; Nash, Rupert W.; Coveney, Peter V.

2018-01-01

Drug targeting promises to substantially enhance future therapies, for example through the focussing of chemotherapeutic drugs at the site of a tumor, thus reducing the exposure of healthy tissue to unwanted damage. Promising work on the steering of medication in the human body employs magnetic fields acting on nanoparticles made of paramagnetic materials. We develop a computational tool to aid in the optimization of the physical parameters of these particles and the magnetic configuration, estimating the fraction of particles reaching a given target site in a large patient-specific vascular system for different physiological states (heart rate, cardiac output, etc.). We demonstrate the excellent computational performance of our model by its application to the simulation of paramagnetic-nanoparticle-laden flows in a circle of Willis geometry obtained from an MRI scan. The results suggest a strong dependence of the particle density at the target site on the strength of the magnetic forcing and the velocity of the background fluid flow. PMID:29725303

Modeling Patient-Specific Magnetic Drug Targeting Within the Intracranial Vasculature.

PubMed

Patronis, Alexander; Richardson, Robin A; Schmieschek, Sebastian; Wylie, Brian J N; Nash, Rupert W; Coveney, Peter V

2018-01-01

Drug targeting promises to substantially enhance future therapies, for example through the focussing of chemotherapeutic drugs at the site of a tumor, thus reducing the exposure of healthy tissue to unwanted damage. Promising work on the steering of medication in the human body employs magnetic fields acting on nanoparticles made of paramagnetic materials. We develop a computational tool to aid in the optimization of the physical parameters of these particles and the magnetic configuration, estimating the fraction of particles reaching a given target site in a large patient-specific vascular system for different physiological states (heart rate, cardiac output, etc.). We demonstrate the excellent computational performance of our model by its application to the simulation of paramagnetic-nanoparticle-laden flows in a circle of Willis geometry obtained from an MRI scan. The results suggest a strong dependence of the particle density at the target site on the strength of the magnetic forcing and the velocity of the background fluid flow.

A search for stratiform massive-sulfide exploration targets in Appalachian Devonian rocks; a case study using computer-assisted attribute-coincidence mapping

USGS Publications Warehouse

Wedow, Helmuth

1983-01-01

The empirical model for sediment-associated, stratiform, exhalative, massive-sulfide deposits presented by D. Large in 1979 and 1980 has been redesigned to permit its use in a computer-assisted search for exploration-target areas in Devonian rocks of the Appalachian region using attribute-coincidence mapping (ACM). Some 36 gridded-data maps and selected maps derived therefrom were developed to show the orthogonal patterns, using the 7-1/2 minute quadrangle as an information cell, of geologic data patterns relevant to the empirical model. From these map and data files, six attribute-coincidence maps were prepared to illustrate both variation in the application of ACM techniques and the extent of possible significant exploration-target areas. As a result of this preliminary work in ACM, four major (and some lesser) exploration-target areas needing further study and analysis have been defined as follows: 1) in western and central New York in the outcrop area of lowermost Upper Devonian rocks straddling the Clarendon-Linden fault; 2) in western Virginia and eastern West Virginia in an area largely coincident with the well-known 'Oriskany' Mn-Fe ores; 3) an area in West Virginia, Maryland, and Virginia along and nearby the trend of the Alabama-New York lineament of King and Zietz approximately between 38- and 40-degrees N. latitude; and 4) an area in northeastern Ohio overlying an area coincident with a significant thickness of Silurian salt and high modern seismic activity. Some lesser, smaller areas suggested by relatively high coincidence may also be worthy of further study.

Cell-type-specific, Aptamer-functionalized Agents for Targeted Disease Therapy

PubMed Central

Zhou, Jiehua; Rossi, John J.

2014-01-01

One hundred years ago, Dr. Paul Ehrlich popularized the “magic bullet” concept for cancer therapy in which an ideal therapeutic agent would only kill the specific tumor cells it targeted. Since then, “targeted therapy” that specifically targets the molecular defects responsible for a patient's condition has become a long-standing goal for treating human disease. However, safe and efficient drug delivery during the treatment of cancer and infectious disease remains a major challenge for clinical translation and the development of new therapies. The advent of SELEX technology has inspired many groundbreaking studies that successfully adapted cell-specific aptamers for targeted delivery of active drug substances in both in vitro and in vivo models. By covalently linking or physically functionalizing the cell-specific aptamers with therapeutic agents, such as siRNA, microRNA, chemotherapeutics or toxins, or delivery vehicles, such as organic or inorganic nanocarriers, the targeted cells and tissues can be specifically recognized and the therapeutic compounds internalized, thereby improving the local concentration of the drug and its therapeutic efficacy. Currently, many cell-type-specific aptamers have been developed that can target distinct diseases or tissues in a cell-type-specific manner. In this review, we discuss recent advances in the use of cell-specific aptamers for targeted disease therapy, as well as conjugation strategies and challenges. PMID:24936916

Applang - A DSL for specification of mobile applications for android platform based on textX

NASA Astrophysics Data System (ADS)

Kosanović, Milan; Dejanović, Igor; Milosavljević, Gordana

2016-06-01

Mobile platforms become a ubiquitous part of our daily lives thus making more pressure to software developers to develop more applications faster and with the support for different mobile operating systems. To foster the faster development of mobile services and applications and to support various mobile operating systems a new software development approaches must be undertaken. Domain-Specific Languages (DSL) are a viable approach that promise to solve a problem of target platform diversity as well as to facilitate rapid application development and shorter time-to-market. This paper presents Applang, a DSL for the specification of mobile applications for the Android platform, based on textX meta-language. The application is described using Applang DSL and the source code for a target platform is automatically generated by the provided code generator. The same application defined using single Applang source can be transformed to various targets with little or no manual modifications.

Numerical simulation of magnetic nano drug targeting in patient-specific lower respiratory tract

NASA Astrophysics Data System (ADS)

Russo, Flavia; Boghi, Andrea; Gori, Fabio

2018-04-01

Magnetic nano drug targeting, with an external magnetic field, can potentially improve the drug absorption in specific locations of the body. However, the effectiveness of the procedure can be reduced due to the limitations of the magnetic field intensity. This work investigates this technique with the Computational Fluid Dynamics (CFD) approach. A single rectangular coil generates the external magnetic field. A patient-specific geometry of the Trachea, with its primary and secondary bronchi, is reconstructed from Digital Imaging and Communications in Medicine (DICOM) formatted images, throughout the Vascular Modelling Tool Kit (VMTK) software. A solver, coupling the Lagrangian dynamics of the magnetic nanoparticles with the Eulerian dynamics of the air, is used to perform the simulations. The resistive pressure, the pulsatile inlet velocity and the rectangular coil magnetic field are the boundary conditions. The dynamics of the injected particles is investigated without and with the magnetic probe. The flow field promotes particles adhesion to the tracheal wall. The particles volumetric flow rate in both cases has been calculated. The magnetic probe is shown to increase the particles flow in the target region, but at a limited extent. This behavior has been attributed to the small particle size and the probe configuration.

PhytoCRISP-Ex: a web-based and stand-alone application to find specific target sequences for CRISPR/CAS editing.

PubMed

Rastogi, Achal; Murik, Omer; Bowler, Chris; Tirichine, Leila

2016-07-01

With the emerging interest in phytoplankton research, the need to establish genetic tools for the functional characterization of genes is indispensable. The CRISPR/Cas9 system is now well recognized as an efficient and accurate reverse genetic tool for genome editing. Several computational tools have been published allowing researchers to find candidate target sequences for the engineering of the CRISPR vectors, while searching possible off-targets for the predicted candidates. These tools provide built-in genome databases of common model organisms that are used for CRISPR target prediction. Although their predictions are highly sensitive, the applicability to non-model genomes, most notably protists, makes their design inadequate. This motivated us to design a new CRISPR target finding tool, PhytoCRISP-Ex. Our software offers CRIPSR target predictions using an extended list of phytoplankton genomes and also delivers a user-friendly standalone application that can be used for any genome. The software attempts to integrate, for the first time, most available phytoplankton genomes information and provide a web-based platform for Cas9 target prediction within them with high sensitivity. By offering a standalone version, PhytoCRISP-Ex maintains an independence to be used with any organism and widens its applicability in high throughput pipelines. PhytoCRISP-Ex out pars all the existing tools by computing the availability of restriction sites over the most probable Cas9 cleavage sites, which can be ideal for mutant screens. PhytoCRISP-Ex is a simple, fast and accurate web interface with 13 pre-indexed and presently updating phytoplankton genomes. The software was also designed as a UNIX-based standalone application that allows the user to search for target sequences in the genomes of a variety of other species.

Collagen like peptide bioconjugates for targeted drug delivery applications

NASA Astrophysics Data System (ADS)

Luo, Tianzhi

the coil/globule conformational transition of the PDEGMEMA building block above its LCST with stabilization of the nanostructures by the hydrophilic CLP. To the best of our knowledge, this is the first report on such assembled nanostructures from collagen-like peptide containing copolymers. Due to the strong propensity for CLPs to bind to natural collagen via strand invasion processes, these nanosized vesicles may be used as drug carriers for targeted delivery. In addition to synthetic polymers, the collagen like peptide is then conjugated with a thermoresponsive elastin-like peptide (ELP). The resulting ELP-CLP diblock conjugates show a remarkable reduction in the inverse transition temperature of the ELP domain, attributed to the anchoring effect of the CLP triple helix. The lower transition temperature of the conjugate enables facile formation of well-defined vesicles at physiological temperature and the unexpected resolubilization of the vesicles at elevated temperatures upon unfolding of the CLP domain. Given the ability of CLPs to modify collagens, this work provides not only a simple and versatile avenue for controlling the inverse transition behavior of elastin-like peptides, but also suggest future opportunities for these thermoresponsive nanostructures in biologically relevant environments. In the last section, the potential of using the ELP-CLP nanoparticles as drug delivery vehicles for targeting collagen containing matrices is evaluated. A sustained release of clinically relevant amount of encapsulated modelled drug is achieved within three weeks, followed by a thermally controlled burst release. As expected, the ELP-CLP nanoparticles show strong retention on collagen substrate, via specific binding through collagen triple helix hybridization. Additionally, cell viability and proliferation studies using fibroblasts and chondrocytes suggest the nanoparticles are non-cytotoxic. Additionally, almost no TNF-alpha expression from macrophages is observed

PEG-lipid micelles as drug carriers: physiochemical attributes, formulation principles and biological implication.

PubMed

Gill, Kanwaldeep K; Kaddoumi, Amal; Nazzal, Sami

2015-04-01

PEG-lipid micelles, primarily conjugates of polyethylene glycol (PEG) and distearyl phosphatidylethanolamine (DSPE) or PEG-DSPE, have emerged as promising drug-delivery carriers to address the shortcomings associated with new molecular entities with suboptimal biopharmaceutical attributes. The flexibility in PEG-DSPE design coupled with the simplicity of physical drug entrapment have distinguished PEG-lipid micelles as versatile and effective drug carriers for cancer therapy. They were shown to overcome several limitations of poorly soluble drugs such as non-specific biodistribution and targeting, lack of water solubility and poor oral bioavailability. Therefore, considerable efforts have been made to exploit the full potential of these delivery systems; to entrap poorly soluble drugs and target pathological sites both passively through the enhanced permeability and retention (EPR) effect and actively by linking the terminal PEG groups with targeting ligands, which were shown to increase delivery efficiency and tissue specificity. This article reviews the current state of PEG-lipid micelles as delivery carriers for poorly soluble drugs, their biological implications and recent developments in exploring their active targeting potential. In addition, this review sheds light on the physical properties of PEG-lipid micelles and their relevance to the inherent advantages and applications of PEG-lipid micelles for drug delivery.

Linker-free conjugation and specific cell targeting of antibody functionalized iron-oxide nanoparticles

PubMed Central

Xu, Yaolin; Baiu, Dana C.; Sherwood, Jennifer A.; McElreath, Meghan R.; Qin, Ying; Lackey, Kimberly H.; Otto, Mario; Bao, Yuping

2015-01-01

Specific targeting is a key step to realize the full potential of iron oxide nanoparticles in biomedical applications, especially tumor-associated diagnosis and therapy. Here, we developed anti-GD2 antibody conjugated iron oxide nanoparticles for highly efficient neuroblastoma cell targeting. The antibody conjugation was achieved through an easy, linker-free method based on catechol reactions. The targeting efficiency and specificity of the antibody-conjugated nanoparticles to GD2-positive neuroblastoma cells were confirmed by flow cytometry, fluorescence microscopy, Prussian blue staining and transmission electron microscopy. These detailed studies indicated that the receptor-recognition capability of the antibody was fully retained after conjugation and the conjugated nanoparticles quickly attached to GD2-positive cells within four hours. Interestingly, longer treatment (12 h) led the cell membrane-bound nanoparticles to be internalized into cytosol, either by directly penetrating the cell membrane or escaping from the endosomes. Last but importantly, the uniquely designed functional surfaces of the nanoparticles allow easy conjugation of other bioactive molecules. PMID:26660881

PEGylated and targeted extracellular vesicles display enhanced cell specificity and circulation time.

PubMed

Kooijmans, S A A; Fliervoet, L A L; van der Meel, R; Fens, M H A M; Heijnen, H F G; van Bergen En Henegouwen, P M P; Vader, P; Schiffelers, R M

2016-02-28

Extracellular vesicles (EVs) are increasingly being recognized as candidate drug delivery systems due to their ability to functionally transfer biological cargo between cells. However, the therapeutic applicability of EVs may be limited due to a lack of cell-targeting specificity and rapid clearance of exogenous EVs from the circulation. In order to improve EV characteristics for drug delivery to tumor cells, we have developed a novel method for decorating EVs with targeting ligands conjugated to polyethylene glycol (PEG). Nanobodies specific for the epidermal growth factor receptor (EGFR) were conjugated to phospholipid (DMPE)-PEG derivatives to prepare nanobody-PEG-micelles. When micelles were mixed with EVs derived from Neuro2A cells or platelets, a temperature-dependent transfer of nanobody-PEG-lipids to the EV membranes was observed, indicative of a 'post-insertion' mechanism. This process did not affect EV morphology, size distribution, or protein composition. After introduction of PEG-conjugated control nanobodies to EVs, cellular binding was compromised due to the shielding properties of PEG. However, specific binding to EGFR-overexpressing tumor cells was dramatically increased when EGFR-specific nanobodies were employed. Moreover, whereas unmodified EVs were rapidly cleared from the circulation within 10min after intravenous injection in mice, EVs modified with nanobody-PEG-lipids were still detectable in plasma for longer than 60min post-injection. In conclusion, we propose post-insertion as a novel technique to confer targeting capacity to isolated EVs, circumventing the requirement to modify EV-secreting cells. Importantly, insertion of ligand-conjugated PEG-derivatized phospholipids in EV membranes equips EVs with improved cell specificity and prolonged circulation times, potentially increasing EV accumulation in targeted tissues and improving cargo delivery. Copyright © 2015. Published by Elsevier B.V.

Application of Mutated miR-206 Target Sites Enables Skeletal Muscle-specific Silencing of Transgene Expression of Cardiotropic AAV9 Vectors

PubMed Central

Geisler, Anja; Schön, Christian; Größl, Tobias; Pinkert, Sandra; Stein, Elisabeth A; Kurreck, Jens; Vetter, Roland; Fechner, Henry

2013-01-01

Insertion of completely complementary microRNA (miR) target sites (miRTS) into a transgene has been shown to be a valuable approach to specifically repress transgene expression in non-targeted tissues. miR-122TS have been successfully used to silence transgene expression in the liver following systemic application of cardiotropic adeno-associated virus (AAV) 9 vectors. For miR-206–mediated skeletal muscle-specific silencing of miR-206TS–bearing AAV9 vectors, however, we found this approach failed due to the expression of another member (miR-1) of the same miR family in heart tissue, the intended target. We introduced single-nucleotide substitutions into the miR-206TS and searched for those which prevented miR-1–mediated cardiac repression. Several mutated miR-206TS (m206TS), in particular m206TS-3G, were resistant to miR-1, but remained fully sensitive to miR-206. All these variants had mismatches in the seed region of the miR/m206TS duplex in common. Furthermore, we found that some m206TS, containing mismatches within the seed region or within the 3′ portion of the miR-206, even enhanced the miR-206– mediated transgene repression. In vivo expression of m206TS-3G– and miR-122TS–containing transgene of systemically applied AAV9 vectors was strongly repressed in both skeletal muscle and the liver but remained high in the heart. Thus, site-directed mutagenesis of miRTS provides a new strategy to differentiate transgene de-targeting of related miRs. PMID:23439498

Literature-based condition-specific miRNA-mRNA target prediction.

PubMed

Oh, Minsik; Rhee, Sungmin; Moon, Ji Hwan; Chae, Heejoon; Lee, Sunwon; Kang, Jaewoo; Kim, Sun

2017-01-01

miRNAs are small non-coding RNAs that regulate gene expression by binding to the 3'-UTR of genes. Many recent studies have reported that miRNAs play important biological roles by regulating specific mRNAs or genes. Many sequence-based target prediction algorithms have been developed to predict miRNA targets. However, these methods are not designed for condition-specific target predictions and produce many false positives; thus, expression-based target prediction algorithms have been developed for condition-specific target predictions. A typical strategy to utilize expression data is to leverage the negative control roles of miRNAs on genes. To control false positives, a stringent cutoff value is typically set, but in this case, these methods tend to reject many true target relationships, i.e., false negatives. To overcome these limitations, additional information should be utilized. The literature is probably the best resource that we can utilize. Recent literature mining systems compile millions of articles with experiments designed for specific biological questions, and the systems provide a function to search for specific information. To utilize the literature information, we used a literature mining system, BEST, that automatically extracts information from the literature in PubMed and that allows the user to perform searches of the literature with any English words. By integrating omics data analysis methods and BEST, we developed Context-MMIA, a miRNA-mRNA target prediction method that combines expression data analysis results and the literature information extracted based on the user-specified context. In the pathway enrichment analysis using genes included in the top 200 miRNA-targets, Context-MMIA outperformed the four existing target prediction methods that we tested. In another test on whether prediction methods can re-produce experimentally validated target relationships, Context-MMIA outperformed the four existing target prediction methods. In summary

Culture, attribution and automaticity: a social cognitive neuroscience view

PubMed Central

Morris, Michael W.

2010-01-01

A fundamental challenge facing social perceivers is identifying the cause underlying other people’s behavior. Evidence indicates that East Asian perceivers are more likely than Western perceivers to reference the social context when attributing a cause to a target person’s actions. One outstanding question is whether this reflects a culture’s influence on automatic or on controlled components of causal attribution. After reviewing behavioral evidence that culture can shape automatic mental processes as well as controlled reasoning, we discuss the evidence in favor of cultural differences in automatic and controlled components of causal attribution more specifically. We contend that insights emerging from social cognitive neuroscience research can inform this debate. After introducing an attribution framework popular among social neuroscientists, we consider findings relevant to the automaticity of attribution, before speculating how one could use a social neuroscience approach to clarify whether culture affects automatic, controlled or both types of attribution processes. PMID:20460302

Chemical probes targeting epigenetic proteins: Applications beyond oncology

PubMed Central

Ackloo, Suzanne; Brown, Peter J.; Müller, Susanne

2017-01-01

ABSTRACT Epigenetic chemical probes are potent, cell-active, small molecule inhibitors or antagonists of specific domains in a protein; they have been indispensable for studying bromodomains and protein methyltransferases. The Structural Genomics Consortium (SGC), comprising scientists from academic and pharmaceutical laboratories, has generated most of the current epigenetic chemical probes. Moreover, the SGC has shared about 4 thousand aliquots of these probes, which have been used primarily for phenotypic profiling or to validate targets in cell lines or primary patient samples cultured in vitro. Epigenetic chemical probes have been critical tools in oncology research and have uncovered mechanistic insights into well-established targets, as well as identify new therapeutic starting points. Indeed, the literature primarily links epigenetic proteins to oncology, but applications in inflammation, viral, metabolic and neurodegenerative diseases are now being reported. We summarize the literature of these emerging applications and provide examples where existing probes might be used. PMID:28080202

Vector design for liver specific expression of multiple interfering RNAs that target hepatitis B virus transcripts

PubMed Central

Snyder, Lindsey L.; Esser, Jonathan M.; Pachuk, Catherine J.; Steel, Laura F.

2008-01-01

RNA interference (RNAi) is a process that can target intracellular RNAs for degradation in a highly sequence specific manner, making it a powerful tool that is being pursued in both research and therapeutic applications. Hepatitis B virus (HBV) is a serious public health problem in need of better treatment options, and aspects of its life cycle make it an excellent target for RNAi-based therapeutics. We have designed a vector that expresses interfering RNAs that target HBV transcripts, including both viral RNA replicative intermediates and mRNAs encoding viral proteins. Our vector design incorporates many features of endogenous microRNA (miRNA) gene organization that are proving useful for the development of reagents for RNAi. In particular, our vector contains an RNA pol II driven gene cassette that leads to tissue specific expression and efficient processing of multiple interfering RNAs from a single transcript, without the co-expression of any protein product. This vector shows potent silencing of HBV targets in cell culture models of HBV infection. The vector design will be applicable to silencing of additional cellular or disease-related genes. PMID:18499277

Improving sensitivity and specificity of capturing and detecting targeted cancer cells with anti-biofouling polymer coated magnetic iron oxide nanoparticles.

PubMed

Lin, Run; Li, Yuancheng; MacDonald, Tobey; Wu, Hui; Provenzale, James; Peng, Xingui; Huang, Jing; Wang, Liya; Wang, Andrew Y; Yang, Jianyong; Mao, Hui

2017-02-01

Detecting circulating tumor cells (CTCs) with high sensitivity and specificity is critical to management of metastatic cancers. Although immuno-magnetic technology for in vitro detection of CTCs has shown promising potential for clinical applications, the biofouling effect, i.e., non-specific adhesion of biomolecules and non-cancerous cells in complex biological samples to the surface of a device/probe, can reduce the sensitivity and specificity of cell detection. Reported herein is the application of anti-biofouling polyethylene glycol-block-allyl glycidyl ether copolymer (PEG-b-AGE) coated iron oxide nanoparticles (IONPs) to improve the separation of targeted tumor cells from aqueous phase in an external magnetic field. PEG-b-AGE coated IONPs conjugated with transferrin (Tf) exhibited significant anti-biofouling properties against non-specific protein adsorption and off-target cell uptake, thus substantially enhancing the ability to target and separate transferrin receptor (TfR) over-expressed D556 medulloblastoma cells. Tf conjugated PEG-b-AGE coated IONPs exhibited a high capture rate of targeted tumor cells (D556 medulloblastoma cell) in cell media (58.7±6.4%) when separating 100 targeted tumor cells from 1×10 5 non-targeted cells and 41 targeted tumor cells from 100 D556 medulloblastoma cells spiked into 1mL blood. It is demonstrated that developed nanoparticle has higher efficiency in capturing targeted cells than widely used micron-sized particles (i.e., Dynabeads ® ). Copyright © 2016 Elsevier B.V. All rights reserved.

A tribal abstraction network for SNOMED CT target hierarchies without attribute relationships.

PubMed

Ochs, Christopher; Geller, James; Perl, Yehoshua; Chen, Yan; Agrawal, Ankur; Case, James T; Hripcsak, George

2015-05-01

Large and complex terminologies, such as Systematized Nomenclature of Medicine-Clinical Terms (SNOMED CT), are prone to errors and inconsistencies. Abstraction networks are compact summarizations of the content and structure of a terminology. Abstraction networks have been shown to support terminology quality assurance. In this paper, we introduce an abstraction network derivation methodology which can be applied to SNOMED CT target hierarchies whose classes are defined using only hierarchical relationships (ie, without attribute relationships) and similar description-logic-based terminologies. We introduce the tribal abstraction network (TAN), based on the notion of a tribe-a subhierarchy rooted at a child of a hierarchy root, assuming only the existence of concepts with multiple parents. The TAN summarizes a hierarchy that does not have attribute relationships using sets of concepts, called tribal units that belong to exactly the same multiple tribes. Tribal units are further divided into refined tribal units which contain closely related concepts. A quality assurance methodology that utilizes TAN summarizations is introduced. A TAN is derived for the Observable entity hierarchy of SNOMED CT, summarizing its content. A TAN-based quality assurance review of the concepts of the hierarchy is performed, and erroneous concepts are shown to appear more frequently in large refined tribal units than in small refined tribal units. Furthermore, more erroneous concepts appear in large refined tribal units of more tribes than of fewer tribes. In this paper we introduce the TAN for summarizing SNOMED CT target hierarchies. A TAN was derived for the Observable entity hierarchy of SNOMED CT. A quality assurance methodology utilizing the TAN was introduced and demonstrated. © The Author 2014. Published by Oxford University Press on behalf of the American Medical Informatics Association. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Enriching the national map database for multi-scale use: Introducing the visibilityfilter attribution

USGS Publications Warehouse

Stauffer, Andrew J.; Webinger, Seth; Roche, Brittany

2016-01-01

The US Geological Survey’s (USGS) National Geospatial Technical Operations Center is prototyping and evaluating the ability to filter data through a range of scales using 1:24,000-scale The National Map (TNM) datasets as the source. A “VisibilityFilter” attribute is under evaluation that can be added to all TNM vector data themes and will permit filtering of data to eight target scales between 1:24,000 and 1:5,000,000, thus defining each feature’s smallest applicable scale-of-use. For a prototype implementation, map specifications for 1:100,000- and 1:250,000-scale USGS Topographic Map Series are being utilized to define feature content appropriate at fixed mapping scales to guide generalization decisions that are documented in a ScaleMaster diagram. This paper defines the VisibilityFilter attribute, the generalization decisions made for each TNM data theme, and how these decisions are embedded into the data to support efficient data filtering.

Target specific compound identification using a support vector machine.

PubMed

Plewczynski, Dariusz; von Grotthuss, Marcin; Spieser, Stephane A H; Rychlewski, Leszek; Wyrwicz, Lucjan S; Ginalski, Krzysztof; Koch, Uwe

2007-03-01

In many cases at the beginning of an HTS-campaign, some information about active molecules is already available. Often known active compounds (such as substrate analogues, natural products, inhibitors of a related protein or ligands published by a pharmaceutical company) are identified in low-throughput validation studies of the biochemical target. In this study we evaluate the effectiveness of a support vector machine applied for those compounds and used to classify a collection with unknown activity. This approach was aimed at reducing the number of compounds to be tested against the given target. Our method predicts the biological activity of chemical compounds based on only the atom pairs (AP) two dimensional topological descriptors. The supervised support vector machine (SVM) method herein is trained on compounds from the MDL drug data report (MDDR) known to be active for specific protein target. For detailed analysis, five different biological targets were selected including cyclooxygenase-2, dihydrofolate reductase, thrombin, HIV-reverse transcriptase and antagonists of the estrogen receptor. The accuracy of compound identification was estimated using the recall and precision values. The sensitivities for all protein targets exceeded 80% and the classification performance reached 100% for selected targets. In another application of the method, we addressed the absence of an initial set of active compounds for a selected protein target at the beginning of an HTS-campaign. In such a case, virtual high-throughput screening (vHTS) is usually applied by using a flexible docking procedure. However, the vHTS experiment typically contains a large percentage of false positives that should be verified by costly and time-consuming experimental follow-up assays. The subsequent use of our machine learning method was found to improve the speed (since the docking procedure was not required for all compounds from the database) and also the accuracy of the HTS hit lists (the

Applications of CRISPR/Cas9 technology for targeted mutagenesis, gene replacement and stacking of genes in higher plants.

PubMed

Luo, Ming; Gilbert, Brian; Ayliffe, Michael

2016-07-01

Mutagenesis continues to play an essential role for understanding plant gene function and, in some instances, provides an opportunity for plant improvement. The development of gene editing technologies such as TALENs and zinc fingers has revolutionised the targeted mutation specificity that can now be achieved. The CRISPR/Cas9 system is the most recent addition to gene editing technologies and arguably the simplest requiring only two components; a small guide RNA molecule (sgRNA) and Cas9 endonuclease protein which complex to recognise and cleave a specific 20 bp target site present in a genome. Target specificity is determined by complementary base pairing between the sgRNA and target site sequence enabling highly specific, targeted mutation to be readily engineered. Upon target site cleavage, error-prone endogenous repair mechanisms produce small insertion/deletions at the target site usually resulting in loss of gene function. CRISPR/Cas9 gene editing has been rapidly adopted in plants and successfully undertaken in numerous species including major crop species. Its applications are not restricted to mutagenesis and target site cleavage can be exploited to promote sequence insertion or replacement by recombination. The multiple applications of this technology in plants are described.

Attribution of global foodborne disease to specific foods: Findings from a World Health Organization structured expert elicitation.

PubMed

Hoffmann, Sandra; Devleesschauwer, Brecht; Aspinall, Willy; Cooke, Roger; Corrigan, Tim; Havelaar, Arie; Angulo, Frederick; Gibb, Herman; Kirk, Martyn; Lake, Robin; Speybroeck, Niko; Torgerson, Paul; Hald, Tine

2017-01-01

Recently the World Health Organization, Foodborne Disease Burden Epidemiology Reference Group (FERG) estimated that 31 foodborne diseases (FBDs) resulted in over 600 million illnesses and 420,000 deaths worldwide in 2010. Knowing the relative role importance of different foods as exposure routes for key hazards is critical to preventing illness. This study reports the findings of a structured expert elicitation providing globally comparable food source attribution estimates for 11 major FBDs in each of 14 world subregions. We used Cooke's Classical Model to elicit and aggregate judgments of 73 international experts. Judgments were elicited from each expert individually and aggregated using both equal and performance weights. Performance weighted results are reported as they increased the informativeness of estimates, while retaining accuracy. We report measures of central tendency and uncertainty bounds on food source attribution estimate. For some pathogens we see relatively consistent food source attribution estimates across subregions of the world; for others there is substantial regional variation. For example, for non-typhoidal salmonellosis, pork was of minor importance compared to eggs and poultry meat in the American and African subregions, whereas in the European and Western Pacific subregions the importance of these three food sources were quite similar. Our regional results broadly agree with estimates from earlier European and North American food source attribution research. As in prior food source attribution research, we find relatively wide uncertainty bounds around our median estimates. We present the first worldwide estimates of the proportion of specific foodborne diseases attributable to specific food exposure routes. While we find substantial uncertainty around central tendency estimates, we believe these estimates provide the best currently available basis on which to link FBDs and specific foods in many parts of the world, providing guidance

Attribution of global foodborne disease to specific foods: Findings from a World Health Organization structured expert elicitation

PubMed Central

Devleesschauwer, Brecht; Aspinall, Willy; Cooke, Roger; Corrigan, Tim; Havelaar, Arie; Angulo, Frederick; Gibb, Herman; Kirk, Martyn; Lake, Robin; Speybroeck, Niko; Torgerson, Paul; Hald, Tine

2017-01-01

Background Recently the World Health Organization, Foodborne Disease Burden Epidemiology Reference Group (FERG) estimated that 31 foodborne diseases (FBDs) resulted in over 600 million illnesses and 420,000 deaths worldwide in 2010. Knowing the relative role importance of different foods as exposure routes for key hazards is critical to preventing illness. This study reports the findings of a structured expert elicitation providing globally comparable food source attribution estimates for 11 major FBDs in each of 14 world subregions. Methods and findings We used Cooke’s Classical Model to elicit and aggregate judgments of 73 international experts. Judgments were elicited from each expert individually and aggregated using both equal and performance weights. Performance weighted results are reported as they increased the informativeness of estimates, while retaining accuracy. We report measures of central tendency and uncertainty bounds on food source attribution estimate. For some pathogens we see relatively consistent food source attribution estimates across subregions of the world; for others there is substantial regional variation. For example, for non-typhoidal salmonellosis, pork was of minor importance compared to eggs and poultry meat in the American and African subregions, whereas in the European and Western Pacific subregions the importance of these three food sources were quite similar. Our regional results broadly agree with estimates from earlier European and North American food source attribution research. As in prior food source attribution research, we find relatively wide uncertainty bounds around our median estimates. Conclusions We present the first worldwide estimates of the proportion of specific foodborne diseases attributable to specific food exposure routes. While we find substantial uncertainty around central tendency estimates, we believe these estimates provide the best currently available basis on which to link FBDs and specific foods in

Spatial variation in attributable risks.

PubMed

Congdon, Peter

2015-01-01

The attributable risk (AR) measures the contribution of a particular risk factor to a disease, and allows estimation of disease rates specific to that risk. While previous studies consider variability in ARs over demographic categories, this paper considers the extent of spatial variability in ARs estimated from multilevel data with confounders both at individual and geographic levels. A case study considers the AR for diabetes in relation to elevated BMI, and area rates for diabetes attributable to excess weight. Contextual adjustment includes known area variables, and unobserved spatially clustered influences, while spatial heterogeneity (effect modification) is considered in terms of varying effects of elevated BMI by neighbourhood deprivation category. The application is to patient register data in London, with clear evidence of spatial variation in ARs, and in small area diabetes rates attributable to excess weight. Copyright © 2015 Elsevier Ltd. All rights reserved.

Engineering RNA for Targeted siRNA Delivery and Medical Application

PubMed Central

Guo, Peixuan; Coban, Oana; Snead, Nick; Trebley, Joe; Hoeprich, Steve; Guo, Songchuan; Shu, Yi

2010-01-01

RNA engineering for nanotechnology and medical applications is an exciting emerging research field. RNA has intrinsically defined features on the nanometer scale and is a particularly interesting candidate for such applications due to its amazing diversity, flexibility and versatility in structure and function. Specifically, the current use of siRNA to silence target genes involved in disease has generated much excitement in the scientific community. The intrinsic ability to sequence-specifically down-regulate gene expression in a temporally- and spatially-controlled fashion has led to heightened interest and rapid development of siRNA-based therapeutics. Though methods for gene silencing with high efficacy and specificity have been achieved in vitro, the effective delivery of nucleic acids to specific cells in vivo has been a hurdle for RNA therapeutics. This review covers different RNA-based approaches for diagnosis, prevention and treatment of human disease, with a focus on the latest developments of nonviral carriers of siRNA for delivery in vivo. The applications and challenges of siRNA therapy, as well as potential solutions to these problems, the approaches for using phi29 pRNA-based vectors as polyvalent vehicles for specific delivery of siRNA, ribozymes, drugs or other therapeutic agents to specific cells for therapy will also be addressed. PMID:20230868

A comparative analysis of user preference-based and existing knowledge management systems attributes in the aerospace industry

NASA Astrophysics Data System (ADS)

Varghese, Nishad G.

Knowledge management (KM) exists in various forms throughout organizations. Process documentation, training courses, and experience sharing are examples of KM activities performed daily. The goal of KM systems (KMS) is to provide a tool set which serves to standardize the creation, sharing, and acquisition of business critical information. Existing literature provides numerous examples of targeted evaluations of KMS, focusing on specific system attributes. This research serves to bridge the targeted evaluations with an industry-specific, holistic approach. The user preferences of aerospace employees in engineering and engineering-related fields were compared to profiles of existing aerospace KMS based on three attribute categories: technical features, system administration, and user experience. The results indicated there is a statistically significant difference between aerospace user preferences and existing profiles in the user experience attribute category, but no statistically significant difference in the technical features and system administration attribute categories. Additional analysis indicated in-house developed systems exhibit higher technical features and user experience ratings than commercial-off-the-self (COTS) systems.

Semantic attributes for people's appearance description: an appearance modality for video surveillance applications

NASA Astrophysics Data System (ADS)

Frikha, Mayssa; Fendri, Emna; Hammami, Mohamed

2017-09-01

Using semantic attributes such as gender, clothes, and accessories to describe people's appearance is an appealing modeling method for video surveillance applications. We proposed a midlevel appearance signature based on extracting a list of nameable semantic attributes describing the body in uncontrolled acquisition conditions. Conventional approaches extract the same set of low-level features to learn the semantic classifiers uniformly. Their critical limitation is the inability to capture the dominant visual characteristics for each trait separately. The proposed approach consists of extracting low-level features in an attribute-adaptive way by automatically selecting the most relevant features for each attribute separately. Furthermore, relying on a small training-dataset would easily lead to poor performance due to the large intraclass and interclass variations. We annotated large scale people images collected from different person reidentification benchmarks covering a large attribute sample and reflecting the challenges of uncontrolled acquisition conditions. These annotations were gathered into an appearance semantic attribute dataset that contains 3590 images annotated with 14 attributes. Various experiments prove that carefully designed features for learning the visual characteristics for an attribute provide an improvement of the correct classification accuracy and a reduction of both spatial and temporal complexities against state-of-the-art approaches.

In Vitro Targeted Photodynamic Therapy with a Pyropheophorbide-a Conjugated Inhibitor of Prostate Specific Membrane Antigen

PubMed Central

Liu, Tiancheng; Wu, Lisa Y.; Choi, Joseph K.; Berkman, Clifford E.

2009-01-01

BACKROUND The lack of specific delivery of photosensitizers (PSs), represents a significant limitation of photodynamic therapy (PDT) of cancer. The biomarker prostate-specific membrane antigen (PSMA) has attracted considerable attention as a target for imaging and therapeutic applications for prostate cancer. Although recent efforts have been made to conjugate inhibitors of PSMA with imaging agents, there have been no reports on photosensitizer-conjugated PSMA inhibitors for targeted PDT of prostate cancer. The present study focuses on the use of a PSMA inhibitor-conjugate of pyropheophorbide-a (Ppa-conjugate 2) for targeted PDT to achieve apoptosis in PSMA+ LNCaP cells. METHODS Confocal laser scanning microscopy with a combination of nuclear staining and immunofluorescence methods were employed to monitor the specific imaging and PDT-mediated apoptotic effects on PSMA-positive LNCaP and PSMA-negative (PC-3) cells. RESULTS Our results demonstrated that PDT-mediated effects by Ppa-conjugate 2 were specific to LNCaP cells, but not PC-3 cells. Cell permeability was detected as early as 2 h by HOE33342/PI double-staining, becoming more intense by 4 h. Evidence for the apoptotic caspase cascade being activated was based on the appearance of PARP p85 fragment. TUNEL assay detected DNA fragmentation 16 h post-PDT, confirming apoptotic events. CONCLUSIONS Cell permeability by HOE33342/PI double-staining as well as PARP p85 fragment and TUNEL assays confirm cellular apoptosis in PSMA+ cells when treated with PS-inhibitor conjugate 2 and subsequently irradiated. It is expected that the PSMA targeting small-molecule of this conjugate can serve as a delivery vehicle for PDT and other therapeutic applications for prostate cancer. PMID:19142895

Differences in DNA Binding Specificity of Floral Homeotic Protein Complexes Predict Organ-Specific Target Genes.

PubMed

Smaczniak, Cezary; Muiño, Jose M; Chen, Dijun; Angenent, Gerco C; Kaufmann, Kerstin

2017-08-01

Floral organ identities in plants are specified by the combinatorial action of homeotic master regulatory transcription factors. However, how these factors achieve their regulatory specificities is still largely unclear. Genome-wide in vivo DNA binding data show that homeotic MADS domain proteins recognize partly distinct genomic regions, suggesting that DNA binding specificity contributes to functional differences of homeotic protein complexes. We used in vitro systematic evolution of ligands by exponential enrichment followed by high-throughput DNA sequencing (SELEX-seq) on several floral MADS domain protein homo- and heterodimers to measure their DNA binding specificities. We show that specification of reproductive organs is associated with distinct binding preferences of a complex formed by SEPALLATA3 and AGAMOUS. Binding specificity is further modulated by different binding site spacing preferences. Combination of SELEX-seq and genome-wide DNA binding data allows differentiation between targets in specification of reproductive versus perianth organs in the flower. We validate the importance of DNA binding specificity for organ-specific gene regulation by modulating promoter activity through targeted mutagenesis. Our study shows that intrafamily protein interactions affect DNA binding specificity of floral MADS domain proteins. Differential DNA binding of MADS domain protein complexes plays a role in the specificity of target gene regulation. © 2017 American Society of Plant Biologists. All rights reserved.

TargetMiner: microRNA target prediction with systematic identification of tissue-specific negative examples.

PubMed

Bandyopadhyay, Sanghamitra; Mitra, Ramkrishna

2009-10-15

Prediction of microRNA (miRNA) target mRNAs using machine learning approaches is an important area of research. However, most of the methods suffer from either high false positive or false negative rates. One reason for this is the marked deficiency of negative examples or miRNA non-target pairs. Systematic identification of non-target mRNAs is still not addressed properly, and therefore, current machine learning approaches are compelled to rely on artificially generated negative examples for training. In this article, we have identified approximately 300 tissue-specific negative examples using a novel approach that involves expression profiling of both miRNAs and mRNAs, miRNA-mRNA structural interactions and seed-site conservation. The newly generated negative examples are validated with pSILAC dataset, which elucidate the fact that the identified non-targets are indeed non-targets.These high-throughput tissue-specific negative examples and a set of experimentally verified positive examples are then used to build a system called TargetMiner, a support vector machine (SVM)-based classifier. In addition to assessing the prediction accuracy on cross-validation experiments, TargetMiner has been validated with a completely independent experimental test dataset. Our method outperforms 10 existing target prediction algorithms and provides a good balance between sensitivity and specificity that is not reflected in the existing methods. We achieve a significantly higher sensitivity and specificity of 69% and 67.8% based on a pool of 90 feature set and 76.5% and 66.1% using a set of 30 selected feature set on the completely independent test dataset. In order to establish the effectiveness of the systematically generated negative examples, the SVM is trained using a different set of negative data generated using the method in Yousef et al. A significantly higher false positive rate (70.6%) is observed when tested on the independent set, while all other factors are kept the

Attributional processes in the learned helplessness paradigm: behavioral effects of global attributions.

PubMed

Mikulincer, M

1986-12-01

Following the learned helplessness paradigm, I assessed in this study the effects of global and specific attributions for failure on the generalization of performance deficits in a dissimilar situation. Helplessness training consisted of experience with noncontingent failures on four cognitive discrimination problems attributed to either global or specific causes. Experiment 1 found that performance in a dissimilar situation was impaired following exposure to globally attributed failure. Experiment 2 examined the behavioral effects of the interaction between stable and global attributions of failure. Exposure to unsolvable problems resulted in reduced performance in a dissimilar situation only when failure was attributed to global and stable causes. Finally, Experiment 3 found that learned helplessness deficits were a product of the interaction of global and internal attribution. Performance deficits following unsolvable problems were recorded when failure was attributed to global and internal causes. Results were discussed in terms of the reformulated learned helplessness model.

A systematic review of ecological attributes that confer resilience to climate change in environmental restoration

PubMed Central

Timpane-Padgham, Britta L.

2017-01-01

Ecological restoration is widely practiced as a means of rehabilitating ecosystems and habitats that have been degraded or impaired through human use or other causes. Restoration practices now are confronted by climate change, which has the potential to influence long-term restoration outcomes. Concepts and attributes from the resilience literature can help improve restoration and monitoring efforts under changing climate conditions. We systematically examined the published literature on ecological resilience to identify biological, chemical, and physical attributes that confer resilience to climate change. We identified 45 attributes explicitly related to climate change and classified them as individual- (9), population- (6), community- (7), ecosystem- (7), or process-level attributes (16). Individual studies defined resilience as resistance to change or recovery from disturbance, and only a few studies explicitly included both concepts in their definition of resilience. We found that individual and population attributes generally are suited to species- or habitat-specific restoration actions and applicable at the population scale. Community attributes are better suited to habitat-specific restoration at the site scale, or system-wide restoration at the ecosystem scale. Ecosystem and process attributes vary considerably in their type and applicability. We summarize these relationships in a decision support table and provide three example applications to illustrate how these classifications can be used to prioritize climate change resilience attributes for specific restoration actions. We suggest that (1) including resilience as an explicit planning objective could increase the success of restoration projects, (2) considering the ecological context and focal scale of a restoration action is essential in choosing appropriate resilience attributes, and (3) certain ecological attributes, such as diversity and connectivity, are more commonly considered to confer

A systematic review of ecological attributes that confer resilience to climate change in environmental restoration.

PubMed

Timpane-Padgham, Britta L; Beechie, Tim; Klinger, Terrie

2017-01-01

Ecological restoration is widely practiced as a means of rehabilitating ecosystems and habitats that have been degraded or impaired through human use or other causes. Restoration practices now are confronted by climate change, which has the potential to influence long-term restoration outcomes. Concepts and attributes from the resilience literature can help improve restoration and monitoring efforts under changing climate conditions. We systematically examined the published literature on ecological resilience to identify biological, chemical, and physical attributes that confer resilience to climate change. We identified 45 attributes explicitly related to climate change and classified them as individual- (9), population- (6), community- (7), ecosystem- (7), or process-level attributes (16). Individual studies defined resilience as resistance to change or recovery from disturbance, and only a few studies explicitly included both concepts in their definition of resilience. We found that individual and population attributes generally are suited to species- or habitat-specific restoration actions and applicable at the population scale. Community attributes are better suited to habitat-specific restoration at the site scale, or system-wide restoration at the ecosystem scale. Ecosystem and process attributes vary considerably in their type and applicability. We summarize these relationships in a decision support table and provide three example applications to illustrate how these classifications can be used to prioritize climate change resilience attributes for specific restoration actions. We suggest that (1) including resilience as an explicit planning objective could increase the success of restoration projects, (2) considering the ecological context and focal scale of a restoration action is essential in choosing appropriate resilience attributes, and (3) certain ecological attributes, such as diversity and connectivity, are more commonly considered to confer

Growing Fixed With Age: Lay Theories of Malleability Are Target Age-Specific.

PubMed

Neel, Rebecca; Lassetter, Bethany

2015-11-01

Beliefs about whether people can change ("lay theories" of malleability) are known to have wide-ranging effects on social motivation, cognition, and judgment. Yet rather than holding an overarching belief that people can or cannot change, perceivers may hold independent beliefs about whether different people are malleable-that is, lay theories may be target-specific. Seven studies demonstrate that lay theories are target-specific with respect to age: Perceivers hold distinct, uncorrelated lay theories of people at different ages, and younger targets are considered to be more malleable than older targets. Both forms of target-specificity are consequential, as target age-specific lay theories predict policy support for learning-based senior services and the rehabilitation of old and young drug users. The implications of target age-specific lay theories for a number of psychological processes, the social psychology of aging, and theoretical frameworks of malleability beliefs are discussed. © 2015 by the Society for Personality and Social Psychology, Inc.

Engineering of a target site-specific recombinase by a combined evolution- and structure-guided approach

PubMed Central

Abi-Ghanem, Josephine; Chusainow, Janet; Karimova, Madina; Spiegel, Christopher; Hofmann-Sieber, Helga; Hauber, Joachim; Buchholz, Frank; Pisabarro, M. Teresa

2013-01-01

Site-specific recombinases (SSRs) can perform DNA rearrangements, including deletions, inversions and translocations when their naive target sequences are placed strategically into the genome of an organism. Hence, in order to employ SSRs in heterologous hosts, their target sites have to be introduced into the genome of an organism before the enzyme can be practically employed. Engineered SSRs hold great promise for biotechnology and advanced biomedical applications, as they promise to extend the usefulness of SSRs to allow efficient and specific recombination of pre-existing, natural genomic sequences. However, the generation of enzymes with desired properties remains challenging. Here, we use substrate-linked directed evolution in combination with molecular modeling to rationally engineer an efficient and specific recombinase (sTre) that readily and specifically recombines a sequence present in the HIV-1 genome. We elucidate the role of key residues implicated in the molecular recognition mechanism and we present a rationale for sTre’s enhanced specificity. Combining evolutionary and rational approaches should help in accelerating the generation of enzymes with desired properties for use in biotechnology and biomedicine. PMID:23275541

High capacity hydrogen storage materials: attributes for automotive applications and techniques for materials discovery.

PubMed

Yang, Jun; Sudik, Andrea; Wolverton, Christopher; Siegel, Donald J

2010-02-01

Widespread adoption of hydrogen as a vehicular fuel depends critically upon the ability to store hydrogen on-board at high volumetric and gravimetric densities, as well as on the ability to extract/insert it at sufficiently rapid rates. As current storage methods based on physical means--high-pressure gas or (cryogenic) liquefaction--are unlikely to satisfy targets for performance and cost, a global research effort focusing on the development of chemical means for storing hydrogen in condensed phases has recently emerged. At present, no known material exhibits a combination of properties that would enable high-volume automotive applications. Thus new materials with improved performance, or new approaches to the synthesis and/or processing of existing materials, are highly desirable. In this critical review we provide a practical introduction to the field of hydrogen storage materials research, with an emphasis on (i) the properties necessary for a viable storage material, (ii) the computational and experimental techniques commonly employed in determining these attributes, and (iii) the classes of materials being pursued as candidate storage compounds. Starting from the general requirements of a fuel cell vehicle, we summarize how these requirements translate into desired characteristics for the hydrogen storage material. Key amongst these are: (a) high gravimetric and volumetric hydrogen density, (b) thermodynamics that allow for reversible hydrogen uptake/release under near-ambient conditions, and (c) fast reaction kinetics. To further illustrate these attributes, the four major classes of candidate storage materials--conventional metal hydrides, chemical hydrides, complex hydrides, and sorbent systems--are introduced and their respective performance and prospects for improvement in each of these areas is discussed. Finally, we review the most valuable experimental and computational techniques for determining these attributes, highlighting how an approach that

In vitro targeted photodynamic therapy with a pyropheophorbide--a conjugated inhibitor of prostate-specific membrane antigen.

PubMed

Liu, Tiancheng; Wu, Lisa Y; Choi, Joseph K; Berkman, Clifford E

2009-05-01

The lack of specific delivery of photosensitizers (PSs), represents a significant limitation of photodynamic therapy (PDT) of cancer. The biomarker prostate-specific membrane antigen (PSMA) has attracted considerable attention as a target for imaging and therapeutic applications for prostate cancer. Although recent efforts have been made to conjugate inhibitors of PSMA with imaging agents, there have been no reports on PS-conjugated PSMA inhibitors for targeted PDT of prostate cancer. The present study focuses on the use of a PSMA inhibitor-conjugate of pyropheophorbide-a (Ppa-conjugate 2) for targeted PDT to achieve apoptosis in PSMA+ LNCaP cells. Confocal laser scanning microscopy with a combination of nuclear staining and immunofluorescence methods were employed to monitor the specific imaging and PDT-mediated apoptotic effects on PSMA-positive LNCaP and PSMA-negative (PC-3) cells. Our results demonstrated that PDT-mediated effects by Ppa-conjugate 2 were specific to LNCaP cells, but not PC-3 cells. Cell permeability was detected as early as 2 hr by HOE33342/PI double staining, becoming more intense by 4 hr. Evidence for the apoptotic caspase cascade being activated was based on the appearance of poly-ADP-ribose polymerase (PARP) p85 fragment. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay detected DNA fragmentation 16 hr post-PDT, confirming apoptotic events. Cell permeability by HOE33342/PI double staining as well as PARP p85 fragment and TUNEL assays confirm cellular apoptosis in PSMA+ cells when treated with PS-inhibitor conjugate 2 and subsequently irradiated. It is expected that the PSMA targeting small-molecule of this conjugate can serve as a delivery vehicle for PDT and other therapeutic applications for prostate cancer. (c) 2009 Wiley-Liss, Inc.

New agrophysics divisions: application of GIS and fuzzy multi attributive comparison of alternatives (review)

USDA-ARS?s Scientific Manuscript database

This review paper is devoted to review the new scientific divisions that emerged in agrophysics in the last 10-15 years. Among them are the following: 1) application of Geographic Information Systems, 2) development and application of fuzzy multi attributive comparison of alternatives. In recent yea...

Applying an efficient K-nearest neighbor search to forest attribute imputation

Treesearch

Andrew O. Finley; Ronald E. McRoberts; Alan R. Ek

2006-01-01

This paper explores the utility of an efficient nearest neighbor (NN) search algorithm for applications in multi-source kNN forest attribute imputation. The search algorithm reduces the number of distance calculations between a given target vector and each reference vector, thereby, decreasing the time needed to discover the NN subset. Results of five trials show gains...

STAT3 or USF2 Contributes to HIF Target Gene Specificity

PubMed Central

Pawlus, Matthew R.; Wang, Liyi; Murakami, Aya; Dai, Guanhai; Hu, Cheng-Jun

2013-01-01

The HIF1- and HIF2-mediated transcriptional responses play critical roles in solid tumor progression. Despite significant similarities, including their binding to promoters of both HIF1 and HIF2 target genes, HIF1 and HIF2 proteins activate unique subsets of target genes under hypoxia. The mechanism for HIF target gene specificity has remained unclear. Using siRNA or inhibitor, we previously reported that STAT3 or USF2 is specifically required for activation of endogenous HIF1 or HIF2 target genes. In this study, using reporter gene assays and chromatin immuno-precipitation, we find that STAT3 or USF2 exhibits specific binding to the promoters of HIF1 or HIF2 target genes respectively even when over-expressed. Functionally, HIF1α interacts with STAT3 to activate HIF1 target gene promoters in a HIF1α HLH/PAS and N-TAD dependent manner while HIF2α interacts with USF2 to activate HIF2 target gene promoters in a HIF2α N-TAD dependent manner. Physically, HIF1α HLH and PAS domains are required for its interaction with STAT3 while both N- and C-TADs of HIF2α are involved in physical interaction with USF2. Importantly, addition of functional USF2 binding sites into a HIF1 target gene promoter increases the basal activity of the promoter as well as its response to HIF2+USF2 activation while replacing HIF binding site with HBS from a HIF2 target gene does not change the specificity of the reporter gene. Importantly, RNA Pol II on HIF1 or HIF2 target genes is primarily associated with HIF1α or HIF2α in a STAT3 or USF2 dependent manner. Thus, we demonstrate here for the first time that HIF target gene specificity is achieved by HIF transcription partners that are required for HIF target gene activation, exhibit specific binding to the promoters of HIF1 or HIF2 target genes and selectively interact with HIF1α or HIF2α protein. PMID:23991099

Highly sensitive and specific colorimetric detection of cancer cells via dual-aptamer target binding strategy.

PubMed

Wang, Kun; Fan, Daoqing; Liu, Yaqing; Wang, Erkang

2015-11-15

Simple, rapid, sensitive and specific detection of cancer cells is of great importance for early and accurate cancer diagnostics and therapy. By coupling nanotechnology and dual-aptamer target binding strategies, we developed a colorimetric assay for visually detecting cancer cells with high sensitivity and specificity. The nanotechnology including high catalytic activity of PtAuNP and magnetic separation & concentration plays a vital role on the signal amplification and improvement of detection sensitivity. The color change caused by small amount of target cancer cells (10 cells/mL) can be clearly distinguished by naked eyes. The dual-aptamer target binding strategy guarantees the detection specificity that large amount of non-cancer cells and different cancer cells (10(4) cells/mL) cannot cause obvious color change. A detection limit as low as 10 cells/mL with detection linear range from 10 to 10(5) cells/mL was reached according to the experimental detections in phosphate buffer solution as well as serum sample. The developed enzyme-free and cost effective colorimetric assay is simple and no need of instrument while still provides excellent sensitivity, specificity and repeatability, having potential application on point-of-care cancer diagnosis. Copyright © 2015 Elsevier B.V. All rights reserved.

Biomimetics: reconstitution of low-density lipoprotein for targeted drug delivery and related theranostic applications.

PubMed

Zhu, Chunlei; Xia, Younan

2017-12-11

Low-density lipoprotein (LDL), one of the four major groups of lipoproteins for lipid transport in vivo, is emerging as an attractive carrier for the targeted delivery of theranostic agents. In contrast to the synthetic systems, LDL particles are intrinsically biocompatible and biodegradable, together with reduced immunogenicity and natural capabilities to target cancerous cells and to escape from the recognition and elimination by the reticuloendothelial system. Enticed by these attributes, a number of strategies have been developed for reconstituting LDL particles, including conjugation to the apolipoprotein, insertion into the phospholipid layer, and loading into the core. Here we present a tutorial review on the development of reconstituted LDL (rLDL) particles for theranostic applications. We start with a brief introduction to LDL and LDL receptor, as well as the advantages of using rLDL particles as a natural and versatile platform for the targeted delivery of theranostic agents. After a discussion of commonly used strategies for the reconstitution of LDL, we highlight the applications of rLDL particles in the staging of disease progression, treatment of lesioned tissues, and delivery of photosensitizers for photodynamic cancer therapy. We finish this review with a perspective on the remaining challenges and future directions.

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.

Terrain feature recognition for synthetic aperture radar (SAR) imagery employing spatial attributes of targets

NASA Astrophysics Data System (ADS)

Iisaka, Joji; Sakurai-Amano, Takako

1994-08-01

This paper describes an integrated approach to terrain feature detection and several methods to estimate spatial information from SAR (synthetic aperture radar) imagery. Spatial information of image features as well as spatial association are key elements in terrain feature detection. After applying a small feature preserving despeckling operation, spatial information such as edginess, texture (smoothness), region-likeliness and line-likeness of objects, target sizes, and target shapes were estimated. Then a trapezoid shape fuzzy membership function was assigned to each spatial feature attribute. Fuzzy classification logic was employed to detect terrain features. Terrain features such as urban areas, mountain ridges, lakes and other water bodies as well as vegetated areas were successfully identified from a sub-image of a JERS-1 SAR image. In the course of shape analysis, a quantitative method was developed to classify spatial patterns by expanding a spatial pattern through the use of a series of pattern primitives.

Specificity of jumping to conclusions and attributional biases: a comparison between patients with schizophrenia, depression, and anorexia nervosa.

PubMed

Wittorf, Andreas; Giel, Katrin E; Hautzinger, Martin; Rapp, Alexander; Schönenberg, Michael; Wolkenstein, Larissa; Zipfel, Stephan; Mehl, Stephanie; Fallgatter, Andreas J; Klingberg, Stefan

2012-05-01

The knowledge of the specificity of cognitive biases in psychiatric disorders is important in order to develop disorder-specific cognitive models and therapies. This cross-sectional study aimed to investigate the specificity of jumping to conclusions (JTC) and attributional biases (AB) for patients with schizophrenia. Twenty patients with paranoid schizophrenia were compared with patients with depression (n=20) and with anorexia nervosa (n=15) and nonclinical controls (n=55). All participants were administered a modified version of the beads task (JTC), a revised German version of the Internal, Personal, and Situational Attributions Questionnaire (AB), and several symptom and neurocognitive measures. The proportion of patients with JTC bias in the schizophrenia group was, at the descriptive level, higher than in the depression and the anorexia groups. Regarding AB, the schizophrenia group showed a significantly stronger externalising but not personalising bias than the clinical control groups. Neither JTC nor attributional biases were significantly associated with delusions in general or persecutory delusion. We found evidence for the specificity of an externalising bias for paranoid schizophrenia. Concerning JTC bias the evidence was less clear. Whether the modification of those biases through psychological interventions would have an effect on psychopathology should be investigated in the context of clinical trials.

A study and meta-analysis of lay attributions of cures for overcoming specific psychological problems.

PubMed

Furnham, A; Hayward, R

1997-09-01

Lay beliefs about the importance of 24 different contributors to overcoming 4 disorders that constitute primarily cognitive deficits were studied. A meta-analysis of previous programmatic studies in the area was performed so that 22 different psychological problems could be compared. In the present study, 107 participants completed a questionnaire indicating how effective 24 factors were in overcoming 4 specific problems: dyslexia, fear of flying, amnesia, and learning difficulties. Factor analysis revealed almost identical clusters (inner control, social consequences, understanding, receiving help, and fate) for each problem. The perceived relevance of those factors differed significantly between problems. Some individual difference factors (sex and religion) were found to predict certain factor attributions for specific disorders. A meta-analysis of the 5 studies in this series yielded a 6-factor structure comparable to those of the individual studies and provided results indicating the benefits and limitations of this kind of investigation. The clinical relevance of studying attributions for cure is considered.

Feature Integration in the Mapping of Multi-Attribute Visual Stimuli to Responses

PubMed Central

Ishizaki, Takuya; Morita, Hiromi; Morita, Masahiko

2015-01-01

In the human visual system, different attributes of an object, such as shape and color, are separately processed in different modules and then integrated to elicit a specific response. In this process, different attributes are thought to be temporarily “bound” together by focusing attention on the object; however, how such binding contributes to stimulus-response mapping remains unclear. Here we report that learning and performance of stimulus-response tasks was more difficult when three attributes of the stimulus determined the correct response than when two attributes did. We also found that spatially separated presentations of attributes considerably complicated the task, although they did not markedly affect target detection. These results are consistent with a paired-attribute model in which bound feature pairs, rather than object representations, are associated with responses by learning. This suggests that attention does not bind three or more attributes into a unitary object representation, and long-term learning is required for their integration. PMID:25762010

Influence of quasi-specific sites on kinetics of target DNA search by a sequence-specific DNA-binding protein.

PubMed

Kemme, Catherine A; Esadze, Alexandre; Iwahara, Junji

2015-11-10

Functions of transcription factors require formation of specific complexes at particular sites in cis-regulatory elements of genes. However, chromosomal DNA contains numerous sites that are similar to the target sequences recognized by transcription factors. The influence of such "quasi-specific" sites on functions of the transcription factors is not well understood at present by experimental means. In this work, using fluorescence methods, we have investigated the influence of quasi-specific DNA sites on the efficiency of target location by the zinc finger DNA-binding domain of the inducible transcription factor Egr-1, which recognizes a 9 bp sequence. By stopped-flow assays, we measured the kinetics of Egr-1's association with a target site on 143 bp DNA in the presence of various competitor DNAs, including nonspecific and quasi-specific sites. The presence of quasi-specific sites on competitor DNA significantly decelerated the target association by the Egr-1 protein. The impact of the quasi-specific sites depended strongly on their affinity, their concentration, and the degree of their binding to the protein. To quantitatively describe the kinetic impact of the quasi-specific sites, we derived an analytical form of the apparent kinetic rate constant for the target association and used it for fitting to the experimental data. Our kinetic data with calf thymus DNA as a competitor suggested that there are millions of high-affinity quasi-specific sites for Egr-1 among the 3 billion bp of genomic DNA. This study quantitatively demonstrates that naturally abundant quasi-specific sites on DNA can considerably impede the target search processes of sequence-specific DNA-binding proteins.

Radiological assessment of target materials for accelerator transmutation of waste (ATW) applications

NASA Astrophysics Data System (ADS)

Vickers, Linda Diane

This dissertation issues the first published document of the radiation absorbed dose rate (rad-h-1) to tissue from radioactive spallation products in Ta, W, Pb, Bi, and LBE target materials used in Accelerator Transmutation of Waste (ATW) applications. No previous works have provided an estimate of the absorbed dose rate (rad-h-1) from activated targets for ATW applications. The results of this dissertation are useful for planning the radiological safety assessment to personnel, and for the design, construction, maintenance, and disposition of target materials of high-energy particle accelerators for ATW applications (Charlton, 1996). In addition, this dissertation provides the characterization of target materials of high-energy particle accelerators for the parameters of: (1) spallation neutron yield (neutrons/proton), (2) spallation products yield (nuclides/proton), (3) energy-dependent spallation neutron fluence distribution, (4) spallation neutron flux, (5) identification of radioactive spallation products for consideration in safety of personnel to high radiation dose rates, and (6) identification of the optimum geometrical dimensions for the target applicable to the maximum radial spallation neutron leakage from the target. Pb and Bi target materials yielded the lowest absorbed dose rates (rad-h -1) for a 10-year irradiation/50-year decay scheme, and would be the preferred target materials for consideration of the radiological safety of personnel during ATW operations. A beneficial characteristic of these target materials is that they do not produce radioactive transuranic isotopes, which have very long half-lives and require special handling and disposition requirements. Furthermore, the targets are not considered High-Level Waste (HLW) such as reactor spent fuel for disposal purposes. It is a basic ATW system requirement that the spallation target after it has been expended should be disposable as Class C low-level radioactive waste. Therefore, the disposal

Geotextiles : a specific application of biofibers

Treesearch

B. W. English

1995-01-01

Geotextiles are any textile like material used to enhance soil structural performance. Biobased geotextiles are used for short term (6 months to 10 year) applications where biodegradability is a positive attribute, such as mulching and erosion control. Fiber options for biobased geotextiles include cereal straws, coir, jute, kenaf, flax, sisal, hemp, cotton, woodfiber...

Heterogeneous Face Attribute Estimation: A Deep Multi-Task Learning Approach.

PubMed

Han, Hu; K Jain, Anil; Shan, Shiguang; Chen, Xilin

2017-08-10

Face attribute estimation has many potential applications in video surveillance, face retrieval, and social media. While a number of methods have been proposed for face attribute estimation, most of them did not explicitly consider the attribute correlation and heterogeneity (e.g., ordinal vs. nominal and holistic vs. local) during feature representation learning. In this paper, we present a Deep Multi-Task Learning (DMTL) approach to jointly estimate multiple heterogeneous attributes from a single face image. In DMTL, we tackle attribute correlation and heterogeneity with convolutional neural networks (CNNs) consisting of shared feature learning for all the attributes, and category-specific feature learning for heterogeneous attributes. We also introduce an unconstrained face database (LFW+), an extension of public-domain LFW, with heterogeneous demographic attributes (age, gender, and race) obtained via crowdsourcing. Experimental results on benchmarks with multiple face attributes (MORPH II, LFW+, CelebA, LFWA, and FotW) show that the proposed approach has superior performance compared to state of the art. Finally, evaluations on a public-domain face database (LAP) with a single attribute show that the proposed approach has excellent generalization ability.

Attribute-based classification for zero-shot visual object categorization.

PubMed

Lampert, Christoph H; Nickisch, Hannes; Harmeling, Stefan

2014-03-01

We study the problem of object recognition for categories for which we have no training examples, a task also called zero--data or zero-shot learning. This situation has hardly been studied in computer vision research, even though it occurs frequently; the world contains tens of thousands of different object classes, and image collections have been formed and suitably annotated for only a few of them. To tackle the problem, we introduce attribute-based classification: Objects are identified based on a high-level description that is phrased in terms of semantic attributes, such as the object's color or shape. Because the identification of each such property transcends the specific learning task at hand, the attribute classifiers can be prelearned independently, for example, from existing image data sets unrelated to the current task. Afterward, new classes can be detected based on their attribute representation, without the need for a new training phase. In this paper, we also introduce a new data set, Animals with Attributes, of over 30,000 images of 50 animal classes, annotated with 85 semantic attributes. Extensive experiments on this and two more data sets show that attribute-based classification indeed is able to categorize images without access to any training images of the target classes.

Influence of Quasi-Specific Sites on Kinetics of Target DNA Search by a Sequence-Specific DNA-Binding Protein

PubMed Central

2015-01-01

Functions of transcription factors require formation of specific complexes at particular sites in cis-regulatory elements of genes. However, chromosomal DNA contains numerous sites that are similar to the target sequences recognized by transcription factors. The influence of such “quasi-specific” sites on functions of the transcription factors is not well understood at present by experimental means. In this work, using fluorescence methods, we have investigated the influence of quasi-specific DNA sites on the efficiency of target location by the zinc finger DNA-binding domain of the inducible transcription factor Egr-1, which recognizes a 9 bp sequence. By stopped-flow assays, we measured the kinetics of Egr-1’s association with a target site on 143 bp DNA in the presence of various competitor DNAs, including nonspecific and quasi-specific sites. The presence of quasi-specific sites on competitor DNA significantly decelerated the target association by the Egr-1 protein. The impact of the quasi-specific sites depended strongly on their affinity, their concentration, and the degree of their binding to the protein. To quantitatively describe the kinetic impact of the quasi-specific sites, we derived an analytical form of the apparent kinetic rate constant for the target association and used it for fitting to the experimental data. Our kinetic data with calf thymus DNA as a competitor suggested that there are millions of high-affinity quasi-specific sites for Egr-1 among the 3 billion bp of genomic DNA. This study quantitatively demonstrates that naturally abundant quasi-specific sites on DNA can considerably impede the target search processes of sequence-specific DNA-binding proteins. PMID:26502071

Genus-specific PCR Primers Targeting Intracellular Parasite Euduboscquella (Dinoflagellata: Syndinea)

NASA Astrophysics Data System (ADS)

Jung, Jae-Ho; Choi, Jung Min; Kim, Young-Ok

2018-03-01

We designed a genus-specific primer pair targeting the intracellular parasite Euduboscquella. To increase target specificity and inhibit untargeted PCR, two nucleotides were added at the 3' end of the reverse primer, one being a complementary nucleotide to the Euduboscquella-specific SNP (single-nucleotide polymorphism) and the other a deliberately mismatched nucleotide. Target specificity of the primer set was verified experimentally using PCR of two Euduboscquella species (positive controls) and 15 related species (negative controls composed of ciliates, diatoms and dinoflagellates), and analytical comparison with SILVA SSU rRNA gene database (release 119) in silico. In addition, we applied the Euduboscquella-specific primer set to four environmental samples previously determined by cytological staining to be either positive or negative for Euduboscquella. As expected, only positive controls and environmental samples known to contain Euduboscquella were successfully amplified by the primer set. An inferred SSU rRNA gene phylogeny placed environmental samples containing aloricate ciliates infected by Euduboscquella in a cluster discrete from Euduboscquella groups a-d previously reported from loricate, tintinnid ciliates.

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.

Attribution and Eating Disorders: An Investigation of the Attribution Styles of College Women.

ERIC Educational Resources Information Center

Forsyth, John P.; And Others

Current research on eating disorders places considerable emphasis upon cognitive components of those disorders. The possibility of a specific eating disorder attributional style is suggested by attributional analyses of clinical depression. This study was conducted to examine attributional style and eating disorders among 55 college women who…

Software Attribution for Geoscience Applications in the Computational Infrastructure for Geodynamics

NASA Astrophysics Data System (ADS)

Hwang, L.; Dumit, J.; Fish, A.; Soito, L.; Kellogg, L. H.; Smith, M.

2015-12-01

Scientific software is largely developed by individual scientists and represents a significant intellectual contribution to the field. As the scientific culture and funding agencies move towards an expectation that software be open-source, there is a corresponding need for mechanisms to cite software, both to provide credit and recognition to developers, and to aid in discoverability of software and scientific reproducibility. We assess the geodynamic modeling community's current citation practices by examining more than 300 predominantly self-reported publications utilizing scientific software in the past 5 years that is available through the Computational Infrastructure for Geodynamics (CIG). Preliminary results indicate that authors cite and attribute software either through citing (in rank order) peer-reviewed scientific publications, a user's manual, and/or a paper describing the software code. Attributions maybe found directly in the text, in acknowledgements, in figure captions, or in footnotes. What is considered citable varies widely. Citations predominantly lack software version numbers or persistent identifiers to find the software package. Versioning may be implied through reference to a versioned user manual. Authors sometimes report code features used and whether they have modified the code. As an open-source community, CIG requests that researchers contribute their modifications to the repository. However, such modifications may not be contributed back to a repository code branch, decreasing the chances of discoverability and reproducibility. Survey results through CIG's Software Attribution for Geoscience Applications (SAGA) project suggest that lack of knowledge, tools, and workflows to cite codes are barriers to effectively implement the emerging citation norms. Generated on-demand attributions on software landing pages and a prototype extensible plug-in to automatically generate attributions in codes are the first steps towards reproducibility.

Screening and Identification of Peptides Specifically Targeted to Gastric Cancer Cells from a Phage Display Peptide Library

PubMed

Sahin, Deniz; Taflan, Sevket Onur; Yartas, Gizem; Ashktorab, Hassan; Smoot, Duane T

2018-04-25

Background: Gastric cancer is the second most common cancer among the malign cancer types. Inefficiency of traditional techniques both in diagnosis and therapy of the disease makes the development of alternative and novel techniques indispensable. As an alternative to traditional methods, tumor specific targeting small peptides can be used to increase the efficiency of the treatment and reduce the side effects related to traditional techniques. The aim of this study is screening and identification of individual peptides specifically targeted to human gastric cancer cells using a phage-displayed peptide library and designing specific peptide sequences by using experimentally-eluted peptide sequences. Methods: Here, MKN-45 human gastric cancer cells and HFE-145 human normal gastric epithelial cells were used as the target and control cells, respectively. 5 rounds of biopannning with a phage display 12-peptide library were applied following subtraction biopanning with HFE-145 control cells. The selected phage clones were established by enzyme-linked immunosorbent assay and immunofluorescence detection. We first obtain random phage clones after five biopanning rounds, determine the binding levels of each individual clone. Then, we analyze the frequencies of each amino acid in best binding clones to determine positively overexpressed amino acids for designing novel peptide sequences. Results: DE532 (VETSQYFRGTLS) phage clone was screened positive, showing specific binding on MKN-45 gastric cancer cells. DE-Obs (HNDLFPSWYHNY) peptide, which was designed by using amino acid frequencies of experimentally selected peptides in the 5th round of biopanning, showed specific binding in MKN-45 cells. Conclusion: Selection and characterization of individual clones may give us specifically binding peptides, but more importantly, data extracted from eluted phage clones may be used to design theoretical peptides with better binding properties than even experimentally selected ones

Bulk production and evaluation of high specific activity 186g Re for cancer therapy using enriched 186 WO 3 targets in a proton beam

DOE PAGES

Mastren, Tara; Radchenko, Valery; Bach, Hong T.; ...

2017-06-01

Rhenium-186 g (t 1/2 = 3.72 d) is a β– emitting isotope suitable for theranostic applications. Current production methods rely on reactor production by way of the reaction 185Re(n,γ) 186gRe, which results in low specific activities limiting its use for cancer therapy. Production via charged particle activation of enriched 186W results in a 186gRe product with a much specific activity, allowing it to be used more broadly for targeted radiotherapy applications. Furthermore, this targets the unmet clinical need for more efficient radiotherapeutics.

Bulk production and evaluation of high specific activity 186g Re for cancer therapy using enriched 186 WO 3 targets in a proton beam

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

Mastren, Tara; Radchenko, Valery; Bach, Hong T.

Rhenium-186 g (t 1/2 = 3.72 d) is a β– emitting isotope suitable for theranostic applications. Current production methods rely on reactor production by way of the reaction 185Re(n,γ) 186gRe, which results in low specific activities limiting its use for cancer therapy. Production via charged particle activation of enriched 186W results in a 186gRe product with a much specific activity, allowing it to be used more broadly for targeted radiotherapy applications. Furthermore, this targets the unmet clinical need for more efficient radiotherapeutics.

Developing attributes and attribute-levels for a discrete choice experiment on micro health insurance in rural Malawi

PubMed Central

2014-01-01

Background Discrete choice experiments (DCEs) are attribute-driven experimental techniques used to elicit stakeholders’ preferences to support the design and implementation of policy interventions. The validity of a DCE, therefore, depends on the appropriate specification of the attributes and their levels. There have been recent calls for greater rigor in implementing and reporting on the processes of developing attributes and attribute-levels for discrete choice experiments (DCEs). This paper responds to such calls by carefully reporting a systematic process of developing micro health insurance attributes and attribute-levels for the design of a DCE in rural Malawi. Methods Conceptual attributes and attribute-levels were initially derived from a literature review which informed the design of qualitative data collection tools to identify context specific attributes and attribute-levels. Qualitative data was collected in August-September 2012 from 12 focus group discussions with community residents and 8 in-depth interviews with health workers. All participants were selected according to stratified purposive sampling. The material was tape-recorded, fully transcribed, and coded by three researchers to identify context-specific attributes and attribute-levels. Expert opinion was used to scale down the attributes and levels. A pilot study confirmed the appropriateness of the selected attributes and levels for a DCE. Results First, a consensus, emerging from an individual level analysis of the qualitative transcripts, identified 10 candidate attributes. Levels were assigned to all attributes based on data from transcripts and knowledge of the Malawian context, derived from literature. Second, through further discussions with experts, four attributes were discarded based on multiple criteria. The 6 remaining attributes were: premium level, unit of enrollment, management structure, health service benefit package, transportation coverage and copayment levels. A final

Developing attributes and attribute-levels for a discrete choice experiment on micro health insurance in rural Malawi.

PubMed

Abiiro, Gilbert Abotisem; Leppert, Gerald; Mbera, Grace Bongololo; Robyn, Paul J; De Allegri, Manuela

2014-05-22

Discrete choice experiments (DCEs) are attribute-driven experimental techniques used to elicit stakeholders' preferences to support the design and implementation of policy interventions. The validity of a DCE, therefore, depends on the appropriate specification of the attributes and their levels. There have been recent calls for greater rigor in implementing and reporting on the processes of developing attributes and attribute-levels for discrete choice experiments (DCEs). This paper responds to such calls by carefully reporting a systematic process of developing micro health insurance attributes and attribute-levels for the design of a DCE in rural Malawi. Conceptual attributes and attribute-levels were initially derived from a literature review which informed the design of qualitative data collection tools to identify context specific attributes and attribute-levels. Qualitative data was collected in August-September 2012 from 12 focus group discussions with community residents and 8 in-depth interviews with health workers. All participants were selected according to stratified purposive sampling. The material was tape-recorded, fully transcribed, and coded by three researchers to identify context-specific attributes and attribute-levels. Expert opinion was used to scale down the attributes and levels. A pilot study confirmed the appropriateness of the selected attributes and levels for a DCE. First, a consensus, emerging from an individual level analysis of the qualitative transcripts, identified 10 candidate attributes. Levels were assigned to all attributes based on data from transcripts and knowledge of the Malawian context, derived from literature. Second, through further discussions with experts, four attributes were discarded based on multiple criteria. The 6 remaining attributes were: premium level, unit of enrollment, management structure, health service benefit package, transportation coverage and copayment levels. A final step of revision and piloting

Antigen sensitivity of CD22-specific chimeric TCR is modulated by target epitope distance from the cell membrane.

PubMed

James, Scott E; Greenberg, Philip D; Jensen, Michael C; Lin, Yukang; Wang, Jinjuan; Till, Brian G; Raubitschek, Andrew A; Forman, Stephen J; Press, Oliver W

2008-05-15

We have targeted CD22 as a novel tumor-associated Ag for recognition by human CTL genetically modified to express chimeric TCR (cTCR) recognizing this surface molecule. CD22-specific cTCR targeting different epitopes of the CD22 molecule promoted efficient lysis of target cells expressing high levels of CD22 with a maximum lytic potential that appeared to decrease as the distance of the target epitope from the target cell membrane increased. Targeting membrane-distal CD22 epitopes with cTCR(+) CTL revealed defects in both degranulation and lytic granule targeting. CD22-specific cTCR(+) CTL exhibited lower levels of maximum lysis and lower Ag sensitivity than CTL targeting CD20, which has a shorter extracellular domain than CD22. This diminished sensitivity was not a result of reduced avidity of Ag engagement, but instead reflected weaker signaling per triggered cTCR molecule when targeting membrane-distal epitopes of CD22. Both of these parameters were restored by targeting a ligand expressing the same epitope, but constructed as a truncated CD22 molecule to approximate the length of a TCR:peptide-MHC complex. The reduced sensitivity of CD22-specific cTCR(+) CTL for Ag-induced triggering of effector functions has potential therapeutic applications, because such cells selectively lysed B cell lymphoma lines expressing high levels of CD22, but demonstrated minimal activity against autologous normal B cells, which express lower levels of CD22. Thus, our results demonstrate that cTCR signal strength, and consequently Ag sensitivity, can be modulated by differential choice of target epitopes with respect to distance from the cell membrane, allowing discrimination between targets with disparate Ag density.

Innovation Attributes, Policy Intervention, and the Diffusion of Computer Applications Among Local Governments

ERIC Educational Resources Information Center

Perry, James L.; Kraemer, Kenneth L.

1978-01-01

Argues that innovation attributes, together with policies associated with the diffusion on an innovation, account for significant differences in diffusion patterns. An empirical analysis of this thesis focuses on the diffusion of computer applications software in local government. Available from Elsevier Scientific Publishing Co., Box 211,…

Stigmatizing attitudes towards individuals with anorexia nervosa: an investigation of attribution theory.

PubMed

Zwickert, Kristy; Rieger, Elizabeth

2013-01-01

Guided by Attribution Theory, this study assessed stigmatizing attitudes towards an individual with anorexia nervosa (AN) compared to obesity and skin cancer, and examined the extent to which manipulating a target individual's level of blameworthiness affects levels of stigmatizing attitudes. One hundred and thirty-five female undergraduate students were randomly assigned to one of three conditions. Before and after receiving blameworthy or non-blameworthy information relating to the target's condition, participants completed a series of self-report inventories measuring their emotional reactions, desire for social distance, and causal attributions regarding the target. Participants reported a significantly greater desire for social distance from the target with AN compared to targets with obesity or skin cancer, and yet (contrary to Attribution Theory) attributed less blame to the target with AN. There were significant increases in stigmatization towards targets described as blameworthy relative to targets described as non-blameworthy. The findings provide insight into the elevated levels of stigmatizing attitudes held towards individuals with AN, and the role of Attribution Theory in partially accounting for this stigma.

Engineered Peptides for Applications in Cancer-Targeted Drug Delivery and Tumor Detection.

PubMed

Soudy, R; Byeon, N; Raghuwanshi, Y; Ahmed, S; Lavasanifar, A; Kaur, K

2017-01-01

Cancer-targeting peptides as ligands for targeted delivery of anticancer drugs or drug carriers have the potential to significantly enhance the selectivity and the therapeutic benefit of current chemotherapeutic agents. Identification of tumor-specific biomarkers like integrins, aminopeptidase N, and epidermal growth factor receptor as well as the popularity of phage display techniques along with synthetic combinatorial methods used for peptide design and structure optimization have fueled the advancement and application of peptide ligands for targeted drug delivery and tumor detection in cancer treatment, detection and guided therapy. Although considerable preclinical data have shown remarkable success in the use of tumor targeting peptides, peptides generally suffer from poor pharmacokinetics, enzymatic instability, and weak receptor affinity, and they need further structural modification before successful translation to clinics is possible. The current review gives an overview of the different engineering strategies that have been developed for peptide structure optimization to confer selectivity and stability. We also provide an update on the methods used for peptide ligand identification, and peptide- receptor interactions. Additionally, some applications for the use of peptides in targeted delivery of chemotherapeutics and diagnostics over the past 5 years are summarized. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Whole-body multicolor spectrally resolved fluorescence imaging for development of target-specific optical contrast agents using genetically engineered probes

NASA Astrophysics Data System (ADS)

Kobayashi, Hisataka; Hama, Yukihiro; Koyama, Yoshinori; Barrett, Tristan; Urano, Yasuteru; Choyke, Peter L.

2007-02-01

Target-specific contrast agents are being developed for the molecular imaging of cancer. Optically detectable target-specific agents are promising for clinical applications because of their high sensitivity and specificity. Pre clinical testing is needed, however, to validate the actual sensitivity and specificity of these agents in animal models, and involves both conventional histology and immunohistochemistry, which requires large numbers of animals and samples with costly handling. However, a superior validation tool takes advantage of genetic engineering technology whereby cell lines are transfected with genes that induce the target cell to produce fluorescent proteins with characteristic emission spectra thus, identifying them as cancer cells. Multicolor fluorescence imaging of these genetically engineered probes can provide rapid validation of newly developed exogenous probes that fluoresce at different wavelengths. For example, the plasmid containing the gene encoding red fluorescent protein (RFP) was transfected into cell lines previously developed to either express or not-express specific cell surface receptors. Various antibody-based or receptor ligand-based optical contrast agents with either green or near infrared fluorophores were developed to concurrently target and validate cancer cells and their positive and negative controls, such as β-D-galactose receptor, HER1 and HER2 in a single animal/organ. Spectrally resolved fluorescence multicolor imaging was used to detect separate fluorescent emission spectra from the exogenous agents and RFP. Therefore, using this in vivo imaging technique, we were able to demonstrate the sensitivity and specificity of the target-specific optical contrast agents, thus reducing the number of animals needed to conduct these experiments.

Specific c-Jun target genes in malignant melanoma.

PubMed

Schummer, Patrick; Kuphal, Silke; Vardimon, Lily; Bosserhoff, Anja K; Kappelmann, Melanie

2016-05-03

A fundamental event in the development and progression of malignant melanoma is the de-regulation of cancer-relevant transcription factors. We recently showed that c-Jun is a main regulator of melanoma progression and, thus, is the most important member of the AP-1 transcription factor family in this disease. Surprisingly, no cancer-related specific c-Jun target genes in melanoma were described in the literature, so far. Therefore, we focused on pre-existing ChIP-Seq data (Encyclopedia of DNA Elements) of 3 different non-melanoma cell lines to screen direct c-Jun target genes. Here, a specific c-Jun antibody to immunoprecipitate the associated promoter DNA was used. Consequently, we identified 44 direct c-Jun targets and a detailed analysis of 6 selected genes confirmed their deregulation in malignant melanoma. The identified genes were differentially regulated comparing 4 melanoma cell lines and normal human melanocytes and we confirmed their c-Jun dependency. Direct interaction between c-Jun and the promoter/enhancer regions of the identified genes was confirmed by us via ChIP experiments. Interestingly, we revealed that the direct regulation of target gene expression via c-Jun can be independent of the existence of the classical AP-1 (5´-TGA(C/G)TCA-3´) consensus sequence allowing for the subsequent down- or up-regulation of the expression of these cancer-relevant genes. In summary, the results of this study indicate that c-Jun plays a crucial role in the development and progression of malignant melanoma via direct regulation of cancer-relevant target genes and that inhibition of direct c-Jun targets through inhibition of c-Jun is a potential novel therapeutic option for treatment of malignant melanoma.

A computational imaging target specific detectivity metric

NASA Astrophysics Data System (ADS)

Preece, Bradley L.; Nehmetallah, George

2017-05-01

Due to the large quantity of low-cost, high-speed computational processing available today, computational imaging (CI) systems are expected to have a major role for next generation multifunctional cameras. The purpose of this work is to quantify the performance of theses CI systems in a standardized manner. Due to the diversity of CI system designs that are available today or proposed in the near future, significant challenges in modeling and calculating a standardized detection signal-to-noise ratio (SNR) to measure the performance of these systems. In this paper, we developed a path forward for a standardized detectivity metric for CI systems. The detectivity metric is designed to evaluate the performance of a CI system searching for a specific known target or signal of interest, and is defined as the optimal linear matched filter SNR, similar to the Hotelling SNR, calculated in computational space with special considerations for standardization. Therefore, the detectivity metric is designed to be flexible, in order to handle various types of CI systems and specific targets, while keeping the complexity and assumptions of the systems to a minimum.

Searchable attribute-based encryption scheme with attribute revocation in cloud storage.

PubMed

Wang, Shangping; Zhao, Duqiao; Zhang, Yaling

2017-01-01

Attribute based encryption (ABE) is a good way to achieve flexible and secure access control to data, and attribute revocation is the extension of the attribute-based encryption, and the keyword search is an indispensable part for cloud storage. The combination of both has an important application in the cloud storage. In this paper, we construct a searchable attribute-based encryption scheme with attribute revocation in cloud storage, the keyword search in our scheme is attribute based with access control, when the search succeeds, the cloud server returns the corresponding cipher text to user and the user can decrypt the cipher text definitely. Besides, our scheme supports multiple keywords search, which makes the scheme more practical. Under the assumption of decisional bilinear Diffie-Hellman exponent (q-BDHE) and decisional Diffie-Hellman (DDH) in the selective security model, we prove that our scheme is secure.

Stigmatizing attitudes towards individuals with anorexia nervosa: an investigation of attribution theory

PubMed Central

2013-01-01

Background Guided by Attribution Theory, this study assessed stigmatizing attitudes towards an individual with anorexia nervosa (AN) compared to obesity and skin cancer, and examined the extent to which manipulating a target individual’s level of blameworthiness affects levels of stigmatizing attitudes. One hundred and thirty-five female undergraduate students were randomly assigned to one of three conditions. Before and after receiving blameworthy or non-blameworthy information relating to the target’s condition, participants completed a series of self-report inventories measuring their emotional reactions, desire for social distance, and causal attributions regarding the target. Results Participants reported a significantly greater desire for social distance from the target with AN compared to targets with obesity or skin cancer, and yet (contrary to Attribution Theory) attributed less blame to the target with AN. There were significant increases in stigmatization towards targets described as blameworthy relative to targets described as non-blameworthy. Conclusion The findings provide insight into the elevated levels of stigmatizing attitudes held towards individuals with AN, and the role of Attribution Theory in partially accounting for this stigma. PMID:24764528

Tailoring folic acid and methotrexate-attributed quantum dots for integrated cancer cell imaging and therapy

NASA Astrophysics Data System (ADS)

Fahmi, Mochamad Zakki; Chang, Jia-Yaw

2016-03-01

Potential application of folic acid and methotrexate-attributed AgInS2-ZnS quantum dots on both detection and therapeutic of cancer cell were intensively investigated on this study. In the initial step, the bright luminescent of QDs, with % QY up to 55.3, were synthesized with one-pot two-step process resulting narrow particle distribution and successfully transferred to water phase without significant effect on optical properties. The water-soluble AgInS2-ZnS quantum dots (QDs) encapsulated with oleylamine have been successfully prepared by ultrasonication assisting. Several aspect including QDs characterization, pH stability, ionic strength, and bonding properties were investigated to reach desired condition of water-soluble AgInS2-ZnS QDs. Folic acid was further conjugated to QDs for HeLa and MCF7 cancer cell imaging to performs the targeting capability. Moreover, folic acid is efficiently internalized into cell through the receptor-mediated endocytosis even when conjugated with a wide variety of molecules. Confocal imaging characterization further informs folic acid-conjugated AgInS2-ZnS QDs could most specific targeted to the human cervical (HeLa) cells. The therapeutic feature of QDs on HeLa cancer cell was conjugated by attributing methotrexate on the QDs, instead of folic acid, and the design could improve on inhibiting the cancer cell viability as well as its fluorescent intensity.

Methotrexate transport mechanisms: the basis for targeted drug delivery and ß-folate-receptor-specific treatment.

PubMed

Fiehn, C

2010-01-01

Methotrexate (MTX) plays a pivotal role in the treatment of rheumatoid arthritis (RA). The transport mechanisms with which MTX reaches is target after application are an important part of MTX pharmacology and its concentration in target tissue such as RA synovial membrane might strongly influence the effectiveness of the drug. Physiological plasma protein binding of MTX to albumin is important for the distribution of MTX in the body and relative high concentrations of the drug are found in the liver. However, targeted drug delivery into inflamed joints and increased anti-arthritic efficiency can be obtained by covalent coupling of MTX ex-vivo to human serum albumin (MTX-HSA) or in-vivo to endogenous albumin mediated through the MTX-pro-drug AWO54. High expression of the folate receptor β (FR-β) on synovial macrophages of RA patients and its capacity to mediate binding and uptake of MTX has been demonstrated. To further improve drug treatment of RA, FR-β specific drugs have been developed and were characterised for their therapeutic potency in synovial inflammation. Therefore, different approaches to improve folate inhibitory and FR-β specific therapy of RA beyond MTX are in development and will be described.

Internal Targeting and External Control: Phototriggered Targeting in Nanomedicine.

PubMed

Arrue, Lily; Ratjen, Lars

2017-12-07

The photochemical control of structure and reactivity bears great potential for chemistry, biology, and life sciences. A key feature of photochemistry is the spatiotemporal control over secondary events. Well-established applications of photochemistry in medicine are photodynamic therapy (PDT) and photopharmacology (PP). However, although both are highly localizable through the application of light, they lack cell- and tissue-specificity. The combination of nanomaterial-based drug delivery and targeting has the potential to overcome limitations for many established therapy concepts. Even more privileged seems the merger of nanomedicine and cell-specific targeting (internal targeting) controlled by light (external control), as it can potentially be applied to many different areas of medicine and pharmaceutical research, including the aforementioned PDT and PP. In this review a survey of the interface of photochemistry, medicine and targeted drug delivery is given, especially focusing on phototriggered targeting in nanomedicine. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

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.

A generalized target theory and its applications.

PubMed

Zhao, Lei; Mi, Dong; Hu, Bei; Sun, Yeqing

2015-09-28

Different radiobiological models have been proposed to estimate the cell-killing effects, which are very important in radiotherapy and radiation risk assessment. However, most applied models have their own scopes of application. In this work, by generalizing the relationship between "hit" and "survival" in traditional target theory with Yager negation operator in Fuzzy mathematics, we propose a generalized target model of radiation-induced cell inactivation that takes into account both cellular repair effects and indirect effects of radiation. The simulation results of the model and the rethinking of "the number of targets in a cell" and "the number of hits per target" suggest that it is only necessary to investigate the generalized single-hit single-target (GSHST) in the present theoretical frame. Analysis shows that the GSHST model can be reduced to the linear quadratic model and multitarget model in the low-dose and high-dose regions, respectively. The fitting results show that the GSHST model agrees well with the usual experimental observations. In addition, the present model can be used to effectively predict cellular repair capacity, radiosensitivity, target size, especially the biologically effective dose for the treatment planning in clinical applications.

Status Differences in Target-Specific Prosocial Behavior and Aggression.

PubMed

Closson, Leanna M; Hymel, Shelley

2016-09-01

Previous studies exploring the link between social status and behavior have predominantly utilized measures that do not provide information regarding toward whom aggression or prosocial behavior is directed. Using a contextualized target-specific approach, this study examined whether high- and low-status adolescents behave differently toward peers of varying levels of status. Participants, aged 11-15 (N = 426, 53 % females), completed measures assessing aggression and prosocial behavior toward each same-sex grademate. A distinct pattern of findings emerged regarding the likeability, popularity, and dominance status of adolescents and their peer targets. Popular adolescents reported more direct aggression, indirect aggression, and prosocial behavior toward popular peers than did unpopular adolescents. Well-accepted adolescents reported more prosocial behavior toward a wider variety of peers than did rejected adolescents. Finally, compared to subordinate adolescents, dominant adolescents reported greater direct and indirect aggression toward dominant than subordinate peers. The results highlight the importance of studying target-specific behavior to better understand the status-behavior link.

Generator-specific targets of mitochondrial reactive oxygen species.

PubMed

Bleier, Lea; Wittig, Ilka; Heide, Heinrich; Steger, Mirco; Brandt, Ulrich; Dröse, Stefan

2015-01-01

To understand the role of reactive oxygen species (ROS) in oxidative stress and redox signaling it is necessary to link their site of generation to the oxidative modification of specific targets. Here we have studied the selective modification of protein thiols by mitochondrial ROS that have been implicated as deleterious agents in a number of degenerative diseases and in the process of biological aging, but also as important players in cellular signal transduction. We hypothesized that this bipartite role might be based on different generator sites for "signaling" and "damaging" ROS and a directed release into different mitochondrial compartments. Because two main mitochondrial ROS generators, complex I (NADH:ubiquinone oxidoreductase) and complex III (ubiquinol:cytochrome c oxidoreductase; cytochrome bc1 complex), are known to predominantly release superoxide and the derived hydrogen peroxide (H2O2) into the mitochondrial matrix and the intermembrane space, respectively, we investigated whether these ROS generators selectively oxidize specific protein thiols. We used redox fluorescence difference gel electrophoresis analysis to identify redox-sensitive targets in the mitochondrial proteome of intact rat heart mitochondria. We observed that the modified target proteins were distinctly different when complex I or complex III was employed as the source of ROS. These proteins are potential targets involved in mitochondrial redox signaling and may serve as biomarkers to study the generator-dependent dual role of mitochondrial ROS in redox signaling and oxidative stress. Copyright © 2014 Elsevier Inc. All rights reserved.

The Relationship Between Interpersonal Cognitive Distortions and Attribution Styles Among Divorce Applicant Couples and its Impact on Sexual Satisfaction.

PubMed

Mahdoodizaman, Morteza; Razaghi, Samira; Amirsardari, Lili; Hobbi, Omran; Ghaderi, Davod

2016-09-01

The current study aimed to investigate the relationship between cognitive distortions and attribution styles among divorce applicant couples and its impact on sexual satisfaction. It was a cross-sectional study and its statistical samples were 55 divorce applicant couples (110 individuals) referred to Urmia courts, Urmia, Iran, from 2012 to 2013. The required data were gathered by interpersonal cognitive distortions, Larson sexual satisfaction and attribution style questionnaire. The findings of the research indicated the existence of a significant relationship between attribution styles for pleasant events and cognitive distortions. The results showed that an increasing amount of pleasant events reduces cognitive distortions among the divorce applicant couples (P < 0.05, r = 0.19). Attribution style has a significant relationship with sexual satisfaction among the divorced couples. As stable-unstable variables increase (P < 0.05, r = 0.22), pleasant events, (P < 0.05, r = 0.19), attribution styles (total) (P < 0.05, r = 0.19) and sexual satisfaction increases and vice versa. Also, there was no significant relationship between sexual satisfaction and cognitive distortions (P < 0.05, r = 0.04). Normal and abnormal cognitive components are among the main factors affecting satisfaction or dissatisfaction in couples who are living together (sexual satisfaction is one of its main elements).

The Relationship Between Interpersonal Cognitive Distortions and Attribution Styles Among Divorce Applicant Couples and its Impact on Sexual Satisfaction

PubMed Central

Mahdoodizaman, Morteza; Razaghi, Samira; Amirsardari, Lili; Hobbi, Omran; Ghaderi, Davod

2016-01-01

Background The current study aimed to investigate the relationship between cognitive distortions and attribution styles among divorce applicant couples and its impact on sexual satisfaction. Materials and Methods It was a cross-sectional study and its statistical samples were 55 divorce applicant couples (110 individuals) referred to Urmia courts, Urmia, Iran, from 2012 to 2013. The required data were gathered by interpersonal cognitive distortions, Larson sexual satisfaction and attribution style questionnaire. Results The findings of the research indicated the existence of a significant relationship between attribution styles for pleasant events and cognitive distortions. The results showed that an increasing amount of pleasant events reduces cognitive distortions among the divorce applicant couples (P < 0.05, r = 0.19). Attribution style has a significant relationship with sexual satisfaction among the divorced couples. As stable-unstable variables increase (P < 0.05, r = 0.22), pleasant events, (P < 0.05, r = 0.19), attribution styles (total) (P < 0.05, r = 0.19) and sexual satisfaction increases and vice versa. Also, there was no significant relationship between sexual satisfaction and cognitive distortions (P < 0.05, r = 0.04). Conclusions Normal and abnormal cognitive components are among the main factors affecting satisfaction or dissatisfaction in couples who are living together (sexual satisfaction is one of its main elements). PMID:27822285

Development of Small-molecule HIV Entry Inhibitors Specifically Targeting gp120 or gp41

PubMed Central

Lu, Lu; Yu, Fei; Cai, Lifeng; Debnath, Asim K.; Jiang, Shibo

2015-01-01

Human immunodeficiency virus type 1 (HIV-1) envelope (Env) glycoprotein surface subunit gp120 and transmembrane subunit gp41 play important roles in HIV-1 entry, thus serving as key targets for the development of HIV-1 entry inhibitors. T20 peptide (enfuvirtide) is the first U.S. FDA-approved HIV entry inhibitor; however, its clinical application is limited by the lack of oral availability. Here, we have described the structure and function of the HIV-1 gp120 and gp41 subunits and reviewed advancements in the development of small-molecule HIV entry inhibitors specifically targeting these two Env glycoproteins. We then compared the advantages and disadvantages of different categories of HIV entry inhibitor candidates and further predicted the future trend of HIV entry inhibitor development. PMID:26324044

Attentional Control via Parallel Target-Templates in Dual-Target Search

PubMed Central

Barrett, Doug J. K.; Zobay, Oliver

2014-01-01

Simultaneous search for two targets has been shown to be slower and less accurate than independent searches for the same two targets. Recent research suggests this ‘dual-target cost’ may be attributable to a limit in the number of target-templates than can guide search at any one time. The current study investigated this possibility by comparing behavioural responses during single- and dual-target searches for targets defined by their orientation. The results revealed an increase in reaction times for dual- compared to single-target searches that was largely independent of the number of items in the display. Response accuracy also decreased on dual- compared to single-target searches: dual-target accuracy was higher than predicted by a model restricting search guidance to a single target-template and lower than predicted by a model simulating two independent single-target searches. These results are consistent with a parallel model of dual-target search in which attentional control is exerted by more than one target-template at a time. The requirement to maintain two target-templates simultaneously, however, appears to impose a reduction in the specificity of the memory representation that guides search for each target. PMID:24489793

Strategic aspects of cyberattack, attribution, and blame.

PubMed

Edwards, Benjamin; Furnas, Alexander; Forrest, Stephanie; Axelrod, Robert

2017-03-14

Cyber conflict is now a common and potentially dangerous occurrence. The target typically faces a strategic choice based on its ability to attribute the attack to a specific perpetrator and whether it has a viable punishment at its disposal. We present a game-theoretic model, in which the best strategic choice for the victim depends on the vulnerability of the attacker, the knowledge level of the victim, payoffs for different outcomes, and the beliefs of each player about their opponent. The resulting blame game allows analysis of four policy-relevant questions: the conditions under which peace (i.e., no attacks) is stable, when attacks should be tolerated, the consequences of asymmetric technical attribution capabilities, and when a mischievous third party or an accident can undermine peace. Numerous historical examples illustrate how the theory applies to cases of cyber or kinetic conflict involving the United States, Russia, China, Japan, North Korea, Estonia, Israel, Iran, and Syria.

Strategic aspects of cyberattack, attribution, and blame

PubMed Central

Edwards, Benjamin; Furnas, Alexander; Forrest, Stephanie

2017-01-01

Cyber conflict is now a common and potentially dangerous occurrence. The target typically faces a strategic choice based on its ability to attribute the attack to a specific perpetrator and whether it has a viable punishment at its disposal. We present a game-theoretic model, in which the best strategic choice for the victim depends on the vulnerability of the attacker, the knowledge level of the victim, payoffs for different outcomes, and the beliefs of each player about their opponent. The resulting blame game allows analysis of four policy-relevant questions: the conditions under which peace (i.e., no attacks) is stable, when attacks should be tolerated, the consequences of asymmetric technical attribution capabilities, and when a mischievous third party or an accident can undermine peace. Numerous historical examples illustrate how the theory applies to cases of cyber or kinetic conflict involving the United States, Russia, China, Japan, North Korea, Estonia, Israel, Iran, and Syria. PMID:28242700

Analysis of illegitimate genomic integration mediated by zinc-finger nucleases: implications for specificity of targeted gene correction

PubMed Central

2010-01-01

Background Formation of site specific genomic double strand breaks (DSBs), induced by the expression of a pair of engineered zinc-finger nucleases (ZFNs), dramatically increases the rates of homologous recombination (HR) between a specific genomic target and a donor plasmid. However, for the safe use of ZFN induced HR in practical applications, possible adverse effects of the technology such as cytotoxicity and genotoxicity need to be well understood. In this work, off-target activity of a pair of ZFNs has been examined by measuring the ratio between HR and illegitimate genomic integration in cells that are growing exponentially, and in cells that have been arrested in the G2/M phase. Results A reporter cell line that contained consensus ZFN binding sites in an enhanced green fluorescent protein (EGFP) reporter gene was used to measure ratios between HR and non-homologous integration of a plasmid template. Both in human cells (HEK 293) containing the consensus ZFN binding sites and in cells lacking the ZFN binding sites, a 3.5 fold increase in the level of illegitimate integration was observed upon ZFN expression. Since the reporter gene containing the consensus ZFN target sites was found to be intact in cells where illegitimate integration had occurred, increased rates of illegitimate integration most likely resulted from the formation of off-target genomic DSBs. Additionally, in a fraction of the ZFN treated cells the co-occurrence of both specific HR and illegitimate integration was observed. As a mean to minimize unspecific effects, cell cycle manipulation of the target cells by induction of a transient G2/M cell cycle arrest was shown to stimulate the activity of HR while having little effect on the levels of illegitimate integration, thus resulting in a nearly eight fold increase in the ratio between the two processes. Conclusions The demonstration that ZFN expression, in addition to stimulating specific gene targeting by HR, leads to increased rates of

Prostate-specific membrane antigen-directed nanoparticle targeting for extreme nearfield ablation of prostate cancer cells.

PubMed

Lee, Seung S; Roche, Philip Jr; Giannopoulos, Paresa N; Mitmaker, Elliot J; Tamilia, Michael; Paliouras, Miltiadis; Trifiro, Mark A

2017-03-01

Almost all biological therapeutic interventions cannot overcome neoplastic heterogeneity. Physical ablation therapy is immune to tumor heterogeneity, but nearby tissue damage is the limiting factor in delivering lethal doses. Multi-walled carbon nanotubes offer a number of unique properties: chemical stability, photonic properties including efficient light absorption, thermal conductivity, and extensive surface area availability for covalent chemical ligation. When combined together with a targeting moiety such as an antibody or small molecule, one can deliver highly localized temperature increases and cause extensive cellular damage. We have functionalized multi-walled carbon nanotubes by conjugating an antibody against prostate-specific membrane antigen. In our in vitro studies using prostate-specific membrane antigen-positive LNCaP prostate cancer cells, we have effectively demonstrated cell ablation of >80% with a single 30-s exposure to a 2.7-W, 532-nm laser for the first time without bulk heating. We also confirmed the specificity and selectivity of prostate-specific membrane antigen targeting by assessing prostate-specific membrane antigen-null PC3 cell lines under the same conditions (<10% cell ablation). This suggests that we can achieve an extreme nearfield cell ablation effect, thus restricting potential tissue damage when transferred to in vivo clinical applications. Developing this new platform will introduce novel approaches toward current therapeutic modalities and will usher in a new age of effective cancer treatment squarely addressing tumoral heterogeneity.

Improving the Accuracy of Attribute Extraction using the Relatedness between Attribute Values

NASA Astrophysics Data System (ADS)

Bollegala, Danushka; Tani, Naoki; Ishizuka, Mitsuru

Extracting attribute-values related to entities from web texts is an important step in numerous web related tasks such as information retrieval, information extraction, and entity disambiguation (namesake disambiguation). For example, for a search query that contains a personal name, we can not only return documents that contain that personal name, but if we have attribute-values such as the organization for which that person works, we can also suggest documents that contain information related to that organization, thereby improving the user's search experience. Despite numerous potential applications of attribute extraction, it remains a challenging task due to the inherent noise in web data -- often a single web page contains multiple entities and attributes. We propose a graph-based approach to select the correct attribute-values from a set of candidate attribute-values extracted for a particular entity. First, we build an undirected weighted graph in which, attribute-values are represented by nodes, and the edge that connects two nodes in the graph represents the degree of relatedness between the corresponding attribute-values. Next, we find the maximum spanning tree of this graph that connects exactly one attribute-value for each attribute-type. The proposed method outperforms previously proposed attribute extraction methods on a dataset that contains 5000 web pages.

Theranostic nanoparticles carrying doxorubicin attenuate targeting ligand specific antibody responses following systemic delivery.

PubMed

Yang, Emmy; Qian, Weiping; Cao, Zehong; Wang, Liya; Bozeman, Erica N; Ward, Christina; Yang, Bin; Selvaraj, Periasamy; Lipowska, Malgorzata; Wang, Y Andrew; Mao, Hui; Yang, Lily

2015-01-01

Understanding the effects of immune responses on targeted delivery of nanoparticles is important for clinical translations of new cancer imaging and therapeutic nanoparticles. In this study, we found that repeated administrations of magnetic iron oxide nanoparticles (IONPs) conjugated with mouse or human derived targeting ligands induced high levels of ligand specific antibody responses in normal and tumor bearing mice while injections of unconjugated mouse ligands were weakly immunogenic and induced a very low level of antibody response in mice. Mice that received intravenous injections of targeted and polyethylene glycol (PEG)-coated IONPs further increased the ligand specific antibody production due to differential uptake of PEG-coated nanoparticles by macrophages and dendritic cells. However, the production of ligand specific antibodies was markedly inhibited following systemic delivery of theranostic nanoparticles carrying a chemotherapy drug, doxorubicin. Targeted imaging and histological analysis revealed that lack of the ligand specific antibodies led to an increase in intratumoral delivery of targeted nanoparticles. Results of this study support the potential of further development of targeted theranostic nanoparticles for the treatment of human cancers.

EDB Fibronectin Specific Peptide for Prostate Cancer Targeting.

PubMed

Han, Zheng; Zhou, Zhuxian; Shi, Xiaoyue; Wang, Junpeng; Wu, Xiaohui; Sun, Da; Chen, Yinghua; Zhu, Hui; Magi-Galluzzi, Cristina; Lu, Zheng-Rong

2015-05-20

Extradomain-B fibronectin (EDB-FN), one of the oncofetal fibronectin (onfFN) isoforms, is a high-molecular-weight glycoprotein that mediates cell adhesion and migration. The expression of EDB-FN is associated with a number of cancer-related biological processes such as tumorigenesis, angiogenesis, and epithelial-to-mesenchymal transition (EMT). Here, we report the development of a small peptide specific to EDB-FN for targeting prostate cancer. A cyclic nonapeptide, CTVRTSADC (ZD2), was identified using peptide phage display. A ZD2-Cy5 conjugate was synthesized to accomplish molecular imaging of prostate cancer in vitro and in vivo. ZD2-Cy5 demonstrated effective binding to up-regulated EDB-FN secreted by TGF-β-induced PC3 cancer cells following EMT. Following intravenous injections, the targeted fluorescent probe specifically bound to and delineated PC3-GFP prostate tumors in nude mice bearing the tumor xenografts. ZD2-Cy5 also showed stronger binding to human prostate tumor specimens with a higher Gleason score (GS9) compared to those with a lower score (GS 7), with no binding in benign prostatic hyperplasia (BPH). Thus, the ZD2 peptide is a promising strategy for molecular imaging and targeted therapy of prostate cancer.

Application of the marine Ex-Bz transient system for delineating near shore resistive targets

NASA Astrophysics Data System (ADS)

Levi, Eldad; Goldman, Mark

2017-09-01

Under certain conditions, multidimensional coastal effect significantly enhances relative target response of the broadside transient marine Ex-Bz system. The effect is caused by a redistribution of the induced currents between the resistive target and the sea bottom compared to that existing in a 1-D geometry. As a result, the effect strongly depends on specific geoelectric conditions in the near-shore environment. The first study of the effect in the Mediterranean coast of central Israel was addressing shallow groundwater problem under specific geoelectric, hydrogeological and geomorphological conditions. Under different conditions (e.g. deep targets and sharp near-shore bathymetry), the influence of the effect on target response might be significantly different. More general analysis carried out in this study comprises various geoelectric scenarios that include both shallow and deep resistive targets at different distances from the shore line as well as various geometries of the target and the near-shore bathymetry. The study includes three major exploration aspects of the system, namely signal detectability, lateral and vertical resolution. Taking into account poor lateral resolution of the classical frequency domain CSEM and the limited application in shallow sea, the described broadside transient Ex-Bz system might represent a desired alternative for delineating shallow and deep resistive targets in transition zone.

Comparing integral and incidental emotions: Testing insights from emotions as social information theory and attribution theory.

PubMed

Hillebrandt, Annika; Barclay, Laurie J

2017-05-01

Studies have indicated that observers can infer information about others' behavioral intentions from others' emotions and use this information in making their own decisions. Integrating emotions as social information (EASI) theory and attribution theory, we argue that the interpersonal effects of emotions are not only influenced by the type of discrete emotion (e.g., anger vs. happiness) but also by the target of the emotion (i.e., how the emotion relates to the situation). We compare the interpersonal effects of emotions that are integral (i.e., related to the situation) versus incidental (i.e., lacking a clear target in the situation) in a negotiation context. Results from 4 studies support our general argument that the target of an opponent's emotion influences the degree to which observers attribute the emotion to their own behavior. These attributions influence observers' inferences regarding the perceived threat of an impasse or cooperativeness of an opponent, which can motivate observers to strategically adjust their behavior. Specifically, emotion target influenced concessions for both anger and happiness (Study 1, N = 254), with perceived threat and cooperativeness mediating the effects of anger and happiness, respectively (Study 2, N = 280). Study 3 (N = 314) demonstrated the mediating role of attributions and moderating role of need for closure. Study 4 (N = 193) outlined how observers' need for cognitive closure influences how they attribute incidental anger. We discuss theoretical implications related to the social influence of emotions as well as practical implications related to the impact of personality on negotiators' biases and behaviors. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

A FRAMEWORK FOR ATTRIBUTE-BASED COMMUNITY DETECTION WITH APPLICATIONS TO INTEGRATED FUNCTIONAL GENOMICS.

PubMed

Yu, Han; Hageman Blair, Rachael

2016-01-01

Understanding community structure in networks has received considerable attention in recent years. Detecting and leveraging community structure holds promise for understanding and potentially intervening with the spread of influence. Network features of this type have important implications in a number of research areas, including, marketing, social networks, and biology. However, an overwhelming majority of traditional approaches to community detection cannot readily incorporate information of node attributes. Integrating structural and attribute information is a major challenge. We propose a exible iterative method; inverse regularized Markov Clustering (irMCL), to network clustering via the manipulation of the transition probability matrix (aka stochastic flow) corresponding to a graph. Similar to traditional Markov Clustering, irMCL iterates between "expand" and "inflate" operations, which aim to strengthen the intra-cluster flow, while weakening the inter-cluster flow. Attribute information is directly incorporated into the iterative method through a sigmoid (logistic function) that naturally dampens attribute influence that is contradictory to the stochastic flow through the network. We demonstrate advantages and the exibility of our approach using simulations and real data. We highlight an application that integrates breast cancer gene expression data set and a functional network defined via KEGG pathways reveal significant modules for survival.

Application specific serial arithmetic arrays

NASA Technical Reports Server (NTRS)

Winters, K.; Mathews, D.; Thompson, T.

1990-01-01

High performance systolic arrays of serial-parallel multiplier elements may be rapidly constructed for specific applications by applying hardware description language techniques to a library of full-custom CMOS building blocks. Single clock pre-charged circuits have been implemented for these arrays at clock rates in excess of 100 Mhz using economical 2-micron (minimum feature size) CMOS processes, which may be quickly configured for a variety of applications. A number of application-specific arrays are presented, including a 2-D convolver for image processing, an integer polynomial solver, and a finite-field polynomial solver.

Target-specific copper hybrid T7 phage particles.

PubMed

Dasa, Siva Sai Krishna; Jin, Qiaoling; Chen, Chin-Tu; Chen, Liaohai

2012-12-18

Target-specific nanoparticles have attracted significant attention recently, and have greatly impacted life and physical sciences as new agents for imaging, diagnosis, and therapy, as well as building blocks for the assembly of novel complex materials. While most of these particles are synthesized by chemical conjugation of an affinity reagent to polymer or inorganic nanoparticles, we are promoting the use of phage particles as a carrier to host organic or inorganic functional components, as well as to display the affinity reagent on the phage surface, taking advantage of the fact that some phages host well-established vectors for protein expression. An affinity reagent can be structured in a desired geometry on the surface of phage particles, and more importantly, the number of the affinity reagent molecules per phage particle can be precisely controlled. We previously have reported the use of the T7 phage capsid as a template for synthesizing target-specific metal nanoparticles. In this study herein, we reported the synthesis of nanoparticles using an intact T7 phage as a scaffold from which to extend 415 copies of a peptide that contains a hexahistidine (6His) motif for capture of copper ions and staging the conversion of copper ions to copper metal, and a cyclic Arginine-Glycine-Aspartic Acid (RGD4C) motif for targeting integrin and cancer cells. We demonstrated that the recombinant phage could load copper ions under low bulk copper concentrations without interfering with its target specificity. Further reduction of copper ions to copper metal rendered a very stable copper hybrid T7 phage, which prevents the detachment of copper from phage particles and maintains the phage structural integrity even under harsh conditions. Cancer cells (MCF-7) can selectively uptake copper hybrid T7 phage particles through ligand-mediated transmembrane transportation, whereas normal control cells (MCF-12F) uptake 1000-fold less. We further demonstrated that copper hybrid T7

Sex- and Tissue-specific Functions of Drosophila Doublesex Transcription Factor Target Genes

PubMed Central

Clough, Emily; Jimenez, Erin; Kim, Yoo-Ah; Whitworth, Cale; Neville, Megan C.; Hempel, Leonie; Pavlou, Hania J.; Chen, Zhen-Xia; Sturgill, David; Dale, Ryan; Smith, Harold E.; Przytycka, Teresa M.; Goodwin, Stephen F.; Van Doren, Mark; Oliver, Brian

2014-01-01

Primary sex determination “switches” evolve rapidly, but Doublesex (DSX) related transcription factors (DMRTs) act downstream of these switches to control sexual development in most animal species. Drosophila dsx encodes female- and male-specific isoforms (DSXF and DSXM), but little is known about how dsx controls sexual development, whether DSXF and DSXM bind different targets, or how DSX proteins direct different outcomes in diverse tissues. We undertook genome-wide analyses to identify DSX targets using in vivo occupancy, binding site prediction, and evolutionary conservation. We find that DSXF and DSXM bind thousands of the same targets in multiple tissues in both sexes, yet these targets have sex- and tissue-specific functions. Interestingly, DSX targets show considerable overlap with targets identified for mouse DMRT1. DSX targets include transcription factors and signaling pathway components providing for direct and indirect regulation of sex-biased expression. PMID:25535918

Target Context Specification Can Reduce Costs in Nonfocal Prospective Memory

ERIC Educational Resources Information Center

Lourenço, Joana S.; White, Katherine; Maylor, Elizabeth A.

2013-01-01

Performing a nonfocal prospective memory (PM) task results in a cost to ongoing task processing, but the precise nature of the monitoring processes involved remains unclear. We investigated whether target context specification (i.e., explicitly associating the PM target with a subset of ongoing stimuli) can trigger trial-by-trial changes in task…

Compiler writing system detail design specification. Volume 1: Language specification

NASA Technical Reports Server (NTRS)

Arthur, W. J.

1974-01-01

Construction within the Meta language for both language and target machine specification is reported. The elements of the function language as a meaning and syntax are presented, and the structure of the target language is described which represents the target dependent object text representation of applications programs.

Primer-BLAST: A tool to design target-specific primers for polymerase chain reaction

PubMed Central

2012-01-01

Background Choosing appropriate primers is probably the single most important factor affecting the polymerase chain reaction (PCR). Specific amplification of the intended target requires that primers do not have matches to other targets in certain orientations and within certain distances that allow undesired amplification. The process of designing specific primers typically involves two stages. First, the primers flanking regions of interest are generated either manually or using software tools; then they are searched against an appropriate nucleotide sequence database using tools such as BLAST to examine the potential targets. However, the latter is not an easy process as one needs to examine many details between primers and targets, such as the number and the positions of matched bases, the primer orientations and distance between forward and reverse primers. The complexity of such analysis usually makes this a time-consuming and very difficult task for users, especially when the primers have a large number of hits. Furthermore, although the BLAST program has been widely used for primer target detection, it is in fact not an ideal tool for this purpose as BLAST is a local alignment algorithm and does not necessarily return complete match information over the entire primer range. Results We present a new software tool called Primer-BLAST to alleviate the difficulty in designing target-specific primers. This tool combines BLAST with a global alignment algorithm to ensure a full primer-target alignment and is sensitive enough to detect targets that have a significant number of mismatches to primers. Primer-BLAST allows users to design new target-specific primers in one step as well as to check the specificity of pre-existing primers. Primer-BLAST also supports placing primers based on exon/intron locations and excluding single nucleotide polymorphism (SNP) sites in primers. Conclusions We describe a robust and fully implemented general purpose primer design tool

Target cell specific antibody-based photosensitizers for photodynamic therapy

NASA Astrophysics Data System (ADS)

Rosenblum, Lauren T.; Mitsunaga, Makoto; Kakareka, John W.; Morgan, Nicole Y.; Pohida, Thomas J.; Choyke, Peter L.; Kobayashi, Hisataka

2011-03-01

In photodynamic therapy (PDT), localized monochromatic light is used to activate targeted photosensitizers (PS) to induce cellular damage through the generation of cytotoxic species such as singlet oxygen. While first-generation PS passively targeted malignancies, a variety of targeting mechanisms have since been studied, including specifically activatable agents. Antibody internalization has previously been employed as a fluorescence activation system and could potentially enable similar activation of PS. TAMRA, Rhodamine-B and Rhodamine-6G were conjugated to trastuzumab (brand name Herceptin), a humanized monoclonal antibody with specificity for the human epidermal growth factor receptor 2 (HER2), to create quenched PS (Tra-TAM, Tra-RhoB, and Tra-Rho6G). Specific PDT with Tra-TAM and Tra-Rho6G, which formed covalently bound H-dimers, was demonstrated in HER2+ cells: Minimal cell death (<6%) was observed in all treatments of the HER2- cell line (BALB/3T3) and in treatments the HER2+ cell line (3T3/HER2) with light or trastuzumab only. There was significant light-induced cell death in HER2 expressing cells using Tra-TAM (3% dead without light, 20% at 50 J/cm2, 46% at 100 J/cm2) and Tra-Rho6G (5% dead without light, 22% at 50 J/cm2, 46% at 100 J/cm2). No efficacy was observed in treatment with Tra-RhoB, which was also non-specifically taken up by BALB/3T3 cells and which had weaker PS-antibody interactions (as demonstrated by visualization of protein and fluorescence on SDS-PAGE).

Lost in the crowd: entitative group membership reduces mind attribution.

PubMed

Morewedge, Carey K; Chandler, Jesse J; Smith, Robert; Schwarz, Norbert; Schooler, Jonathan

2013-12-01

This research examined how and why group membership diminishes the attribution of mind to individuals. We found that mind attribution was inversely related to the size of the group to which an individual belonged (Experiment 1). Mind attribution was affected by group membership rather than the total number of entities perceived at once (Experiment 2). Moreover, mind attribution to an individual varied with the perception that the individual was a group member. Participants attributed more mind to an individual that appeared distinct or distant from other group members than to an individual that was perceived to be similar or proximal to a cohesive group (Experiments 3 and 4). This effect occurred for both human and nonhuman targets, and was driven by the perception of the target as an entitative group member rather than by the knowledge that the target was an entitative group member (Experiment 5). Copyright © 2013 Elsevier Inc. All rights reserved.

Ontology for Life-Cycle Modeling of Water Distribution Systems: Application of Model View Definition Attributes

DTIC Science & Technology

2013-06-01

ER D C/ CE RL C R- 13 -5 Ontology for Life-Cycle Modeling of Water Distribution Systems : Application of Model View Definition...2013 Ontology for Life-Cycle Modeling of Water Distribution Systems : Application of Model View Definition Attributes Kristine K. Fallon, Robert A...interior plumbing systems and the information exchange requirements for every participant in the design. The findings were used to develop an

Plasmonic nanobubbles for target cell-specific gene and drug delivery and multifunctional processing of heterogeneous cell systems

NASA Astrophysics Data System (ADS)

Lukianova-Hleb, Ekaterina Y.; Huye, Leslie E.; Brenner, Malcolm K.; Lapotko, Dmitri O.

2014-03-01

Cell and gene cancer therapies require ex vivo cell processing of human grafts. Such processing requires at least three steps - cell enrichment, cell separation (destruction), and gene transfer - each of which requires the use of a separate technology. While these technologies may be satisfactory for research use, they are of limited usefulness in the clinical treatment setting because they have a low processing rate, as well as a low transfection and separation efficacy and specificity in heterogeneous human grafts. Most problematic, because current technologies are administered in multiple steps - rather than in a single, multifunctional, and simultaneous procedure - they lengthen treatment process and introduce an unnecessary level of complexity, labor, and resources into clinical treatment; all these limitations result in high losses of valuable cells. We report a universal, high-throughput, and multifunctional technology that simultaneously (1) inject free external cargo in target cells, (2) destroys unwanted cells, and (3) preserve valuable non-target cells in heterogeneous grafts. Each of these functions has single target cell specificity in heterogeneous cell system, processing rate > 45 mln cell/min, injection efficacy 90% under 96% viability of the injected cells, target cell destruction efficacy > 99%, viability of not-target cells >99% The developed technology employs novel cellular agents, called plasmonic nanobubbles (PNBs). PNBs are not particles, but transient, intracellular events, a vapor nanobubbles that expand and collapse in mere nanoseconds under optical excitation of gold nanoparticles with short picosecond laser pulses. PNBs of different, cell-specific, size (1) inject free external cargo with small PNBs, (2) Destroy other target cells mechanically with large PNBs and (3) Preserve non-target cells. The multi-functionality, precision, and high throughput of all-in-one PNB technology will tremendously impact cell and gene therapies and other

Performing target specific band reduction using artificial neural networks and assessment of its efficacy using various target detection algorithms

NASA Astrophysics Data System (ADS)

Yadav, Deepti; Arora, M. K.; Tiwari, K. C.; Ghosh, J. K.

2016-04-01

Hyperspectral imaging is a powerful tool in the field of remote sensing and has been used for many applications like mineral detection, detection of landmines, target detection etc. Major issues in target detection using HSI are spectral variability, noise, small size of the target, huge data dimensions, high computation cost, complex backgrounds etc. Many of the popular detection algorithms do not work for difficult targets like small, camouflaged etc. and may result in high false alarms. Thus, target/background discrimination is a key issue and therefore analyzing target's behaviour in realistic environments is crucial for the accurate interpretation of hyperspectral imagery. Use of standard libraries for studying target's spectral behaviour has limitation that targets are measured in different environmental conditions than application. This study uses the spectral data of the same target which is used during collection of the HSI image. This paper analyze spectrums of targets in a way that each target can be spectrally distinguished from a mixture of spectral data. Artificial neural network (ANN) has been used to identify the spectral range for reducing data and further its efficacy for improving target detection is verified. The results of ANN proposes discriminating band range for targets; these ranges were further used to perform target detection using four popular spectral matching target detection algorithm. Further, the results of algorithms were analyzed using ROC curves to evaluate the effectiveness of the ranges suggested by ANN over full spectrum for detection of desired targets. In addition, comparative assessment of algorithms is also performed using ROC.

Drug-Target Interactions: Prediction Methods and Applications.

PubMed

Anusuya, Shanmugam; Kesherwani, Manish; Priya, K Vishnu; Vimala, Antonydhason; Shanmugam, Gnanendra; Velmurugan, Devadasan; Gromiha, M Michael

2018-01-01

Identifying the interactions between drugs and target proteins is a key step in drug discovery. This not only aids to understand the disease mechanism, but also helps to identify unexpected therapeutic activity or adverse side effects of drugs. Hence, drug-target interaction prediction becomes an essential tool in the field of drug repurposing. The availability of heterogeneous biological data on known drug-target interactions enabled many researchers to develop various computational methods to decipher unknown drug-target interactions. This review provides an overview on these computational methods for predicting drug-target interactions along with available webservers and databases for drug-target interactions. Further, the applicability of drug-target interactions in various diseases for identifying lead compounds has been outlined. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Paramagnetic and fluorescent liposomes for target-specific imaging and therapy of tumor angiogenesis

PubMed Central

Kluza, Ewelina; Van Tilborg, Geralda A. F.; van der Schaft, Daisy W. J.; Griffioen, Arjan W.; Mulder, Willem J. M.; Nicolay, Klaas

2010-01-01

Angiogenesis is essential for tumor growth and metastatic potential and for that reason considered an important target for tumor treatment. Noninvasive imaging technologies, capable of visualizing tumor angiogenesis and evaluating the efficacy of angiostatic therapies, are therefore becoming increasingly important. Among the various imaging modalities, magnetic resonance imaging (MRI) is characterized by a superb spatial resolution and anatomical soft-tissue contrast. Revolutionary advances in contrast agent chemistry have delivered versatile angiogenesis-specific molecular MRI contrast agents. In this paper, we review recent advances in the preclinical application of paramagnetic and fluorescent liposomes for noninvasive visualization of the molecular processes involved in tumor angiogenesis. This liposomal contrast agent platform can be prepared with a high payload of contrast generating material, thereby facilitating its detection, and is equipped with one or more types of targeting ligands for binding to specific molecules expressed at the angiogenic site. Multimodal liposomes endowed with contrast material for complementary imaging technologies, e.g., MRI and optical, can be exploited to gain important preclinical insights into the mechanisms of binding and accumulation at angiogenic vascular endothelium and to corroborate the in vivo findings. Interestingly, liposomes can be designed to contain angiostatic therapeutics, allowing for image-supervised drug delivery and subsequent monitoring of therapeutic efficacy. PMID:20390447

Technology, attributions, and emotions in post-secondary education: An application of Weiner's attribution theory to academic computing problems.

PubMed

Maymon, Rebecca; Hall, Nathan C; Goetz, Thomas; Chiarella, Andrew; Rahimi, Sonia

2018-01-01

As technology becomes increasingly integrated with education, research on the relationships between students' computing-related emotions and motivation following technological difficulties is critical to improving learning experiences. Following from Weiner's (2010) attribution theory of achievement motivation, the present research examined relationships between causal attributions and emotions concerning academic computing difficulties in two studies. Study samples consisted of North American university students enrolled in both traditional and online universities (total N = 559) who responded to either hypothetical scenarios or experimental manipulations involving technological challenges experienced in academic settings. Findings from Study 1 showed stable and external attributions to be emotionally maladaptive (more helplessness, boredom, guilt), particularly in response to unexpected computing problems. Additionally, Study 2 found stable attributions for unexpected problems to predict more anxiety for traditional students, with both external and personally controllable attributions for minor problems proving emotionally beneficial for students in online degree programs (more hope, less anxiety). Overall, hypothesized negative effects of stable attributions were observed across both studies, with mixed results for personally controllable attributions and unanticipated emotional benefits of external attributions for academic computing problems warranting further study.

Extrinsic attributes that influence parents' purchase of chocolate milk for their children.

PubMed

Li, Xiaomeng E; Lopetcharat, Kannapon; Drake, MaryAnne

2014-07-01

The consumption of milk is essential for children's heath; and flavored milk, especially chocolate milk, is often purchased to increase children's milk consumption. However, the sugar content of chocolate milk has raised health concerns. As such, it is important to understand chocolate milk extrinsic attributes that influence parents' purchase decisions when they are purchasing chocolate milk for their children. The objective of this study was to determine the key extrinsic attributes for parents when they purchase chocolate milk for their children. An online survey with a conjoint analysis design, emotions questions, and Kano questionnaire that focused on chocolate milk was conducted targeting parents. Three hundred and twelve parents participated in the survey. Parents reported positive emotions including good, good natured, happy, loving, and satisfied when purchasing chocolate milk for their kids. Three segments of parents were identified with subtle but distinct differences in their key preferences for chocolate milk attributes for their children. Type of sweetener was the primary driver of choice for purchasing chocolate milk for children followed by fat content. Among sweetener types, natural noncaloric/nonnutritive sweeteners or sucrose were preferred over artificial sweeteners, and reduced fat was preferred over full fat or skim milk. Kano results revealed that reduced fat and sugar with an all natural label and added vitamins, minerals, and protein were attractive to the majority of parents when purchasing chocolate milk for their kids. Understanding the driving extrinsic attributes for parents when they purchase chocolate milk for their children will assist manufacturers to target extrinsic attributes that are attractive to parents for chocolate milk. This study established that sweetener type and fat content are the primary extrinsic attributes affecting parents purchase decisions when choosing chocolate milk for their children. Different segments of

Checkpoint Blockade Cancer Immunotherapy Targets Tumour-Specific Mutant Antigens

PubMed Central

Gubin, Matthew M.; Zhang, Xiuli; Schuster, Heiko; Caron, Etienne; Ward, Jeffrey P.; Noguchi, Takuro; Ivanova, Yulia; Hundal, Jasreet; Arthur, Cora D.; Krebber, Willem-Jan; Mulder, Gwenn E.; Toebes, Mireille; Vesely, Matthew D.; Lam, Samuel S.K.; Korman, Alan J.; Allison, James P.; Freeman, Gordon J.; Sharpe, Arlene H.; Pearce, Erika L.; Schumacher, Ton N.; Aebersold, Ruedi; Rammensee, Hans-Georg; Melief, Cornelis J. M.; Mardis, Elaine R.; Gillanders, William E.; Artyomov, Maxim N.; Schreiber, Robert D.

2014-01-01

The immune system plays key roles in determining the fate of developing cancers by not only functioning as a tumour promoter facilitating cellular transformation, promoting tumour growth and sculpting tumour cell immunogenicity1–6, but also as an extrinsic tumour suppressor that either destroys developing tumours or restrains their expansion1,2,7. Yet clinically apparent cancers still arise in immunocompetent individuals in part as a consequence of cancer induced immunosuppression. In many individuals, immunosuppression is mediated by Cytotoxic T-Lymphocyte Associated Antigen-4 (CTLA-4) and Programmed Death-1 (PD-1), two immunomodulatory receptors expressed on T cells8,9. Monoclonal antibody (mAb) based therapies targeting CTLA-4 and/or PD-1 (checkpoint blockade) have yielded significant clinical benefits—including durable responses—to patients with different malignancies10–13. However, little is known about the identity of the tumour antigens that function as the targets of T cells activated by checkpoint blockade immunotherapy and whether these antigens can be used to generate vaccines that are highly tumour-specific. Herein, we use genomics and bioinformatics approaches to identify tumour-specific mutant proteins as a major class of T cell rejection antigens following αPD-1 and/or αCTLA-4 therapy of mice bearing progressively growing sarcomas and show that therapeutic synthetic long peptide (SLP) vaccines incorporating these mutant epitopes induce tumour rejection comparably to checkpoint blockade immunotherapy. Whereas, mutant tumour antigen-specific T cells are present in progressively growing tumours, they are reactivated following treatment with αPD-1- and/or αCTLA-4 and display some overlapping but mostly treatment-specific transcriptional profiles rendering them capable of mediating tumour rejection. These results reveal that tumour-specific mutant antigens (TSMA) are not only important targets of checkpoint blockade therapy but also can be

Child and parent attributions in chronic pediatric conditions: phenylketonuria (PKU) as an exemplar.

PubMed

Antshel, Kevin M; Brewster, Scott; Waisbren, Susan E

2004-03-01

Attribution theory, self-regulation, self-handicapping and sick role theories all suggest that children with chronic disease may be held to different standards. This study assesses child and parent attributions in pediatric chronic health conditions and addresses how attributional style may be related to treatment adherence. Four different vignettes were utilized to compare the attributional style of children with phenylketonuria (PKU) and parents of children with PKU to two comparison groups: children with other chronic medical conditions and medically healthy children. In addition, the relationship between metabolic control and attribution ratings was assessed in the PKU sample. Parents of children with medical conditions provided attributions of less child control and more stability as well as more positive affective reactions when compared to parents of healthy children. Children without a medical condition viewed childhood problems as less controllable and more stable. Mothers were more disturbed affectively by behavioral dysregulation and fathers were more disturbed by academic difficulties. In the PKU sample, the higher the phenylalanine level in the child, the more likely the parent and child alike were to attribute childhood problems to external loci of control. Attributional styles appear not to be diagnosis-specific in pediatric populations. Attributional style may be an important variable to consider when targeting treatment adherence.

Potential or problem? An investigation of secondary school teachers' attributions of the educational outcomes of students with specific learning difficulties.

PubMed

Woodcock, Stuart; Hitches, Elizabeth

2017-10-01

Despite strong support for inclusive education in principle, many teachers and administrators still demonstrate mixed responses to the inclusion of certain students in their classrooms. Students with specific learning difficulties (SpLD) form a large group of students in inclusive classrooms yet some provincial, state and national jurisdictions fail to acknowledge the existence of these students. Not acknowledging and understanding these students can deny them the recognition and resources necessary for their genuine participation in education and, in turn, society. The aim of this study was to examine British in-service secondary teachers' attributional responses to students with and without specific learning difficulties. The participants included 122 British secondary school teachers who were surveyed in response to vignettes of hypothetical male students who had failed a class test. The study found that while teachers attributed more positive causes towards students without SpLD, they exhibited more negative causes towards students with SpLD. Teachers' causal attributional outcomes of students' level of achievement can impact upon the students' own attributions, with teachers' responses for students with SpLD having the potential to, unintentionally, influence students' own sense of self-efficacy and motivation. The paper concludes with a consideration of the implications of the research and recommendations for practice.

Prostate Specific Membrane Antigen (PSMA) Targeted Bio-orthogonal Therapy for Metastatic Prostate Cancer

DTIC Science & Technology

2017-10-01

AWARD NUMBER: W81XWH-16-1-0595 TITLE: Prostate-Specific Membrane Antigen (PSMA) Targeted Bio -orthogonal Therapy for Metastatic Prostate Cancer...Sep 2016 - 14 Sep 2017 4. TITLE AND SUBTITLE Prostate-Specific Membrane Antigen (PSMA) Targeted Bio -orthogonal Therapy for Metastatic Prostate

Fear extinction causes target-specific remodeling of perisomatic inhibitory synapses

PubMed Central

Trouche, Stéphanie; Sasaki, Jennifer M.; Tu, Tiffany; Reijmers, Leon G.

2013-01-01

SUMMARY A more complete understanding of how fear extinction alters neuronal activity and connectivity within fear circuits may aid in the development of strategies to treat human fear disorders. Using a c-fos based transgenic mouse, we found that contextual fear extinction silenced basal amygdala (BA) excitatory neurons that had been previously activated during fear conditioning. We hypothesized that the silencing of BA fear neurons was caused by an action of extinction on BA inhibitory synapses. In support of this hypothesis, we found extinction-induced target-specific remodeling of BA perisomatic inhibitory synapses originating from parvalbumin and cholecystokinin-positive interneurons. Interestingly, the predicted changes in the balance of perisomatic inhibition matched the silent and active states of the target BA fear neurons. These observations suggest that target-specific changes in perisomatic inhibitory synapses represent a mechanism through which experience can sculpt the activation patterns within a neural circuit. PMID:24183705

46 CFR 171.130 - Specific applicability.

Code of Federal Regulations, 2011 CFR

2011-10-01

... 46 Shipping 7 2011-10-01 2011-10-01 false Specific applicability. 171.130 Section 171.130 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) SUBDIVISION AND STABILITY SPECIAL RULES PERTAINING TO VESSELS CARRYING PASSENGERS Drainage of Weather Decks § 171.130 Specific applicability. (a...

46 CFR 171.130 - Specific applicability.

Code of Federal Regulations, 2014 CFR

2014-10-01

... 46 Shipping 7 2014-10-01 2014-10-01 false Specific applicability. 171.130 Section 171.130 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) SUBDIVISION AND STABILITY SPECIAL RULES PERTAINING TO VESSELS CARRYING PASSENGERS Drainage of Weather Decks § 171.130 Specific applicability. (a...

46 CFR 171.130 - Specific applicability.

Code of Federal Regulations, 2013 CFR

2013-10-01

... 46 Shipping 7 2013-10-01 2013-10-01 false Specific applicability. 171.130 Section 171.130 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) SUBDIVISION AND STABILITY SPECIAL RULES PERTAINING TO VESSELS CARRYING PASSENGERS Drainage of Weather Decks § 171.130 Specific applicability. (a...

46 CFR 171.130 - Specific applicability.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 46 Shipping 7 2010-10-01 2010-10-01 false Specific applicability. 171.130 Section 171.130 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) SUBDIVISION AND STABILITY SPECIAL RULES PERTAINING TO VESSELS CARRYING PASSENGERS Drainage of Weather Decks § 171.130 Specific applicability. (a...

46 CFR 171.130 - Specific applicability.

Code of Federal Regulations, 2012 CFR

2012-10-01

... 46 Shipping 7 2012-10-01 2012-10-01 false Specific applicability. 171.130 Section 171.130 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) SUBDIVISION AND STABILITY SPECIAL RULES PERTAINING TO VESSELS CARRYING PASSENGERS Drainage of Weather Decks § 171.130 Specific applicability. (a...

46 CFR 170.160 - Specific applicability

Code of Federal Regulations, 2010 CFR

2010-10-01

... 46 Shipping 7 2010-10-01 2010-10-01 false Specific applicability 170.160 Section 170.160 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) SUBDIVISION AND STABILITY STABILITY REQUIREMENTS FOR ALL INSPECTED VESSELS Weather Criteria § 170.160 Specific applicability (a) Except as provided...

Glioma Dual-Targeting Nanohybrid Protein Toxin Constructed by Intein-Mediated Site-Specific Ligation for Multistage Booster Delivery

PubMed Central

Chen, Yingzhi; Zhang, Meng; Jin, Hongyue; Li, Dongdong; Xu, Fan; Wu, Aihua; Wang, Jinyu; Huang, Yongzhuo

2017-01-01

Malignant glioma is one of the most untreatable cancers because of the formidable blood-brain barrier (BBB), through which few therapeutics can penetrate and reach the tumors. Biologics have been booming in cancer therapy in the past two decades, but their application in brain tumor has long been ignored due to the impermeable nature of BBB against effective delivery of biologics. Indeed, it is a long unsolved problem for brain delivery of macromolecular drugs, which becomes the Holy Grail in medical and pharmaceutical sciences. Even assisting by targeting ligands, protein brain delivery still remains challenging because of the synthesis difficulties of ligand-modified proteins. Herein, we propose a rocket-like, multistage booster delivery system of a protein toxin, trichosanthin (TCS), for antiglioma treatment. TCS is a ribosome-inactivating protein with the potent activity against various solid tumors but lack of specific action and cell penetration ability. To overcome the challenge of its poor druggability and site-specific modification, intein-mediated ligation was applied, by which a gelatinase-cleavable peptide and cell-penetrating peptide (CPP)-fused recombinant TCS toxin can be site-specifically conjugated to lactoferrin (LF), thus constructing a BBB-penetrating, gelatinase-activatable cell-penetrating nanohybrid TCS toxin. This nanohybrid TCS system is featured by the multistage booster strategy for glioma dual-targeting delivery. First, LF can target to the BBB-overexpressing low-density lipoprotein receptor-related protein-1 (LRP-1), and assist with BBB penetration. Second, once reaching the tumor site, the gelatinase-cleavable peptide acts as a separator responsive to the glioma-associated matrix metalloproteinases (MMPs), thus releasing to the CPP-fused toxin. Third, CPP mediates intratumoral and intracellular penetration of TCS toxin, thereby enhancing its antitumor activity. The BBB penetration and MMP-2-activability of this delivery system were

Wavefront attributes in anisotropic media

NASA Astrophysics Data System (ADS)

Vanelle, C.; Abakumov, I.; Gajewski, D.

2018-07-01

Surface-measured wavefront attributes are the key ingredient to multiparameter methods, which are nowadays standard tools in seismic data processing. However, most operators are restricted to application to isotropic media. Whereas application of an isotropic operator will still lead to satisfactory stack results, further processing steps that interpret isotropic stacking parameters in terms of wavefront attributes will lead to erroneous results if anisotropy is present but not accounted for. In this paper, we derive relationships between the stacking parameters and anisotropic wavefront attributes that allow us to apply the common reflection surface type operator to 3-D media with arbitrary anisotropy for the zero-offset and finite-offset configurations including converted waves. The operator itself is expressed in terms of wavefront attributes that are measured in the acquisition surface, that is, no model assumptions are made. Numerical results confirm that the accuracy of the new anisotropic operator is of the same magnitude as that of its isotropic counterpart.

Targeted microbubbles: a novel application for the treatment of kidney stones.

PubMed

Ramaswamy, Krishna; Marx, Vanessa; Laser, Daniel; Kenny, Thomas; Chi, Thomas; Bailey, Michael; Sorensen, Mathew D; Grubbs, Robert H; Stoller, Marshall L

2015-07-01

Kidney stone disease is endemic. Extracorporeal shockwave lithotripsy was the first major technological breakthrough where focused shockwaves were used to fragment stones in the kidney or ureter. The shockwaves induced the formation of cavitation bubbles, whose collapse released energy at the stone, and the energy fragmented the kidney stones into pieces small enough to be passed spontaneously. Can the concept of microbubbles be used without the bulky machine? The logical progression was to manufacture these powerful microbubbles ex vivo and inject these bubbles directly into the collecting system. An external source can be used to induce cavitation once the microbubbles are at their target; the key is targeting these microbubbles to specifically bind to kidney stones. Two important observations have been established: (i) bisphosphonates attach to hydroxyapatite crystals with high affinity; and (ii) there is substantial hydroxyapatite in most kidney stones. The microbubbles can be equipped with bisphosphonate tags to specifically target kidney stones. These bubbles will preferentially bind to the stone and not surrounding tissue, reducing collateral damage. Ultrasound or another suitable form of energy is then applied causing the microbubbles to induce cavitation and fragment the stones. This can be used as an adjunct to ureteroscopy or percutaneous lithotripsy to aid in fragmentation. Randall's plaques, which also contain hydroxyapatite crystals, can also be targeted to pre-emptively destroy these stone precursors. Additionally, targeted microbubbles can aid in kidney stone diagnostics by virtue of being used as an adjunct to traditional imaging methods, especially useful in high-risk patient populations. This novel application of targeted microbubble technology not only represents the next frontier in minimally invasive stone surgery, but a platform technology for other areas of medicine. © 2014 The Authors BJU International © 2014 BJU International Published

Zinc-finger protein-targeted gene regulation: Genomewide single-gene specificity

PubMed Central

Tan, Siyuan; Guschin, Dmitry; Davalos, Albert; Lee, Ya-Li; Snowden, Andrew W.; Jouvenot, Yann; Zhang, H. Steven; Howes, Katherine; McNamara, Andrew R.; Lai, Albert; Ullman, Chris; Reynolds, Lindsey; Moore, Michael; Isalan, Mark; Berg, Lutz-Peter; Campos, Bradley; Qi, Hong; Spratt, S. Kaye; Case, Casey C.; Pabo, Carl O.; Campisi, Judith; Gregory, Philip D.

2003-01-01

Zinc-finger protein transcription factors (ZFP TFs) can be designed to control the expression of any desired target gene, and thus provide potential therapeutic tools for the study and treatment of disease. Here we report that a ZFP TF can repress target gene expression with single-gene specificity within the human genome. A ZFP TF repressor that binds an 18-bp recognition sequence within the promoter of the endogenous CHK2 gene gives a >10-fold reduction in CHK2 mRNA and protein. This level of repression was sufficient to generate a functional phenotype, as demonstrated by the loss of DNA damage-induced CHK2-dependent p53 phosphorylation. We determined the specificity of repression by using DNA microarrays and found that the ZFP TF repressed a single gene (CHK2) within the monitored genome in two different cell types. These data demonstrate the utility of ZFP TFs as precise tools for target validation, and highlight their potential as clinical therapeutics. PMID:14514889

Fear extinction causes target-specific remodeling of perisomatic inhibitory synapses.

PubMed

Trouche, Stéphanie; Sasaki, Jennifer M; Tu, Tiffany; Reijmers, Leon G

2013-11-20

A more complete understanding of how fear extinction alters neuronal activity and connectivity within fear circuits may aid in the development of strategies to treat human fear disorders. Using a c-fos-based transgenic mouse, we found that contextual fear extinction silenced basal amygdala (BA) excitatory neurons that had been previously activated during fear conditioning. We hypothesized that the silencing of BA fear neurons was caused by an action of extinction on BA inhibitory synapses. In support of this hypothesis, we found extinction-induced target-specific remodeling of BA perisomatic inhibitory synapses originating from parvalbumin and cholecystokinin-positive interneurons. Interestingly, the predicted changes in the balance of perisomatic inhibition matched the silent and active states of the target BA fear neurons. These observations suggest that target-specific changes in perisomatic inhibitory synapses represent a mechanism through which experience can sculpt the activation patterns within a neural circuit. Copyright © 2013 Elsevier Inc. All rights reserved.

Perception and Attribution of Poverty by Youth.

ERIC Educational Resources Information Center

Luce, Terrence S.

A study was conducted to examine the perceptions of young people in attributing the causes of poverty in our society. The study also examined youth's attribution of the state of poverty of three target groups: blacks, whites, and American Indians. Data were collected through structured interviews with 842 white and black children aged five through…

Future perspectives in target-specific immunotherapies of myasthenia gravis

PubMed Central

Dalakas, Marinos C.

2015-01-01

Myasthenia gravis (MG) is an autoimmune disease caused by complement-fixing antibodies against acetylcholine receptors (AChR); antigen-specific CD4+ T cells, regulatory T cells (Tregs) and T helper (Th) 17+ cells are essential in antibody production. Target-specific therapeutic interventions should therefore be directed against antibodies, B cells, complement and molecules associated with T cell signaling. Even though the progress in the immunopathogenesis of the disease probably exceeds any other autoimmune disorder, MG is still treated with traditional drugs or procedures that exert a non-antigen specific immunosuppression or immunomodulation. Novel biological agents currently on the market, directed against the following molecular pathways, are relevant and specific therapeutic targets that can be tested in MG: (a) T cell intracellular signaling molecules, such as anti-CD52, anti-interleukin (IL) 2 receptors, anti- costimulatory molecules, and anti-Janus tyrosine kinases (JAK1, JAK3) that block the intracellular cascade associated with T-cell activation; (b) B cells and their trophic factors, directed against key B-cell molecules; (c) complement C3 or C5, intercepting the destructive effect of complement-fixing antibodies; (d) cytokines and cytokine receptors, such as those targeting IL-6 which promotes antibody production and IL-17, or the p40 subunit of IL-12/1L-23 that affect regulatory T cells; and (e) T and B cell transmigration molecules associated with lymphocyte egress from the lymphoid organs. All drugs against these molecular pathways require testing in controlled trials, although some have already been tried in small case series. Construction of recombinant AChR antibodies that block binding of the pathogenic antibodies, thereby eliminating complement and antibody-depended-cell-mediated cytotoxicity, are additional novel molecular tools that require exploration in experimental MG. PMID:26600875

An evolution of image source camera attribution approaches.

PubMed

Jahanirad, Mehdi; Wahab, Ainuddin Wahid Abdul; Anuar, Nor Badrul

2016-05-01

Camera attribution plays an important role in digital image forensics by providing the evidence and distinguishing characteristics of the origin of the digital image. It allows the forensic analyser to find the possible source camera which captured the image under investigation. However, in real-world applications, these approaches have faced many challenges due to the large set of multimedia data publicly available through photo sharing and social network sites, captured with uncontrolled conditions and undergone variety of hardware and software post-processing operations. Moreover, the legal system only accepts the forensic analysis of the digital image evidence if the applied camera attribution techniques are unbiased, reliable, nondestructive and widely accepted by the experts in the field. The aim of this paper is to investigate the evolutionary trend of image source camera attribution approaches from fundamental to practice, in particular, with the application of image processing and data mining techniques. Extracting implicit knowledge from images using intrinsic image artifacts for source camera attribution requires a structured image mining process. In this paper, we attempt to provide an introductory tutorial on the image processing pipeline, to determine the general classification of the features corresponding to different components for source camera attribution. The article also reviews techniques of the source camera attribution more comprehensively in the domain of the image forensics in conjunction with the presentation of classifying ongoing developments within the specified area. The classification of the existing source camera attribution approaches is presented based on the specific parameters, such as colour image processing pipeline, hardware- and software-related artifacts and the methods to extract such artifacts. The more recent source camera attribution approaches, which have not yet gained sufficient attention among image forensics

Prostate-specific membrane antigen-targeted liposomes specifically deliver the Zn(2+) chelator TPEN inducing oxidative stress in prostate cancer cells.

PubMed

Stuart, Christopher H; Singh, Ravi; Smith, Thomas L; D'Agostino, Ralph; Caudell, David; Balaji, K C; Gmeiner, William H

2016-05-01

To evaluate the potential use of zinc chelation for prostate cancer therapy using a new liposomal formulation of the zinc chelator, N,N,N',N'-tetrakis(2-pyridylmethyl)-ethylenediamine (TPEN). TPEN was encapsulated in nontargeted liposomes or liposomes displaying an aptamer to target prostate cancer cells overexpression prostate-specific membrane antigen. The prostate cancer selectivity and therapeutic efficacy of liposomal (targeted and nontargeted) and free TPEN were evaluated in vitro and in tumor-bearing mice. TPEN chelates zinc and results in reactive oxygen species imbalance leading to cell death. Delivery of TPEN using aptamer-targeted liposomes results in specific delivery to targeted cells. In vivo experiments show that TPEN-loaded, aptamer-targeted liposomes reduce tumor growth in a human prostate cancer xenograft model.

Progress In Magnetized Target Fusion Driven by Plasma Liners

NASA Technical Reports Server (NTRS)

Thio, Francis Y. C.; Kirkpatrick, Ronald C.; Knapp, Charles E.; Cassibry, Jason; Eskridge, Richard; Lee, Michael; Smith, James; Martin, Adam; Wu, S. T.; Schmidt, George;

Drug Target Validation Methods in Malaria - Protein Interference Assay (PIA) as a Tool for Highly Specific Drug Target Validation.

PubMed

Meissner, Kamila A; Lunev, Sergey; Wang, Yuan-Ze; Linzke, Marleen; de Assis Batista, Fernando; Wrenger, Carsten; Groves, Matthew R

2017-01-01

The validation of drug targets in malaria and other human diseases remains a highly difficult and laborious process. In the vast majority of cases, highly specific small molecule tools to inhibit a proteins function in vivo are simply not available. Additionally, the use of genetic tools in the analysis of malarial pathways is challenging. These issues result in difficulties in specifically modulating a hypothetical drug target's function in vivo. The current "toolbox" of various methods and techniques to identify a protein's function in vivo remains very limited and there is a pressing need for expansion. New approaches are urgently required to support target validation in the drug discovery process. Oligomerisation is the natural assembly of multiple copies of a single protein into one object and this self-assembly is present in more than half of all protein structures. Thus, oligomerisation plays a central role in the generation of functional biomolecules. A key feature of oligomerisation is that the oligomeric interfaces between the individual parts of the final assembly are highly specific. However, these interfaces have not yet been systematically explored or exploited to dissect biochemical pathways in vivo. This mini review will describe the current state of the antimalarial toolset as well as the potentially druggable malarial pathways. A specific focus is drawn to the initial efforts to exploit oligomerisation surfaces in drug target validation. As alternative to the conventional methods, Protein Interference Assay (PIA) can be used for specific distortion of the target protein function and pathway assessment in vivo. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Thermodynamic basis for engineering high-affinity, high-specificity binding-induced DNA clamp nanoswitches.

PubMed

Idili, Andrea; Plaxco, Kevin W; Vallée-Bélisle, Alexis; Ricci, Francesco

2013-12-23

Naturally occurring chemoreceptors almost invariably employ structure-switching mechanisms, an observation that has inspired the use of biomolecular switches in a wide range of artificial technologies in the areas of diagnostics, imaging, and synthetic biology. In one mechanism for generating such behavior, clamp-based switching, binding occurs via the clamplike embrace of two recognition elements onto a single target molecule. In addition to coupling recognition with a large conformational change, this mechanism offers a second advantage: it improves both affinity and specificity simultaneously. To explore the physics of such switches we have dissected here the thermodynamics of a clamp-switch that recognizes a target DNA sequence through both Watson-Crick base pairing and triplex-forming Hoogsteen interactions. When compared to the equivalent linear DNA probe (which relies solely on Watson-Crick interactions), the extra Hoogsteen interactions in the DNA clamp-switch increase the probe's affinity for its target by ∼0.29 ± 0.02 kcal/mol/base. The Hoogsteen interactions of the clamp-switch likewise provide an additional specificity check that increases the discrimination efficiency toward a single-base mismatch by 1.2 ± 0.2 kcal/mol. This, in turn, leads to a 10-fold improvement in the width of the "specificity window" of this probe relative to that of the equivalent linear probe. Given these attributes, clamp-switches should be of utility not only for sensing applications but also, in the specific field of DNA nanotechnology, for applications calling for a better control over the building of nanostructures and nanomachines.

Metatraits and assessment of attributional style.

PubMed

Chamberlain, John M; Haaga, David A F; Thorndike, Frances P; Ahrens, Anthony H

2004-11-01

Some personality trait dimensions may not be equally applicable to all people. The degree of applicability of a given trait, or traitedness, is conceptually distinct from trait level. In this study, 3 ways of assessing traitedness--interitem variance (R. F. Baumeister & D. M. Tice, 1988), scalability (K. Lanning, 1988), and construct similarity (W. F. Chaplin, 1991)--were applied to attributional style. A nonclinical sample (N = 123) completed measures of attributional style and depressive symptoms. In a series of multiple regression analyses, none of the traitedness indicators significantly moderated the relation of attributional style with depressive symptoms. The authors discuss several methodological and conceptual explanations for these null results.

DNA mismatch-specific targeting and hypersensitivity of mismatch-repair-deficient cells to bulky rhodium(III) intercalators

PubMed Central

Hart, Jonathan R.; Glebov, Oleg; Ernst, Russell J.; Kirsch, Ilan R.; Barton, Jacqueline K.

2006-01-01

Mismatch repair (MMR) is critical to maintaining the integrity of the genome, and deficiencies in MMR are correlated with cancerous transformations. Bulky rhodium intercalators target DNA base mismatches with high specificity. Here we describe the application of bulky rhodium intercalators to inhibit cellular proliferation differentially in MMR-deficient cells compared with cells that are MMR-proficient. Preferential inhibition by the rhodium complexes associated with MMR deficiency is seen both in a human colon cancer cell line and in normal mouse fibroblast cells; the inhibition of cellular proliferation depends strictly on the MMR deficiency of the cell. Furthermore, our assay of cellular proliferation is found to correlate with DNA mismatch targeting by the bulky metallointercalators. It is the Δ-isomer that is active both in targeting base mismatches and in inhibiting DNA synthesis. Additionally, the rhodium intercalators promote strand cleavage at the mismatch site with photoactivation, and we observe that the cellular response is enhanced with photoactivation. Targeting DNA mismatches may therefore provide a cell-selective strategy for chemotherapeutic design. PMID:17030786

Virus Capsids as Targeted Nanoscale Delivery Vessels of Photoactive Compounds for Site-Specific Photodynamic Therapy

NASA Astrophysics Data System (ADS)

Cohen, Brian A.

-virus-aptamer constructs selectively target and kill cancer cells versus non-cancer cells. Specifically, the results show that MS2 is a viable candidate as an addressable nanodelivery vessel of photoactive compounds, and the implications are that the nucleotide-driven packaging approach for modifying MS2 can be used to impart new functionalities for a host of diagnostic or therapeutic applications.

Drosophila CLOCK target gene characterization: implications for circadian tissue-specific gene expression

PubMed Central

Abruzzi, Katharine Compton; Rodriguez, Joseph; Menet, Jerome S.; Desrochers, Jennifer; Zadina, Abigail; Luo, Weifei; Tkachev, Sasha; Rosbash, Michael

2011-01-01

CLOCK (CLK) is a master transcriptional regulator of the circadian clock in Drosophila. To identify CLK direct target genes and address circadian transcriptional regulation in Drosophila, we performed chromatin immunoprecipitation (ChIP) tiling array assays (ChIP–chip) with a number of circadian proteins. CLK binding cycles on at least 800 sites with maximal binding in the early night. The CLK partner protein CYCLE (CYC) is on most of these sites. The CLK/CYC heterodimer is joined 4–6 h later by the transcriptional repressor PERIOD (PER), indicating that the majority of CLK targets are regulated similarly to core circadian genes. About 30% of target genes also show cycling RNA polymerase II (Pol II) binding. Many of these generate cycling RNAs despite not being documented in prior RNA cycling studies. This is due in part to different RNA isoforms and to fly head tissue heterogeneity. CLK has specific targets in different tissues, implying that important CLK partner proteins and/or mechanisms contribute to gene-specific and tissue-specific regulation. PMID:22085964

[Progress in application of targeting viral vector regulated by microRNA in gene therapy: a review].

PubMed

Zhang, Guohai; Wang, Qizhao; Zhang, Jinghong; Xu, Ruian

2010-06-01

A safe and effective targeting viral vector is the key factor for successful clinical gene therapy. microRNA, a class of small, single-stranded endogenous RNAs, act as post-transcriptional regulators of gene expression. The discovery of these kind regulatory elements provides a new approach to regulate gene expression more accurately. In this review, we elucidated the principle of microRNA in regulation of targeting viral vector. The applications of microRNA in the fields of elimination contamination from replication competent virus, reduction of transgene-specific immunity, promotion of cancer-targeted gene therapy and development of live attenuated vaccines were also discussed.

A distributed computational search strategy for the identification of diagnostics targets: application to finding aptamer targets for methicillin-resistant staphylococci.

PubMed

Flanagan, Keith; Cockell, Simon; Harwood, Colin; Hallinan, Jennifer; Nakjang, Sirintra; Lawry, Beth; Wipat, Anil

2014-06-30

The rapid and cost-effective identification of bacterial species is crucial, especially for clinical diagnosis and treatment. Peptide aptamers have been shown to be valuable for use as a component of novel, direct detection methods. These small peptides have a number of advantages over antibodies, including greater specificity and longer shelf life. These properties facilitate their use as the detector components of biosensor devices. However, the identification of suitable aptamer targets for particular groups of organisms is challenging. We present a semi-automated processing pipeline for the identification of candidate aptamer targets from whole bacterial genome sequences. The pipeline can be configured to search for protein sequence fragments that uniquely identify a set of strains of interest. The system is also capable of identifying additional organisms that may be of interest due to their possession of protein fragments in common with the initial set. Through the use of Cloud computing technology and distributed databases, our system is capable of scaling with the rapidly growing genome repositories, and consequently of keeping the resulting data sets up-to-date. The system described is also more generically applicable to the discovery of specific targets for other diagnostic approaches such as DNA probes, PCR primers and antibodies.

A distributed computational search strategy for the identification of diagnostics targets: Application to finding aptamer targets for methicillin-resistant staphylococci.

PubMed

Flanagan, Keith; Cockell, Simon; Harwood, Colin; Hallinan, Jennifer; Nakjang, Sirintra; Lawry, Beth; Wipat, Anil

2014-06-01

The rapid and cost-effective identification of bacterial species is crucial, especially for clinical diagnosis and treatment. Peptide aptamers have been shown to be valuable for use as a component of novel, direct detection methods. These small peptides have a number of advantages over antibodies, including greater specificity and longer shelf life. These properties facilitate their use as the detector components of biosensor devices. However, the identification of suitable aptamer targets for particular groups of organisms is challenging. We present a semi-automated processing pipeline for the identification of candidate aptamer targets from whole bacterial genome sequences. The pipeline can be configured to search for protein sequence fragments that uniquely identify a set of strains of interest. The system is also capable of identifying additional organisms that may be of interest due to their possession of protein fragments in common with the initial set. Through the use of Cloud computing technology and distributed databases, our system is capable of scaling with the rapidly growing genome repositories, and consequently of keeping the resulting data sets up-to-date. The system described is also more generically applicable to the discovery of specific targets for other diagnostic approaches such as DNA probes, PCR primers and antibodies.

Authorship Attribution of Source Code

ERIC Educational Resources Information Center

Tennyson, Matthew F.

2013-01-01

Authorship attribution of source code is the task of deciding who wrote a program, given its source code. Applications include software forensics, plagiarism detection, and determining software ownership. A number of methods for the authorship attribution of source code have been presented in the past. A review of those existing methods is…

Attribution of somatic symptoms in hypochondriasis.

PubMed

Neng, Julia M B; Weck, Florian

2015-01-01

The misinterpretation of bodily symptoms as an indicator of a serious illness is a key feature of the criteria and the cognitive-behavioural models of hypochondriasis. Previous research suggests that individuals suffering from health anxiety endorse attributions of physical disease, whereas persons with elevated general anxiety have the tendency to attribute psychological causes to their symptoms. However, whether a somatic attribution style is specific to patients with hypochondriasis, as opposed to those with anxiety disorders, has not yet been investigated and is therefore part of the present study. Fifty patients with hypochondriasis, 50 patients with a primary anxiety disorder and 50 healthy participants were presented with nine common bodily sensations and had to spontaneously attribute possible causes to the symptoms. Patients with hypochondriasis differed from patients with anxiety disorders and healthy controls in giving significantly fewer normalizing explanations, but attributing more often in terms of moderate or serious diseases. Patients with anxiety disorders also made significantly fewer normalizing attributions and more somatic attributions to a severe illness than healthy controls. There were no differences between the groups in the frequency of psychological attributions and somatic attributions concerning mild diseases. The present study demonstrates that hypochondriasis is associated with a disorder-specific attribution style connecting somatic symptoms primarily with moderate and serious diseases. By contrast, normalizing attributions are largely omitted from consideration by patients with hypochondriasis. The findings conform with the cognitive conception of hypochondriasis and support the strategy of modifying symptom attributions, as practiced in cognitive-behavioural therapy. Copyright © 2013 John Wiley & Sons, Ltd.

Televised relational and physical aggression and children's hostile intent attributions.

PubMed

Martins, Nicole

2013-12-01

An experiment was conducted with 150 children (mean age=10.1years) in third to fifth grades to test whether exposure to different forms of aggression in the media affected hostile attributional biases in response to different forms of provocation scenarios. Children were randomly assigned to watch a clip containing physical aggression, relational aggression, or no aggression. After exposure, children were asked to respond to a series of written provocation scenarios where a character caused some form of harm (instrumental or relational) to a target person, but the intent of the provocateur was ambiguous. Results revealed that exposure to relationally aggressive portrayals resulted in a hostile attributional bias in response to relational scenarios, whereas exposure to portrayals of physical aggression was associated with a hostile attributional bias in response to instrumental scenarios. Moreover, these biases were shown to be specific to the exposure condition (physical or relational) and not simply associated with exposure to aggression in general. The findings are discussed in terms of the general aggression model and children's social information processing. Copyright © 2013 Elsevier Inc. All rights reserved.

A Novel Method for Gene-Specific Enhancement of Protein Translation by Targeting 5’UTRs of Selected Tumor Suppressors

PubMed Central

Master, Adam; Wójcicka, Anna; Giżewska, Kamilla; Popławski, Piotr; Williams, Graham R.; Nauman, Alicja

2016-01-01

Background Translational control is a mechanism of protein synthesis regulation emerging as an important target for new therapeutics. Naturally occurring microRNAs and synthetic small inhibitory RNAs (siRNAs) are the most recognized regulatory molecules acting via RNA interference. Surprisingly, recent studies have shown that interfering RNAs may also activate gene transcription via the newly discovered phenomenon of small RNA-induced gene activation (RNAa). Thus far, the small activating RNAs (saRNAs) have only been demonstrated as promoter-specific transcriptional activators. Findings We demonstrate that oligonucleotide-based trans-acting factors can also specifically enhance gene expression at the level of protein translation by acting at sequence-specific targets within the messenger RNA 5’-untranslated region (5’UTR). We designed a set of short synthetic oligonucleotides (dGoligos), specifically targeting alternatively spliced 5’UTRs in transcripts expressed from the THRB and CDKN2A suppressor genes. The in vitro translation efficiency of reporter constructs containing alternative TRβ1 5’UTRs was increased by up to more than 55-fold following exposure to specific dGoligos. Moreover, we found that the most folded 5’UTR has higher translational regulatory potential when compared to the weakly folded TRβ1 variant. This suggests such a strategy may be especially applied to enhance translation from relatively inactive transcripts containing long 5’UTRs of complex structure. Significance This report represents the first method for gene-specific translation enhancement using selective trans-acting factors designed to target specific 5’UTR cis-acting elements. This simple strategy may be developed further to complement other available methods for gene expression regulation including gene silencing. The dGoligo-mediated translation-enhancing approach has the potential to be transferred to increase the translation efficiency of any suitable target gene

TargetLink, a new method for identifying the endogenous target set of a specific microRNA in intact living cells.

PubMed

Xu, Yan; Chen, Yan; Li, Daliang; Liu, Qing; Xuan, Zhenyu; Li, Wen-Hong

2017-02-01

MicroRNAs are small non-coding RNAs acting as posttranscriptional repressors of gene expression. Identifying mRNA targets of a given miRNA remains an outstanding challenge in the field. We have developed a new experimental approach, TargetLink, that applied locked nucleic acid (LNA) as the affinity probe to enrich target genes of a specific microRNA in intact cells. TargetLink also consists a rigorous and systematic data analysis pipeline to identify target genes by comparing LNA-enriched sequences between experimental and control samples. Using miR-21 as a test microRNA, we identified 12 target genes of miR-21 in a human colorectal cancer cell by this approach. The majority of the identified targets interacted with miR-21 via imperfect seed pairing. Target validation confirmed that miR-21 repressed the expression of the identified targets. The cellular abundance of the identified miR-21 target transcripts varied over a wide range, with some targets expressed at a rather low level, confirming that both abundant and rare transcripts are susceptible to regulation by microRNAs, and that TargetLink is an efficient approach for identifying the target set of a specific microRNA in intact cells. C20orf111, one of the novel targets identified by TargetLink, was found to reside in the nuclear speckle and to be reliably repressed by miR-21 through the interaction at its coding sequence.

Technology, attributions, and emotions in post-secondary education: An application of Weiner’s attribution theory to academic computing problems

PubMed Central

Hall, Nathan C.; Goetz, Thomas; Chiarella, Andrew; Rahimi, Sonia

2018-01-01

As technology becomes increasingly integrated with education, research on the relationships between students’ computing-related emotions and motivation following technological difficulties is critical to improving learning experiences. Following from Weiner’s (2010) attribution theory of achievement motivation, the present research examined relationships between causal attributions and emotions concerning academic computing difficulties in two studies. Study samples consisted of North American university students enrolled in both traditional and online universities (total N = 559) who responded to either hypothetical scenarios or experimental manipulations involving technological challenges experienced in academic settings. Findings from Study 1 showed stable and external attributions to be emotionally maladaptive (more helplessness, boredom, guilt), particularly in response to unexpected computing problems. Additionally, Study 2 found stable attributions for unexpected problems to predict more anxiety for traditional students, with both external and personally controllable attributions for minor problems proving emotionally beneficial for students in online degree programs (more hope, less anxiety). Overall, hypothesized negative effects of stable attributions were observed across both studies, with mixed results for personally controllable attributions and unanticipated emotional benefits of external attributions for academic computing problems warranting further study. PMID:29529039

Nanoparticle-macrophage interactions: A balance between clearance and cell-specific targeting

PubMed Central

Rattan, Rahul; Bhattacharjee, Somnath; Zong, Hong; Swain, Corban; Siddiqui, Muneeb A.; Visovatti, Scott H.; Kanthi, Yogendra; Desai, Sajani; Pinsky, David J.; Goonewardena, Sascha N.

2017-01-01

The surface properties of nanoparticles (NPs) are a major factor that influences how these nanomaterials interact with biological systems. Interactions between NPs and macrophages of the reticuloendothelial system (RES) can reduce the efficacy of NP diagnostics and therapeutics. Traditionally, to limit NP clearance by the RES system, the NP surface is neutralized with molecules like poly(ethylene glycol) (PEG) which are known to resist protein adsorption and RES clearance. Unfortunately, PEG modification is not without drawbacks including difficulties with the synthesis and associations with immune reactions. To overcome some of these obstacles, we neutralized the NP surface by acetylation and compared this modification to PEGylation for RES clearance and tumor-specific targeting. We found that acetylation was comparable to PEGylation in reducing RES clearance. Additionally, we found that dendrimer acetylation did not impact folic acid (FA)-mediated targeting of tumor cells whereas PEG surface modification reduced the targeting ability of the NP. These results clarify the impact of different NP surface modifications on RES clearance and cell-specific targeting and provide insights into the design of more effective NPs. PMID:28705434

Highly specific targeting of the TMPRSS2/ERG fusion gene using liposomal nanovectors

PubMed Central

Shao, Longjiang; Tekedereli, Ibrahim; Wang, Jianghua; Yuca, Erkan; Tsang, Susan; Sood, Anil; Lopez-Berestein, Gabriel; Ozpolat, Bulent; Ittmann, Michael

2012-01-01

Purpose The TMPRSS2/ERG (T/E) fusion gene is present in half of all prostate cancer (PCa) tumors. Fusion of the oncogenic ERG gene with the androgen-regulated TMPRSS2 gene promoter results in expression of fusion mRNAs in PCa cells. The junction of theTMPRSS2 and ERG derived portions of the fusion mRNA constitutes a cancer specific target in cells containing the T/E fusion gene. Targeting the most common alternatively spliced fusion gene mRNA junctional isoforms in vivo using siRNAs in liposomal nanovectors may potentially be a novel, low toxicity treatment for PCa. Experimental Design We designed and optimized siRNAs targeting the two most common T/E fusion gene mRNA junctional isoforms (Type III or Type VI). Specificity of siRNAs was assessed by transient co-transfection in vitro. To test their ability to inhibit growth of PCa cells expressing these fusion gene isoforms in vivo, specific siRNAs in liposomal nanovectors were used to treat mice bearing orthotopic or subcutaneous xenograft tumors expressing the targeted fusion isoforms. Results The targeting siRNAs were both potent and highly specific in vitro. In vivo they significantly inhibited tumor growth. The degree of growth inhibition was variable and was correlated with the extent of fusion gene knockdown. The growth inhibition was associated with marked inhibition of angiogenesis and, to a lesser degree, proliferation and a marked increase in apoptosis of tumor cells. No toxicity was observed. Conclusions Targeting the T/E fusion junction in vivo with specific siRNAs delivered via liposomal nanovectors is a promising therapy for men with PCa. PMID:23052253

Highly specific targeting of the TMPRSS2/ERG fusion gene using liposomal nanovectors.

PubMed

Shao, Longjiang; Tekedereli, Ibrahim; Wang, Jianghua; Yuca, Erkan; Tsang, Susan; Sood, Anil; Lopez-Berestein, Gabriel; Ozpolat, Bulent; Ittmann, Michael

2012-12-15

The TMPRSS2/ERG (T/E) fusion gene is present in half of all prostate cancer tumors. Fusion of the oncogenic ERG gene with the androgen-regulated TMPRSS2 gene promoter results in expression of fusion mRNAs in prostate cancer cells. The junction of theTMPRSS2- and ERG-derived portions of the fusion mRNA constitutes a cancer-specific target in cells containing the T/E fusion gene. Targeting the most common alternatively spliced fusion gene mRNA junctional isoforms in vivo using siRNAs in liposomal nanovectors may potentially be a novel, low-toxicity treatment for prostate cancer. We designed and optimized siRNAs targeting the two most common T/E fusion gene mRNA junctional isoforms (type III or type VI). Specificity of siRNAs was assessed by transient co-transfection in vitro. To test their ability to inhibit growth of prostate cancer cells expressing these fusion gene isoforms in vivo, specific siRNAs in liposomal nanovectors were used to treat mice bearing orthotopic or subcutaneous xenograft tumors expressing the targeted fusion isoforms. The targeting siRNAs were both potent and highly specific in vitro. In vivo they significantly inhibited tumor growth. The degree of growth inhibition was variable and was correlated with the extent of fusion gene knockdown. The growth inhibition was associated with marked inhibition of angiogenesis and, to a lesser degree, proliferation and a marked increase in apoptosis of tumor cells. No toxicity was observed. Targeting the T/E fusion junction in vivo with specific siRNAs delivered via liposomal nanovectors is a promising therapy for men with prostate cancer. ©2012 AACR.

Bifunctional Coupling Agents for Radiolabeling of Biomolecules and Target-Specific Delivery of Metallic Radionuclides

PubMed Central

Liu, Shuang

2008-01-01

Receptor-based radiopharmaceuticals are of great current interest in early molecular imaging and radiotherapy of cancers, and provide a unique tool for target-specific delivery of radionuclides to the diseased tissues. In general, a target-specific radiopharmaceutical can be divided into four parts: targeting biomolecule (BM), pharmacokinetic modifying (PKM) linker, bifunctional coupling or chelating agent (BFC), and radionuclide. The targeting biomolecule serves as a “carrier” for specific delivery of the radionuclide. PKM linkers are used to modify radiotracer excretion kinetics. BFC is needed for radiolabeling of biomolecules with a metallic radionuclide. Different radiometals have significant difference in their coordination chemistry, and require BFCs with different donor atoms and chelator frameworks. Since the radiometal chelate can have a significant impact on physical and biological properties of the target-specific radiopharmaceutical, its excretion kinetics can be altered by modifying the coordination environment with various chelators or coligand, if needed. This review will focus on the design of BFCs and their coordination chemistry with technetium, copper, gallium, indium, yttrium and lanthanide radiometals. PMID:18538888

Species-specific identification of Dekkera/Brettanomyces yeasts by fluorescently labeled DNA probes targeting the 26S rRNA.

PubMed

Röder, Christoph; König, Helmut; Fröhlich, Jürgen

2007-09-01

Sequencing of the complete 26S rRNA genes of all Dekkera/Brettanomyces species colonizing different beverages revealed the potential for a specific primer and probe design to support diagnostic PCR approaches and FISH. By analysis of the complete 26S rRNA genes of all five currently known Dekkera/Brettanomyces species (Dekkera bruxellensis, D. anomala, Brettanomyces custersianus, B. nanus and B. naardenensis), several regions with high nucleotide sequence variability yet distinct from the D1/D2 domains were identified. FISH species-specific probes targeting the 26S rRNA gene's most variable regions were designed. Accessibility of probe targets for hybridization was facilitated by the construction of partially complementary 'side'-labeled probes, based on secondary structure models of the rRNA sequences. The specificity and routine applicability of the FISH-based method for yeast identification were tested by analyzing different wine isolates. Investigation of the prevalence of Dekkera/Brettanomyces yeasts in the German viticultural regions Wonnegau, Nierstein and Bingen (Rhinehesse, Rhineland-Palatinate) resulted in the isolation of 37 D. bruxellensis strains from 291 wine samples.

Structure and specificity of the RNA-guided endonuclease Cas9 during DNA interrogation, target binding and cleavage

PubMed Central

Josephs, Eric A.; Kocak, D. Dewran; Fitzgibbon, Christopher J.; McMenemy, Joshua; Gersbach, Charles A.; Marszalek, Piotr E.

2015-01-01

CRISPR-associated endonuclease Cas9 cuts DNA at variable target sites designated by a Cas9-bound RNA molecule. Cas9's ability to be directed by single ‘guide RNA’ molecules to target nearly any sequence has been recently exploited for a number of emerging biological and medical applications. Therefore, understanding the nature of Cas9's off-target activity is of paramount importance for its practical use. Using atomic force microscopy (AFM), we directly resolve individual Cas9 and nuclease-inactive dCas9 proteins as they bind along engineered DNA substrates. High-resolution imaging allows us to determine their relative propensities to bind with different guide RNA variants to targeted or off-target sequences. Mapping the structural properties of Cas9 and dCas9 to their respective binding sites reveals a progressive conformational transformation at DNA sites with increasing sequence similarity to its target. With kinetic Monte Carlo (KMC) simulations, these results provide evidence of a ‘conformational gating’ mechanism driven by the interactions between the guide RNA and the 14th–17th nucleotide region of the targeted DNA, the stabilities of which we find correlate significantly with reported off-target cleavage rates. KMC simulations also reveal potential methodologies to engineer guide RNA sequences with improved specificity by considering the invasion of guide RNAs into targeted DNA duplex. PMID:26384421

Attributions and self-efficacy for physical activity in multiple sclerosis.

PubMed

Nickel, D; Spink, K; Andersen, M; Knox, K

2014-01-01

Self-efficacy is an important predictor of health-related physical activity in multiple sclerosis (MS). While past experiences are believed to influence efficacy beliefs, the explanations individuals provide for these experiences also may be critical. Our objective was to test the hypothesis that perceived success or failure to accumulate 150 min of physical activity in the previous week would moderate the relationship between the attributional dimension of stability and self-efficacy to exercise in the future. Forty-two adults with MS participated in this cross-sectional descriptive study. Participants completed questions assessing physical activity, perceived outcome for meeting the recommended level of endurance activity, attributions for the outcome, and exercise self-efficacy. Results from hierarchical multiple regression revealed a significant main effect for perceived outcome predicting self-efficacy that was qualified by a significant interaction. The final model, which included perceived outcome, stability, and the interaction term, predicted 37% of the variance in exercise self-efficacy, F (3, 38) = 7.27, p = .001. Our findings suggest that the best prediction of self-efficacy in the MS population may include the interaction of specific attributional dimensions with success/failure at meeting the recommended physical activity dose. Attributions may be another target for interventions aimed at increasing the physical activity in MS.

A screen of chemical modifications identifies position-specific modification by UNA to most potently reduce siRNA off-target effects

PubMed Central

Bramsen, Jesper B.; Pakula, Malgorzata M.; Hansen, Thomas B.; Bus, Claus; Langkjær, Niels; Odadzic, Dalibor; Smicius, Romualdas; Wengel, Suzy L.; Chattopadhyaya, Jyoti; Engels, Joachim W.; Herdewijn, Piet; Wengel, Jesper; Kjems, Jørgen

2010-01-01

Small interfering RNAs (siRNAs) are now established as the preferred tool to inhibit gene function in mammalian cells yet trigger unintended gene silencing due to their inherent miRNA-like behavior. Such off-target effects are primarily mediated by the sequence-specific interaction between the siRNA seed regions (position 2–8 of either siRNA strand counting from the 5′-end) and complementary sequences in the 3′UTR of (off-) targets. It was previously shown that chemical modification of siRNAs can reduce off-targeting but only very few modifications have been tested leaving more to be identified. Here we developed a luciferase reporter-based assay suitable to monitor siRNA off-targeting in a high throughput manner using stable cell lines. We investigated the impact of chemically modifying single nucleotide positions within the siRNA seed on siRNA function and off-targeting using 10 different types of chemical modifications, three different target sequences and three siRNA concentrations. We found several differently modified siRNAs to exercise reduced off-targeting yet incorporation of the strongly destabilizing unlocked nucleic acid (UNA) modification into position 7 of the siRNA most potently reduced off-targeting for all tested sequences. Notably, such position-specific destabilization of siRNA–target interactions did not significantly reduce siRNA potency and is therefore well suited for future siRNA designs especially for applications in vivo where siRNA concentrations, expectedly, will be low. PMID:20453030

Eliminating Inhibition of Return by Changing Salient Non-spatial Attributes in a Complex Environment

PubMed Central

Hu, Frank K; Samuel, Arthur G.; Chan, Agnes S.

2010-01-01

Inhibition of Return (IOR) occurs when a target is preceded by an irrelevant stimulus (cue) at the same location: Target detection is slowed, relative to uncued locations. In the present study, we used relatively complex displays to examine the effect of repetition of nonspatial attributes. For both color and shape, attribute repetition produced a robust inhibitory effect that followed a time course similar to that for location-based IOR. However, the effect only occurred when the target shared both the feature (i.e., color or shape) and location with the cue; this constraint implicates a primary role for location. The data are consistent with the idea that the system integrates consecutive stimuli into a single object file when attributes repeat, hindering detection of the second stimulus. The results are also consistent with an interpretation of IOR as a form of habituation, with greater habituation occurring with increasing featural overlap of a repeated stimulus. Critically, both of these interpretations bring the IOR effect within more general approaches to attention and perception, rather than requiring a specialized process with a limited function. In this view, there is no process specifically designed to inhibit return, suggesting that “IOR” may be the wrong framing of inhibitory repetition effects. Instead, we suggest that repetition of stimulus properties can interfere with the ability to focus attention on the aspects of a complex display that are needed to detect the occurrence of the target stimulus; this is a failure of activation, not an inhibition of processing. PMID:21171801

Privacy-Preserving Evaluation of Generalization Error and Its Application to Model and Attribute Selection

NASA Astrophysics Data System (ADS)

Sakuma, Jun; Wright, Rebecca N.

Privacy-preserving classification is the task of learning or training a classifier on the union of privately distributed datasets without sharing the datasets. The emphasis of existing studies in privacy-preserving classification has primarily been put on the design of privacy-preserving versions of particular data mining algorithms, However, in classification problems, preprocessing and postprocessing— such as model selection or attribute selection—play a prominent role in achieving higher classification accuracy. In this paper, we show generalization error of classifiers in privacy-preserving classification can be securely evaluated without sharing prediction results. Our main technical contribution is a new generalized Hamming distance protocol that is universally applicable to preprocessing and postprocessing of various privacy-preserving classification problems, such as model selection in support vector machine and attribute selection in naive Bayes classification.

A Chance for Attributable Agency.

PubMed

Briegel, Hans J; Müller, Thomas

Can we sensibly attribute some of the happenings in our world to the agency of some of the things around us? We do this all the time, but there are conceptual challenges purporting to show that attributable agency, and specifically one of its most important subspecies, human free agency, is incoherent. We address these challenges in a novel way: rather than merely rebutting specific arguments, we discuss a concrete model that we claim positively illustrates attributable agency in an indeterministic setting. The model, recently introduced by one of the authors in the context of artificial intelligence, shows that an agent with a sufficiently complex memory organization can employ indeterministic happenings in a meaningful way. We claim that these considerations successfully counter arguments against the coherence of libertarian (indeterminism-based) free will.

Premature deaths attributed to source-specific BC emissions in six urban US regions

NASA Astrophysics Data System (ADS)

Turner, Matthew D.; Henze, Daven K.; Capps, Shannon L.; Hakami, Amir; Zhao, Shunliu; Resler, Jaroslav; Carmichael, Gregory R.; Stanier, Charles O.; Baek, Jaemeen; Sandu, Adrian; Russell, Armistead G.; Nenes, Athanasios; Pinder, Rob W.; Napelenok, Sergey L.; Bash, Jesse O.; Percell, Peter B.; Chai, Tianfeng

2015-11-01

Recent studies have shown that exposure to particulate black carbon (BC) has significant adverse health effects and may be more detrimental to human health than exposure to PM2.5 as a whole. Mobile source BC emission controls, mostly on diesel-burning vehicles, have successfully decreased mobile source BC emissions to less than half of what they were 30 years ago. Quantification of the benefits of previous emissions controls conveys the value of these regulatory actions and provides a method by which future control alternatives could be evaluated. In this study we use the adjoint of the Community Multiscale Air Quality (CMAQ) model to estimate highly-resolved spatial distributions of benefits related to emission reductions for six urban regions within the continental US. Emissions from outside each of the six chosen regions account for between 7% and 27% of the premature deaths attributed to exposure to BC within the region. While we estimate that nonroad mobile and onroad diesel emissions account for the largest number of premature deaths attributable to exposure to BC, onroad gasoline is shown to have more than double the benefit per unit emission relative to that of nonroad mobile and onroad diesel. Within the region encompassing New York City and Philadelphia, reductions in emissions from large industrial combustion sources that are not classified as EGUs (i.e., non-EGU) are estimated to have up to triple the benefits per unit emission relative to reductions to onroad diesel sectors, and provide similar benefits per unit emission to that of onroad gasoline emissions in the region. While onroad mobile emissions have been decreasing in the past 30 years and a majority of vehicle emission controls that regulate PM focus on diesel emissions, our analysis shows the most efficient target for stricter controls is actually onroad gasoline emissions.

Population attribute compression

DOEpatents

White, James M.; Faber, Vance; Saltzman, Jeffrey S.

1995-01-01

An image population having a large number of attributes is processed to form a display population with a predetermined smaller number of attributes that represent the larger number of attributes. In a particular application, the color values in an image are compressed for storage in a discrete look-up table (LUT). Color space containing the LUT color values is successively subdivided into smaller volumes until a plurality of volumes are formed, each having no more than a preselected maximum number of color values. Image pixel color values can then be rapidly placed in a volume with only a relatively few LUT values from which a nearest neighbor is selected. Image color values are assigned 8 bit pointers to their closest LUT value whereby data processing requires only the 8 bit pointer value to provide 24 bit color values from the LUT.

46 CFR 174.300 - Specific applicability.

Code of Federal Regulations, 2014 CFR

2014-10-01

... 46 Shipping 7 2014-10-01 2014-10-01 false Specific applicability. 174.300 Section 174.300 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) SUBDIVISION AND STABILITY SPECIAL RULES PERTAINING TO SPECIFIC VESSEL TYPES Hopper Dredges With Working Freeboard Assignments § 174.300 Specific...

46 CFR 174.030 - Specific applicability.

Code of Federal Regulations, 2013 CFR

2013-10-01

... PERTAINING TO SPECIFIC VESSEL TYPES Special Rules Pertaining to Mobile Offshore Drilling Units § 174.030 Specific applicability. Each mobile offshore drilling unit (MODU) inspected under Subchapter IA of this...

46 CFR 174.030 - Specific applicability.

Code of Federal Regulations, 2010 CFR

2010-10-01

... PERTAINING TO SPECIFIC VESSEL TYPES Special Rules Pertaining to Mobile Offshore Drilling Units § 174.030 Specific applicability. Each mobile offshore drilling unit (MODU) inspected under Subchapter IA of this...

46 CFR 174.300 - Specific applicability.

Code of Federal Regulations, 2010 CFR

2010-10-01

... PERTAINING TO SPECIFIC VESSEL TYPES Hopper Dredges With Working Freeboard Assignments § 174.300 Specific applicability. This subpart applies to each self-propelled hopper dredge for which a working freeboard...

46 CFR 174.300 - Specific applicability.

Code of Federal Regulations, 2011 CFR

2011-10-01

... PERTAINING TO SPECIFIC VESSEL TYPES Hopper Dredges With Working Freeboard Assignments § 174.300 Specific applicability. This subpart applies to each self-propelled hopper dredge for which a working freeboard...

Cathepsin B-degradable, NIR-responsive nanoparticulate platform for target-specific cancer therapy

NASA Astrophysics Data System (ADS)

Tarassoli, Sam P.; Martinez de Pinillos Bayona, Alejandra; Pye, Hayley; Mosse, C. Alexander; Callan, John F.; MacRobert, Alexander; McHale, Anthony P.; Nomikou, Nikolitsa

2017-02-01

Stimuli-responsive anticancer formulations can promote drug release and activation within the target tumour, facilitate cellular uptake, as well as improve the therapeutic efficacy of drugs and reduce off-target effects. In the present work, indocyanine green (ICG)-containing polyglutamate (PGA) nanoparticles were developed and characterized. Digestion of nanoparticles with cathepsin B, a matrix metalloproteinase overexpressed in the microenvironment of advanced tumours, decreased particle size and increased ICG cellular uptake. Incorporation of ICG in PGA nanoparticles provided the NIR-absorbing agent with time-dependent altered optical properties in the presence of cathepsin B. Having minimal dark toxicity, the formulation exhibited significant cytotoxicity upon NIR exposure. Combined use of the formulation with saporin, a ribosome-inactivating protein, resulted in synergistically enhanced cytotoxicity attributed to the photo-induced release of saporin from endo/lysosomes. The results suggest that this therapeutic approach can offer significant therapeutic benefit in the treatment of superficial malignancies, such as head and neck tumours.

Application of Magnetized Target Fusion to High-Energy Space Propulsion

NASA Technical Reports Server (NTRS)

Thio, Y. C. F.; Schmidt, G. R.; Kirkpatrick, R. C.; Rodgers, Stephen L. (Technical Monitor)

2001-01-01

Most fusion propulsion concepts that have been investigated in the past employ some form of inertial or magnetic confinement. Although the prospective performance of these concepts is excellent, the fusion processes on which these concepts are based still require considerable development before they can be seriously considered for actual applications. Furthermore, these processes are encumbered by the need for sophisticated plasma and power handling systems that are generally quite inefficient and have historically resulted in large, massive spacecraft designs. Here we present a comparatively new approach, Magnetized Target Fusion (MTF), which offers a nearer-term avenue for realizing the tremendous performance benefits of fusion propulsion'. The key advantage of MTF is its less demanding requirements for driver energy and power processing. Additional features include: 1) very low system masses and volumes, 2) high gain and relatively low waste heat, 3) substantial utilization of energy from product neutrons, 4) efficient, low peak-power drivers based on existing pulsed power technology, and 5) very high Isp, specific power and thrust. MTF overcomes many of the problems associated with traditional fusion techniques, thus making it particularly attractive for space applications. Isp greater than 50,000 seconds and specific powers greater than 50 kilowatts/kilogram appear feasible using relatively near-term pulse power and plasma gun technology.

Meigo governs dendrite targeting specificity by modulating Ephrin level and N-glycosylation

PubMed Central

Sekine, Sayaka U; Haraguchi, Shuka; Chao, Kinhong; Kato, Tomoko; Luo, Liqun; Miura, Masayuki; Chihara, Takahiro

2016-01-01

Neural circuit assembly requires precise dendrite and axon targeting. We identified an evolutionarily conserved endoplasmic reticulum (ER) protein, Meigo, from a mosaic genetic screen in Drosophila melanogaster. Meigo was cell-autonomously required in olfactory receptor neurons and projection neurons to target their axons and dendrites to the lateral antennal lobe and to refine projection neuron dendrites into individual glomeruli. Loss of Meigo induced an unfolded protein response and reduced the amount of neuronal cell surface proteins, including Ephrin. Ephrin overexpression specifically suppressed the projection neuron dendrite refinement defect present in meigo mutant flies, and ephrin knockdown caused a similar projection neuron dendrite refinement defect. Meigo positively regulated the level of Ephrin N-glycosylation, which was required for its optimal function in vivo. Thus, Meigo, an ER-resident protein, governs neuronal targeting specificity by regulating ER folding capacity and protein N-glycosylation. Furthermore, Ephrin appears to be an important substrate that mediates Meigo’s function in refinement of glomerular targeting. PMID:23624514

Search guidance is proportional to the categorical specificity of a target cue.

PubMed

Schmidt, Joseph; Zelinsky, Gregory J

2009-10-01

Visual search studies typically assume the availability of precise target information to guide search, often a picture of the exact target. However, search targets in the real world are often defined categorically and with varying degrees of visual specificity. In five target preview conditions we manipulated the availability of target visual information in a search task for common real-world objects. Previews were: a picture of the target, an abstract textual description of the target, a precise textual description, an abstract + colour textual description, or a precise + colour textual description. Guidance generally increased as information was added to the target preview. We conclude that the information used for search guidance need not be limited to a picture of the target. Although generally less precise, to the extent that visual information can be extracted from a target label and loaded into working memory, this information too can be used to guide search.

Design criteria for a high energy Compton Camera and possible application to targeted cancer therapy

NASA Astrophysics Data System (ADS)

Conka Nurdan, T.; Nurdan, K.; Brill, A. B.; Walenta, A. H.

2015-07-01

The proposed research focuses on the design criteria for a Compton Camera with high spatial resolution and sensitivity, operating at high gamma energies and its possible application for molecular imaging. This application is mainly on the detection and visualization of the pharmacokinetics of tumor targeting substances specific for particular cancer sites. Expected high resolution (< 0.5 mm) permits monitoring the pharmacokinetics of labeled gene constructs in vivo in small animals with a human tumor xenograft which is one of the first steps in evaluating the potential utility of a candidate gene. The additional benefit of high sensitivity detection will be improved cancer treatment strategies in patients based on the use of specific molecules binding to cancer sites for early detection of tumors and identifying metastasis, monitoring drug delivery and radionuclide therapy for optimum cell killing at the tumor site. This new technology can provide high resolution, high sensitivity imaging of a wide range of gamma energies and will significantly extend the range of radiotracers that can be investigated and used clinically. The small and compact construction of the proposed camera system allows flexible application which will be particularly useful for monitoring residual tumor around the resection site during surgery. It is also envisaged as able to test the performance of new drug/gene-based therapies in vitro and in vivo for tumor targeting efficacy using automatic large scale screening methods.

Prostate-specific membrane antigen for prostate cancer theranostics: from imaging to targeted therapy.

PubMed

Arsenault, Frédéric; Beauregard, Jean-Mathieu; Pouliot, Frédéric

2018-06-22

In recent years, major advances in molecular imaging of prostate cancers (PCa) were made with the development and clinical validation of highly accurate PET tracers to stage and restage the disease. Prostate-specific membrane antigen (PSMA) is a transmembrane protein highly expressed in PCa, and its expression has led to the development of PSMA-binding radiopharmaceuticals for molecular imaging or radioligand therapy (RLT). We herein review the recent literature published on diagnostic and therapeutic (i.e. theranostic) PSMA tracers. Development in small PSMA-targeted molecules labeled with gallium-68 and fluorine-18 show promising results for primary staging and detection of disease at biochemical recurrence using PET/computed tomography (PET/CT). Studies show a higher sensitivity and specificity, along with an improved detection rate over conventional imaging (CT scan and bone scan) or choline PET tracers, especially for restaging after prostate-specific antigen failure following loco-regional therapy. In addition, some PSMA tracers can be labeled with beta-minus and alpha particle emitters, yielding encouraging response rates and low toxicity, and potentially offering a new line of targeted therapy for metastatic castration-resistant PCa. PSMA-targeted tracers have shown unprecedented accuracy to stage and restage PCa using PET/CT. Given their specific biodistribution toward PCa tissue, PSMA RLT now offers new therapeutic possibilities to target metastatic PCa. Prospective multicenter randomized studies investigating the clinical impact management impacts of PSMA-targeted molecules are urgently needed.

Optimization of cell receptor-specific targeting through multivalent surface decoration of polymeric nanocarriers

PubMed Central

D’Addio, Suzanne M.; Baldassano, Steven; Shi, Lei; Cheung, Lila; Adamson, Douglas H.; Bruzek, Matthew; Anthony, John E.; Laskin, Debra L.; Sinko, Patrick J.; Prud’homme, Robert K.

2013-01-01

Treatment of tuberculosis is impaired by poor drug bioavailability, systemic side effects, patient non-compliance, and pathogen resistance to existing therapies. The mannose receptor (MR) is known to be involved in the recognition and internalization of Mycobacterium tuberculosis. We present a new assembly process to produce nanocarriers with variable surface densities of mannose targeting ligands in a single step, using kinetically-controlled, block copolymer-directed assembly. Nanocarrier association with murine macrophage J774 cells expressing the MR is examined as a function of incubation time and temperature, nanocarrier size, dose, and PEG corona properties. Amphiphilic diblock copolymers are prepared with terminal hydroxyl, methoxy, or mannoside functionality and incorporated into nanocarrier formulations at specific ratios by Flash NanoPrecipitation. Association of nanocarriers protected by a hydroxyl-terminated PEG corona with J774 cells is size dependent, while nanocarriers with methoxy-terminated PEG coronas do not associate with cells, regardless of size. Specific targeting of the MR is investigated using nanocarriers having 0-75% mannoside-terminated PEG chains in the PEG corona. This is a wider range of mannose densities than has been previously studied. Maximum nanocarrier association is attained with 9% mannoside-terminated PEG chains, increasing uptake more than 3-fold compared to non-targeted nanocarriers with a 5 kg mol−1 methoxy-terminated PEG corona. While a 5 kg mol−1 methoxy-terminated PEG corona prevents non-specific uptake, a 1.8 kg mol−1 methoxy-terminated PEG corona does not sufficiently protect the nanocarriers from nonspecific association. There is continuous uptake of MR-targeted nanocarriers at 37°C, but a saturation of association at 4°C. The majority of targeted nanocarriers associate with J774E cells are internalized at 37°C and uptake is receptor-dependent, diminishing with competitive inhibition by dextran. This

Target-specific stigma change: a strategy for impacting mental illness stigma.

PubMed

Corrigan, Patrick W

2004-01-01

In the past decade, mental health advocates and researchers have sought to better understand stigma so that the harm it causes can be erased. In this paper, we propose a target-specific stigma change model to organize the diversity of information into a cogent framework. "Target" here has a double meaning: the power groups that have some authority over the life goals of people with mental illness and specific discriminatory behaviors which power groups might produce that interfere with these goals. Key power groups in the model include landlords, employers, health care providers, criminal justice professionals, policy makers, and the media. Examples are provided of stigmatizing attitudes that influence the discriminatory behavior and social context in which the power group interacts with people with mental illness. Stigma change is most effective when it includes all the components that describe how a specific power group impacts people with mental illness.

Semiconductor nanocrystal-aptamer bioconjugate probes for specific prostate carcinoma cell targeting

NASA Astrophysics Data System (ADS)

Shieh, Felice; Lavery, Laura; Chu, Chitai T.; Richards-Kortum, Rebecca; Ellington, Andrew D.; Korgel, Brian A.

2005-04-01

Cancer of the prostate affects approximately 1 in 11 men. Current early screening for prostate cancer utilizes digital rectal examinations to detect anomalies in the prostate gland and blood test screenings for upregulated levels of prostate specific antigen (PSA). Many of these tests are invasive and can often be inconclusive as PSA levels may be heightened due to benign factors. Prostate specific membrane antigen (PSMA), a well-characterized integral membrane protein, is expressed in virtually all prostate cancers and often correlates with cancer aggressiveness. Therefore, it may be used as an indicator of cancer growth and metastases. PSMA-specific antibodies have been identified and conjugated to fluorescent markers for cancer cell targeting; however, both the antibodies and markers possess significant limitations in their pharmaceutical and diagnostic value. Here we report the use of semiconductor nanocrystals bioconjugated to PSMA-specific aptamer recognition molecules for prostate carcinoma cell targeting. The nanocrystal/aptamer bioconjugates are small biocompatible probes with the potential for color-tunability for multicolor imaging. Ongoing in vitro and in vivo research seeks to introduce these nanoparticle bioconjugates into medical diagnostics.

Towards development of aptamers that specifically bind to lactate dehydrogenase of Plasmodium falciparum through epitopic targeting.

PubMed

Frith, Kelly-Anne; Fogel, Ronen; Goldring, J P Dean; Krause, Robert G E; Khati, Makobetsa; Hoppe, Heinrich; Cromhout, Mary E; Jiwaji, Meesbah; Limson, Janice L

2018-05-03

Early detection is crucial for the effective treatment of malaria, particularly in those cases infected with Plasmodium falciparum. There is a need for diagnostic devices with the capacity to distinguish P. falciparum from other strains of malaria. Here, aptamers generated against targeted species-specific epitopes of P. falciparum lactate dehydrogenase (rPfLDH) are described. Two classes of aptamers bearing high binding affinity and specificity for recombinant P. falciparum lactate dehydrogenase (rPfLDH) and P. falciparum-specific lactate dehydrogenase epitopic oligopeptide (LDHp) were separately generated. Structurally-relevant moieties with particular consensus sequences (GGTAG and GGCG) were found in aptamers reported here and previously published, confirming their importance in recognition of the target, while novel moieties particular to this work (ATTAT and poly-A stretches) were identified. Aptamers with diagnostically-supportive functions were synthesized, prime examples of which are the aptamers designated as LDHp 1, LDHp 11 and rLDH 4 and rLDH 15 in work presented herein. Of the sampled aptamers raised against the recombinant protein, rLDH 4 showed the highest binding to the target rPfLDH in the ELONA assay, with both rLDH 4 and rLDH 15 indicating an ability to discriminate between rPfLDH and rPvLDH. LDHp 11 was generated against a peptide selected as a unique P. falciparum LDH peptide. The aptamer, LDHp 11, like antibodies against the same peptide, only detected rPfLDH and discriminated between rPfLDH and rPvLDH. This was supported by affinity binding experiments where only aptamers generated against a unique species-specific epitope showed an ability to preferentially bind to rPfLDH relative to rPvLDH rather than those generated against the whole recombinant protein. In addition, rLDH 4 and LDHp 11 demonstrated in situ binding to P. falciparum cells during confocal microscopy. The utilization and application of LDHp 11, an aptamer generated against a

Augmenting the Efficacy of Immunotoxins and Other Targeted Protein Toxins by Endosomal Escape Enhancers.

PubMed

Fuchs, Hendrik; Weng, Alexander; Gilabert-Oriol, Roger

2016-07-01

The toxic moiety of almost all protein-based targeted toxins must enter the cytosol of the target cell to mediate its fatal effect. Although more than 500 targeted toxins have been investigated in the past decades, no antibody-targeted protein toxin has been approved for tumor therapeutic applications by the authorities to date. Missing efficacy can be attributed in many cases to insufficient endosomal escape and therefore subsequent lysosomal degradation of the endocytosed toxins. To overcome this drawback, many strategies have been described to weaken the membrane integrity of endosomes. This comprises the use of lysosomotropic amines, carboxylic ionophores, calcium channel antagonists, various cell-penetrating peptides of viral, bacterial, plant, animal, human and synthetic origin, other organic molecules and light-induced techniques. Although the efficacy of the targeted toxins was typically augmented in cell culture hundred or thousand fold, in exceptional cases more than million fold, the combination of several substances harbors new problems including additional side effects, loss of target specificity, difficulties to determine the therapeutic window and cell type-dependent variations. This review critically scrutinizes the chances and challenges of endosomal escape enhancers and their potential role in future developments.

Augmenting the Efficacy of Immunotoxins and Other Targeted Protein Toxins by Endosomal Escape Enhancers

PubMed Central

Fuchs, Hendrik; Weng, Alexander; Gilabert-Oriol, Roger

2016-01-01

The toxic moiety of almost all protein-based targeted toxins must enter the cytosol of the target cell to mediate its fatal effect. Although more than 500 targeted toxins have been investigated in the past decades, no antibody-targeted protein toxin has been approved for tumor therapeutic applications by the authorities to date. Missing efficacy can be attributed in many cases to insufficient endosomal escape and therefore subsequent lysosomal degradation of the endocytosed toxins. To overcome this drawback, many strategies have been described to weaken the membrane integrity of endosomes. This comprises the use of lysosomotropic amines, carboxylic ionophores, calcium channel antagonists, various cell-penetrating peptides of viral, bacterial, plant, animal, human and synthetic origin, other organic molecules and light-induced techniques. Although the efficacy of the targeted toxins was typically augmented in cell culture hundred or thousand fold, in exceptional cases more than million fold, the combination of several substances harbors new problems including additional side effects, loss of target specificity, difficulties to determine the therapeutic window and cell type-dependent variations. This review critically scrutinizes the chances and challenges of endosomal escape enhancers and their potential role in future developments. PMID:27376327

Lifelong-RL: Lifelong Relaxation Labeling for Separating Entities and Aspects in Opinion Targets.

PubMed

Shu, Lei; Liu, Bing; Xu, Hu; Kim, Annice

2016-11-01

It is well-known that opinions have targets. Extracting such targets is an important problem of opinion mining because without knowing the target of an opinion, the opinion is of limited use. So far many algorithms have been proposed to extract opinion targets. However, an opinion target can be an entity or an aspect (part or attribute) of an entity. An opinion about an entity is an opinion about the entity as a whole, while an opinion about an aspect is just an opinion about that specific attribute or aspect of an entity. Thus, opinion targets should be separated into entities and aspects before use because they represent very different things about opinions. This paper proposes a novel algorithm, called Lifelong-RL , to solve the problem based on lifelong machine learning and relaxation labeling . Extensive experiments show that the proposed algorithm Lifelong-RL outperforms baseline methods markedly.

Multishot Targeted PROPELLER Magnetic Resonance Imaging: Description of the Technique and Initial Applications

PubMed Central

Deng, Jie; Larson, Andrew C.

2010-01-01

Objectives To test the feasibility of combining inner-volume imaging (IVI) techniques with conventional multishot periodically rotated overlapping parallel lines with enhanced reconstruction (PROPELLER) techniques for targeted-PROPELLER magnetic resonance imaging. Materials and Methods Perpendicular section-selective gradients for spatially selective excitation and refocusing RF pulses were applied to limit the refocused field-of-view (FOV) along the phase-encoding direction for each rectangular blade image. We performed comparison studies in phantoms and normal volunteers by using targeted-PROPELLER methods for a wide range of imaging applications that commonly use turbo-spin-echo (TSE) approaches (brain, abdominal, vessel wall, cardiac). Results In these initial studies, we demonstrated the feasibility of using targeted-PROPELLER approaches to limit the imaging FOV thereby reducing the number of blades or permitting increased spatial resolution without commensurate increases in scan time. Both phantom and in vivo motion studies demonstrated the potential for more robust regional self-navigated motion correction compared with conventional full FOV PROPELLER methods. Conclusion We demonstrated that the reduced FOV targeted-PROPELLER technique offers the potential for reducing imaging time, increasing spatial resolution, and targeting specific areas for robust regional motion correction. PMID:19465860

Hierarchical mesosilicalite nanoformulation integrated with cisplatin exhibits target-specific efficient anticancer activity

NASA Astrophysics Data System (ADS)

Jermy, B. Rabindran; Acharya, Sadananda; Ravinayagam, Vijaya; Alghamdi, Hajer Saleh; Akhtar, Sultan; Basuwaidan, Rehab S.

2018-04-01

Hierarchically structured zeolitic ZSM-5 and meso MCM-41 interlinked domain had an impeccable use as catalysis in many applications. The aim of the study was to develop a new drug delivery nanoformulation, specifically, cisplatin/mesosilicalite using top-down approach for cancer therapy. Hierarchical mesosilicalite with variable porosity was synthesized using alkaline molar solution (0.2 and 0.7 M NaOH) and was loaded with cisplatin through equilibrium adsorption technique. Physico-chemical properties of the nanoformulation (IAUM-56—Imam Abdulrahman Bin Faisal University Mesosilicalite-56) were characterized using X-ray diffraction, surface area analysis (BET), Fourier transformed infrared spectroscopy (FT-IR), diffuse reflectance UV-Vis spectroscopy, and transmission electron microscopy. Drug release study and anticancer activity were assayed on HeLa and MCF7 cancer cells using MTT assay. X-ray diffraction pattern showed interrelated meso- and microphases, while BET analysis revealed considerable mesoporosity formation with a remodulation of isotherm hysteresis indicating the presence of hierarchical pores. FT-IR showed the presence of nanozeolitic subunits into mesostructure with a band at about 550 cm-1. IAUM-56 demonstrated high cytotoxic activity against HeLa cancer cells with an LC50 of 0.02 mg/ml, MCF7 cancer cells with an LC50 of 0.05 mg/ml, and less toxic to normal fibroblast cells with an LC50 of approximately ten times higher at 0.5 mg/ml. Overall, IAUM-56 showed a high rate of sustained release of cisplatin imparting target specific cytotoxic effect against tumor cells with at least tenfold lower toxicity on normal fibroblast cells. Our nanoformulation has the potential use in cancer therapy as a targeted drug delivery system.

Russia-specific relative risks and their effects on the estimated alcohol-attributable burden of disease.

PubMed

Shield, Kevin D; Rehm, Jürgen

2015-05-10

Alcohol consumption is a major risk factor for the burden of disease globally. This burden is estimated using Relative Risk (RR) functions for alcohol from meta-analyses that use data from all countries; however, for Russia and surrounding countries, country-specific risk data may need to be used. The objective of this paper is to compare the estimated burden of alcohol consumption calculated using Russia-specific alcohol RRs with the estimated burden of alcohol consumption calculated using alcohol RRs from meta-analyses. Data for 2012 on drinking indicators were calculated based on the Global Information System on Alcohol and Health. Data for 2012 on mortality, Years of Life Lost, Years Lived with Disability, and Disability-Adjusted Life Years (DALYs) lost by cause were obtained by country from the World Health Organization. Alcohol Population-Attributable Fractions (PAFs) were calculated based on a risk modelling methodology from Russia. These PAFs were compared to PAFs calculated using methods applied for all other countries. The 95% Uncertainty Intervals (UIs) for the alcohol PAFs were calculated using a Monte Carlo-like method. Using Russia-specific alcohol RR functions, in Russia in 2012 alcohol caused an estimated 231,900 deaths (95% UI: 185,600 to 278,200) (70,800 deaths among women and 161,100 deaths among men) and 13,295,000 DALYs lost (95% UI: 11,242,000 to 15,348,000) (3,670,000 DALYs lost among women and 9,625,000 DALYs lost among men) among people 0 to 64 years of age. This compares to an estimated 165,600 deaths (95% UI: 97,200 to 228,100) (29,700 deaths among women and 135,900 deaths among men) and 10,623,000 DALYs lost (95% UI: 7,265,000 to 13,754,000) (1,783,000 DALYs lost among women and 8,840,000 DALYs lost among men) among people 0 to 64 years of age caused by alcohol when non-Russia-specific alcohol RRs were used. Results indicate that if the Russia-specific RRs are used when estimating the health burden attributable to alcohol consumption in

Fabrication of 14 different RNA nanoparticles for specific tumor targeting without accumulation in normal organs

PubMed Central

Shu, Yi; Haque, Farzin; Shu, Dan; Li, Wei; Zhu, Zhenqi; Kotb, Malak; Lyubchenko, Yuri; Guo, Peixuan

2013-01-01

Due to structural flexibility, RNase sensitivity, and serum instability, RNA nanoparticles with concrete shapes for in vivo application remain challenging to construct. Here we report the construction of 14 RNA nanoparticles with solid shapes for targeting cancers specifically. These RNA nanoparticles were resistant to RNase degradation, stable in serum for >36 h, and stable in vivo after systemic injection. By applying RNA nanotechnology and exemplifying with these 14 RNA nanoparticles, we have established the technology and developed “toolkits” utilizing a variety of principles to construct RNA architectures with diverse shapes and angles. The structure elements of phi29 motor pRNA were utilized for fabrication of dimers, twins, trimers, triplets, tetramers, quadruplets, pentamers, hexamers, heptamers, and other higher-order oligomers, as well as branched diverse architectures via hand-in-hand, foot-to-foot, and arm-on-arm interactions. These novel RNA nanostructures harbor resourceful functionalities for numerous applications in nanotechnology and medicine. It was found that all incorporated functional modules, such as siRNA, ribozymes, aptamers, and other functionalities, folded correctly and functioned independently within the nanoparticles. The incorporation of all functionalities was achieved prior, but not subsequent, to the assembly of the RNA nanoparticles, thus ensuring the production of homogeneous therapeutic nanoparticles. More importantly, upon systemic injection, these RNA nanoparticles targeted cancer exclusively in vivo without accumulation in normal organs and tissues. These findings open a new territory for cancer targeting and treatment. The versatility and diversity in structure and function derived from one biological RNA molecule implies immense potential concealed within the RNA nanotechnology field. PMID:23604636

Selective layer-free blood serum ionogram based on ion-specific interactions with a nanotransistor

NASA Astrophysics Data System (ADS)

Sivakumarasamy, R.; Hartkamp, R.; Siboulet, B.; Dufrêche, J.-F.; Nishiguchi, K.; Fujiwara, A.; Clément, N.

2018-05-01

Despite being ubiquitous in the fields of chemistry and biology, the ion-specific effects of electrolytes pose major challenges for researchers. A lack of understanding about ion-specific surface interactions has hampered the development and application of materials for (bio-)chemical sensor applications. Here, we show that scaling a silicon nanotransistor sensor down to 25 nm provides a unique opportunity to understand and exploit ion-specific surface interactions, yielding a surface that is highly sensitive to cations and inert to pH. The unprecedented sensitivity of these devices to Na+ and divalent ions can be attributed to an overscreening effect via molecular dynamics. The surface potential of multi-ion solutions is well described by the sum of the electrochemical potentials of each cation, enabling selective measurements of a target ion concentration without requiring a selective organic layer. We use these features to construct a blood serum ionogram for Na+, K+, Ca2+ and Mg2+, in an important step towards the development of a versatile, durable and mobile chemical or blood diagnostic tool.

Morphology targets: What do seedling morphological attributes tell us?

Treesearch

Jeremiah R. Pinto

2011-01-01

Morphology is classically defined as the form and structure of individual organisms, as distinct from their anatomy or physiology. We use morphological targets in the nursery because they are easy to measure, and because we can often quantitatively link seedling morphological traits with survival and growth performance in the field. In the 20 years since the Target...

Age- and gender-specific population attributable risks of metabolic disorders on all-cause and cardiovascular mortality in Taiwan

PubMed Central

2012-01-01

Background The extent of attributable risks of metabolic syndrome (MetS) and its components on mortality remains unclear, especially with respect to age and gender. We aimed to assess the age- and gender-specific population attributable risks (PARs) for cardiovascular disease (CVD)-related mortality and all-cause mortality for public health planning. Methods A total of 2,092 men and 2,197 women 30 years of age and older, who were included in the 2002 Taiwan Survey of Hypertension, Hyperglycemia, and Hyperlipidemia (TwSHHH), were linked to national death certificates acquired through December 31, 2009. Cox proportional hazard models were used to calculate adjusted hazard ratios and PARs for mortality, with a median follow-up of 7.7 years. Results The respective PAR percentages of MetS for all-cause and CVD-related mortality were 11.6 and 39.2 in men, respectively, and 18.6 and 44.4 in women, respectively. Central obesity had the highest PAR for CVD mortality in women (57.5%), whereas arterial hypertension had the highest PAR in men (57.5%). For all-cause mortality, younger men and post-menopausal women had higher PARs related to Mets and its components; for CVD mortality, post-menopausal women had higher overall PARs than their pre-menopausal counterparts. Conclusions MetS has a limited application to the PAR for all-cause mortality, especially in men; its PAR for CVD mortality is more evident. For CVD mortality, MetS components have higher PARs than MetS itself, especially hypertension in men and waist circumference in post-menopausal women. In addition, PARs for diabetes mellitus and low HDL-cholesterol may exceed 20%. We suggest differential control of risk factors in different subpopulation as a strategy to prevent CVD-related mortality. PMID:22321049

A new highly sensitive and specific real-time PCR assay targeting the malate dehydrogenase gene of Kingella kingae and application to 201 pediatric clinical specimens.

PubMed

Houmami, Nawal El; Durand, Guillaume André; Bzdrenga, Janek; Darmon, Anne; Minodier, Philippe; Seligmann, Hervé; Raoult, Didier; Fournier, Pierre-Edouard

2018-06-06

Kingella kingae is a significant pediatric pathogen responsible for bone and joint infections, occult bacteremia, and endocarditis in early childhood. Past efforts to detect this bacterium by culture and broad-range 16S rRNA gene polymerase chain reaction (PCR) assays from clinical specimens have proven unsatisfactory and were gradually let out for the benefit of specific real-time PCR tests targeting the groEL gene and RTX locus of K. kingae by the late 2000s. However, recent studies showed that real-time PCR (RT-PCR) assays targeting the Kingella sp. RTX locus that are currently available for the diagnosis of K. kingae infection lack of specificity because they could not distinguish between K. kingae and the recently described K. negevensis species. Furthermore, in silico analysis of the groEL gene from a large collection of 45 K. kingae strains showed that primers and probes from K. kingae groEL -based RT-PCR assays display a few mismatches with K. kingae groEL variations that may result in a decreased detection sensitivity, especially in paucibacillary clinical specimens. In order to provide an alternative to groEL - and RTX-targeting RT-PCR assays that may suffer from suboptimal specificity and sensitivity, a K. kingae -specific RT-PCR assay targeting the malate dehydrogenase ( mdh ) gene was developed for predicting no mismatch against 18 variants of the K. kingae mdh gene from 20 distinct sequences types of K. kingae This novel K. kingae -specific RT-PCR assay demonstrated a high specificity and sensitivity and was successfully used to diagnose K. kingae infections and carriage in 104 clinical specimens from children aged between 7 months and 7 years old. Copyright © 2018 American Society for Microbiology.

Belief attribution despite verbal interference.

PubMed

Forgeot d'Arc, Baudouin; Ramus, Franck

2011-05-01

False-belief (FB) tasks have been widely used to study the ability of individuals to represent the content of their conspecifics' mental states (theory of mind). However, the cognitive processes involved are still poorly understood, and it remains particularly debated whether language and inner speech are necessary for the attribution of beliefs to other agents. We present a completely nonverbal paradigm consisting of silent animated cartoons in five closely related conditions, systematically teasing apart different aspects of scene analysis and allowing the assessment of the attribution of beliefs, goals, and physical causation. In order to test the role of language in belief attribution, we used verbal shadowing as a dual task to inhibit inner speech. Data on 58 healthy adults indicate that verbal interference decreases overall performance, but has no specific effect on belief attribution. Participants remained able to attribute beliefs despite heavy concurrent demands on their verbal abilities. Our results are most consistent with the hypothesis that belief attribution is independent from inner speech.

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

PubMed

Sadekar, S; Figueroa, I; Tabrizi, M

2015-07-01

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

Target-Specific Delivery of an Antibody That Blocks the Formation of Collagen Deposits in Skin and Lung.

PubMed

Fertala, Jolanta; Romero, Freddy; Summer, Ross; Fertala, Andrzej

2017-10-01

Regardless of the cause of organ fibrosis, its main unwanted consequence is the formation of collagen fibril-rich deposits that hamper the structure and function of affected tissues. Although many strategies have been proposed for the treatment of fibrotic diseases, no therapy has been developed, which can effectively block the formation of collagen fibril deposits. With this in mind, we recently developed an antibody-based therapy to block key interactions that drive collagen molecules into fibrils. In this study, we analyzed target specificity, which is a main parameter that defines the safe use of all antibody-based therapies in humans. We hypothesized that, regardless of the route of administration, our antibody would preferentially bind to free collagen molecules synthesized at the sites of fibrosis and have minimal off-target interactions when applied in various tissues. To test this hypothesis, we used two experimental models of organ fibrosis: (1) a keloid model, in which antibody constructs were directly implanted under the skin of nude mice and (2) an experimental model of pulmonary fibrosis, in which our antibody was administered systemically by intravenous injection. Following administration, we studied the distribution of our antibody within target and off-target sites as well as analyzed its effects on fibrotic tissue formation. We found that local and systemic application of our antibody had high specificity for targeting collagen fibrillogenesis and also appeared safe and therapeutically effective. In summary, this study provides the basis for further testing our antifibrotic antibody in a broad range of disease conditions and suggests that this treatment approach will be effective if delivered by local or systemic administration.

Antigen sensitivity of CD22-specific chimeric T cell receptors is modulated by target epitope distance from the cell membrane

PubMed Central

James, Scott E.; Greenberg, Philip D.; Jensen, Michael C.; Lin, Yukang; Wang, Jinjuan; Till, Brian G.; Raubitschek, Andrew A.; Forman, Stephen J.; Press, Oliver W.

2008-01-01

We have targeted CD22 as a novel tumor-associated antigen for recognition by human CTL genetically modified to express chimeric T cell receptors (cTCR) recognizing this surface molecule. CD22-specifc cTCR targeting different epitopes of the CD22 molecule promoted efficient lysis of target cells expressing high levels of CD22 with a maximum lytic potential that appeared to decrease as the distance of the target epitope from the target cell membrane increased. Targeting membrane-distal CD22 epitopes with cTCR+ CTL revealed defects in both degranulation and lytic granule targeting. CD22-specific cTCR+ CTL exhibited lower levels of maximum lysis and lower antigen sensitivity than CTL targeting CD20, which has a shorter extracellular domain than CD22. This diminished sensitivity was not a result of reduced avidity of antigen engagement, but instead reflected weaker signaling per triggered cTCR molecule when targeting membrane-distal epitopes of CD22. Both of these parameters were restored by targeting a ligand expressing the same epitope but constructed as a truncated CD22 molecule to approximate the length of a TCR:pMHC complex. The reduced sensitivity of CD22-specific cTCR+ CTL for antigen-induced triggering of effector functions has potential therapeutic applications, as such cells selectively lysed B cell lymphoma lines expressing high levels of CD22 but demonstrated minimal activity against autologous normal B cells, which express lower levels of CD22. Thus, our results demonstrate that cTCR signal strength – and consequently antigen sensitivity – can be modulated by differential choice of target epitopes with respect to distance from the cell membrane, allowing discrimination between targets with disparate antigen density. PMID:18453625

Mapping target signatures via partial unmixing of AVIRIS data

NASA Technical Reports Server (NTRS)

Boardman, Joseph W.; Kruse, Fred A.; Green, Robert O.

1995-01-01

A complete spectral unmixing of a complicated AVIRIS scene may not always be possible or even desired. High quality data of spectrally complex areas are very high dimensional and are consequently difficult to fully unravel. Partial unmixing provides a method of solving only that fraction of the data inversion problem that directly relates to the specific goals of the investigation. Many applications of imaging spectrometry can be cast in the form of the following question: 'Are my target signatures present in the scene, and if so, how much of each target material is present in each pixel?' This is a partial unmixing problem. The number of unmixing endmembers is one greater than the number of spectrally defined target materials. The one additional endmember can be thought of as the composite of all the other scene materials, or 'everything else'. Several workers have proposed partial unmixing schemes for imaging spectrometry data, but each has significant limitations for operational application. The low probability detection methods described by Farrand and Harsanyi and the foreground-background method of Smith et al are both examples of such partial unmixing strategies. The new method presented here builds on these innovative analysis concepts, combining their different positive attributes while attempting to circumvent their limitations. This new method partially unmixes AVIRIS data, mapping apparent target abundances, in the presence of an arbitrary and unknown spectrally mixed background. It permits the target materials to be present in abundances that drive significant portions of the scene covariance. Furthermore it does not require a priori knowledge of the background material spectral signatures. The challenge is to find the proper projection of the data that hides the background variance while simultaneously maximizing the variance amongst the targets.

Hypoxia-inducible tumour-specific promoters as a dual-targeting transcriptional regulation system for cancer gene therapy

PubMed Central

Javan, Bita; Shahbazi, Majid

2017-01-01

Transcriptional targeting is the best approach for specific gene therapy. Hypoxia is a common feature of the tumour microenvironment. Therefore, targeting gene expression in hypoxic cells by placing transgene under the control of a hypoxia-responsive promoter can be a good strategy for cancer-specific gene therapy. The hypoxia-inducible gene expression system has been investigated more in suicide gene therapy and it can also be of great help in knocking down cancer gene therapy with siRNAs. However, this system needs to be optimised to have maximum efficacy with minimum side effects in normal tissues. The combination of tissue-/tumour-specific promoters with HRE core sequences has been found to enhance the specificity and efficacy of this system. In this review, hypoxia-inducible gene expression system as well as gene therapy strategies targeting tumour hypoxia will be discussed. This review will also focus on hypoxia-inducible tumour-specific promoters as a dual-targeting transcriptional regulation systems developed for cancer-specific gene therapy. PMID:28798809

Intercepting moving targets: does memory from practice in a specific condition of target displacement affect movement timing?

PubMed

de Azevedo Neto, Raymundo Machado; Teixeira, Luis Augusto

2011-05-01

This investigation aimed at assessing the extent to which memory from practice in a specific condition of target displacement modulates temporal errors and movement timing of interceptive movements. We compared two groups practicing with certainty of future target velocity either in unchanged target velocity or in target velocity decrease. Following practice, both experimental groups were probed in the situations of unchanged target velocity and target velocity decrease either under the context of certainty or uncertainty about target velocity. Results from practice showed similar improvement of temporal accuracy between groups, revealing that target velocity decrease did not disturb temporal movement organization when fully predictable. Analysis of temporal errors in the probing trials indicated that both groups had higher timing accuracy in velocity decrease in comparison with unchanged velocity. Effect of practice was detected by increased temporal accuracy of the velocity decrease group in situations of decreased velocity; a trend consistent with the expected effect of practice was observed for temporal errors in the unchanged velocity group and in movement initiation at a descriptive level. An additional point of theoretical interest was the fast adaptation in both groups to a target velocity pattern different from that practiced. These points are discussed under the perspective of integration of vision and motor control by means of an internal forward model of external motion.

Specification Patent Management for Web Application Platform Ecosystem

NASA Astrophysics Data System (ADS)

Fukami, Yoshiaki; Isshiki, Masao; Takeda, Hideaki; Ohmukai, Ikki; Kokuryo, Jiro

Diversified usage of web applications has encouraged disintegration of web platform into management of identification and applications. Users make use of various kinds of data linked to their identity with multiple applications on certain social web platforms such as Facebook or MySpace. There has emerged competition among web application platforms. Platformers can design relationship with developers by controlling patent of their own specification and adopt open technologies developed external organizations. Platformers choose a way to open according to feature of the specification and their position. Patent management of specification come to be a key success factor to build competitive web application platforms. Each way to attract external developers such as standardization, open source has not discussed and analyzed all together.

46 CFR 160.061-1 - Applicable specifications.

Code of Federal Regulations, 2012 CFR

2012-10-01

... Applicable specifications. (a) The following specifications, of the issue in effect on the date emergency..., fiber, hard sheet. CCC-F-451—Flannel, canton. (2) Military specifications: MIL-H-2846—Hooks, fish, steel...

46 CFR 160.061-1 - Applicable specifications.

Code of Federal Regulations, 2013 CFR

2013-10-01

... Applicable specifications. (a) The following specifications, of the issue in effect on the date emergency..., fiber, hard sheet. CCC-F-451—Flannel, canton. (2) Military specifications: MIL-H-2846—Hooks, fish, steel...

46 CFR 160.061-1 - Applicable specifications.

Code of Federal Regulations, 2014 CFR

2014-10-01

... Applicable specifications. (a) The following specifications, of the issue in effect on the date emergency..., fiber, hard sheet. CCC-F-451—Flannel, canton. (2) Military specifications: MIL-H-2846—Hooks, fish, steel...

46 CFR 160.054-1 - Applicable specification.

Code of Federal Regulations, 2014 CFR

2014-10-01

...: SPECIFICATIONS AND APPROVAL LIFESAVING EQUIPMENT Kits, First-Aid, for Inflatable Liferafts § 160.054-1 Applicable specification. (a) Specification. The following specification of the issue in effect on the date first aid kits are manufactured forms a part of this subpart: (1) Coast Guard specification 160.041—Kits, First-Aid...

46 CFR 160.054-1 - Applicable specification.

Code of Federal Regulations, 2012 CFR

2012-10-01

...: SPECIFICATIONS AND APPROVAL LIFESAVING EQUIPMENT Kits, First-Aid, for Inflatable Liferafts § 160.054-1 Applicable specification. (a) Specification. The following specification of the issue in effect on the date first aid kits are manufactured forms a part of this subpart: (1) Coast Guard specification 160.041—Kits, First-Aid...

46 CFR 160.054-1 - Applicable specification.

Code of Federal Regulations, 2011 CFR

2011-10-01

...: SPECIFICATIONS AND APPROVAL LIFESAVING EQUIPMENT Kits, First-Aid, for Inflatable Liferafts § 160.054-1 Applicable specification. (a) Specification. The following specification of the issue in effect on the date first aid kits are manufactured forms a part of this subpart: (1) Coast Guard specification 160.041—Kits, First-Aid...

46 CFR 160.054-1 - Applicable specification.

Code of Federal Regulations, 2013 CFR

2013-10-01

...: SPECIFICATIONS AND APPROVAL LIFESAVING EQUIPMENT Kits, First-Aid, for Inflatable Liferafts § 160.054-1 Applicable specification. (a) Specification. The following specification of the issue in effect on the date first aid kits are manufactured forms a part of this subpart: (1) Coast Guard specification 160.041—Kits, First-Aid...

46 CFR 160.054-1 - Applicable specification.

Code of Federal Regulations, 2010 CFR

2010-10-01

...: SPECIFICATIONS AND APPROVAL LIFESAVING EQUIPMENT Kits, First-Aid, for Inflatable Liferafts § 160.054-1 Applicable specification. (a) Specification. The following specification of the issue in effect on the date first aid kits are manufactured forms a part of this subpart: (1) Coast Guard specification 160.041—Kits, First-Aid...

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

PubMed Central

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

2016-01-01

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

Drug-targeting methodologies with applications: A review

PubMed Central

Kleinstreuer, Clement; Feng, Yu; Childress, Emily

2014-01-01

Targeted drug delivery to solid tumors is a very active research area, focusing mainly on improved drug formulation and associated best delivery methods/devices. Drug-targeting has the potential to greatly improve drug-delivery efficacy, reduce side effects, and lower the treatment costs. However, the vast majority of drug-targeting studies assume that the drug-particles are already at the target site or at least in its direct vicinity. In this review, drug-delivery methodologies, drug types and drug-delivery devices are discussed with examples in two major application areas: (1) inhaled drug-aerosol delivery into human lung-airways; and (2) intravascular drug-delivery for solid tumor targeting. The major problem addressed is how to deliver efficiently the drug-particles from the entry/infusion point to the target site. So far, most experimental results are based on animal studies. Concerning pulmonary drug delivery, the focus is on the pros and cons of three inhaler types, i.e., pressurized metered dose inhaler, dry powder inhaler and nebulizer, in addition to drug-aerosol formulations. Computational fluid-particle dynamics techniques and the underlying methodology for a smart inhaler system are discussed as well. Concerning intravascular drug-delivery for solid tumor targeting, passive and active targeting are reviewed as well as direct drug-targeting, using optimal delivery of radioactive microspheres to liver tumors as an example. The review concludes with suggestions for future work, considereing both pulmonary drug targeting and direct drug delivery to solid tumors in the vascular system. PMID:25516850

Target and (Astro-)WISE technologies Data federations and its applications

NASA Astrophysics Data System (ADS)

Valentijn, E. A.; Begeman, K.; Belikov, A.; Boxhoorn, D. R.; Brinchmann, J.; McFarland, J.; Holties, H.; Kuijken, K. H.; Verdoes Kleijn, G.; Vriend, W.-J.; Williams, O. R.; Roerdink, J. B. T. M.; Schomaker, L. R. B.; Swertz, M. A.; Tsyganov, A.; van Dijk, G. J. W.

2017-06-01

After its first implementation in 2003 the Astro-WISE technology has been rolled out in several European countries and is used for the production of the KiDS survey data. In the multi-disciplinary Target initiative this technology, nicknamed WISE technology, has been further applied to a large number of projects. Here, we highlight the data handling of other astronomical applications, such as VLT-MUSE and LOFAR, together with some non-astronomical applications such as the medical projects Lifelines and GLIMPS; the MONK handwritten text recognition system; and business applications, by amongst others, the Target Holding. We describe some of the most important lessons learned and describe the application of the data-centric WISE type of approach to the Science Ground Segment of the Euclid satellite.

Understanding perceptions of stuttering among school-based speech-language pathologists: an application of attribution theory.

PubMed

Boyle, Michael P

2014-01-01

The purpose of this study was to investigate whether attribution theory could explain speech-language pathologists (SLPs) perceptions of children with communication disorders such as stuttering. Specifically, it was determined whether perceptions of onset and offset controllability, as well as biological and non-biological attributions for communication disorders were related to willingness to help, sympathy, and anger toward children with these disorders. It was also of interest to determine if blame for stuttering was related to perceived controllability of stuttering and negative attitudes toward people who stutter (PWS). A survey was developed to measure perceived onset and offset controllability, biological and non-biological attributions, willingness to help, sympathy, and anger toward middle school children with developmental stuttering, functional articulation disorders, and cerebral palsy. In addition, a scale was developed to measure blame and negative attitudes toward PWS in general. Surveys were mailed to 1000 school-based SLPs. Data from 330 participants were analyzed. Supporting the hypotheses of attribution theory, higher perceived onset and offset controllability of the disorder was linked to less willingness to help, lower sympathy, and more anger across conditions. Increased biological attributions were associated with more reported sympathy. Increased blame for stuttering was linked to higher perceived controllability of stuttering, more dislike of PWS, and more agreement with negative stereotypes about PWS. Educating SLPs about the variable loss of control inherent in stuttering could improve attitudes and increase understanding of PWS. Reductions in blame may facilitate feelings of sympathy and empathy for PWS and reduce environmental barriers for clients. Learning outcomes Readers should be able to: (1) identify the main principles of Weiner's attribution theory (2) identify common negative perceptions of people who stutter (3) describe how

Targeted activation of diverse CRISPR-Cas systems for mammalian genome editing via proximal CRISPR targeting.

PubMed

Chen, Fuqiang; Ding, Xiao; Feng, Yongmei; Seebeck, Timothy; Jiang, Yanfang; Davis, Gregory D

2017-04-07

Bacterial CRISPR-Cas systems comprise diverse effector endonucleases with different targeting ranges, specificities and enzymatic properties, but many of them are inactive in mammalian cells and are thus precluded from genome-editing applications. Here we show that the type II-B FnCas9 from Francisella novicida possesses novel properties, but its nuclease function is frequently inhibited at many genomic loci in living human cells. Moreover, we develop a proximal CRISPR (termed proxy-CRISPR) targeting method that restores FnCas9 nuclease activity in a target-specific manner. We further demonstrate that this proxy-CRISPR strategy is applicable to diverse CRISPR-Cas systems, including type II-C Cas9 and type V Cpf1 systems, and can facilitate precise gene editing even between identical genomic sites within the same genome. Our findings provide a novel strategy to enable use of diverse otherwise inactive CRISPR-Cas systems for genome-editing applications and a potential path to modulate the impact of chromatin microenvironments on genome modification.

Targeted activation of diverse CRISPR-Cas systems for mammalian genome editing via proximal CRISPR targeting

PubMed Central

Chen, Fuqiang; Ding, Xiao; Feng, Yongmei; Seebeck, Timothy; Jiang, Yanfang; Davis, Gregory D.

2017-01-01

Bacterial CRISPR–Cas systems comprise diverse effector endonucleases with different targeting ranges, specificities and enzymatic properties, but many of them are inactive in mammalian cells and are thus precluded from genome-editing applications. Here we show that the type II-B FnCas9 from Francisella novicida possesses novel properties, but its nuclease function is frequently inhibited at many genomic loci in living human cells. Moreover, we develop a proximal CRISPR (termed proxy-CRISPR) targeting method that restores FnCas9 nuclease activity in a target-specific manner. We further demonstrate that this proxy-CRISPR strategy is applicable to diverse CRISPR–Cas systems, including type II-C Cas9 and type V Cpf1 systems, and can facilitate precise gene editing even between identical genomic sites within the same genome. Our findings provide a novel strategy to enable use of diverse otherwise inactive CRISPR–Cas systems for genome-editing applications and a potential path to modulate the impact of chromatin microenvironments on genome modification. PMID:28387220

Exploring Genetic Attributions Underlying Radiotherapy-Induced Fatigue in Prostate Cancer Patients.

PubMed

Hashemi, Sepehr; Fernandez Martinez, Juan Luis; Saligan, Leorey; Sonis, Stephen

2017-09-01

Despite numerous proposed mechanisms, no definitive pathophysiology underlying radiotherapy-induced fatigue (RIF) has been established. However, the dysregulation of a set of 35 genes was recently validated to predict development of fatigue in prostate cancer patients receiving radiotherapy. To hypothesize novel pathways, and provide genetic targets for currently proposed pathways implicated in RIF development through analysis of the previously validated gene set. The gene set was analyzed for all phenotypic attributions implicated in the phenotype of fatigue. Initially, a "directed" approach was used by querying specific fatigue-related sub-phenotypes against all known phenotypic attributions of the gene set. Then, an "undirected" approach, reviewing the entirety of the literature referencing the 35 genes, was used to increase analysis sensitivity. The dysregulated genes attribute to neural, immunological, mitochondrial, muscular, and metabolic pathways. In addition, certain genes suggest phenotypes not previously emphasized in the context of RIF, such as ionizing radiation sensitivity, DNA damage, and altered DNA repair frequency. Several genes also associated with prostate cancer depression, possibly emphasizing variable radiosensitivity by RIF-prone patients, which may have palliative care implications. Despite the relevant findings, many of the 35 RIF-predictive genes are poorly characterized, warranting their investigation. The implications of herein presented RIF pathways are purely theoretical until specific end-point driven experiments are conducted in more congruent contexts. Nevertheless, the presented attributions are informative, directing future investigation to definitively elucidate RIF's pathoetiology. This study demonstrates an arguably comprehensive method of approaching known differential expression underlying a complex phenotype, to correlate feasible pathophysiology. Copyright © 2017 American Academy of Hospice and Palliative Medicine. All

Eliminating Inhibition of Return by Changing Salient Nonspatial Attributes in a Complex Environment

ERIC Educational Resources Information Center

Hu, Frank K.; Samuel, Arthur G.; Chan, Agnes S.

2011-01-01

Inhibition of return (IOR) occurs when a target is preceded by an irrelevant stimulus (cue) at the same location: Target detection is slowed, relative to uncued locations. In the present study, we used relatively complex displays to examine the effect of repetition of nonspatial attributes. For both color and shape, attribute repetition produced a…

46 CFR 160.013-1 - Applicable specification and plan.

Code of Federal Regulations, 2014 CFR

2014-10-01

... 46 Shipping 6 2014-10-01 2014-10-01 false Applicable specification and plan. 160.013-1 Section 160... Vessels § 160.013-1 Applicable specification and plan. (a) Specification. The following specification, of... Specification: GGG-A-926—Axes. (b) Plan. The following plan, of the issue in effect on the date hatchets are...

46 CFR 160.013-1 - Applicable specification and plan.

Code of Federal Regulations, 2013 CFR

2013-10-01

... 46 Shipping 6 2013-10-01 2013-10-01 false Applicable specification and plan. 160.013-1 Section 160... Vessels § 160.013-1 Applicable specification and plan. (a) Specification. The following specification, of... Specification: GGG-A-926—Axes. (b) Plan. The following plan, of the issue in effect on the date hatchets are...

10 CFR 33.16 - Application for other specific licenses.

Code of Federal Regulations, 2011 CFR

2011-01-01

....16 Energy NUCLEAR REGULATORY COMMISSION SPECIFIC DOMESTIC LICENSES OF BROAD SCOPE FOR BYPRODUCT MATERIAL Specific Licenses of Broad Scope § 33.16 Application for other specific licenses. An application filed pursuant to part 30 of this chapter for a specific license other than one of broad scope will be...

10 CFR 33.16 - Application for other specific licenses.

Code of Federal Regulations, 2010 CFR

2010-01-01

....16 Energy NUCLEAR REGULATORY COMMISSION SPECIFIC DOMESTIC LICENSES OF BROAD SCOPE FOR BYPRODUCT MATERIAL Specific Licenses of Broad Scope § 33.16 Application for other specific licenses. An application filed pursuant to part 30 of this chapter for a specific license other than one of broad scope will be...

10 CFR 33.16 - Application for other specific licenses.

Code of Federal Regulations, 2013 CFR

2013-01-01

....16 Energy NUCLEAR REGULATORY COMMISSION SPECIFIC DOMESTIC LICENSES OF BROAD SCOPE FOR BYPRODUCT MATERIAL Specific Licenses of Broad Scope § 33.16 Application for other specific licenses. An application filed pursuant to part 30 of this chapter for a specific license other than one of broad scope will be...

10 CFR 33.16 - Application for other specific licenses.

Code of Federal Regulations, 2012 CFR

2012-01-01

....16 Energy NUCLEAR REGULATORY COMMISSION SPECIFIC DOMESTIC LICENSES OF BROAD SCOPE FOR BYPRODUCT MATERIAL Specific Licenses of Broad Scope § 33.16 Application for other specific licenses. An application filed pursuant to part 30 of this chapter for a specific license other than one of broad scope will be...

10 CFR 33.16 - Application for other specific licenses.

Code of Federal Regulations, 2014 CFR

2014-01-01

....16 Energy NUCLEAR REGULATORY COMMISSION SPECIFIC DOMESTIC LICENSES OF BROAD SCOPE FOR BYPRODUCT MATERIAL Specific Licenses of Broad Scope § 33.16 Application for other specific licenses. An application filed pursuant to part 30 of this chapter for a specific license other than one of broad scope will be...

An Agent-Based Intervention to Assist Drivers Under Stereotype Threat: Effects of In-Vehicle Agents' Attributional Error Feedback.

PubMed

Joo, Yeon Kyoung; Lee-Won, Roselyn J

2016-10-01

For members of a group negatively stereotyped in a domain, making mistakes can aggravate the influence of stereotype threat because negative stereotypes often blame target individuals and attribute the outcome to their lack of ability. Virtual agents offering real-time error feedback may influence performance under stereotype threat by shaping the performers' attributional perception of errors they commit. We explored this possibility with female drivers, considering the prevalence of the "women-are-bad-drivers" stereotype. Specifically, we investigated how in-vehicle voice agents offering error feedback based on responsibility attribution (internal vs. external) and outcome attribution (ability vs. effort) influence female drivers' performance under stereotype threat. In addressing this question, we conducted an experiment in a virtual driving simulation environment that provided moment-to-moment error feedback messages. Participants performed a challenging driving task and made mistakes preprogrammed to occur. Results showed that the agent's error feedback with outcome attribution moderated the stereotype threat effect on driving performance. Participants under stereotype threat had a smaller number of collisions when the errors were attributed to effort than to ability. In addition, outcome attribution feedback moderated the effect of responsibility attribution on driving performance. Implications of these findings are discussed.

Oligonucleotide Aptamers: New Tools for Targeted Cancer Therapy

PubMed Central

Sun, Hongguang; Zhu, Xun; Lu, Patrick Y; Rosato, Roberto R; Tan, Wen; Zu, Youli

2014-01-01

Aptamers are a class of small nucleic acid ligands that are composed of RNA or single-stranded DNA oligonucleotides and have high specificity and affinity for their targets. Similar to antibodies, aptamers interact with their targets by recognizing a specific three-dimensional structure and are thus termed “chemical antibodies.” In contrast to protein antibodies, aptamers offer unique chemical and biological characteristics based on their oligonucleotide properties. Hence, they are more suitable for the development of novel clinical applications. Aptamer technology has been widely investigated in various biomedical fields for biomarker discovery, in vitro diagnosis, in vivo imaging, and targeted therapy. This review will discuss the potential applications of aptamer technology as a new tool for targeted cancer therapy with emphasis on the development of aptamers that are able to specifically target cell surface biomarkers. Additionally, we will describe several approaches for the use of aptamers in targeted therapeutics, including aptamer-drug conjugation, aptamer-nanoparticle conjugation, aptamer-mediated targeted gene therapy, aptamer-mediated immunotherapy, and aptamer-mediated biotherapy. PMID:25093706

Tissue factor is an angiogenic-specific receptor for factor VII-targeted immunotherapy and photodynamic therapy.

PubMed

Hu, Zhiwei; Cheng, Jijun; Xu, Jie; Ruf, Wolfram; Lockwood, Charles J

2017-02-01

Identification of target molecules specific for angiogenic vascular endothelial cells (VEC), the inner layer of pathological neovasculature, is critical for discovery and development of neovascular-targeting therapy for angiogenesis-dependent human diseases, notably cancer, macular degeneration and endometriosis, in which vascular endothelial growth factor (VEGF) plays a central pathophysiological role. Using VEGF-stimulated vascular endothelial cells (VECs) isolated from microvessels, venous and arterial blood vessels as in vitro angiogenic models and unstimulated VECs as a quiescent VEC model, we examined the expression of tissue factor (TF), a membrane-bound receptor on the angiogenic VEC models compared with quiescent VEC controls. We found that TF is specifically expressed on angiogenic VECs in a time-dependent manner in microvessels, venous and arterial vessels. TF-targeted therapeutic agents, including factor VII (fVII)-IgG1 Fc and fVII-conjugated photosensitizer, can selectively bind angiogenic VECs, but not the quiescent VECs. Moreover, fVII-targeted photodynamic therapy can selectively and completely eradicate angiogenic VECs. We conclude that TF is an angiogenic-specific receptor and the target molecule for fVII-targeted therapeutics. This study supports clinical trials of TF-targeted therapeutics for the treatment of angiogenesis-dependent diseases such as cancer, macular degeneration and endometriosis.

Targeting prostate cancer: Prostate-specific membrane antigen based diagnosis and therapy.

PubMed

Wüstemann, Till; Haberkorn, Uwe; Babich, John; Mier, Walter

2018-05-17

The high incidence rates of prostate cancer (PCa) raise demand for improved therapeutic strategies. Prostate tumors specifically express the prostate-specific membrane antigen (PSMA), a membrane-bound protease. As PSMA is highly overexpressed on malignant prostate tumor cells and as its expression rate correlates with the aggressiveness of the disease, this tumor-associated biomarker provides the possibility to develop new strategies for diagnostics and therapy of PCa. Major advances have been made in PSMA targeting, ranging from immunotherapeutic approaches to therapeutic small molecules. This review elaborates the diversity of PSMA targeting agents while focusing on the radioactively labeled tracers for diagnosis and endoradiotherapy. A variety of radionuclides have been shown to either enable precise diagnosis or efficiently treat the tumor with minimal effects to nontargeted organs. Most small molecules with affinity for PSMA are based on either a phosphonate or a urea-based binding motif. Based on these pharmacophores, major effort has been made to identify modifications to achieve ideal pharmacokinetics while retaining the specific targeting of the PSMA binding pocket. Several tracers have now shown excellent clinical usability in particular for molecular imaging and therapy as proven by the efficiency of theranostic approaches in current studies. The archetypal expression profile of PSMA may be exploited for the treatment with alpha emitters to break radioresistance and thus to bring the power of systemic therapy to higher levels. © 2018 Wiley Periodicals, Inc.

Virus-mimetic polyplex particles for systemic and inflammation-specific targeted delivery of large genetic contents.

PubMed

Kang, S; Lu, K; Leelawattanachai, J; Hu, X; Park, S; Park, T; Min, I M; Jin, M M

2013-11-01

Systemic and target-specific delivery of large genetic contents has been difficult to achieve. Although viruses effortlessly deliver kilobase-long genome into cells, its clinical use has been hindered by serious safety concerns and the mismatch between native tropisms and desired targets. Nonviral vectors, in contrast, are limited by low gene transfer efficiency and inherent cytotoxicity. Here we devised virus-mimetic polyplex particles (VMPs) based on electrostatic self-assembly among polyanionic peptide (PAP), cationic polymer polyethyleneimine (PEI) and nucleic acids. We fused PAP to the engineered ligand-binding domain of integrin αLβ2 to target intercellular adhesion molecule-1 (ICAM-1), an inducible marker of inflammation. Fully assembled VMPs packaged large genetic contents, bound specifically to target molecules, elicited receptor-mediated endocytosis and escaped endosomal pathway, resembling intracellular delivery processes of viruses. Unlike conventional PEI-mediated transfection, molecular interaction-dependent gene delivery of VMPs was unaffected by the presence of serum and achieved higher efficiency without toxicity. By targeting overexpressed ICAM-1, VMPs delivered genes specifically to inflamed endothelial cells and macrophages both in vitro and in vivo. Simplicity and versatility of the platform and inflammation-specific delivery may open up opportunities for multifaceted gene therapy that can be translated into the clinic and treat a broad range of debilitating immune and inflammatory diseases.

Specific GFP-binding artificial proteins (αRep): a new tool for in vitro to live cell applications

PubMed Central

Chevrel, Anne; Urvoas, Agathe; de la Sierra-Gallay, Ines Li; Aumont-Nicaise, Magali; Moutel, Sandrine; Desmadril, Michel; Perez, Franck; Gautreau, Alexis; van Tilbeurgh, Herman; Minard, Philippe; Valerio-Lepiniec, Marie

2015-01-01

A family of artificial proteins, named αRep, based on a natural family of helical repeat was previously designed. αRep members are efficiently expressed, folded and extremely stable proteins. A large αRep library was constructed creating proteins with a randomized interaction surface. In the present study, we show that the αRep library is an efficient source of tailor-made specific proteins with direct applications in biochemistry and cell biology. From this library, we selected by phage display αRep binders with nanomolar dissociation constants against the GFP. The structures of two independent αRep binders in complex with the GFP target were solved by X-ray crystallography revealing two totally different binding modes. The affinity of the selected αReps for GFP proved sufficient for practically useful applications such as pull-down experiments. αReps are disulfide free proteins and are efficiently and functionally expressed in eukaryotic cells: GFP-specific αReps are clearly sequestrated by their cognate target protein addressed to various cell compartments. These results suggest that αRep proteins with tailor-made specificity can be selected and used in living cells to track, modulate or interfere with intracellular processes. PMID:26182430

Microtubule-Actin Crosslinking Factor 1 and Plakins as Therapeutic Drug Targets.

PubMed

Quick, Quincy A

2018-01-26

Plakins are a family of seven cytoskeletal cross-linker proteins (microtubule-actin crosslinking factor 1 (MACF), bullous pemphigoid antigen (BPAG1) desmoplakin, envoplakin, periplakin, plectin, epiplakin) that network the three major filaments that comprise the cytoskeleton. Plakins have been found to be involved in disorders and diseases of the skin, heart, nervous system, and cancer that are attributed to autoimmune responses and genetic alterations of these macromolecules. Despite their role and involvement across a spectrum of several diseases, there are no current drugs or pharmacological agents that specifically target the members of this protein family. On the contrary, microtubules have traditionally been targeted by microtubule inhibiting agents, used for the treatment of diseases such as cancer, in spite of the deleterious toxicities associated with their clinical utility. The Research Collaboratory for Structural Bioinformatics (RCSB) was used here to identify therapeutic drugs targeting the plakin proteins, particularly the spectraplakins MACF1 and BPAG1, which contain microtubule-binding domains. RCSB analysis revealed that plakin proteins had 329 ligands, of which more than 50% were MACF1 and BPAG1 ligands and 10 were documented, clinically or experimentally, to have several therapeutic applications as anticancer, anti-inflammatory, and antibiotic agents.

Direct target NOTES: prospective applications for next generation robotic platforms.

PubMed

Atallah, S; Hodges, A; Larach, S W

2018-05-01

A new era in surgical robotics has centered on alternative access to anatomic targets and next generation designs include flexible, single-port systems which follow circuitous rather than straight pathways. Such systems maintain a small footprint and could be utilized for specialized operations based on direct organ target natural orifice transluminal endoscopic surgery (NOTES), of which transanal total mesorectal excision (taTME) is an important derivative. During two sessions, four direct target NOTES operations were conducted on a cadaveric model using a flexible robotic system to demonstrate proof-of-concept of the application of a next generation robotic system to specific types of NOTES operations, all of which required removal of a direct target organ through natural orifice access. These four operations were (a) robotic taTME, (b) robotic transvaginal hysterectomy in conjunction with (c) robotic transvaginal salpingo-oophorectomy, and in an ex vivo model, (d) trans-cecal appendectomy. Feasibility was demonstrated in all cases using the Flex ® Robotic System with Colorectal Drive. During taTME, the platform excursion was 17 cm along a non-linear path; operative time was 57 min for the transanal portion of the dissection. Robotic transvaginal hysterectomy was successfully completed in 78 min with transvaginal extraction of the uterus, although laparoscopic assistance was required. Robotic transvaginal unilateral salpingo-oophorectomy with transvaginal extraction of the ovary and fallopian tube was performed without laparoscopic assistance in 13.5 min. In an ex vivo model, a robotic trans-cecal appendectomy was also successfully performed for the purpose of demonstrating proof-of-concept only; this was completed in 24 min. A flexible robotic system has the potential to access anatomy along circuitous paths, making it a suitable platform for direct target NOTES. The conceptual operations posed could be considered suitable for next generation robotics once

Design of the hairpin ribozyme for targeting specific RNA sequences.

PubMed

Hampel, A; DeYoung, M B; Galasinski, S; Siwkowski, A

1997-01-01

The following steps should be taken when designing the hairpin ribozyme to cleave a specific target sequence: 1. Select a target sequence containing BN*GUC where B is C, G, or U. 2. Select the target sequence in areas least likely to have extensive interfering structure. 3. Design the conventional hairpin ribozyme as shown in Fig. 1, such that it can form a 4 bp helix 2 and helix 1 lengths up to 10 bp. 4. Synthesize this ribozyme from single-stranded DNA templates with a double-stranded T7 promoter. 5. Prepare a series of short substrates capable of forming a range of helix 1 lengths of 5-10 bp. 6. Identify these by direct RNA sequencing. 7. Assay the extent of cleavage of each substrate to identify the optimal length of helix 1. 8. Prepare the hairpin tetraloop ribozyme to determine if catalytic efficiency can be improved.

Mechanism of Genome Interrogation: How CRISPR RNA-Guided Cas9 Proteins Locate Specific Targets on DNA.

PubMed

Shvets, Alexey A; Kolomeisky, Anatoly B

2017-10-03

The ability to precisely edit and modify a genome opens endless opportunities to investigate fundamental properties of living systems as well as to advance various medical techniques and bioengineering applications. This possibility is now close to reality due to a recent discovery of the adaptive bacterial immune system, which is based on clustered regularly interspaced short palindromic repeats (CRISPR)-associated proteins (Cas) that utilize RNA to find and cut the double-stranded DNA molecules at specific locations. Here we develop a quantitative theoretical approach to analyze the mechanism of target search on DNA by CRISPR RNA-guided Cas9 proteins, which is followed by a selective cleavage of nucleic acids. It is based on a discrete-state stochastic model that takes into account the most relevant physical-chemical processes in the system. Using a method of first-passage processes, a full dynamic description of the target search is presented. It is found that the location of specific sites on DNA by CRISPR Cas9 proteins is governed by binding first to protospacer adjacent motif sequences on DNA, which is followed by reversible transitions into DNA interrogation states. In addition, the search dynamics is strongly influenced by the off-target cutting. Our theoretical calculations allow us to explain the experimental observations and to give experimentally testable predictions. Thus, the presented theoretical model clarifies some molecular aspects of the genome interrogation by CRISPR RNA-guided Cas9 proteins. Copyright © 2017 Biophysical Society. Published by Elsevier Inc. All rights reserved.

Using attribute amnesia to test the limits of hyper-binding and associative deficits in working memory.

PubMed

McCormick-Huhn, John M; Chen, Hui; Wyble, Bradley P; Dennis, Nancy A

2018-02-01

Previous work has shown mixed evidence regarding age-related deficits for binding in working memory. The current study used the newly developed attribute amnesia effect (H. Chen & Wyble, 2015a) to test the associative-deficit hypothesis during working memory and to probe whether hyper-binding extends to include binding of de-selected information. In studies of attribute amnesia, participants use target attributes (e.g., identity, color) to demonstrate near ceiling levels of reporting of a second target attribute (e.g., location) across a series of trials (H. Chen & Wyble, 2015a, 2016). Yet, despite having just processed the target-defining attribute, they have difficulty reporting it on a surprise trial. This effect provides several predictions for associative binding in aging. The associative-deficit hypothesis predicts age-related decline on the surprise trial, whereas an extension of hyper-binding predicts age-related increase in performance in older adults. In Experiment 1, when working memory load was low, older adults demonstrated attribute amnesia equal to that found in younger adults. When load increased in Experiment 2, older adults again demonstrated attribute amnesia as well as an age deficit for reporting target attributes. In lieu of spontaneous binding, results suggest that expectancy plays a critical role in older adults' propensity to encode and bind target attributes in working memory. Results further suggest that expectancy alone is not enough for older adults to form bound representations when task demands are high. Taken together results revealed a boundary condition of hyper-binding and further provided conditional support for the associative-deficit hypothesis in working memory. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

Multiple-attribute group decision making with different formats of preference information on attributes.

PubMed

Xu, Zeshui

2007-12-01

Interval utility values, interval fuzzy preference relations, and interval multiplicative preference relations are three common uncertain-preference formats used by decision-makers to provide their preference information in the process of decision making under fuzziness. This paper is devoted in investigating multiple-attribute group-decision-making problems where the attribute values are not precisely known but the value ranges can be obtained, and the decision-makers provide their preference information over attributes by three different uncertain-preference formats i.e., 1) interval utility values; 2) interval fuzzy preference relations; and 3) interval multiplicative preference relations. We first utilize some functions to normalize the uncertain decision matrix and then transform it into an expected decision matrix. We establish a goal-programming model to integrate the expected decision matrix and all three different uncertain-preference formats from which the attribute weights and the overall attribute values of alternatives can be obtained. Then, we use the derived overall attribute values to get the ranking of the given alternatives and to select the best one(s). The model not only can reflect both the subjective considerations of all decision-makers and the objective information but also can avoid losing and distorting the given objective and subjective decision information in the process of information integration. Furthermore, we establish some models to solve the multiple-attribute group-decision-making problems with three different preference formats: 1) utility values; 2) fuzzy preference relations; and 3) multiplicative preference relations. Finally, we illustrate the applicability and effectiveness of the developed models with two practical examples.

Actinium-225 in targeted alpha-particle therapeutic applications

PubMed Central

Scheinberg, David A.; McDevit, Michael R.

2017-01-01

Alpha particle-emitting isotopes are being investigated in radioimmunotherapeutic applications because of their unparalleled cytotoxicity when targeted to cancer and their relative lack of toxicity towards untargeted normal tissue. Actinium-225 has been developed into potent targeting drug constructs and is in clinical use against acute myelogenous leukemia. The key properties of the alpha particles generated by 225Ac are the following: i) limited range in tissue of a few cell diameters; ii) high linear energy transfer leading to dense radiation damage along each alpha track; iii) a 10 day half-life; and iv) four net alpha particles emitted per decay. Targeting 225Ac-drug constructs have potential in the treatment of cancer. PMID:22202153

Comparison of taxon-specific versus general locus sets for targeted sequence capture in plant phylogenomics.

PubMed

Chau, John H; Rahfeldt, Wolfgang A; Olmstead, Richard G

2018-03-01

Targeted sequence capture can be used to efficiently gather sequence data for large numbers of loci, such as single-copy nuclear loci. Most published studies in plants have used taxon-specific locus sets developed individually for a clade using multiple genomic and transcriptomic resources. General locus sets can also be developed from loci that have been identified as single-copy and have orthologs in large clades of plants. We identify and compare a taxon-specific locus set and three general locus sets (conserved ortholog set [COSII], shared single-copy nuclear [APVO SSC] genes, and pentatricopeptide repeat [PPR] genes) for targeted sequence capture in Buddleja (Scrophulariaceae) and outgroups. We evaluate their performance in terms of assembly success, sequence variability, and resolution and support of inferred phylogenetic trees. The taxon-specific locus set had the most target loci. Assembly success was high for all locus sets in Buddleja samples. For outgroups, general locus sets had greater assembly success. Taxon-specific and PPR loci had the highest average variability. The taxon-specific data set produced the best-supported tree, but all data sets showed improved resolution over previous non-sequence capture data sets. General locus sets can be a useful source of sequence capture targets, especially if multiple genomic resources are not available for a taxon.

Epidermal growth factor receptor-targeted lipid nanoparticles retain self-assembled nanostructures and provide high specificity

NASA Astrophysics Data System (ADS)

Zhai, Jiali; Scoble, Judith A.; Li, Nan; Lovrecz, George; Waddington, Lynne J.; Tran, Nhiem; Muir, Benjamin W.; Coia, Gregory; Kirby, Nigel; Drummond, Calum J.; Mulet, Xavier

2015-02-01

Next generation drug delivery utilising nanoparticles incorporates active targeting to specific sites. In this work, we combined targeting with the inherent advantages of self-assembled lipid nanoparticles containing internal nano-structures. Epidermal growth factor receptor (EGFR)-targeting, PEGylated lipid nanoparticles using phytantriol and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-PEG-maleimide amphiphiles were created. The self-assembled lipid nanoparticles presented here have internal lyotropic liquid crystalline nano-structures, verified by synchrotron small angle X-ray scattering and cryo-transmission electron microscopy, that offer the potential of high drug loading and enhanced cell penetration. Anti-EGFR Fab' fragments were conjugated to the surface of nanoparticles via a maleimide-thiol reaction at a high conjugation efficiency and retained specificity following conjugation to the nanoparticles. The conjugated nanoparticles were demonstrated to have high affinity for an EGFR target in a ligand binding assay.Next generation drug delivery utilising nanoparticles incorporates active targeting to specific sites. In this work, we combined targeting with the inherent advantages of self-assembled lipid nanoparticles containing internal nano-structures. Epidermal growth factor receptor (EGFR)-targeting, PEGylated lipid nanoparticles using phytantriol and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-PEG-maleimide amphiphiles were created. The self-assembled lipid nanoparticles presented here have internal lyotropic liquid crystalline nano-structures, verified by synchrotron small angle X-ray scattering and cryo-transmission electron microscopy, that offer the potential of high drug loading and enhanced cell penetration. Anti-EGFR Fab' fragments were conjugated to the surface of nanoparticles via a maleimide-thiol reaction at a high conjugation efficiency and retained specificity following conjugation to the nanoparticles. The conjugated nanoparticles

[siRNAs with high specificity to the target: a systematic design by CRM algorithm].

PubMed

Alsheddi, T; Vasin, L; Meduri, R; Randhawa, M; Glazko, G; Baranova, A

2008-01-01

'Off-target' silencing effect hinders the development of siRNA-based therapeutic and research applications. Common solution to this problem is an employment of the BLAST that may miss significant alignments or an exhaustive Smith-Waterman algorithm that is very time-consuming. We have developed a Comprehensive Redundancy Minimizer (CRM) approach for mapping all unique sequences ("targets") 9-to-15 nt in size within large sets of sequences (e.g. transcriptomes). CRM outputs a list of potential siRNA candidates for every transcript of the particular species. These candidates could be further analyzed by traditional "set-of-rules" types of siRNA designing tools. For human, 91% of transcripts are covered by candidate siRNAs with kernel targets of N = 15. We tested our approach on the collection of previously described experimentally assessed siRNAs and found that the correlation between efficacy and presence in CRM-approved set is significant (r = 0.215, p-value = 0.0001). An interactive database that contains a precompiled set of all human siRNA candidates with minimized redundancy is available at http://129.174.194.243. Application of the CRM-based filtering minimizes potential "off-target" silencing effects and could improve routine siRNA applications.

46 CFR 160.053-1 - Applicable specifications.

Code of Federal Regulations, 2011 CFR

2011-10-01

...: SPECIFICATIONS AND APPROVAL LIFESAVING EQUIPMENT Work Vests, Unicellular Plastic Foam § 160.053-1 Applicable... plastic foam work vests are manufactured, form a part of this subpart: (1) Military specification: MIL-L...

Social workers' attributions towards individuals with dual diagnosis of intellectual disability and mental illness.

PubMed

Araten-Bergman, T; Werner, S

2017-02-01

The present study aimed to explore the applicability of the attribution model to social workers' attributions towards clients with dual diagnosis of intellectual disability and psychiatric illness. Specifically, the study examined the relations between social workers' attribution of responsibility, causality, stereotypes of dangerousness, their emotional reactions and behavioural reactions towards clients with dual diagnosis. Social workers (N = 279) completed questionnaires measuring attributions of responsibility, causation and dangerousness, and reported on their emotional and behavioural reactions to clients diagnosed with DD. Most social workers reported high levels of helping behaviours. The strongest predictor of discriminatory behaviours was the stereotype of dangerousness. Social workers who reported feeling less anger and more pity towards clients with DD tended to report higher levels of helping behaviour. But contrary to attribution theory, fear and anger did not predict discriminatory behaviours. The results are discussed in relation to the core values of social work and to professional identity. © 2016 MENCAP and International Association of the Scientific Study of Intellectual and Developmental Disabilities and John Wiley & Sons Ltd.

46 CFR 160.041-1 - Applicable specification and publication.

Code of Federal Regulations, 2011 CFR

2011-10-01

... 46 Shipping 6 2011-10-01 2011-10-01 false Applicable specification and publication. 160.041-1... Vessels § 160.041-1 Applicable specification and publication. (a) Specification. The following... Contents. (b) Publication. The following publication, of the issue in effect on the date first-aid kits are...

46 CFR 160.041-1 - Applicable specification and publication.

Code of Federal Regulations, 2012 CFR

2012-10-01

... 46 Shipping 6 2012-10-01 2012-10-01 false Applicable specification and publication. 160.041-1... Vessels § 160.041-1 Applicable specification and publication. (a) Specification. The following... Contents. (b) Publication. The following publication, of the issue in effect on the date first-aid kits are...

Incorporating a Discussion of Genetic Attributions into Psychology Courses

ERIC Educational Resources Information Center

Sheldon, Jane P.

2018-01-01

A highly relevant construct that may need more emphasis in our psychology courses is genetic attributions. Attributions are causal explanations people make for specific behaviors, characteristics, occurrences, or differences. Research has found that genetic attributions are related to numerous biopsychosocial phenomena (e.g., perceptions about…

Engineered Cpf1 variants with altered PAM specificities increase genome targeting range

PubMed Central

Gao, Linyi; Cox, David B.T.; Yan, Winston X.; Manteiga, John C.; Schneider, Martin W.; Yamano, Takashi; Nishimasu, Hiroshi; Nureki, Osamu; Crosetto, Nicola; Zhang, Feng

2017-01-01

The RNA-guided endonuclease Cpf1 is a promising tool for genome editing in eukaryotic cells1–7. However, the utility of the commonly used Acidaminococcus sp. BV3L6 Cpf1 (AsCpf1) and Lachnospiraceae bacterium ND2006 Cpf1 (LbCpf1) is limited by their requirement of a TTTV protospacer adjacent motif (PAM) in the DNA substrate. To address this limitation, we performed a structure-guided mutagenesis screen to increase the targeting range of Cpf1. We engineered two AsCpf1 variants carrying the mutations S542R/K607R and S542R/K548V/N552R, which recognize TYCV and TATV PAMs, respectively, with enhanced activities in vitro and in human cells. Genome-wide assessment of off-target activity using BLISS7 assay indicated that these variants retain high DNA targeting specificity, which we further improved by introducing an additional non-PAM-interacting mutation. Introducing the identified mutations at their corresponding positions in LbCpf1 similarly altered its PAM specificity. Together, these variants increase the targeting range of Cpf1 by approximately three-fold in human coding sequences to one cleavage site per ~11 bp. PMID:28581492

XML-Based Visual Specification of Multidisciplinary Applications

NASA Technical Reports Server (NTRS)

Al-Theneyan, Ahmed; Jakatdar, Amol; Mehrotra, Piyush; Zubair, Mohammad

2001-01-01

The advancements in the Internet and Web technologies have fueled a growing interest in developing a web-based distributed computing environment. We have designed and developed Arcade, a web-based environment for designing, executing, monitoring, and controlling distributed heterogeneous applications, which is easy to use and access, portable, and provides support through all phases of the application development and execution. A major focus of the environment is the specification of heterogeneous, multidisciplinary applications. In this paper we focus on the visual and script-based specification interface of Arcade. The web/browser-based visual interface is designed to be intuitive to use and can also be used for visual monitoring during execution. The script specification is based on XML to: (1) make it portable across different frameworks, and (2) make the development of our tools easier by using the existing freely available XML parsers and editors. There is a one-to-one correspondence between the visual and script-based interfaces allowing users to go back and forth between the two. To support this we have developed translators that translate a script-based specification to a visual-based specification, and vice-versa. These translators are integrated with our tools and are transparent to users.

The Identification and Validation Process of Proportional Reasoning Attributes: An Application of a Proportional Reasoning Modeling Framework

ERIC Educational Resources Information Center

Tjoe, Hartono; de la Torre, Jimmy

2014-01-01

In this paper, we discuss the process of identifying and validating students' abilities to think proportionally. More specifically, we describe the methodology we used to identify these proportional reasoning attributes, beginning with the selection and review of relevant literature on proportional reasoning. We then continue with the…

Performance Measurement and Target-Setting in California's Safety Net Health Systems.

PubMed

Hemmat, Shirin; Schillinger, Dean; Lyles, Courtney; Ackerman, Sara; Gourley, Gato; Vittinghoff, Eric; Handley, Margaret; Sarkar, Urmimala

Health policies encourage implementing quality measurement with performance targets. The 2010-2015 California Medicaid waiver mandated quality measurement and reporting. In 2013, California safety net hospitals participating in the waiver set a voluntary performance target (the 90th percentile for Medicare preferred provider organization plans) for mammography screening and cholesterol control in diabetes. They did not reach the target, and the difference-in-differences analysis suggested that there was no difference for mammography ( P = .39) and low-density lipoprotein control ( P = .11) performance compared to measures for which no statewide quality improvement initiative existed. California's Medicaid waiver was associated with improved performance on a number of metrics, but this performance was not attributable to target setting on specific health conditions. Performance may have improved because of secular trends or systems improvements related to waiver funding. Relying on condition-specific targets to measure performance may underestimate improvements and disadvantage certain health systems. Achieving ambitious targets likely requires sustained fiscal, management, and workforce investments.

Multi-Attribute Task Battery - Applications in pilot workload and strategic behavior research

NASA Technical Reports Server (NTRS)

Arnegard, Ruth J.; Comstock, J. R., Jr.

1991-01-01

The Multi-Attribute Task (MAT) Battery provides a benchmark set of tasks for use in a wide range of lab studies of operator performance and workload. The battery incorporates tasks analogous to activities that aircraft crewmembers perform in flight, while providing a high degree of experimenter control, performance data on each subtask, and freedom to nonpilot test subjects. Features not found in existing computer based tasks include an auditory communication task (to simulate Air Traffic Control communication), a resource management task permitting many avenues or strategies of maintaining target performance, a scheduling window which gives the operator information about future task demands, and the option of manual or automated control of tasks. Performance data are generated for each subtask. In addition, the task battery may be paused and onscreen workload rating scales presented to the subject. The MAT Battery requires a desktop computer with color graphics. The communication task requires a serial link to a second desktop computer with a voice synthesizer or digitizer card.

Tumor-targeting CTL expressing a single-chain Fv specific for VEGFR2.

PubMed

Kanagawa, Naoko; Yanagawa, Tatsuya; Mukai, Yohei; Yoshioka, Yasuo; Okada, Naoki; Nakagawa, Shinsaku

2010-03-26

Cytotoxic T lymphocytes (CTL) are critical effector cells in tumor immunity. Adoptive transfer therapy with in vitro-expanded tumor-specific CTL is a promising approach for preventing cancer metastasis and recurrence. Transferred CTL are not effective in clinical trials, however, due to inadequate tumor-infiltration. Therefore, the development of functionally modified CTL, such as tumor-targeting CTL, is widely desired. Here, we designed the tumor-targeting CTL expressing a single-chain antibody fragment (scFv-CTL) specific for vascular endothelial growth factor receptor 2 (VEGFR2/flk1) by transducing the CTL with a retroviral vector. The scFv-CTL bound to VEGFR2/flk1-expressing cells and retained their cytotoxic activity against tumor cells. In addition, adoptive transfer of scFv-CTL into tumor-bearing mice effectively suppressed tumor growth due to the augmented accumulation of the transferred CTL in the tumor tissue. These findings indicate that the creation of CTL capable of targeting tumor vascular endothelial cells by scFv-expression technique is considerably promising for improvement of efficacy in adoptive immunotherapy. Copyright (c) 2010 Elsevier Inc. All rights reserved.

Sequential Axon-derived Signals Couple Target Survival and Layer Specificity in the Drosophila Visual System

PubMed Central

Pecot, Matthew Y.; Chen, Yi; Akin, Orkun; Chen, Zhenqing; Tsui, C.Y. Kimberly; Zipursky, S. Lawrence

2015-01-01

SUMMARY Neural circuit formation relies on interactions between axons and cells within the target field. While it is well established that target-derived signals act on axons to regulate circuit assembly, the extent to which axon-derived signals control circuit formation is not known. In the Drosophila visual system, anterograde signals numerically match R1–R6 photoreceptors with their targets by controlling target proliferation and neuronal differentiation. Here we demonstrate that additional axon-derived signals selectively couple target survival with layer-specificity. We show that Jelly belly (Jeb) produced by R1–R6 axons interacts with its receptor, anaplastic lymphoma kinase (Alk), on budding dendrites to control survival of L3 neurons, one of three postsynaptic targets. L3 axons then produce Netrin, which regulates the layer-specific targeting of another neuron within the same circuit. We propose that a cascade of axon-derived signals, regulating diverse cellular processes, provides a strategy for coordinating circuit assembly across different regions of the nervous system. PMID:24742459

Quantification of sand fraction from seismic attributes using Neuro-Fuzzy approach

NASA Astrophysics Data System (ADS)

Verma, Akhilesh K.; Chaki, Soumi; Routray, Aurobinda; Mohanty, William K.; Jenamani, Mamata

2014-12-01

In this paper, we illustrate the modeling of a reservoir property (sand fraction) from seismic attributes namely seismic impedance, seismic amplitude, and instantaneous frequency using Neuro-Fuzzy (NF) approach. Input dataset includes 3D post-stacked seismic attributes and six well logs acquired from a hydrocarbon field located in the western coast of India. Presence of thin sand and shale layers in the basin area makes the modeling of reservoir characteristic a challenging task. Though seismic data is helpful in extrapolation of reservoir properties away from boreholes; yet, it could be challenging to delineate thin sand and shale reservoirs using seismic data due to its limited resolvability. Therefore, it is important to develop state-of-art intelligent methods for calibrating a nonlinear mapping between seismic data and target reservoir variables. Neural networks have shown its potential to model such nonlinear mappings; however, uncertainties associated with the model and datasets are still a concern. Hence, introduction of Fuzzy Logic (FL) is beneficial for handling these uncertainties. More specifically, hybrid variants of Artificial Neural Network (ANN) and fuzzy logic, i.e., NF methods, are capable for the modeling reservoir characteristics by integrating the explicit knowledge representation power of FL with the learning ability of neural networks. In this paper, we opt for ANN and three different categories of Adaptive Neuro-Fuzzy Inference System (ANFIS) based on clustering of the available datasets. A comparative analysis of these three different NF models (i.e., Sugeno-type fuzzy inference systems using a grid partition on the data (Model 1), using subtractive clustering (Model 2), and using Fuzzy c-means (FCM) clustering (Model 3)) and ANN suggests that Model 3 has outperformed its counterparts in terms of performance evaluators on the present dataset. Performance of the selected algorithms is evaluated in terms of correlation coefficients (CC), root

Identification of specific posttranslational O-mycoloylations mediating protein targeting to the mycomembrane.

PubMed

Carel, Clément; Marcoux, Julien; Réat, Valérie; Parra, Julien; Latgé, Guillaume; Laval, Françoise; Demange, Pascal; Burlet-Schiltz, Odile; Milon, Alain; Daffé, Mamadou; Tropis, Maryelle G; Renault, Marie A M

2017-04-18

The outer membranes (OMs) of members of the Corynebacteriales bacterial order, also called mycomembranes, harbor mycolic acids and unusual outer membrane proteins (OMPs), including those with α-helical structure. The signals that allow precursors of such proteins to be targeted to the mycomembrane remain uncharacterized. We report here the molecular features responsible for OMP targeting to the mycomembrane of Corynebacterium glutamicum , a nonpathogenic member of the Corynebacteriales order. To better understand the mechanisms by which OMP precursors were sorted in C. glutamicum , we first investigated the partitioning of endogenous and recombinant PorA, PorH, PorB, and PorC between bacterial compartments and showed that they were both imported into the mycomembrane and secreted into the extracellular medium. A detailed investigation of cell extracts and purified proteins by top-down MS, NMR spectroscopy, and site-directed mutagenesis revealed specific and well-conserved posttranslational modifications (PTMs), including O -mycoloylation, pyroglutamylation, and N -formylation, for mycomembrane-associated and -secreted OMPs. PTM site sequence analysis from C. glutamicum OMP and other O -acylated proteins in bacteria and eukaryotes revealed specific patterns. Furthermore, we found that such modifications were essential for targeting to the mycomembrane and sufficient for OMP assembly into mycolic acid-containing lipid bilayers. Collectively, it seems that these PTMs have evolved in the Corynebacteriales order and beyond to guide membrane proteins toward a specific cell compartment.

Identification of specific posttranslational O-mycoloylations mediating protein targeting to the mycomembrane

PubMed Central

Carel, Clément; Réat, Valérie; Parra, Julien; Latgé, Guillaume; Laval, Françoise; Burlet-Schiltz, Odile; Milon, Alain; Daffé, Mamadou; Tropis, Maryelle G.; Renault, Marie A. M.

2017-01-01

The outer membranes (OMs) of members of the Corynebacteriales bacterial order, also called mycomembranes, harbor mycolic acids and unusual outer membrane proteins (OMPs), including those with α-helical structure. The signals that allow precursors of such proteins to be targeted to the mycomembrane remain uncharacterized. We report here the molecular features responsible for OMP targeting to the mycomembrane of Corynebacterium glutamicum, a nonpathogenic member of the Corynebacteriales order. To better understand the mechanisms by which OMP precursors were sorted in C. glutamicum, we first investigated the partitioning of endogenous and recombinant PorA, PorH, PorB, and PorC between bacterial compartments and showed that they were both imported into the mycomembrane and secreted into the extracellular medium. A detailed investigation of cell extracts and purified proteins by top-down MS, NMR spectroscopy, and site-directed mutagenesis revealed specific and well-conserved posttranslational modifications (PTMs), including O-mycoloylation, pyroglutamylation, and N-formylation, for mycomembrane-associated and -secreted OMPs. PTM site sequence analysis from C. glutamicum OMP and other O-acylated proteins in bacteria and eukaryotes revealed specific patterns. Furthermore, we found that such modifications were essential for targeting to the mycomembrane and sufficient for OMP assembly into mycolic acid-containing lipid bilayers. Collectively, it seems that these PTMs have evolved in the Corynebacteriales order and beyond to guide membrane proteins toward a specific cell compartment. PMID:28373551

Prostate-Specific and Tumor-Specific Targeting of an Oncolytic HSV-1 Amplicon/Helper Virus for Prostate Cancer Treatment

DTIC Science & Technology

2009-11-01

that differentially expressed tumor suppressor miRNAs can be utilized to control the replication of an oncolytic DNA virus in a tumor-specific...demonstrated that the utilization of the tissue-specific promoter and the miRNA-mediated 3’UTRs in a targeted virotherapy is a viable approach with...elements into the whole HSV-1 viral genome should increase the safety margin substantially. The major advantage of the amplicon/helper system is its

Identification and quantification of flavor attributes present in chicken, lamb, pork, beef, and turkey.

PubMed

Maughan, Curtis; Martini, Silvana

2012-02-01

The objectives of this study were to use a meat flavor lexicon to identify and quantify flavor differences among different types of meats such as beef, chicken, lamb, pork, and turkey, and to identify and quantify specific flavor attributes associated with "beef flavor" notes. A trained descriptive panel with 11 participants used a previously developed meat lexicon composed of 18 terms to evaluate the flavor of beef, chicken, pork, turkey, and lamb samples. Results show that beef and lamb samples can be described by flavor attributes such as barny, bitter, gamey, grassy, livery, metallic, and roast beef. Inversely related to these samples were pork and turkey and those attributes that were closely related to them, namely brothy, fatty, salty, sweet, and umami. Chicken was not strongly related to the other types of meats or the attributes used. The descriptive panel also evaluated samples of ground beef mixed with chicken to identify and quantify flavor attributes associated with a "beef flavor." Meat patties for this portion consisted of ground beef mixed with ground chicken in varying amounts: 0%, 25%, 50%, 75%, and 100% beef, with the remainder made up of chicken. Beef and beef-rich patties (75% beef) were more closely related to flavor attributes such as astringent, bloody, fatty, gamey, metallic, livery, oxidized, grassy, and roast beef, while chicken was more closely associated with brothy, juicy, sour, sweet, and umami. This research provides information regarding the specific flavor attributes that differentiate chicken and beef products and provides the first set of descriptors that can be associated with "beefy" notes. POTENTIAL APPLICATION: The use of a standardized flavor lexicon will allow meat producers to identify specific flavors present in their products. The impact is to identify and quantify negative and positive flavors in the product with the ultimate goal of optimizing processing or cooking conditions and improve the quality of meat products. �

Combined interpretation of 3D seismic reflection attributes for geothermal exploration in the Polish Basin using self-organizing maps

NASA Astrophysics Data System (ADS)

Bauer, Klaus; Pussak, Marcin; Stiller, Manfred; Bujakowski, Wieslaw

2014-05-01

Self-organizing maps (SOM) are neural network techniques which can be used for the joint interpretation of multi-disciplinary data sets. In this investigation we apply SOM within a geothermal exploration project using 3D seismic reflection data. The study area is located in the central part of the Polish basin. Several sedimentary target horizons were identified at this location based on fluid flow rate measurements in the geothermal research well Kompina-2. The general objective is a seismic facies analysis and characterization of the major geothermal target reservoir. A 3D seismic reflection experiment with a sparse acquisition geometry was carried out around well Kompina-2. Conventional signal processing (amplitude corrections, filtering, spectral whitening, deconvolution, static corrections, muting) was followed by normal-moveout (NMO) stacking, and, alternatively, by common-reflection-surface (CRS) stacking. Different signal attributes were then derived from the stacked images including root-mean-square (RMS) amplitude, instantaneous frequency and coherency. Furthermore, spectral decomposition attributes were calculated based on the continuous wavelet transform. The resulting attribute maps along major target horizons appear noisy after the NMO stack and clearly structured after the CRS stack. Consequently, the following SOM-based multi-parameter signal attribute analysis was applied only to the CRS images. We applied our SOM work flow, which includes data preparation, unsupervised learning, segmentation of the trained SOM using image processing techniques, and final application of the learned knowledge. For the Lower Jurassic target horizon Ja1 we derived four different clusters with distinct seismic attribute signatures. As the most striking feature, a corridor parallel to a fault system was identified, which is characterized by decreased RMS amplitudes and low frequencies. In our interpretation we assume that this combination of signal properties can be

Designing Micro- and Nanoswimmers for Specific Applications.

PubMed

Katuri, Jaideep; Ma, Xing; Stanton, Morgan M; Sánchez, Samuel

2017-01-17

Self-propelled colloids have emerged as a new class of active matter over the past decade. These are micrometer sized colloidal objects that transduce free energy from their surroundings and convert it to directed motion. The self-propelled colloids are in many ways, the synthetic analogues of biological self-propelled units such as algae or bacteria. Although they are propelled by very different mechanisms, biological swimmers are typically powered by flagellar motion and synthetic swimmers are driven by local chemical reactions, they share a number of common features with respect to swimming behavior. They exhibit run-and-tumble like behavior, are responsive to environmental stimuli, and can even chemically interact with nearby swimmers. An understanding of self-propelled colloids could help us in understanding the complex behaviors that emerge in populations of natural microswimmers. Self-propelled colloids also offer some advantages over natural microswimmers, since the surface properties, propulsion mechanisms, and particle geometry can all be easily modified to meet specific needs. From a more practical perspective, a number of applications, ranging from environmental remediation to targeted drug delivery, have been envisioned for these systems. These applications rely on the basic functionalities of self-propelled colloids: directional motion, sensing of the local environment, and the ability to respond to external signals. Owing to the vastly different nature of each of these applications, it becomes necessary to optimize the design choices in these colloids. There has been a significant effort to develop a range of synthetic self-propelled colloids to meet the specific conditions required for different processes. Tubular self-propelled colloids, for example, are ideal for decontamination processes, owing to their bubble propulsion mechanism, which enhances mixing in systems, but are incompatible with biological systems due to the toxic propulsion fuel and

Single nucleotide polymorphism-specific regulation of matrix metalloproteinase-9 by multiple miRNAs targeting the coding exon

PubMed Central

Duellman, Tyler; Warren, Christopher; Yang, Jay

2014-01-01

Microribonucleic acids (miRNAs) work with exquisite specificity and are able to distinguish a target from a non-target based on a single nucleotide mismatch in the core nucleotide domain. We questioned whether miRNA regulation of gene expression could occur in a single nucleotide polymorphism (SNP)-specific manner, manifesting as a post-transcriptional control of expression of genetic polymorphisms. In our recent study of the functional consequences of matrix metalloproteinase (MMP)-9 SNPs, we discovered that expression of a coding exon SNP in the pro-domain of the protein resulted in a profound decrease in the secreted protein. This missense SNP results in the N38S amino acid change and a loss of an N-glycosylation site. A systematic study demonstrated that the loss of secreted protein was due not to the loss of an N-glycosylation site, but rather an SNP-specific targeting by miR-671-3p and miR-657. Bioinformatics analysis identified 41 SNP-specific miRNA targeting MMP-9 SNPs, mostly in the coding exon and an extension of the analysis to chromosome 20, where the MMP-9 gene is located, suggesting that SNP-specific miRNAs targeting the coding exon are prevalent. This selective post-transcriptional regulation of a target messenger RNA harboring genetic polymorphisms by miRNAs offers an SNP-dependent post-transcriptional regulatory mechanism, allowing for polymorphic-specific differential gene regulation. PMID:24627221

Chemical structure determines target organ carcinogenesis in rats

PubMed Central

Carrasquer, C. A.; Malik, N.; States, G.; Qamar, S.; Cunningham, S.L.; Cunningham, A.R.

2012-01-01

SAR models were developed for 12 rat tumour sites using data derived from the Carcinogenic Potency Database. Essentially, the models fall into two categories: Target Site Carcinogen – Non-Carcinogen (TSC-NC) and Target Site Carcinogen – Non-Target Site Carcinogen (TSC-NTSC). The TSC-NC models were composed of active chemicals that were carcinogenic to a specific target site and inactive ones that were whole animal non-carcinogens. On the other hand, the TSC-NTSC models used an inactive category also composed of carcinogens but to any/all other sites but the target site. Leave one out validations produced an overall average concordance value for all 12 models of 0.77 for the TSC-NC models and 0.73 for the TSC-NTSC models. Overall, these findings suggest that while the TSC-NC models are able to distinguish between carcinogens and non-carcinogens, the TSC-NTSC models are identifying structural attributes that associate carcinogens to specific tumour sites. Since the TSC-NTSC models are composed of active and inactive compounds that are genotoxic and non-genotoxic carcinogens, the TSC-NTSC models may be capable of deciphering non-genotoxic mechanisms of carcinogenesis. Together, models of this type may also prove useful in anticancer drug development since they essentially contain chemicals moieties that target specific tumour site. PMID:23066888

In vivo targeted peripheral nerve imaging with a nerve-specific nanoscale magnetic resonance probe.

PubMed

Zheng, Linfeng; Li, Kangan; Han, Yuedong; Wei, Wei; Zheng, Sujuan; Zhang, Guixiang

2014-11-01

Neuroimaging plays a pivotal role in clinical practice. Currently, computed tomography (CT), magnetic resonance imaging (MRI), ultrasonography, and positron emission tomography (PET) are applied in the clinical setting as neuroimaging modalities. There is no optimal imaging modality for clinical peripheral nerve imaging even though fluorescence/bioluminescence imaging has been used for preclinical studies on the nervous system. Some studies have shown that molecular and cellular MRI (MCMRI) can be used to visualize and image the cellular and molecular level of the nervous system. Other studies revealed that there are different pathological/molecular changes in the proximal and distal sites after peripheral nerve injury (PNI). Therefore, we hypothesized that in vivo peripheral nerve targets can be imaged using MCMRI with specific MRI probes. Specific probes should have higher penetrability for the blood-nerve barrier (BNB) in vivo. Here, a functional nanometre MRI probe that is based on nerve-specific proteins as targets, specifically, using a molecular antibody (mAb) fragment conjugated to iron nanoparticles as an MRI probe, was constructed for further study. The MRI probe allows for imaging the peripheral nerve targets in vivo. Copyright © 2014 Elsevier Ltd. All rights reserved.

Environmental application of biochar: Current status and perspectives.

PubMed

Oliveira, Fernanda R; Patel, Anil K; Jaisi, Deb P; Adhikari, Sushil; Lu, Hui; Khanal, Samir Kumar

2017-12-01

In recent years, there has been a significant interest on biochar for various environmental applications, e.g., pollutants removal, carbon sequestration, and soil amelioration. Biochar has several unique properties, which makes it an efficient, cost-effective and environmentally-friendly material for diverse contaminants removal. The variability in physicochemical properties (e.g., surface area, microporosity, and pH) provides an avenue for biochar to maximize its efficacy to targeted applications. This review aims to highlight the vital role of surface architecture of biochar in different environmental applications. Particularly, it provides a critical review of current research updates related to the pollutants interaction with surface functional groups of biochars and the effect of the parameters variability on biochar attributes pertinent to specific pollutants removal, involved mechanisms, and competence for these removals. Moreover, future research directions of biochar research are also discussed. Copyright © 2017 Elsevier Ltd. All rights reserved.

46 CFR 170.174 - Specific applicability.

Code of Federal Regulations, 2013 CFR

2013-10-01

... REQUIREMENTS FOR ALL INSPECTED VESSELS Determination of Lightweight Displacement and Centers of Gravity § 170.174 Specific applicability. This subpart applies to each vessel for which the lightweight displacement...

46 CFR 170.174 - Specific applicability.

Code of Federal Regulations, 2010 CFR

2010-10-01

... REQUIREMENTS FOR ALL INSPECTED VESSELS Determination of Lightweight Displacement and Centers of Gravity § 170.174 Specific applicability. This subpart applies to each vessel for which the lightweight displacement...

46 CFR 170.174 - Specific applicability.

Code of Federal Regulations, 2012 CFR

2012-10-01

... REQUIREMENTS FOR ALL INSPECTED VESSELS Determination of Lightweight Displacement and Centers of Gravity § 170.174 Specific applicability. This subpart applies to each vessel for which the lightweight displacement...

46 CFR 170.174 - Specific applicability.

Code of Federal Regulations, 2014 CFR

2014-10-01

... REQUIREMENTS FOR ALL INSPECTED VESSELS Determination of Lightweight Displacement and Centers of Gravity § 170.174 Specific applicability. This subpart applies to each vessel for which the lightweight displacement...

46 CFR 170.174 - Specific applicability.

Code of Federal Regulations, 2011 CFR

2011-10-01

... REQUIREMENTS FOR ALL INSPECTED VESSELS Determination of Lightweight Displacement and Centers of Gravity § 170.174 Specific applicability. This subpart applies to each vessel for which the lightweight displacement...

UAHuntsville-NASA MSFC Heliophysics REU: A Model for Recruiting Targeted Groups

NASA Astrophysics Data System (ADS)

Farid, S.; Heerikhuisen, J.; Winebarger, A. R.

2014-12-01

In 2011, researchers from the University of Alabama-Huntsville Center for Space Plasma and Aeronomic Research Center (CSPAR) and NASA Marshall Space Fight Center (MSFC) received a 3-year NSF award to create a REU site specifically designed to increase the participation of underrepresented groups in the Geo-sciences, specifically Heliophysics, and to reduce the attrition rate of sophomores by engaging them in research. This program has been highly successful. In three years of operation, we have increased in the diversity of applicant pool and selected participants, increased the number of inexperienced participants and made measurable impacts on the students' perceptions of graduate school and Heliophysics careers, and produced research with significant scientific merit. We attribute the success of the program to our proactive recruitment of first and second year students, underrepresented groups, and students from small universities. Key factors in our efforts include: 1) In person school visits of targeted schools 2.) Establishing relationships with faculty at targeted schools. 3.) An inclusive selection process that considers the availability of research at the students home institution 4.) A reduced focus on GPA and more focus on recommendation letters as indicators of success 5.) A successful cohort of experienced and inexperienced students 6.) The unique learning environment fostered by UAH-CSPAR and NASA-MSFC scientists. In this presentation, we review our strategies and suggest techniques to recruit targeted groups to similar REU programs.

Does targeted, disease-specific public research funding influence pharmaceutical innovation?

PubMed

Blume-Kohout, Margaret E

2012-01-01

Public funding for biomedical research is often justified as a means to encourage development of more (and better) treatments for disease. However, few studies have investigated the relationship between these expenditures and downstream pharmaceutical innovation. In particular, although recent analyses have shown a clear contribution of federally funded research to drug development, there exists little evidence to suggest that increasing targeted public research funding for any specific disease will result in increased development of drugs to treat that disease. This paper evaluates the impact of changes in the allocation of U. S. National Institutes of Health (NIH) extramural research grant funding across diseases on the number of drugs entering clinical testing to treat those diseases, using new longitudinal data on NIH extramural research grants awarded by disease for years 1975 through 2006. Results from a variety of distributed lag models indicate that a sustained 10 percent increase in targeted, disease-specific NIH funding yields approximately a 4. 5 percent increase in the number of related drugs entering clinical testing (phase I trials) after a lag of up to 12 years, reflecting the continuing influence of NIH funding on discovery and testing of new molecular entities. In contrast, we do not see evidence that increases in NIH extramural grant funding for research focused on specific diseases will increase the number of related treatments investigated in the more expensive, late-stage (phase III) trials.

Identity, Attribution, and the Challenge of Targeting in the Cyberdomain

DTIC Science & Technology

2018-03-07

icts, hybrid warfare, Islamic State, terrorism, biometrics, net- work analysis, big data, activity-based intelligence, high -value individuals One of...environment, combatant identity and pattern of life information became crucial elements of high -value targeting and the process of removing...alytical methods deeply infl uenced by social network theory and targeting pro- cesses specifi cally designed for engaging high -value individuals and

Applications of polymeric micelles with tumor targeted in chemotherapy

NASA Astrophysics Data System (ADS)

Ding, Hui; Wang, Xiaojun; Zhang, Song; Liu, Xinli

2012-11-01

Polymeric micelles (PMs) have gained more progress as a carrier system with the quick development of biological and nanoparticle techniques. In particular, PMs with smart targeting can deliver anti-cancer drugs directly into tumor cells at a sustained rate. PMs with core-shell structure (with diameters of 10 100 nm) have been prepared by a variety of biodegradable and biocompatible polymers via a self-assembly process. The preparation of polymeric micelles with stimuli-responsive block copolymers or modification of target molecules on polymeric micelles' surface are able to significantly improve the efficiency of drug delivery. Polymeric micelles, which have been considered as a novel promising drug carrier for cancer therapeutics, are rapidly evolving and being introduced in an attempt to overcome several limitations of traditional chemotherapeutics, including water solubility, tumor-specific accumulation, anti-tumor efficacy, and non-specific toxicity. This review describes the preparation of polymeric micelles and the targeted modification which greatly enhance the effects of chemotherapeutic agents.

Design attributes of long-circulating polymeric drug delivery vehicles.

PubMed

Beck-Broichsitter, Moritz; Nicolas, Julien; Couvreur, Patrick

2015-11-01

Following systemic administration polymeric drug delivery vehicles allow for a controlled and targeted release of the encapsulated medication at the desired site of action. For an elevated and organ specific accumulation of their cargo, nanocarriers need to avoid opsonization, activation of the complement system and uptake by macrophages of the mononuclear phagocyte system. In this respect, camouflaged vehicles revealed a delayed elimination from systemic circulation and an improved target organ deposition. For instance, a steric shielding of the carrier surface by poly(ethylene glycol) substantially decreased interactions with the biological environment. However, recent studies disclosed possible deficits of this approach, where most notably, poly(ethylene glycol)-modified drug delivery vehicles caused significant immune responses. At present, identification of novel potential carrier coating strategies facilitating negligible immune reactions is an emerging field of interest in drug delivery research. Moreover, physical carrier properties including geometry and elasticity seem to be very promising design attributes to surpass numerous biological barriers, in order to improve the efficacy of the delivered medication. Copyright © 2015 Elsevier B.V. All rights reserved.

The effect of extrinsic attributes on liking of cottage cheese.

PubMed

Hubbard, E M; Jervis, S M; Drake, M A

2016-01-01

Preference mapping studies with cottage cheese have demonstrated that cottage cheese liking is influenced by flavor, texture, curd size, and dressing content. However, extrinsic factors such as package, label claims, and brand name may also influence liking and have not been studied. The objective of this study was to evaluate the role of package attributes and brand on the liking of cottage cheese. A conjoint survey with Kano analysis (n=460) was conducted to explore the effect of extrinsic attributes (brand, label claim, milkfat content, and price) on liking. Following the survey, 150 consumers evaluated intrinsic attributes of 7 cottage cheeses with and without brand information in a 2-d crossover design. Results were evaluated by 2-way ANOVA and multivariate analyses. Milkfat content and price had the highest influence on liking by conjoint analysis. Cottage cheese with 2% milkfat and a low price was preferred. Specific label claims such as "excellent source of calcium (>10%)" were more attractive to consumers than "low sodium" or "extra creamy." Branding influenced overall liking and purchase intent for cottage cheeses to differing degrees. For national brands, acceptance scores were enhanced in the presence of the brand. An all-natural claim was more appealing than organic by conjoint analysis and this result was also confirmed with consumer acceptance testing. Findings from this study can help manufacturers, as well as food marketers, better target their products and brands with attributes that drive consumer choice. Copyright © 2016 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.

A Targeting Microbubble for Ultrasound Molecular Imaging

PubMed Central

Yeh, James Shue-Min; Sennoga, Charles A.; McConnell, Ellen; Eckersley, Robert; Tang, Meng-Xing; Nourshargh, Sussan; Seddon, John M.; Haskard, Dorian O.; Nihoyannopoulos, Petros

2015-01-01

Rationale Microbubbles conjugated with targeting ligands are used as contrast agents for ultrasound molecular imaging. However, they often contain immunogenic (strept)avidin, which impedes application in humans. Although targeting bubbles not employing the biotin-(strept)avidin conjugation chemistry have been explored, only a few reached the stage of ultrasound imaging in vivo, none were reported/evaluated to show all three of the following properties desired for clinical applications: (i) low degree of non-specific bubble retention in more than one non-reticuloendothelial tissue; (ii) effective for real-time imaging; and (iii) effective for acoustic quantification of molecular targets to a high degree of quantification. Furthermore, disclosures of the compositions and methodologies enabling reproduction of the bubbles are often withheld. Objective To develop and evaluate a targeting microbubble based on maleimide-thiol conjugation chemistry for ultrasound molecular imaging. Methods and Results Microbubbles with a previously unreported generic (non-targeting components) composition were grafted with anti-E-selectin F(ab’)2 using maleimide-thiol conjugation, to produce E-selectin targeting microbubbles. The resulting targeting bubbles showed high specificity to E-selectin in vitro and in vivo. Non-specific bubble retention was minimal in at least three non-reticuloendothelial tissues with inflammation (mouse heart, kidneys, cremaster). The bubbles were effective for real-time ultrasound imaging of E-selectin expression in the inflamed mouse heart and kidneys, using a clinical ultrasound scanner. The acoustic signal intensity of the targeted bubbles retained in the heart correlated strongly with the level of E-selectin expression (|r|≥0.8), demonstrating a high degree of non-invasive molecular quantification. Conclusions Targeting microbubbles for ultrasound molecular imaging, based on maleimide-thiol conjugation chemistry and the generic composition described

Final report SI 08-SI-004: Fusion application targets

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

Biener, J; Kucheyev, S O; Wang, M Y

2010-12-03

Complex target structures are necessary to take full advantage of the unique laboratory environment created by inertial confinement fusion experiments. For example, uses-of-ignition targets that contain a thin layer of a low density nanoporous material inside a spherical ablator shell allow placing dopants in direct contact with the DT fuel. The ideal foam for this application is a low-density hydrocarbon foam that is strong enough to survive wetting with cryogenic hydrogen, and low enough in density (density less than {approx}30 mg/cc) to not reduce the yield of the target. Here, we discuss the fabrication foam-lined uses-of-ignition targets, and the developmentmore » of low-density foams that can be used for this application. Much effort has been directed over the last 20 years toward the development of spherical foam targets for direct-drive and fast-ignition experiments. In these targets, the spherical foam shell is used to define the shape of the cryogenic DT fuel layer, or acts as a surrogate to simulate the cryogenic fuel layer. These targets are fabricated from relatively high-density aerogels (>100 mg/cc) and coated with a few micron thick permeation barrier. With exception of the above mentioned fast ignition targets, the wall of these targets is typically larger than 100 microns. In contrast, the fusion application targets for indirect-drive experiments on NIF will require a much thinner foam shell surrounded by a much thicker ablator shell. The design requirements for both types of targets are compared in Table 1. The foam shell targets for direct-drive experiments can be made in large quantities and with reasonably high yields using an encapsulation technique pioneered by Takagi et al. in the early 90's. In this approach, targets are made by first generating unsupported foam shells using a triple-orifice droplet generator, followed by coating the dried foam shells with a thin permeation barrier. However, this approach is difficult, if not impossible

Magnetized Target Fusion Driven by Plasma Liners

NASA Technical Reports Server (NTRS)

Thio, Y. C. Francis; Eskridge, Richard; Smith, James; Lee, Michael; Richeson, Jeff; Schmidt, George; Knapp, Charles E.; Kirkpatrick, Ronald C.; Turchi, Peter J.; Rodgers, Stephen L. (Technical Monitor)

2001-01-01

Magnetized target fusion (MTF) attempts to combine the favorable attributes of magnetic confinement fusion (MCF) for energy confinement with the attributes of inertial confinement fusion (ICF) for efficient compression heating and wall-free containment of the fusing plasma. It uses a material liner to compress and contain a magnetized plasma. For practical applications, standoff drivers to deliver the imploding momentum flux to the target plasma remotely are required. Spherically converging plasma jets have been proposed as standoff drivers for this purpose. The concept involves the dynamic formation of a spherical plasma liner by the merging of plasma jets, and the use of the liner so formed to compress a spheromak or a field reversed configuration (FRC). For the successful implementation of the scheme, plasma jets of the requisite momentum flux density need to be produced. Their transport over sufficiently large distances (a few meters) needs to be assured. When they collide and merge into a liner, relative differences in velocity, density and temperature of the jets could give rise to instabilities in the development of the liner. Variation in the jet properties must be controlled to ensure that the growth rate of the instabilities are not significant over the time scale of the liner formation before engaging with the target plasma. On impact with the target plasma, some plasma interpenetration might occur between the liner and the target. The operating parameter space needs to be identified to ensure that a reasonably robust and conducting contact surface is formed between the liner and the target. A mismatch in the "impedance" between the liner and the target plasma could give rise to undesirable shock heating of the liner leading to increased entropy (thermal losses) in the liner. Any irregularities in the liner will accentuate the Rayleigh-Taylor instabilities during the compression of the target plasma by the liner.

A generalizable platform for interrogating target- and signal-specific consequences of electrophilic modifications in redox-dependent cell signaling.

PubMed

Lin, Hong-Yu; Haegele, Joseph A; Disare, Michael T; Lin, Qishan; Aye, Yimon

2015-05-20

Despite the known propensity of small-molecule electrophiles to react with numerous cysteine-active proteins, biological actions of individual signal inducers have emerged to be chemotype-specific. To pinpoint and quantify the impacts of modifying one target out of the whole proteome, we develop a target-protein-personalized "electrophile toolbox" with which specific intracellular targets can be selectively modified at a precise time by specific reactive signals. This general methodology, T-REX (targetable reactive electrophiles and oxidants), is established by (1) constructing a platform that can deliver a range of electronic and sterically different bioactive lipid-derived signaling electrophiles to specific proteins in cells; (2) probing the kinetics of targeted delivery concept, which revealed that targeting efficiency in cells is largely driven by initial on-rate of alkylation; and (3) evaluating the consequences of protein-target- and small-molecule-signal-specific modifications on the strength of downstream signaling. These data show that T-REX allows quantitative interrogations into the extent to which the Nrf2 transcription factor-dependent antioxidant response element (ARE) signaling is activated by selective electrophilic modifications on Keap1 protein, one of several redox-sensitive regulators of the Nrf2-ARE axis. The results document Keap1 as a promiscuous electrophile-responsive sensor able to respond with similar efficiencies to discrete electrophilic signals, promoting comparable strength of Nrf2-ARE induction. T-REX is also able to elicit cell activation in cases in which whole-cell electrophile flooding fails to stimulate ARE induction prior to causing cytotoxicity. The platform presents a previously unavailable opportunity to elucidate the functional consequences of small-molecule-signal- and protein-target-specific electrophilic modifications in an otherwise unaffected cellular background.

The application of antitumor drug-targeting models on liver cancer.

PubMed

Yan, Yan; Chen, Ningbo; Wang, Yunbing; Wang, Ke

2016-06-01

Hepatocarcinoma animal models, such as the induced tumor model, transplanted tumor model, gene animal model, are significant experimental tools for the evaluation of targeting drug delivery system as well as the pre-clinical studies of liver cancer. The application of antitumor drug-targeting models not only furnishes similar biological characteristics to human liver cancer but also offers guarantee of pharmacokinetic indicators of the liver-targeting preparations. In this article, we have reviewed some kinds of antitumor drug-targeting models of hepatoma and speculated that the research on this field would be capable of attaining a deeper level and expecting a superior achievement in the future.

Placenta-specific drug delivery by trophoblast-targeted nanoparticles in mice

PubMed Central

Zhang, Baozhen; Tan, Lunbo; Yu, Yan; Wang, Baobei; Chen, Zhilong; Han, Jinyu; Li, Mengxia; Chen, Jie; Xiao, Tianxia; Ambati, Balamurali K; Cai, Lintao; Yang, Qing; Nayak, Nihar R; Zhang, Jian; Fan, Xiujun

2018-01-01

Rationale: The availability of therapeutics to treat pregnancy complications is severely lacking, mainly due to the risk of harm to the fetus. In placental malaria, Plasmodium falciparum-infected erythrocytes (IEs) accumulate in the placenta by adhering to chondroitin sulfate A (CSA) on the surfaces of trophoblasts. Based on this principle, we have developed a method for targeted delivery of payloads to the placenta using a synthetic placental CSA-binding peptide (plCSA-BP) derived from VAR2CSA, a CSA-binding protein expressed on IEs. Methods: A biotinylated plCSA-BP was used to examine the specificity of plCSA-BP binding to mouse and human placental tissue in tissue sections in vitro. Different nanoparticles, including plCSA-BP-conjugated nanoparticles loaded with indocyanine green (plCSA-INPs) or methotrexate (plCSA-MNPs), were administered intravenously to pregnant mice to test their efficiency at drug delivery to the placenta in vivo. The tissue distribution and localization of the plCSA-INPs were monitored in live animals using an IVIS imaging system. The effect of plCSA-MNPs on fetal and placental development and pregnancy outcome were examined using a small-animal high-frequency ultrasound (HFUS) imaging system, and the concentrations of methotrexate in fetal and placental tissues were measured using high-performance liquid chromatography (HPLC). Results: plCSA-BP binds specifically to trophoblasts and not to other cell types in the placenta or to CSA-expressing cells in other tissues. Moreover, we found that intravenously administered plCSA-INPs accumulate in the mouse placenta, and ex vivo analysis of the fetuses and placentas confirmed placenta-specific delivery of these nanoparticles. We also demonstrate successful delivery of methotrexate specifically to placental cells by plCSA-BP-conjugated nanoparticles, resulting in dramatic impairment of placental and fetal development. Importantly, plCSA-MNPs treatment had no apparent adverse effects on maternal

46 CFR 160.038-1 - Applicable specifications.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 46 Shipping 6 2010-10-01 2010-10-01 false Applicable specifications. 160.038-1 Section 160.038-1 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) EQUIPMENT, CONSTRUCTION, AND MATERIALS: SPECIFICATIONS AND APPROVAL LIFESAVING EQUIPMENT Magazine Chests, Portable, for Merchant Vessels § 160.038-1...

Synthesis and bio-applications of targeted magnetic-fluorescent composite nanoparticles

NASA Astrophysics Data System (ADS)

Xia, Hui; Tong, Ruijie; Song, Yanling; Xiong, Fang; Li, Jiman; Wang, Shichao; Fu, Huihui; Wen, Jirui; Li, Dongze; Zeng, Ye; Zhao, Zhiwei; Wu, Jiang

2017-04-01

Magnetic-fluorescent nanoparticles have a tremendous potential in biology. As the benefits of these materials gained recognition, increasing attention has been given to the conjugation of magnetic-fluorescent nanoparticles with targeting ligands. The magnetic and fluorescent properties of nanoparticles offer several functionalities, including imaging, separation, and visualization, while the presence of a targeting ligand allows for selective cell and tissue targeting. In this review, methods for the synthesis of targeted magnetic-fluorescent nanoparticles are explored, and recent applications of these nanocomposites to the detection and separation of biomolecules, fluorescent and magnetic resonance imaging, and cancer diagnosis and treatment will be summarized. As these materials are further optimized, targeted magnetic-fluorescent nanoparticles hold great promise for the diagnosis and treatment of some diseases.

Biotechnological applications of mobile group II introns and their reverse transcriptases: gene targeting, RNA-seq, and non-coding RNA analysis.

PubMed

Enyeart, Peter J; Mohr, Georg; Ellington, Andrew D; Lambowitz, Alan M

2014-01-13

Mobile group II introns are bacterial retrotransposons that combine the activities of an autocatalytic intron RNA (a ribozyme) and an intron-encoded reverse transcriptase to insert site-specifically into DNA. They recognize DNA target sites largely by base pairing of sequences within the intron RNA and achieve high DNA target specificity by using the ribozyme active site to couple correct base pairing to RNA-catalyzed intron integration. Algorithms have been developed to program the DNA target site specificity of several mobile group II introns, allowing them to be made into 'targetrons.' Targetrons function for gene targeting in a wide variety of bacteria and typically integrate at efficiencies high enough to be screened easily by colony PCR, without the need for selectable markers. Targetrons have found wide application in microbiological research, enabling gene targeting and genetic engineering of bacteria that had been intractable to other methods. Recently, a thermostable targetron has been developed for use in bacterial thermophiles, and new methods have been developed for using targetrons to position recombinase recognition sites, enabling large-scale genome-editing operations, such as deletions, inversions, insertions, and 'cut-and-pastes' (that is, translocation of large DNA segments), in a wide range of bacteria at high efficiency. Using targetrons in eukaryotes presents challenges due to the difficulties of nuclear localization and sub-optimal magnesium concentrations, although supplementation with magnesium can increase integration efficiency, and directed evolution is being employed to overcome these barriers. Finally, spurred by new methods for expressing group II intron reverse transcriptases that yield large amounts of highly active protein, thermostable group II intron reverse transcriptases from bacterial thermophiles are being used as research tools for a variety of applications, including qRT-PCR and next-generation RNA sequencing (RNA-seq). The

Microtubule-Actin Crosslinking Factor 1 and Plakins as Therapeutic Drug Targets

PubMed Central

Quick, Quincy A.

2018-01-01

Plakins are a family of seven cytoskeletal cross-linker proteins (microtubule-actin crosslinking factor 1 (MACF), bullous pemphigoid antigen (BPAG1) desmoplakin, envoplakin, periplakin, plectin, epiplakin) that network the three major filaments that comprise the cytoskeleton. Plakins have been found to be involved in disorders and diseases of the skin, heart, nervous system, and cancer that are attributed to autoimmune responses and genetic alterations of these macromolecules. Despite their role and involvement across a spectrum of several diseases, there are no current drugs or pharmacological agents that specifically target the members of this protein family. On the contrary, microtubules have traditionally been targeted by microtubule inhibiting agents, used for the treatment of diseases such as cancer, in spite of the deleterious toxicities associated with their clinical utility. The Research Collaboratory for Structural Bioinformatics (RCSB) was used here to identify therapeutic drugs targeting the plakin proteins, particularly the spectraplakins MACF1 and BPAG1, which contain microtubule-binding domains. RCSB analysis revealed that plakin proteins had 329 ligands, of which more than 50% were MACF1 and BPAG1 ligands and 10 were documented, clinically or experimentally, to have several therapeutic applications as anticancer, anti-inflammatory, and antibiotic agents. PMID:29373494

Targeted Nanodiamonds as Phenotype Specific Photoacoustic Contrast Agents for Breast Cancer

PubMed Central

Zhang, Ti; Cui, Huizhong; Fang, Chia-Yi; Cheng, Kun; Yang, Xinmai; Chang, Huan-Cheng; Forrest, M. Laird

2015-01-01

Aim The aim is to develop irradiated nanodiamonds (INDs) as a molecularly-targeted contrast agent for high resolution and phenotype-specific detection of breast cancer with photoacoustic (PA) imaging. Materials & Methods The surface of acid treated radiation-damaged nanodiamonds was grafted with polyethylene glycol (PEG) to improve its stability and circulation time in blood, followed by conjugation to an anti-Human epidermal growth factor receptor-2 (HER2) peptide (KCCYSL) with a final nanoparticle size of ca. 92 nm. Immunocompetent mice bearing orthotopic HER2 positive or negative tumors were administered INDs and PA imaged using an 820-nm near infrared laser. Results PA images demonstrated that INDs accumulate in tumors and completely delineated the entire tumor within 10 hours. HER2 targeting significantly enhanced imaging of HER2-positive tumors. Pathological examination demonstrated INDs are non-toxic. Conclusions PA technology is adaptable to low-cost bedside medicine, and with new contrast agents described herein, PA can achieve high resolution (sub-mm) and phenotype specific monitoring of cancer growth. PMID:25723091

46 CFR 160.053-1 - Applicable specifications.

Code of Federal Regulations, 2014 CFR

2014-10-01

...: SPECIFICATIONS AND APPROVAL LIFESAVING EQUIPMENT Work Vests, Unicellular Plastic Foam § 160.053-1 Applicable... plastic foam work vests are manufactured, form a part of this subpart: (1) Military specification: MIL-L-17653A—Life Preserver, Vest, Work Type, Unicellular Plastic. (2) [Reserved] (b) Copies on file. Copies of...

46 CFR 160.053-1 - Applicable specifications.

Code of Federal Regulations, 2013 CFR

2013-10-01

...: SPECIFICATIONS AND APPROVAL LIFESAVING EQUIPMENT Work Vests, Unicellular Plastic Foam § 160.053-1 Applicable... plastic foam work vests are manufactured, form a part of this subpart: (1) Military specification: MIL-L-17653A—Life Preserver, Vest, Work Type, Unicellular Plastic. (2) [Reserved] (b) Copies on file. Copies of...

46 CFR 160.053-1 - Applicable specifications.

Code of Federal Regulations, 2012 CFR

2012-10-01

...: SPECIFICATIONS AND APPROVAL LIFESAVING EQUIPMENT Work Vests, Unicellular Plastic Foam § 160.053-1 Applicable... plastic foam work vests are manufactured, form a part of this subpart: (1) Military specification: MIL-L-17653A—Life Preserver, Vest, Work Type, Unicellular Plastic. (2) [Reserved] (b) Copies on file. Copies of...

46 CFR 160.053-1 - Applicable specifications.

Code of Federal Regulations, 2010 CFR

2010-10-01

... plastic foam work vests are manufactured, form a part of this subpart: (1) Military specification: MIL-L-17653A—Life Preserver, Vest, Work Type, Unicellular Plastic. (2) [Reserved] (b) Copies on file. Copies of...: SPECIFICATIONS AND APPROVAL LIFESAVING EQUIPMENT Work Vests, Unicellular Plastic Foam § 160.053-1 Applicable...

Attribution of extreme events in the western US to human activities

NASA Astrophysics Data System (ADS)

Mera, R. J.

2015-12-01

A project to investigate the role of human activities on the changing nature of extreme events in the western US began as part of a CLIVAR-sponsored Postdocs Applying Climate Expertise (PACE) project. The climate institution was the Oregon State University and the application partner was the Oregon Department of Land Conservation and Development (DLCD). DLCD was interested in the changes in weather extremes in the Pacific Northwest, specifically extreme rainfall, flooding, and droughts. The project employs very large ensembles of regional model simulations through volunteer computing resources and allows for probabilistic event attribution (PEA), an important climate research technique. The model was found to have good representation of atmospheric rivers, a major source of extreme precipitation in the Pacific Northwest. The model domain also encompasses California and Nevada. One of the studies focused on attribution of extreme heat in relation to vulnerable populations in California's Central Valley, where heat waves have become progressively more severe due to increasing nighttime temperatures. Specifically, we found that that (1) simulations of the hottest summer days during the 2000s were twice as likely to occur using observed levels of greenhouse gases than in a counterfactual world without major human activities, (2) detrimental impacts of heat on public health-relevant variables, such as the number of days above 40°C, can be quantified and attributed to human activities using PEA, and (3) PEA can serve as a tool for addressing climate justice concerns of populations within developed nations. The research conducted through the PACE program has also provided a framework for a pioneering climate attribution study at the Union of Concerned Scientists (UCS). The UCS project takes advantage of new research that shows that nearly two-thirds of carbon pollution released into the atmosphere, reported as carbon dioxide equivalent with hundred-year global warming

Development of prostate specific membrane antigen targeted ultrasound microbubbles using bioorthogonal chemistry

PubMed Central

Zlitni, Aimen; Yin, Melissa; Janzen, Nancy; Chatterjee, Samit; Lisok, Ala; Gabrielson, Kathleen L.; Nimmagadda, Sridhar; Pomper, Martin G.; Foster, F. Stuart

2017-01-01

Prostate specific membrane antigen (PSMA) targeted microbubbles (MBs) were developed using bioorthogonal chemistry. Streptavidin-labeled MBs were treated with a biotinylated tetrazine (MBTz) and targeted to PSMA expressing cells using trans-cyclooctene (TCO)-functionalized anti-PSMA antibodies (TCO-anti-PSMA). The extent of MB binding to PSMA positive cells for two different targeting strategies was determined using an in vitro flow chamber. The initial approach involved pretargeting, where TCO-anti-PSMA was first incubated with PSMA expressing cells and followed by MBTz, which subsequently showed a 2.8 fold increase in the number of bound MBs compared to experiments performed in the absence of TCO-anti-PSMA. Using direct targeting, where TCO-anti-PSMA was linked to MBTz prior to initiation of the assay, a 5-fold increase in binding compared to controls was observed. The direct targeting approach was subsequently evaluated in vivo using a human xenograft tumor model and two different PSMA-targeting antibodies. The US signal enhancements observed were 1.6- and 5.9-fold greater than that for non-targeted MBs. The lead construct was also evaluated in a head-to-head study using mice bearing both PSMA positive or negative tumors in separate limbs. The human PSMA expressing tumors exhibited a 2-fold higher US signal compared to those tumors deficient in human PSMA. The results demonstrate both the feasibility of preparing PSMA-targeted MBs and the benefits of using bioorthogonal chemistry to create targeted US probes. PMID:28472168

UniDrug-target: a computational tool to identify unique drug targets in pathogenic bacteria.

PubMed

Chanumolu, Sree Krishna; Rout, Chittaranjan; Chauhan, Rajinder S

2012-01-01

pathogen-specific drug targets identification which will increase their success and durability as drugs developed against them have less chance to develop resistances and adverse impact on environment. The server is freely available at http://117.211.115.67/UDT/main.html. The standalone application (source codes) is available at http://www.bioinformatics.org/ftp/pub/bioinfojuit/UDT.rar.

Reconciling the Structural Attributes of Avian Antibodies*

PubMed Central

Conroy, Paul J.; Law, Ruby H. P.; Gilgunn, Sarah; Hearty, Stephen; Caradoc-Davies, Tom T.; Lloyd, Gordon; O'Kennedy, Richard J.; Whisstock, James C.

2014-01-01

Antibodies are high value therapeutic, diagnostic, biotechnological, and research tools. Combinatorial approaches to antibody discovery have facilitated access to unique antibodies by surpassing the diversity limitations of the natural repertoire, exploitation of immune repertoires from multiple species, and tailoring selections to isolate antibodies with desirable biophysical attributes. The V-gene repertoire of the chicken does not utilize highly diverse sequence and structures, which is in stark contrast to the mechanism employed by humans, mice, and primates. Recent exploitation of the avian immune system has generated high quality, high affinity antibodies to a wide range of antigens for a number of therapeutic, diagnostic and biotechnological applications. Furthermore, extensive examination of the amino acid characteristics of the chicken repertoire has provided significant insight into mechanisms employed by the avian immune system. A paucity of avian antibody crystal structures has limited our understanding of the structural consequences of these uniquely chicken features. This paper presents the crystal structure of two chicken single chain fragment variable (scFv) antibodies generated from large libraries by phage display against important human antigen targets, which capture two unique CDRL1 canonical classes in the presence and absence of a non-canonical disulfide constrained CDRH3. These structures cast light on the unique structural features of chicken antibodies and contribute further to our collective understanding of the unique mechanisms of diversity and biochemical attributes that render the chicken repertoire of particular value for antibody generation. PMID:24737329

A Generalizable Platform for Interrogating Target- and Signal-Specific Consequences of Electrophilic Modifications in Redox-Dependent Cell Signaling

PubMed Central

Lin, Hong-Yu; Haegele, Joseph A.; Disare, Michael T.; Lin, Qishan; Aye, Yimon

2015-01-01

Despite the known propensity of small-molecule electrophiles to react with numerous cysteine-active proteins, biological actions of individual signal inducers have emerged to be chemotype-specific. To pinpoint and quantify the impacts of modifying one target out of the whole proteome, we develop a target-protein-personalized “electrophile toolbox” with which specific intracellular targets can be selectively modified at a precise time by specific reactive signals. This general methodology—T-REX (targetable reactive electrophiles & oxidants)—is established by: (1) constructing a platform that can deliver a range of electronic and sterically different bioactive lipid-derived signaling electrophiles to specific proteins in cells; (2) probing the kinetics of targeted delivery concept which revealed that targeting efficiency in cells is largely driven by initial on-rate of alkylation; and (3) evaluating the consequences of protein-target- and small-molecule-signal-specific modifications on the strength of downstream signaling. These data show that T-REX allows quantitative interrogations into the extent to which the Nrf2 transcription factor-dependent antioxidant response element (ARE) signaling is activated by selective electrophilic modifications on Keap1 protein—one of several redox-sensitive regulators of the Nrf2–ARE axis. The results document Keap1 as a promiscuous electrophile-responsive sensor able to respond with similar efficiencies to discrete electrophilic signals, promoting comparable strength of Nrf2–ARE induction. T-REX is also able to elicit cell activation in cases in which whole-cell electrophile flooding fails to stimulate ARE induction prior to causing cytotoxicity. The platform presents a previously unavailable opportunity to elucidate the functional consequences of small-molecule-signal- and protein-target-specific electrophilic modifications in an otherwise unaffected cellular background. PMID:25909755

Cross-Situational Specificity in Managers’ Perceptions of Subordinate Performance, Attributions, and Leader Behaviors.

DTIC Science & Technology

1982-05-20

Dansereau et al., 1975; Davis & Luthans , 1979; Zahn & Wolf, 1981). For example, Dansereau et al. (1975) reported that leaders tended to develop a...of Subordinate Performance,6PEFRIGO.RPRTNMR Attributions, and Leader Behaviors PEORIGRGRPRTNMR GT-ONR-2. IBR 82-7 17. UTHO~s)S CONTRACT OR GRANT...8217 performance, causes (attributions of subordinates’ performance, and leader behaviors employed toward subordinates aL-u were examined from the standpoint of

The self-attribution bias and paranormal beliefs.

PubMed

van Elk, Michiel

2017-03-01

The present study investigated the relation between paranormal beliefs, illusory control and the self-attribution bias, i.e., the motivated tendency to attribute positive outcomes to oneself while negative outcomes are externalized. Visitors of a psychic fair played a card guessing game and indicated their perceived control over randomly selected cards as a function of the congruency and valence of the card. A stronger self-attribution bias was observed for paranormal believers compared to skeptics and this bias was specifically related to traditional religious beliefs and belief in superstition. No relation between paranormal beliefs and illusory control was found. Self-report measures indicated that paranormal beliefs were associated to being raised in a spiritual family and to anomalous experiences during childhood. Thereby this study suggests that paranormal beliefs are related to specific cognitive biases that in turn are shaped by socio-cultural factors. Copyright © 2017 Elsevier Inc. All rights reserved.

46 CFR 188.05-5 - Specific application noted in text.

Code of Federal Regulations, 2012 CFR

2012-10-01

... 46 Shipping 7 2012-10-01 2012-10-01 false Specific application noted in text. 188.05-5 Section 188.05-5 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) OCEANOGRAPHIC RESEARCH VESSELS GENERAL PROVISIONS Application § 188.05-5 Specific application noted in text. (a) At the beginning of the...

46 CFR 188.05-5 - Specific application noted in text.

Code of Federal Regulations, 2013 CFR

2013-10-01

... 46 Shipping 7 2013-10-01 2013-10-01 false Specific application noted in text. 188.05-5 Section 188.05-5 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) OCEANOGRAPHIC RESEARCH VESSELS GENERAL PROVISIONS Application § 188.05-5 Specific application noted in text. (a) At the beginning of the...

46 CFR 188.05-5 - Specific application noted in text.

Code of Federal Regulations, 2014 CFR

2014-10-01

... 46 Shipping 7 2014-10-01 2014-10-01 false Specific application noted in text. 188.05-5 Section 188.05-5 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) OCEANOGRAPHIC RESEARCH VESSELS GENERAL PROVISIONS Application § 188.05-5 Specific application noted in text. (a) At the beginning of the...

46 CFR 188.05-5 - Specific application noted in text.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 46 Shipping 7 2010-10-01 2010-10-01 false Specific application noted in text. 188.05-5 Section 188.05-5 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) OCEANOGRAPHIC RESEARCH VESSELS GENERAL PROVISIONS Application § 188.05-5 Specific application noted in text. (a) At the beginning of the...

46 CFR 188.05-5 - Specific application noted in text.

Code of Federal Regulations, 2011 CFR

2011-10-01

... 46 Shipping 7 2011-10-01 2011-10-01 false Specific application noted in text. 188.05-5 Section 188.05-5 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) OCEANOGRAPHIC RESEARCH VESSELS GENERAL PROVISIONS Application § 188.05-5 Specific application noted in text. (a) At the beginning of the...

Heterobivalent Imaging Agents for Simultaneous Targeting Prostate-Specific Membrane Antigen (PSMA) and Hepsin

DTIC Science & Technology

2014-11-01

Prostate-Specific Membrane Antigen ( PSMA ) and Hepsin PRINCIPAL INVESTIGATOR: Youngjoo Byun, Ph. D. CONTRACTING ORGANIZATION: Korea...Simultaneous Targeting Prostate-Specific Membrane Antigen ( PSMA ) and Hepsin 5b. GRANT NUMBER W81XWH-10-1-0189 5c. PROGRAM ELEMENT NUMBER 6...heterobivalent conjugates of PSMA /hepsin-binding ligands labeled with optical dyes or radionuclides. The sensitivity and accuracy of prostate cancer

10 CFR 40.31 - Application for specific licenses.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 10 Energy 1 2010-01-01 2010-01-01 false Application for specific licenses. 40.31 Section 40.31 Energy NUCLEAR REGULATORY COMMISSION DOMESTIC LICENSING OF SOURCE MATERIAL License Applications § 40.31... application for a source material license, other than a license exempted from part 170 of this chapter, shall...

Targeting of Magnetic Nanoparticle-coated Microbubbles to the Vascular Wall Empowers Site-specific Lentiviral Gene Delivery in vivo.

PubMed

Heun, Yvonn; Hildebrand, Staffan; Heidsieck, Alexandra; Gleich, Bernhard; Anton, Martina; Pircher, Joachim; Ribeiro, Andrea; Mykhaylyk, Olga; Eberbeck, Dietmar; Wenzel, Daniela; Pfeifer, Alexander; Woernle, Markus; Krötz, Florian; Pohl, Ulrich; Mannell, Hanna

2017-01-01

In the field of vascular gene therapy, targeting systems are promising advancements to improve site-specificity of gene delivery. Here, we studied whether incorporation of magnetic nanoparticles (MNP) with different magnetic properties into ultrasound sensitive microbubbles may represent an efficient way to enable gene targeting in the vascular system after systemic application. Thus, we associated novel silicon oxide-coated magnetic nanoparticle containing microbubbles (SO-Mag MMB) with lentiviral particles carrying therapeutic genes and determined their physico-chemical as well as biological properties compared to MMB coated with polyethylenimine-coated magnetic nanoparticles (PEI-Mag MMB). While there were no differences between both MMB types concerning size and lentivirus binding, SO-Mag MMB exhibited superior characteristics regarding magnetic moment, magnetizability as well as transduction efficiency under static and flow conditions in vitro . Focal disruption of lentiviral SO-Mag MMB by ultrasound within isolated vessels exposed to an external magnetic field decisively improved localized VEGF expression in aortic endothelium ex vivo and enhanced the angiogenic response. Using the same system in vivo , we achieved a highly effective, site-specific lentiviral transgene expression in microvessels of the mouse dorsal skin after arterial injection. Thus, we established a novel lentiviral MMB technique, which has great potential towards site-directed vascular gene therapy.

Precision Modeling Of Targets Using The VALUE Computer Program

NASA Astrophysics Data System (ADS)

Hoffman, George A.; Patton, Ronald; Akerman, Alexander

1989-08-01

The 1976-vintage LASERX computer code has been augmented to produce realistic electro-optical images of targets. Capabilities lacking in LASERX but recently incorporated into its VALUE successor include: •Shadows cast onto the ground •Shadows cast onto parts of the target •See-through transparencies (e.g.,canopies) •Apparent images due both to atmospheric scattering and turbulence •Surfaces characterized by multiple bi-directional reflectance functions VALUE provides not only realistic target modeling by its precise and comprehensive representation of all target attributes, but additionally VALUE is very user friendly. Specifically, setup of runs is accomplished by screen prompting menus in a sequence of queries that is logical to the user. VALUE also incorporates the Optical Encounter (OPEC) software developed by Tricor Systems,Inc., Elgin, IL.

Mathematical description of drug-target interactions: application to biologics that bind to targets with two binding sites.

PubMed

Gibiansky, Leonid; Gibiansky, Ekaterina

2018-02-01

The emerging discipline of mathematical pharmacology occupies the space between advanced pharmacometrics and systems biology. A characteristic feature of the approach is application of advance mathematical methods to study the behavior of biological systems as described by mathematical (most often differential) equations. One of the early application of mathematical pharmacology (that was not called this name at the time) was formulation and investigation of the target-mediated drug disposition (TMDD) model and its approximations. The model was shown to be remarkably successful, not only in describing the observed data for drug-target interactions, but also in advancing the qualitative and quantitative understanding of those interactions and their role in pharmacokinetic and pharmacodynamic properties of biologics. The TMDD model in its original formulation describes the interaction of the drug that has one binding site with the target that also has only one binding site. Following the framework developed earlier for drugs with one-to-one binding, this work aims to describe a rigorous approach for working with similar systems and to apply it to drugs that bind to targets with two binding sites. The quasi-steady-state, quasi-equilibrium, irreversible binding, and Michaelis-Menten approximations of the model are also derived. These equations can be used, in particular, to predict concentrations of the partially bound target (RC). This could be clinically important if RC remains active and has slow internalization rate. In this case, introduction of the drug aimed to suppress target activity may lead to the opposite effect due to RC accumulation.

Anticancer efficacy of the metabolic blocker 3-bromopyruvate: specific molecular targeting.

PubMed

Ganapathy-Kanniappan, Shanmugasundaram; Kunjithapatham, Rani; Geschwind, Jean-Francois

2013-01-01

The anticancer efficacy of the pyruvate analog 3-bromopyruvate has been demonstrated in multiple tumor models. The chief principle underlying the antitumor effects of 3-bromopyruvate is its ability to effectively target the energy metabolism of cancer cells. Biochemically, the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) has been identified as the primary target of 3-bromopyruvate. Its inhibition results in the depletion of intracellular ATP, causing cell death. Several reports have also demonstrated that in addition to GAPDH inhibition, the induction of cellular stress also contributes to 3-bromopyruvate treatment-dependent apoptosis. Furthermore, recent evidence shows that 3-bromopyruvate is taken up selectively by tumor cells via the monocarboxylate transporters (MCTs) that are frequently overexpressed in cancer cells (for the export of lactate produced during aerobic glycolysis). The preferential uptake of 3-bromopyruvate via MCTs facilitates selective targeting of tumor cells while leaving healthy and non-malignant tissue untouched. Taken together, the specificity of molecular (GAPDH) targeting and selective uptake by tumor cells, underscore the potential of 3-bromopyruvate as a potent and promising anticancer agent. In this review, we highlight the mechanistic characteristics of 3-bromopyruvate and discuss its potential for translation into the clinic.

Design specification for the European Spallation Source neutron generating target element

NASA Astrophysics Data System (ADS)

Aguilar, A.; Sordo, F.; Mora, T.; Mena, L.; Mancisidor, M.; Aguilar, J.; Bakedano, G.; Herranz, I.; Luna, P.; Magan, M.; Vivanco, R.; Jimenez-Villacorta, F.; Sjogreen, K.; Oden, U.; Perlado, J. M.; Martinez, J. L.; Bermejo, F. J.

2017-06-01

The paper addresses some of the most relevant issues concerning the thermal hydraulics and radiation damage of the neutron generation target to be built at the European Spallation Source as recently approved after a critical design review. The target unit consists of a set of Tungsten blocks placed inside a wheel of 2.5 m diameter which rotates at some 0.5 Hz in order to distribute the heat generated from incoming protons which reach the target in the radial direction. The spallation material elements are composed of an array of Tungsten pieces which rest on a rotating steel support (the cassette) and are distributed in a cross-flow configuration. The thermal, mechanical and radiation effects resulting from the impact of a 2 GeV proton pulse are analysed in detail as well as an evaluation of the inventory of spallation products. The current design is found to conform to specifications and found to be robust enough to deal with several accident scenarios.

Landscape-level movement patterns by lions in western Serengeti: comparing the influence of inter-specific competitors, habitat attributes and prey availability.

PubMed

Kittle, Andrew M; Bukombe, John K; Sinclair, Anthony R E; Mduma, Simon A R; Fryxell, John M

2016-01-01

Where apex predators move on the landscape influences ecosystem structure and function and is therefore key to effective landscape-level management and species-specific conservation. However the factors underlying predator distribution patterns within functional ecosystems are poorly understood. Predator movement should be sensitive to the spatial patterns of inter-specific competitors, spatial variation in prey density, and landscape attributes that increase individual prey vulnerability. We investigated the relative role of these fundamental factors on seasonal resource utilization by a globally endangered apex carnivore, the African lion (Panthera leo) in Tanzania's Serengeti National Park. Lion space use was represented by novel landscape-level, modified utilization distributions (termed "localized density distributions") created from telemetry relocations of individual lions from multiple neighbouring prides. Spatial patterns of inter-specific competitors were similarly determined from telemetry re-locations of spotted hyenas (Crocuta crocuta), this system's primary competitor for lions; prey distribution was derived from 18 months of detailed census data; and remote sensing data was used to represent relevant habitat attributes. Lion space use was consistently influenced by landscape attributes that increase individual prey vulnerability to predation. Wet season activity, when available prey were scarce, was concentrated near embankments, which provide ambush opportunities, and dry season activity, when available prey were abundant, near remaining water sources where prey occurrence is predictable. Lion space use patterns were positively associated with areas of high prey biomass, but only in the prey abundant dry season. Finally, at the broad scale of this analysis, lion and hyena space use was positively correlated in the comparatively prey-rich dry season and unrelated in the wet season, suggesting lion movement was unconstrained by the spatial patterns

Mental state attribution and the gaze cueing effect.

PubMed

Cole, Geoff G; Smith, Daniel T; Atkinson, Mark A

2015-05-01

Theory of mind is said to be possessed by an individual if he or she is able to impute mental states to others. Recently, some authors have demonstrated that such mental state attributions can mediate the "gaze cueing" effect, in which observation of another individual shifts an observer's attention. One question that follows from this work is whether such mental state attributions produce mandatory modulations of gaze cueing. Employing the basic gaze cueing paradigm, together with a technique commonly used to assess mental-state attribution in nonhuman animals, we manipulated whether the gazing agent could see the same thing as the participant (i.e., the target) or had this view obstructed by a physical barrier. We found robust gaze cueing effects, even when the observed agent in the display could not see the same thing as the participant. These results suggest that the attribution of "seeing" does not necessarily modulate the gaze cueing effect.

Condom-associated erection problems: behavioural responses and attributions in young, heterosexual men

PubMed Central

Hill, Brandon J.; Sanders, Stephanie A.; Crosby, Richard A.; Ingelhart, Kara N.; Janssen, Erick

2015-01-01

Background Previous studies have associated men who experience condom-associated erection problems (CAEP) with incomplete condom use and/or foregoing using condoms altogether. However, how men respond to CAEP and what they attribute CAEP to, remains unclear. Understanding young men's CAEP responses and attributions could help improve sexually transmissible infections (STI)/HIV prevention programs and interventions. Methods Behavioural responses to, and attributions for, CAEP during application (CAEP-Application) and/or during penile-vaginal intercourse (CAEP-PVI) were reported using an online questionnaire by 295 young, heterosexual men (aged 18–24 years) who were recruited via social media websites and university Listservs across major cities in the Midwestern USA. Results Behavioural responses to CAEP-Application included receiving oral or manual stimulation, stimulating a partner, self-stimulation, foregoing condom use and applying the condom after starting intercourse. Attributions for CAEP-Application included: distraction, fit and feel problems, application taking too long and having consumed too much alcohol. Behavioural responses to CAEP-PVI included increasing the intensity of intercourse, removing the condom to receive oral or manual stimulation and removing condom and continuing intercourse. Attributions for CAEP-PVI included: lack of sensation, taking too long to orgasm, not being ‘turned on’ enough, fit and feel problems and partner-related factors. Conclusions Men who report CAEP respond with both STI/HIV risk-reducing and potentially risk-increasing behaviours (e.g. forgoing condom use). Men attribute their experiences to a wide range of individual- and partner-level factors. Addressing men's CAEP behavioural responses and attributions may increase the efficacious value of condom programs and STI/HIV prevention interventions – particularly among men who experience CAEP. PMID:26166025

Joint Attributes and Event Analysis for Multimedia Event Detection.

PubMed

Ma, Zhigang; Chang, Xiaojun; Xu, Zhongwen; Sebe, Nicu; Hauptmann, Alexander G

2017-06-15

Semantic attributes have been increasingly used the past few years for multimedia event detection (MED) with promising results. The motivation is that multimedia events generally consist of lower level components such as objects, scenes, and actions. By characterizing multimedia event videos with semantic attributes, one could exploit more informative cues for improved detection results. Much existing work obtains semantic attributes from images, which may be suboptimal for video analysis since these image-inferred attributes do not carry dynamic information that is essential for videos. To address this issue, we propose to learn semantic attributes from external videos using their semantic labels. We name them video attributes in this paper. In contrast with multimedia event videos, these external videos depict lower level contents such as objects, scenes, and actions. To harness video attributes, we propose an algorithm established on a correlation vector that correlates them to a target event. Consequently, we could incorporate video attributes latently as extra information into the event detector learnt from multimedia event videos in a joint framework. To validate our method, we perform experiments on the real-world large-scale TRECVID MED 2013 and 2014 data sets and compare our method with several state-of-the-art algorithms. The experiments show that our method is advantageous for MED.

A Domain-Specific Terminology for Retinopathy of Prematurity and Its Applications in Clinical Settings.

PubMed

Zhang, Yinsheng; Zhang, Guoming

2018-01-01

A terminology (or coding system) is a formal set of controlled vocabulary in a specific domain. With a well-defined terminology, each concept in the target domain is assigned with a unique code, which can be identified and processed across different medical systems in an unambiguous way. Though there are lots of well-known biomedical terminologies, there is currently no domain-specific terminology for ROP (retinopathy of prematurity). Based on a collection of historical ROP patients' data in the electronic medical record system, we extracted the most frequent terms in the domain and organized them into a hierarchical coding system-ROP Minimal Standard Terminology, which contains 62 core concepts in 4 categories. This terminology has been successfully used to provide highly structured and semantic-rich clinical data in several ROP-related applications.

Global preamplification simplifies targeted mRNA quantification

PubMed Central

Kroneis, Thomas; Jonasson, Emma; Andersson, Daniel; Dolatabadi, Soheila; Ståhlberg, Anders

2017-01-01

The need to perform gene expression profiling using next generation sequencing and quantitative real-time PCR (qPCR) on small sample sizes and single cells is rapidly expanding. However, to analyse few molecules, preamplification is required. Here, we studied global and target-specific preamplification using 96 optimised qPCR assays. To evaluate the preamplification strategies, we monitored the reactions in real-time using SYBR Green I detection chemistry followed by melting curve analysis. Next, we compared yield and reproducibility of global preamplification to that of target-specific preamplification by qPCR using the same amount of total RNA. Global preamplification generated 9.3-fold lower yield and 1.6-fold lower reproducibility than target-specific preamplification. However, the performance of global preamplification is sufficient for most downstream applications and offers several advantages over target-specific preamplification. To demonstrate the potential of global preamplification we analysed the expression of 15 genes in 60 single cells. In conclusion, we show that global preamplification simplifies targeted gene expression profiling of small sample sizes by a flexible workflow. We outline the pros and cons for global preamplification compared to target-specific preamplification. PMID:28332609

Site-Specific Targeting of Platelet-Rich Plasma via Superparamagnetic Nanoparticles

PubMed Central

Talaie, Tara; Pratt, Stephen J.P.; Vanegas, Camilo; Xu, Su; Henn, R. Frank; Yarowsky, Paul; Lovering, Richard M.

2015-01-01

. Platelets without SPIONs did not respond to the magnetic field. In vivo experiments showed that the SPION-containing platelets can be noninvasively maintained at a specific site with the application of a magnetic field. Conclusion: PRP may be a useful product in the clinical treatment of muscle injuries, but one problem with using it as a therapeutic tool is retaining PRP at the site of injury. This study proposes a potential solution, with findings that support this method at the cell, whole muscle, and in vivo levels. Controlling the location of PRP will allow the clustering of PRP to enrich the target area with growth factors and will prevent loss of platelets over time at the site of injury. PMID:25664326

Characterization of parasite-specific indels and their proposed relevance for selective anthelminthic drug targeting

PubMed Central

Wang, Qi; Heizer, Esley; Rosa, Bruce A.; Wildman, Scott A.; Janetka, James W.; Mitreva, Makedonka

2016-01-01

Insertions and deletions (indels) are important sequence variants that are considered as phylogenetic markers that reflect evolutionary adaptations in different species. In an effort to systematically study indels specific to the phylum Nematoda and their structural impact on the proteins bearing them, we examined over 340,000 polypeptides from 21 nematode species spanning the phylum, compared them to non-nematodes and identified indels unique to nematode proteins in more than 3,000 protein families. Examination of the amino acid composition revealed uneven usage of amino acids for insertions and deletions. The amino acid composition and cost, along with the secondary structure constitution of the indels, were analyzed in the context of their biological pathway associations. Species-specific indels could enable indel-based targeting for drug design in pathogens/parasites. Therefore, we screened the spatial locations of the indels in the parasite’s protein 3D structures, determined the location of the indel and identified potential unique drug targeting sites. These indels could be confirmed by RNA-Seq data. Examples are presented that illustrate the close proximity of the indel to established small-molecule binding pockets that can potentially facilitate selective targeting to the parasites and bypassing their host, thus reducing or eliminating the toxicity of the potential drugs. The study presents an approach for understanding the adaptation of pathogens/parasites at a molecular level, and outlines a strategy to identify such nematode-selective targets that remain essential to the organism. With further experimental characterization and validation, it opens a possible channel for the development of novel treatments with high target specificity, addressing both host toxicity and resistance concerns. PMID:26829384

Characterization of parasite-specific indels and their proposed relevance for selective anthelminthic drug targeting.

PubMed

Wang, Qi; Heizer, Esley; Rosa, Bruce A; Wildman, Scott A; Janetka, James W; Mitreva, Makedonka

2016-04-01

Insertions and deletions (indels) are important sequence variants that are considered as phylogenetic markers that reflect evolutionary adaptations in different species. In an effort to systematically study indels specific to the phylum Nematoda and their structural impact on the proteins bearing them, we examined over 340,000 polypeptides from 21 nematode species spanning the phylum, compared them to non-nematodes and identified indels unique to nematode proteins in more than 3000 protein families. Examination of the amino acid composition revealed uneven usage of amino acids for insertions and deletions. The amino acid composition and cost, along with the secondary structure constitution of the indels, were analyzed in the context of their biological pathway associations. Species-specific indels could enable indel-based targeting for drug design in pathogens/parasites. Therefore, we screened the spatial locations of the indels in the parasite's protein 3D structures, determined the location of the indel and identified potential unique drug targeting sites. These indels could be confirmed by RNA-Seq data. Examples are presented illustrating the close proximity of some indels to established small-molecule binding pockets that can potentially facilitate selective targeting to the parasites and bypassing their host, thus reducing or eliminating the toxicity of the potential drugs. This study presents an approach for understanding the adaptation of pathogens/parasites at a molecular level, and outlines a strategy to identify such nematode-selective targets that remain essential to the organism. With further experimental characterization and validation, it opens a possible channel for the development of novel treatments with high target specificity, addressing both host toxicity and resistance concerns. Copyright © 2016 Elsevier B.V. All rights reserved.

Quantitative sediment source attribution with compound-specific isotope analysis in a C3 plant-dominated catchment (central Switzerland)

NASA Astrophysics Data System (ADS)

Alewell, Christine; Birkholz, Axel; Meusburger, Katrin; Schindler Wildhaber, Yael; Mabit, Lionel

2016-03-01

As sediment loads impact freshwater systems and infrastructure, their origin in complex landscape systems is of crucial importance for sustainable management of agricultural catchments. We differentiated the sediment source contribution to a lowland river in central Switzerland by using compound-specific isotope analysis (CSIA). We found a clear distinction of sediment sources originating from forest and agricultural land use. Our results demonstrate that it is possible to reduce the uncertainty of sediment source attribution in: (i) using compound content (in our case, long-chain fatty acids; FAs) rather than soil organic matter content to transfer δ13C signal of FAs to soil contribution and (ii) restricting the investigation to the long-chain FAs (> C22 : 0) not to introduce errors due to aquatic contributions from algae and microorganisms. Results showed unambiguously that during base flow, agricultural land contributed up to 65 % of the suspended sediments, while forest was the dominant sediment source during high flow. This indicates that connectivity of sediment source areas within the river changes between base and high flow conditions. Uncertainty, which might occur in complex, large-scale studies due to undetected source attribution and/or CSSI signature degradation, is low because of limited data complexity in our study (i.e., two-three sources and two tracers). Our findings are the first published results highlighting (i) significant differences in compound-specific stable isotope (CSSI) signature of sediment sources from land uses dominated by C3 plant cultivation and (ii) the use of these differences to quantify sediment contribution to a small river.

Antibody derivatization and conjugation strategies: application in preparation of stealth immunoliposome to target chemotherapeutics to tumor.

PubMed

Manjappa, Arehalli S; Chaudhari, Kiran R; Venkataraju, Makam P; Dantuluri, Prudhviraju; Nanda, Biswarup; Sidda, Chennakesavulu; Sawant, Krutika K; Murthy, Rayasa S Ramachandra

2011-02-28

A great deal of effort has been made over the years to develop liposomes that have targeting vectors (oligosaccharides, peptides, proteins and vitamins) attached to the bilayer surface. Most studies have focused on antibody conjugates since procedures for producing highly specific monoclonal antibodies are well established. Antibody conjugated liposomes have recently attracted a great deal of interest, principally because of their potential use as targeted drug delivery systems and in diagnostic applications. A number of methods have been reported for coupling antibodies to the surface of stealth liposomes. The objective of this review is to enumerate various strategies which are employed in the modification and conjugation of antibodies to the surface of stealth liposomes. This review also describes various derivatization techniques of lipids prior and after their use in the preparation of liposomes. The use of single chain variable fragments and affibodies as targeting ligands in the preparation of immunoliposomes is also discussed. Copyright © 2010 Elsevier B.V. All rights reserved.

Mitochondrial targeting increases specific activity of a heterologous valine assimilation pathway in Saccharomyces cerevisiae.

PubMed

Solomon, Kevin V; Ovadia, Elisa; Yu, Fujio; Mizunashi, Wataru; O'Malley, Michelle A

2016-12-01

Bio-based isobutantol is a sustainable 'drop in' substitute for petroleum-based fuels. However, well-studied production routes, such as the Ehrlich pathway, have yet to be commercialized despite more than a century of research. The more versatile bacterial valine catabolism may be a competitive alternate route producing not only an isobutanol precursor but several carboxylic acids with applications as biomonomers, and building blocks for other advanced biofuels. Here, we transfer the first two committed steps of the pathway from pathogenic Pseudomonas aeruginosa PAO1 to yeast to evaluate their activity in a safer model organism. Genes encoding the heteroligomeric branched chain keto-acid dehydrogenase (BCKAD; bkdA1, bkdA2, bkdB, lpdV ), and the homooligomeric acyl-CoA dehydrogenase (ACD; acd1 ) were tagged with fluorescence epitopes and targeted for expression in either the mitochondria or cytoplasm of S. cerevisiae . We verified the localization of our constructs with confocal fluorescence microscopy before measuring the activity of tag-free constructs. Despite reduced heterologous expression of mitochondria-targeted enzymes, their specific activities were significantly improved with total enzyme activities up to 138% greater than those of enzymes expressed in the cytoplasm. In total, our results demonstrate that the choice of protein localization in yeast has significant impact on heterologous activity, and suggests a new path forward for isobutanol production.

Inferring source attribution from a multiyear multisource data set of Salmonella in Minnesota.

PubMed

Ahlstrom, C; Muellner, P; Spencer, S E F; Hong, S; Saupe, A; Rovira, A; Hedberg, C; Perez, A; Muellner, U; Alvarez, J

2017-12-01

Salmonella enterica is a global health concern because of its widespread association with foodborne illness. Bayesian models have been developed to attribute the burden of human salmonellosis to specific sources with the ultimate objective of prioritizing intervention strategies. Important considerations of source attribution models include the evaluation of the quality of input data, assessment of whether attribution results logically reflect the data trends and identification of patterns within the data that might explain the detailed contribution of different sources to the disease burden. Here, more than 12,000 non-typhoidal Salmonella isolates from human, bovine, porcine, chicken and turkey sources that originated in Minnesota were analysed. A modified Bayesian source attribution model (available in a dedicated R package), accounting for non-sampled sources of infection, attributed 4,672 human cases to sources assessed here. Most (60%) cases were attributed to chicken, although there was a spike in cases attributed to a non-sampled source in the second half of the study period. Molecular epidemiological analysis methods were used to supplement risk modelling, and a visual attribution application was developed to facilitate data exploration and comprehension of the large multiyear data set assessed here. A large amount of within-source diversity and low similarity between sources was observed, and visual exploration of data provided clues into variations driving the attribution modelling results. Results from this pillared approach provided first attribution estimates for Salmonella in Minnesota and offer an understanding of current data gaps as well as key pathogen population features, such as serotype frequency, similarity and diversity across the sources. Results here will be used to inform policy and management strategies ultimately intended to prevent and control Salmonella infection in the state. © 2017 Blackwell Verlag GmbH.

46 CFR 170.160 - Specific applicability.

Code of Federal Regulations, 2012 CFR

2012-10-01

...) A vessel that performs one of the simplified stability proof tests described in subpart C of part... COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) SUBDIVISION AND STABILITY STABILITY REQUIREMENTS FOR ALL INSPECTED VESSELS Intact Stability Criteria § 170.160 Specific applicability. (a) Except...

46 CFR 170.160 - Specific applicability.

Code of Federal Regulations, 2011 CFR

2011-10-01

...) A vessel that performs one of the simplified stability proof tests described in subpart C of part... COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) SUBDIVISION AND STABILITY STABILITY REQUIREMENTS FOR ALL INSPECTED VESSELS Intact Stability Criteria § 170.160 Specific applicability. (a) Except...

46 CFR 170.160 - Specific applicability.

Code of Federal Regulations, 2014 CFR

2014-10-01

...) A vessel that performs one of the simplified stability proof tests described in subpart C of part... COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) SUBDIVISION AND STABILITY STABILITY REQUIREMENTS FOR ALL INSPECTED VESSELS Intact Stability Criteria § 170.160 Specific applicability. (a) Except...

46 CFR 170.160 - Specific applicability.

Code of Federal Regulations, 2013 CFR

2013-10-01

...) A vessel that performs one of the simplified stability proof tests described in subpart C of part... COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) SUBDIVISION AND STABILITY STABILITY REQUIREMENTS FOR ALL INSPECTED VESSELS Intact Stability Criteria § 170.160 Specific applicability. (a) Except...

CRISPR-Cas9 technology: applications in genome engineering, development of sequence-specific antimicrobials, and future prospects.

PubMed

de la Fuente-Núñez, César; Lu, Timothy K

2017-02-20

The development of CRISPR-Cas9 technology has revolutionized our ability to edit DNA and to modulate expression levels of genes of interest, thus providing powerful tools to accelerate the precise engineering of a wide range of organisms. In addition, the CRISPR-Cas system can be harnessed to design "precision" antimicrobials that target bacterial pathogens in a DNA sequence-specific manner. This capability will enable killing of drug-resistant microbes by selectively targeting genes involved in antibiotic resistance, biofilm formation and virulence. Here, we review the origins and mechanistic basis of CRISPR-Cas systems, discuss how this technology can be leveraged to provide a range of applications in both eukaryotic and prokaryotic systems, and finish by outlining limitations and future prospects.

Analysis of Individuals from a Dengue-Endemic Region Helps Define the Footprint and Repertoire of Antibodies Targeting Dengue Virus 3 Type-Specific Epitopes

PubMed Central

Andrade, Daniela V.; Katzelnick, Leah C.; Widman, Doug G.; Balmaseda, Angel; de Silva, Aravinda M.; Baric, Ralph S.

2017-01-01

ABSTRACT The four dengue virus serotypes (DENV1 to 4) cause dengue, a major public health problem worldwide. Individuals exposed to primary DENV infections develop serotype-specific neutralizing antibodies, including strongly neutralizing antibodies targeting quaternary epitopes. To date, no studies have measured the levels and kinetics of serum antibodies directed to such epitopes among populations in regions where dengue is endemic. Here, we use a recombinant DENV4 (rDENV4/3-M14) displaying a major DENV3 type-specific quaternary epitope recognized by human monoclonal antibody 5J7 to measure the proportion, magnitude, and kinetics of DENV3 type-specific neutralizing antibody responses targeting this epitope. Primary DENV3 sera from 30 individuals in a dengue hospital-based study in Nicaragua were studied 3, 6, 12, and 18 months post-infection, alongside samples collected annually 1 to 4 years post-primary DENV3 infection from 10 individuals in a cohort study in Nicaragua. We found substantial individual variation in the proportion of DENV3 type-specific neutralizing antibody titers attributed to the 5J7 epitope (range, 0 to 100%), with the mean significantly increasing from 22.6% to 41.4% from 3 to 18 months. We extended the transplanted DENV3 5J7 epitope on the virion (rDENV4/3-M16), resulting in increased recognition in several individuals, helping define the footprint of the epitope. However, 37% and 13% of the subjects still showed little to no recognition of the 5J7 epitope at 3 and 18 months, respectively, indicating that one or more additional DENV3 type-specific epitopes exist. Overall, this study demonstrates how DENV-immune plasma from populations from areas of endemicity, when coupled with structurally guided recombinant viruses, can help characterize the epitope-specific neutralizing antibody response in natural DENV infections, with direct implications for design and evaluation of dengue vaccines. PMID:28928210

Charomers-Interleukin-6 Receptor Specific Aptamers for Cellular Internalization and Targeted Drug Delivery.

PubMed

Hahn, Ulrich

2017-12-06

Interleukin-6 (IL-6) is a key player in inflammation and the main factor for the induction of acute phase protein biosynthesis. Further to its central role in many aspects of the immune system, IL-6 regulates a variety of homeostatic processes. To interfere with IL-6 dependent diseases, such as various autoimmune diseases or certain cancers like multiple myeloma or hepatocellular carcinoma associated with chronic inflammation, it might be a sensible strategy to target human IL-6 receptor (hIL-6R) presenting cells with aptamers. We therefore have selected and characterized different DNA and RNA aptamers specifically binding IL-6R. These IL-6R aptamers, however, do not interfere with the IL-6 signaling pathway but are internalized with the receptor and thus can serve as vehicles for the delivery of different cargo molecules like therapeutics. We succeeded in the construction of a chlorin e6 derivatized aptamer to be delivered for targeted photodynamic therapy (PDT). Furthermore, we were able to synthesize an aptamer intrinsically comprising the cytostatic 5-Fluoro-2'-deoxy-uridine for targeted chemotherapy. The α6β4 integrin specific DNA aptamer IDA, also selected in our laboratory is internalized, too. All these aptamers can serve as vehicles for targeted drug delivery into cells. We call them charomers-in memory of Charon, the ferryman in Greek mythology, who ferried the deceased into the underworld.

Physical property control in core/shell inorganic nanostructures for fluorescence and magnetic targeting applications

NASA Astrophysics Data System (ADS)

Roberts, Stephen K.

Nanomaterials show immense promise for the future in numerous areas of application. Properties that are unique from the bulk material and are tunable allow for innovation in material design. This thesis will focus on controlling the physical properties of core/shell nanostructures to enhance the utility of the materials. The first focus is on the impact of different solvent mixtures during the shell growth phase of SILAR based core/shell quantum dot synthesis is studied. Gaining insight into the mechanism for SILAR growth of core/shell nanoparticles allows improved synthetic yields and precursor binding, providing enhanced control to synthesis of core/shell nanoparticles. The second focus of this thesis is exploring the use of magnetic nanoparticles for magnetic drug targeting for cardiovascular conditions. Magnetic targeting for drug delivery enables increased local drug concentration, while minimizing non-specific interactions. In order to be effective for magnetic targeting, it must be shown that low magnetic strength is sufficient to capture flowing nanoparticles. By demonstrating the binding of a therapeutic agent to the surface at medicinal levels, the viability for use as a nanoparticle drug delivery system is improved.

Applications of CRISPR genome editing technology in drug target identification and validation.

PubMed

Lu, Quinn; Livi, George P; Modha, Sundip; Yusa, Kosuke; Macarrón, Ricardo; Dow, David J

2017-06-01

The analysis of pharmaceutical industry data indicates that the major reason for drug candidates failing in late stage clinical development is lack of efficacy, with a high proportion of these due to erroneous hypotheses about target to disease linkage. More than ever, there is a requirement to better understand potential new drug targets and their role in disease biology in order to reduce attrition in drug development. Genome editing technology enables precise modification of individual protein coding genes, as well as noncoding regulatory sequences, enabling the elucidation of functional effects in human disease relevant cellular systems. Areas covered: This article outlines applications of CRISPR genome editing technology in target identification and target validation studies. Expert opinion: Applications of CRISPR technology in target validation studies are in evidence and gaining momentum. Whilst technical challenges remain, we are on the cusp of CRISPR being applied in complex cell systems such as iPS derived differentiated cells and stem cell derived organoids. In the meantime, our experience to date suggests that precise genome editing of putative targets in primary cell systems is possible, offering more human disease relevant systems than conventional cell lines.

The use of nodes attributes in social network analysis with an application to an international trade network

NASA Astrophysics Data System (ADS)

de Andrade, Ricardo Lopes; Rêgo, Leandro Chaves

2018-02-01

The social network analysis (SNA) studies the interactions among actors in a network formed through some relationship (friendship, cooperation, trade, among others). The SNA is constantly approached from a binary point of view, i.e., it is only observed if a link between two actors is present or not regardless of the strength of this link. It is known that different information can be obtained in weighted and unweighted networks and that the information extracted from weighted networks is more accurate and detailed. Another rarely discussed approach in the SNA is related to the individual attributes of the actors (nodes), because such analysis is usually focused on the topological structure of networks. Features of the nodes are not incorporated in the SNA what implies that there is some loss or misperception of information in those analyze. This paper aims at exploring more precisely the complexities of a social network, initially developing a method that inserts the individual attributes in the topological structure of the network and then analyzing the network in four different ways: unweighted, edge-weighted and two methods for using both edge-weights and nodes' attributes. The international trade network was chosen in the application of this approach, where the nodes represent the countries, the links represent the cash flow in the trade transactions and countries' GDP were chosen as nodes' attributes. As a result, it is possible to observe which countries are most connected in the world economy and with higher cash flows, to point out the countries that are central to the intermediation of the wealth flow and those that are most benefited from being included in this network. We also made a principal component analysis to study which metrics are more influential in describing the data variability, which turn out to be mostly the weighted metrics which include the nodes' attributes.

"Mind the gap!" Evaluation of the performance gap attributable to exception reporting and target thresholds in the new GMS contract: National database analysis.

PubMed

Fleetcroft, Robert; Steel, Nicholas; Cookson, Richard; Howe, Amanda

2008-06-17

The 2003 revision of the UK GMS contract rewards general practices for performance against clinical quality indicators. Practices can exempt patients from treatment, and can receive maximum payment for less than full coverage of eligible patients. This paper aims to estimate the gap between the percentage of maximum incentive gained and the percentage of patients receiving indicated care (the pay-performance gap), and to estimate how much of the gap is attributable respectively to thresholds and to exception reporting. Analysis of Quality Outcomes Framework data in the National Primary Care Database and exception reporting data from the Information Centre from 8407 practices in England in 2005 - 6. The main outcome measures were the gap between the percentage of maximum incentive gained and the percentage of patients receiving indicated care at the practice level, both for individual indicators and a combined composite score. An additional outcome was the percentage of that gap attributable respectively to exception reporting and maximum threshold targets set at less than 100%. The mean pay-performance gap for the 65 aggregated clinical indicators was 13.3% (range 2.9% to 48%). 52% of this gap (6.9% of eligible patients) is attributable to thresholds being set at less than 100%, and 48% to patients being exception reported. The gap was greater than 25% in 9 indicators: beta blockers and cholesterol control in heart disease; cholesterol control in stroke; influenza immunization in asthma; blood pressure, sugar and cholesterol control in diabetes; seizures in epilepsy and treatment of hypertension. Threshold targets and exception reporting introduce an incentive ceiling, which substantially reduces the percentage of eligible patients that UK practices need to treat in order to receive maximum incentive payments for delivering that care. There are good clinical reasons for exception reporting, but after unsuitable patients have been exempted from treatment, there is

10 CFR 33.12 - Applications for specific licenses of broad scope.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 10 Energy 1 2014-01-01 2014-01-01 false Applications for specific licenses of broad scope. 33.12 Section 33.12 Energy NUCLEAR REGULATORY COMMISSION SPECIFIC DOMESTIC LICENSES OF BROAD SCOPE FOR BYPRODUCT MATERIAL Specific Licenses of Broad Scope § 33.12 Applications for specific licenses of broad scope. A...

10 CFR 33.12 - Applications for specific licenses of broad scope.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 10 Energy 1 2013-01-01 2013-01-01 false Applications for specific licenses of broad scope. 33.12 Section 33.12 Energy NUCLEAR REGULATORY COMMISSION SPECIFIC DOMESTIC LICENSES OF BROAD SCOPE FOR BYPRODUCT MATERIAL Specific Licenses of Broad Scope § 33.12 Applications for specific licenses of broad scope. A...

10 CFR 33.12 - Applications for specific licenses of broad scope.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 10 Energy 1 2011-01-01 2011-01-01 false Applications for specific licenses of broad scope. 33.12 Section 33.12 Energy NUCLEAR REGULATORY COMMISSION SPECIFIC DOMESTIC LICENSES OF BROAD SCOPE FOR BYPRODUCT MATERIAL Specific Licenses of Broad Scope § 33.12 Applications for specific licenses of broad scope. A...

10 CFR 33.12 - Applications for specific licenses of broad scope.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 10 Energy 1 2010-01-01 2010-01-01 false Applications for specific licenses of broad scope. 33.12 Section 33.12 Energy NUCLEAR REGULATORY COMMISSION SPECIFIC DOMESTIC LICENSES OF BROAD SCOPE FOR BYPRODUCT MATERIAL Specific Licenses of Broad Scope § 33.12 Applications for specific licenses of broad scope. A...

10 CFR 33.12 - Applications for specific licenses of broad scope.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 10 Energy 1 2012-01-01 2012-01-01 false Applications for specific licenses of broad scope. 33.12 Section 33.12 Energy NUCLEAR REGULATORY COMMISSION SPECIFIC DOMESTIC LICENSES OF BROAD SCOPE FOR BYPRODUCT MATERIAL Specific Licenses of Broad Scope § 33.12 Applications for specific licenses of broad scope. A...

A novel Trojan-horse targeting strategy to reduce the non-specific uptake of nanocarriers by non-cancerous cells.

PubMed

Shen, Zheyu; Wu, Hao; Yang, Sugeun; Ma, Xuehua; Li, Zihou; Tan, Mingqian; Wu, Aiguo

2015-11-01

One big challenge with active targeting of nanocarriers is non-specific binding between targeting molecules and non-target moieties expressed on non-cancerous cells, which leads to non-specific uptake of nanocarriers by non-cancerous cells. Here, we propose a novel Trojan-horse targeting strategy to hide or expose the targeting molecules of nanocarriers on-demand. The non-specific uptake by non-cancerous cells can be reduced because the targeting molecules are hidden in hydrophilic polymers. The nanocarriers are still actively targetable to cancer cells because the targeting molecules can be exposed on-demand at tumor regions. Typically, Fe3O4 nanocrystals (FN) as magnetic resonance imaging (MRI) contrast agents were encapsulated into albumin nanoparticles (AN), and then folic acid (FA) and pH-sensitive polymers (PP) were grafted onto the surface of AN-FN to construct PP-FA-AN-FN nanoparticles. Fourier transform infrared spectroscopy (FT-IR), dynamic light scattering (DLS), transmission electron microscope (TEM) and gel permeation chromatography (GPC) results confirm successful construction of PP-FA-AN-FN. According to difference of nanoparticle-cellular uptake between pH 7.4 and 5.5, the weight ratio of conjugated PP to nanoparticle FA-AN-FN (i.e. graft density) and the molecular weight of PP (i.e. graft length) are optimized to be 1.32 and 5.7 kDa, respectively. In vitro studies confirm that the PP can hide ligand FA to prevent it from binding to cells with FRα at pH 7.4 and shrink to expose FA at pH 5.5. In vivo studies demonstrate that our Trojan-horse targeting strategy can reduce the non-specific uptake of the PP-FA-AN-FN by non-cancerous cells. Therefore, our PP-FA-AN-FN might be used as an accurately targeted MRI contrast agent. Copyright © 2015 Elsevier Ltd. All rights reserved.

Artificial small RNA for sequence specific cleavage of target RNA through RNase III endonuclease Dicer

PubMed Central

Liu, Yali; Liu, Li; Zhan, Yonghao; Zhuang, Chengle; Lin, Junhao; Chen, Mingwei; Li, Jianfa; Cai, Zhiming; Huang, Weiren; Zhang, Yong

2016-01-01

CRISPR-Cas9 system uses a guide RNA which functions in conjunction with Cas9 proteins to target a DNA and cleaves double-strand DNA. This phenomenon raises a question whether an artificial small RNA (asRNA), composed of a Dicer–binding RNA element and an antisense RNA, could also be used to induce Dicer to process and degrade a specific RNA. If so, we could develop a new method which is named DICERi for gene silencing or RNA editing. To prove the feasibility of asRNA, we selected MALAT-1 as target and used Hela and MDA-MB-231 cells as experimental models. The results of qRT-PCR showed that the introduction of asRNA decreased the relative expression level of target gene significantly. Next, we analyzed cell proliferation using CCK-8 and EdU staining assays, and then cell migration using wound scratch and Transwell invasion assays. We found that cell proliferation and cell migration were both suppressed remarkably after asRNA was expressed in Hela and MDA-MB-231 cells. Cell apoptosis was also detected through Hoechst staining and ELISA assays and the data indicated that he numbers of apoptotic cell in experimental groups significantly increased compared with negative controls. In order to prove that the gene silencing effects were caused by Dicer, we co-transfected shRNA silencing Dicer and asRNA. The relative expression levels of Dicer and MALAT-1 were both detected and the results indicated that when the cleavage role of Dicer was silenced, the relative expression level of MALAT-1 was not affected after the introduction of asRNA. All the above results demonstrated that these devices directed by Dicer effectively excised target RNA and repressed the target genes, thus causing phenotypic changes. Our works adds a new dimension to gene regulating technologies and may have broad applications in construction of gene circuits. PMID:27231846

Artificial small RNA for sequence specific cleavage of target RNA through RNase III endonuclease Dicer.

PubMed

Xu, Wen; Liu, Yuchen; Liu, Yali; Liu, Li; Zhan, Yonghao; Zhuang, Chengle; Lin, Junhao; Chen, Mingwei; Li, Jianfa; Cai, Zhiming; Huang, Weiren; Zhang, Yong

2016-08-23

CRISPR-Cas9 system uses a guide RNA which functions in conjunction with Cas9 proteins to target a DNA and cleaves double-strand DNA. This phenomenon raises a question whether an artificial small RNA (asRNA), composed of a Dicer-binding RNA element and an antisense RNA, could also be used to induce Dicer to process and degrade a specific RNA. If so, we could develop a new method which is named DICERi for gene silencing or RNA editing. To prove the feasibility of asRNA, we selected MALAT-1 as target and used Hela and MDA-MB-231 cells as experimental models. The results of qRT-PCR showed that the introduction of asRNA decreased the relative expression level of target gene significantly. Next, we analyzed cell proliferation using CCK-8 and EdU staining assays, and then cell migration using wound scratch and Transwell invasion assays. We found that cell proliferation and cell migration were both suppressed remarkably after asRNA was expressed in Hela and MDA-MB-231 cells. Cell apoptosis was also detected through Hoechst staining and ELISA assays and the data indicated that he numbers of apoptotic cell in experimental groups significantly increased compared with negative controls. In order to prove that the gene silencing effects were caused by Dicer, we co-transfected shRNA silencing Dicer and asRNA. The relative expression levels of Dicer and MALAT-1 were both detected and the results indicated that when the cleavage role of Dicer was silenced, the relative expression level of MALAT-1 was not affected after the introduction of asRNA. All the above results demonstrated that these devices directed by Dicer effectively excised target RNA and repressed the target genes, thus causing phenotypic changes. Our works adds a new dimension to gene regulating technologies and may have broad applications in construction of gene circuits.

Technical attributes, health attribute, consumer attributes and their roles in adoption intention of healthcare wearable technology.

PubMed

Zhang, Min; Luo, Meifen; Nie, Rui; Zhang, Yan

2017-12-01

This paper aims to explore factors influencing the healthcare wearable technology adoption intention from perspectives of technical attributes (perceived convenience, perceived irreplaceability, perceived credibility and perceived usefulness), health attribute (health belief) and consumer attributes (consumer innovativeness, conspicuous consumption, informational reference group influence and gender difference). By integrating technology acceptance model, health belief model, snob effect and conformity and reference group theory, hypotheses and research model are proposed. The empirical investigation (N=436) collects research data through questionnaire. Results show that the adoption intention of healthcare wearable technology is influenced by technical attributes, health attribute and consumer attributes simultaneously. For technical attributes, perceived convenience and perceived credibility both positively affect perceived usefulness, and perceived usefulness influences adoption intention. The relation between perceived irreplaceability and perceived usefulness is only supported by males. For health attribute, health belief affects perceived usefulness for females. For consumer attributes, conspicuous consumption and informational reference group influence can significantly moderate the relation between perceived usefulness and adoption intention and the relation between consumer innovativeness and adoption intention respectively. What's more, consumer innovativeness significantly affects adoption intention for males. This paper aims to discuss technical attributes, health attribute and consumer attributes and their roles in the adoption intention of healthcare wearable technology. Findings may provide enlightenment to differentiate product developing and marketing strategies and provide some implications for clinical medicine. Copyright © 2017 Elsevier B.V. All rights reserved.

Estimating source-attributable health impacts of ambient fine particulate matter exposure: global premature mortality from surface transportation emissions in 2005

NASA Astrophysics Data System (ADS)

Chambliss, S. E.; Silva, R.; West, J. J.; Zeinali, M.; Minjares, R.

2014-10-01

Exposure to ambient fine particular matter (PM2.5) was responsible for 3.2 million premature deaths in 2010 and is among the top ten leading risk factors for early death. Surface transportation is a significant global source of PM2.5 emissions and a target for new actions. The objective of this study is to estimate the global and national health burden of ambient PM2.5 exposure attributable to surface transportation emissions. This share of health burden is called the transportation attributable fraction (TAF), and is assumed equal to the proportional decrease in modeled ambient particulate matter concentrations when surface transportation emissions are removed. National population-weighted TAFs for 190 countries are modeled for 2005 using the MOZART-4 global chemical transport model. Changes in annual average concentration of PM2.5 at 0.5 × 0.67 degree horizontal resolution are based on a global emissions inventory and removal of all surface transportation emissions. Global population-weighted average TAF was 8.5 percent or 1.75 μg m-3 in 2005. Approximately 242 000 annual premature deaths were attributable to surface transportation emissions, dominated by China, the United States, the European Union and India. This application of TAF allows future Global Burden of Disease studies to estimate the sector-specific burden of ambient PM2.5 exposure. Additional research is needed to capture intraurban variations in emissions and exposure, and to broaden the range of health effects considered, including the effects of other pollutants.

Phosphorylation regulates the Star-PAP-PIPKIα interaction and directs specificity toward mRNA targets

PubMed Central

Mohan, Nimmy; AP, Sudheesh; Francis, Nimmy; Anderson, Richard; Laishram, Rakesh S.

2015-01-01

Star-PAP is a nuclear non-canonical poly(A) polymerase (PAP) that shows specificity toward mRNA targets. Star-PAP activity is stimulated by lipid messenger phosphatidyl inositol 4,5 bisphoshate (PI4,5P2) and is regulated by the associated Type I phosphatidylinositol-4-phosphate 5-kinase that synthesizes PI4,5P2 as well as protein kinases. These associated kinases act as coactivators of Star-PAP that regulates its activity and specificity toward mRNAs, yet the mechanism of control of these interactions are not defined. We identified a phosphorylated residue (serine 6, S6) on Star-PAP in the zinc finger region, the domain required for PIPKIα interaction. We show that S6 is phosphorylated by CKIα within the nucleus which is required for Star-PAP nuclear retention and interaction with PIPKIα. Unlike the CKIα mediated phosphorylation at the catalytic domain, Star-PAP S6 phosphorylation is insensitive to oxidative stress suggesting a signal mediated regulation of CKIα activity. S6 phosphorylation together with coactivator PIPKIα controlled select subset of Star-PAP target messages by regulating Star-PAP-mRNA association. Our results establish a novel role for phosphorylation in determining Star-PAP target mRNA specificity and regulation of 3′-end processing. PMID:26138484

The Research and Applications of Quantum Dots as Nano-Carriers for Targeted Drug Delivery and Cancer Therapy

NASA Astrophysics Data System (ADS)

Zhao, Mei-Xia; Zhu, Bing-Jie

2016-04-01

Quantum dots (QDs), nano-carriers for drugs, can help realize the targeting of drugs, and improve the bioavailability of drugs in biological fields. And, a QD nano-carrier system for drugs has the potential to realize early detection, monitoring, and localized treatments of specific disease sites. In addition, QD nano-carrier systems for drugs can improve stability of drugs, lengthen circulation time in vivo, enhance targeted absorption, and improve the distribution and metabolism process of drugs in organization. So, the development of QD nano-carriers for drugs has become a hotspot in the fields of nano-drug research in recent years. In this paper, we review the advantages and applications of the QD nano-carriers for drugs in biological fields.

Multi-Interval Discretization of Continuous-Valued Attributes for Classification Learning

NASA Technical Reports Server (NTRS)

Fayyad, U.; Irani, K.

1993-01-01

Since most real-world applications of classification learning involve continuous-valued attributes, properly addressing the discretization process is an important problem. This paper addresses the use of the entropy minimization heuristic for discretizing the range of a continuous-valued attribute into multiple intervals.

Scale-up of high specific activity 186gRe production using graphite-encased thick 186W targets and demonstration of an efficient target recycling process

DOE PAGES

Balkin, Ethan R.; Gagnon, Katherine; Dorman, Eric; ...

2017-08-18

Production of high specific activity 186gRe is of interest for development of theranostic radiopharmaceuticals. Previous studies have shown that high specific activity 186gRe can be obtained by cyclotron irradiation of enriched 186W via the 186W(d,2n) 186gRe reaction, but most irradiations were conducted at low beam currents and for short durations. In this paper, enriched 186W metal targets were irradiated at high incident deuteron beam currents to demonstrate production rates and contaminants produced when using thick targets. Full-stopping thick targets, as determined using SRIM, were prepared by uniaxial pressing of powdered natural abundance W metal or 96.86% enriched 186W metal encasedmore » between two layers of graphite flakes for target material stabilization. An assessment of structural integrity was made on each target preparation. To assess the performance of graphite-encased thick 186W metal targets, along with the impact of encasing on the separation chemistry, targets were first irradiated using a 22 MeV deuteron beam for 10 min at 10, 20, and 27 μA, with an estimated nominal deuteron energy of 18.7 MeV on the 186W target material (after energy degradation correction from top graphite layer). Gamma-ray spectrometry was performed post EOB on all targets to assess production yields and radionuclidic byproducts. The investigation also evaluated a method to recover and recycle enriched target material from a column isolation procedure. Material composition analyses of target materials, pass-through/wash solutions and recycling process isolates were conducted with SEM, FTIR, XRD, EDS and ICP-MS spectrometry. Finally, to demonstrate scaled-up production, a graphite-encased 186W target made from recycled 186W was irradiated for ~2 h with 18.7 MeV deuterons at a beam current of 27 μA to provide 0.90 GBq (24.3 mCi) of 186gRe, decay-corrected to the end of bombardment. ICP-MS analysis of the isolated 186gRe solution provided data that indicated the

Scale-up of high specific activity 186gRe production using graphite-encased thick 186W targets and demonstration of an efficient target recycling process

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

Balkin, Ethan R.; Gagnon, Katherine; Dorman, Eric

Production of high specific activity 186gRe is of interest for development of theranostic radiopharmaceuticals. Previous studies have shown that high specific activity 186gRe can be obtained by cyclotron irradiation of enriched 186W via the 186W(d,2n) 186gRe reaction, but most irradiations were conducted at low beam currents and for short durations. In this paper, enriched 186W metal targets were irradiated at high incident deuteron beam currents to demonstrate production rates and contaminants produced when using thick targets. Full-stopping thick targets, as determined using SRIM, were prepared by uniaxial pressing of powdered natural abundance W metal or 96.86% enriched 186W metal encasedmore » between two layers of graphite flakes for target material stabilization. An assessment of structural integrity was made on each target preparation. To assess the performance of graphite-encased thick 186W metal targets, along with the impact of encasing on the separation chemistry, targets were first irradiated using a 22 MeV deuteron beam for 10 min at 10, 20, and 27 μA, with an estimated nominal deuteron energy of 18.7 MeV on the 186W target material (after energy degradation correction from top graphite layer). Gamma-ray spectrometry was performed post EOB on all targets to assess production yields and radionuclidic byproducts. The investigation also evaluated a method to recover and recycle enriched target material from a column isolation procedure. Material composition analyses of target materials, pass-through/wash solutions and recycling process isolates were conducted with SEM, FTIR, XRD, EDS and ICP-MS spectrometry. Finally, to demonstrate scaled-up production, a graphite-encased 186W target made from recycled 186W was irradiated for ~2 h with 18.7 MeV deuterons at a beam current of 27 μA to provide 0.90 GBq (24.3 mCi) of 186gRe, decay-corrected to the end of bombardment. ICP-MS analysis of the isolated 186gRe solution provided data that indicated the

High School Students' Attributions of Success in English Language Learning

ERIC Educational Resources Information Center

Bouchaib, Benzehaf; Ahmadou, Bouylmani; Abdelkader, Sabil

2018-01-01

Research into students' attributional causes for success in language acquisition is currently receiving considerable attention. Situated within Weiner's attribution theory (1992), the present study aims to research factors contributing to success in foreign language learning with specific focus on the role of perceived causal attributions. The…

Development and use of fluorescent 16S rRNA-targeted probes for the specific detection of Methylophaga species by in situ hybridization in marine sediments.

PubMed

Janvier, Monique; Regnault, Béatrice; Grimont, Patrick

2003-09-01

Methylotrophic bacteria are widespread in nature. They may play an important role in the cycling of carbon and in the metabolism of dimethylsulfide in a marine environment. Bacteria belonging to the genus Methylophaga are a unique group of aerobic, halophilic, non-methane-utilizing methylotrophs. Two 16S rRNA-targeted oligonucleotide probes were developed for the specific detection of Methylophaga species, marine methylobacteria, by fluorescence in situ hybridization. Probe MPH-730 was highly specific for all members of the genus Methylophaga while probe MPHm-994 targeted exclusively M. marina. The application of these probes were demonstrated by the detection of Methylophaga species in enrichment cultures from various marine sediments. All isolates recovered were visualized by using the genus specific probe MPH-730. The results were confirmed by 16S rDNA sequencing which demonstrated that all selected isolates belong to Methylophaga. Five isolates could be detected by the M. marina-specific probe MPHm-994 and were confirmed by rRNA gene restriction pattern (ribotyping). With the development of these specific probes, fluorescence in situ hybridization shows that the genus Methylophaga is widespread in marine samples.

Enhanced Structural Interpretation Using Multitrace Seismic Attribute For Oligo-Miocene Target at Madura Strait Offshore

NASA Astrophysics Data System (ADS)

Pratama Wahyu Hidayat, Putra; Hary Murti, Antonius; Sudarmaji; Shirly, Agung; Tiofan, Bani; Damayanti, Shinta

2018-03-01

Geometry is an important parameter for the field of hydrocarbon exploration and exploitation, it has significant effect to the amount of resources or reserves, rock spreading, and risk analysis. The existence of geological structure or fault becomes one factor affecting geometry. This study is conducted as an effort to enhance seismic image quality in faults dominated area namely offshore Madura Strait. For the past 10 years, Oligo-Miocene carbonate rock has been slightly explored on Madura Strait area, the main reason because migration and trap geometry still became risks to be concern. This study tries to determine the boundary of each fault zone as subsurface image generated by converting seismic data into variance attribute. Variance attribute is a multitrace seismic attribute as the derivative result from amplitude seismic data. The result of this study shows variance section of Madura Strait area having zero (0) value for seismic continuity and one (1) value for discontinuity of seismic data. Variance section shows the boundary of RMKS fault zone with Kendeng zone distinctly. Geological structure and subsurface geometry for Oligo-Miocene carbonate rock could be identified perfectly using this method. Generally structure interpretation to identify the boundary of fault zones could be good determined by variance attribute.

46 CFR 171.115 - Specific applicability.

Code of Federal Regulations, 2011 CFR

2011-10-01

... 46 Shipping 7 2011-10-01 2011-10-01 false Specific applicability. 171.115 Section 171.115 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) SUBDIVISION AND STABILITY SPECIAL RULES PERTAINING TO VESSELS CARRYING PASSENGERS Openings in the Side of a Vessel Below the Bulkhead or Weather Deck...

46 CFR 171.115 - Specific applicability.

Code of Federal Regulations, 2012 CFR

2012-10-01

... 46 Shipping 7 2012-10-01 2012-10-01 false Specific applicability. 171.115 Section 171.115 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) SUBDIVISION AND STABILITY SPECIAL RULES PERTAINING TO VESSELS CARRYING PASSENGERS Openings in the Side of a Vessel Below the Bulkhead or Weather Deck...

46 CFR 171.115 - Specific applicability.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 46 Shipping 7 2010-10-01 2010-10-01 false Specific applicability. 171.115 Section 171.115 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) SUBDIVISION AND STABILITY SPECIAL RULES PERTAINING TO VESSELS CARRYING PASSENGERS Openings in the Side of a Vessel Below the Bulkhead or Weather Deck...

46 CFR 171.115 - Specific applicability.

Code of Federal Regulations, 2013 CFR

2013-10-01

... 46 Shipping 7 2013-10-01 2013-10-01 false Specific applicability. 171.115 Section 171.115 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) SUBDIVISION AND STABILITY SPECIAL RULES PERTAINING TO VESSELS CARRYING PASSENGERS Openings in the Side of a Vessel Below the Bulkhead or Weather Deck...

46 CFR 171.115 - Specific applicability.

Code of Federal Regulations, 2014 CFR

2014-10-01

... 46 Shipping 7 2014-10-01 2014-10-01 false Specific applicability. 171.115 Section 171.115 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) SUBDIVISION AND STABILITY SPECIAL RULES PERTAINING TO VESSELS CARRYING PASSENGERS Openings in the Side of a Vessel Below the Bulkhead or Weather Deck...

Forced Attention to Specific Applicant Qualifications: Impact on Physical Attractiveness and Sex of Applicant Biases.

ERIC Educational Resources Information Center

Cann, Arnie; And Others

1981-01-01

Undergraduates evaluated the qualifications of an attractive, average, or unattractive male or female applicant. Ratings of specific qualifications preceded or followed an overall and hiring decision rating. The order variable influenced ratings of specific qualifications but not the overall or hiring decision. Male and attractive applicants were…

Generating target system specifications from a domain model using CLIPS

NASA Technical Reports Server (NTRS)

Sugumaran, Vijayan; Gomaa, Hassan; Kerschberg, Larry

1991-01-01

The quest for reuse in software engineering is still being pursued and researchers are actively investigating the domain modeling approach to software construction. There are several domain modeling efforts reported in the literature and they all agree that the components that are generated from domain modeling are more conducive to reuse. Once a domain model is created, several target systems can be generated by tailoring the domain model or by evolving the domain model and then tailoring it according to the specified requirements. This paper presents the Evolutionary Domain Life Cycle (EDLC) paradigm in which a domain model is created using multiple views, namely, aggregation hierarchy, generalization/specialization hierarchies, object communication diagrams and state transition diagrams. The architecture of the Knowledge Based Requirements Elicitation Tool (KBRET) which is used to generate target system specifications is also presented. The preliminary version of KBRET is implemented in the C Language Integrated Production System (CLIPS).

The unique peptidome: Taxon-specific tryptic peptides as biomarkers for targeted metaproteomics.

PubMed

Mesuere, Bart; Van der Jeugt, Felix; Devreese, Bart; Vandamme, Peter; Dawyndt, Peter

2016-09-01

The Unique Peptide Finder (http://unipept.ugent.be/peptidefinder) is an interactive web application to quickly hunt for tryptic peptides that are unique to a particular species, genus, or any other taxon. Biodiversity within the target taxon is represented by a set of proteomes selected from a monthly updated list of complete and nonredundant UniProt proteomes, supplemented with proprietary proteomes loaded into persistent local browser storage. The software computes and visualizes pan and core peptidomes as unions and intersections of tryptic peptides occurring in the selected proteomes. In addition, it also computes and displays unique peptidomes as the set of all tryptic peptides that occur in all selected proteomes but not in any UniProt record not assigned to the target taxon. As a result, the unique peptides can serve as robust biomarkers for the target taxon, for example, in targeted metaproteomics studies. Computations are extremely fast since they are underpinned by the Unipept database, the lowest common ancestor algorithm implemented in Unipept and modern web technologies that facilitate in-browser data storage and parallel processing. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Explicating the role of sexual coercion and vulnerability alcohol expectancies in rape attributions.

PubMed

Starfelt, Louise C; Young, Ross McD; White, Katherine M; Palk, Gavan R M

2015-07-01

Despite evidence suggesting that alcohol expectancies may influence people's rape perceptions, no study to date has measured context-specific expectancies comprehensively. This study represents an initial investigation of the role of sexual coercion and vulnerability alcohol expectancies in young Australian adults' rape blame attributions. Using a vignette method, it was hypothesized that participants' stronger expectancy endorsement would predict lesser perpetrator blame and greater victim blame. Participants (n = 210; 34.9% males; 18-25 years) read a hypothetical rape scenario and rated dimensions of blameworthiness attributed to the intoxicated sexual perpetrator and victim. Participants completed the Sexual Coercion and Sexual Vulnerability subscales of the Drinking Expectancy Sexual Vulnerabilities Questionnaire for the targets self, men, and women in addition to measures of traditional gender role attitudes and rape myth acceptance. Hierarchical multiple regressions revealed that, as expected, stronger sexual coercion expectancy predicted lower perpetrator blame and greater victim blame. Self-oriented expectancy predicted evaluations of the perpetrator whereas other-oriented expectancy predicted victim evaluations. These effects were robust after controlling for gender role attitudes and rape myth acceptance. Alcohol expectancies appear to be part of a network of beliefs and attitudes which perpetuate biased rape attributions and may be useful to challenge in altering rape perceptions. © The Author(s) 2014.

Target Specificity of the E3 Ligase LUBAC for Ubiquitin and NEMO Relies on Different Minimal Requirements*

PubMed Central

Smit, Judith J.; van Dijk, Willem J.; El Atmioui, Dris; Merkx, Remco; Ovaa, Huib; Sixma, Titia K.

2013-01-01

The ubiquitination of NEMO with linear ubiquitin chains by the E3-ligase LUBAC is important for the activation of the canonical NF-κB pathway. NEMO ubiquitination requires a dual target specificity of LUBAC, priming on a lysine on NEMO and chain elongation on the N terminus of the priming ubiquitin. Here we explore the minimal requirements for these specificities. Effective linear chain formation requires a precise positioning of the ubiquitin N-terminal amine in a negatively charged environment on the top of ubiquitin. Whereas the RBR-LDD region on HOIP is sufficient for targeting the ubiquitin N terminus, the priming lysine modification on NEMO requires catalysis by the RBR domain of HOIL-1L as well as the catalytic machinery of the RBR-LDD domains of HOIP. Consequently, target specificity toward NEMO is determined by multiple LUBAC components, whereas linear ubiquitin chain elongation is realized by a specific interplay between HOIP and ubiquitin. PMID:24030825

The CAMELS data set: catchment attributes and meteorology for large-sample studies

NASA Astrophysics Data System (ADS)

Addor, Nans; Newman, Andrew J.; Mizukami, Naoki; Clark, Martyn P.

2017-10-01

We present a new data set of attributes for 671 catchments in the contiguous United States (CONUS) minimally impacted by human activities. This complements the daily time series of meteorological forcing and streamflow provided by Newman et al. (2015b). To produce this extension, we synthesized diverse and complementary data sets to describe six main classes of attributes at the catchment scale: topography, climate, streamflow, land cover, soil, and geology. The spatial variations among basins over the CONUS are discussed and compared using a series of maps. The large number of catchments, combined with the diversity of the attributes we extracted, makes this new data set well suited for large-sample studies and comparative hydrology. In comparison to the similar Model Parameter Estimation Experiment (MOPEX) data set, this data set relies on more recent data, it covers a wider range of attributes, and its catchments are more evenly distributed across the CONUS. This study also involves assessments of the limitations of the source data sets used to compute catchment attributes, as well as detailed descriptions of how the attributes were computed. The hydrometeorological time series provided by Newman et al. (2015b, target="_blank">https://doi.org/10.5065/D6MW2F4D) together with the catchment attributes introduced in this paper (target="_blank">https://doi.org/10.5065/D6G73C3Q) constitute the freely available CAMELS data set, which stands for Catchment Attributes and MEteorology for Large-sample Studies.

[Technical specification for clinical application of critical ultrasonography].

PubMed

Yin, M G; Wang, X T; Liu, D W; Chao, Y G; Guan, X D; Kang, Y; Yan, J; Ma, X C; Tang, Y Q; Hu, Z J; Yu, K J; Chen, D C; Ai, Y H; Zhang, L N; Zhang, H M; Wu, J; Liu, L X; Zhu, R; He, W; Zhang, Q; Ding, X; Li, L; Li, Y; Liu, H T; Zeng, Q B; Si, X; Chen, H; Zhang, J W; Xu, Q H; Chen, W J; Chen, X K; Huang, D Z; Cai, S H; Shang, X L; Guan, J; Du, J; Zhao, L; Wang, M J; Cui, S; Wang, X M; Zhou, R; Zeng, X Y; Wang, Y P; Lyu, L W; Zhu, W H; Zhu, Y; Duan, J; Yang, J; Yang, H

2018-06-01

Critical ultrasonography(CUS) is different from the traditional diagnostic ultrasound, the examiner and interpreter of the image are critical care medicine physicians. The core content of CUS is to evaluate the pathophysiological changes of organs and systems and etiology changes. With the idea of critical care medicine as the soul, it can integrate the above information and clinical information, bedside real-time diagnosis and titration treatment, and evaluate the therapeutic effect so as to improve the outcome. CUS is a traditional technique which is applied as a new application method. The consensus of experts on critical ultrasonography in China released in 2016 put forward consensus suggestions on the concept, implementation and application of CUS. It should be further emphasized that the accurate and objective assessment and implementation of CUS requires the standardization of ultrasound image acquisition and the need to establish a CUS procedure. At the same time, the standardized training for CUS accepted by critical care medicine physicians requires the application of technical specifications, and the establishment of technical specifications is the basis for the quality control and continuous improvement of CUS. Chinese Critical Ultrasound Study Group and Critical Hemodynamic Therapy Collabration Group, based on the rich experience of clinical practice in critical care and research, combined with the essence of CUS, to learn the traditional ultrasonic essence, established the clinical application technical specifications of CUS, including in five parts: basic view and relevant indicators to obtain in CUS; basic norms for viscera organ assessment and special assessment; standardized processes and systematic inspection programs; examples of CUS applications; CUS training and the application of qualification certification. The establishment of applied technology standard is helpful for standardized training and clinical correct implementation. It is helpful